WO2021025656A1 - Fast and effective purification method in dermal filler production - Google Patents
Fast and effective purification method in dermal filler production Download PDFInfo
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- WO2021025656A1 WO2021025656A1 PCT/TR2020/050695 TR2020050695W WO2021025656A1 WO 2021025656 A1 WO2021025656 A1 WO 2021025656A1 TR 2020050695 W TR2020050695 W TR 2020050695W WO 2021025656 A1 WO2021025656 A1 WO 2021025656A1
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- 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
-
- 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
Definitions
- the present invention relates to the reduction of production time significantly by improving the purification process in the production of dermal filler and the effective removal of the residual cross-linking agent (BDDE) which can be relatively toxic.
- BDDE residual cross-linking agent
- Hyaluronic acid (HA) based fillers are the most common and popular dermal fillers used for aesthetic purposes. Hyaluronic acid substances are normally found under the skin. Skin aging and defects on facial contours can be eliminated with fillers and a more vivid bright appearance can be obtained.
- Dermal fillers based on hyaluronic acid are generally gel-like structures containing more than 95% water and 0.5 to 3% HA.
- HA is a polysaccharide composed of repetitive disaccharide units of (l,4)-gluronic acid-P(l,3)-N- acetylglucosamine, linked by glycosidic bonds. This disaccharide structure is the same among all living organisms. This feature makes HA a biocompatible molecule compared to protein-based fillers such as collagen.
- HA when used as a dermal filler is the rapid degradation by the hyaluronidase family of enzymes in the tissue. Many chemical modifications have been made to increase the half-life of HA in the tissue.
- the most preferred method is the crosslinking of HA polymer chains with the help of synthetic agents and providing more resistance towards enzymatic degradation. With this method, dermal fillers can maintain their effect in the tissue for 3 to 24 months.
- cross-linking agents methacrylamide, hydrazide, carbodiimide, divinyl sulfone (DVS), 1,4-butanediol diglycidyl ether (BDDE) and poly (ethylene glycol) diglycidyl ether were used.
- the most widely used agent among these is BDDE.
- BDDE is a biodegradable substance with less toxicity than other ether-based crosslinking agents.
- hydrogels have been proven safe for a long time, the crosslinking agents used are reactive agents that can be cytotoxic and, in some cases, mutagenic. Therefore, the concentration of BDDE, which may be present as a residue in the final product, is limited by the FDA to ⁇ 2 ppm (two in a million).
- Purification processes are generally carried out in distilled water or phosphate buffer solution. The gels placed into these solutions swell over time and purification is provided by removing the impurities that are not reacted.
- purification is also performed by precipitation of cross-linked hydrogels in alcohol solvent such as ethanol.
- alcohol solvent such as ethanol.
- crosslinked gels settle to bottom of the vessels as white solids.
- the precipitation process is repeated several times, allowing the entire gel to settle completely.
- the precipitated solid is filtered or decanted from the liquid medium and dried. Residual BDDE and other impurities are removed from the medium in the liquid phase.
- US patent document US 20070224277 A 1 mentions that the purification of cross-linked hydrogels based on hyaluronic acid (HA) is carried out in distilled water for 7 days.
- HA hyaluronic acid
- hydrogels were obtained using HA and BDDE crosslinker and the purification process was carried out in phosphate buffer solution for 185 hours.
- the aim of the invention is to shorten the purification process, which is the most time-consuming process in the production of dermal fillers, thereby saving time.
- Another object of the invention is to significantly reduce the concentration of residual BDDE in the dermal filler production process.
- Another object of the invention is to easily remove impurities from the medium by using the multiple washing-filtering processes.
- the invention is the dermal filler production process
- a dermal filler production process comprising the steps of
- the process of the invention is to obtain gels that allow HA and BDDE to be used as dermal fillers as a result of the cross-linking reaction.
- the non-crosslinked HA was added to the final formulation (0.25-0.60%) to ensure easy extrusion.
- Total HA concentration is 20 mg / ml and contains lidocaine HC1, which is 0.25-0.30% anesthetic agent.
- the residual BDDE content found in hydrogels is determined by fluorescence spectrophotometry. Epoxy compounds in the content of BDDE can react with nicotinamide to produce fluorescence under excitation at 370 nm. The fluorescent intensity is directly proportional to the epoxide content, which can be detected at an emission wavelength of 430 nm. Accordingly, BDDE solutions were prepared and analyzes were carried out to obtain the standard graphic. BDDE is diluted to different concentrations with ultrapure water. 20 pL of diluted BDDE solution was mixed with 10 pL of 0.125 M nicotinamide. The mixtures were incubated in a water bath at 37 0 C for 2 hours.
- hydrogels were incubated in hyaluronidase enzyme at 37 0 C for 24 hours and then centrifugation was carried out. The supernatant was filtered through a 0.22 pm pore size membrane and analyzed by fluorescence spectrophotometer.
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Dermatology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Molecular Biology (AREA)
- Dispersion Chemistry (AREA)
- Engineering & Computer Science (AREA)
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Abstract
The invention is a purification method required for a dermal filler production process. The object of the invention is to save considerable time and to effectively remove the residual cross-linking agent in the formulation, in contrast to conventionally used purification methods. After the production of cross-linked dermal filler gels, the particle sizes of the gels are reduced to approximately 500-2000 microns with the help of a homogenizer, then washed 7 more times with PBS solution during one hour in each washing, then filtering, bringing the gels to the desired particle sizes, adding Lidocaine HCl to the final mixture to provide an anesthetic effect, adjusting the pH of the final mixture to 7, filling 1 ml syringes under vacuum and performing steam sterilization of the filled syringes.
Description
FAST AND EFFECTIVE PURIFICATION METHOD IN DERMAL
FILLER PRODUCTION
Technical Field
The present invention relates to the reduction of production time significantly by improving the purification process in the production of dermal filler and the effective removal of the residual cross-linking agent (BDDE) which can be relatively toxic.
Background Of The Invention Dermal fillers that offer different solutions for each region in humans and generally contain hyaluronic acid are frequently used for the facial area where aging is clearly seen. Hyaluronic acid (HA) based fillers are the most common and popular dermal fillers used for aesthetic purposes. Hyaluronic acid substances are normally found under the skin. Skin aging and defects on facial contours can be eliminated with fillers and a more vivid bright appearance can be obtained.
Dermal fillers based on hyaluronic acid (HA) are generally gel-like structures containing more than 95% water and 0.5 to 3% HA. HA is a polysaccharide composed of repetitive disaccharide units of (l,4)-gluronic acid-P(l,3)-N- acetylglucosamine, linked by glycosidic bonds. This disaccharide structure is the same among all living organisms. This feature makes HA a biocompatible molecule compared to protein-based fillers such as collagen.
The major disadvantage of HA when used as a dermal filler is the rapid degradation by the hyaluronidase family of enzymes in the tissue. Many chemical modifications have been made to increase the half-life of HA in the tissue. The most preferred method is the crosslinking of HA polymer chains with the help of synthetic agents
and providing more resistance towards enzymatic degradation. With this method, dermal fillers can maintain their effect in the tissue for 3 to 24 months.
As cross-linking agents, methacrylamide, hydrazide, carbodiimide, divinyl sulfone (DVS), 1,4-butanediol diglycidyl ether (BDDE) and poly (ethylene glycol) diglycidyl ether were used. The most widely used agent among these is BDDE. BDDE is a biodegradable substance with less toxicity than other ether-based crosslinking agents. Although hydrogels have been proven safe for a long time, the crosslinking agents used are reactive agents that can be cytotoxic and, in some cases, mutagenic. Therefore, the concentration of BDDE, which may be present as a residue in the final product, is limited by the FDA to < 2 ppm (two in a million).
In order to remove residual BDDE, it is necessary to perform purification processes after the cross-linking reaction. Purification processes are generally carried out in distilled water or phosphate buffer solution. The gels placed into these solutions swell over time and purification is provided by removing the impurities that are not reacted.
In some studies in the technique, purification is also performed by precipitation of cross-linked hydrogels in alcohol solvent such as ethanol. In this case, crosslinked gels settle to bottom of the vessels as white solids. The precipitation process is repeated several times, allowing the entire gel to settle completely. The precipitated solid is filtered or decanted from the liquid medium and dried. Residual BDDE and other impurities are removed from the medium in the liquid phase.
In the state of the art, “Evaluation of in-vitro degradation rate of hyaluronic acid- based hydrogel cross-linked with 1,4-butanediol diglycidyl ether (BDDE) using RP-HPLC and UV-Vis spectroscopy”, published in Journal of Drug Delivery Science and Technology, Volume 29, October 2015 between pages 24-30, purification of HA / BDDE cross-linked gels was carried out and the process was continued in distilled water for 2 days.
In the state of the art, in the article titled “Influence of Molecular Weight on Swelling and Elastic Modulus of Hyaluronic Acid Dermal Fillers” published on 03/08/2015 by Deuk Yong Lee, Cheolbyung Cheon, Siwon Son, Young-Zu Kim, Jin-Tae Kim, Ju-Woong Jang, and Seok-Soon Kim, hydrogels were obtained as a result of the crosslinking reaction with HA and BDDE. In order to remove impurities and residual BDDE in the gel, purification was done for 3 days in phosphate buffer solution and then for 3 more days in distilled water.
In another known state of the art, Reactive and Functional Polymers, Volume 109, published on December 2016, in the article between pages 42-51 "Preparation and fracture process of high strength hyaluronic acid hydrogels cross-linked by ethylene glycol diglycidyl ether" was obtained by reaction of HA and ethylene glycol diglycidyl ether (EGDE) crosslinker. It is stated that the applied time for swelling and purification of the gel is 4 days.
In another known state of the art, US patent document US 20070224277 A 1 mentions that the purification of cross-linked hydrogels based on hyaluronic acid (HA) is carried out in distilled water for 7 days.
In the European patent document EP2988791A1 known in the art, it is mentioned that the purification processes of the cross-linked silk and HA hydrogels are carried out in phosphate buffer solution for 8 days.
As mentioned in the European patent document EP2988791A1 known in the art, hydrogels were obtained using HA and BDDE crosslinker and the purification process was carried out in phosphate buffer solution for 185 hours.
Since the purification processes in distilled water or phosphate buffer solution have noticeably long durations, it takes considerably long time during production. Generally, these processes aim to remove the unreacted BDDE and other impurities by placing the gels in large pieces into the buffer solution and swelling the gel over
time. This not only lengthens the process in terms of time, but also carries the risk that the residual BDDE cannot be removed sufficiently.
After the purification processes carried out by settling in alcohol solvents such as ethanol, prolonged drying processes under vacuum for the complete removal of alcohol lead to extension of the process. Problems also arise when the structural properties of the gels obtained after drying are disturbed and re-swollen. Presence of residual alcohol in the final product should be determined by analytical methods. The necessity of additional tools or equipment is another disadvantage. In addition, the excess alcohol solvent used in the precipitation process causes additional costs.
Brief Description of the Invention
The aim of the invention is to shorten the purification process, which is the most time-consuming process in the production of dermal fillers, thereby saving time.
Another object of the invention is to significantly reduce the concentration of residual BDDE in the dermal filler production process.
Another object of the invention is to easily remove impurities from the medium by using the multiple washing-filtering processes.
Detailed Description of the Invention
The invention is the dermal filler production process,
A dermal filler production process comprising the steps of
- preparation of 1% NaOH solution in deionized water,
- gradually adding and dissolving HA in the solution, adding BDDE to HA mixture to obtain a homogeneous mixture,
- carrying out the crosslinking reaction by keeping the mixture in a water bath at 40°C for 4 hours,
- breaking up the gelled structure that is hardened after the reaction to sizes of approximately 1-2 cm and neutralization thereof with 0.1 M hydrochloric acid (HC1) in phosphate buffer solution (PBS) until the pH is 6.8-7.4,
- continuing neutralization until the pH of the solution is constant,
- filtering the gel structure by means of a sieve,
- adding new PBS solution to the filtered gel and ensuring that the gel swells for 5 hours, and characterized by the steps of
- reducing the size of the swollen gel to approximately 500-2000 microns by means of a homogenizer,
- washing with PBS solution 7 more times with an interval of one hour between the washes, and then filtering,
- bringing the gels to the desired particle sizes,
- adding non-crosslinked HA to the final mixture to facilitate extrusion, and adding lidocaine HC1 to the same to provide an anesthetic effect,
- adjusting the pH of the final mixture to 7, filling it into syringes of 1 ml under vacuum, and performing steam sterilization of the filled syringes.
The process of the invention is to obtain gels that allow HA and BDDE to be used as dermal fillers as a result of the cross-linking reaction. The non-crosslinked HA was added to the final formulation (0.25-0.60%) to ensure easy extrusion. Total HA concentration is 20 mg / ml and contains lidocaine HC1, which is 0.25-0.30% anesthetic agent.
The formulation specified in Table 1 was repeated three times (Trial 1), and the analyzes were repeated three times for each trial. The residual BDDE amounts are shown in Table 2 by taking the average of the repeated analysis results. In addition to the results, the results obtained in the other experiment (Trial 2) prepared with the same components and ratios are also shown in Table 2. In the study named Trial 2 mentioned in Table 2, the purification process was done without breaking the gels into small particles in PBS. Total purification time is in the range of 48-144 hours, and final products are obtained by taking samples every day. BDDE analyzes of the obtained gels were made and shown in Table 2.
Residual BDDE Analysis
The residual BDDE content found in hydrogels is determined by fluorescence spectrophotometry. Epoxy compounds in the content of BDDE can react with nicotinamide to produce fluorescence under excitation at 370 nm. The fluorescent intensity is directly proportional to the epoxide content, which can be detected at an
emission wavelength of 430 nm. Accordingly, BDDE solutions were prepared and analyzes were carried out to obtain the standard graphic. BDDE is diluted to different concentrations with ultrapure water. 20 pL of diluted BDDE solution was mixed with 10 pL of 0.125 M nicotinamide. The mixtures were incubated in a water bath at 37 0 C for 2 hours. Then, 100 pL of 15% acetophenone (dissolved in ethyl alcohol) and 100 pL of 1 M potassium hydroxide (KOH) were added to the mixtures and mixed in an ice bath. Then 500 pL of methanoic acid was added and the mixtures were incubated for 5 more minutes at 600 C in a water bath. The standard graphic was prepared using fluoro spectrophotometry.
The obtained hydrogels were incubated in hyaluronidase enzyme at 37 0 C for 24 hours and then centrifugation was carried out. The supernatant was filtered through a 0.22 pm pore size membrane and analyzed by fluorescence spectrophotometer.
Table 2. Amount of residual BDDE after purification process
In the results of the analysis, it is seen that the residual BDDE amounts in the purification process by reducing the particle size are well below the 2 ppm determined by the FDA as the limit (0.13 ppm). It is seen that these values are higher than 2 ppm in the purification processes of the dermal filler gel without decreasing the particle size (in the range of 24-120 hours). However, when 144 hours of purification is done, the amount of BDDE drops below the desired level.
Since the surface areas of the dermal filler gels, which are broken into small pieces, are getting smaller, they enter the water molecules faster and faster and swell and remove the impurities inside. As a very effective and fast method, breaking the gels into small pieces during purification provides ease of production and time saving.
Claims
1. A dermal filler production process comprising the steps of
- preparation of 1% NaOH solution in deionized water,
- gradually adding and dissolving HA in the solution,
- adding BDDE to HA mixture to obtain a homogeneous mixture,
- carrying out the crosslinking reaction by keeping the mixture in a water bath at 40°C for 4 hours,
- breaking up the gelled structure that is hardened after the reaction to sizes of approximately 1-2 cm and neutralization thereof with 0.1 M hydrochloric acid (HC1) in phosphate buffer solution (PBS) until the pH is 6.8-7.4,
- continuing neutralization until the pH of the solution is constant,
- filtering the gel structure by means of a sieve,
- adding new PBS solution to the filtered gel and ensuring that the gel swells for 5 hours, and characterized by the steps of
- reducing the size of the swollen gel to approximately 500-2000 microns by means of a homogenizer,
- washing with PBS solution 7 more times with an interval of one hour between the washes, and then filtering,
- bringing the gels to the desired particle sizes,
- adding non-crosslinked HA to the final mixture to facilitate extrusion, and adding lidocaine HC1 to the same to provide an anesthetic effect,
adjusting the pH of the final mixture to 7, filling it into syringes of 1 ml under vacuum, and - performing steam sterilization of the filled syringes.
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EP20849479.9A EP4010040A4 (en) | 2019-08-08 | 2020-08-07 | Fast and effective purification method in dermal filler production |
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TR2019/12107 | 2019-08-08 | ||
TR2019/12107A TR201912107A2 (en) | 2019-08-08 | 2019-08-08 | FAST AND EFFECTIVE PURIFICATION METHOD IN DERMAL FILLER PRODUCTION |
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EP (1) | EP4010040A4 (en) |
TR (1) | TR201912107A2 (en) |
WO (1) | WO2021025656A1 (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130203696A1 (en) * | 2011-06-03 | 2013-08-08 | Allergan, Inc. | Dermal filler compositions for fine line treatment |
WO2019002369A1 (en) * | 2017-06-28 | 2019-01-03 | Nestlé Skin Health Sa | Glycosaminoglycan hydrogel with grafted dextran or cyclodextrin |
-
2019
- 2019-08-08 TR TR2019/12107A patent/TR201912107A2/en unknown
-
2020
- 2020-08-07 EP EP20849479.9A patent/EP4010040A4/en active Pending
- 2020-08-07 WO PCT/TR2020/050695 patent/WO2021025656A1/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130203696A1 (en) * | 2011-06-03 | 2013-08-08 | Allergan, Inc. | Dermal filler compositions for fine line treatment |
WO2019002369A1 (en) * | 2017-06-28 | 2019-01-03 | Nestlé Skin Health Sa | Glycosaminoglycan hydrogel with grafted dextran or cyclodextrin |
Non-Patent Citations (1)
Title |
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See also references of EP4010040A4 * |
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Publication number | Publication date |
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EP4010040A4 (en) | 2023-06-14 |
EP4010040A1 (en) | 2022-06-15 |
TR201912107A2 (en) | 2021-02-22 |
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