WO2013156547A1 - Biomatériaux à base de gellane pour une utilisation en tant que charges en chirurgie - Google Patents

Biomatériaux à base de gellane pour une utilisation en tant que charges en chirurgie Download PDF

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Publication number
WO2013156547A1
WO2013156547A1 PCT/EP2013/058045 EP2013058045W WO2013156547A1 WO 2013156547 A1 WO2013156547 A1 WO 2013156547A1 EP 2013058045 W EP2013058045 W EP 2013058045W WO 2013156547 A1 WO2013156547 A1 WO 2013156547A1
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WO
WIPO (PCT)
Prior art keywords
hyaluronic acid
gellan
biomaterials
use according
sulphated
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PCT/EP2013/058045
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English (en)
Inventor
Cristina Longinotti
Alessandra Pavesio
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Anika Therapeutics S.R.L.
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Publication of WO2013156547A1 publication Critical patent/WO2013156547A1/fr

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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
    • A61L27/14—Macromolecular materials
    • A61L27/26—Mixtures of macromolecular compounds

Definitions

  • the present invention relates to biomaterials in the form of gel or fibres, comprising gellan or derivatives thereof, alone or in association with hyaluronic acid or derivatives thereof, for use as cellular fillers in the surgical field.
  • a wide range of materials such as membranes, sponges, gauzes (or meshes) and gels, are used in surgery.
  • the material to be used is selected on the basis of the type of surgery to be performed.
  • the material must be biocompatible but not biodegradable, in which case a second surgical operation is required to remove the material (for example in urogynaecological and ENT surgery). In other cases, the material must be both biocompatible and biodegradable, in particular in dermocosmetic surgery.
  • the first filler to be used in the Seventies, was silicone oil, which is now prohibited because of its serious side effects.
  • bovine collagen introduced in the late Seventies, gave very good results but also triggered some allergic reactions.
  • MERSILENE polyamides and polypropylene (Dolphin mesh) are used in gynaecological surgery, and in particular as materials for the prevention of urinary incontinence (AMS SPARCTM, AMS MonarcTM, AMS BioArcTM SP and AMS BioArcTM TO); sponges made of partly resorbable derivatives are used in ENT surgery (Meropack, Nasopore); and gels or membranes based on modified/crosslinked hyaluronic acid, either alone or combined with other polymers, are mainly used in dermocosmetic surgery (HydrelleTM, Juvederm®, Perlane® and Restylene®).
  • membranes made of PTFE or polypropylene
  • gels involves the implant of a synthetic material foreign to the human body, which is not biodegradable and may require a second surgical operation to remove the material, which causes adverse reactions such as inflammation or, as in the case of nasal packing in ENT surgery, often causes pain and bleeding.
  • WO 2006/037592 describes formulations based on gellan, used alone or in combination with hyaluronic acid derivatives, in particular with sulphated hyaluronic acid, for use in the prevention of surgical adhesions, in particular in the prevention of spinal adhesions.
  • the present invention relates to biomaterials comprising gellan or derivatives thereof, either alone or in combination with hyaluronic acid or derivatives thereof, for use as fillers in surgery.
  • the present invention relates to the use of biomaterials, comprising gellan or derivatives thereof, either alone or in combination with hyaluronic acid (HA) or derivatives thereof, as fillers in the surgical field.
  • biomaterials comprising gellan or derivatives thereof, either alone or in combination with hyaluronic acid (HA) or derivatives thereof, as fillers in the surgical field.
  • HA hyaluronic acid
  • Said biomaterials are characterised by high biocompatibility and are completely biodegradable; they are therefore suitable for a variety of uses in surgery, and a second surgical operation is not required to remove them from the sites of application.
  • the biomaterials can preferably be in the form of gels or fibres.
  • Gellan is a linear anionic heteropolysaccharide with a repeating unit consisting of glucose-glucuronic acid-glucose-rhamnose.
  • a gellan derivative which can preferably be used is deacetylated gellan.
  • gellan is an inert material which can be advantageously used as a filler.
  • Gellan does not perform an active biological role, and is characterised by lengthy residence at the site of application and high viscosity.
  • Gellan presents biocompatibility, prolonged residence at the site of application, a degree of bioadhesion and a consistency which allow it to be used as an injectable gel or fibre in biomedical applications.
  • Gellan is preferably pyrogen-free; in other words it is obtained by following a particular purification procedure which leads to a product with endotoxin content limits of less than 24 EU per millilitre of gel.
  • Gellan or deacetylated gellan is preferably freeze-dried and soluble up to concentrations of 20-30 mg/ml in saline solutions at 85-90°C.
  • the hyaluronic acid used in the present invention can derive from any source; for example, it can be obtained by extraction from rooster combs (EP 0138572 B l), by fermentation (EP 0716688 B l) or by a technological process.
  • Hyaluronic acid can have a molecular weight of between 400 and 3x10 ⁇ 6 Da, in particular between 10,000 and lxlO "6 Da, and more particularly between 100,000 and 250,000 Da.
  • hyaluronic acid is functionalised with sulphate groups, i.e. is sulphated hyaluronic acid (HA-S).
  • HA derivatives which can be used to undergo the sulphation process are listed below:
  • Salified HA with organic and/or inorganic bases having a molecular weight of 50-730 KDa (EP0138572 B l) or a high molecular weight of 750- 1230 KDa (EP 535200 Bl); preferably having a molecular weight of between 100 and 250 KDa;
  • Hyaff® HA esters with alcohols of the aliphatic, araliphatic, cycloaliphatic, aromatic, cyclic and heterocyclic series (EP 216453 B l); the percentage esterification of hyaluronic acid subsequently subjected to the sulphation process ranges between 5 and 65%, depending on the type and length of the alcohol used, because the product obtained must be soluble in water;
  • ACP® inner HA esters (EP 0341745 B l); the percentage esterification of hyaluronic acid subsequently subjected to the sulphation process ranges from 1 to 15%, because the product obtained must be soluble in water;
  • HyoxxTM percarboxylated derivatives of HA obtained by oxidation of the primary hydroxyl of the N-acetylglucosamine fraction (EP1339753); the percentage percarboxylation of hyaluronic acid subsequently subjected to the sulphation process ranges from 1 to 50%.
  • All the HA-free carboxyl groups can be salified with organic and/or inorganic bases.
  • the degree of sulphation of hyaluronic acid and/or of the derivatives thereof listed above, measured as the number of sulphate groups per repeating unit, can range from 0.5 to 3.5, and is preferably 3.
  • solubility in water or saline solutions is directly proportional to the degree of sulphation of hyaluronic acid.
  • Hyaluronic acid is normally characterised by very rapid resorption times, whereas it is not processable when it is incorporated in the biomaterials according to the invention.
  • the association of hyaluronic acid or derivatives thereof with gellan or derivatives thereof therefore allows it to be administered during surgery.
  • Biomaterials containing gellan or derivatives thereof and hyaluronic acid or derivatives thereof can be used as fillers, as they also have biological properties conferred by hyaluronic acid or derivatives thereof.
  • Said biomaterials can be used as biorevitalising fillers, for example in the dermocosmetic field.
  • the biomaterial consists of a mixture comprising deacetylated gellan and sulphated hyaluronic acid (HA-S).
  • H-S Sulphated hyaluronic acid
  • the biomaterials comprise freeze-dried, pyrogen-free gellan or deacetylated gellan and grade 3 sulphated hyaluronic acid.
  • the biomaterials preferably only consist of gellan or deacetylated gellan at the maximum concentration of 30 mg/ml (3% solution) or of a mixture comprising gellan or deacetylated gellan with a concentration ranging from 18 to 29 mg/ml and sulphated hyaluronic acid with a concentration ranging from 1 to 12 mg/ml; even more preferably, the biomaterial comprises gellan or deacetylated gellan with a concentration of 20 mg/ml and sulphated hyaluronic acid with a concentration of 10 mg/ml.
  • the weight ratio between gellan or derivatives thereof and hyaluronic acid or derivatives thereof, preferably sulphated hyaluronic acid, can range between the ratios 1.5: 1 , 2: 1 and 2: 1.5; the weight ratio 2: 1 is preferable.
  • the biomaterials have similar characteristics to native hyaluronic acid, but with residence times suitable to perform the various functions required, according to the type of surgery in which they are used.
  • the biomaterial based on deacetylated gellan alone or combined with sulphated hyaluronic acid presents a long residence in situ together with a very high tolerability profile, demonstrated by the results of the biocompatibility tests according to ISO 10993 conducted on the central nervous system. During said tests, it was demonstrated that a biomaterial based on deacetylated gellan and sulphated hyaluronic acid according to the present invention does not induce sensitisation reactions after application. The biomaterial also presents a residence time after application exceeding two years.
  • biomaterials according to the present invention can be used as acellular fillers in surgery, in particular in dermocosmetic surgery, urogynaecological surgery and ENT surgery, for example to increase the physiological tissue for biofunctional or cosmetic purposes.
  • fillers in the urogynaecological field they can be used to solve problems caused by urinary incontinence due to their characteristics of residence time and injectability.
  • the primary indication of the fillers is ISD (intrinsic sphincter deficiency), but they are also used in cases of urinary incontinence caused by hypermobility of the bladder. In this case the action of the filler is to improve the sphincter function.
  • the characteristics of the ideal filler include, as well as the tolerability profile, ease of injection, maintenance of volume over time and persistence at the site of injection, despite constant stresses due to movement, for at least 2 years.
  • the biomaterials according to the present invention can be used in phonosurgery, in vocal fold surgery, for example to restore the vibratile activities of the vocal folds by medialisation of cords affected by paresis, or in rhinosurgery, when a barrier between the paranasal sinuses is required.
  • the ideal filler In the case of applications in the field of vocal fold surgery, the ideal filler must be biocompatible, not immunogenic, injectable through needles with dimensions compatible with common surgical practice, have an adequate residence time and possess viscoelastic properties similar to the physiological properties of the vocal folds so as to guarantee biofunctional reinstatement.
  • biomaterials can be used as fillers, injected into the skin of the face through a very fine needle, to fill wrinkles, folds or depressions or increase the volume of the lips, chin and cheekbones.
  • biomaterials according to the present invention comprising gellan or deacetylated gellan and hyaluronic acid and/or derivatives thereof, can be advantageously obtained, for example, by simple dry mechanical mixing, with no need for the formation of new chemical bonds between the ingredients to obtain derivatives of various kinds, such as crosslinked substances, esters, ethers, starches, ion complexes, etc.
  • the HA is sulphated according to EP 0702699 Bl with a degree of sulphation of 3.
  • a solution of 20 mg/ml of deacetylated gellan (Gelrite®) is prepared by heating (75-85°C) and dissolving 1 g of deacetylated gellan in 50 ml of NaCl, 0.9%. Once solubilisation is complete, 500 mg of sulphated HA is added and left to dissolve completely. The mixture is then cooled to room temperature until a hydrogel is obtained which can then be steam-sterilised.
  • Example 1 dissolving 750 mg of deacetylated gellan and 500 mg of sulphated HA.
  • the deacetylated gellan solution is prepared as described in Example 1. 500 mg of sulphated HA benzyl ester is then added and left till solubilisation is complete. It is then left to cool to room temperature giving a hydrogel that can then be steam-sterilised.
  • the mixture of powders is placed in a mixer, and 125 ml of water is added slowly. A mixture with a concentration of 80 mg/ml is obtained.
  • the mixture is transferred to a screw extruder connected to a 60 ⁇ die.
  • the temperature of the extrusion chamber is set to 54°C, and the material is extruded.
  • the mixture of powders is placed in a mixer, and 1 10 ml of water is added slowly. A mixture with a final concentration of approx. 90 mg/ml is obtained. The mixture is transferred to a screw extruder connected to a 40 ⁇ die. The temperature of the extrusion chamber is set to 54°C, and the material is extruded.
  • a fibre with an average diameter of 15-25 ⁇ is obtained.
  • the mixture of the two polymers is placed in a mixer, and 100 ml of water is added slowly. A mixture with a final concentration of 100 mg/ml is obtained. The mixture is transferred to a screw extruder connected to a 150 ⁇ die. The temperature of the extrusion chamber is set to 54°C, and the material is extruded.
  • a fibre with an average diameter of 50-70 ⁇ is obtained.
  • Kelcogel ® CG-LA deacetylated gellan is mixed dry with 0.5 grams of powdered HYADDTM-4 (hexadecyl amide with 2% amidation).
  • the mixture of the two polymers is placed in a mixer, and 125 ml of water is added slowly. A mixture with a final concentration of 80 mg/ml is obtained. The mixture is transferred to a screw extruder connected to a 60 ⁇ die. The temperature of the extrusion chamber is set to 54°C, and the material is extruded.
  • a fibre with an average diameter of 25-30 ⁇ is obtained.
  • Kelcogel ® CG-LA deacetylated gellan is mixed dry with 0.5 grams of powdered ACP ® (autocrosslinked hyaluronic acid).
  • the mixture of the two polymers is placed in a mixer, and 1 10 ml of water is added slowly. A mixture with a final concentration of approx. 90 mg/ml is obtained. The mixture is transferred to a screw extruder connected to a 100 ⁇ die. The temperature of the extrusion chamber is set to 50°C, and the material is extruded.
  • a fibre with an average diameter of 30-50 ⁇ is obtained.
  • the mixture of powders is placed in a mixer, and 125 ml of water is added slowly. A mixture with a concentration of 80 mg/ml is obtained. The mixture is transferred to a screw extruder connected to a 60 ⁇ die. The temperature of the extrusion chamber is set to 54°C, and the material is extruded.
  • a fibre with an average diameter of 25-30 ⁇ is obtained.
  • Stage 1 Preparation of a solution of gellan TBA (tetrabutylammonium salt) 25 grams of powdered Kelcogel ® CG-LA deacetylated gellan, sieved and collected between 140 and 38 micron sieves, is added to 300 ml of water and maintained under slow stirring in a thermostated mixer at a temperature of 60°C. After approx. 10 minutes another 100 ml of water is added, and stirring is continued for a further 30 minutes until a homogenous mixture is obtained. Stirring is stopped and 150 ml of activated TBA resin suspended in 100 ml of water is added to the hot gellan mixture. Stirring is resumed, always maintaining the minimum speed.
  • gellan TBA tetrabutylammonium salt
  • the ion exchange takes place after 4 to 6 hours, leading to complete dissolution of the gellan gum.
  • the solution of gellan TBA is separated from the resin by filtration through a steel filter with a porosity of 45 microns.
  • the gellan solution obtained must have a pH of between 7 and 8, and the deacetylated gellan content must be between 45 and 60 mg/ml.
  • the deacetylated gellan solution prepared according to example 10 is filtered through a filter cloth with 20 micron pores and transferred to an extrusion reactor thermostated at 55°C connected to a spinneret for multiple strand wet-extrusion consisting of 3000 80-micron holes.
  • the material is extruded through a first coagulation bath with continuous recirculation of 3 litres of a solution of sodium chloride in ethanol/water.
  • the threads are introduced through transport rollers into a second coagulation tank filled with 0.5 litres of a solution of calcium chloride in ethanol, into 3 successive washing tanks filled with 0.5 litres each of absolute ethanol, and finally into a last washing tank filled with 0.5 litres of acetone.
  • the extrusion process has been completed, the fibre is continuously dried with hot-air ejectors and wound onto a reel.
  • a deacetylated gellan fibre with a diameter of 10-30 microns is obtained.
  • the gellan filler and the commercially available filler (control) were applied bilaterally in the subdural space of 21 rabbits.
  • the cerebrospinal fluid and some blood values were analysed, and histological analysis of the target organs was conducted. Finally, macroscopic and histological analysis of the implant sites was performed.
  • control material was no longer detectable at the follow up (3 months), whereas the deacetylated gellan and sulphated hyaluronic acid gel under study presents a very slow degradation process which had not been completed after 24 months.
  • the deacetylated gellan and sulphated hyaluronic acid gel was tested immediately after preparation (Time 0) and after aging processes at ambient temperature and at 40°C. A test was also conducted after freezing (-20°C) of the material.
  • the larynx specimens injected with the filler based on deacetylated gellan and sulphated hyaluronic acid showed a foam cell formation indicating resorption, and inflammation was found in 4 specimens. Signs of fibrosis were found in 2 cases.
  • the mucosal waves of all except one of the vocal folds treated with the gel based on deacetylated gellan and sulphated hyaluronic acid were excellent, and similar between the paralysed and normal vocal folds.
  • the mucosal waves of the vocal folds were preserved in amplitude and periodicity, and were still well detected during the follow-up periods.
  • the gel based on deacetylated gellan gum and sulphated hyaluronic acid is a safe, lasting filler in the vocal folds, and can be considered to be a suitable material for laryngoplasty injections, on a par with the products currently on the market.
  • the control material has the added value of a better effect on the restoration of the natural characteristics and mucosal waves of paralysed vocal folds due to the superior stroboscopic results and lower inflammatory reactions associated with administration of the gel based on deacetylated gellan gum and sulphated hyaluronic acid.
  • the type of material injected during the laryngoplasty procedure influences the result in terms of quality.

Abstract

La présente invention concerne l'utilisation de biomatériaux sous la forme de gels ou de fibres, comprenant de la gellane ou des dérivés de celle-ci, seuls ou en association avec de l'acide hyaluronique ou des dérivés de celui-ci, en tant que charges dans le domaine chirurgical. Lesdits biomatériaux peuvent notamment être utilisés dans une chirurgie dermocosmétique, urogynécologique et oto-rhino-laryngologique (ORL).
PCT/EP2013/058045 2012-04-20 2013-04-18 Biomatériaux à base de gellane pour une utilisation en tant que charges en chirurgie WO2013156547A1 (fr)

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IT000664A ITMI20120664A1 (it) 2012-04-20 2012-04-20 Biomateriali a base di gellano per l'uso come filler in chirurgia

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019135216A1 (fr) 2018-01-02 2019-07-11 Cartiheal (2009) Ltd. Outil d'implantation et protocole pour substrats solides optimisés favorisant la croissance cellulaire et tissulaire

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EP0341745B1 (fr) 1988-05-13 1994-12-14 FIDIA S.p.A. Polysaccharides carboxylés réticulés
EP0216453B1 (fr) 1985-07-08 1996-03-20 FIDIA S.p.A. Esters de l'acide hyaluronique et leurs sels.
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EP0702699B1 (fr) 1994-03-23 2000-05-17 Fidia Advanced Biopolymers S.R.L. Acide hyaluronique sulfate ayant un nombre de groupes sulfates par unite repetitive de 0.5 a moins de 2
EP1339753A2 (fr) 2000-08-31 2003-09-03 FIDIA FARMACEUTICI S.p.A. Polysaccharides percaboxyles, et procede d'elaboration
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019135216A1 (fr) 2018-01-02 2019-07-11 Cartiheal (2009) Ltd. Outil d'implantation et protocole pour substrats solides optimisés favorisant la croissance cellulaire et tissulaire

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