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WO2025116844A1 - Procédé de production d'une charge contenant de l'acide hyaluronique ayant des valeurs de score de cohésion élevées, qui peuvent être appliquées au derme superficiel, intermédiaire ou profond - Google Patents

Procédé de production d'une charge contenant de l'acide hyaluronique ayant des valeurs de score de cohésion élevées, qui peuvent être appliquées au derme superficiel, intermédiaire ou profond Download PDF

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Publication number
WO2025116844A1
WO2025116844A1 PCT/TR2024/050549 TR2024050549W WO2025116844A1 WO 2025116844 A1 WO2025116844 A1 WO 2025116844A1 TR 2024050549 W TR2024050549 W TR 2024050549W WO 2025116844 A1 WO2025116844 A1 WO 2025116844A1
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WIPO (PCT)
Prior art keywords
value
cross
mixture
acid
hydrogels
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/TR2024/050549
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English (en)
Inventor
Faruk OYTUN
Murat GUMUS
Fatih AYDIN
Safak CELIK
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.)
VSY Biyoteknoloji ve Ilac Sanayi AS
Original Assignee
VSY Biyoteknoloji ve Ilac Sanayi AS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from TR2023/016209 external-priority patent/TR2023016209A1/tr
Application filed by VSY Biyoteknoloji ve Ilac Sanayi AS filed Critical VSY Biyoteknoloji ve Ilac Sanayi AS
Publication of WO2025116844A1 publication Critical patent/WO2025116844A1/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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/042—Gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/91—Injection

Definitions

  • the invention relates to a method in the medical aesthetic technical field for producing dermal fillers with the highest cohesiveness score values, even if they have variable rheological properties depending on the upper, middle or deep dermis.
  • Dermal fillers are shown as an option for the treatment of lack of volume, scars and wrinkles, as well as for facial contouring. Fillers are also used for facial contouring and enlargement of certain anatomical areas, such as the lips.
  • the perfect dermal filler should be safe, inexpensive, hypoallergenic, easy to distribute, easy to store, injectable in a short time, and painless to inject; it should not require allergy testing and should not involve any risk of interruption and complications to the patient. In addition, the results should feel natural under the skin, be long-lasting, consistent, predictable, and easy to remove when necessary.
  • Dermatologists and cosmetic surgeons should regularly review treatment options to provide patients with safe and effective filler options.
  • Injectable dermal fillers are widely used to treat signs of aging on the face and provide facial beautification.
  • hyaluronic acid (HA)-based fillers have become the most commonly used soft tissue fillers for facial rejuvenation.
  • HA fillers seem to be similar, their physical properties and production methods are not the same. These differences have clinical consequences for the physician as they may affect the injection technique, use and quality of the result. Manufacturers are also complementing these properties by introducing new HA filler formulations with the aim of stabilizing and increasing tissue longevity and improving their tolerability.
  • Different proprietary technologies are being developed using various means of production, HA concentrations, degree of cross-linking, particle size, swelling rate, cohesiveness levels, and rheological properties.
  • Rheology is the most important characterization method for dermal fillers.
  • Dermal filler rheology refers to the flow and deformation properties of fillers under mechanical stress. It describes how the material behaves under different conditions and how it interacts with surrounding tissues.
  • the rheological properties of dermal fillers are clinically important since they play a critical role in determining how the hydrogel behaves after injection. Variations in rheological properties have an impact on the clinical indications and applications of a particular filler.
  • Rheology can help clinicians select both the best product and the best injection technique for each specific indication and facial area.
  • the key rheological parameters are determined as elastic modulus, G'; viscous modulus, G"; complex viscosity, q* and loss factor, tan 5.
  • G' measures the energy stored by the HA filler during deformation, which regenerates its original shape when the shear stress is removed. It corresponds to the elastic part of its viscoelastic properties (or semi-solid state). G' has conventionally been defined as an indicator of the lifting capacity of a filler. Clinically, dermal fillers with a higher G' value are expected to provide greater structural support and volumization. Filler with lower G' are less viscous and injected more superficially. Such fillers are used for fine lines and wrinkles.
  • G measures the energy lost in shear deformation due to internal friction. It characterizes the viscous segment of the viscoelastic properties (or liquid state) of the sample. This feature suggests that the HA filler is not able to fully regain its shape after deformation.
  • G" is associated with G' and is used to indicate the viscoelastic character of the gel. If G' is greater than G", the gel shows a gel-like or solid structure and can be called a viscoelastic solid material. However, if G" is greater than G', the sample shows a fluid structure and can be called a viscoelastic liquid. All HA fillers have a G' > G" value. This means that they have a gel-like structure and are viscoelastic solid materials.
  • the complex viscosity, q* shows the ability of the gel to resist the shear forces exerted on a filler during injection and when applied into soft tissue. It measures the resistance of the filler to flow when shear stress is applied and the force required to inject the filler. Since HA fillers are considered non-Newtonian liquids, their viscosity decreases when the applied shear force reaches a level where the viscosity decreases. Therefore, when an HA filler is started to be injected, a high resistance to flow is perceived until the pressure on the piston is increased. At this point, the "shear thinning point" is reached and the filler can be injected more easily.
  • Tan 5 refers to the flexibility of a material, which indicates the spreadability of the filler in soft tissues. It is defined as the ratio between the viscous modulus G" and the elastic modulus G'. It shows whether the material has mainly an elastic behavior or a viscous behavior. Tan 5 ⁇ 1 means that the elastic component is more pronounced in the gel structure. In cross-linked HA fillers, tan 5 usually ranges from 0.05 to 0.80; therefore, it is noted that under low shear stress the elastic behavior dominates over the viscous behavior. In addition, tan 5 is often linked to a product's capacity to migrate or otherwise, and low tan 5 is claimed to be related to limited product migration from the injection site. It is a good indicator of whether the filler can be injected more superficially (i.e., higher tan 5) or more deeply (i.e., lower tan 5).
  • Cohesiveness plays a crucial role in defining how well the filler or soft tissue is integrated.
  • the cohesiveness value ensures the structural integrity of the gel, helps to provide natural tissue support with smooth contours and reduces surface irregularities. Essentially, it reflects the binding forces within the gel and describes how a filler behaves as a gel deposit after it is injected. This makes cohesiveness values a very important factor to consider when assessing the overall performance of a filler.
  • HA hyaluronic acid
  • Cohesiveness can also be defined as the ability of a material to stay together due to the strong attraction between its molecules. It is essential that both the solid and liquid components of a gel remain intact and that the overall integrity of the gel is maintained.
  • Cohesiveness can be defined as a more recently discovered property of hyaluronic acid gels and the force between particles that holds them together.
  • the strength of particle cohesion is determined as a function of the cross-linking technology used. It is suggested that products with high cohesive properties are associated with greater integration (intradermally) and lifting capacity.
  • HA hyaluronic acid
  • All cross-linked hyaluronic acid hydrogels must have the highest cohesiveness in the relevant technical field. Although there are products with high cohesiveness in the art, these are gels with low elastic modulus value and which are referred to as soft.
  • the present invention relates to a method for producing a dermal filler to eliminate the above-mentioned disadvantages and bring new advantages to the relevant technical field.
  • hyaluronic acid-containing dermal fillers to be applied in the medical aesthetics field are expected to have high cohesiveness score values depending on their appropriate rheological values.
  • Table 1 it is known in the art that hyaluronic acid-containing dermal fillers prepared in accordance with upper, middle or deep dermis structures have variable cohesiveness values depending on different rheological properties. For example, it is known that when a soft gel suitable for the upper dermis is desired to obtain a hyaluronic acid-containing dermal filler, a product with a high cohesiveness value can be obtained, while when a harder gel product is obtained when a product suitable for the lower dermis is desired to be obtained, cohesiveness score values are low.
  • the inventors of the present invention provide a production method that does not have variable cohesiveness values while obtaining soft, hard or medium hard gel suitable for the upper, medium or deep dermis, and in which the cohesiveness values of the product can have the highest score as a result of each production.
  • the primary object of the inventors of the present invention is to provide a filler production method in which all gel types can be obtained at the highest cohesiveness score values regardless of the product to be produced being soft or hard gel.
  • Another object of the invention is to provide dermal filler with a reduced risk of nodules due to material accumulation.
  • Another object of the invention is to produce dermal filler with high intradermal integration properties.
  • Another object of the invention is to produce dermal filler with high lifting capacity.
  • the subject of the invention relates to a method for a dermal filler in which the highest cohesiveness score values can be obtained; and is described by way of non-limiting examples only for a better understanding of the subject matter.
  • Dermal fillers used in the medical aesthetics field in the art are in the form of soft or hard gels depending on the upper, medium or deep dermis to which they will be applied.
  • the most important factor that determines the soft or hard gel form mentioned is the degree of cross-linking of the gel and the viscosity values accordingly. It is also critical to obtain the highest cohesiveness score values in accordance with the viscosity values of dermal fillers in order to obtain high-efficiency products and to perform high- efficiency dermal filler operations depending on the area they will be applied.
  • cohesiveness refers to tightness of the internal molecular structure of the dermal filler and its ability to stay together due to the strong attraction between said molecules. Cohesiveness ensures the structural integrity of the gel, helps provide natural tissue support, and reduces post-injection surface irregularities.
  • cohesiveness score values as is known in the art, the full cohesiveness is 5-point score value, while the poor cohesiveness value is 1 point score value.
  • rheology refers to a branch of science that examines the fluidity and deformation properties of materials.
  • the dermal filler is in the form of a hydrogel. It is the hyaluronic acid component that determines the physical and chemical properties of said hydrogel. For this reason, the cross-linking technology and rheological values of the hyaluronic acid in the hydrogel are of critical importance.
  • the dermal filler contains hyaluronic acid and at least one cross-linker. The amounts of hyaluronic acid and at least one cross-linker in said dermal filler are determined according to the rheological properties of said dermal filler. The rheological properties of said dermal filler include G', G", q* and tan 5 values.
  • a method for producing hyaluronic acid-containing hydrogel with high cohesiveness score values, even if it has variable G', G", q* and tan 5 values depending on the upper, middle or deep dermis.
  • the process steps of the mentioned production method are characterized in the following lines.
  • sodium hyaluronate (abbreviated as NaHA) is preferably dissolved in a solution.
  • at least one basic component is present in the solution.
  • the pH value of the solution to be obtained in this process step should be between 10-13.
  • At least one of the components such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethyl amine, pyridine is used as said basic component.
  • sodium hydroxide (abbreviated as NaOH) is present as a basic component.
  • sodium hydroxide with a value of 0.25 M is used as a basic component.
  • NaHA is completely immersed in a NaOH solution at low temperatures.
  • the preparation temperature of the solution is at a temperature value between 2 to 8 °C.
  • the amount of said sodium hyaluronate compound is at a value in the range of 5% to 15% by weight.
  • the prepared solution is held for at least 1 hour. In this way, sodium hyaluronate becomes fully hydrated in the basic solution. Obtaining the homogeneous first mixture
  • mixing processes are performed in order to completely homogenize the mixture obtained after being held for at least 1 hour.
  • the mixing process is performed by means of any mixer.
  • the preferred mixing process is performed under vacuum.
  • Said vacuum pressure value is at least 1.0 bar.
  • the sodium hyaluronate chains become more linear than a complex intertwined structure, and therefore its complete dissolution is achieved. In this way, the first homogeneous mixture is obtained.
  • the cross-linker is added to the first mixture obtained.
  • at least one of a group of materials such as 1 ,4-butanediol diglycidyl ether, divinyl sulfone, glutaraldehyde, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) is used as the cross-linker.
  • EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • 1 ,4-butanediol diglycidyl ether abbreviated as BDDE
  • BDDE 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • the ratio of the cross-linker to hyaluronic acid by weight is important for obtaining hyaluronic acid-containing dermal fillers at the targeted cohesiveness score values.
  • said cross-linker usage values are optimized according to the sodium hyaluronate ratio and G' and q* values. Accordingly, wherein the ratio of cross-linker to hyaluronic acid in said second mixture is as follows; - in order to obtain hydrogels with a G' value at a value between 20 to 150 Pa and a q* value between 3 to 45, m C ross-iinker/mhyaiuronic acid is at a value between 0.02 to 0.13,
  • m C ross-iinker/mhyaiuronic acid is at a value between 0.04 to 0.20
  • m C ross-iinker/mhyaiuronic acid is at a value between 0.08 to 0.35.
  • the temperature at which the cross-linking reaction takes place is a temperature value between 35 °C to 50 °C.
  • temperature is one of the parameters that catalyze the cross-linking reaction.
  • the temperature values provided in the present invention are critical values at which the optimum conditions are determined for catalyzing the cross-linking reactions and also the non-degradation of sodium hyaluronate.
  • the mixing process of the prepared solution is performed.
  • the mixing process takes place for at least 1 minute.
  • the added cross-linker and the NaHA mixture are homogeneously dispersed and the cross-linking reaction is initiated.
  • the mixing process of the prepared solution is performed under vacuum.
  • Said vacuum pressure values are at a value of at least 1 .0 bar.
  • a cross-linking reaction is initiated in the prepared solution.
  • the reaction process takes place for 150 to 200 minutes. In this way, with the completion of said reaction, a homogeneous second mixture is obtained.
  • the mixing process for the mixture prepared where crosslinking processes have taken place is performed under vacuum.
  • Said vacuum pressure values are at a value of at least 1.0 bar.
  • the cutting process of the component obtained as a result of cross-linking with the second mixture is performed.
  • the cutting process is performed such that the components are at least at a value of 2.5 ⁇ 0.3 cm.
  • the resulting parts are added to a buffer solution.
  • phosphate buffer solution is present as a buffer solution.
  • the neutralization process of the obtained parts is performed.
  • An acid solution with a molarity value in the range of 0.1 -1.0 is added in order to neutralize the solution to be obtained in this process step.
  • at least one of the acid solution hydrochloric acid, acetic acid, phosphoric acid, carbonic acid, formic acid group must be used.
  • hydrochloric acid (abbreviated as HCI) is present as the required component for neutralization processes.
  • the molarity value of said HCI compound is 0.1 mol/L.
  • the holding time of the gel particles in the buffer solution continues until the swelling amount of the hydrogels reaches between 2 to 10 times of value. In this way, it is ensured that the parts are neutralized by swelling.
  • the purification process of the particles obtained is performed.
  • Said purification process is performed by dialysis.
  • the dialysis process is performed in PBS using dialysis membranes.
  • lidocaine hydrochloride is added to the hydrogels obtained after performing dialysis processes. Said lidocaine hydrochloride is present in the mixture at a value between 0.1% to 0.8% by weight. The lidocaine hydrochloride mentioned is present in the products to act as a pain reliever.
  • the hydrogels are subjected to an autoclave process.
  • the autoclave process takes place in syringes.
  • the syringes are at least 1 mL in volume.
  • the autoclave temperature of the hydrogels is at a temperature value between 115 °C to 125 °C.
  • Example 1-3 behave like soft gels and have a lower elastic modulus than other gels. Since the elastic modulus is proportional to the number of cross-linking points, this result suggests that soft gels have fewer cross-linking points between molecules.
  • Example 4-6 The samples obtained with Example 4-6 behave like medium hard gels and have a lower elastic modulus than hard gels and higher than soft gels. This behavior happens between soft gels and hard gels.
  • Example 7-9 behave as hard gels. In fact, it can be characterized by an elastic response that is almost constant with frequency and has a loss factor of about 0.1. Due to the presence of permanent chemical cross-links between molecules, under conditions of small deformation, these strong gels exhibit the typical behavior of viscoelastic solids, and elastic deformation seems to be the only way to compensate the stress. These gels have low tan 5 values, high G', high viscosity and consequently the highest cross-link density and thus the hardest internal structure.
  • example 1 -3 which is injected into the upper dermis and is an ideal filler for superficial wrinkles, is characterized by the lowest G' value and the highest tan 5 value.
  • Example 7-9 which is injected into the medium to deep dermis and is an ideal product for deeper lines and volume increase, is characterized by the highest G' and q* value and the lowest tan 5 value.
  • the obtained hydrogels exhibit a very compatible behavior in terms of cohesiveness scores. Cohesiveness is evaluated almost equally between the measured scores, and no statistically significant difference is detected. The gels maintain their "integrity" throughout the experiment. It is observed that the gel structure is preserved at an optimum level: No disintegration or dispersion is recorded in the gels. Based on the observed behavior, all HA hydrogels are rated as “fully cohesive” (cohesiveness score: “5”) throughout the experiment.
  • HA hydrogels still have hydroxyl and carboxylic acid groups. This suggests that although the hydrogels have a cross-linked structure, they still resemble the natural HA structure. These groups interact with tissues. It allows the gel to adhere to the tissue. In this case, a bond occurs between the gel and the tissue. This bond is called gel-tissue integration.
  • the hydrogels obtained in the invention have high cohesiveness.
  • the hydrogels obtained according to this having higher cohesiveness than other products in the art can be explained by the effects of dissolution of HA used during the cross-linking reaction, homogenization of the cross-linker, removal of bubbles and purification stage.
  • the protection scope of the invention is specified in the appended claims and cannot be limited to what is described for illustrative purposes in this detailed description. It is clear that a person skilled in the art can produce similar embodiments in the light of what is explained above, without deviating from the main theme of the invention.

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  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Gerontology & Geriatric Medicine (AREA)
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Abstract

L'invention concerne un procédé relatif au domaine technique esthétique médical permettant de produire des charges dermiques présentant les valeurs de score de cohésion les plus élevées, même si elles présentent des propriétés rhéologiques variables en fonction du derme superficiel, intermédiaire ou profond.
PCT/TR2024/050549 2023-11-30 2024-05-28 Procédé de production d'une charge contenant de l'acide hyaluronique ayant des valeurs de score de cohésion élevées, qui peuvent être appliquées au derme superficiel, intermédiaire ou profond Pending WO2025116844A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2023016209 2023-11-30
TR2023/016209 TR2023016209A1 (tr) 2023-11-30 Yüksek kohezi̇vi̇te skor değerleri̇ne sahi̇p, üst, orta veya deri̇n dermi̇se uygulanabi̇len hyalüroni̇k asi̇t i̇çeri̇kli̇ dolgu malzemesi̇ üreti̇mi̇ i̇çi̇n bi̇r yöntem

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Publication Number Publication Date
WO2025116844A1 true WO2025116844A1 (fr) 2025-06-05

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PCT/TR2024/050549 Pending WO2025116844A1 (fr) 2023-11-30 2024-05-28 Procédé de production d'une charge contenant de l'acide hyaluronique ayant des valeurs de score de cohésion élevées, qui peuvent être appliquées au derme superficiel, intermédiaire ou profond

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3175840A1 (fr) * 2011-12-08 2017-06-07 Allergan, Inc. Compositions de remplissage dermique
EP3900750A1 (fr) * 2018-12-21 2021-10-27 LG Chem, Ltd. Charge comprenant un hydrogel d'acide hyaluronique présentant d'excellentes propriétés de remplissage
US11382853B2 (en) * 2016-11-11 2022-07-12 Anteis S.A. Hyaluronic acid dermal fillers crosslinked with citric acid, method for making same and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3175840A1 (fr) * 2011-12-08 2017-06-07 Allergan, Inc. Compositions de remplissage dermique
US11382853B2 (en) * 2016-11-11 2022-07-12 Anteis S.A. Hyaluronic acid dermal fillers crosslinked with citric acid, method for making same and uses thereof
EP3900750A1 (fr) * 2018-12-21 2021-10-27 LG Chem, Ltd. Charge comprenant un hydrogel d'acide hyaluronique présentant d'excellentes propriétés de remplissage

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