TR201908025A2 - A HYBRID HYDROGEL USED AS A DERMAL FILLING AND ITS PRODUCTION METHOD - Google Patents
A HYBRID HYDROGEL USED AS A DERMAL FILLING AND ITS PRODUCTION METHOD Download PDFInfo
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- TR201908025A2 TR201908025A2 TR2019/08025A TR201908025A TR201908025A2 TR 201908025 A2 TR201908025 A2 TR 201908025A2 TR 2019/08025 A TR2019/08025 A TR 2019/08025A TR 201908025 A TR201908025 A TR 201908025A TR 201908025 A2 TR201908025 A2 TR 201908025A2
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- hyaluronic acid
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- carboxymethyl cellulose
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- 230000002500 effect on skin Effects 0.000 title claims abstract description 51
- 239000000017 hydrogel Substances 0.000 title claims abstract description 26
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 24
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 146
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 145
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- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 claims abstract description 9
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- 239000000203 mixture Substances 0.000 claims description 58
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 2
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- 229960004393 lidocaine hydrochloride Drugs 0.000 abstract description 3
- 230000002688 persistence Effects 0.000 abstract description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 28
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 28
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 28
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- 229920002678 cellulose Polymers 0.000 description 7
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- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 6
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- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
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- 230000009471 action Effects 0.000 description 2
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 2
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
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- 102000001974 Hyaluronidases Human genes 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
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- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
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- 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
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- 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
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- A61K8/042—Gels
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- 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
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- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
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- A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
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- 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
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L27/52—Hydrogels or hydrocolloids
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- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
- C08B15/005—Crosslinking of cellulose derivatives
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
- C08L1/08—Cellulose derivatives
- C08L1/26—Cellulose ethers
- C08L1/28—Alkyl ethers
- C08L1/286—Alkyl ethers substituted with acid radicals, e.g. carboxymethyl cellulose [CMC]
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- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
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- 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
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- A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction
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Abstract
Bu buluş, sağlık sektöründe, özellikle dermal dolgu medikal cihaz üretiminde, çapraz bağlı karboksimetil selüloz ve hiyaluronik asit hibrit hidrojel (hibrojel) (100) üretimi ve bunun dermal dolgu olarak kullanılması ile ilgilidir. Buluşun amacı, biyolojik olarak çok iyi bir biyouyumluluk, yüksek kalıcılık ve su tutma, immünojenik olmama ve vücut tarafından güvenli emilim gibi avantajlar sağlayan, geleneksel olarak üretilen çapraz bağlı hiyaluronik asit (HA) dermal dolgulara göre reolojik özellik bakımından daha çok gelişmiş ve uygulama sırasında ağrıyı azaltmak amacıyla anestezik etkiye sahip olan lidokain hidroklorür ile formülüze edilen hibrojeller (100) üretilmesidir.The present invention relates to the production of cross-linked carboxymethyl cellulose and hyaluronic acid hybrid hydrogel (hybrid) (100) and its use as dermal fillers in the healthcare industry, particularly in the manufacture of dermal filler medical devices. The aim of the invention is that it is more developed in terms of rheological properties compared to traditionally produced cross-linked hyaluronic acid (HA) dermal fillers, which provides advantages such as a very good biocompatibility, high persistence and water retention, non-immunogenicity and safe absorption by the body and reduce pain during application. It is the production of hybrid gels (100) formulated with lidocaine hydrochloride, which has an anesthetic effect in order to reduce it.
Description
TARIFNAME DERMAL DOLGU OLARAK KULLANILAN BIR HIBRIT HIDROJEL VE BUNUN ÜRETIM YÖNTEMI Teknik Alan Bu bulus, saglik sektöründe, özellikle dermal dolgu medikal cihaz üretiminde, çapraz bagli karboksimetil selüloz ve hiyaluronik asit hibrit hidrojel üretimi ve bunun dermal dolgu olarak kullanilmasi ile ilgilidir. Önceki Teknik Dermal dolgu olarak sentetik bilesikler, ucuz maliyeti, seri üretimde kullanim kolayligi, sinirli immünojeniklik ve uzun süre kalicilik gibi özelliklerinden dolayi yumusak doku büyütme ajanlari olarak önem kazanmaktadir. Sentetik dermal dolgular, polilaktik asit (PLA), kalsiyum hidroksiapatit (CaHA) ve polimetilmetakrilat (PMMA) gibi biyosentetik polimerlerden olusmakta olup, bu polimerler deri altinda uzun bir kalicilik saglamaktadir. Fakat, uzun süre boyunca deri altinda kalmalari yan etkilerin riskini ve bunun getirdigi komplikasyonlarin olasiligini artirmaktadir. Özellikle uzak doguda estetik cerrahlar arasinda oldukça popülerlik kazanan bu ürünlerden biri poliakrilamid hidrojellerdir. Literatürde bu ürünün kullanimiyla alakali olarak pek çok vaka rapor edilmektedir. Özellikle granülom olusumu ve subklinik enfeksiyonlar uzun dönem boyunca endise uyandirmaktadir. DESCRIPTION A HYBRID HYDROJEL USED AS DERMAL FILLER AND PRODUCTION METHOD OF THIS Technical Area This invention is used in the health sector, especially in the production of dermal filler medical devices, production of cross-linked carboxymethyl cellulose and hyaluronic acid hybrid hydrogel and it's about using it as a dermal filler. Prior Art Synthetic compounds as dermal fillers, cheap cost, mass production use due to its properties such as ease, limited immunogenicity, and long-term persistence. It is gaining importance as soft tissue growth agents. synthetic dermal fillers, polylactic acid (PLA), calcium hydroxyapatite (CaHA) and It consists of biosynthetic polymers such as polymethyl methacrylate (PMMA), which polymers provide a long permanence under the skin. But for a long time being under the skin reduces the risk of side effects and the complications it brings. increases the probability. It is quite common among aesthetic surgeons, especially in the far east. One of these products gaining popularity is polyacrylamide hydrogels. In the literature this Many cases are reported related to the use of the product. Especially granuloma formation and subclinical infections are a long-term concern. it awakens.
Kalsiyum hidroksiapatit (CaHA) çok düsük antijenisiteye sahip bir dolgudur. Calcium hydroxyapatite (CaHA) is a filler with very low antigenicity.
Herhangi bir su tutma etkisi olmayan bu dolgunun, kollajen stimüle etkisi azdir ve bu yüzden yarattigi hacim etkisi hemen görülür ve ek bir hacim dolgunlugu beklenmez. Bu dolgular yalnizca deep-dermal ve sub-dermal katmana enjekte edilebilir [1]. Bu da kullanimi sinirlamaktadir. Yüzeye yakin bölgeye enjekte edilmesi durumunda hem renklerinin daha opak olmasi ve görünür duruma gelmesi hem de yüzeyde elle hissedilebilir parçacik olusumu nedeniyle dudak dolgusunda kullanilmalari önerilmemektedir [2]. This filler, which does not have any water retention effect, has little collagen stimulating effect and Therefore, the volume effect it creates is immediately visible and an additional voluminous fullness. not expected. These fillers are only injected into the deep-dermal and sub-dermal layer. can be [1]. This limits its use. Inject near the surface If it is used, both the colors will be more opaque and become visible. and lip augmentation due to palpable particle formation on the surface. their use is not recommended [2].
Polimetil metakrilat (PMMA) dermal dolgular kollajen sentezini stimüle eder ve deri altindaki kaliciligi oldukça yüksektir. Bu dolgu çesiti de yalnizca deep-dermal ve sub-dermal katmanda kullanilabilir. PMMA bazli dermal dolgularin kullanimindan sonra uzun süreli kasinti ve kizarikliklar görülmektedir. Allerjik reaksiyon gelistirebilme potansiyeli yüksektir ve bu yüzden önceden mutlaka test yapilmalidir. Bazi durumlarda spertrofik skar olusumlari da görülmektedir [3]. Polymethyl methacrylate (PMMA) dermal fillers stimulate collagen synthesis and Its permanence under the skin is quite high. This type of filler is only deep-dermal. and can be used in the sub-dermal layer. PMMA-based dermal fillers After its use, long-term itching and redness are observed. allergic It has a high potential to develop a reaction and therefore, be sure to test beforehand. should be done. In some cases, spertrophic scar formations are also observed [3].
Silikon en eski dolgu maddelerinden biridir, ancak granülom olusmasi, enfeksiyon veya migrasyon gibi yan etkileri olabilecegi için yüz bölgesinde kullanimi son Polilaktik Asit (PLA) dolgular zamanla rezorpsiyona ugrayan ancak uygulandiktan sonra kalici etkilerinin iki seneden fazla oldugu dolgulardir. PLA ayni zamanda kollajen sentezini de stimüle etmektedir ve bu yüzden yarattigi etkinin zamanla artmasi ve yaklasik 6 hafta sonra hacim arttirici etkisinin maksimum düzeyde olmasi beklenmektedir. Silicone is one of the oldest fillers, but granuloma formation, infection It should not be used in the face area as it may have side effects such as migration or migration. Polylactic Acid (PLA) fillings resorption over time, but These are fillings that have permanent effects for more than two years after application. PLA It also stimulates collagen synthesis and therefore creates the effect increases with time and after about 6 weeks the bulking effect expected to be maximum.
Hiyaluronik asit (HA) günümüzde en sik kullanilan dolgu maddesidir ve çok yüksek oranda su tutma etkisine sahiptir. Hem uygulamasi kolay hem de dokuya enjekte edildikten sonra istenilen yere ve dolgunluga ulasmasi için el ile kontrolü kolaydir. Yanlis uygulanmasi veya kisinin fazla dolgunluga bagli sikâyet etmesi durumunda da hiyaluronidaz ile eritilebilmesi de önemli artilarindan biridir. Ancak etki süresinin kisa olmasi ve hacim olusturma konusunda yetersizligi nedeniyle, özellikle fazla hacim kaybi olan yerlerde kullanilmasi hem hasta memnuniyetini düsürmekte hem de uygulama fiyatinin oldukça yüksek olmasi dezavantajlari arasindadir. HA viskoelastik özelliklerinin gelistirilmesi ve kalicilik özelliginin artmasi amaciyla BDDE veya divinil sülfon (DVS) gibi çapraz baglayicilarla çapraz baglama islemlerine maruz birakilir. Çapraz baglanma derecesinin arttirilmasiyla HA°nin fiziksel, kimyasal ve biyolojik özellikleri belirgin bir sekilde degismektedir. Asiri derecede çapraz baglanmis HA jelleri hücreler tarafindan yabanci cisim olarak algilanmakta ve bu da çevresinde fibrotik kapsüllerin olusumuyla birlikte enflamatuar reaksiyonlara sebep olmaktadir. Ayrica kollojen sentezinin uyarilmasi etkisine sahip olan HA jelleri, asiri çapraz bagli olmasi durumunda bu etkisini gösterememektedir. Hyaluronic acid (HA) is the most commonly used filler today and is very It has a high water retention effect. Easy to apply and texture After it is injected, it is manually controlled to reach the desired place and fullness. it is easy. Improper application or complaining about excessive fullness One of its important advantages is that it can be dissolved with hyaluronidase in case of However Due to its short duration of action and its inability to create volume, Especially in places with excessive volume loss, its use both increases patient satisfaction. the disadvantages of reducing the cost and the high application price are in between. Developing HA viscoelastic properties and improving the permanence cross-linkers such as BDDE or divinyl sulfone (DVS) to increase subjected to tying operations. By increasing the degree of crosslinking The physical, chemical and biological properties of HA are clearly visible. is changing. Extremely cross-linked HA gels are removed by cells. It is perceived as a foreign body and this causes fibrotic capsules around it. It causes inflammatory reactions with its formation. Also collagen HA gels, which have the effect of stimulating the synthesis of case, it does not show this effect.
Karboksimetil selüloz (CMC) ilk olarak çapraz baglanmamis serbest formda polietilen oksit ile kombine edilerek kullanilmistir. Bu tip dermal dolgular uzun süren sonuçlarla iyi etkinlik ve güvenlik göstermistir. 2012 yilindan sonra ise çapraz bagli dolgu olarak tek bir bilesende üretilip doku büyütme ve kirisikliklarin giderilmesi amaciyla satisa sunulmustur. Günümüzde bazi firmalar CMCiyi tasiyici veya dolgu olarak kullanmaktadir [4-6]. Carboxymethyl cellulose (CMC) is first formed in uncrosslinked free form. It was used in combination with polyethylene oxide. This type of dermal fillers is long. It has shown good efficacy and safety with lasting results. If after 2012 It is produced in a single component as a cross-linked filling and reduces tissue enlargement and wrinkles. It has been put up for sale for remediation. Today, some companies carry the CMC. or as a filler [4-6].
Teknikte bilinen uygulamalardan EP2772273B1 sayili Avrupa patent basvurusu dokümaninda, dermal dolgu olarak, hiyalüronik asidin (HA) 1,4-bütandiol diglisidil eterle (BDDE) çapraz baglanmis hiyaluronik asit türeviyle, farkli oranlarda karistirilmasiyla elde edilebilen biyomalzemeler kullanilmaktadir. basvurusu dokümaninda, dermal dolgu bilesimi olarak, polimetilmetakrilat (PMMA), çapraz bagli dekstran, hidroksipropil metil selüloz (HPMC) içeriginden bahsedilmektedir. European patent application no. EP2772273B1 from applications known in the art In the document, 1,4-butanediol diglycidyl of hyaluronic acid (HA) as a dermal filler with ether (BDDE) cross-linked hyaluronic acid derivative, in different proportions Biomaterials that can be obtained by mixing are used. In the application document, polymethylmethacrylate as a dermal filler composition (PMMA), cross-linked dextran, hydroxypropyl methyl cellulose (HPMC) content is mentioned.
Teknikte bilinen uygulamalardan EP2323617B1 sayili Avrupa patent basvurusu dokümaninda, hazirlanan dermal dolgu formülasyonlari için hiyalüronik asit bazli bilesimler, terapötik olarak etkili bir miktarda anestetik ajan olan lidokain içeriginin bulunmasindan bahsedilmektedir. European patent application no. EP2323617B1 from applications known in the art Hyaluronic acid-based formulations for prepared dermal filler formulations The compositions contain a therapeutically effective amount of the anesthetic agent, lidocaine. being mentioned.
Teknikte bilinen uygulamalardan EP2773319B1 sayili Avrupa patent basvurusu dokümaninda, dermal dolgu formülasyonlari için kullanilan hiyalüronik asit ve kollajenin çapraz bagli bir kombinasyonundan bahsedilmektedir. European patent application no. EP2773319B1 from applications known in the art document, hyaluronic acid used for dermal filler formulations and a cross-linked combination of collagen is mentioned.
Teknikte bilinen uygulamalardan EP3218023B1 sayili Avrupa patent basvurusu dokümani, çapraz bagli hiyalüronik asit (HA) ile karboksimetil selüloz (CMC) ve istege bagli olarak kalsiyum hidroksiapatit (CaHAP) mikro partikülleri gibi mikro parçaciklar içeren bir jel formundaki enjekte edilebilir dermal dolgu kompozisyonlari ile ilgilidir. CMC bu patentte ekstrüzyonu kolaylastirma ajani olarak kullanilmaktadir. EP3218023B1 nolu patentte dermal dolgu kompozisyonu HA ve CMC içermektedir. Yalniz bu formülasyonlarda CMC sadece ekstrüzyonu kolaylastirmak için formülasyona ilave edilmistir. Ekstrüzyonu kolaylastirmak için kullanilan yardimci ajanlar formülasyon içerisinde yer almazsa, çapraz bagli jel partiküllerinin boyutu çok küçük olsa bile enjekte edilmesi çok zordur. Bu zorlugun üstesinden gelmek için, bazi dermal dolgu maddesi üreticileri enjeksiyon sirasinda ekstrüzyonu kolaylastirmak için yaglama maddesi olarak çapraz baglanmamis CMC ve HA gibi biyouyumlu polimerleri ekler ve böylelikle enjeksiyon için gereken kuvveti kolaylastirir. Bu çapraz baglanmamis polimerler, dermal dolgu maddesinin kalicilik özelligine katkida bulunmaz, aksine çok kisa bir kalicilik süresine sahip olup, en fazla 2 gün içerisinde vücutta bulunan enzimler araciligi ile biyolojik olarak parçalanarak atilirlar. Bu nedenle dokuda kalici büyütmeye katkida bulunmaz.[7] Yani EP3218023B1 sayili patentte kullanilan CMC dermal dolgunun performansina katki saglamaz ve kisa süre içerisinde vücut tarafindan biyolojik olarak parçalanarak uzaklasir. Sadece uygulamayi yapan kisinin enjeksiyonu daha Bulusun Kisa Açiklamasi Bulusun amaci sentetik dermal dolgu malzemesi olarak kullanilan karboksimetil selüloz (CMC) ile hiyalüronik asit (HA) polimerlerini 1,4-bütandiol diglisidil eter (BDDE) çapraz baglama ajanini kullanarak birbirlerine baglanmasi ile hibrit hidrojel (hibrojel) (100) elde edilmesidir. European patent application no. EP3218023B1 from applications known in the art cross-linked hyaluronic acid (HA) and carboxymethyl cellulose (CMC) and optionally, microparticles such as calcium hydroxyapatite (CaHAP) microparticles injectable dermal filler in the form of a gel containing particles related to their composition. CMC is the extrusion facilitating agent in this patent. is used as Dermal filler composition in patent EP3218023B1 Contains HA and CMC. Only in these formulations CMC only extrusion It has been added to the formulation to make it easier. To facilitate extrusion If the auxiliary agents used are not included in the formulation, the cross-linked gel Even if the particles are very small in size, they are very difficult to inject. This is your challenge To overcome this, some dermal filler manufacturers Uncrosslinked as lubricant to facilitate extrusion It adds biocompatible polymers such as CMC and HA, thus making it suitable for injection. facilitates the required force. These non-crosslinked polymers, dermal filler does not contribute to the permanence feature of the substance, on the contrary, it has a very short permanence. It has a duration of time, and it is processed by enzymes in the body within a maximum of 2 days. are biodegradable. Therefore, it contributes to the permanent growth of the tissue. [7] In other words, the CMC dermal filler used in the patent number EP3218023B1 does not contribute to the performance of the body and in a short time biological disintegrates away. Only the injection of the person making the application is more Brief Description of the Invention The aim of the invention is to use carboxymethyl as a synthetic dermal filler. cellulose (CMC) and hyaluronic acid (HA) polymers 1,4-butanediol diglycidyl ether Hybrid by bonding to each other using cross-linking agent (BDDE) hydrogel (hybrogel) (100) is obtained.
Bulusun diger amaci, biyolojik olarak çok iyi bir biyouyumluluk, yüksek kalicilik ve su tutma, immünojenik olmama ve vücut tarafindan güvenli emilim gibi avantajlar saglayan hibrojeller (100) üretilmesidir. Another object of the invention is a very good biocompatibility, high permanence biologically. and water retention, non-immunogenicity, and safe absorption by the body. production of hybrid gels (100), which provides advantages.
Bulusun bir diger amaci, geleneksel olarak üretilen çapraz bagli HA dermal dolgulara göre reolojik özellik bakimindan daha çok gelismis hibrojel (100) üretilmesidir. Another object of the invention is the conventionally produced cross-linked HA dermal more advanced hybrid gel in terms of rheological properties than fillings (100) is to be produced.
Bulusun bir diger amaci, uygulama sirasinda agriyi azaltmak amaciyla anestezik etkiye sahip olan lidokain hidroklorür ile formülüze edilen hidrojeller üretilmesidir. Another aim of the invention is to use anesthetics to reduce pain during administration. production of hydrogels formulated with lidocaine hydrochloride.
Bulusun Ayrintili Açiklamasi Bu bulusun amacina ulasmak için gerçeklestirilen “Dermal dolgu olarak kullanilan bir hibrit hidrojel ve bunun üretim yöntemi” ekli sekillerde gösterilmis olup; bu sekillerden: Sekil 1 - Hiyaluronik Asit (HA) ve karboksimetil selüloz (CMC) arasindaki çapraz baglanma reaksiyonunun sematik gösterimidir. Detailed Description of the Invention In order to reach the aim of this invention, "As a dermal filler" A hybrid hydrogel used and its production method” are given in the attached figures. has been shown; of these sequences: Figure 1 - Between Hyaluronic Acid (HA) and carboxymethyl cellulose (CMC) It is a schematic representation of the cross-linking reaction.
Bulus, dermal dolgu olarak kullanilmasi amaciyla gelistirilen çapraz bagli karboksimetil selüloz ve hiyaluronik asit hibrit hidrojel (hibrojel) (100) üretimi yöntemi olup, - Hiyaluronik asit (HA) ve karboksimetil selüloz (CMC) solüsyonlarinin hazirlanmasi, o Deiyonize su içerisinde %1”lik NaOH çözeltisi hazirlanmasi ve bu çözeltinin üzerine yavas yavas hiyaluronik asit (HA) eklenerek çözülmesi ile hiyaluronik asit (HA) çözeltisinin hazirlanmasi, o Deiyonize su içerisinde %1*lik NaOH çözeltisi hazirlanmasi ve bu çözeltinin üzerine yavas yavas karboksimetil selüloz (CMC) eklenerek çözülmesi ile karboksimetil selüloz (CMC) çözeltisinin hazirlanmasi, Hazirlanan hiyaluronik asit (HA) ve karboksimetil selüloz (CMC) çözeltilerinin in-situ olarak çapraz baglama ajani ile çapraz baglanmasi için, 1,4-bütandiol diglisidil eter (BDDE) çapraz baglama aj aninin çözeltilerin üzerine eklenerek homojen bir sekilde karistirilmasi, Karisimin 40 oC'de 4 saat boyunca su banyosu içerisinde çapraz baglanma reaksiyonuna birakilmasi, Reaksiyon sonrasinda jelin oda sicakligina gelene kadar sogutulmasi, Fosfat tampon çözeltisi (PBS) içerisinde pH: 6,8-7,4 olana kadar 01 M hidroklorik asit (HCl) ile nötralize edilmesi (bu isleme pH sabit olana kadar devam edilmesi), Karisimin 5 saat sonra elek yardimiyla süzülmesi ve yeni PBS çözeltisi ilave edilerek jelin 10 saat boyunca daha da sismesinin saglanmasi, Sisen jelin ardi ardina yeni PBS çözeltisi ile 8-10 defa yikanmasi, Sonrasinda jelin 500 mikronluk parçacik boyutlarina gelecek sekilde parçalanmasi, Nihai karisima, ekstrüzyonu kolaylastirmak için çapraz bagli olmayan hiyaluronik asit (HA) ve anestezik etki saglanmasi için lidokain HC] eklenmesi, Nihai karisimin pH degeri 7°ye ayarlanmasi ve vakum altinda 1 mlilik siringalara dolumu yapilmasi, Dolumu yapilan siringalara buhar sterilizasyonu isleminin gerçeklestirilmesi Nihai ürün olan hibrojelin (100) elde edilmesi adimlarindan olusmaktadir. The invention is a cross-linked dermal filler developed for use as a dermal filler. production of carboxymethyl cellulose and hyaluronic acid hybrid hydrogel (hybrogel) (100) is the method, - Solutions of hyaluronic acid (HA) and carboxymethyl cellulose (CMC) preparation, o Preparation of 1% NaOH solution in deionized water and by slowly adding hyaluronic acid (HA) to the solution Preparation of hyaluronic acid (HA) solution by dissolving o Preparation of 1% NaOH solution in deionized water and slowly over the solution of carboxymethyl cellulose (CMC). by adding and dissolving the carboxymethyl cellulose (CMC) solution preparation, Prepared hyaluronic acid (HA) and carboxymethyl cellulose (CMC) crossover of solutions in-situ 1,4-butanediol diglycidyl ether for crosslinking with the binding agent (BDDE) cross-linking agent is added onto the solutions to form a homogeneous mixing in a way, Cross-linking of the mixture in a water bath for 4 hours at 40 °C. left to the reaction, After the reaction, cooling the gel until it reaches room temperature, 01 M until pH: 6.8-7.4 in phosphate buffer solution (PBS) neutralization with hydrochloric acid (HCl) (this is done until the pH is stable). continue) After 5 hours, the mixture is filtered through a sieve and new PBS solution is added. allowing the gel to swell further for 10 hours, Washing the swollen gel consecutively with new PBS solution 8-10 times, Afterwards, the gel will be shaped into 500 micron particle sizes. fragmentation, The final mix is non-cross-linked to facilitate extrusion. hyaluronic acid (HA) and lidocaine HC for anesthetic effect] adding, Adjusting the pH value of the final mixture to 7° and making it 1 ml under vacuum. filling the syringes, Steam sterilization process for filled syringes realization It consists of the steps of obtaining the final product, the hydrogel (100).
Günümüzde en çok tercih edilen dermal dolgular hiyaluronik asit (HA) içeren formülasyonlardir. Hiyaluronik asit (HA), yüksek biyouyumluluk ve su tutma etkisi, biyobozunur olmasi, imunojenite riskinin düsük olmasi ve insan vücudunda da dogal olarak bulunmasi gibi pek çok avantajlari bulunmaktadir. Fakat kalicilik özellikleri PMMA (Polimetil metakrilat) ve PLA (Polilaktik Asit) gibi sentetik dolgu maddelerine göre daha düsüktür. Bu sebeple bulus kapsaminda, sentetik dermal dolgu malzemesi olarak kullanilan karboksimetil selüloz (CMC) ile hiyaluronik asit (HA) polimerlerini çapraz baglama aj anini kullanarak birbirlerine baglayip hibrit hidrojel (hibrojel) (100) elde edilmesi saglanmaktadir. Today, the most preferred dermal fillers contain hyaluronic acid (HA). are formulations. Hyaluronic acid (HA), high biocompatibility and water retention effect, biodegradability, low risk of immunogenicity and It also has many advantages such as being naturally found. But quality Synthetic properties such as PMMA (Polymethyl methacrylate) and PLA (Polylactic Acid) lower than fillers. Therefore, within the scope of the invention, synthetic with carboxymethyl cellulose (CMC) used as a dermal filler. cross-link hyaluronic acid (HA) polymers Using the bonding agent, a hybrid hydrogel (hybrogel) (100) is obtained by bonding them to each other. is provided.
Karboksimetil selüloz (CMC) ideal bir dolgu maddesinin özellikleri olan, kirisikliklari azaltmada, dokulara yerlestirilmesinin kolay ve güvenli olmasi, uzun bir etki süresine sahip olmasi, biyouyumlu ve biyobozunur olmasi ve agrili veya hacimli bir doku tepkisini tetiklememesi gibi özelliklere sahip olmasindan dolayi kullanimi pek çok avantaj saglamaktadir. Karboksimetil selüloz (CMC)`un hayvansal ve bakteriyel kaynaktan üretilmemesi ona pek çok avantaj saglamaktadir. Carboxymethyl cellulose (CMC) has the characteristics of an ideal filler, It is easy and safe to place in tissues, reducing wrinkles, long have a duration of action, be biocompatible and biodegradable, and be painful or because it does not trigger a voluminous tissue response. Its use provides many advantages. Carboxymethyl cellulose (CMC) The fact that it is not produced from animal and bacterial sources gives it many advantages.
Bu karakteristigi onun alerjik reaksiyonlar gösterme riskini ortadan kaldinnaktadir. This characteristic eliminates the risk of allergic reactions.
Ayrica antibakteriyel özelliklere sahip olan karboksimetil selüloz (CMC) ticari olarak kullanilmasina ragmen, günümüze kadar herhangi bir enfeksiyon vakasi görülmemistir. Karboksimetil selüloz (CMC) dermal dolgular alt yüzdeki yaslanma belirtilerinin düzeltilmesinde çok yüksek bir memnuniyet orani ve güvenli profil sunmaktadir. Bu nedenle, çapraz bagli karboksimetil selüloz (CMC) dolgusu, klinik uygulamalarda kullanilmak üzere gelecek vaat eden bir ürün olmaktadir. In addition, carboxymethyl cellulose (CMC), which has antibacterial properties, is commercially available. To date, no case of infection has been reported. not seen. Carboxymethyl cellulose (CMC) dermal fillers a very high satisfaction rate and a safe profile in the correction of symptoms offers. Therefore, cross-linked carboxymethyl cellulose (CMC) filler, It is a promising product for use in clinical applications.
Hiyaluronik asit (HA) ve karboksimetil selüloz (CMC) farkli oranlarda in-situ olarak çapraz baglayici ile çapraz baglanarak üretilen hibrit hidrojel (hibrojel) (100) ilk defa bulus kapsaminda gerçeklestirilmektedir (Sekil 1). Hiyaluronik asit (HA) ve karboksimetil selüloz (CMC) polimerleri birbirlerine çapraz baglayici ile baglanarak bir ag yapisi olustururlar ve su varliginda siserek jel formunu olustururlar. Bulus kapsaminda kullanilan karboksimetil selüloz (CMC) ekstrüzyonu kolaylastirmasi amaciyla degil, ana matrikste hiyaluronik asit (HA) ile birlikte çapraz bagli bir yapi olusturmak için kullanilmaktadir. Bulus kapsaminda yer alan karboksimetil selüloz (CMC) serbest özellikte degil, tamamiyla aktif rolü oynayan çapraz bagli forma gelerek bambaska bir yapiya dönüsmektedir. Bu yöntemle, yeni bir dermal dolgu malzemesi olarak hibrit hidrojeller (hibrojeller) (100) elde edilmektedir. Burada kullanilan “hibrit hidrojel” terimi “hibrojel” (100) olarak adlandirilmistir. Yani hibrojel (100) diye bahsedilecek terimler çapraz bagli hiyaluronik asit (HA) ve karboksimetil selüloz (CMC)'dan olusan dermal dolguya verilen isimdir. Üretilen hibrojel (100) geleneksel olarak üretilen çapraz bagli hiyaluronik asit (HA) dermal dolgulara göre reolojik özellik bakimindan daha çok gelismistir. Hyaluronic acid (HA) and carboxymethyl cellulose (CMC) in different proportions in-situ by cross-linking with a cross-linker The hybrid hydrogel (hybrogel) (100) produced for the first time is within the scope of the invention. performed (Figure 1). Hyaluronic acid (HA) and carboxymethyl cellulose (CMC) polymers are linked to each other by crosslinking to form a network structure. They form and swell in the presence of water to form a gel form. within the scope of the invention Carboxymethyl cellulose (CMC) used to facilitate extrusion but a cross-linked structure with hyaluronic acid (HA) in the main matrix. used to create. Carboxymethyl cellulose within the scope of the invention (CMC) is not a freestyle, but a cross-linked jersey that plays a fully active role. it turns into a completely different structure. With this method, a new dermal filler Hybrid hydrogels (hybrogels) (100) are obtained as material. Here The term “hybrid hydrogel” used was named “hybrogel” (100). well Terms to be referred to as hybrid (100) are cross-linked hyaluronic acid (HA) and It is the name given to the dermal filler consisting of carboxymethyl cellulose (CMC). The produced hybrid (100) is traditionally produced cross-linked hyaluronic acid (HA). It is more developed in terms of rheological properties compared to dermal fillers.
Dahiyaluronik asit (HA) kalici dermal dolgu için hiyaluronik asit (HA) jeller yüksek çapraz baglanma reaksiyonuna maruz birakilmaktadir. Bu durum hiyaluronik asit (HA) jellerin biyouyumlulugunu azaltarak, yabanci cisim olarak algilanmasini saglar. Üretilen hibrojel (100) ile bu riskler ortadan kaldirilmaktadir. Hyaluronic acid (HA) gels for permanent dermal fillers exposed to high cross-linking reaction. This situation by reducing the biocompatibility of hyaluronic acid (HA) gels, allows it to be perceived. These risks are eliminated with the produced hybrid gel (100).
Ayrica, hibrojeller (100) uygulama sirasinda agriyi azaltmak amaciyla anestezik etkiye sahip olan lidokain hidroklorür ile formülüze edilmektedir. Üretilen hibrojel (100), ideal dermal dolgu maddesi olarak kullanim için arzu edilen fiziksel ve reolojik özelliklere sahip olup, biyolojik olarak çok iyi bir biyouyumluluk, yüksek kalicilik ve su tutma, immünojenik olmama ve vücut tarafindan güvenli emilim gibi avantajlar saglamaktadir. Çapraz bagli hiyaluronik asit (HA) ve karboksimetil selüloz (CMC) hibrojel (100) geleneksel olarak üretilen ayni derisimdeki çapraz bagli hiyaluronik asit (HA) dermal dolgulara göre yüksek hiyaluronik asit (HA)cimlendirme potansiyeline ve yüksek elastiklik modülüne (G') sahiptir. Elde edilen hibrojel (100) düsük ekstrüzyon kuvvetine sahip olup uygulama kolayligi ve ayrica, hiyaluronik asit (HA)°nin yüksek maliyetlerinden dolayi formülasyonda kullanilan diger aktif bilesen karboksimetil selüloz (CMC), üretim maliyetlerinin azaltilmasi saglanmaktadir. In addition, the hydrogels (100) are anesthetic to reduce pain during administration. It is formulated with lidocaine hydrochloride. Produced hybrid gel (100), the desired physical and chemical properties for use as an ideal dermal filler. It has rheological properties, has very good biological biocompatibility, high such as persistence and water retention, non-immunogenicity and safe absorption by the body. provides advantages. Cross-linked hyaluronic acid (HA) and carboxymethyl cellulose (CMC) hybrid gel (100) traditionally produced in the same skin cross Hyaluronic acid (HA) is higher than dermal fillers. It has (HA) sprouting potential and high modulus of elasticity (G'). in hand The hybrid gel (100) produced has low extrusion strength and is easy to apply and In addition, due to the high costs of hyaluronic acid (HA) The other active ingredient used is carboxymethyl cellulose (CMC), production costs. reduction is provided.
Deneysel Çalismalar Hiyaluronik asit (HA) ve karboksimetil selüloz (CMC)”un farkli oranlarda hazirlanarak in-situ olarak çapraz baglama ajani ile çapraz baglanarak hibrojel (100) elde edilmesine ait prosedürler asagida belirtilmistir. Örnek 1 sadece çapraz bagli hiyaluronik asit (HA) jel (Kontrol 1) ve ekstrüzyonu kolaylastirmak için çapraz bagli olmayan hiyaluronik asit (HA), Örnek 2 sadece karboksimetil selüloz (CMC) içeren çapraz bagli `jel (Kontrol 2) ve ekstrüzyonu kolaylastirmak için çapraz bagli olmayan hiyaluronik asit (HA), Örnek 3 yüzde olarak çapraz bagli jel ve ekstrüzyonu kolaylastirmak için çapraz bagli olmayan hiyaluronik asit (HA), Örnek 4 yüzde olarak 50/50 oraninda hiyaluronik asit (HA)/ karboksimetil selüloz (CMC) çapraz bagli jel ve ekstrüzyonu kolaylastirmak için çapraz bagli olmayan hiyaluronik asit (HA), Örnek 5 yüzde olarak 25/75 oraninda hiyaluronik asit (HA)/ karboksimetil selüloz (CMC) çapraz bagli jel ve ekstrüzyonu kolaylastirmak için çapraz bagli olmayan hiyaluronik asit (HA) içermektedir. Tüm formülasyonlarin toplam aktif bilesen konsantrasyonu ise 20 mg/ml”dir. Bu konsantrasyonun 15 mg/ml`si çapraz bagli jellere, 5 mg/mfsi ise ekstrüzyonu kolaylastirmak için çapraz baglama reaksiyonundan sonra elde edilen jelin üzerine eklenen çapraz bagli olmayan hiyaluronik asit (HA)”ya aittir. Ayrica tüm formülasyonlar 2-3 mg/ml konsantrasyonunda anestezik ajan olan lidokain HCl içermektedir. Experimental Studies Different ratios of hyaluronic acid (HA) and carboxymethyl cellulose (CMC) cross-linking in-situ by preparation The procedures for obtaining hybrid gel (100) by cross-linking with the agent are given below. specified. Example 1 only cross-linked hyaluronic acid (HA) gel (Control 1) and non-cross-linked hyaluronic acid (HA) to facilitate extrusion, Example 2 cross-linked `gel (Control 2) containing only carboxymethyl cellulose (CMC) and non-cross-linked hyaluronic acid (HA) to facilitate extrusion, Example as 3 percent cross-linked gel and non-cross-linked to facilitate extrusion hyaluronic acid (HA), Example 4 50/50 percent hyaluronic acid (HA)/ carboxymethyl cellulose (CMC) to facilitate cross-linked gel and extrusion non-cross-linked hyaluronic acid (HA), Example 5 25/75 percent hyaluronic acid (HA)/ carboxymethyl cellulose (CMC) cross-linked gel and extrusion Contains non-cross-linked hyaluronic acid (HA) to facilitate All The total active ingredient concentration of the formulations is 20 mg/ml. This 15 mg/ml of the concentration is applied to cross-linked gels, and 5 mg/mf is extrusion. on the gel obtained after the cross-linking reaction to facilitate It belongs to the added non-cross-linked hyaluronic acid (HA). Also all formulations lidocaine HCl, anesthetic agent at a concentration of 2-3 mg/ml contains.
Tüm formülasyonlarda çapraz bagli jel konsantrasyonunun, kolay ekstrüzyonu saglamasi için eklenen çapraz bagli olmayan hiyaluronik asit (HA)”n1n konsantrasyonuna orani yüzde olarak 75:25 olarak belirlenmistir. Karsilastirma yapabilmek adina Örnek 1”de sadece hiyaluronik asit (HA) içeren çapraz bagli jel (Kontrol 1) ve Örnek 2”de ise sadece karboksimetil selüloz (CMC) içeren çapraz bagli jel (Kontrol 2) üretimi gösterilmistir. Easy extrusion of cross-linked gel concentration in all formulations non-cross-linked hyaluronic acid (HA) added to provide The ratio to the concentration was determined as 75:25 percent. To compare In Example 1, cross-linked gel containing only hyaluronic acid (HA) In (Control 1) and Example 2, cross-links containing only carboxymethyl cellulose (CMC) The production of bound gel (Control 2) is shown.
Anestezik Ajan içeren Çapraz Bagli hiyaluronik asit (HA) Dermal Dolgu Sentezi (Kontrol 1) Formülasyon Tablo l,deki oranlar çerçevesinde hazirlanmis olup, jel hazirlanis prosedürü asagidaki gibidir. Cross-linked hyaluronic acid (HA) Dermal Filler Synthesis with Anesthetic Agent (Control 1) The formulation was prepared within the framework of the ratios in Table 1, and the gel was prepared. procedure is as below.
Etken ve Yardimci Birim Formülü Maddeler (%) Hiyaluronik Asit l ,4-Bütandiol Diglisidil Eter % 0, Deiyonize su % 80-95 1.Deiyonize su içerisinde %1 'lik NaOH çözeltisi hazirlanir. 2.Bu çözeltinin üzerine yavas yavas hiyaluronik asit (HA) eklenerek çözülmesi saglanir. karisimina eklenerek homojen bir sekilde karismasi saglanir. 4.Karisim, 40 °C'de 4 saat boyunca su banyosu içerisinde çapraz baglanma reaksiyonuna birakilir. Active and Auxiliary Unit Formula Substances (%) Hyaluronic Acid l ,4-Butanediol Diglycidyl Ether 0%, Deionized water 80-95% 1. Prepare 1% NaOH solution in deionized water. 2. Dissolving by slowly adding hyaluronic acid (HA) to this solution is provided. adding to the mix homogeneous mixing is ensured. 4. Mixture, crosslinking in water bath for 4 hours at 40 °C left to the reaction.
. Reaksiyon sonrasi jel oda sicakligina kadar gelene kadar sogutulur ve fosfat tampon çözeltisi (PBS) içerisinde pH: 6,8-7,4 olana kadar 0.1 M hidroklorik asit (HCl) ile nötralize edilir. Bu isleme pH sabit olana kadar devam edilir. 6. Karisim 5 saat sonra elek yardimiyla süzülür ve yeni PBS çözeltisi ilave edilerek jelin 10 saat boyunca daha sismesi saglanir. 7. Sisen jel ardi ardina yeni PBS çözeltisiyle ile 8-10 defa daha yikama yapilip, 8. Sonra jel 500 mikronluk parçacik boyutlarina getirilir. 9. Çapraz bagli olmayan hiyaluronik asit (HA) ekstrüzyonu kolaylastirmak için, lidokain HCl ise anestezik etki saglamasi için son nihai karisima eklenir. . After the reaction, the gel is cooled to room temperature and the phosphate 0.1 M hydrochloric acid until pH: 6.8-7.4 in buffer solution (PBS) It is neutralized with (HCl). This process is continued until the pH is constant. 6. After 5 hours, the mixture is filtered through a sieve and new PBS solution is added. The gel is allowed to swell for another 10 hours. 7. Washing the bottled gel with new PBS solution one after another 8-10 times, 8. Next, the gel is brought to a particle size of 500 microns. 9. Non-crosslinked hyaluronic acid (HA) to facilitate extrusion, lidocaine HCl is added to the final final mixture to provide anesthetic effect.
. Nihai karisimin pH”si Tye ayarlanir ve vakum altinda 1 ml”lik siringalara dolumu yapilir. 1 l. Dolumu yapilan siringalara buhar sterilizasyonu islemi gerçeklestirilir. . The pH of the final mixture is adjusted to T and poured into 1 ml syringes under vacuum. filling is done. 1 liter Steam sterilization is performed on the filled syringes.
Anestezik Ajan içeren Çapraz, Bagli karboksimetil selüloz (CMC) Dermal Dolgu Sentezi (Kontrol 2) Formülasyon Tablo 2'deki oranlar çerçevesinde hazirlanmis olup, jel hazirlanis prosedürü asagidaki gibidir. Cross-Linked Carboxymethyl Cellulose (CMC) Dermal Filler with Anesthetic Agent Synthesis (Control 2) The formulation was prepared according to the ratios in Table 2, and the gel was prepared. procedure is as below.
Etken ve Yardimci Birim Formülü Maddeler (%) Karboksimetil Selüloz (CMC) % 7-17 1,4-Bütandiol Diglisidil Eter % 0, Deiyonize su % 80-95 1.Deiyonize su içerisinde %1 'lik NaOH çözeltisi hazirlanir. 2.Bu çözeltinin üzerine yavas yavas karboksimetil selüloz (CMC) eklenerek çözülmesi saglanir. karisimina eklenerek homojen bir sekilde karismasi saglanir. 4.Karisim, 40 °C'de 4 saat boyunca su banyosu içerisinde çapraz baglanma reaksiyonuna birakilir. Active and Auxiliary Unit Formula Substances (%) Carboxymethyl Cellulose (CMC) 7-17% 1,4-Butanediol Diglycidyl Ether 0%, Deionized water 80-95% 1. Prepare 1% NaOH solution in deionized water. 2. Add carboxymethyl cellulose (CMC) slowly to this solution. solution is achieved. to your mix added to ensure homogeneous mixing. 4. Mixture, crosslinking in water bath for 4 hours at 40 °C left to the reaction.
. Reaksiyon sonrasi jel oda sicakligina kadar gelene kadar sogutulur ve fosfat tampon çözeltisi (PBS) içerisinde pH: 6,8-7,4 olana kadar 0.1 M hidroklorik asit (HCl) ile nötralize edilir. Bu isleme pH sabit olana kadar devam edilir. 6. Karisim 5 saat sonra elek yardimiyla süzülür ve yeni PBS çözeltisi ilave edilerek jelin 10 saat boyunca daha sismesi saglanir. 7. Sisen jel ardi ardina yeni PBS çözeltisiyle ile 8-10 defa daha yikama yapilip. 8. Sonra jel 500 mikronluk parçacik boyutlarina getirilir. 9. Çapraz bagli olmayan hiyaluronik asit (HA) ekstrüzyonu kolaylastirmak için, lidokain HCl ise anestezik etki saglamasi için son nihai karisima eklenir. . After the reaction, the gel is cooled to room temperature and the phosphate 0.1 M hydrochloric acid until pH: 6.8-7.4 in buffer solution (PBS) It is neutralized with (HCl). This process is continued until the pH is constant. 6. After 5 hours, the mixture is filtered through a sieve and new PBS solution is added. The gel is allowed to swell for another 10 hours. 7. Wash the bottled gel one after another 8-10 times with fresh PBS solution. 8. Next, the gel is brought to a particle size of 500 microns. 9. Non-crosslinked hyaluronic acid (HA) to facilitate extrusion, lidocaine HCl is added to the final final mixture to provide anesthetic effect.
. Nihai karisimin pHisi Tye ayarlanir ve vakum altinda 1 ml°lik siringalara dolumu yapilir. 11. Dolumu yapilan siringalara buhar sterilizasyonu islemi gerçeklestirilir. Örnek 3 (Hibrojel (100)-A) Anestezik Ajan içeren Çapraz Bagli Hiyalamnik Asit (HA) ve karboksimetil selüloz, (CMC) Hibrojel (100) Dermal Dalga Sentezi (HiyalamnikAsir (HA)/Karb0ksimetil Selüloz (CMC): 75/25) Formülasyon Tablo Siteki oranlar çerçevesinde hazirlanmis olup, jel hazirlanis prosedürü asagidaki gibidir. . The pH of the final mixture is adjusted to T and poured into 1 ml syringes under vacuum. filling is done. 11. Steam sterilization is performed on the filled syringes. Example 3 (Hybrogel (100)-A) Cross-linked Hyalamnic Acid (HA) and carboxymethyl cellulose containing Anesthetic Agent, (CMC) Hybrogel (100) Dermal Wave Synthesis (HyalamnicAsir (HA)/Carboxymethyl Cellulose (CMC): 75/25) Formulation Table is prepared within the framework of the rates on the site, gel is prepared. procedure is as below.
Etken ve Yardimci Birim Formülü Maddeler (%) Hiyaluronik Asit Karboksimetil Selüloz (CMC) 1 ,4-bütandiol diglisidil eter % 0, Deiyonize su % 80-95 1.Deiyonize su içerisinde % 1 ,lik NaOH çözeltisi hazirlanir. 2.Bu çözeltinin üzerine yavas yavas Hiyaluronik Asit (HA) ve Karboksimetil Selüloz (CMC) eklenerek çözülmesi saglanir. Active and Auxiliary Unit Formula Substances (%) Hyaluronic Acid Carboxymethyl Cellulose (CMC) 1,4-butanediol diglycidyl ether 0%, Deionized water 80-95% 1. Prepare a 1% NaOH solution in deionized water. 2. Slowly add Hyaluronic Acid (HA) and Carboxymethyl to this solution. It is dissolved by adding cellulose (CMC).
- Karboksimetil Selüloz (CMC) karisimina eklenerek homojen bir sekilde karismasi saglanir. 4.Karisim, 40 DC'de 4 saat boyunca su banyosu içerisinde çapraz baglanma reaksiyonuna birakilir. - Carboxymethyl It is added to the cellulose (CMC) mixture to ensure homogeneous mixing. 4. Mixture, cross-linking in water bath for 4 hours at 40 DC left to the reaction.
. Reaksiyon sonrasi jel oda sicakligina kadar gelene kadar sogutulur ve fosfat tampon çözeltisi (PBS) içerisinde pH: 6,8-7,4 olana kadar 0.1 M hidroklorik asit (HCl) ile nötralize edilir. Bu isleme pH sabit olana kadar devam edilir. 6. Karisim 5 saat sonra elek yardimiyla süzülür ve yeni PBS çözeltisi ilave edilerek jelin 10 saat boyunca daha sismesi saglanir. 7. Sisen jel ardi ardina yeni PBS çözeltisiyle ile 8-10 defa daha yikama yapilip, 8. Sonra jel 500 mikronluk parçacik boyutlarina getirilir. 9. Çapraz bagli olmayan hiyaluronik asit (HA) ekstrüzyonu kolaylastirmak için, lidokain HCl ise anestezik etki saglamasi için son nihai karisima eklenir. . After the reaction, the gel is cooled to room temperature and the phosphate 0.1 M hydrochloric acid until pH: 6.8-7.4 in buffer solution (PBS) It is neutralized with (HCl). This process is continued until the pH is constant. 6. After 5 hours, the mixture is filtered through a sieve and new PBS solution is added. The gel is allowed to swell for another 10 hours. 7. Washing the bottled gel with new PBS solution one after another 8-10 times, 8. Next, the gel is brought to a particle size of 500 microns. 9. Non-crosslinked hyaluronic acid (HA) to facilitate extrusion, lidocaine HCl is added to the final final mixture to provide anesthetic effect.
. Nihai karisimin pH”si 7°ye ayarlanir ve vakum altinda 1 m1”lik siringalara dolumu yapilir. 11. Dolumu yapilan siringalara buhar sterilizasyonu islemi gerçeklestirilir. Örnek 4 (Hibrojel (100)-13) Anestezik Ajan içeren Çapraz Bagli Hiyaluronik Asit (HA ) ve karboksimetil selüloz ( CM C) Hibrojel (100) Dermal Dolgu Sentezi (Hiyaluronik Asit (HA )/Karb0ksimeril Selüloz (CMC): 50/50) Formülasyon Tablo 47teki oranlar çerçevesinde hazirlanmis olup, jel hazirlanis prosedürü asagidaki gibidir. . The pH of the final mixture is adjusted to 7° and poured into 1 m1 syringes under vacuum. filling is done. 11. Steam sterilization is performed on the filled syringes. Example 4 (Hybrogel (100)-13) Cross-linked Hyaluronic Acid (HA) and carboxymethyl cellulose with Anesthetic Agent ( CM C) Hybrogel (100) Dermal Filler Synthesis (Hyaluronic Acid (HA)/Carboxymeryl Cellulose (CMC): 50/50) The formulation was prepared within the framework of the ratios in Table 47, and the gel was prepared. procedure is as below.
Etken ve Yardimci Birim Formülü Maddeler (%) Hiyaluronik Asit Karboksimetil Selüloz (CMC) 1,4-bütandiol diglisidil eter % 0, Deiyonize su % 80-95 1.Deiyonize su içerisinde %1 ,lik NaOH çözeltisi hazirlanir. 2.Bu çözeltinin üzerine yavas yavas hiyaluronik asit (HA) ve karboksimetil selüloz (CMC) eklenerek çözülmesi saglanir. -karboksimetil selüloz (CMC) karisimina eklenerek homojen bir sekilde karismasi saglanir. 4.Karisim, 40 OC'de 4 saat boyunca su banyosu içerisinde çapraz baglanma reaksiyonuna birakilir. Active and Auxiliary Unit Formula Substances (%) Hyaluronic Acid Carboxymethyl Cellulose (CMC) 1,4-butanediol diglycidyl ether 0%, Deionized water 80-95% 1. Prepare a 1% NaOH solution in deionized water. 2. Slowly add hyaluronic acid (HA) and carboxymethyl cellulose to this solution. (CMC) is added to dissolve it. -carboxymethyl It is added to the cellulose (CMC) mixture and it is mixed homogeneously. 4.The mixture did not cross-link in a water bath at 40°C for 4 hours. left to the reaction.
. Reaksiyon sonrasi jel oda sicakligina kadar gelene kadar sogutulur ve fosfat tampon çözeltisi (PBS) içerisinde pH: 6,8-7,4 olana kadar 0.1 M hidroklorik asit (HCl) ile nötralize edilir. Bu isleme pH sabit olana kadar devam edilir. 6. Karisim 5 saat sonra elek yardimiyla süzülür ve yeni PBS çözeltisi ilave edilerek jelin 10 saat boyunca daha sismesi saglanir. 7. Sisen jel ardi ardina yeni PBS çözeltisiyle ile 8-10 defa daha yikama yapilip, 8. Sonrajel 500 mikronluk parçacik boyutlarina getirilir. 9. Çapraz bagli olmayan hiyaluronik asit (HA) ekstrüzyonu kolaylastirmak için, lidokain HCl ise anestezik etki saglamasi için son nihai karisima eklenir. . After the reaction, the gel is cooled to room temperature and the phosphate 0.1 M hydrochloric acid until pH: 6.8-7.4 in buffer solution (PBS) It is neutralized with (HCl). This process is continued until the pH is constant. 6. After 5 hours, the mixture is filtered through a sieve and new PBS solution is added. The gel is allowed to swell for another 10 hours. 7. Washing the bottled gel with new PBS solution one after another 8-10 times, 8. Next, the gel is brought to a particle size of 500 microns. 9. Non-crosslinked hyaluronic acid (HA) to facilitate extrusion, lidocaine HCl is added to the final final mixture to provide anesthetic effect.
. Nihai karisimin pH*si Tye ayarlanir ve vakum altinda 1 ml”lik siringalara dolumu yapilir. 1 1. Dolumu yapilan siringalara buhar sterilizasyonu islemi gerçeklestirilir. Örnek 5 (Hibrojel (100)-C) Anestezik Ajan içeren Çapraz Bagli Hiyaluronik Asit (HA) ve karboksimetil selülaz (CMC) Hibrojel (100) Dermal Dolgu Sentezi (Hiyaluronik Asit (HA)/karb0ksimeril selüloz (CMC): 25/75) Formülasyon Tablo 5'deki oranlar çerçevesinde hazirlanmis olup, jel hazirlamis prosedürü asagidaki gibidir. . The pH of the final mixture is adjusted to T and poured into 1 ml syringes under vacuum. filling is done. 1 1. Steam sterilization is performed on the filled syringes. Example 5 (Hybrogel (100)-C) Cross-linked Hyaluronic Acid (HA) with Anesthetic Agent and carboxymethyl cellulase (CMC) Hybrogel (100) Dermal Filler Synthesis (Hyaluronic Acid (HA)/carboxymeryl cellulose (CMC): 25/75) The formulation was prepared in accordance with the ratios in Table 5 and gel was prepared. procedure is as below.
Etken ve Yardimci Birim Formülü Maddeler (%) Hiyaluronik Asit Karboksimetil Selüloz (CMC) 1 ,4-bütandiol diglisidil eter % 0, Deiyonize su % 80-95 1.Deiyonize su içerisinde %'1'1ik NaOH çözeltisi hazirlanir. 2.Bu çözeltinin üzerine yavas yavas hiyaluronik asit (HA) ve karboksimetil selüloz (CMC) eklenerek çözülmesi saglanir. -karb0ksimetil selüloz (CMC) karisimina eklenerek homojen bir sekilde karismasi saglanir. 4.Karisim, 40 °C'de 4 saat boyunca su banyosu içerisinde çapraz baglanma reaksiyonuna birakilir. Active and Auxiliary Unit Formula Substances (%) Hyaluronic Acid Carboxymethyl Cellulose (CMC) 1,4-butanediol diglycidyl ether 0%, Deionized water 80-95% 1. 1% NaOH solution is prepared in deionized water. 2. Slowly add hyaluronic acid (HA) and carboxymethyl cellulose to this solution. (CMC) is added to dissolve it. -carboxymethyl It is added to the cellulose (CMC) mixture and it is mixed homogeneously. 4. Mixture, crosslinking in water bath for 4 hours at 40 °C left to the reaction.
. Reaksiyon sonrasi jel oda sicakligina kadar gelene kadar sogutulur ve fosfat tampon çözeltisi (PBS) içerisinde pH: 6,8-7,4 olana kadar 0.1 M hidroklorik asit (HCl) ile nötralize edilir. Bu isleme pH sabit olana kadar devam edilir. 6. Karisim 5 saat sonra elek yardimiyla süzülür ve yeni PBS çözeltisi ilave edilerek jelin 10 saat boyunca daha sismesi saglanir. 7. Sisen jel ardi ardina yeni PBS çözeltisiyle ile 8-10 defa daha yikama yapilip, 8. Sonra jel 500 mikronluk parçacik boyutlarina getirilir. 9. Çapraz bagli olmayan hiyaluronik asit (HA) ekstrüzyonu kolaylastirmak için, lidokain HC] ise anestezik etki saglamasi için son nihai karisima eklenir. . After the reaction, the gel is cooled to room temperature and the phosphate 0.1 M hydrochloric acid until pH: 6.8-7.4 in buffer solution (PBS) It is neutralized with (HCl). This process is continued until the pH is constant. 6. After 5 hours, the mixture is filtered through a sieve and new PBS solution is added. The gel is allowed to swell for another 10 hours. 7. Washing the bottled gel with new PBS solution one after another 8-10 times, 8. Next, the gel is brought to a particle size of 500 microns. 9. Non-crosslinked hyaluronic acid (HA) to facilitate extrusion, lidocaine HC] is added to the final final mixture to provide anesthetic effect.
. Nihai karisimin pH”si 7°ye ayarlanir ve vakum altinda 1 ml”lik siringalara dolumu yapilir. 11. Dolumu yapilan siringalara buhar sterilizasyonu islemi gerçeklestirilir. . The pH of the final mixture is adjusted to 7° and poured into 1 ml syringes under vacuum. filling is done. 11. Steam sterilization is performed on the filled syringes.
SONUÇLAR Dermal dolgu maddelerinin üretim asamalarinda, içeriklerinde bulunan aktif bilesenlerin akis özelliklerinin incelenmesinde ve maddelerin karistirilmasinda ve dolgunun dokuda kalma süresinin belirlenmesinde, aslinda ürünün tüm özelliklerinin belirlenmesinde reolojik sonuçlar kullanilmaktadir. Dolgu maddelerinin reolojik özellikleri ürünün fiziksel stabilitesine, uygulandiklai'i dokudaki davranislarina ve biyolojik yararlanimina (uygulama sonrasi doku ile uyumlu olmasi ve tamamen metabolize olmasi) etki etmektedir. Hatta dolgu maddesinin dokulara uygulanirken enjektörden geçisi ve seçilecek ignelerin çapi bile reolojik özelliklerine baglidir. RESULTS During the production stages of dermal fillers, the active ingredients in in examining the flow properties of components and mixing substances and In determining the residence time of the filler in the tissue, in fact, the entire product Rheological results are used to determine its properties. Filling The rheological properties of the materials depend on the physical stability of the product. its behavior in the tissue and its biological utilization (with the tissue after application). being compatible and completely metabolized). Even the padding the passage of the substance through the injector while applying to the tissues and the diameter of the needles to be selected It even depends on its rheological properties.
Hiyaluronik asit (HA) gibi pek çok dermal dolgu maddeleri viskoelastik özellik göstermektedir. Viskoelastik maddeler için reolojik olarak tanimlanan en önemli parametre dolgu maddesinin elastikliginin ölçüsü olan G' degerleridir. Bu terim dolgunun elastik özellik ölçüsü yani “Elastik modulus” olarak tanimlanir. Dolguya kuvvet uygulandiginda deforme olmasi ve tekrar eski sekline dönmesi sirasinda dolguda biriken enerjiyi tanimlar. G' ayni zamanda dolgunun sertligi anlamina gelmektedir. Bu da klinik olarak dokuya uygulandiginda derin ve orta kirisikliklarda ne kadar etkili olabilecegini göstermektedir. Ayrica dokuda içsel ve dissal kuvvetler karsisinda ne kadar stabil kalabildigi anlamina da gelmektedir. Many dermal fillers such as hyaluronic acid (HA) have viscoelastic properties. shows. The most important rheologically defined for viscoelastic materials The parameter is the G' values, which is a measure of the elasticity of the filler. this term It is defined as the elastic property measure of the filling, namely “Elastic modulus”. to the fill deforming when force is applied and returning to its original shape defines the energy accumulated in the filling. G' also means the hardness of the filling. is coming. When this is clinically applied to tissue, deep and medium It shows how effective it can be on wrinkles. In addition, intrinsic and It also means how stable it can stay in the face of external forces.
Hazirlanan dermal dolgularin reolojik özellikleri 25 mm'lik çapa sahip olan bir plaka ile 1 mm°lik bosluk yüksekligindeki sartlarda reometre cihazi ile ölçülmü stür. 0.7 Hzideki frekansta gerçeklestirilen ölçümlerin kompleks viskozite (n) ve elastiklik modülü (G') sonuçlari Tablo 63da gösterilmistir. Tüm ölçümler siringalarin ucuna 27 G kanül takilarak gerçeklestirilmistir. The rheological properties of the dermal fillers prepared are a 25 mm diameter It was measured with a rheometer device under conditions with a gap height of 1 mm with a plate. The complex viscosity (n) and The modulus of elasticity (G') results are shown in Table 63. All measurements It was carried out by attaching a 27 G cannula to the tip of the syringes.
Numune G' (Pa) 1] (Pa.s) Kontrol l 285 75 Kontrol 2 985 394 Hibrojel (100)-A 360 125 Hibrojel (100)-B 486 198 Hibrojel (100)-C 752 276 Sonuçlar degerlendirildiginde formülasyonda kullanilan karboksimetil selüloz (CMC) oranin artmasi kompleks viskozite ve elastik modulus sonuçlarini önemli oranda artirmistir. Kontrol 1 olarak adlandirilan ve sadece çapraz bagli hiyaluronik asit (HA) ve serbest hiyaluronik asit (HATden hazirlanan forinülasyon en düsük G' özelliklerini ve dolayisiyla en düsük 11 degerlerini göstermistir. Fakat formülasyonda kullanilan çapraz bagli hiyaluronik asit (HA)”nin yani sira çapraz bagli karboksimetil selüloz (CMC) orani arttikça bu reolojik degerlerin arttigi görülmüstür. Bu durum karboksimetil selüloz (CMC)°un formülasyon üzerinde reolojik karakterleri önemli oranda gelistirdigini göstermektedir. Sample G' (Pa) 1] (Pa.s) Control l 285 75 Control 2 985 394 Hybrogel (100)-A 360 125 Hybrogel (100)-B 486 198 Hybrogel (100)-C 752 276 When the results are evaluated, the carboxymethyl cellulose used in the formulation Increasing the (CMC) ratio significantly affects the complex viscosity and elastic modulus results. rate increased. Only cross-linked hyaluronic acid called Control 1 acid (HA) and free hyaluronic acid (forinulation prepared from HAT lowest G' showed its properties and therefore the lowest 11 values. But cross-linked hyaluronic acid (HA) used in the formulation as well as cross-linked As the ratio of bound carboxymethyl cellulose (CMC) increases, these rheological values increase. has been seen. This is the effect of carboxymethyl cellulose (CMC) on the formulation. shows that it significantly improves the rheological characters.
Artan G' dermal dolgunun kaliciliginin artmasi anlamina gelmektedir. Bu sonuçlar yüksek G' degerinin her zaman en iyi dermal dolgu oldugu anlamina gelmemelidir. Increasing G' means an increase in the permanence of the dermal filler. These results A high G' value should not always mean that it is the best dermal filler.
Farkli kullanim yerlerine göre dermal dolgular farkli reolojik özellik göstermektedir. Örnegin yüzeye yakin olan kirisikliklara çok yüksek G' degerine sahip dermal dolgu Önerilmemektedir. Nispeten daha yumusak olan dolgular yani daha düsük G' degerine sahip dermal dolgular bu bölgelerde tercih edilmektedir. Dermal fillers have different rheological properties according to different usage areas. shows. For example, wrinkles close to the surface may have a very high G' value. dermal fillers are not recommended. Relatively softer fillings Dermal fillers with a lower G' value are preferred in these regions.
Ekstrüzyon kuvveti yani dolgunun kanülden uygulanmasi sirasinda gerekli kuvvet dolgunun viskozitesine baglidir. Ayrica igne ya da kanülün uzunlugu ve iç çapi da önemlidir. Yüksek viskoz dolgular yüksek ekstrüzyon kuvveti gerektirmektedir, yani bunlarin dokulara enjeksiyonu daha zordur. Bu zorluk uygulama sirasinda daha yüksek doku hasari anlamina gelmektedir. The force of extrusion, that is, the force required during the application of the filler through the cannula It depends on the viscosity of the filler. Also the length and inside diameter of the needle or cannula is important. High viscous fillings require high extrusion force, that is, their injection into tissues is more difficult. During this difficulty means higher tissue damage.
Numune F (N) Kontrol l 14 Kontrol 2 41 Hibrojel (100)-A 20 Hibrojel (100)-B 27 Hibrojel (100)-C 34 Tablo 7, ekstrüzyon testlerinin sonuçlarini 12 mm/dk sikistirma oraninda göstermektedir. Tablodan da görülecegi üzere karboksimetil selüloz (CMC) bilesiminin artmasi enjeksiyon kuvveti degerlerinin artmasina sebep olmustur. Çok yüksek karboksimetil selüloz (CMC) ihtiva eden jeller islem sirasinda zorlanmaya yol açabilme riskine sahiptir. Bu sebepten dolayi genellikle 35 N dan daha düsük ekstrüzyon kuvvetine sahip dermal dolgular tercih edilmektedir. Sample F (N) Control l 14 Control 2 41 Hybrogel (100)-A 20 Hybrogel (100)-B 27 Hybrogel (100)-C 34 Table 7 shows the results of the extrusion tests at a compression ratio of 12 mm/min. shows. As can be seen from the table, carboxymethyl cellulose (CMC) The increase in its composition caused an increase in the injection force values. A lot Gels containing high carboxymethyl cellulose (CMC) tend to have difficulties during processing. has the risk of causing For this reason it is usually lower than 35 N. dermal fillers with extrusion strength are preferred.
Sonuç olarak, yukaridaki örnekler çapraz bagli jel matriksinde bulunan karboksimetil selüloz (CMC)”un hiyaluronik asit (HATnin reolojik özelliklerini gelistirerek klinik sonuçlara pozitif yönde katki saglayacak olan G' ve 1] degerlerini artirdigi görülmüstür. Hem G' degerindeki artis hem de 1] degerindeki yükselis, elde edilen hibrojellerin (100) enjekte edildikten sonra daha da gelistirilmis bir kaldirma etkisine sahip olacagini göstermistir. Ayrica bu hibrojeller (100) çapraz bagli yapisindan dolayi uzun süreli bir kalicilik saglayacaktir. As a result, the above examples show that the cross-linked gel matrix hyaluronic acid (rheological properties of HAT) of carboxymethyl cellulose (CMC) G' and 1] values, which will contribute positively to clinical results by improving has been seen to increase. Both the increase in the G' value and the increase in the 1] value are obtained. A further improved removal of the injected hybrid gels (100) after injection has proven to have an effect. In addition, these hydrogels (100) are cross-linked. Due to its structure, it will provide a long-term permanence.
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