Monodisperse reabsorbable polyester polymer compositions

Abstract

Monodisperse resorbable polyester polymer compositions. Novel compositions comprising resorbable polyester polymers, such as poly-L-lactic acid particles, are described herein, including novel compositions that function as neocollagenous dermal implants and that exhibit unique physical properties compared to similar compositions previously known and / or used in the art. Novel systems comprising these compositions, related compositions, and methods of use of such compositions and systems, such as for aesthetic treatment, are also provided herein.

Description

1 / 84 Monodisperse Reabsorbable Polyester Polymer Compositions: Cross-Referenced with Related Patent Applications

[001] This application claims the benefit of priority of US provisional patent application 62 / 856,000, filed June 1, 2019, the entire contents of which are incorporated herein by reference. FIELD OF THE INVENTION

[002] This invention relates to novel compositions comprising resorbable polyester polymers, such as poly-L-lactic acid particles, including compositions that function as neocollagenous dermal implants and injections; to systems comprising such compositions; and to methods of using such compositions and systems, such as in aesthetic treatment. BACKGROUND OF THE INVENTION

[003] A variety of products have been developed for human use in plastic or reconstructive surgery and in aesthetic dermatology; for example, for filling wrinkles, fine lines, skin cracks, acne scars and other scars. Products that have been developed for such applications are often referred to as dermal fillers. Several different materials have been used as dermal fillers in the past, with varying degrees of success in their application.

[004] Unfortunately, many dermal filler materials are not safe. For example, silicone gel (or silicone oil) is associated with a number of concerning properties, including the migration of silicone droplets into tissues outside the injection site; and because silicone is not biodegradable, it can be found in locations distant from the injection site, such as the liver. Although silicone may be tolerated in many cases, the side effects, including chronic inflammation, granuloma formation, and allergic reactions, are often extreme and / or permanent. As the side effects of silicone fillers are known to be irreversible, their use is prohibited in cosmetic applications in the European Union and the United States. Some amount of use outside of therapeutic indications still occurs, citing established ways to avoid adverse effects. Teflon paste is another example of a dermal filler with concerning properties.This product, typically. Petition 870210111618, dated 01 / 12 / 2021, pp. 216 / 307 2 / 84 A suspension of polytetrafluoroethylene particles, with diameters ranging from approximately 10 to 100 micrometers (µm) in glycerin, has in several cases been associated with serious and chronic infections and migration from injection sites, and in many patients required removal from dermal and subdermal tissues after several months. Similarly, bioplastics composed of polymerized silicone particles with diameters of approximately 70 to 140 µm, typically dispersed in polyvinylpyrrolidone, have been proposed; however, they are now largely discarded as products or product candidates, as clinical experience has shown that rejection reactions and chronic inflammation are commonly associated with the use of such products. Alginate-derived fillers have also been associated with safety concerns (for example, the product Novabel® was withdrawn from the market shortly after launch due to granuloma formation).

[005] Other products that have shown better safety profiles have still demonstrated less than ideal results. Collagen suspensions, for example, have been widely used in the past; however, while safer than other products, results with collagen fillers have been disappointing, as exogenous collagen is typically reabsorbed within one to four months. This short-term efficacy represents a problematic cost and satisfaction barrier for the user. Allergic reactions have also been observed in about 2% of patients using collagen suspensions. Most collagen products are derived from bovine sources, creating additional safety concerns. While believed to be safer and generally longer-lasting, human-derived or even autologous collagen products have not proven to be a strong alternative to date.For example, autologous fat injections have been associated with high failure rates and significant costs. Calcium hydroxyapatite, used in the Radiesse® cosmetic filler, and acrylic hydrogel, polyacrylamide gel, polyalkylimide gel, silicone elastomer particles, and mineral oils, paraffin, and other lipid-derived products have also been used, but these products have limited effectiveness in aesthetic medicine applications, and in some cases have also been associated with safety concerns. Petition 870210111618, dated 01 / 12 / 2021, pp. 217 / 307 3 / 84

[006] Hyaluronate gels have proven to be an effective alternative to many of these other methods, due to their biocompatibility and lack of toxicity.

[007] Hyaluronic acid (HA) is present in all animal species, and hyaluronate gels have been shown to be almost free of foreign proteins, thus reducing the risk of allergic reactions. Hyaluronic acid preparations are common, and hundreds are currently commercially available. However, the rapid bio-reabsorption capacity of HA products, which have an average period of maximum effectiveness of 2 to 6 months (depending on molecular size, cross-linking methods, and injection site), has left many users dissatisfied with the performance of these products, especially in aesthetic applications.

[008] More recently, there has been interest in the development of polymethylmethacrylate (PMMA) microspheres as dermal fillers. These products are composed of non-biodegradable microspheres contained in a suspension solution, typically gelatin or collagen, having a diameter ranging from approximately 20 μm to 40 μm. Not enough time has passed to reliably understand the safety and efficacy of these products. Furthermore, the delivery system for these products typically remains a bovine collagen solution, bringing known risks related to patient allergy as discussed above. For example, PMMA granules suspended in bovine collagen marketed under the brand name Artecoll® (and more recently as Artefill® and Artesense®) have been reported as being associated with concerns about allergic response.

[009] An alternative approach to the dermal filler compositions described above has been to administer microparticle compositions of poly-L-lactic acid (PLLA). PLLA has been used for decades in medicine and surgery, but these products are a relatively new addition to aesthetic medicine. Unlike true dermal fillers, these products lead to the generation of new endogenous collagen (i.e., they are neocollagenic products). Thus, the aesthetic effects of PLLA products have been shown to last for more than two years. SCULPTRA®, a product currently marketed by Galderma Laboratories for aesthetic applications [e.g., treatment of nasolabial folds, marionette lines (smile lines)]. Petition 870210111618, dated 01 / 12 / 2021, pp. 218 / 307 [referring to the use of pluromental and chin wrinkles], and approved by the FDA (Food and Drug Administration of the United States) for more than 12 years, comprises PLLA microparticles as a primary functional component. SCULPTRA® is provided as two vials of lyophilized powder for reconstitution in water, prior to administration, for injection via a needle. After proper injection of rehydrated SCULPTRA®, collagen formation occurs in the skin, resulting in long-term filling effects. US Patent No. 6,716,251 describes such PLLA injections for subcutaneous or intradermal injection.Although SCULPTRA® was developed by Aventis, one of the world's leading companies in research and development of healthcare products, several problems and limitations associated with SCULPTRA® have limited its adoption and use, and little has been done to improve the product in the two decades since its initial market introduction, indicating that improvements in similar products are unlikely to be expected without new inventive approaches and discoveries. SUMMARY OF THE INVENTION

[010] The invention described herein provides novel compositions comprising particles of one or more types of resorbable polyester polymers (abbreviated as PPR elsewhere in this specification), such as poly-L-lactic acid particles having novel properties and characteristics (e.g., with respect to the size and shape of such particles, and the consistency of such particles in terms of one or both factors). Typically, the compositions of the invention can be characterized as having a monodisperse collection of such particles. In several respects, these particles can function as neocollagenizing agents and, consequently, form an active part of compositions suitable for use as implants and / or dermal injections. Novel systems comprising these compositions are also provided (such as needle and cannula delivery systems for injecting these compositions into mammalian recipients, such as human patients).Furthermore, methods are provided for making and using such compositions and systems, such as in the context of aesthetic modifications and medicine. Petition 870210111618, dated 01 / 12 / 2021, pp. 219 / 307 5 / 84 [Oil] In a specific exemplary aspect, the invention provides dermatological compositions for implantation / injection comprising (a) a particle component composed of an effective amount of polyester polymer particles, which are at least mainly composed of one or more resorbable polyester polymers (typically having a monodisperse composition); and (b) a carrier component configured (i.e., suitable) for dermatological administration, wherein at least about 70% of the polyester polymer particles have a maximum particle diameter that is within (+ / -) about 30% of the average particle diameter size of the polyester polymer particles in the composition. In one aspect, about 65%, approximately 75%, or about 80% of the PPR particles have a maximum particle diameter that is within approximately 20% of the average particle size, or within about 35% of the average particle size.In a preferred embodiment, the particles are also or alternatively collagenous, that is, they are capable of inducing a detectable amount of neocollagenesis after implantation in a suitable mammalian recipient, such as a human patient undergoing cosmetic treatment.

[012] In certain respects, the particles are typically primarily characterized by, or consist essentially of, microspheres. Because the microsphere compositions of the invention are typically monodisperse among themselves (at least approximately 87.5%, at least approximately 92.5%, at least approximately 95%, or at least approximately 97.5% of the particles have a maximum diameter that is within a range of less than about 20 μm, less than approximately 15 μm, less than about 12 μm, or less than approximately 10 μm), such PPR particles may also be referred to as monospheres. It should be understood that any aspect of this invention described herein in terms of particles or microspheres also inherently provides support for, and description of, monospheres.

[013] Exemplary materials that can be used to make PPR particles, such as monospheres, include polyglycolide (PGA), polylactic acid (PLA), polycaprolactone (PCL), and polyhydroxybutyrate (PHB) particles; copolymers of two or more of these materials; and mixtures of any two or more of these materials. Petition 870210111618, dated 01 / 12 / 2021, pages 220 / 307 6 / 84 of these materials. Such compositions generally include other excipients or components that can be considered a formulation, a carrier, or a functional vector, which may include surfactants, preservatives, and / or buffers. In some embodiments, the composition includes gel-forming agents. The formulation may be dried by lyophilization (also known as freeze-drying or cryodesiccation), and the dried forms of such products may be reconstituted for ease of administration via needle and cannula systems. Frequently and advantageously, the compositions exhibit low allergenicity and are non-pyrogenic. In exemplary embodiments, the PPR particles and all functional elements, vectors, or carriers of the formulation may be lyophilized with water for injection alone, used as a diluent for reconstitution.In alternative incorporation methods, only the PPR particles can be lyophilized, with all functional, vector, or carrier elements of the formulation being a component of the diluent in combination with water for injection, for reconstitution.

[014] In another aspect, the invention provides a delivery system for a neocollagenous dermatological implant / injection product comprising (a) a storage component containing an effective amount of a neocollagenous dermatological implant / injection composition having one or more of the properties described above, particularly in terms of shape, size, or both, and possessing the consistency of the polyester polymer particles of the composition; and (b) a needle or cannula configured to deliver the composition to the mammal after the application of a delivery force. The systems of the invention can be used with relatively less injection force than previously known similar systems, and are associated with fewer injection failures than prior art systems.The systems of these aspects are also or alternatively associated with needle sizes that are relatively smaller than those used to dispense products currently on the market, which do not have the size, shape, and consistency of the polyester polymer particles of the invention (for example, the system may comprise a 27G needle, a 28G needle, or a 29G needle). The storage components may be any storage component. Petition 870210111618, dated 01 / 12 / 2021, pp. 221 / 307 7 / 84 suitable device capable of storing and dispensing the composition for implant / injection. The storage component may typically be a syringe or device comprising the components of a syringe. The term syringe generally refers to a device or component comprising three main components / subcomponents: (1) a cylinder or storage component capable of holding the material for injection; (2) a mechanism capable of pushing the material for injection out of the cylinder after the application of a force to such mechanism, such as a plunger or piston;(3) a connecting device capable of coupling an implant / injection dispensing device, such as a needle or cannula, to the material storage unit. Such a storage compartment may be a typical manually operated syringe, commonly used in the medical sciences. The term syringe may also be used to describe an alternative system capable of dispensing an implant / injection composition via a needle, with such systems having the components of a syringe, such as a material storage compartment, means for expelling the material from the storage compartment, and a means for coupling the dispensing device, such as a needle, to the storage compartment. For example, such systems may be characterized as, but not limited to, those possessing an electronic circuit, a motor or a computer-controlled system; a pneumatically operated device;A device comprising a multi-syringe or multi-needle injection system, with multiple material housing components existing within the system; an ergonomically designed, manually operated device; a system having audible injected volume indicators; systems comprising a composition storage component for implantation / injection of a single-dose injection volume; systems capable of selectively setting an injection volume so that multiple injections of a precise volume can be administered (an adjustable injection syringe system); a pen-like device; an adjustable injectable flow rate device; or a fully automated and autonomous computer-controlled system. The invention also provides kits including the components of such dispensing systems and compositions (e.g., a set; Petition 870210111618, dated 01 / 12 / 2021, pp. 222 / 307 8 / 84 of a needle or cannula, a lyophilized product comprising such particles and only a particle formulation, and a sufficient quantity of water for injection or a diluent containing water for injection together with other functional elements, vectors or carriers of the formulation, for reconstitution).

[015] In still other aspects, the invention provides methods for delivering polyester polymer particles, which are preferably bio-resorbable, safe, and neocollagenic, to a mammalian recipient, such as a human individual. In a particular exemplary aspect, the method is used in performing aesthetic augmentation or aesthetic treatment of a condition in a human individual. In a preferred exemplary embodiment, performing such methods results in an aesthetic modification that is sustained over a substantial period of time (at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 40 months, or more), if not permanent, in the recipient, due to the stimulation of a detectable amount of new endogenous collagen in the patient in response to the injection or implantation of the particles.

[016] By way of example, the invention can be used for aesthetic skin modification, including, but not limited to, the aesthetic treatment of nasolabial folds (commonly referred to as smile lines) and areas of the chin and jawline, including, but not limited to, marionette lines. The present invention can also be used to promote collagen production in the cheeks and temples, serving to treat wrinkles, to smooth bony areas, or to fill shallow areas of the face in order to promote a more youthful appearance.

[017] These and several other aspects are described below. Any suitable aspect of this Summary of the Invention may be combined with any aspect described below. BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a graph of the injectability test results of SCULPTRA® samples using a 26G 5 / 8 needle; Figure 2 is a graph of the injectability test results of monodisperse PLLA microsphere test formulations using a 5 / 8" 26G needle; Petition 870210111618, dated 01 / 12 / 2021, pp. 223 / 307 9 / 84 Figure 3 is a graphical overlay of injectability measurements of SCULPTRA® versus test formulations of monodisperse PLLA microspheres using a 5 / 8" 26G needle (i.e., an overlay of Figures 2 and 3); Figure 4 is a particle size comparison between SCULPTRA® particles and monodisperse PLLA microspheres; Figure 5 is an accurate representation of a scanning electron micrograph image of SCULPTRA® particles; Figure 6 is an accurate representation of a scanning electron micrograph image of monodisperse PLLA microspheres of the invention. DETAILED DESCRIPTION OF THE INVENTION

[018] The invention described herein provides, inter alia, neocollagenous dermatological compositions for injection / implantation, comprising (a) a particle component composed of an effective amount of polyester polymer particles, which particles are at least principally composed of one or more resorbable polyester polymers; and (b) a carrier suitable for dermatological administration, the particles of the composition having substantially uniform size and shape (for example, with at least about 65%, at least approximately 70%, or at least about 75% of the polyester polymer particles in the composition having a maximum particle diameter that is within (+ / -) about 35%, approximately 30%, about 25%, approximately 25%, or about 20% of the average particle diameter size of the polyester polymer particles in the composition).

[019] It has been determined that known microparticle products, including previously described polyester polymer microparticle products such as SCULPTRA®, contain polydisperse particles of markedly inconsistent sizes and shapes, and often exhibit a size coefficient of variation (CV) greater than approximately 20%. For example, in the experiments described herein, it was demonstrated that SCULPTRA® samples exhibited microsphere particle sizes measured in a single batch (#1A6112) having a CV of 42%. Large, irregularly shaped particles in SCULPTRA® [with such disparity of Petition 870210111618, dated 01 / 12 / 2021, pp. 224 / 307 [10 / 84 size and shape within SCULPTRA® being shown in the scanning electron micrograph (SEM) provided herein] and similar compositions can lead to clogging of delivery systems, such as needles, and may be associated with other disadvantageous properties. It has been found that by applying alternative production methods to resorbable polyester polymer particles, it is possible to make compositions that overcome these deficiencies, while maintaining and improving the advantageous properties of such compositions, for example, promoting neocollagenesis (the detectable stimulation of endogenous collagen production), in mammalian recipients, such as humans undergoing aesthetic medical treatment with such compositions.

[020] These particles, compositions comprising such particles, systems comprising such particles, and methods, compositions and systems for making and using such particles, are further described below, following an explanation of the construction principles that the reader should consider when reading the description provided herein. CONSTRUCTION PRINCIPLES

[021] The following principles provide guidelines for understanding this invention.

[022] All references, including publications, patent applications, and patents, mentioned herein, including the patents and patent applications cited above, are incorporated herein by reference, equally as if each reference were individually and specifically indicated so as to be incorporated by reference and were hereby set forth in its entirety. Consequently, the reader should examine and consider such references in order to understand the entire content of this description. For example, unless clearly contradicted by the context or by an explicit statement, the description of such documents relating to formulations, methods of production, and methods of use of compositions and devices may be combined with the teachings provided herein to provide additional useful compositions and applications.However, the reader should understand that here the citation and incorporation of patent documents is limited to the technical description of such patent documents, and does not reflect any view of their validity, patentability, or viability.

[023] All titles and subtitles are used here for convenience only and should not be construed in any way as limiting the invention. The use of Petition 870210111618, dated 01 / 12 / 2021, pp. 225 / 307 11 / 84 terms "a" and "an" and similar references, in the context of the invention description, should be interpreted as encompassing both the singular and plural forms, unless otherwise indicated herein or clearly contradicted by the context.

[024] The recitation of value ranges is hereby merely intended to serve as a shorthand method of individually referencing each separate value within the range, within an order of magnitude of the range order, including endpoints (e.g., a range of 1 to 2 shall be interpreted as providing support for 1.0, 1.1, 1.2, 1.3,... 1.9 and 2.0; a range of 10 to 20 shall be interpreted as providing support for 10, 11, 12, 13,... 19 and 20), unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually quoted. All ranges provided herein include the endpoints of the range given, unless the exclusion of such endpoints is clearly stated or clearly indicated.Unless otherwise indicated, all exact values ​​given herein are representative of the corresponding approximate values ​​(e.g., all exact example values ​​given with respect to a given factor or measure may be considered as also providing a corresponding approximate measure, modified by about or approximately, where appropriate; for example, the expression about 10 should be understood as also providing support for the numeral 10, exactly). Approximating terms, such as about or approximately, are used herein where the measures are understood as varying due to measurement problems or population variability, such as results from clinical studies. The scope of such terms will depend on the context of the element in question and the understanding of those skilled in the art.In the absence of such guidance in the technique, through relevant teachings or examples, about and approximately should be understood as meaning + / -10% of the indicated value(s).

[025] As used here, the singular forms um, uma and o / a include plural references, unless clearly indicated otherwise.

[026] The use of the term or here does not mean that the alternatives are mutually exclusive, unless clearly stated or clearly contradicted by the context. Petition 870210111618, dated 01 / 12 / 2021, pp. 226 / 307 12 / 84 Thus, in this patent application, the use of "or" means "and / or," unless expressly stated or understood by those skilled in the art, and provides support for both aspects.

[027] All methods described herein may be carried out in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context. Unless clearly indicated or contradicted by the context, the elements of a composition described herein (e.g., a pharmaceutical formulation) may be formulated in any suitable manner and by any suitable method. Unless explicitly stated otherwise or clearly contradicted by the context, any combination of the various elements, steps, components and / or features of the aspects of the invention described herein, and all possible variations thereof, shall be deemed to be encompassed by the invention.

[028] The use of any and all examples or exemplary language (e.g., such as) provided herein is merely intended to better clarify the invention and does not represent a limitation on the scope of the invention unless otherwise indicated. No language in this specification should be construed as indicating that any element is essential to the practice of the invention unless explicitly stated. The breadth and scope of the present invention shall not be limited by any of the exemplary embodiments described above.

[029] Herein, the description of any aspect or embodiment of the invention, using terms such as comprising, having, including or containing with reference to an element, composition or set of compositions or elements, shall be interpreted, whether or not explicitly stated, as simultaneously providing support for a similar aspect or embodiment of the invention which consists of, consists largely of, consists substantially of, substantially comprises, and predominantly comprises that particular element, unless otherwise indicated or clearly contradicted by the context (i.e., a composition described herein comprising a particular element shall be understood as also describing a composition consisting of that element, substantially comprising that element, predominantly comprising that element, Petition 870210111618, dated 01 / 12 / 2021, pages 227 / 307 13 / 84 consisting largely of this element, and consisting substantially of this element, unless otherwise indicated or clearly contradicted by the context). Terms such as including, containing, possessing and having should here be interpreted broadly, for example, with the meaning of including, but not limited to, including, without limitation, or comprising, unless otherwise clearly contradicted. Any aspect described as including or comprising elements should be interpreted as also or alternatively including such elements, together with the other elements of this description.

[030] Substantially comprises means that at least about 1% of a composition, population or similar collection consists of, or is made up of, the referenced feature, species or element, and normally means (and should be understood as providing support for) the relevant feature that constitutes or represents at least about 5%, at least approximately 10%, at least approximately 15%, and at least approximately 20% of the total amount of the composition or population number.

[031] Comprises predominantly means account for more than half (i.e., more than 50%) of an element (e.g., a composition or a population of things). This quantity and similar quantities used in relation to the terms defined herein may be based on a percentage weight (weight / weight), on a molecule / molecule basis, or on another relevant basis used in the context of the relevant description. For example, if a composition is described as predominantly comprising an element / species A, more than 50% of the composition on a molecular and / or weight basis will be composed of element or species A. Wherever this term is used, it should be understood as simultaneously providing support for more than 60%, more than 70%, and more than 80% of the component, composition, or collection comprised of the feature, species, or element in question. The term more should also be interpreted similarly herein.

[032] Consists largely of means that at least about 75% of the composition, population or similar consists of, or is composed of, the referenced characteristic, species or element, and should be understood as providing the information that by Petition 870210111618, dated 01 / 12 / 2021, pp. 228 / 307 14 / 84 minus 82.5%, at least 87.5%, at least 92.5%, and at least 97.5% of the composition, population, or similar consists of, or is made up of, the referenced characteristic, species, or element. Obviously, the remaining minority portion of the composition, collection, and similar may be composed of other compounds, materials, or other relevant elements. The phrases "largely all" and "largely most" should be interpreted similarly.

[033] Consists substantially of meaning that at least about 90% of the composition, population or similar is made up of the referenced characteristic, species or element, and should also be understood as providing information that at least about 95%, at least approximately 99%, or at least about 99.9% of the composition, collection, etc., is made up of the relevant element, characteristic or thing. The phrases almost all and almost entirely should be interpreted similarly.

[034] Changes in verb tense or in the presentation of phrases defined herein (for example, using predominantly understands instead of understands predominantly) will not change the meaning of the defined phrase unless clearly indicated otherwise.

[035] Here, the use of section titles serves the purpose and convenience of guiding the reader and separating parts of the description, and should not be interpreted as limiting the description of the associated section or any other section.

[036] The description of the specific embodiments provided herein will reveal the general nature of the invention so that others, applying knowledge within the art or technique, may readily modify and / or adapt such specific embodiments for various applications without undue experimentation and without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the embodiments described, based on the teachings and guidance presented herein. It should be understood that the phraseology or terminology used herein is for descriptive purposes and not for limitation, so that the terminology or phraseology of the present Petition 870210111618, dated 01 / 12 / 2021, pp. 229 / 307 Specification 15 / 84 should be interpreted by those skilled in the art in light of these teachings and guidelines. PPR PARTICLE COMPOSITION

[037] In one aspect, the invention described herein relates to novel compositions comprising (i.e., substantially comprising, predominantly comprising, substantially consisting of, or consisting of) resorbable polyester polymer (RPP) particles.

[038] The PPR(s) constituting the particles of the compositions of the invention may be composed of known PPR materials, such as PLLA. The novel aspect of such compositions is typically found, inter alia, in the size of the PPR particles, in the shape of the PPR particles, and in the consistency of the particle composition in terms of one or both of these aspects.

[039] The PPR particles of the invention can be used to prepare (and therefore can be components of) a variety of compositions, which can in turn be used for a range of applications. Several applications of PPR compositions, such as PLLA microparticle compositions, are already known in the state of the art, and the PPR particles provided herein can generally be used for any of these uses [e.g., acting as delivery systems for pharmaceutical products, being used for applications in 3D printers, acting as a substitute for PET (Polyethylene Terephthalate) particles, and the like]. For example, the PPR particle compositions of the invention can be used as dermatological injections or implants, which constitute the main focus of application herein.In one aspect, such dermatological injections or implants can be characterized as being neocollagenic, that is, as resulting in the detectable formation of new endogenous collagen after the injection or other administration of the implant or injection (in some cases, this new collagen formation is detected after two, three, four or more months).

[040] The particles provided by the invention and used in the compositions provided herein may also include other components besides one or more PPR components. For example, the particles may include one or more additional compositions that are also neocollagenic; lead to the stimulation of other endogenous biomolecules, Petition 870210111618, dated 01 / 12 / 2021, pages 230 / 307 16 / 84 such as elastin (i.e., they are elastogenic), helping to increase the health, volume, or other aspect of a recipient's skin; or compositions that otherwise assist in promoting the function of the particles.

[041] In one aspect, the compositions of the invention can be characterized by comprising a particle component comprising substantially, predominantly, or consisting substantially of, particles consisting essentially of one or more PPR materials, which also or alternatively can be characterized by such particles (a) being substantially uniform in size (for example, are at least predominantly composed of particles varying in size by no more than approximately 20%, no more than about 15%, or even no more than approximately 10% of the maximum diameter, or the average maximum dimension, the average dimension, and / or the average minimum dimension);(b) being substantially uniform in shape (for example, with at least about 70%, at least approximately 80%, at least about 90% or more of the particles being spherical, having a diameter in all directions varying not more than approximately 10%, not more than about 5%, not more than approximately 2%, not more than about 1%, not more than approximately 0.5%, or not more than about 0.1% in distance);or (c) exhibit substantial uniformity in size and shape. The compositions may be considered as consisting essentially of one or more PPR materials, wherein the particles provide or retain the desired function of the PPR particles, for example, in terms of stable space filling, promoting endogenous collagen production, and / or one or more other desired structural and / or functional aspects associated with the PPR particles. Thus, if such particles include additional materials, such as stabilizers, dermal fillers, or products that lead to the production of other endogenous biomolecules, such particles will still consist essentially of one or more PPRs contained therein, because they have retained the fundamental characteristics of the PPR particles. This aspect of the compositions will be recognizable by those skilled in the art.

[042] PPR particles are at least predominantly composed of polyester compounds, and most commonly will consist substantially of, or Petition 870210111618, dated 01 / 12 / 2021, pp. 231 / 307 17 / 84 will consist entirely of (within reasonable levels of production and / or purification, as well as detection and / or isolation) polyester compounds.

[043] PPR particles are typically, generally and preferably bio-absorbable (or resorbable), meaning that they can, over a period of time, be broken down and assimilated by the body. In the case of PPR particles, reabsorption can occur over several weeks, more typically over a period of several months (e.g., about 2 to 6 months), but in some forms of incorporation up to years (e.g., about 1 to 3 years).

[044] According to certain embodiments, PPR is a homopolymer. According to some aspects, PPR is an aliphatic resorbable polyester homopolymer. It can be imagined that other resorbable polymers comprising polyester monomer components mixed with other components, and having the other properties associated with the particles of the invention (e.g., substantially uniform size and / or shape), could also or alternatively be incorporated into the compositions and systems of this invention, and / or used in the methods of the invention. The PPR particles of the invention may also or alternatively be characterized as biodegradable, biocompatible and / or biologically inert, as such terms would be understood in the art or technique.

[045] In one aspect, the invention provides compositions comprising an effective quantity of particles comprising, consisting substantially of, or consisting of, one or more types of PPR particles. The term effective quantity means a quantity that is effective for the intended application of the referenced composition, device, substance or thing, and / or that has been shown to be effective for such application in relevant tests (e.g., in one or more well-designed, conducted and well-controlled clinical studies suitable for regulatory approval of a product). Thus, for example, an effective quantity of a composition for dermal implantation / injection means a quantity that is effective or has been shown to be effective in detectably modifying the condition and / or appearance of the skin, or in causing a biological result, such as neocollagenesis. The phrase effective quantity is used in such contexts to indicate that there is a quantity of such particles. Petition 870210111618, dated 01 / 12 / 2021, pp. 232 / 307 18 / 84 present to lead to such a modification or result, rather than there being only some non-substantial quantity of such particles present or, alternatively, a quantity that is too large to be adequate.

[046] Numerous compositions described herein are characterized as compositions for injection, implantation, or injection / implantation. In many aspects of the invention, the compositions provided herein are suitable for administration to parts of the body of recipient mammals, such as the skin of a human individual undergoing aesthetic modification. The particles of the invention can be delivered to such recipients / individuals by any suitable means. In most cases, it is anticipated that the delivery / administration of the composition will occur by injection or implantation by other means. The particles can be injected in any suitable manner, and various techniques for injecting particles into the body, such as into the skin, are already known in the art. Typically, the particles will be injected in an aqueous composition as a suspension through a suitable needle, with examples being described elsewhere in this specification.Alternatively, the particles can be implanted by delivery via a cannula, surgical implantation, or another delivery method. Except where characteristics are described as being specific to one or another form of delivery, the compositions for implantation or injection should be viewed as non-limiting and even supportive of each other, since in most cases the particles will be suitable for delivery via any technique.

[047] PPR particles are normally present in a composition. The composition may be any composition suitable for the storage, transport and / or use (injection / implantation) of the particles contained therein. In one aspect, the other primary component of the composition is a carrier (which may also be described as a carrier system or vector). In most aspects, the carrier will be a carrier suitable for dermatological administration (e.g., implantation, injection via a needle, or both). Further aspects of exemplary carrier systems are described elsewhere in this specification. Petition 870210111618, dated 01 / 12 / 2021, pp. 233 / 307 19 / 84

[048] As described elsewhere in this specification, the invention provides particle compositions in which the particles consist essentially of one or more resorbable polyester polymers. That is, the fundamental properties of such particles, such as causing neocollagenesis when distributed in the skin of a recipient, leading to a sustained, if not permanent, modification of the skin or its appearance, are maintained, even if the particles contain other features, compounds or parts different from those of the PPR(s) that constitute some, most or almost all of the particles.

[049] PPR polymers will often be characterized as having a neutral charge, that is, having little positive or negative charge.

[050] It is expected that most of the compositions of the invention will be neocollagenic. To provide such a result, it is anticipated that typically the PPR particles of the invention will comprise substantially particles that are themselves neocollagenic (as determined, for example, by testing substantially identical particles in clinical trials, in vitro assays and the like, and producing the present particles with substantially similar or substantially identical specifications, under substantially similar or substantially identical protocols).

[051] PPR materials are typically synthetic (produced through chemical synthesis, starting with synthetic or natural materials, or both). Thus, such materials avoid the inclusion of bovine and other animal-derived materials. A number of PPR products are, however, derived from plant materials (e.g., PLLA can be derived from plant-based sources). In one context, PPR particles may be derived from such natural sources. In another context, PPR particles may also or alternatively be produced through chemical synthesis, using synthetic starting materials.

[052] As indicated elsewhere in this specification, a number of PPR compositions are known, and several have been used to varying degrees for aesthetic modification of humans. These PPR materials may constitute most, if not all, of the PPR component of most, if not all, of the particles of any composition provided herein. In one aspect, the PPR material includes, consists of Petition 870210111618, dated 01 / 12 / 2021, pp. 234 / 307 20 / 84 substantially consists of, essentially of, or comprises (at least within the detection level) a polyglycolide (a PGA block). Polyglycolides are known in the prior art and will be discussed elsewhere in this specification. In another aspect, the PPR material of the particles is similarly, or includes, a polycaprolactone (a PCL block). These materials are also known in the prior art. In yet another aspect, the PPR composition is similarly, or includes, a polyhydroxybutyrate (a PHB block), which is a material known in the prior art. In yet another aspect, the PPR is similarly, or includes, a polylactic acid (or a PLA). PLAs are described and exemplified elsewhere in this specification and are also known in the prior art. PPR particles may also include mixtures of two, three, or more of these materials, and / or may include copolymers formed from two or more of these materials.In some respects, PPR particles will consist substantially of, or will consist of only one type of, PPR material. In some respects, PPR particles will consist substantially of, or will consist only of, a PPR material. In some respects, PPR particles will consist substantially of, or will consist of, a PPR material consisting of only one type of PPR (for example, the particles will consist entirely of a PLA, such as PLLA).

[053] Suitable and sometimes advantageous examples of PPR materials include polylactic-co-glycolic acid (PLGA) materials, polylactic acid (PLA) materials, and materials that are composed of a mixture of such materials. In one particular aspect, at least 50% of the polyester polymer content of the composition is composed of (or consists essentially of) a polylactic acid (PLA) (for example, at least approximately 65% ​​of the particle content is composed of a PLA, at least approximately 80% of the content is composed of a PLA, at least approximately 90% of the content is composed of a PLA, or at least approximately 99% of the content is composed of a PLA).

[054] A preferred PPR material in many contexts is polylactic acid (PLA). Polylactic acid contains an asymmetric α-carbon that is typically described as having a D or L shape. It can also be described as having an R and S shape. The shapes Petition 870210111618, dated 01 / 12 / 2021, pp. 235 / 307 21 / 84 enantiomeric PLA compounds are optically pure poly-D-lactic acid (PDLA) and poly-L-lactic acid (PLLA). PLA can be made in highly crystalline form (PLLA and PDLA), or it can be amorphous (poly-D,L-lactic acid, PDLA) due to the atactically ordered polymer chains. In one aspect, PPR particles comprise, substantially comprise, consist essentially of, consist substantially of, or consist entirely of PLA, which is selected from poly-L-lactic acid (PLLA) (crystalline) or poly-D-lactic acid (PDLA) (crystalline), or a mixture thereof [PLLA and PDLA (homopolymer, crystalline) or PDLA (copolymer, amorphous)]. In one aspect, PPR particles include, or consist of, such a quantity of PLLA.

[055] PLA polymers can range from amorphous glassy polymers to semicrystalline and highly crystalline polymers. It is known that different technologies can be used to modify or improve the mechanical properties of PLA. As non-limiting examples, annealing, addition of nucleating agents, formation of composites with fibers or nanoparticles, chain extension, and introduction of crosslinking structures are all ways to modify the mechanical properties of PLA. Examples of such annealing technology can be found in Pramono et al., Polymer Degradation and Stability, 72 (2): 337 to 343 (2001); Horioshi et al. (2003), Polymer, 44 (19): 5635 to 5641; Tsuji, H., Polymer, 36 (14): 2709 to 2716 (1995); Hiroshi et al., Macromolecular Materials and Engineering, 288 (7): 562 to 568 doi: 10562 to 568 (2003); Trimaille et al.(2003) Colloid and Polymer Science, 281 (12): 1184 to 1190; and Hu et al., Macromolecular Materials and Engineering, 292 (5): 646 to 654 (2007). Examples of the formation of composites with fibers or nanoparticles can be found in Hiroshi et al., Macromolecular Materials and Engineering, 288 (7): 562 to 568 (2003); Trimaille et al., Colloid and Polymer Science, 281 (12): 1184 to 1190 (2003); and Hu et al., Macromolecular Materials and Engineering, 292 (5): 646 to 654 (2007). Examples of chain extension technology can be found in Li et al., Polymers for Advanced Technologies. Petition 870210111618, dated 01 / 12 / 2021, pages 236 / 307 22 / 84 Advanced), 17 (6): 439 to 443 (2006); Di et al., Macromolecular Materials and Engineering, 290 (11): 1083 to 1090 (2005).

[056] In an alternative embodiment, PPR particles also or alternatively include, consist substantially of, consist essentially of, or simply consist of, PLGA. PLGA is a copolymer of polylactic acid (PLA) and polyglycolic acid (PGA). PLGA is generally an acronym for poly-D,L-lactic-co-glycolic acid, where the D-lactic and L-lactic forms are in equal proportions. PLGA is a biodegradable and biocompatible polymer capable of exhibiting a variety of degradation times.

[057] As already understood in the state of the art and discussed elsewhere in this specification, the constituents of PPR copolymers can be modified to alter the properties of the PPR material. For example, PGA does not have methyl side groups, and has a higher crystalline structure than PLA, while the methyl side groups of PLA make it more hydrophobic than PGA. Therefore, PLA-richer PLGA copolymers are less hydrophilic, absorb less water and, as a result, degrade more slowly in the body. Adjusting, for example, the hydrophilicity, hydrolytic group interaction, crystallinity and volume-to-surface ratio of PLGA allows a user to obtain degradation times ranging from less than one (1) month to more than six (6) months. See, for example, Makadia and Siegel, Polymers (Basel), September 1, 2011; 3 (3): 1377 to 1397. doi: 10.3390 / polym3031377.

[058] According to the embodiments, a collection of PPR particles having the size and / or shape characteristics of the various embodiments of the invention is provided, wherein the PPR particles predominantly comprise particles that are at least predominantly composed of PLLA. In more particular aspects, the invention provides compositions wherein the particles consist largely of particles consisting, at least largely, of PLLA (for example, at least 75% of the particles in the composition have a content of at least 75% PLLA). In still other aspects, at least about 80%, at least approximately 90%, at least about 95% or more of the particles in the composition consist essentially of PLLA, or consist substantially of, or consist of, Petition 870210111618, dated 01 / 12 / 2021, pages 237 / 307 23 / 84 PLLA. PPR PLLA particles can be composed of any suitable type of PLLA, and those skilled in the art can apply known principles to select and prepare PLLA materials having the desired properties. See, for example, Lasprilla et al., Biotechnology Advances, 30 (2012) 321-328 (doi: 10.1016).

[059] According to the forms of incorporation, PPR particles comprise, consist largely of, or consist substantially of, and / or consist essentially of, or consist entirely of, PLLA particles, which are composed of poly-L-lactic acid (crystalline), poly-D-lactic acid (amorphous), or a mixture thereof. PDLA is typically used in situations where a shorter duration of the material in the body is desired.

[060] The molecular mass of a PPR polymer, such as a PLA polymer, or more specifically a PLLA polymer, which constitutes most, if not substantially all, or all, of the particles of a composition of the invention, calculated by viscometry, is typically from about 10,000 to approximately 650,000 Daltons. According to more particular embodiments, the molecular mass of the polymer is from about 50,000 to approximately 250,000 Daltons. In an even more precise aspect, the polymer has a molecular mass of about 90,000 to approximately 110,000 Daltons.

[061] According to the embodiments, the inherent viscosity of a PPR polymer, such as a PLA polymer, or more specifically a PLLA polymer, which constitutes most, if not substantially all, or all, of the particles of a composition of the invention, is also or alternatively between approximately 0.1 dL / g and about 4.0 dL / g. In more specific embodiments, the PPR polymer has an inherent viscosity of about 0.4 to approximately 2.0 dL / g. In an even more precise aspect, the PPR polymer has an inherent viscosity of about 0.90 to approximately 1.10 dL / g. Petition 870210111618, dated 01 / 12 / 2021, pp. 238 / 307 24 / 84

[062] In a further aspect, the PPR polymer of the particles of the invention, as exemplified by PLA, can be a chiral polymer. In a more specific aspect, the polymer can be an optically active levorotatory polymer. In exemplary aspects, the polymer can be PLLA having a specific rotation between about -150 and -160 cm2 / g, commonly abbreviated simply as degrees (°).

[063] In yet another aspect, the PPR polymer of the particles of the invention, such as a PLLA used in most, in substantially all, or in all, particles, has a melting point between about 100 °C and approximately 300 °C, such as between about 150 °C and approximately 200 °C, such as between 175 and 195 °C, and in a more specific embodiment between 177 and 192 °C (for example, between 178.0 and 190.1 °C). Alternatively, with the heat of fusion (also referred to as enthalpy of fusion) of 100% crystalline PLLA being about 90 J / g, the PPR polymer of the particles in the present invention, such as, for the most part, PLA, having a mixture of crystalline (PLLA and / or PDLA) and amorphous (PDLLA) polymers, may have a heat of fusion ranging from approximately 25 J / g to about 150 J / g, such as from 50 J / g to 125 J / g, such as, for example, from about 60 J / g to about 95 J / g, for example, and more specifically from 65 J / g to 90 J / g.

[064] Those skilled in the art will recognize that often the particle compositions will not be completely pure due to the normal aspects of the production process. Thus, for example, PPR particle compositions may contain some amount of residual solvents, residual monomers, or both. Residual solvents are solvents remaining from the manufacturing process, which are not removed, but are considered to be present at an acceptable level. Residual monomers (e.g., lactic acid in the case of PLA) are monomers of a PPR polymer that were not polymerized during the polymer production process, which are also generally present at a level considered adequate.The PPR polymer(s) used in the particles will be associated, according to some incorporation methods, with less than 1%, less than 0.1%, less than 0.05% or less than 0.01% of residual solvents (for example, with less than 0.005% or less than 0.001% of residual solvents). The PPR polymers used in the particles. Petition 870210111618, dated 01 / 12 / 2021, pp. 239 / 307 25 / 84 will also or alternatively be associated with less than about 2%, less than approximately 1%, less than about 0.5%, or less than approximately 0.1% of residual monomer (e.g., lactic acid) (such as less than approximately 0.05%, less than about 0.025%, or less than approximately 0.01% of residual monomer). These percentages are also sometimes described here as ratios.

[065] Products that meet the various characteristics described above are known or can be produced using methods known in the state of the art. For example, a PLLA product having a low residual monomer content, a low residual solvent content, a high melting point and a high heat of fusion, characteristic of the aspects provided above, is currently commercially available from the company Corbion (Gorinchem, Netherlands) and the company Evonik Nutrition & Care GmbH (Essen, Germany).

[066] PPR polymers typically biodegrade in vivo via nonspecific hydrolysis, usually releasing monomeric constituent(s), which are naturally endogenous and / or are readily metabolized at a mammalian receptor, such as lactic acid, glycolic acid, or both compounds. PPR PARTICLE SIZE CHARACTERISTICS

[067] The PPR particles of the invention can typically be characterized as being substantially uniform in size, shape, or both. Thus, for example, the PPR particles of the invention can be characterized, for example, by at least about 65%, at least about 70%, or at least about 75% of the resorbable polyester polymer particles having a maximum particle diameter that is within (+ / -) approximately 35%, + / - (or within) about 30%, within approximately 25%, or within about 20%, of the average particle diameter size of the polyester polymer particles present in the particle population, or of the relevant composition in which such particles are contained.

[068] PPR particles can also or alternatively be characterized as having a shape that is substantially uniform. The particles of this and other Petition 870210111618, dated 01 / 12 / 2021, pp. 240 / 307 26 / 84 compositions of the invention may have any suitable shape. The shapes of the particles may include disc shapes, diamond shapes, square shapes with rounded corners, and the like. However, in most cases, the particles will be spherical or sphere-like (approaching a sphere, or more like a sphere), or spheroids. Thus, for example, the particles may also typically be characterized by at least approximately 70%, at least approximately 80%, at least approximately 90%, at least approximately 95%, or at least approximately 99% of the particles having a diameter that varies by no more than about 35%, no more than approximately 30%, no more than about 25%, no more than approximately 20%, no more than about 15%, no more than approximately 10%, or no more than about 5%, in any direction.According to the forms of incorporation, such particles may consist largely of, consist substantially of, or consist of microspheres, so that the particles may also or alternatively be characterized as being substantially spherical. Thus, for example, the particle population may be characterized by at least about 65%, at least about 70%, or at least about 75% of the particles having, for example, dimensions that are within about 2%, about 1%, about 0.5%, or even about 0.1% of all other dimensions.In one aspect, PPR particles are substantially spherical, such that PPR particles can be characterized as comprising predominantly micro-spherical particles or microspheres (the term micro in this context indicates that the size of the particles in question is less than 1 mm, and typically less than 200 μm, 150 μm or 100 μm, or the relevant particle composition or population consists substantially of particles that are smaller than the indicated amounts). This substantially similar or substantially identical diameter of such particles is an indicator that the particles are spherical (sometimes also being informally described as round or rounded). However, in other aspects, the particles can also or alternatively be determined to be spherical by means of other shape determination methods known in the state of the art. Petition 870210111618, dated 01 / 12 / 2021, pp. 241 / 307 27 / 84 including visual inspection with a microscope, as demonstrated with respect to the exemplary particles of the invention shown in the figures provided herein. Microspheres represent a preferred aspect of the invention. Therefore, in all cases where the term particle is used herein, it should be understood as also supporting a similar aspect of the invention in which such particles are microspheres, unless such understanding is contradicted by the description, context or suitability.

[069] As already demonstrated, the substantially similar or substantially uniform size of the PPR particles is an important way to characterize the compositions of the invention. In an exemplary aspect, the invention provides compositions in which at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% of the polyester polymer particles in the composition have a maximum particle diameter that is within about 30%, about 25%, or about 20% (for example, within about 5%, about 2%, or about 1%) of the average particle diameter of the polyester polymer particles in the relevant collection / population or composition.Thus, an exemplary aspect of the invention is embodied in a neocollagenous dermal implant / injection comprising an effective amount of PPR particles, herein being at least approximately 80%, or at least about 85%, of the polyester polymer particles of the composition having a maximum particle diameter that is within 20% (e.g., within about 25%) of the average particle diameter of the polyester polymer particles in the composition. In another similar exemplary aspect, at least about 90% of the polyester polymer particles of the composition have a maximum particle diameter that is within 19%, within 18%, within 17%, within 16%, or within 15% of the average particle diameter of the polyester polymer particles in the composition.In yet another aspect, at least about 75% of the polyester polymer particles of a composition of the invention also or alternatively have a maximum particle diameter that is within 15% of the diameter of... Petition 870210111618, dated 01 / 12 / 2021, pp. 242 / 307 28 / 84 average particle size of the polyester polymer particles in the composition. In another aspect, in at least about 85%, at least approximately 90%, at least 92.5%, or at least about 95% of the PPR particles, the diameter in any direction varies by no more than approximately 25%, no more than about 20%, or no more than approximately 15%.

[070] In some cases, the particles of the invention may be characterized by having measured size characteristics that fall within a desired measurement range. In one aspect, the particles of the invention may be characterized by having an average diameter and / or a maximum diameter within the range of 10 gm to 200 μm, and more typically the particles of the invention will have a size characterized by average and / or maximum diameters that both fall within the range of about 20 μm to approximately 140 μm, about 20 μm to approximately 150 μm, or about 20 μg to approximately 100 μm. In still other aspects, the particles can be characterized by having a maximum diameter and / or an average diameter within the range of approximately 25 μm to about 75 μm.Thus, for example, the invention provides compositions in which the particles of the composition consist largely or substantially of particles that meet these size characteristics. In one aspect of the invention, most of the particles of the composition have a size defined by an average and / or maximum diameter that is less than about 60 μm, less than approximately 55 μm, or even less than 50 μm, such as for example less than about 40 μm, such as approximately 30 μm.

[071] According to another aspect, the PPR particles of the composition may also or alternatively be characterized by including a limited / small number of particles (e.g., less than about 10%, less than 7.5%, less than approximately 5%, less than about 2%, less than approximately 1%, less than about 0.5%, or less than approximately 0.1%) having a maximum diameter in any direction of less than 20 μπ in size. In one aspect, the PPR particles of the composition may be characterized as comprising less than 5% of the particles, such as less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the particles being smaller than 10 μπ in size, such as Petition 870210111618, dated 01 / 12 / 2021, pp. 243 / 307 29 / 84 as smaller than 9 gm in size, smaller than 8 gm in size, smaller than 7 gm in size, or for example smaller than 6 gm in size. In a further aspect, compositions are provided in which less than about 10%, less than 7.5%, less than approximately 5%, less than about 2%, less than approximately 1%, less than about 0.5%, or less than approximately 0.1% of the particles have a maximum diameter in any direction smaller than 5 μm, such as smaller than 4 gm in size, or for example smaller than 3 gm in size.

[072] In certain aspects, at least about 75%, at least approximately 80%, at least about 85%, at least approximately 90%, at least about 95%, or at least approximately 97.5% of the particles are microspheres, and at least about 40%, at least approximately 50%, at least about 60%, or at least approximately 70% of the microspheres have a maximum diameter within a range of 30 + / -17.5 gm, 30 + / -15 gm, 30 + / -12.5 gm, 30 + / - 22 μίτι, or 30 + / - 7.5 gm.

[073] In a particular aspect, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 97.5%, or at least about 99% of the PPR particles in the composition have an average diameter and / or a maximum diameter of about 10 gm to approximately 62.5 gm in size. In a more particular aspect, at least about 70%, at least about 80%, at least about 90%, at least about 97.5%, or at least about 99% of the PPR particles have a maximum and / or average diameter of about 13 to 60 gm in size.In a more particular aspect, at least about 60%, at least approximately 65%, at least about 70%, or at least approximately 80% of the PPR particles in the composition have a maximum particle diameter and / or an average particle diameter of about 20 g / m² to approximately 57 g / m². According to one aspect, such particles further comprise predominantly PLA particles. According to one aspect, such particles further comprise predominantly... Petition 870210111618, dated 01 / 12 / 2021, pp. 244 / 307 30 / 84 consist largely of, consist substantially of, or consist entirely of PLLA particles.

[074] In another aspect, a composition of the invention may also or alternatively be characterized in that, with respect to at least about 70%, at least approximately 80%, at least about 85%, at least approximately 90%, or at least about 95% of the polyester polymer particles in the composition, the maximum diameter of any polyester polymer particle is no more than 300% of the minimum diameter size of any other detected PPR particle (or of a minimum size detected in a defined quantity of particles, such as at least 0.1%, at least 0.5%, or at least 1% of the particles).In yet another aspect, the particles of a composition of the invention may also or alternatively be characterized in that, for at least approximately 40%, at least approximately 50%, at least approximately 60%, at least approximately 70%, or even for at least approximately 80% of the polyester polymer particles in the composition, the maximum diameter of any polyester polymer particle is not greater than 200% of the minimum diameter size detected for the PPR particles in the composition (for example, the minimum diameter detected in a quantity of particles estimated at at least 0.1%, at least 0.5%, or at least 1% of the particles in the composition).

[075] In yet another aspect of the invention, the composition can be characterized in that the number of particles having a maximum diameter that is within approximately 30%, about 25%, or approximately 20% of the average maximum diameter of all PPR particles in the composition is at least twice (i.e., at least 2x, or 200%) greater (for example, at least 2.25x greater, at least 2.5x greater, or at least 2.75x greater) than the number of particles having a maximum diameter that differs from the average diameter by 150% or more, 200% or more, or 250% or more. In particular embodiments, the number of particles within this uniform size distribution (within about 25%, within approximately 20%, or even within about 15% of the average maximum diameter of all particles) is at least 3 times greater than the number of polydisperse particles in the composition (for example, the number of Petition 870210111618, dated 01 / 12 / 2021, pages 245 / 307 31 / 84 particles having a maximum diameter that varies by 1.75x, 2x, 2.25x or 2.5x relative to the average particle diameter). In a particular aspect, the number of particles in the composition having a maximum diameter that is within 15% of the average maximum diameter is at least 2.5 times greater (for example, at least 2.75x, at least 3.25x or at least 3.5x) than the number of particles having a maximum diameter that differs from the average maximum diameter by 250% or more.

[076] The compositions of the invention can further be characterized by the maximum size of potential collections of agglomerated particles. The agglomeration of particles in a composition, such as a composition for injection, can be important with regard to the use of such products, as it can, for example, lead to the blockage of a needle or other delivery system, or lead to other undesirable effects. Because of the relatively small and relatively uniform or even size of the particles of the invention, the maximum size of the PPR particle agglomerates of the invention will typically and significantly be smaller than the agglomerates formed from particles of previously known products, such as SCULPTRA®.

[077] According to an exemplary embodiment, the maximum average dimension of three agglomerated PPR particles of the composition of the invention is less than 250 µm. In another aspect, the particles consist largely of, or substantially of, particles which, when three particles are agglomerated, have a maximum size of less than 200 µm (for example, with at least 95%, at least 97.5% or at least 99% of the particles meeting this limitation). In such cases, the shape of the particles is such that, even when agglomerated in a manner that aligns the largest dimension of all three particles, the size of the agglomerate formed will not exceed 200 µm, 250 µm, or a similar measure (for example, not exceeding 180 µm, not exceeding 170 µm, or even not exceeding 160 µm or 150 µm).

[078] In another aspect, less than about 5%, less than approximately 3%, less than about 2%, or less than approximately 1% (for example, less than about 0.5% or less than approximately 0.2%) of the PPR particles in the composition will have a maximum diameter that allows an agglomerate of three particles having the same Petition 870210111618, dated 01 / 12 / 2021, pages 246 / 307 32 / 84 maximum diameter is equal to or greater than 250 µm in maximum diameter. In yet another aspect, less than about 10%, less than approximately 5%, or less than about 2% of the PPR particles in the composition will have a maximum diameter such that an agglomerate of three particles having the same maximum diameter is equal to or greater than 200 µm or 180 µm in diameter. In yet another form of incorporation, less than about 5%, such as less than approximately 2.5%, or less than about 1% of the PPR particles in a composition will also or alternatively have a maximum diameter such that if a large-diameter particle is agglomerated with two additional PPR particles having the average maximum diameter, this would result in an agglomerate having a maximum diameter equal to or greater than 250 µm, 200 µm, 180 µm, or 150 µm.

[079] The compositions of the invention are expected to exhibit measurably different characteristics from previously known compositions in terms of agglomeration. In low-concentration suspensions, such as those described elsewhere in this specification, the particles contained in the invention are expected to exhibit a markedly lower frequency and / or intensity / magnitude of agglomeration compared with SCULPTRA®, due to the relatively smaller and significantly more uniform particle size, which, in many embodiments, will be spherical or substantially spherical. Thus, for example, the invention provides compositions in which the frequency of agglomeration formation in a solution having a particle concentration comparable to SCULPTRA® is reduced by at least approximately 5%, by at least approximately 10%, by at least approximately 15%, by at least approximately 20%, by at least approximately 25%, by at least approximately 35%, or more.For the same reasons, the particles of the invention will be, under different circumstances, amenable to tighter and more efficient packing than the polydisperse particle composition of SCULPTRA®.

[080] The PPR particles of the invention can be formed by any means, techniques, or any suitable combination of methods. Devices and methods for generating shaped particles, including microspheres, having uniform and relatively smaller size and relatively uniform shape, and which can be used for Petition 870210111618, dated 01 / 12 / 2021, pages 247 / 307 33 / 84 producing PPR particles of the invention, such as PPR microparticles, are described in international patent application WO 2005 / 115599 (PCT / NL2005 / 000385).

[081] In a particular aspect of the invention, the average PPR particle size of the composition is from about 10 to approximately 60 μm (normally reflected in the maximum diameter of such particles), such as from about 20 to approximately 40 μm, for example, from about 25 to approximately 35 μm.

[082] According to the forms of incorporation, PPR particle compositions or collections are typically monodisperse, having at least about 85%, at least about 90%, at least about 95% or more (for example, at least about 97.5%, or at least about 99%) of the PPR particles having a maximum average diameter that is within about 15 μm, within about 12.5 μm, within about 22 μm, or within about 5 μm from each other.The compositions may also or alternatively be characterized by comprising at least 90%, such as at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or sometimes at least 99.5% of the particles (e.g., about 100%) of the composition having a particle size coefficient of variation (CV) of less than approximately 50%, such as less than 45%, less than about 40%, less than 35%, less than approximately 30%, less than 25%, less than about 20%, less than 15%, less than approximately 12.5%, less than about 10%, or less than approximately 7.5%, such as less than 7%, less than 6%, or less than about 5%.In one aspect, the composition for injection / implantation may comprise particles having an average particle size ranging between 5 μm and 250 μm, wherein the particle size CV within each of these compositions is not greater than 50%, such as less than 45%, less than 40%, less than 35%, about 30% or less, less than 25%, about 20% or less, about 15% or less, about 15% or less, or about 5% or less.

[083] According to the forms of incorporation, the PPR material in the composition particles is also or alternatively predominantly semicrystalline, or is essentially all or totally semicrystalline. According to the aspects, the Petition 870210111618, dated 01 / 12 / 2021, pp. 248 / 307 The 34 / 84 composition is characterized by having approximately 2 to 6%, approximately 3 to 5%, or approximately 4% crystallinity. Depending on the aspect, the molecular weight of the PPR material in the particles is approximately 70 to 200 kDa, approximately 80 to 160 kDa, approximately 90 to 120 kDa, or approximately 110 kDa. The PPR particles may also or alternatively be characterized by having a water content of less than approximately 3%, less than approximately 2%, or less than approximately 1% (e.g., a water content of less than approximately 0.5%). The compositions may further be characterized by having a residual DCM level of less than approximately 700 ppm, less than approximately 650 ppm, less than approximately 600 ppm, less than approximately 550 ppm, or less than approximately 500 ppm.

[084] In certain respects, the average particle size of the particles of the compositions having one or more of the above-described characteristics also or alternatively does not decrease by more than about 10%, such as by more than approximately 8%, by more than about 6%, by more than approximately 4%, by more than about 2%, or in some respects by more than approximately 1%, or in some respects by even more than about 0.5%, over a significant period of time (e.g., at least 3 months, at least 4 months, at least 6 months or more), under typical long-term / normal or accelerated stability conditions used in pharmaceutical product / device testing.In certain respects, the particles of a composition do not exhibit a decrease in size greater than about 10% (e.g., greater than approximately 8%, 6%, 4%, 2% or 1%), when maintained (a) at about 40 °C (e.g., 38 to 42 °C), at approximately 75% (e.g., 70 to 80%) relative humidity (RH), for 6 months (representative of a typical accelerated stability study of a device / drug); (b) when maintained under typical long-term / normal stability conditions, e.g., at about 25 °C (e.g., ± 2 °C) and approximately 60% RH (e.g., ± 5%), at about 30 °C (e.g., ± 2 °C) and approximately 65% ​​RH (e.g., ± 5%), or in both conditions, for 12 months or more (e.g., 18 months or 24 months); or (c) when maintained under long-term / normal or accelerated stability testing conditions. Any. Petition 870210111618, dated 01 / 12 / 2021, pp. 249 / 307 35 / 84 description in this document relating to accelerated stability test conditions implicitly also or alternatively provides support for achieving the same results under long-term / normal stability test conditions. STABILITY

[085] In some respects, the PPR particle formulations described herein have the ability to be stably sustained for significant periods of time, for example, for at least approximately 3 months, 4 months, 6 months, 12 months, 18 months, 24 months or more, under (a) typical stability test or storage conditions, or under (b) accelerated stability test conditions (which are considered indicative of long-term storage capability), or under (c) both conditions (specific aspects of which are presented above, being known in the state of the art). In an exemplary aspect, particles maintained under accelerated stability conditions, for example, at about °C and 75% relative humidity, can be maintained for 3, 4 or 6 months without loss of suitability for use or significant alteration in particle size characteristics.In certain respects, the average molecular weight of particles (Pm, in kDa) maintained under accelerated storage conditions, for example, from 3 to 12 months (e.g., 4 to 8 months), or under real-time storage from 12 to 36 months (e.g., 18 to 30 months), or both, varies by less than about 5% from an initial time point (t = 0) up to six months, when maintained under such conditions. In certain respects, the average molecular weight of the particles maintained under such conditions during these periods varies by less than about 4.5%, less than approximately 4%, less than about 3.5%, less than approximately 3%, less than about 2.5%, less than approximately 2%, less than about 1.7%, less than approximately 1.5%, less than about 1.3%, or less than approximately 1%, such as, in certain respects, by less than about 0.5%, or even less than approximately 0.1%.

[086] In certain respects, PPR particle formulations can maintain an average molecular weight between about 105 kDa and 115 kDa, as well as between about 106 kDa and approximately 114 kDa, for at least 3, 4 or 6 months when maintained under accelerated stability conditions (e.g., 40 °C and 75% relative humidity), or Petition 870210111618, dated 01 / 12 / 2021, pp. 250 / 307 36 / 84 when kept under normal conditions of prolonged storage (at typical ambient temperature and humidity for 12 to 36 months, for example, 18 to 30 months), or both.

[087] In some respects, the polydispersity index (PDI) (a measure of the amplitude of the molecular weight distribution) in the particle compositions varies, throughout the storage / stability test, over periods and conditions similar to those described above (e.g., during 6 months at 40 °C and 75% relative humidity), by less than about 5%, such as for example less than approximately 4.5%, less than about 4%, less than approximately 3.5%, less than about 3%, less than approximately 2.5%, or less than about 2%, such as less than approximately 1.5%, or in some cases even less than about 1%. In some respects, the PPR formulations described herein can maintain an average IPD between approximately 1.30 and 1.40, as well as between approximately 1.20 and approximately 1.38, for at least six months when maintained at 40 °C and 75% relative humidity.

[088] In some respects, the PPR particle formulations described herein are capable of maintaining a degree of crystallinity, when kept under accelerated storage conditions or common long-term storage conditions, as exemplified above (e.g., at 40 °C and 75% relative humidity for 6 months), which varies by not more than approximately 20%, such as, for example, not more than about 18%, not more than approximately 16%, not more than about 14%, or, for example, not more than approximately 12%, or not more than about 10%. In certain respects, the PPR particle formulations described herein can maintain an average degree of crystallinity between about 3 and approximately 12, such as between about 4 and approximately 11, for at least six months, when kept at 40 °C and 75% relative humidity.

[089] In certain respects, the PPR particle formulations described herein are able to maintain a d 10 (i.e., a particle population where 10% of the particles have a diameter smaller than a given value), when maintained under accelerated stability conditions (at 40 °C and 75% relative humidity for 6 months), under common / long-term storage conditions, or both, which varies Petition 870210111618, dated 01 / 12 / 2021, pp. 251 / 307 37 / 84 in less than 5%, less than about 4.5%, less than approximately 4%, less than about 3.5%, less than approximately 3%, less than about 2.5%, less than approximately 2%, less than about 1.5%, less than approximately 1%, or, in certain respects, even less than about 0.5%.

[090] In some respects, the PPR particle formulations described herein are able to maintain a d50 (i.e., a particle population in which 50% of the particles have a diameter smaller than a given value), when maintained at 40 °C and 75% relative humidity for 6 months (or under normal / long-term storage conditions for at least 12 months, or both), which varies by less than 5%, such as less than approximately 4.5%, less than about 4%, less than approximately 3.5%, less than about 3%, less than approximately 2.5%, less than about 2%, less than approximately 1.5%, less than about 1%, or in certain respects, even less than approximately 0.5%.In some respects, the PPR particle formulations described herein are capable of maintaining a d90 (i.e., a particle population in which 90% of the particles have a diameter smaller than a given value), when kept at 40 °C and 75% relative humidity for 6 months (or under normal / long-term storage conditions for at least 12 months, or both), which varies by less than 60%, such as for example less than about 50%, less than approximately 40%, less than about 35%, less than approximately 30%, less than about 25%, or less than approximately 20%, such as for example less than about 15%, less than approximately 10%, less than about 5%, less than approximately 4%, less than about 3.5%, less than approximately 3%, less than about 2.5%, less than approximately 2%, less than about 1.5%, or, in certain respects, less than approximately 1%.

[091] In certain respects, the PPR particle formulations described herein are able to maintain an average diameter, when held under such regular or accelerated long-term stability test conditions (e.g., when held at 40 °C and 75% relative humidity for 6 months), under long-term / normal storage conditions, or both, that varies by less than about 50%, such as, for example, Petition 870210111618, dated 01 / 12 / 2021, pp. 252 / 307 38 / 84 less than approximately 45%, less than approximately 40%, less than approximately 35%, less than approximately 30%, less than approximately 25%, or less than approximately 20%, such as, for example, less than approximately 15%, less than approximately 10%, less than approximately 5%, less than approximately 4.5%, less than approximately 4%, less than approximately 3.5%, less than approximately 3%, less than approximately 2.5%, less than approximately 2%, less than approximately 1.5%, or in certain aspects less than approximately 1%, or less than approximately 0.5%.

[092] In certain respects, the PPR particle formulations described herein may maintain a dlO value between 25 gm and 30 gm when held under such common or accelerated long-term stability test conditions (e.g., when held for at least six months at 40 °C and 75% relative humidity), under normal / long-term storage conditions, or both. In some respects, the PPR particle formulations described herein may maintain a d50 value between 25 gm and 35 gm for at least six months when held at 40 °C and 75% relative humidity (or under other stability test conditions, e.g., for 2 years at TA, Ambient Temperature). In some respects, the PPR formulations described herein may maintain a d90 value between 70 gm and 75 gm for at least six months when held at 40 °C and 75% relative humidity.In some respects, the PPR particle formulations described herein can maintain a d90 value between 30 gm and 35 gm for at least six months when kept at 40 °C and 75% relative humidity. In some respects, the PPR particle formulations described herein can maintain an average diameter between 38 gm and 40 gm for at least six months when kept at 40 °C and 75% relative humidity. In some respects, the PPR formulations described herein can maintain an average diameter between 28 gm and 32 gm for at least six months at 40 °C and 75% relative humidity. CARRIERS AND COMPOSITIONS

[093] As noted elsewhere in this specification, the PPR particle compositions of the invention can be combined with other compounds to form compositions possessing desirable properties. For example, the particle compositions of the invention can be combined with a carrier system (carrier Petition 870210111618, dated 01 / 12 / 2021, pages 253 / 307 39 / 84 or vector) to generate a suspension (or formulation) comprising the particles, a suitable base carrier or diluent [typically water, such as water for injection (WFI)], and optionally one or more additional functional / structural compounds to improve the performance of the suspension / formulation (excipients or additives).

[094] Examples of excipients and additives for injectable and implantable products, such as dermatological fillers, are well known in the state of the art, and in general any safe and suitable excipient or set of excipients can be combined with the PPR particles of the invention, to improve the performance of the resulting composition in the context of its intended use.

[095] In an exemplary embodiment, the invention provides compositions comprising an effective amount of PPR particles according to any of the various aspects described herein, in combination with (a) an effective amount of one or more physiologically acceptable surfactants, and (b) an effective amount of one or more physiologically acceptable viscosity-increasing and / or gelling agents, such that the combination of the excipients and particles can form a viscous solution and / or a gel. It should be understood that any formulation described herein may be a viscous solution comprising a dispersion of particles, a gel, or any other suitable form of formulation, which will typically be a liquid, which may be, for example, a gel. Furthermore, viscosity-increasing and / or gelling agents may be incorporated into the compositions or methods of the invention.In some cases, viscosity-increasing agents may also be referred to as gelling agents in the art, or understood as falling within the category of compounds referred to as gelling agents.

[096] The excipient components of the formulation are typically reabsorbable within about six months or less, within about four months or less, within about three months or less, within 2.5 months or less, or within two months or less (for example, within six to 12 weeks, such as seven to 10 weeks), for example, as can be determined in the case of at least approximately 95% of such liquids or gels, at least about 99% of such gels, or at least Petition 870210111618, dated 01 / 12 / 2021, pp. 254 / 307 40 / 84 approximately 99.9% of such liquids or gels, when tested under repeated conditions, such as when used in quality control procedures for medical / pharmaceutical devices known in the state of the art, and / or through clinical trials in one or more well-controlled, well-conducted, and otherwise appropriate studies. The particles, however, will normally be retained in the body for longer periods, for example, at least for about six months, typically for at least about 12 months, for at least about 18 months, or even for approximately two years (for example, on average, as determined by administration to a population of individuals in an appropriate and well-controlled clinical trial).

[097] Liquid formulation compositions according to typical aspects are mainly composed of water for injection (sterile water, normally produced by reverse osmosis and having other characteristics known in the state of the art). These compositions can be considered dispersions or suspensions of particles in a liquid, which is sometimes a viscous liquid, and in other cases is a gel. In general, the description of any type of formulation can be interchanged. The terms liquid and gel are sometimes used separately to emphasize that the formulation compositions of the invention can be non-gel liquid formulations, such as a dispersion of particles in an aqueous liquid composition. In certain specific aspects, the formulation composition will also comprise one or more gelling agents, which are normally authorized for injection formulations by the relevant regulatory agencies. In one aspect, the invention provides gels or liquids of PPR particles.comprising an effective amount of one or more cellulose derivatives, such as carboxymethyl cellulose (CMC). The amount of such material may be an amount that is effective in providing the desired property in the composition (i.e., an effective amount). A range of amounts may result, for example, in the formation of a gel, while a narrower range will provide a gel having a certain viscosity and / or other rheological characteristics, but in other respects the formulation will remain a non-gel liquid. In an exemplary aspect, the invention provides a liquid or gel formulation comprising CMC at a mass concentration of about 0.1 a. Petition 870210111618, dated 01 / 12 / 2021, pages 255 / 307 41 / 84 approximately 7.5%, such as from approximately 0.1 to approximately 5.0%. In another aspect, the gel also or alternatively comprises hydroxypropyl methylcellulose (HPMC). Other components of the formulation may also or alternatively include, for example, hyaluronic acid, chitosan, collagen, other gelling agents, such as gelling agents capable of forming, supporting and / or maintaining a solid colloidal suspension. According to the embodiments, the compositions of the invention may also or alternatively further comprise hyaluronic acid (typically synthetic), and / or esters, such as lactic acid esters or caproic acid esters.

[098] In another embodiment, the dispersion of the PPR particles / microspheres of the invention and / or the homogeneity of the liquid or gel will be provided or enhanced by the use of an effective amount of one or more surfactants. The surfactants used in such compositions will typically be selected based on safety, and will generally be agents authorized for subcutaneous and intradermal use by regulatory authorities, such as the US FDA. The surfactant will also typically or alternatively be a non-ionic surfactant. Polyoxyethylene sorbitan monooleate compositions are examples of such suitable surfactants. These surfactants are known in the art and, for example, are marketed under the name Tween®, such as Tween® 80. Other known surfactants include Pluronic / poloxamer surfactants [see for example HH Bearat and BL Vernon, in Injectable Biomaterials, 2011].Other possible surfactants include, but may not be limited to, those having characteristics similar to Tween 80, other non-ionic surfactants possessing a similar viscosity (approximately 300 to 500 centistokes at 25 °C), similar molar mass (approximately 1310 g / mol), similar density (1.06 to 1.10), and / or similar pH (pH between 6 and 8 for a 5% aqueous solution), which may confer a comparable capacity to provide sufficient dispersion of the microspheres and maintain the homogeneity of the liquid or gel. In yet another aspect, compositions are also or alternatively provided comprising polysorbate 20 (e.g., Tween® 20) or its equivalents.

[099] In certain forms of incorporation, the surfactant may be selected from any number of surfactants useful for providing particle homogeneity or Petition 870210111618, dated 01 / 12 / 2021, pp. 256 / 307 42 / 84 microspheres dispersed in a formulation composition. These surfactants may be non-ionic surfactants other than Tween 80, such as other sorbitan surfactants, for example, SPAN® 80, SPAN® 85, SPAN® 65, SPAN® 60, SPAN® 40, SPAN® 20, TWEEN® 40, TWEEN® 20, TWEEN® 21, TWEEN® 60, Triton-X® 100, or any mixture thereof. In other embodiments, the non-ionic surfactant may be an alkyl glucoside, or PEG-400.

[0100] In still other embodiments, the surfactant component of a formulation may be a nonionic surfactant having a molecular weight of about 100 Daltons to approximately 2000 Daltons. In one or more embodiments, a nonionic surfactant of the present invention may have a molecular weight as low as about 100, approximately 200, or about 300 Daltons, and / or a molecular weight as high as approximately 2500, about 2000, approximately 1500, about 1300, approximately 1200, or about 1000 Daltons.

[0101] Another aspect of the invention provides a composition of PPR particles, wherein the composition is in the form of an aqueous liquid or a gel. In such aspects, a formulation composition typically comprises one or more physiologically acceptable buffers, one or more physiologically acceptable salts, one or more physiologically acceptable preservatives, or a combination of two or more thereof. In a set of exemplary aspects, compositions are provided comprising at least about 90% water, approximately 0.05 to 2% of a preservative, such as citric acid, about 0.05 to 0.75%, such as approximately 0.05 to 0.25% of salts and / or buffers (for example, disodium hydrogen phosphate dihydrate, sodium chloride and / or sodium hydroxide), and approximately 1 to 5%, such as about 1.5 to approximately 4.5%, about 1.75% to approximately 3.5%, for example, about 2 to 3% of a gelling agent, such as CMC or HPMC.Physiologically acceptable buffers, physiologically acceptable salts, and physiologically acceptable preservatives are types of excipients known in the state of the art. Exemplary buffer components, salts, and preservatives that may be used in any formulation composition are exemplified elsewhere in this specification. Petition 870210111618, dated 01 / 12 / 2021, pages 257 / 307 43 / 84

[0102] The excipients and particles of any formulation composition are typically selected and configured so that the effect of the implantation / injection of the particles is detectable in human recipients for at least about 6 months, at least about 12 months, at least about 18 months, at least about 24 months or more (e.g., at least about TJ months, at least about 30 months, or at least about 36 months) in human recipients (e.g., on average, as determined in clinical trials in one or more suitable and well-controlled studies).

[0103] A formulation composition of the invention will desirably be safe for administration to a human recipient. In one aspect, the invention provides formulation compositions in which a detectable allergic reaction occurs in less than about 1%, such as in less than approximately 0.5%, or in less than about 0.1% of human recipients (for example, as determined through clinical studies). In another aspect, the invention provides formulation compositions that may also or alternatively be classified as non-pyrogenic, resulting in a detectable inflammatory response in less than about 1%, such as in less than approximately 0.5%, or in less than about 0.1% of human recipients (for example, as determined by one or more clinical studies).

[0104] The formulation compositions of the invention and other PPR particle compositions provided herein may have any suitable volume, and may comprise any quantity of PPR particles that are effective for the intended application of the composition.

[0105] In one aspect, the invention provides compositions comprising 100 mg to about 300 mg of one or more PPR particles. In another aspect, the invention provides compositions comprising 125 mg to about 175 mg of PPR particles. In yet another particular aspect, the invention provides compositions containing about 140 mg to approximately 160 mg of PPR particles. In a still more specific aspect, the invention provides compositions comprising about 145 mg to approximately 155 mg of one or more PPR particles, such as PLLA particles. These compositions may or may not include other excipients. Petition 870210111618, dated 01 / 12 / 2021, pp. 258 / 307 44 / 84

[0106] In certain aspects, compositions comprising excipients and PPR particles are provided, but without water or other diluents. These dry compositions may be useful, for example, for transport and storage of particle compositions. In such cases, the excipient / particle formulation may be reconstituted with a diluent, such as water for injection (WFI), prior to injection or implantation. In some aspects, a sugar alcohol, such as mannitol, may be used as a diluent and / or as a lyophilization aid. For example, a reconstituted / wet composition of the invention may comprise from about 0.5% to approximately 2.5% mannitol (w / w) in some aspects.These compositions may and will typically comprise from about 200 mg to approximately 500 mg of a dry formulation comprising excipients and PPR particles, such as from about 225 to 450 mg of a dry formulation, for example, approximately 250 to 425 mg of a dry formulation, such as from about 275 mg to approximately 400 mg of a dry formulation, or from about 300 to approximately 400 mg, or from about 350 to approximately 400 mg of a dry formulation of excipients and particles.

[0107] In the aqueous suspension / formulation compositions of the invention, the particles may be present in any suitable concentration. In one aspect, the invention provides suspensions in which the concentration of PPR particles in the suspension is from about 10 to approximately 30 mg / mL. In a more specific aspect, the concentration of PPR particles in such a suspension is from about 15 to 25 mg / mL. In an exemplary aspect, the concentration of PPR particles in a composition is from about 20 mg / mL.

[0108] Particle concentration can also be characterized based on weight percentage, which can be especially useful when considering the concentration of PPR particles in dry formulations. As an example, the concentration of polyester polymer particles in a composition (without water or diluent) is approximately 25% to approximately 50% (w / w). More specifically, the concentration of PPR particles in such a dry formulation composition is approximately 30% to approximately 42.5%, as is approximately 35% to approximately 40%. Petition 870210111618, dated 01 / 12 / 2021, pp. 259 / 307 45 / 84

[0109] Dry particle formulations can be generated by any suitable means. In one aspect, the dry formulation is prepared by freeze-drying (lyophilization) applied to a formulation comprising the excipients and the particles.

[0110] Reconstituted formulations may include any suitable amount of WFI or other diluent. In one aspect, compositions comprising about 3.5 to about 10.5 mL of water for injection or other suitable diluents are provided. In a more particular aspect, such a composition comprises about 4 to about 9 mL of water for injection or other suitable diluent. In a still more particular aspect, the composition comprises about 4.5 mL to about 8.5 mL of water for injection or a suitable replacement diluent.

[0111] The formulation in the reconstituted composition may have any suitable concentration. In one aspect, the concentration of the formulation (comprising the particles and excipients) in the liquid or gel formulation composition is from about 45 to approximately 65 mg / mL. In more particular aspects, this concentration is from about 50 to approximately 60 mg / mL, such as from about 51 to approximately 55 mg / mL. In one aspect, the concentration of the formulation (non-aqueous constituents, i.e., PPR particles plus excipients) in the aqueous gel or liquid composition (final reconstituted formulation) is from about 3.5% by weight to approximately 7.0% by weight, such as from about 4.5% by weight to approximately 6.0% by weight, for example from about 5.0% by weight to approximately 5.5% by weight.The concentration of PPR particles in a resuspended / diluted formulation will typically be from about 0.5% by weight to approximately 5% by weight, such as from about 1% by weight to approximately 4% by weight, or from about 1.5% by weight to approximately 2.5% by weight (e.g., about 1.8% by weight, approximately 2% by weight, or about 2.2% by weight).

[0112] The compositions of the invention can also be characterized based on the concentration of particles in the composition. Typically, the concentration of PPR particles in a fully rehydrated gel or liquid composition will be in the range of about 1.5% by weight to approximately 2.5% by weight, for example, about Petition 870210111618, dated 01 / 12 / 2021, pp. 260 / 307 46 / 84 2%. In more specific aspects, the concentration of PPR particles is from approximately 1.9% by weight to approximately 2.1% by weight. The concentration of PPR particles in the formulation (when dry / undiluted, i.e., the percentage of PPR of all non-aqueous constituents) can, however, vary in some respects, from about 20% to approximately 60%, such as from about 35% to approximately 70%, from about 35% to approximately 50%, or from about 40%. The total amount of PPR particles present can be, for example, from about 100 mg to approximately 300 mg, such as from about 125 mg to approximately 250 mg, such as from about 150 mg.

[0113] The reconstituted or otherwise liquid formulation compositions of the invention, intended for particle injection, are desirably syringe-readable. Syringe-readability refers to the ease of administering the product via syringe, as can be determined by user acceptance studies and the like. In one aspect, the syringe-readability of a composition of the invention is determined, through user studies or user feedback, to be at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, or at least about 35% greater than the syringe-readability level of SCULPTRA®.

[0114] Depending on the form of incorporation, the amount of formulation in the composition (excipients and PPR particles) will vary from about 100 mg to approximately 600 mg, such as from about 250 mg to approximately 500 mg, such as from about 350 mg to approximately 450 mg. Depending on the aspect ratio, the formulation of particles and excipient in a composition will be from about 30 to approximately 90 mg / mL, such as from about 35 to 85 mg / mL.

[0115] The gelling agent, when present, will typically constitute about 30% to approximately 90% of the excipients, such as about 35% to approximately 80%, or about 40% to approximately 75%. This concentration of gelling agent in a combined dry formulation (with PPR particles) will typically be reduced to about 15% to approximately 75%, such as about 35% to Petition 870210111618, dated 01 / 12 / 2021, pages 261 / 307 47 / 84 approximately 55% (w / w), for example, about 40 to approximately 50% (w / w). A weight / volume percentage of this gelling agent will typically be between about 1% and approximately 3% in the final wet formulation. The weight / weight percentage of the gelling agent in a reconstituted formulation will be in the same range (about 1 to approximately 2.5%). In a typical wet formulation, about 75 to approximately 275 mg of gelling agent (e.g., CMC) is present, such as about 100 to approximately 250 mg of gelling agent, for example, about 150 to approximately 200 mg of gelling agent, for example, about 170 to approximately 180 mg.

[0116] The surfactant, if present, will typically constitute about 1.0 to approximately 5% (w / w) of the excipient composition, for example, about 2.0 to approximately 4.0% (w / w), as well as about 2.5% to approximately 3.5% of the excipient composition (w / w). The surfactant, if present, will typically constitute about 0.5 to approximately 3.5% of the final dry formulation (excipients plus PPR particles), for example, about 1.5 to approximately 2.5%, or about 1.75 to approximately 2.0% (for example, about 1.9%) of the final dry formulation (PPR particles plus excipients) (w / w), and about 0.05% to approximately 0.2%, as well as about 0.1% of the concentration (w / v% and / or w / w%) of the final wet formulation. One composition of the invention may comprise from about 5 mg to approximately 10 mg of a nonionic surfactant, such as a polysorbate or a pluronic surfactant.In more specific incorporation forms, the composition will comprise approximately 6 to approximately 9 mg, as well as approximately 7.5 mg of a surfactant.

[0117] The particles in the compositions of the invention will typically exhibit a reabsorption time between about 1 and approximately 3 years when injected into human tissue, such as skin. In more particular aspects, the reabsorption time of the PPR particles in the formulation is between about 1.5 and approximately 2.5 years. DISTRIBUTION SYSTEMS AND 775

[0118] In addition to the compositions described above, the invention also provides distribution systems and kits comprising one or more of these compositions. Petition 870210111618, dated 01 / 12 / 2021, pp. 262 / 307 48 / 84

[0119] In an exemplary embodiment, the invention provides an implant / injection delivery system comprising a device including a storage component, which will typically contain an effective amount of a neocollagenous PPR particle composition described above, and a needle, cannula or other delivery component through which the composition can be delivered into the body of mammalian recipients, such as the skin of a human aesthetic medicine patient. In the case of an injection device, the device is configured to deliver the composition by applying a delivery force.

[0120] Typically, the amount of PPR particles contained in the delivery system will comprise an amount of about 100 to approximately 600 mg, such as about 125 mg to approximately 500 mg, for example, about 135 mg to approximately 400 mg. In a particular aspect, the amount of PPR particle material is about 100 mg to approximately 200 mg, such as about 125 mg to approximately 175 mg, for example, about 150 mg. Typically, these PPR particles are contained in an aqueous gel or liquid, containing about 3.5 mL to approximately 10.5 mL, for example, about 4 to approximately 9 mL of diluent (e.g., WFI), and excipients.

[0121] Needle dispensing devices are an important aspect of the invention. In one aspect, the invention provides a needle dispensing system where the inner diameter of the needle is about 0.1 mm to about 0.4 mm. In another aspect, the inner diameter of the needle dispensing system is about 0.125 mm to about 0.285 mm. In a still more particular aspect, the inner diameter of the needle is about 0.11 mm to about 0.35 mm. The invention also provides needle dispensing systems in which the outer diameter of the needle is also or alternatively about 0.1 mm to about 0.7 mm, such as about 0.2 mm to about 0.6 mm, or more specifically between about 0.23 mm and about 0.59 mm.

[0122] In certain respects, a needle distribution system capable of successfully distributing the PPR particle compositions described herein is one that comprises a smaller internal diameter, such as for example an internal diameter that Petition 870210111618, dated 01 / 12 / 2021, pp. 263 / 307, is at least approximately 1% smaller, at least approximately 3% smaller, at least approximately 5% smaller, at least approximately 10% smaller, or even more, such as at least approximately 12% smaller, approximately 14% smaller, approximately 16% smaller, approximately 18% smaller, or even approximately 20% smaller or more than the internal diameter of a needle delivery system required to provide a product on the market for a similar purpose, such as SCULPTRA®. In certain respects, the ability to use a needle delivery system having a smaller internal diameter allows for a corresponding reduction in the dimensions of the external diameter of the needle, thus providing, in some respects, a better patient experience due to the ability to use reduced needle diameter dimensions to pierce the skin during administration, compared to existing products on the market, such as SCULPTRA®.In certain respects, the maximum force, the minimum force, or both the maximum and minimum forces required for a typical user (e.g., as determined through product usage tests), used to dispense a quantity / dosage of a particle composition through a needle (e.g., a 26G or 28G needle), is less than approximately 75%, for example, less than about 66.6%, such as less than approximately 50%, for example, less than about 33%, or less than approximately 25% of the force required to apply a corresponding quantity of SCULPTRA® through the same needle size.

[0123] A series of needles suitable for injecting such compositions are known in the state of the art. The outer diameter of the needle is typically measured by gauge, and the inner diameters normally increase / decrease in correspondence with the size, as understood in the art. In one aspect of the invention, the dispensing system includes all needles and / or cannulas ranging between 24G and 31G. In more particular aspects, the needle system comprises a 26G needle, a 27G needle, or a 28G needle. In one aspect, the needle is a smaller needle than an average 26G needle in terms of inner and / or outer diameter, such as being one of the smaller diameter needles listed herein, or in any case being at least about 10% smaller. Petition 870210111618, dated 01 / 12 / 2021, pp. 264 / 307 50 / 84 at least approximately 15%, or at least about 20% smaller in terms of internal and / or external diameter.

[0124] A delivery system may comprise a cannula as an alternative to a needle delivery system. Cannula systems suitable for delivering materials such as dermal fillers are known in the art. Thus, for example, the formulation compositions described herein can be injected with a round-tipped dermal filler microcannula. These microcannulas represent an alternative to needles for injecting dermal filler products and may be preferable in certain circumstances. As an example, microcannulas can provide access to a large treatment area from a single injection point, as the cannula can be moved under the skin with less risk of vascular damage. In addition, needles require multiple injection points.As an example, a cheek injection using a microcannula can reach treatment areas from the cheek to the outer edge of the face; from two points at the corners of the mouth, a dermatologist can treat the upper lip, lower lip, and nasolabial folds, as well as marionette lines. Using a needle for injection, additional injection points would be necessary. Other circumstances where microcannula injection versus a needle may be advantageous include treating areas of thin skin, such as the skin around the eyes, where injecting with a needle would be more difficult. In this scenario, the cannula can be inserted closer to the cheek and moved under the skin to the thinner area near the eye.Using a cannula can result in less pain during treatment, as fewer needle pricks may be required, and it can potentially lead to a faster recovery time because the risk of bleeding and bruising is reduced due to the rounded tip of the needle having a lower chance of rupturing the vasculature during injection and / or repositioning. Using a microcannula instead of a needle reduces the risk of injecting filler into a blood vessel, since the rounded end of the cannula can simply push aside any encountered vessels, unlike the sharp tip of a needle, which is likely to puncture an encountered vessel. On the other hand, there are a number of circumstances where using a needle is preferred. Petition 870210111618, dated 01 / 12 / 2021, pages 265 / 307 51 / 84 a cannula for administering the formulations described herein (and such methods are typically more accessible). For such aesthetic treatments, such as the treatment of acne scars, the use of a needle may be preferable from a medical standpoint and / or from the recipient / individual standpoint, as in the case of treating lines to be filled that are particularly superficial or shallow.

[0125] In addition to delivery systems, the invention also provides kits and packaged compositions comprising separate components of the delivery systems described herein. Thus, in one aspect, the invention provides a kit comprising (a) a dry solid composition of PPR particles (typically in combination with excipients, such as gel-forming agents and, optionally, surfactants, buffers and the like), generally in a package or container; (b) a diluent, such as WFI, in a container that maintains volume and prevents contamination; and (c) one or more parts of a delivery system, including a storage container and a needle or other delivery component. The kit or package may include materials and / or instructions for reconstitution and application of the reconstituted product, as well as information, instructions for the patient, or the like.

[0126] The kits and delivery systems may incorporate any of the features of the compositions described above. In one exemplary aspect, the invention provides a kit including (a) a vial comprising lyophilized PLLA (optionally with one or more other excipients present, such as CMC and / or a surfactant, such as a polysorbate surfactant); and (b) a pre-filled syringe comprising a diluent, such as WFI. In some embodiments, the vial containing lyophilized PLLA may be hermetically sealed. In certain embodiments, the vial may be sealed using a needle-penetrable seal. In some embodiments, the diluent contained in the syringe may comprise one or more polysorbate surfactants or other non-ionic surfactant, sodium carboxymethyl cellulose or HPMC and, optionally, disodium hydrogen phosphate dihydrate, anhydrous citric acid, sodium chloride, and / or sodium hydroxide.In some embodiments, water for injection may be used to conform the volume up to 100%. In some embodiments, the pre-filled syringe may also comprise a needle. In some embodiments... Petition 870210111618, dated 01 / 12 / 2021, pages 266 / 307 52 / 84 of incorporation, the kit may also or alternatively comprise an injection needle and an insertion cannula, as known in the state of the art, using the injection needle as a guide. In certain embodiments, the kit may also comprise instructions for the use of the product contained therein, intended for the physician, the patient, or both.

[0127] In a preferred embodiment, the present invention consists of a kit including at least one vial comprising lyophilized powder having between about 50 mg and approximately 250 mg of PLLA, for example about 50 mg, 60 mg, 70 mg or 80 mg of PLLA, approximately 90 mg, about 100 mg, approximately 110 mg, about 120 mg, approximately 130 mg, about 140 mg, approximately 150 mg, about 160 mg, approximately 170 mg, about 180 mg, approximately 190 mg, about 200 mg, approximately 210 mg, about 220 mg, approximately 230 mg, about 240 mg, or approximately 250 mg of PLLA. In a more preferred embodiment, the vial may comprise approximately 100 mg to approximately 200 mg of PLLA. Ideally, the vial should contain approximately 150 mg of PLLA.

[0128] In a preferred embodiment, the kit of the present invention contains a pre-filled syringe including a diluent comprising polysorbate 80 and / or polysorbate 20, in an amount ranging from about 0.01% to approximately 0.30% w / v, for example, approximately 0.02%, 0.03%, 0.04%, 0.05%, approximately 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, or approximately 0.20%, approximately 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, or approximately 0.30% w / v of polysorbate 20. In a more preferred embodiment, the pre-filled syringe comprises a diluent having polysorbate 20 in an amount ranging from 0.05% to approximately 0.15%. Preferably, the vial may contain approximately 0.1% w / v of polysorbate 20.

[0129] In a preferred embodiment, the kit of the present invention contains a pre-filled syringe comprising a diluent having sodium carboxymethyl cellulose in an amount ranging from about 1% to approximately 4% w / v, for example about 1%, approximately 1.1%, about 1.2%, approximately Petition 870210111618, dated 01 / 12 / 2021, pages 267 / 307 53 / 84 1.3%, approximately 1.4%, approximately 1.5%, approximately 1.6%, or approximately 1.7%, for example, approximately 1.8%, approximately 1.9%, approximately 2.0%, approximately 2.1%, approximately 2.2%, or approximately 2.3% w / v of sodium carboxymethyl cellulose, for example, approximately 2.4%, approximately 2.5%, approximately 2.6%, approximately 2.7%, approximately 2.8%, approximately 2.9%, approximately 3.0%, or approximately 3.1%, for example, approximately 3.2%, approximately 3.3%, approximately 3.4%, approximately 3.5%, approximately 3.6%, approximately 3.7%, approximately 3.8%, approximately 3.9%, or approximately 4.0% w / v of sodium carboxymethyl cellulose. In one embodiment, the pre-filled syringe comprises a diluent containing sodium carboxymethyl cellulose in an amount ranging from about 1.5% to 3.5%. Preferably, the vial may contain about 2.3% w / v of sodium carboxymethyl cellulose.

[0130] In certain embodiments, the kit of the present invention also comprises disodium hydrogen phosphate dihydrate (for example, about 0.1 to 0.15%, such as approximately 0.13% w / v); anhydrous citric acid (for example, about 0.05 to 0.15%, such as approximately 0.1% w / v); sodium chloride (for example, about 0.25 to approximately 0.75%, such as approximately 0.6% w / v); and / or sodium hydroxide (for example, about 0.02 to 0.08%, such as approximately 0.05% w / v).

[0131] In some respects, a present invention may comprise more than one vial, each comprising a single administration of a composition described herein. In certain respects, two or more applications or administrations of one or more compositions described herein may be prescribed and thus a plurality of vials within a present invention may be used for such purpose. METHODS OF USE

[0132] The invention also provides a number of new methods for using PPR particles, related compositions, and related distribution systems, as described above and elsewhere in this specification.

[0133] In an exemplary aspect, the invention provides a method for delivering compositions of the invention, such as a composition for neocollagenous dermatological implant / injection, to a mammalian recipient, such as a human patient undergoing aesthetic treatment, comprising contact of the recipient with a system of Petition 870210111618, dated 01 / 12 / 2021, pp. 268 / 307 54 / 84 needle distribution as described above, applying a distribution force to the needle system to deliver an effective amount of the composition to the recipient's body. In most respects, the recipient will be a human patient undergoing cosmetic treatment and the composition will be administered through, or under the direction and / or supervision of, a licensed healthcare professional, such as a licensed physician.

[0134] PPR particle compositions, when combined with the delivery systems provided herein, offer high levels of delivery efficiency, especially when compared with SCULPTRA®. An injection failure means the occurrence of a needle blockage in the injection process of a PPR particle composition. The systems of the invention provided herein (for example, a needle system comprising a 26G or 27G needle, in combination with PLLA microspheres having a maximum average size of 35 to 55 μm for at least about 90% of the particles) are associated with delivery failures of 40% or less. In some respects, such delivery systems and PPR compositions of the invention are associated with injection failure rates of less than approximately 30%, less than about 25%, less than approximately 20%, less than about 15%, less than approximately 10%, or less than about 5%.

[0135] Due to the substantially smaller and more uniform nature of the PPR particles in such systems, the force required to distribute a reconstituted or otherwise liquid PPR particle composition through a standardized needle system (e.g., a conventional 26G needle system) will be significantly less in the system of the invention than in systems using SCULPTRA®.

[0136] Such force can be evaluated by the minimum force required to distribute the composition, the maximum force required to distribute the composition, and the average force used to distribute the composition through the needle distribution system. In one aspect, the minimum force used to distribute the composition through the needle of the system is about 40 to approximately 80 g. In another aspect, the minimum force is about 40 to 55 g, as well as approximately 50 g.

[0137] In another aspect, the maximum force used to distribute the composition is also or alternatively about 100 g approximately 2500 g, as is about Petition 870210111618, dated 01 / 12 / 2021, pp. 269 / 307 55 / 84 175 ga is approximately 1750 g. In even more specific aspects, the maximum force is approximately 200 ga is approximately 1200 g, as is approximately 200 ga is approximately 700 g.

[0138] In yet another form of incorporation, the average force used to distribute the composition through the needle system is about 100 ga approximately 1000 g. In more specific aspects, the average force used to distribute the composition is about 150 ga approximately 750 g, such as about 175 ga approximately 400 g, or, even more specifically, about 200 ga approximately 350 g.

[0139] In certain respects, the average force used to dispense a composition described herein through a given needle dispensing system is significantly less than the force required to dispense a composition of a comparable product on the market, such as SCULPTRA®, through a needle dispensing system of the same size (e.g., same inner diameter of the needle); for example, such average force is at least 1%, at least 3%, at least 5%, at least 8%, at least 10%, at least 15%, or at least 20% or more, less than the average force required for a comparable product.

[0140] The measurement of such forces can be carried out in any suitable manner, and can be applied to a series of systems or to an individual system. In one aspect, such forces are measured according to ISO 11040-4 section E (sliding force test method for evaluating the lubrication of a syringe). Devices that can be used to carry out such measurements are available from Texture Technologies in the USA (see for example http: / / texturetechnologies.com / application-studies / syringability).

[0141] Typically, the delivery systems of the invention distribute the compositions of the invention into the body of a mammalian recipient so as to induce a detectable and generally significantly measurable physiological effect, increasing the recipient's skin volume (for example, to a level at least equivalent to that observed in treatment with SCULPTRA®). Thus, the invention provides a method for modifying the skin or the appearance of the skin of a human patient, comprising subcutaneous or intradermal injection or implantation of a PPR particle composition of Petition 870210111618, dated 01 / 12 / 2021, pages 270 / 307 56 / 84 invention. Such methods can be used to promote or perform reconstructive or plastic surgeries, or to fill wrinkles, fine lines, skin cracks, acne scars and other scars, as well as in dentistry, for gum filling, and for other applications associated with SCULPTRA®.

[0142] Age-related skin laxity and wrinkling result from decreased collagen production and density of collagen and elastin by the body, which provide essential structural integrity to the skin. In the aesthetic treatment of such laxity or wrinkling, dermal fillers and / or PPR compositions can be used. The PPR particles of the invention, such as PLLA monospheres of the formulations of the invention provided herein, are biocompatible and biodegradable polymers that stimulate the process of neocollagenesis, i.e., the production of new collagen by the body itself, in the areas where the formulation is injected. This neogenesis results in a more permanent aesthetic solution compared to dermal fillers, which, upon degradation, eliminate the aesthetic improvement provided by their presence.In some cases, however, it may take approximately 2 to 8 months, or even 3 to 6 months, for the effects of treatment with the PPR particle compositions of the invention to be observed or at least to approach the maximum effect.

[0143] The use of the systems and products of the invention may comprise the repeated administration of such compositions as part of a course of treatment. Thus, for example, a course of treatment may comprise two, three, four or more administrations of the product, which may be separated by one, two, three or four weeks, or approximately 10, approximately 20, approximately 25 or approximately 30 days (for example, approximately 2 to 7 weeks, such as approximately every 3 to 6 weeks). Each treatment session may include the administration of the product at multiple sites, which may or may not be associated with a single area of ​​the body, such as a single area of ​​skin (for example, the nasolabial fold). The amount of a reconstituted / liquid product dispensed in a single injection will typically be from about 1.5 to approximately 5 mL, such as from about 2 to approximately 4 mL, for example, from about 2.5 mL or approximately 3 mL.In some cases, the injection is performed in a grid around a target site. In some aspects, the injection is primarily or... Petition 870210111618, dated 01 / 12 / 2021, pages 271 / 307 57 / 84 entirely administered into the dermis. It may also be the case that this can influence the amount used in a single session, which may be injected into one or more locations in that treatment session.

[0144] In some aspects, the distribution of the composition of the invention is carried out in association with the administration of an effective amount of an anesthetic. In one aspect, the anesthetic is a component of the formulation (for example, it is added with the diluent, during reconstitution). In another aspect, the anesthetic is co-administered or administered in association with the injection / implantation of PPR particles (for example, it is administered before the injection).

[0145] In yet another aspect, the method is applied as an aesthetic treatment in combination with one or more other aesthetic modification methods, which may include other surgical techniques, the application of other dermal fillers, and / or the application of one or more pharmaceuticals or medical devices. Aesthetic products that modify skin aesthetics through ways other than neocollagenesis may be synergistic. Such treatments may include, but are not limited to, dermal fillers [e.g., Restylane®, Juvederm®, Lyft (formerly Perlane®), or other similar dermal fillers that provide volume to target areas of the skin], and neuromodulators [e.g., abobotulinumtoxinA (Dysport®), onabotulinumtoxinA (Botox®), or other similar aesthetic treatments that serve to modify skin aesthetics by modifying nerve stimulation].Other treatments that can be used synergistically are neocollagen treatments using radiofrequency, or light frequency or pulsed light, to stimulate collagen growth (e.g., ReFirme®, FotoFacial®, or similar products). Since the neocollagen dermatological implant described herein works by stimulating collagen production, it may take some time for results to become visible. As such, it may be beneficial to use a dermal filler for volume augmentation, such as, but not limited to, a calcium-based microsphere technology, as exemplified by Radiesse®, or a hyaluronic acid filler (e.g., Juvederm or Restylane), to provide short-term results while the dermatological implant of the present invention begins. Petition 870210111618, dated 01 / 12 / 2021, pp. 272 / 307 58 / 84 to stimulate collagen production. Such dermal fillers can provide an immediate aesthetic improvement while the implant of the present invention takes effect and, as they have a shorter lifespan, they disappear as the effects of the neocollagenic dermatological implant of the present invention begin to appear.

[0146] In one particular aspect, the method of application involves administering the product to patients having relatively thin skin. The individual may have skin, for example, in a target area, that is at least about 15%, at least about 25%, or at least about 30% thinner than the population average. For example, the individual may be a patient who has or is experiencing a condition of skin atrophy (e.g., corticosteroid-induced cutaneous atrophy), or has another condition associated with abnormally thin skin (e.g., anetoderma, vermiculate atrophoderma, or skin thinning associated with rheumatoid arthritis).

[0147] In other respects, the method is performed in an area that is associated with fat loss, such as an area associated with facial lipo-atrophy. Thus, the method may involve the restoration and / or correction of signs of facial fat loss.

[0148] The compositions and methods of the invention are also or alternatively associated with a lower rate of nodule formation than SCULPTRA®. Depending on the embodiment, the amount of nodule formation associated with the methods and compositions of the invention is reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, or more, compared with SCULPTRA® (for example, as can be determined by comparison of clinical data or direct studies of the products).

[0149] Alternatively, the product may also be distributed to an area associated with thinner skin, even in typical populations. In one aspect, the method comprises administering the composition to an area of ​​a human face with an average epidermal thickness of less than 40 μm, an average dermal thickness of less than 1200 μm, or both. In another aspect, the method is performed on an area of ​​skin having an average epidermal thickness of less than 40.75 μm, an average dermal thickness of less than 1200 μm. Petition 870210111618, dated 01 / 12 / 2021, pages 273 / 307 59 / 84 less than 1230 μm, or both. In still other aspects, the average thickness of the epidermis in the treated area is less than 40.5 μm, the average dermal thickness is less than approximately 1200 μm, or both.

[0150] In another aspect, the method comprises administering the composition to an area of ​​a human face having an average epidermal thickness of less than 40 μm, an average dermal thickness of less than 1175 μm, or both.

[0151] In yet another exemplary aspect, the method comprises administering the composition to an area of ​​human skin having an average relative thickness score of less than 1.5. In a more particular aspect, the area has an average relative thickness score of less than 1.35. Relative thickness is described in Chopra et al., Aesthetic Surgery Journal, 2015, Vol 35 (8) 1007 to 1013. Although such methods of assessing thin skin are exemplified here, the scope of the invention is not limited to the patient types described in the article by Chopra et al., but instead may be applied to individuals of different ages, races, conditions, etc.In a more general sense, one aspect of the invention comprises administering a composition of the invention to an individual, in an area of ​​skin that is at least about 5%, at least approximately 10%, at least about 12.5%, at least approximately 15%, at least about 17.5%, at least approximately 20%, at least about 25%, or at least approximately 30% thinner than the average skin of an individual of the same age or age group, sex, race and / or condition.

[0152] In yet another exemplary aspect, the method comprises administering the composition to a target area of ​​human skin on a part of the body, such as the face and neck, wherein the average thickness of the skin in the target area (of a person or group of persons) is at least about 10% less, at least approximately 15% less, at least about 20% less, or at least approximately 30% less than (a) the average skin thickness of the person (or the average of persons of the same age, sex, gender and / or condition), or (b) the part of the person's body (or the average of a group of similar persons) that is associated with the thickest skin of the person (or Petition 870210111618, dated 01 / 12 / 2021, pp. 274 / 307 60 / 84 population). This is another aspect that reflects that the method can be practiced on relatively thin skin areas of patients. EXPERIMENTAL DATA (EXAMPLES)

[0153] The following experimental data (examples) support and exemplify various aspects of the invention. This description is provided to further illustrate the principles of the invention and should not be interpreted in any way as limiting the scope of the invention. MATERIALS

[0154] PLLA particles were produced according to the particle production methods described in patent WO 200511559A1, allowing the production of particles in a monodisperse manner. The method was carried out with the aim of producing particles with an average size of around 35 gm, with 95% of the particles having a size between 25 gm and 45 gm. SCULPTRA® (lot number A7123) was acquired through the company Walter Krebs. EXAMPLE 1

[0155] The following experiment was conducted to demonstrate that monodisperse microspheres or monospheres of a PPR composition, particularly PLLA, lead to less needle blockage and improved product injectability compared to a conventional commercial polydisperse PLLA composition of SCULPTRA®. SAMPLE PREPARATION

[0156] Reconstitution was performed following the label instructions for the Brazilian product SCULPTRA® (reconstitution by hydration with WFI for 2 hours). This resulted in a PLLA suspension density of 18.75 mg / mL at room temperature (RT). From the resulting homogenized suspension, 7 syringes [1 mL disposable Becton Dickinson syringes with luer lock (not included in the SCULPTRA® packaging)] were filled with 1 mL to analyze the injectability of SCULPTRA® in 7 sessions. 26G 5 / 8" (approximately 16 mm) needles from Becton Dickinson (Microlance 3, not included in the SCULPTRA® packaging) were used.

[0157] Monodisperse PLLA microspheres were prepared by dissolving PLLA in dichloromethane (DCM), 10 to 15% by weight. The organic phase was passed through a Petition 870210111618, dated 01 / 12 / 2021, pages 275 / 307 A patented 61 / 84 microsieve (Nanomi) was used for the aqueous phase, allowing the resulting suspension to be extracted for 3 to 24 hours. The microspheres were collected and sieved through 75 and 10 μm sieves. The microspheres were dried by freeze-drying or using a nitrogen stream.

[0158] Monodisperse PLLA monospheres (Nanomi, test material, 2087-EKK040ct2018-A) were reconstituted by adding 7.5 mL of diluent to 150 mg of test PLLA monosphere material, resulting in a suspension density of 20 mg / mL at room temperature. The resulting suspension was kept at room temperature for 2 hours. Six syringes were filled with 1 mL of the suspension for analysis of the Nanomi monospheres in 6 sessions. The remaining diluent volume added to the microspheres is directed, according to Nanomi's instructions, to be included in pre-filled syringes that are currently produced as a main product. Each of these pre-filled syringes contains 2.5 mL of diluent. INJECTION TEST ANALYSIS

[0159] A TA.XTplus texture analyzer [Stable Micro Systems - Surrey, United Kingdom (see https: / / www.stablemicrosystems.com / TAXTplus.html)] was used for this experiment. Injections were performed according to ISO 11040-4 section E (sliding force test method for evaluating syringe lubrication). In short, the syringes were placed in the texture analyzer in a vertical position and ejected at a speed of 100 mm / min. The measured distance was 45 mm. RESULTS

[0160] Figure 1 is a graph of injectability of SCULPTRA® samples using a 26G 5 / 8 needle. The first interval in Figure 1 (space between vertical lines 3 to 1) in the graph illustrates the force required to fill the needle with the suspension. During the second interval (1 to 2), injectability is tested. The results of this interval are reported in Table 2 below. Each curve in the graph of Figure 1 represents an individual injection. The data obtained for the analysis of SCULPTRA® are also presented in Table 1 below. Petition 870210111618, dated 01 / 12 / 2021, pages 276 / 307 62 / 84 TABLE 1 - INJECTABILITY RESULTS FOR SCULPTRA® WITH A 26G NEEDLE 5 / 8 Repetition Number Average Force (g) Minimum Force (g) Maximum Force (g) *1 2050 64 4143 2 151 78 401 *3 1458 58 4108 *4 2822 78 4533 *5 1305 57 3619 6 158 54 177 7 137 41 159 Average 1154 61 2448 Standard Deviation 1059 13 2079

[0161] The asterisks (*) shown in Table 1 for repetition numbers 1, 3, 4 and 5, and the injectability graphs corresponding to each of the repetitions 1, 3, 4 and 5, shown in figure 1, indicate the repetitions in which the needle became blocked during injection.

[0162] Figure 2 shows injectability results for test formulations of monodisperse PLLA Nanomi microspheres injected with a 5 / 8 26G needle. The first interval in Figure 2 (3 to 1) in the graph illustrates the force required to fill the needle with the suspension. During the second interval (1 to 2), injectability is tested. The results of this interval are reported in Table 2 below. Each curve represents an individual injection. These data reflect a failure rate of 4 / 7 for the administration of SCULPTRA® through such needles (approximately 57%).

[0163] The data obtained for the analysis of the Nanomi monodisperse PLLA microsphere test formulations are also presented in Table 2 below, and are graphically represented in Figure 2. TABLE 2 - INJECTABILITY RESULTS FOR MONODISPERSED MICROSPHERES USING A 26G 5 / 8 NEEDLE Number of Repetitions Average Force (g) Minimum Force (g) Maximum Force (g) Petition 870210111618, dated 01 / 12 / 2021, pages 277 / 307 63 / 84 Repetition Number Average Force (g) Minimum Force (g) Maximum Force (g) 1 212 44 234 2 218 35 251 3 404 45 842 4 330 43 479 5 222 47 256 6 278 52 457 Average 277 44 420 Standard Deviation 77 5 234

[0164] The data illustrated in Figures 1 and 2 and presented in Tables 1 and 2 above demonstrate that the exemplary monodisperse PLLA microspheres of the invention exhibit significantly different properties in terms of injection force requirements compared with SCULPTRA®. For example, none of the tested monodisperse PLLA microsphere compositions required the average force of 2000 g observed with SCULPTRA®; in fact, all required about 25% or less force than the 2000 g required by SCULPTRA®, and several required even less force. These lower force requirements associated with the microparticle compositions of the invention represent another aspect of the invention.

[0165] Figure 3 is an overlay of injectability measurements of SCULPTRA® versus monodisperse microspheres, tested with a 5 / 8 26G needle.

[0166] Based on the results shown in Figs. 1 to 3 and Tables 1 and 2, reconstitution following the instructions on the Brazilian label for SCULPTRA® led to formulation conditions where the product did not pass through the 26G needle without problems, specifically because four out of seven injections became blocked. It can be observed that the European label for SCULPTRA® recommends a smaller reconstitution volume, resulting in a more concentrated final product. It is possible that such an increase in concentration produces an even greater possibility of needle blockage. Although it is possible that this blockage can be overcome with the use of a larger needle. Petition 870210111618, dated 01 / 12 / 2021, pages 278 / 307 64 / 84 size, needles having a larger diameter and with larger diameters would not be favored in aesthetic medicine, as they may increase patient discomfort.

[0167] The results obtained for the injectability of monodisperse microspheres prove that these PPR particles passed through the selected 26G needle with a much lower average force (24%), a lower maximum force (17%), and with much less variability compared with SCULPTRA® (see for example Fig. 3). Repeat 3 (long dashed line) of Figure 2, showing the injectability of the monodisperse microspheres, illustrates a small peak in the maximum dispensing force required (842 g) along the approximately 15 mm stroke, representing only about 1 / 3 of the average maximum force observed with SCULPTRA®. This did not result in needle clogging and the measurement continued without operator interference. It is evident that much more force needs to be applied to inject SCULPTRA® compared with the monodisperse microspheres. EXAMPLE 2

[0168] This Example reports the analysis of the particle size and distribution of both SCULPTRA® and PLLA monospheres, in this exemplary aspect of the invention. For this measurement, a Multisizer® 3 Coulter counter, acquired from Beckman, was used. The PLLA particles were resuspended in water and measured using Coulter® Isoton® II diluent.

[0169] As reported above, SCULPTRA® PLLA particles are polydisperse, including a variety of particle sizes. However, the monodisperse microspheres of the invention are typically monodisperse having a narrow size distribution (e.g., at least about 90% of the particles have a maximum diameter and / or an average diameter of about 10 μm to each other). Figure 4 shows a comparison between SCULPTRA® particles (samples labeled 2087-sculptra...) and the monodisperse PLLA microspheres of the invention formulation (samples labeled 2087-EKK...).

[0170] As shown in Figure 4, the particles in SCULPTRA® have varying sizes, with detected sizes ranging from 0 to 150 μm. On the other hand, the monodisperse monosphere formulation contains polymeric particles that are Petition 870210111618, dated 01 / 12 / 2021, pp. 279 / 307 65 / 84 within a narrow range of 25 to 70 μm, with most particles being in the 35 to 45 gm range.

[0171] Typically, a 26G needle has an inner diameter of 260 μπ. In the case of monodisperse monospheres, for three agglomerate particles up to 70 μηη, the 26G needle will not be blocked, as an agglomerate of approximately 210 μηη is created, which is still smaller than the 260 μηη inner diameter of the 26G needle (the same would be true for four particles of about 50 gm maximum diameter). However, in the case of SCULPTRA®, for three agglomerate particles having 150 μηη, the risk of needle clogging is quite high, as this creates an agglomerate of approximately 450 μηη, well above the 260 μηη inner diameter of a 26G needle.

[0172] It appears clear, therefore, that a needle of even smaller size than the 26G needle used in this Example could be used to inject a dermal filler, using the inventive PLLA monospheres tested herein, leading to greater patient comfort and compliance, and less product waste. EXAMPLE 3

[0173] The SCULPTRA® particles and PLLA monospheres of the invention described above were examined using scanning electron microscopy or micrography (SEM) acquired from JEOL. Exemplary scans are shown in Figure 5 (SCULPTRA®) and Figure 6 (PLLA monospheres).

[0174] As is evident from Figures 5 and 6, the evaluation of both products using MVE shows a very distinct difference between the SCULPTRA® microspheres compared to the PLLA monospheres of the invention. The PPR particles of SCULPTRA® contain coarse material with sharp edges. This rough and inconsistent conformation increases agglomeration. On the other hand, the PLLA monospheres of the invention are round, uniform and consistent, allowing them to pass through a 26G needle smoothly. EXAMPLE 4

[0175] Three separately manufactured PPR particle formulations were subjected to an industry-standardized stability test protocol under accelerated stability conditions. Initial results, reported as baseline value, Petition 870210111618, dated 01 / 12 / 2021, pages 280 / 307 66 / 84 were obtained after the production of each batch. Stability data, reported as t = 0 months et = 6 months @ 40 °C / 75% RH, were collected at the beginning of the stability study (time point 0) and after six months of storage under accelerated stability conditions at 40 °C and 75% relative humidity.

[0176] The stability protocol measured molecular weight distribution [molecular weight and polydispersity index (PDI)] and crystallinity in two samples from each production batch, after initial production, at the start of the stability study and at a six-month time point.

[0177] Particle size distribution data were collected as a single average for each batch at the beginning of the stability study and at the six-month time point. Data for each of the 3 batches are presented in Tables 3 to 5, respectively: TABLE 3 - T=0 ET=6 MONTHS, STABILITY DATA FOR 2087-DBE-13MAR19-A04 2087-DBE-13MAR19-A04 Molecular Weight Distribution Molecular Weight (Pm) in kDa Sample 1 Sample 2 Mean Initial Value 110.7 111.8 113.3 t = 0 months 112.8 112.6 112.7 t = 6 months @ 40 °C / 75% RH 112.5 112.4 112.5 IPD (Pm / Mn) Sample 1 Sample 2 Mean Initial Value 1.37 1.38 1.38 t = 0 months 1.40 1.38 1.39 t = 6 months @ 40 °C / 75% RH 1.39 1.37 1.38 Crystallinity Sample 1 Sample 2 Mean Initial Value 0 0 0.0 t = 0 months 0 0 0.0 t = 6 months @ 40 °C / 75% RH 0 0 0.0 Petition 870210111618, dated 01 / 12 / 2021, pages 281 / 307 67 / 84 Particle Size Distribution d 10 (μπι) Sample 1 Sample 2 Mean Initial value - t = 0 months 27.19 t = 6 months @ 40 °C / 75% RH 27.56 d50 (μπι) Sample 1 Sample 2 Mean Initial value - t = 0 months 29.17 t = 6 months @ 40 °C / 75% RH 30.19 d90 (μηι) Sample 1 Sample 2 Mean Initial value - t = 0 months 31.37 t = 6 months @ 40 °C / 75% RH 76.17 Mean (μπι) Sample 1 Sample 2 Mean Initial value - t = 0 months 29.71 t = 6 months @ 40 °C / 75% RH 42.12 Petition 870210111618, dated 01 / 12 / 2021, pages 282 / 307 68 / 84 TABLE 4 - T=0 ET=6 MONTHS, STABILITY DATA FOR 2087-DBE-03APR19-A02 2087-DBE-03APR19-A02 Molecular Weight Distribution Molecular Weight (Pm) in kDa Sample 1 Sample 2 Mean Initial value 110.7 111.8 111.3 t = 0 months 112.0 112.1 112.1 t = 6 months @ 40 °C / 75% RH 113.2 112.7 113.0 IPD (Pm / Mn) Sample 1 Sample 2 Mean Initial value 1.37 1.38 1.38 t = 0 months 1.37 1.36 1.37 t = 6 months @ 40 °C / 75% RH 1.37 1.37 1.37 Crystallinity Sample 1 Sample 2 Mean Initial value 5.3 5.3 5.3 t = 0 months 5.3 5.3 5.3 t = 6 months @ 40 °C / 75% RH 4.7 4.7 4.7 Particle Size Distribution d 10 (μηι) Sample 1 Sample 2 Average Initial value - t = 0 months 28.84 t = 6 months @ 40 °C / 75% RH 28.71 d50 (μΓΠ) Sample 1 Sample 2 Average Initial value - t = 0 months 31.93 t = 6 months @ 40 °C / 75% RH 31.88 d90 (μηι) Sample 1 Sample 2 Average Initial value - Petition 870210111618, dated 01 / 12 / 2021, pages 283 / 307 69 / 84 t = 0 months 73.21 t = 6 months @ 40 °C / 75% RH 73.81 Average (μιτι) Sample 1 Sample 2 Average Initial value - t = 0 months 39.26 t = 6 months @ 40 °C / 75% RH 39.24 TABLE 5 - T=0 ET=6 MONTHS, STABILITY DATA FOR 2087-DBE-06MAR19-A01 2087-DBE-06MAR19-A01 Molecular Weight Distribution Molecular Weight (Pm) in kDa Sample 1 Sample 2 Mean Initial value 108.2 107.4 107.8 t = 0 months 108.7 109.3 109.0 t = 6 months @ 40 °C / 75% RH 109.0 108.9 109.0 IPD (Pm / Mn) Sample 1 Sample 2 Mean Initial value 1.29 1.30 1.30 t = 0 months 1.32 1.31 1.32 t = 6 months @ 40 °C / 75% RH 1.32 1.33 1.33 Crystallinity Sample 1 Sample 2 Mean Initial value 10.7 10.0 10.4 t = 0 months 9.6 10.2 9.9 t = 6 months @ 40 °C / 75% RH 9.7 9.3 9.5 Particle Size Distribution d 10 (μιτι) Sample 1 Sample 2 Mean Initial value - t = 0 months 28.07 Petition 870210111618, dated 01 / 12 / 2021, pages 284 / 307 70 / 84 t = 6 months @ 40 °C / 75% RH 28.01 d50 (gm) Sample 1 Sample 2 Average Initial value - t = 0 months 29.57 t = 6 months @ 40 °C / 75% RH 29.52 d90 (gm) Sample 1 Sample 2 Average Initial value - t = 0 months 31.44 t = 6 months @ 40 °C / 75% RH 31.66 Average (gm) Sample 1 Sample 2 Average Initial value - t = 0 months 29.96 t = 6 months @ 40 °C / 75% RH 30.72

[0178] The data for the first batch, 2087-DBE-13MAR19-A04 (Table 3) indicate that the average molecular weight in kDa of the particles varied by approximately 0.7% from the initial value to the value measured at the 6-month stability study time point. The polydispersity index (PDI), a value that indicates the amplitude of the molecular weight distribution of the particles, varied by about 0.7%. The particle size distribution, reported for d10, d50, d90 and for the average particle size in gm, with values ​​indicating the percentage of particles smaller than the indicated d number (e.g., a d10 value of 30 would indicate that 30% of the particles are smaller than 10 gm, and 70% are larger than 10 gm), indicated a variation, from time point 0 of the stability study to the 6-month time point of the stability study, of approximately 1.3% for d10, 3.4% for d50, 58.8% for d90, and 29.5% for the average.It is important to note that such data indicate that the particles in the formulation are not decreasing significantly in volume over time.

[0179] The data for the second batch, 2087-DBE-03APR19-A02 (Table 4) indicate that the average molecular weight of the particles varied by less than 0.1% from the initial measurement to the 6-month stability time point. The IPD varied by approximately 0.7%. The degree of Petition 870210111618, dated 01 / 12 / 2021, pages 285 / 307 Crystallinity of 71 / 84 was measured and is also presented for this batch. Crystallinity varied by approximately 11.3% over the same period. The variance of the particle size distribution was reported at approximately 0.5% for d10, 0.2% for d50, 0.8% for d90, and less than 0.1% for the mean, between the zero time point of the stability study and the 6-month stability time point.

[0180] Data for the third batch, 2087-DBE-06MAR19-A01 (Table 5) indicate that the average molecular weight of the particles varied by approximately 1.1%, the IPD varied by approximately 2.26%, and the crystallinity varied by approximately 8.7% from the initial measurement to the 6-month stability time point. The variance of the particle size distribution was reported as approximately 0.2% for d10, 0.2% for d50, 0.7% for d90, and 2.5% for the mean, between the zero time point of the stability study and the 6-month stability time point.

[0181] These data demonstrate that the particles of the invention exhibit favorable stability characteristics over sustained periods of time. For example, the average particle sizes did not decrease significantly over the course of the accelerated stability test study conducted, and in most cases, any variation in size was within 10% or less, such as within 5%, or within 3% or less. These and other data reflect the stability and other beneficial properties associated with the microparticle formulations of the invention. Illustrative Aspects of the Invention

[0182] Below is a non-limiting list of illustrative aspects of the invention, intended to highlight some of the various ways in which the invention may be embodied: 1. An implant / injection composition comprising an effective quantity of particles, which are at least primarily composed of one or more resorbable polyester polymers and which have a size distribution such that at least about 70% of the particles have a maximum particle diameter that is within about 30% of the average particle diameter in the composition; 2. The implant / injection composition of Aspect 1, wherein the particles consist essentially of one or more resorbable polyester polymers; Petition 870210111618, dated 01 / 12 / 2021, pages 286 / 307 72 / 84 3. The implant / injection composition of Aspect 1 or Aspect 2, in which at least approximately 80% of the particles have a maximum particle diameter that is within 25% of the average particle diameter of the particles in the composition; 4. The implant / injection composition of Aspect 3, wherein at least approximately 85% of the particles in the composition have a maximum particle diameter that is within 20% of the average particle diameter of the particles in the composition; 5. The injection / implant composition of Aspect 4, in which at least approximately 90% of the particles in the composition have a maximum particle diameter that is within 18% of the average particle diameter of the particles in the composition; 6. A composition for injection / implantation of any of Aspects 1 to 5, in which at least approximately 75% of the particles in the composition have a maximum particle diameter that is within 15% of the average particle diameter of the particles in the composition; 7. An injection / implant composition of any one of Aspects 1 to 6, wherein at least the majority of one or more polyester polymers are neocollagenic, such that the composition is detectably neocollagenic when administered to the skin of a human patient; 8. A composition for injection / implantation of any of Aspects 1 to 7, wherein one or more polyester polymers are derived primarily from plant-derived starting materials; 9. A composition for injection / implantation of any of Aspects 1 to 7, in which one or more polyester polymers are produced by means of chemical synthesis; 10. A composition for injection / implantation of Aspect 8 or Aspect 9, wherein one or more polyester polymers are at least principally composed of a polyglycolide (a PGA), a polylactic acid (a PLA), a polycaprolactone (a PCL), a polyhydroxybutyrate (a PHB), or a mixture of two or more of these; 11. The injection / implant composition of Aspect 10, wherein one or more polyester polymers consist essentially of a PGA, a PLA, a PCL, a PHB, a copolymer of two or more thereof, or a mixture of any two or more thereof; Petition 870210111618, dated 01 / 12 / 2021, pp. 287 / 307 73 / 84 12. The injection / implant composition of Aspect 11, wherein the one or more polyester polymers consist of a PGA, a PLA, a PCL, a PHB, a copolymer of two or more thereof, or a mixture of any two or more thereof; 13. The injection / implant composition of Aspect 12, wherein one or more polyester polymers consist essentially of polylactic-co-glycolic acid (PLGA), a PLA, or a mixture thereof; 14. A composition for injection / implantation of any of Aspects 10 to 13, wherein at least 50% of the polyester polymer content of the composition is composed of PLA; 15. A composition for injection / implantation of any of Aspects 10 to 14, in which at least 50% of the particles consist essentially of PLA; 16. The injection / implant composition of Aspect 15, wherein the PLA is poly-L-lactic acid (PLLA) (crystalline), poly-D-lactic acid (PDLA) (crystalline), poly-D,L-lactic acid (PDLLA) (amorphous), or a mixture thereof; 17. The injection / implant composition of Aspect 16, wherein at least 50% of the polyester polymer content of the composition is composed of PLLA; 18. The injection / implant composition of Aspect 16 or Aspect 17, in which at least approximately 70% of the particles consist primarily of PLLA; 19. The injection / implant composition of any of Aspects 10 to 18, wherein the filler particle polymer has a molecular mass between 10,000 and 650,000 Daltons; 20. The Aspect 19 injection / implant composition, in which the filler particle polymer has a molecular mass between 50,000 and 250,000 Daltons; 21. The Aspect 19 injection / implant composition, in which the filler particle polymer has a molecular mass between 90,000 and 110,000 Daltons; 22. The injection / implant composition of any of Aspects 10 to 21, wherein the inherent viscosity of the filler particle polymer is between 0.1 and 4.0 dL / g; 23. The injection / implant composition of Aspect 22, wherein the inherent viscosity of the filler particle polymer is between 0.40 and 2.0 dL / g; Petition 870210111618, dated 01 / 12 / 2021, pp. 288 / 307 74 / 84 24. The injection / implant composition of Aspect 23, where the inherent viscosity of the filler particle polymer is between 0.90 and 1.10 dL / g; 25. The composition for injection / implantation according to any one of Aspects 10 to 24, wherein the specific rotation of the filler particle polymer is between approximately -150 and approximately -160 degrees; 26. The injection / implant composition according to any one of Aspects 10 to 25, wherein the filler particle polymer has a melting point between about 100 and about 300 degrees Celsius; 27. The composition for injection / implantation of Aspect 26, in which the filler particles have a melting point of approximately 150 to approximately 250 degrees Celsius; 28. The composition for injection / implantation of Aspect 27, in which the filler particles have a melting point of approximately 175 to approximately 195 degrees Celsius; 29. The injection / implant composition according to any one of Aspects 10 to 28, wherein the filler particle polymer has a heat of fusion between about 25 J / g and approximately 150 J / g; 30. The composition for injection / implantation according to Aspect 29, wherein the filler particle polymer has a heat of fusion between about 75 J / g and about 125 J / g; 31. The composition for injection / implantation according to Aspect 29, wherein the filler particle polymer has a heat of fusion between about 85 J / g and about 95 J / g; 32. The injection / implant composition in accordance with any one of Aspects 10 to 31, wherein the filler particle polymer has a residual solvent content of less than approximately 0.01%; 33. The injection / implant composition conforms to any one of Aspects 10 to 32, wherein the filler particle polymer has a residual monomer content (e.g., lactic acid) of less than about 0.1%; Petition 870210111618, dated 01 / 12 / 2021, pages 289 / 307 75 / 84 34. The composition for injection / implantation according to any of Aspects 1 to 33, wherein the maximum average diameter or dimension, in any direction, of three agglomerated particles of the composition is less than 250 μm; 35. The composition for injection / implantation of any of Aspects 1 to 34, in which at least approximately 80% of the particles vary in diameter, in any direction, by no more than about 25%; 36. The composition for injection / implantation of Aspect 35, in which at least approximately 90% of the particles vary in diameter, in any direction, by no more than about 15%; 37. The composition for injection / implantation according to any one of Aspects 1 to 36, wherein the particles are microspheres in which at least 90% of the microspheres have a maximum diameter within a range of 30 μm (+ / -12.5 μm from the average particle diameter); 38. The injection / implant composition according to any one of Aspects 1 to 37, wherein the injection / implant results in a measurable increase in dermal volume over an average period of at least about 2 years, in individuals receiving one or more treatments comprising the implantation of an effective amount of implant / injection; 39. The injection / implant composition conforms to any one of Aspects 1 to 38, in which less than 10% of the particles have a maximum diameter of less than 5 μm; 40. The composition for injection / implantation according to Aspect 39, in which less than 5% of the particles have a maximum diameter of less than 6 μm; 41. The composition for injection / implantation according to Aspect 39, in which less than 2% of the particles have a maximum diameter of less than 9 μm; 42. The injection / implant composition conforms to any one of Aspects 1 to 41, wherein at least approximately 95% of the particles in the composition have a coefficient of variation of 50% or less when the average particle size is between 5 and 250 μm; Petition 870210111618, dated 01 / 12 / 2021, pages 290 / 307 76 / 84 43. The composition for injection / implant according to Aspect 42, in which at least 95% of the particles in the composition have a coefficient of variation of 25% or less when the average particle size is between 5 and 250 μΓπ; 44. The injection / implant composition according to Aspect 42, wherein more than 95% of the particles in the composition comprise a coefficient of variation of no more than 15%, measured over a range of 5 to 250 μΓπ; 45. The injection / implant composition according to Aspect 42, Aspect 43 or Aspect 44, wherein the number of particles having a maximum diameter that is within 25% of the average maximum diameter is at least twice as large as the number of particles that differ from the average maximum diameter by 200% or more; 46. ​​The injection / implant composition according to Aspect 45, wherein the number of particles having a maximum diameter that is within 15% of the average maximum diameter is at least 2.5 times greater than the number of particles that differ from the average maximum diameter by 250% or more; 47. The composition for injection / implantation in accordance with any one of Aspects 1 to 46, wherein for at least 95% of the particles in the composition, the maximum size of a three-particle agglomeration for injection / implantation is less than 250 μm; 48. The injection / implant composition conforms to any one of Aspects 1 to 47, wherein for at least 97.5% of the particles in the composition, the maximum size of a three-particle agglomeration for injection / implant is less than 200 μm; 49. An injection / implant composition comprising (a) a filler component consisting of an effective amount of particles consisting essentially of poly-L-lactic acid (PLLA), and (b) a physiologically suitable carrier, wherein at least about 70% of the particles in the composition have a maximum diameter of about 22.5 μm to approximately 62.5 μm; 50. The composition for injection / implantation of Aspect 49, in which at least about 80% of the particles in the composition have a maximum particle diameter of about 27.5 μm to approximately 60 μm in size; Petition 870210111618, dated 01 / 12 / 2021, pages 291 / 307 77 / 84 51. The Aspect 50 injection / implant composition, wherein at least about 65% of the particles in the composition have a maximum particle diameter of about 30 µm to approximately 50 µm in size; 52. The composition for injection / implantation of any of Aspects 49 to 51, in which in at least about 80% of the particles the diameter, in any direction, varies by no more than about 25%; 53. The composition for injection / implantation of Aspect 52, in which at least about 90% of the particles vary in diameter, in any direction, by no more than about 15%; 54. The injection / implant composition according to any one of Aspects 49 to 53, wherein the particles are microspheres, and at least about 85% of them have a maximum average diameter between 30 µm and 40 µm; 55. A composition for injection / implantation of any of Aspects 49 to 54, wherein the composition is in the form of an aqueous liquid or a gel, and the carrier comprises (a) one or more physiologically acceptable surfactants, and (b) one or more physiologically acceptable gelling agents; 56. The composition for injection / implantation of Aspect 55, in which the excipient and diluent components of the liquid or gel have a mean reabsorption time of less than about 4 months in humans; 57. The composition for injection / implantation of Aspect 56, in which the excipient and diluent components of the liquid or gel have a mean reabsorption time of about 2 months or less in humans; 58. The injection / implant composition of Aspect 56 or Aspect 57, wherein the liquid or gel further comprises one or more physiologically acceptable buffers, one or more physiologically acceptable salts, one or more physiologically acceptable preservatives, or a combination of two or more thereof; 59. The injection / implant composition of any of Aspects 49 to 58, wherein for at least 97.5% of the particles in the composition the maximum size of a three-particle agglomeration for injection / implant is less than 200 µm; Petition 870210111618, dated 01 / 12 / 2021, pages 292 / 307 78 / 84 60. A composition for injection / implantation of any of Aspects 49 to 59, in which the presence and / or effect of the particles for injection / implantation is detectable in humans for an average period of at least one year after administration; 61. The composition for injection / implantation of Aspect 60, in which the presence and / or effect of the particles for injection / implantation is detectable in humans for an average time of at least about 2 years after administration; 62. The injection / implant composition of any of Aspects 49 to 61, wherein the injection / implant composition results in a detectable allergic reaction in less than about 1% of human recipients; 63. The injection / implant composition of any of Aspects 49 to 62, wherein the injection / implant composition can be classified as a non-pyrogenic composition, and results in a detectable inflammatory response in less than about 1% of human recipients; 64. A composition of between about 200 mg and approximately 500 mg of an injection / implant composition, comprising an injection / implant composition according to any one of Aspects 1 to 63, and further comprising one or more excipients; 65. The composition of Aspect 64, wherein the composition comprises approximately 250 mg to approximately 450 mg of a composition for injection / implantation; 66. The composition of Aspect 65, wherein the composition comprises approximately 325 mg to approximately 425 mg of a composition for injection / implantation, in accordance with any one of Aspects 1 to 63; 67. The composition of Aspect 66, wherein the composition comprises approximately 350 mg to approximately 410 mg of a composition for injection / implantation, in accordance with any one of Aspects 1 to 56; 68. The composition of any of Aspects 64 to 67, in which the concentration of particles in the composition, when reconstituted with water for injection and therefore prepared for injection, is from about 10 to approximately 30 mg / mL; 69. The composition of Aspect 68, in which the concentration of particles in the composition is approximately 15 to 25 mg / mL; Petition 870210111618, dated 01 / 12 / 2021, pages 293 / 307 79 / 84 70. The composition of Aspect 69, in which the concentration of particles in the composition is approximately 20 mg / mL; 71. The composition of any of Aspects 64 to 70, in which the concentration of particles in the composition (without water or diluent) is from about 25% to approximately 100%; 72. The composition of Aspect 71, in which the concentration of particles in the composition is approximately 50% to approximately 100%; 73. The composition of any of Aspects 64 to 72, wherein the composition is a dry solid composition; 74. The composition of Aspect 73, in which the composition is a freeze-dried composition; 75. The composition of any of Aspects 64 to 72, wherein the composition is an aqueous liquid or gel composition; 76. The composition of Aspect 75, wherein the composition comprises approximately 3.5 to approximately 10.5 mL of water for injection; 77. The composition of Aspect 76, wherein the composition comprises approximately 4 to approximately 9 mL of water for injection; 78. The composition of Aspect 77, wherein the composition comprises approximately 4.5 mL to approximately 8.5 mL of water for injection; 79. The composition of any of Aspects 75 to 78, wherein the concentration of the formulation comprising the combination of particles and the carrier in the aqueous liquid or gel composition is about 35 to 65 mg / mL; 80. The composition of Aspect 79, in which the concentration of the formulation in the aqueous liquid or gel composition is approximately 40 to 60 mg / mL; 81. The composition of Aspect 80, in which the concentration of the formulation in the aqueous liquid or gel composition is approximately 45 to 55 mg / mL; 82. The composition of Aspect 81, in which the concentration of particles in the composition is from approximately 1.5% by weight to approximately 2.5% by weight; 83. The composition of Aspect 82, in which the concentration of particles in the composition is from approximately 1.9% by weight to approximately 2.1% by weight; Petition 870210111618, dated 01 / 12 / 2021, pages 294 / 307 80 / 84 84. The composition of Aspect 80, in which the concentration of the formulation in the aqueous liquid or gel composition is from approximately 3.5% by weight to approximately 6% by weight; 85. The composition of Aspect 80, in which the concentration of the formulation in the aqueous liquid or gel composition is from approximately 4.5% by weight to approximately 5.3% by weight; 86. An injection / implant delivery system comprising (a) a storage component containing an effective quantity of an injection / implant composition according to any one of Aspects 1 to 78, and (b) a needle or cannula configured to deliver the composition to the mammal after the application of a delivery force; 87. The injection / implant delivery system of Aspect 86, wherein the system comprises a needle; 88. The injection / implant delivery system of Aspect 87, in which the inner diameter of the needle is approximately 0.1 mm to approximately 0.4 mm; 89. The injection / implant delivery system of Aspect 88, in which the internal diameter of the needle is approximately 0.125 mm to approximately 0.285 mm; 90. The Aspect 89 injection / implant delivery system, in which the inner diameter of the needle is approximately 0.11 mm to approximately 0.35 mm; 91. The injection / implant delivery system of any of Aspects 88 to 90, in which the outer diameter of the needle is approximately 0.1 mm to approximately 0.7 mm; 92. The injection / implant delivery system of Aspect 91, in which the outer diameter of the needle is approximately 0.23 to approximately 0.59 mm; 93. The Aspect 92 injection / implant delivery system, in which the needle and / or cannula varies in size between 24 Gauge (24G) and 31 Gauge (31G); 94. The Aspect 93 injection / implant delivery system, in which the needle is selected from the group consisting of a 26G needle, a 27G needle, or a 28G needle; 95. The Aspect 94 injection / implant delivery system, in which the needle is a 26G needle; Petition 870210111618, dated 01 / 12 / 2021, pages 295 / 307 81 / 84 96.0 injection delivery system / implant of any of Aspects 86 to 95, wherein the quantity of the composition for injection / implant in the delivery system is from about 200 mg to approximately 500 mg; 97. The Aspect 96 neocollagenous dermatological implant delivery system, in which approximately 200 mg to approximately 500 mg of the implant composition is present in an amount of approximately 3.5 mg to approximately 10.5 mL of water for injection; 98. A kit or packaged product including (a) a container comprising a dry solid composition according to any one of Aspects 1 to 74; (b) an aqueous solution suitable for reconstituting the composition to form an aqueous liquid or gel composition; and (c) a delivery system comprising a needle or cannula configured to deliver the aqueous liquid or gel composition, by applying a delivery force, to a mammalian recipient; 99. The kit according to Aspect 98, wherein the dispensing system comprises a needle; 100. A method of delivering a composition for injection / implantation in the form of an aqueous liquid or gel composition to a mammalian recipient, comprising injecting into a mammalian recipient the needle of a delivery system according to any one of Aspects 86 to 97, and applying a delivery force to the delivery system to deliver an effective amount of the composition for injection / implantation to the mammalian recipient; 101. The Aspect 100 method, in which the mammalian recipient is a human; 102. The Aspect 101 method, in which the human is a patient for aesthetic treatment under the supervision of a licensed healthcare professional; 103. The method described in Aspect 102, in which the risk of injection failure associated with the use of the distribution system is approximately 40% or less; 104. The method described in Aspect 103, in which the risk of injection failure associated with the use of the distribution system is less than approximately 30%; 105. The method described in Aspect 104, in which the risk of injection failure associated with the use of the distribution system is less than approximately 15%; Petition 870210111618, dated 01 / 12 / 2021, pages 296 / 307 82 / 84 106. The method of any of Aspects 100 to 105, in which the minimum force used to deliver the composition for injection / implantation is approximately 40 to approximately g; 107. The method of Aspect 106, in which the minimum force used to distribute the composition is about 40 to 55 g; 108. The method described in Aspect 107, in which the minimum force used to distribute the composition is less than approximately 50 g; 109. The method of any of Aspects 100 to 108, in which the maximum force used to distribute the composition is approximately 150 g to approximately 2500 g; 110. The method of Aspect 109, in which the maximum force used to distribute the composition is approximately 175 g to 1750 g; 111. The method of Aspect 110, in which the maximum force used to distribute the composition is approximately 200 g to approximately 1200 g; 112. The method of Aspect 111, in which the maximum force used to distribute the composition is approximately 200 g to approximately 700 g; 113. The method of any of Aspects 99 to 112, wherein the average force used to distribute the composition is about 100 g to 1000 g; 114. The method of Aspect 113, in which the average force used to distribute the composition is approximately 150 g to 750 g; 115. The method of Aspect 114, in which the average force used to distribute the composition is approximately 175 g, or about 400 g; 116. The method of Aspect 115, in which the average force used to distribute the composition is approximately 200 g to approximately 350 g; 117. Method for increasing skin volume in a mammalian recipient, comprising administering an effective amount of a composition, according to any one of Aspects 1 to 85, to the mammalian recipient; 118. The method of Aspect 110, in which the method comprises the execution of the steps of the method of any of the Aspects 100 to 116; Petition 870210111618, dated 01 / 12 / 2021, pp. 297 / 307 83 / 84 119. The method of Aspect 117 or Aspect 118, wherein the method comprises repeating the administration of the composition for injection / implantation on different days as part of a course of treatment; 120. The method described in Aspect 119, in which the course of treatment comprises 3 to 4 administrations of the injectable / implantable composition; 121. The method of any of Aspects 117 to 120, in which the composition comprises an anesthetic, or the method is performed in association with the administration of an anesthetic; 122. The method of any of Aspects 117 to 121, where the method is performed in combination with the application of another aesthetic method; 123. The method of any of Aspects 117 to 122, wherein the method comprises administering the composition to an area of ​​human skin having an average epidermal thickness of less than 40.75 μπι, an average dermal thickness of less than 1230 μπι, or both; 124. The method of Aspect 123, wherein the method comprises administering the composition to an area of ​​human skin having an average epidermal thickness of less than 40.5 mm, an average dermal thickness of less than 1200 mm, or both; 125. The method of Aspect 123 or Aspect 124, wherein the method comprises administering the composition to an area of ​​human skin having an average epidermal thickness of less than 40 mm; 126. The method of any of Aspects 123 to 125, wherein the method comprises administering the composition to an area of ​​human skin having an average dermal thickness of less than 1175 μm; 127. The method of any of Aspects 117 to 125, wherein the method comprises administering the composition to an area of ​​human skin having an average relative thickness score of less than 1.5; 128. The Aspect 127 method, in which the method comprises administering the composition to an area of ​​human skin having an average relative thickness score of less than 1.35; Petition 870210111618, dated 01 / 12 / 2021, pages 298 / 307 84 / 84 129. The method of any of Aspects 117 to 128, wherein the method comprises administering the composition to an area of ​​human skin on a part of the body, such as the face and neck, having an average thickness at least 30% less than the thickness of the area of ​​human skin on the part of the body that has the thickest skin, on average; 130. A composition conforming to any one of Aspects 1 to 80, in which the average particle size does not decrease by more than 10% over time, represented by, or substantially equivalent to, a 6-month accelerated stability study (where the composition is stored at approximately 40 °C and about 75% relative humidity), a long-term ordinary condition stability study (where the composition is stored at approximately 25 °C and about 60% RH for 12 months), or both. 131. The composition of Aspect 131, in which the particle polydispersity index is stable over time, represented by, or substantially equivalent to, a 6-month accelerated stability study, with the composition being stored at approximately 40 °C and about 75% relative humidity, such that the particle polydispersity index does not vary by more than approximately 5%; 132. The composition of any of Aspects 1 to 80, 130 and 131, in which at least about 90% of the particles are microspheres, and at least about 50% of the microspheres have a maximum diameter within a range of 30 gm + / -12.5 μm; 133. The composition of any of Aspects 1 to 80 and 130 to 132, in which the maximum average size of an agglomeration of three injectable particles is less than 200 μg; 134. The composition of any of Aspects 1 to 80 and 130 to 133, in which the average minimum force, the maximum force, or both, required to deliver a dose of the composition through a needle, are only about 50% or less of the corresponding force required to administer a corresponding dose of Sculptra® through the needle. Petition 870210111618, dated 01 / 12 / 2021, pp. 299 / 307

Claims

1 / 2 Claims 1. SUITABLE COMPOSITION FOR INJECTION, for increasing dermal volume, characterized by comprising an effective quantity of neocollagenous particles that are at least composed mainly of one or more resorbable polyester polymers, selected from the group comprising polylactic-co-glycolic acid (PLGA), a PLA, or a mixture of two or more thereof, and are present in the composition at a concentration of 10 mg / mL to 30 mg / mL, wherein the neocollagenous particles have a size distribution such that at least 70% of the particles have a maximum particle diameter that is within 30% of the average particle diameter, wherein the PLA is poly-L-lactic acid (PLLA), poly-D-lactic acid (PDLA), poly-D,L-lactic acid (PDLLA), or a mixture thereof.

2. COMPOSITION, according to claim 1, characterized in that at least 80% of the particles have a maximum particle diameter that is within 25% of the average particle diameter.

3. COMPOSITION, according to claim 2, characterized in that at least 90% of the particles are microspheres, and at least 50% of the microspheres have a maximum diameter within a range of 30 μm + / - 12.5 μm.

4. COMPOSITION, according to claim 3, characterized in that at least 70% of the particles in the composition have a maximum diameter between 27.5 μm and 62.5 μm.

5. COMPOSITION, according to claim 4, characterized in that the maximum average size of an agglomeration of three injectable particles is less than 200 μm.

6. COMPOSITION, according to claim 5, characterized in that at least 50% of the particles consist essentially of PLA.

7. COMPOSITION, according to claim 6, characterized in that at least 70% of the polyester polymer content of the composition is composed of PLLA.

8. COMPOSITION, according to claim 7, characterized in that at least 50% of the polyester polymer content of the composition is composed of PLLA. Petition 870250065787, dated 07 / 29 / 2025, page 14 / 15 2 / 2 9. COMPOSITION, according to any of the preceding claims, characterized in that the presence, the effect, or both, of the injectable particles are detectable in humans on average for at least one year after administration.

10. COMPOSITION, according to claim 9, characterized in that dermal injection and implantation of an effective amount of the composition results in a measurable increase in dermal volume during an average period of at least 2 years.

11. COMPOSITION, according to any of the preceding claims, characterized in that the composition is in the form of an aqueous liquid or gel, further comprising a physiologically suitable carrier, including one or more physiologically acceptable surfactants, and one or more physiologically acceptable gelling agents.

12. COMPOSITION, according to claim 11, characterized in that the composition can be dispensed by injection through a needle having an internal diameter between 0.1 mm and 0.4 mm, with a failure rate of less than 40%.

13. COMPOSITION, according to claim 11, characterized in that the average minimum force, the maximum force, or both, required to deliver a dose of the composition through a needle, is only 50% or less of the corresponding force required to deliver a corresponding dose of Sculptra® through the needle.

14. COMPOSITION, according to any of the preceding claims, characterized in that the average particle size does not decrease by more than 10% during a 6-month accelerated stability study, where the composition is stored at 38 to 42 °C with 70 to 80% relative humidity.

15. COMPOSITION, according to claim 14, characterized in that the polydispersity index of the particles does not vary by more than 5% when the composition is stored at 38 to 42 °C with 70 to 80% relative humidity, for a period of six months. Petition 870250065787, dated 07 / 29 / 2025, page 15 / 15

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