WO2025244501A1 - Composition de comblement et procédé de réalisation d'une procédure de comblement l'utilisant - Google Patents

Composition de comblement et procédé de réalisation d'une procédure de comblement l'utilisant

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Publication number
WO2025244501A1
WO2025244501A1 PCT/KR2025/095341 KR2025095341W WO2025244501A1 WO 2025244501 A1 WO2025244501 A1 WO 2025244501A1 KR 2025095341 W KR2025095341 W KR 2025095341W WO 2025244501 A1 WO2025244501 A1 WO 2025244501A1
Authority
WO
WIPO (PCT)
Prior art keywords
filler composition
hyaluronic acid
filler
bis
acid polymer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/KR2025/095341
Other languages
English (en)
Korean (ko)
Inventor
양승윤
장상수
성금용
이강오
성학모
최현덕
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Snvia Co Ltd
University Industry Cooperation Foundation of Pusan National University
Original Assignee
Snvia Co Ltd
University Industry Cooperation Foundation of Pusan National University
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Filing date
Publication date
Application filed by Snvia Co Ltd, University Industry Cooperation Foundation of Pusan National University filed Critical Snvia Co Ltd
Publication of WO2025244501A1 publication Critical patent/WO2025244501A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction

Definitions

  • the present invention relates to a filler composition that can be injected subcutaneously and a filler treatment method using the same.
  • Dermal fillers are medical devices injected subcutaneously into facial wrinkles to temporarily improve wrinkles and restore skin volume through physical repair without any pharmacological action. Fillers can be classified based on the properties of their raw materials and their duration of action. Specifically, fillers can be divided into non-absorbable and absorbable fillers based on whether they are absorbed by the body.
  • HA fillers hyaluronic acid (HA)-based absorbable fillers. These fillers are highly safe, can be used without skin reaction testing, and are easily degraded by enzymes. HA fillers are composed of cross-linked particles, which have fixed physical properties. Depending on the injection site, the filler's properties may need to be tailored to the specific injection site. Generally, fillers with good shape retention have high viscosity, requiring high injection pressure, which can be painful during the procedure. Furthermore, existing fillers are already cross-linked hydrogels, making it difficult to incorporate active ingredients such as peptides, proteins, and cells into the filler or deliver them over long periods of time.
  • active ingredients such as peptides, proteins, and cells
  • the main purpose of the present invention is to provide a filler composition that is easy to inject with little force, can be quickly molded into a desired shape, has easy control of mechanical properties, is decomposable by a decomposing enzyme, can be used as a carrier capable of delivering an effective substance, and can be injected into the skin or living tissue.
  • Another object of the present invention is to provide a filler treatment method using the filler composition.
  • the present invention provides a filler composition to be injected subcutaneously, comprising: an uncrosslinked photocrosslinkable hyaluronic acid polymer having a photoreactive functional group; and a photoinitiator.
  • the present invention provides a filler composition in which, when the photocrosslinkable hyaluronic acid polymer is photocrosslinked to form a hydrogel, an active substance therein is released from the hydrogel.
  • the present invention provides a filler treatment method comprising: a first step of preparing a filler composition comprising a photocrosslinkable hyaluronic acid polymer, a photoinitiator, and a solvent; a second step of injecting the filler composition subcutaneously into a predetermined shape, molding the filler composition into a predetermined shape after injection, or mixing an effective substance therein if necessary; and a third step of crosslinking the photocrosslinkable hyaluronic acid polymer by irradiating the molded filler composition with light.
  • the filler composition of the present invention since it is in a solution state containing a photocrosslinkable hyaluronic acid polymer in an uncrosslinked state before being injected into the skin, it can be injected into the skin with a low pressure that can be pressed by hand, and it is possible to quickly form it into a desired shape or form simultaneously with or after injection into the skin, and the form or form formed through photocrosslinking can be stably maintained.
  • the strength of the filler injected into the skin can be varied, and if removal is required after photocrosslinking, it can be easily decomposed by hyaluronic acid decomposing enzyme (Hyaluronidase, HAase).
  • the effective substance since it contains a hyaluronic acid polymer in an uncrosslinked state before being injected into the skin, it can be uniformly mixed with the effective substance and injected into the skin, and after being injected into the skin, it can be photocrosslinked to induce sustained release of the effective substance, thereby serving as a carrier capable of delivering the effective substance.
  • Figures 1a and 1b are images showing the results after enzyme treatment of the filler composition of Example 1 cured in an in vitro environment.
  • Figures 2a and 2b are images and graphs showing the results after enzyme treatment of the filler composition of Example 1 cured in an in vivo environment.
  • FIGS. 3a and 3b are images and graphs measuring the volume change over time of the filler composition of Example 1 cured in an in vivo environment without treatment with HAase.
  • Figure 4 shows an image of a mold used in a moldability test (a) and images of a commercial hyaluronic acid hydrogel filler composition and a filler composition of Example 1 injected subcutaneously into the back of a hairless mouse (b).
  • Figure 5 shows images of the filler compositions of Examples 1, 2, and 3 after photocuring.
  • Figure 6 is a graph and images showing the results of measuring the sustained release ability of the active substance (Rho-Dex) released after in vitro photocuring of the filler compositions of Examples 2 and 3.
  • Figures 7a and 7b are graphs showing the results of measuring the pH and viscosity of the filler compositions of Examples 6 to 9 before and after moist heat sterilization.
  • Figure 8 is a drawing for explaining an experimental process for testing the curing performance of a photocurable filler.
  • Figure 9 is a photograph showing the results of a performance test of fillers using photocurable hyaluronic acids of Examples 10 to 12 and 14.
  • Figure 10 is a photograph of a hydrogel formed after photocuring of fillers using photocurable hyaluronic acids of Examples 10 to 14, respectively.
  • first and second may be used to describe various components, these components should not be limited by these terms. These terms are used solely to distinguish one component from another. For example, without departing from the scope of the present invention, a first component could be referred to as a "second component,” and similarly, a second component could also be referred to as a "first component.”
  • a filler composition according to an embodiment of the present invention may include a photocrosslinkable hyaluronic acid polymer, a photoinitiator, and a solvent.
  • the photocrosslinkable hyaluronic acid polymer may have a photoreactive functional group.
  • the photocrosslinkable hyaluronic acid polymer may include a photoreactive functional group such as a methacyrlate group (MA), a 4-pentenoate group (PA), or the like.
  • the photocrosslinkable hyaluronic acid polymer may include a repeating unit of the following chemical formula 1.
  • the photocrosslinkable hyaluronic acid polymer may include a single repeating unit of the following chemical formula 1, or may include one or more other repeating units together with the repeating unit of the following chemical formula 1.
  • each of R 1 to R 10 may be independently one selected from the group consisting of a hydroxyl group, a carboxyl group, a photoreactive functional group, and the like, and the photoreactive functional group may include at least one selected from the group consisting of glycidyl methacrylate, methacrylate, acrylate, pentyl acrylate, 4-pentenoate, diazirines, aryl azide, benzophenones, norbornene, maleimide, vinyl ester, thiol, vinyl sulfone, and the like.
  • at least one selected from the above R 1 to R 10 may independently be a methacrylate functional group or a 4-pentenoate functional group, and the others may be hydroxy or carboxyl groups.
  • the photocrosslinkable hyaluronic acid polymer may include the methacrylate functional group or the 4-pentenoate functional group at a degree of substitution of about 140% or less, for example, about 10 to 140%, so that it can be decomposed using hyaluronidase (HAase) after photocrosslinking.
  • a degree of substitution of 100% means that one methacrylate functional group and one 4-pentenoate functional group are substituted per repeating unit of Chemical Formula 1, and since there are four substitutable -OH groups per repeating unit before substitution, the maximum degree of substitution is 400%.
  • the photocrosslinkable hyaluronic acid polymer may include both the methacrylate functional group and the 4-pentenoate functional group.
  • the photocrosslinkable hyaluronic acid polymer may include the methacrylate functional group and the 4-pentenoate functional group in a molar ratio of about 9:1 to 7:3.
  • the photocrosslinkable hyaluronic acid polymer may have a problem of being easily broken by external impact after crosslinking, and when the molar ratio of the 4-pentenoate functional group is greater than 7:3, the photocrosslinkable hyaluronic acid polymer may not have sufficient strength after crosslinking, and thus may have a problem of not being able to maintain its shape.
  • the photocrosslinkable hyaluronic acid polymer when the molecular weight of the photocrosslinkable hyaluronic acid polymer is about 1000 kDA or more, the photocrosslinkable hyaluronic acid polymer may include the photoreactive functional group at a degree of substitution of about 20% or more and about 100% or less.
  • the molecular weight of the photocrosslinkable hyaluronic acid polymer when the molecular weight of the photocrosslinkable hyaluronic acid polymer is less than 1000 kDA, even if the photoreactive functional group is included at a degree of substitution of about 50% or more and about 140% or less, it may be decomposed by a hyaluronic acid decomposing enzyme.
  • the photocrosslinkable hyaluronic acid polymer may include a methacrylate group and 4-pentenoate as the photoreactive functional group, and may also include only the methacrylate group.
  • the weight average molecular weight of the photocrosslinkable hyaluronic acid polymer may be, but is not limited to, about 100 to 3000 kDa.
  • the photocrosslinkable hyaluronic acid polymer may exist in an uncrosslinked state before being injected subcutaneously, and may be photocrosslinked to form a hydrogel after being injected subcutaneously.
  • the filler composition when the filler composition includes the photocrosslinkable hyaluronic acid polymer in an uncrosslinked state, compared to a conventional filler composition including a crosslinked hyaluronic acid polymer, the filler composition may have a lower viscosity even when the concentration of the hyaluronic acid polymer is increased, and as a result, the filler composition may be injected subcutaneously with less force, thereby reducing pain to the recipient.
  • the filler composition may include the photocrosslinkable hyaluronic acid polymer in a concentration of about 0.5 to 20 w/v%, for example, about 0.5 to 5 w/v%.
  • the filler composition may contain the photocrosslinkable hyaluronic acid polymer at a concentration of about 0.5 to 2 w/v%, and when the photocrosslinkable hyaluronic acid polymer has a molecular weight of about 100 to 500 kDa, the filler composition may contain the photocrosslinkable hyaluronic acid polymer at a concentration of about 5 to 10 w/v%.
  • the filler composition may have a viscosity of about 50 to 1500 cP, for example, about 100 to 500 cP, at 25°C, but is not limited thereto.
  • the filler composition according to an embodiment of the present invention may further include one or more active substances selected from the group consisting of peptides, proteins, drugs, polymers, cells, etc. Since the conventional filler composition includes a hyaluronic acid polymer that is crosslinked and in the form of a hydrogel, there is a disadvantage in that it is difficult to deliver the active substance into the human body by mixing it together with the hydrogel.
  • the filler composition according to an embodiment of the present invention includes a hyaluronic acid polymer in an uncrosslinked state before being injected subcutaneously, so that the active substance can be uniformly mixed with the hyaluronic acid polymer in an uncrosslinked state, and by photocrosslinking after subcutaneously injecting the same, the active substance can be included in the human body for a long period of time or be slowly released.
  • the active ingredient may be included in a proportion of about 50% or less, for example, about 0.1 to 30%, of the weight of the photocrosslinkable hyaluronic acid polymer.
  • the photoinitiator can absorb light energy to initiate a crosslinking reaction between the photoreactive functional groups.
  • any water-soluble material that can be activated by visible light to form free radicals can be used as the photoinitiator without limitation.
  • the photoinitiator is an ⁇ -hydroxyketone series derivative (irgacure 2959, irgacure 184, irgacure 651, irgacure 369, irgacure 907, etc.), a phosphine series derivative (TPO, TPO-Na, LAP, BAPO, BAPO-ONa, BAPO-OLi, etc.), an azo-initiator (2,2'-azobis[2-methyl-N-(2-hydroxyethyl) promionamide] (VA-086)), an eosin-Y, riboflavin (B2), camphorquinone, an erythrosine (Erythrosine), Rose bengal,
  • the photoinitiator may be a material having a chemical structure represented by Chemical Formula 2 below.
  • the photoinitiator having the chemical structure represented by Chemical Formula 2 is water-soluble and can be activated by visible light having a wavelength of about 400 to 500 nm. Meanwhile, the photoinitiator of Chemical Formula 2 below may have a higher molar extinction coefficient and lower cytotoxicity compared to other photoinitiators.
  • R 1 may be H or F
  • R 2 may be Li + or Mg 2+ .
  • the photoinitiator may be included at a concentration of about 0.01 to 1 w/v%, for example, about 0.05 to 0.15 w/v%.
  • LAP Lithium phenyl-2,4,6-trimethylbenzoylphosphinate
  • the solvent may further include at least one selected from the group consisting of water, saline, phosphate buffered saline, trisodium citrate buffer, tris-HCl buffer, HEPES buffer, etc.
  • the methacrylate group (MA) and 4-pentenoate group (PA) bound within the photocrosslinkable hyaluronic acid polymer may change the pH of the composition when separated due to physical factors during storage
  • a solvent capable of buffering the pH may be used.
  • the solvent may be a phosphate buffered saline solution having a concentration of about 2 to 20 mM, a trisodium citrate buffer solution, a tris-HCl buffer solution, a HEPES buffer solution, or the like, which may be used alone or in combination of two or more thereof.
  • water can be used as the solvent.
  • the filler composition may further include a sugar alcohol such as mannitol or sorbitol.
  • a sugar alcohol such as mannitol or sorbitol.
  • the pH, viscosity, gelation point, etc. of the composition may be stably maintained compared to before performing the moist heat sterilization process.
  • the filler composition of the present invention since it has a low viscosity solution state including an uncrosslinked hyaluronic acid polymer before being injected into the skin, it can be injected into the skin without pain to the recipient, and it is possible to quickly form it into a desired shape or form simultaneously with or after injection into the skin, and the formed shape or form can be stably maintained through photocrosslinking.
  • the strength of the filler injected into the skin can be varied, and if removal is required after photocrosslinking, it can be easily decomposed by hyaluronic acid decomposing enzyme.
  • the effective substance since it contains a hyaluronic acid polymer in an uncrosslinked state before being injected into the skin, it can be uniformly mixed with the effective substance and injected into the skin, and after being injected into the skin, it can be photocrosslinked to induce sustained release of the effective substance, thereby serving as a carrier capable of delivering the effective substance.
  • a filler treatment method may include a first step of preparing a filler composition including a photocrosslinkable hyaluronic acid polymer, a photoinitiator, and a solvent; a second step of injecting the filler composition subcutaneously into a predetermined shape or molding the filler composition into a predetermined shape after injection; and a third step of crosslinking the photocrosslinkable hyaluronic acid polymer by irradiating the molded filler composition with light.
  • the filler composition may be prepared by dissolving the photocrosslinkable hyaluronic acid polymer and the photoinitiator in a solvent.
  • the filler composition may be prepared by additionally dissolving an effective substance in addition to the photocrosslinkable hyaluronic acid polymer and the photoinitiator. Since the filler composition is substantially the same as described above, a detailed description thereof will be omitted.
  • the filler composition can be injected subcutaneously using an injection device such as a syringe.
  • an injection device such as a syringe.
  • a mold having an opening of a desired shape is placed on the skin, and the filler composition is injected into the opening at a location so that the filler composition is injected subcutaneously into a shape corresponding to the opening.
  • the filler composition can be injected subcutaneously and then molded into a desired shape using a mold or the like.
  • the filler composition since the filler composition includes an uncrosslinked photocrosslinkable hyaluronic acid polymer, it can have low viscosity even if it contains a relatively high concentration of photocrosslinkable hyaluronic acid polymer, and as a result, the pressure for injecting the filler composition can be lowered, thereby alleviating pain of the recipient, and the shape of the injected filler composition can be easily molded, and it can be injected subcutaneously in a state where the photocrosslinkable hyaluronic acid polymer and the effective substance are uniformly mixed.
  • the filler composition injected subcutaneously may be cured by irradiating light to crosslink the photocrosslinkable hyaluronic acid polymers.
  • the wavelength and intensity of light for the photocrosslinking may vary depending on the type of photoinitiator included in the composition, and light with a wavelength of about 320 to 600 nm may be used.
  • the mechanical properties of the cured filler composition i.e., strength, degree of curing, etc.
  • the effective substance can be made to remain in the cured filler composition for a long time or be released relatively uniformly.
  • the filler treatment method according to an embodiment of the present invention may further include a step of injecting a hyaluronic acid decomposing enzyme into the cured filler composition to decompose the cross-linked hyaluronic acid polymer.
  • the above photocured HA filler can be easily decomposed by hyaluronic acid decomposing enzymes, like conventional HA fillers.
  • a filler composition of Example 1 was prepared by dissolving 1 w/v% of photocurable hyaluronic acid (HAMA-PA) having a weight average molecular weight (Mw) of 1000 kDa, in which 40% of the hydroxyl groups of hyaluronic acid are substituted with photocurable groups such as methacrylate (MA) and pentaacrylate (PA) groups, and 0.1 w/v% of lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), a photoinitiator, in water.
  • HAMA-PA photocurable hyaluronic acid
  • Mw weight average molecular weight
  • MA methacrylate
  • PA pentaacrylate
  • LAP lithium phenyl-2,4,6-trimethylbenzoylphosphinate
  • Filler compositions of Examples 2 and 3 were prepared by mixing the filler composition of Example 1 and an aqueous solution containing Rho-Dex (rhodamine-labeled dextran) having a molecular weight of 70 kDa at a concentration of about 4 w/v% in a volume ratio (v:v) of 9:1 and 7:3, respectively.
  • Rho-Dex is an organic substance having a molecular weight similar to that of albumin protein (66 kDa) and was used as a model effective substance.
  • the viscosity of the filler composition of Example 1 and the commercial hyaluronic acid hydrogel filler composition was measured using a rheometer (MCR 302, Anton Paar) at 25°C and a shear rate of 300/s. As a result, the viscosity of the filler composition of Example 1 was confirmed to be about 200 to 1500 cP, which is significantly lower than that of the commercial hyaluronic acid hydrogel filler composition having a viscosity of about 2000 cP.
  • Figure 1 is an image showing the results of the filler composition of Example 1 cured in an in vitro environment after treatment with a decomposing enzyme.
  • 0.1 mL of the filler composition of Example 1 contained in an experimental container was cured by irradiating light with a wavelength of 400-500 nm at ⁇ 1 J/cm 2 (30 mW/cm 2 , 35 s), and then treated with hyaluronic acid decomposing enzyme (HAase) to confirm the decomposition ability.
  • HAase hyaluronic acid decomposing enzyme
  • the photocurable filler composition not treated with HAase was not decomposed and maintained its shape even after 6 hours, but it was confirmed that both the photocurable filler compositions treated with 150 U of HAase and 750 U of HAase were completely decomposed within 6 hours.
  • the photocurable filler composition having a weight average molecular weight (Mw) of 100 kDa and 5 w/v% that was not treated with HAase was not decomposed and maintained its shape even after 48 hours, but it was confirmed that all photocurable filler compositions treated with 750 U of HAase were completely decomposed within 48 hours.
  • Mw weight average molecular weight
  • Figures 2a and 2b are images and graphs showing the results after enzyme treatment of the filler composition of Example 1 cured in an in vivo environment.
  • 0.1 mL of the filler composition of Example 1 was injected subcutaneously into the dorsal area of SKH-7 hairless mice and photocured. After about 1 day, 150 U of HAase and 500 U of HAase were injected into the cured filler composition, and the size of the filler over time was measured using a vernier caliper.
  • the shape was maintained without decomposition for 8 days, but in the case of fillers with 150 U of HAase and 500 U of HAase, the volume decreased by about 50 to 80% compared to the initial volume by the second day, and it was confirmed that the higher the HAase concentration, the greater the volume decrease.
  • FIGS. 3a and 3b are images and graphs measuring the volume change over time of the filler composition of Example 1 cured in an in vivo environment without treatment with HAase.
  • Example 1 when 0.1 mL of the filler composition of Example 1 was injected subcutaneously into the dorsal surface of a hairless mouse and maintained without treatment with HAase after photocuring, it was confirmed that a volume of at least 83% of the initial volume was maintained after about 30 days.
  • Figure 4 shows (a) an image of a mold used in a moldability test and (b) images of fillers injected subcutaneously into the dorsal area of a hairless mouse using a commercial hyaluronic acid hydrogel filler composition and the filler composition of Example 1.
  • Figure 4b shows images of fillers formed by placing the star-shaped mold illustrated in Figure 4a on the mouse skin and then injecting the filler subcutaneously into the skin where the mold is located.
  • Figure 5 shows images of the filler compositions of Examples 1, 2, and 3 after photocuring.
  • Figure 6 is a graph and images showing the results of measuring the sustained release ability of the active substance (Rho-Dex) released after in vitro photocuring of the filler compositions of Examples 2 and 3.
  • the photocurable fillers of Examples 4 and 5 were prepared by adding 10 mM PBS and 15 mM PBS, respectively, to the filler composition of Example 1, and then sterilized by moist heat at 121°C for 15 minutes and stored in an incubator at 80°C for 2 weeks.
  • the pH of the filler compositions after moist heat sterilization was measured to be 7.07 for the filler composition of Example 4 (10 mM PBS), and 6.98 for the filler composition of Example 5 (15 mM PBS).
  • the pH of the filler compositions of Examples 4 and 5 was measured to be 6.56 and 6.65, respectively, and after storage at 80°C for two weeks, the pH of the filler compositions of Examples 4 and 5 was measured to be 6.48 and 6.63, respectively, confirming that this is within the range of pH 5.5 to 8.5, which is the filler specification allowed for incorporation into the body. From these results, it can be confirmed that the pH of the filler composition can be relatively stably maintained when a buffer solution is used even under harsh conditions of 80°C.
  • Mannitol and sorbitol were added to the filler composition of Example 1 according to Table 2 below and sterilized by moist heat at 121°C for 20 minutes.
  • Example 1 stabilizers such as mannitol and sorbitol were added to the composition to confirm its stability during the sterilization process. After sterilization by moist heat at 121°C for 20 minutes, pH, viscosity, and crosslinking performance (gelation point) were measured, and the results are shown in Table 3 and Figures 7a and 7b.
  • the filler composition not containing sugar alcohol decreased by up to 60.6% after sterilization compared to before sterilization, but the filler composition of Example 7 containing 4.3% mannitol and the filler composition of Example 9 containing 4.3% sorbitol decreased by only 19.0% and 27.2%, respectively, showing relative stability.
  • the filler composition not containing sugar alcohol changed by +6.5 after sterilization compared to before sterilization, but the filler compositions of Examples 6 to 9 changed only by +0.5, -0.4, +1.8, and +2.6, showing relative stability.
  • PDMS molds were filled with photocurable hyaluronic acid filler solutions having MA:PA ratios of 10:0 (Example 10), 9:1 (Example 11), 7:3 (Example 12), 5:5 (Example 13), and 0:10 (Example 14) (see a in FIG. 8), covered with rat skin on top (see b in FIG. 8), and then photocured by external irradiation with visible light (405 nm) (see b in FIG. 8), and the curing characteristics of the fillers were analyzed.
  • Figure 9 is a photograph showing the results of a performance test of fillers using photocurable hyaluronic acids of Examples 10 to 12 and 14.
  • photocurable hyaluronic acid (HAMA) (Example 10), in which only MA with a relatively short cross-linking length was introduced as a photocurable group, formed a hard hydrogel after curing, which was easily broken by external impact.
  • photocurable hyaluronic acid (HAPA) (Example 14), in which only PA with a relatively long cross-linking length was introduced as a photocurable group, was found to not have sufficient strength after curing and thus could not maintain its shape.
  • HAMA-PA photocurable hyaluronic acid
  • Figure 10 is a photograph of a hydrogel formed after photocuring of fillers using photocurable hyaluronic acids of Examples 10 to 14, respectively.
  • photocurable hyaluronic acid possesses excellent mechanical performance when it contains MA and PA in a molar ratio of 9:1 to 7:3. Since the injected filler is exposed to various external stimuli, such excellent mechanical performance is an important factor in maintaining the filler volume for a long period of time.
  • a first mixture was prepared by adding dimethyl phenylphosphonate (about 187 mg, about 1.1 mmol) to benzoyl chloride (about 140 mg, about 1 mmol) and 2-butanone (about 10 mL), and stirring the mixture at room temperature for about 24 hours under nitrogen.
  • a second mixture was prepared by adding lithium bromide (about 95 mg, about 1.1 mmol) to a 2-butanone (about 10 mL) solution.
  • the first mixture and the second mixture were mixed, heated at about 60 °C for about 20 minutes, and cooled to room temperature to produce a reactant.
  • the reactant was washed sequentially with 2-butanone and diethyl ether, and then dried under vacuum to obtain a photoinitiator for bioprinting, which was named LBP (about 237 mg, about 94% yield).
  • a photoinitiator for bioprinting was prepared in the same manner as in Example 10-1, except that 4-fluorobenzoyl chloride (about 158 mg, about 1 mmol) was used instead of the benzoyl chloride in Example 10-1, and was named LFBP.
  • a photoinitiator for bioprinting was prepared in the same manner as in Example 10-1, except that magnesium bromide (about 203 mg, about 1.1 mmol) was used instead of the lithium bromide in Example 10-1, and was named MBP.

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Abstract

La présente invention concerne une composition de comblement injectée par voie sous-cutanée et un procédé de réalisation d'une procédure de comblement l'utilisant. La composition de comblement comprend une solution aqueuse contenant un photo-initiateur et un polymère d'acide hyaluronique photoréticulable non réticulé ayant un groupe fonctionnel photoréactif. Avant d'être injectée dans la peau, la composition de comblement est dans un état de solution comprenant le polymère d'acide hyaluronique photoréticulable non réticulé et peut ainsi être injectée dans la peau à une basse pression qui peut être appliquée à la main. De plus, la composition de comblement peut être rapidement façonnée en une forme ou apparence souhaitée simultanément avec ou après l'injection dans la peau, et peut maintenir de manière stable la forme ou apparence formée par photoréticulation.
PCT/KR2025/095341 2024-05-21 2025-05-21 Composition de comblement et procédé de réalisation d'une procédure de comblement l'utilisant Pending WO2025244501A1 (fr)

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KR20100043081A (ko) * 2007-08-01 2010-04-27 더 존스 홉킨스 유니버시티 광 개시된 조직 충전제
KR20190067653A (ko) 2017-12-07 2019-06-17 선흥석 피부용 필러 조성물
KR20200036664A (ko) * 2018-09-28 2020-04-07 서울대학교산학협력단 히알루론산-실크 피브로인 복합 하이드로젤 및 이의 제조 방법
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