CA2521961A1 - Crosslinking of low-molecular weight and high-molecular weight polysaccharides; preparation of injectable monophase hydrogels; polysaccharides and hydrogels obtained - Google Patents

Crosslinking of low-molecular weight and high-molecular weight polysaccharides; preparation of injectable monophase hydrogels; polysaccharides and hydrogels obtained Download PDF

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CA2521961A1
CA2521961A1 CA002521961A CA2521961A CA2521961A1 CA 2521961 A1 CA2521961 A1 CA 2521961A1 CA 002521961 A CA002521961 A CA 002521961A CA 2521961 A CA2521961 A CA 2521961A CA 2521961 A1 CA2521961 A1 CA 2521961A1
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molecular weight
advantageously
crosslinking
polymer
process according
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CA2521961C (en
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Pierre Lebreton
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Allergan Industrie SAS
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Corneal Industrie
Pierre Lebreton
Allergan Industrie, Sas
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    • 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
    • A61K31/738—Cross-linked polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—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
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • 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
    • C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
    • 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
    • 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

Abstract

The invention relates to a method for cross-linking at least one polymer, selected from the polysaccharides and the derivatives thereof, application thereof in an aqueous solvent, by the action of an effective and non-excessive quantity of at least one cross-linking agent, characterised in being applied to a mixture including at least one polymer of low molecular weight and at least one polymer of high molecular weight, a method for preparation of an injectable monophase hydrogel with at least one cross-linked polymer selected from polysaccharides and the derivatives thereof and the cross-linked polymers and injectable monophase hydrogels which may be obtained respectively by the methods above.

Description

J
Cr~osslinking of low-molecular weight and high-molecular weight po~lvrsaccharides; preparation of injectable monophase hydrogels;
~o~larsaccharides and hydrogels obtained s The present invention relates to:
- a novel process for the crosslinking of at least one polymer selected from polysaccharides and derivatives thereof;
- a process for the preparation of an injectable monophase hydrogel of at least one such polymer; and to - the crosslinked polymers and injectable monophase hydrogels respectively obtainable by each of said processes.
The hydrogels in question, based on said crosslinked polymers, have numerous outlets, especially as filling materials in plastic, cosmetic and dental surgery, in ophthalmology, in orthopedics, etc., as products for 15 preventing tissue adhesions, in general surgery, in urology, etc. Said hydrogels are particularly suitable for repairing vocal cords. The outlets indicated above for products of this type, without implying any limitation, are familiar to those skilled in the art.
The invention is the result of a genuine effort to optimize the 20 operation of crosslinking the polymers in question with a view to obtaining injectable monophase hydrogels that are of particular value in respect of the following compromise: on the one hand mechanical properties and remanence, and on the other hand injectability (with acceptable injection forces and injection needle diameters).
2s It is pointed out here that the term "injectable" employed in the present text, with reference to both the hydrogels of the prior art and the hydrogels of the invention, denotes manual injectability by means of syringes equipped with conventional needles (having a diameter of between 0.1 and 0.5 mm). Within the framework of the present invention, 3o it is possible in particular to formulate hydrogels that can be injected through hypodermic needles of 30 G~/2, 27 G~/2, 26 G~/z and 25 G.
According to the prior art, hydrogels, especially injectable hydrogels, have already been prepared from polysaccharides and derivatives thereof especially hyaluronic acid salts - having a zero, low or high degree of 35 crosslinking.
With reference to the specific problem of injectability, biphase compositions have been proposed whose continuous phase, in particular, is based on such hydrogels. The continuous phase serves as a plasticizer, injection vehicle for a disperse phase. This disperse phase is more or less s solid and more or less differentiated from the continuous phase. Thus:
- the biphase compositions described in patent application EP'-A-0 466 300 consist of two bioabsorbable phases - continuous and disperse - and take the form of slurries. Said two phases are advantageously prepared from fibers of Hylan (natural hyaluronic acid to chemically modified in situ in order to facilitate its extraction from the tissues);
- the biphase compositions described in patent application WO-A-96 337 51 also have two bioabsorbable phases with a better separation, the disperse phase consisting of insoluble fragments of a highly 15 crosslinked polymer hydrogel (selected from hyaluronic acid and its salts);
- the biphase compositions described in patent application WO-A-00 014 28 contain a non-bioabsorbable disperse phase (particles of at least one hydrogel of a (co)polymer obtained by the polymerization and crosslinking of acrylic acid and/or methacrylic acid and/or at least one 2o derivative of said acids) suspended in an aqueous solution of a crosslinked or non-crosslinked polymer selected from proteins, polysaccharides and derivatives thereof.
These biphase systems are not fully satisfactory insofar as they are as;5ociated with justifiable fears of uneven flow during injection and 2s particularly after injection, a more rapid disappearance of the continuous phase (having a zero or low degree of crosslinking) and hence an at least partial loss of the desired effect, especially filling effect.
Monophase hydrogels, developed from the same types of polymers, wE~re therefore also proposed in parallel.
3o In patent applications WO-A-98 356 39 and WO-A-98 356 40, the product in question is not an injectable hydrogel but a product of solid consistency. Said patent applications in fact describe ocular implants used to temporarily fill a surgically created void. The hydrogel developed in patent US-A-4 716 154 is proposed as a substitute for the vitreous body.
35 The polymer in question (sodium hyaluronate) has a very low degree of crosslinking in order to obtain an injectable hydrogel. The monophase hydrogel described in patent application WO-A-02 057 53 is laden with an antiseptic that is effective in protecting it from free radicals after implantation. Patent application WO-A-02 063 50 describes a process s capable of generating this type of hydrogel that is very homogeneous throughout.
All these monophase hydrogels were obtained from high-molecular wE~ight polymers crosslinked using an effective and non-excessive amount of at least one crosslinking agent, in an aqueous solvent.
io In the light of this prior art, the inventors wished to improve the efficacy of crosslinking of the polymer in question, especially in order to improve the degradation resistance (remanence) of the implanted hydrogel while at the same time preserving the possibility of injecting said hydrogel under acceptable conditions.
15 To improve the crosslinking efficacy, the inventors initially considered using more crosslinking agent. This approach was quickly discarded on the grounds that it inescapably causes denaturation of the polymer in question and chemical contamination of the crosslinked product obtained.
2o Said inventors then considered increasing the concentration of pollymer in the reaction mixture. In the same way, this second approach had to be discarded, a priori, because of the polymers conventionally used hitherto, namely high-molecular weight polymers. Thus sodium hyaluronate is always used with high molecular weights (Mw >_ 106 Da, = 2.106 Da, 2s 3.1.06 Da) at concentrations close to the maximum concentration, which is about 105-110 mg/g. Using it at a higher concentration is difficult (the viscosity of the reaction mixture becomes too high) and inescapably causes problems of solubility, poor homogeneity, etc.
Concentrating the reaction medium, on the other hand, is found to 3o be possible with low-molecular weight polymers (sodium hyaluronate of molecular weight 300,000 Da, having an intrinsic viscosity of 600 ml/g (those skilled in the art are perfectly familiar with the relationship between these two parameters: molecular weight (M) and intrinsic viscosity (ri), which is given by the Mark-Houwink formula: M = k r~°', the values of k 35 and a depending on the nature of the polymer in question), can be ~
concentrated from 110 to 200 mg/g). Unfortunately the crosslinked polymer obtained generates an inhomogeneous, injectable biphase hydrogel under these conditions.
In such a context, the inventors surprisingly established that s associating low-molecular weight polymers) with high-molecular weight polymers) affords an excellent compromise, namely the possibility of generating, for a non-excessive degree of crosslinking (equivalent to that of the prior art), an injectable monophase hydrogel which has improved mechanical and remanence properties. This low-molecular weight/ high io molecular weight association makes it possible to obtain a hydrogel that more than satisfies the following specifications:
- monophase;
- better mechanical properties and remanence than the equivalent products of the prior art;
15 - unaffected or even improved injectability that is still possible with conventional injection forces using conventional injection devices.
The key factor of the crosslinking process of the invention therefore lies in the concentration of the reactants (which is greater than that of the reaction mixtures of the prior art due to the use of low-molecular weight 2o pollymer(s)), although the crosslinking of said concentrated reactants is "governed" by the use of high-molecular weight polymer(s), which guarantee the homogeneity of the crosslinked product obtained and then of the hydrogel obtained.
According to its first subject, the present invention therefore relates 25 to a process for the crosslinking of at least one polymer selected from polysaccharides and derivatives thereof, which is carried out in an aqueous solvent by the action of an effective and non-excessive amount of at least one crosslinking agent, said process being improved in that it is carried out on a mixture containing at least one low-molecular weight polymer and at 30 least one high-molecular weight polymer.
Said mixture of course contains said low-molecular weight polymers) in a sufficient amount to guarantee a relatively high concentration of polymers) in the reaction medium, and said high-molecular weight polymers) in a sufficient amount to guarantee that said 3s crosslinked polymer obtained has a homogeneous consistency.

The crosslinking process of the invention is a process for the crosslinking of polymers selected from polysaccharides and derivatives thereof. The polymers) in question can therefore be natural or synthetic.
Examples of natural polymers are hyaluronic acid and its salts, other s glycosaminoglycans such as chondroitin sulfates, keratan sulfate, heparin and heparan sulfate, alginic acid and its biologically acceptable salts, starch, amylose, dextran, xanthan, pullulan, etc. Examples of synthetic derivatives of natural polysaccharides are carboxy cellulose, carboxymethyl cellulose, alkyl celluloses such as hydroxyethyl cellulose and hydroxypropyl 1o methyl cellulose (HPMC), oxidized starch, etc.
The process of the invention is suitable for the crosslinking of any one of these polymers insofar as said polymer is used with low and high molecular weights.
The process of the invention is suitable for the crosslinking of mixaures of such polymers, said mixtures containing at least one low molecular weight polymer and at least one high-molecular weight polymer.
The terms "low" and "high" applied to the molecular weights in question obviously cannot be defined more precisely at this stage of the description of the invention since they depend on the mixture in question 2o and the nature of the polymers) present. Likewise, it is not generally possible to indicate the relative proportions in which the polymers) present is(,are) used. However, those skilled in the art have a perfect understanding of the spirit of the invention, which is to concentrate the reaction medium containing the low-molecular weight polymer(s), but to introduce at least 2s one high-molecular weight polymer to moderate and control the crosslinking in question. The aim is to obtain a coherent crosslinked product that is the precursor of a monophase hydrogel. It is desirable to avoid the formation of lumps that may be coherent when crosslinking has ended, but capable of losing their coherence when the injectable hydrogel 3o is prepared.
The above explanations are given a posteriori. The result obtained was in no way predictable.
Within the framework of one advantageous variant, the reaction medium contains a single polymer which is used with at least two 35 differentiated molecular weights, at least one being low and at least one being high. Within the framework of this advantageous variant, the same polymer is preferably used with a single low molecular weight and a single high molecular weight.
The polymer in question is advantageously a hyaluronic acid salt. It s is very advantageously selected from the sodium salt, the potassium salt and mixtures thereof. It preferably consists of the sodium salt (NaHA).
In the context of the crosslinking of this type of polymer, those skilled in the art understand that said crosslinking is carried out in a basic aqueous solvent. In general, said crosslinking is obviously carried out under io pH conditions that favor the dissolution of the polymer in question.
In the context of the crosslinking of this type of polymer (hyaluronic acid salt(s)), in one preferred variant of carrying out the crosslinking, the reaction mixture contains:
- at least one hyaluronic acid salt of low molecular weight m, where is m <_ 9.9.105 Da, advantageously 104 Da <_ m <_ 9.9.105 Da; and - at least one hyaluronic acid salt of high molecular weight M, where M >_ 106 Da, advantageously 106 Da <_ M <_ 108 Da and very advantageously 1.1.106Da<_M<_5.106Da, said low-molecular weight and high-molecular weight salts advantageously 2o being of the same nature and very advantageously consisting of sodium hyaluronate (NaHA).
In such a context, said reaction mixture advantageously has an intrinsic viscosity of less than 1900 ml/g, i.e. ~ w; [r~; ]o < 1900 ml/g, where c~, is the mass fraction of polymer fraction i, having an intrinsic viscosity Zs [r~;]o, in the reaction mixture. Those skilled in the art are familiar with the intrinsic viscosity parameter and are aware of the laws of additivity of said parameter.
The condition stated above makes it possible to obtain a monophase hydrogel that is optimized in respect of its remanence and injectability 3o properties. It fixes the relative proportions of the salts of low molecular weight (m) and high molecular weight (M).
In the context referred to here (NaHA of molecular weights m and M), the reaction mixture advantageously contains more than 50% by weight, very advantageously more than 70% by weight, of at least one h~yaluronic acid salt of low molecular weight m, and hence, logically, advantageously less than 50% by weight, very advantageously less than 3iD% by weight, of at least one hyaluronic acid salt of high molecular s weight M.
In general, to obtain the expected effect, there is at least 5% by weight of at least one hyaluronic acid salt of high molecular weight M in the reaction mixture.
The crosslinking process of the invention is advantageously carried io on,~t with the sodium salt of hyaluronic acid used with one low molecular weight m and one high molecular weight M, said parameters then very advantageously being as follows: m ~ 3.105 Da and M ~ 3.106 Da.
Any agent known for crosslinking polysaccharides and derivatives thereof via its hydroxyl groups can be used as the crosslinking agent with is all types of polymer, said crosslinking agent being at least bifunctional in order to ensure crosslinking, an epoxy compound or derivatives thereof being used in particular.
It is recommended to use bifunctional crosslinking agents, by themselves or in a mixture. It is particularly recommended to use 2o epichlorohydrin, divinyl sulfone, 1,4-bis(2,3-epoxypropoxy)butane (or 1,4 bisglycidoxybutane or 1,4-butanediol diglycidyl ether (BDDE)), 1,2-bis(2,3-epoxypropoxy)ethylene, 1-(2,3-epoxypropyl)-2,3-epoxycyclohexane, and aldehydes such as formaldehyde, glutaraldehyde and crotonaldehyde, taken by themselves or in a mixture. It is very particularly recommended to Z5 use 1,4-bis(2,3-epoxypropoxy)butane (BDDE).
Those skilled in the art will know how to determine the effective and non-excessive amount of crosslinking agents) to use. It is recommended to~ use an effective and non-excessive amount such that the degree of crosslinking (~), defined by the following ratio:
Total number of reactive groups in said crosslinking agent x 100 Total number of disaccharide units in the polymer molecules ' is theoretically between 0.5 and 70%, advantageously between 4 and 50%.

The crosslinking process of the invention is novel by virtue of the forms in which the polymers in question are used. In other respects it is carried out in conventional manner with at least one crosslinking agent. It is noted that said crosslinking agent is generally reacted with the dissolved s polymer(s), but reacting it with said polymers) during hydration, by the process described in WO-A-02 06 350, is in no way ruled out.
The crosslinked product obtained after carrying out the crosslinking process of the invention is generally formulated for generating the desired injectable monophase hydrogel. If necessary, it is neutralized beforehand.
io It has been seen that the hyaluronic acid salts are actually crosslinked in a b<3sic medium. The formulation is carried out in a solution buffered to a pH
compatible with the human body (since the hydrogel in question is generally intended for injection into the human body), said pH being between 6.5 and 7.5, advantageously between 7 and 7.4 and very is advantageously between 7.1 and 7.3. The crosslinked polymer is in equilibrium in said solution. It also acquires an osmolarity compatible with that of the human body. Surprisingly, after this formulation step, the dilluted crosslinked polymers of the invention are monophase hydrogels.
In one preferred variant of carrying out the invention, an injectable zo hydrogel of the invention is prepared by crosslinking a mixture of at least one polymer consisting of hyaluronic acid salts) (see above), neutralizing the crosslinked product obtained, and then formulating it into a solution buffered to a pH of between 7.1 and 7.3, at a concentration of between 10 and 40 mg/g, advantageously of between 20 and 30 mg/g.
2s The process for the preparation of the injectable monophase hydrogel from the crosslinked polymer (obtained by the crosslinking process constituting the first subject of the present invention) constitutes the second subject of the present invention.
We now come to the third and fourth subjects, which respectively 3o consist of the crosslinked polymer obtainable after carrying out the crosslinking process (first subject), and the injectable monophase hydrogel obtainable by the formulation (second subject) of said crosslinked polymer, as stated above.
Said polymer and hydrogel advantageously contain low-molecular 3s weight sodium hyaluronate and high-molecular weight sodium hyaluronate, tree proportion of said low-molecular weight sodium hyaluronate very advantageously being more than 50% by weight.
The structure of the injectable monophase hydrogel - fourth subject of the present invention - is novel. Its consistency is resistant to s degradation. This resistance of the hydrogel is far greater than that of the equivalent products of the prior art.
Those skilled in the art are aware that one of the methods of estimating the consistency of a hydrogel, especially of this type, is to measure the following parameter:
G"
to tan.deita = ~, = f (stressing frequency).
The hydrogels of the invention have the outlets indicated in the introduction of the present text. They are found to be particularly efficient for these purposes.
It is now proposed to illustrate the invention in its various features i5 b~y means of the Examples below. More precisely:
- Example 1 illustrates the prior art (crosslinking of a polymer of high molecular weight);
- Example 2 illustrates the remarks made in the introduction of the present text (crosslinking of the same polymer of low molecular weight);
2o and - Examples 3 and 4 illustrate the invention (crosslinking of the same polymer of low and high molecular weight, used in different relative amounts).
These are preceded by a description of a few methods of 2s rneasurement used to characterize the products in question.
Iwleasurement of the intrinsic viscosity The intrinsic viscosity of sodium hyaluronate (NaHA) (in ml/g) is determined according to the European Pharmacopeia for NaHA (2.2.9) 3o using a capillary viscometer of the Ubbelohde type.
Measurement of the ejection force (no specifrc standard for this test) The injectability of the gel based on NaHA is determined by measuring the force (in Newtons, N) required to eject the gel contained in a standard syringe, through a needle of 27 G'h, at a rate of 12.5 mm/min.
T'he tests were performed on a Verstatet~ tensile device marketed by Mlecmesin.
s Measurement of the remanence The consistency of the gel is characterized at 25°C by rheological measurement of the moduli of elasticity (G') and viscosity (G") as a function of the frequency (from 0.05 to 10 Hz), in the constant deformation domains, using a controlled stress rheometer (Carrimed CSL 500 from TA
1o Instruments) and a cone-and-plate geometry of 4 cm 2°. This rheometer is clhecked and calibrated regularly. Degradation of the crosslinked gel results in a change in its consistency, which is measured by the increase in the parameter tangent delta (tan.delta = G"/G') as a function of time, at a frequency of 1 Hz. The gels are degraded by being heated to a tE~mperature of 93°C. The time after which tan.delta reaches a value of 0.65 (corresponding to a degraded gel state) is measured at this tE~mperature. A remanence index of 1 (corresponding to said time) was arbitrarily set for the gel of Example 1. The remanence index values indicated for the other gels are relative values.
Appearance of the hydrogel Monophase h9icroscopic appearance: no apparent liquid phase - fine fragmentation of the gel into facets N9acroscopic appearance: soft and free-flowing Btiphase h9icroscopic appearance: gel fragments bathed in a low-viscosity liquid medium Macroscopic appearance: "puree" that fragments very easily - no cohesion of the gel and no free-flowing appearance EXAMPLE 1: high-molecular weight fibers 3.5 g of sodium hyaluronate (NaHA) fibers of intrinsic viscosity 2800 ml/g and moisture content 8.7% are weighed out and 25.6 g of 0.25 N NaOH are added. Hydration of the fibers takes 2 h with regular manual homogenization using a spatula. 0.96 g of a solution of 1,~4-butanediol diglycidyl ether (BDDE) diluted to 1/5 in 0.25 N sodium hydroxide solution is added to the reaction medium, this being followed by mechanical homogenization for I5 min before immersion in a thermostatically controlled bath at 50°C ~ 1°C.
R = [BDDE]o/[NaHA)o = 6% ; [NaHA]; = 105 mg/g The reaction takes 2 h. The crosslinked product is neutralized to pH 7.2 in a phosphate buffer solution and then dialyzed. The concentration of the resulting hydrogel is then adjusted ([NaHA]f = 26 mg/g) and the 1o hydrogel is mechanically homogenized before being packed into syringes and sterilized in an autoclave by means of moist heat.
Injection force after sterilization: 25 N
R~emanence index of the hydrogel: 1.0 Monophase hydrogel EXAMPLE 2: low-molecular weight fibers 1.56 g of sodium hyaluronate (NaHA) fibers of intrinsic viscosity 600 mi/g and moisture content 5.5% are weighed out and 7.15 g of 0.25 N NaOH are added. Hydration of the fibers takes 2 h with regular 2o manual homogenization using a spatula. 0.31 g of a solution of 1,4-butanediol diglycidyl ether (BDDE) diluted to 1/5 in 0.25 N sodium hydroxide solution is added to the reaction medium, this being followed by mechanical homogenization for 15 min before immersion in a thermostatically controlled bath at 50°C ~ 1°C.
2s R. _ [BDDE]o/[NaHA]p = 6.8%; [NaHA]; = 174 mg/g The reaction takes 2 h. The crosslinked product is neutralized to pH 7.2 in a phosphate solution and then dialyzed. The concentration of the resulting hydrogel is then adjusted ([NaHA]f = 26 mg/g) and the hydroge( is mechanically homogenized before being packed into syringes and 3o sterilized in an autoclave.
Injection force after sterilization: 24 N
R:emanence index of the hydrogel: 6.0 Biphase hydrogel EXAMPLE 3: mixture of fibers 0.763 g of sodium hyaluronate (NaHA) fibers of intrinsic viscosity 600 ml/g and moisture content 5.5% and 0.237 g of sodium hyaluronate fibers of intrinsic viscosity 2800 ml/g and moisture content 9.3% are s v~reighed out. Proportions by weight in the mixture: 600/2800 77/23 (w/w).
The procedure remains identical to that of Example 2.
R, _ [BDDE]o/(NaHA]o = 7%; [NaHA]; = 140 mg/g; (NaHA]f = 26 mg/g Injection force after sterilization: 15 N
io F;emanence index of the hydrogel: 3.6 P~lonophase hydrogel EXAMPLE 4: mixture of fibers The experiment of Example 3 is repeated, modifying the proportions 15 by weight. Proportions by weight in the mixture: 600/2800 : 90/10 (w/w).
The procedure is identical to that of Example 2.
R = [BDDE]o/[NaHA]o = 6.5%; [NaHA]; = 140 mg/g; [NaHA]f = 26 mg/g Injection force after sterilization: 14 N
Remanence index of the hydrogel: 7.7 2o Monophase hydrogel Said Examples are summarized in the Table below.

U

O X
N N
O ~ ~ n (d r-WO M I~

L

a ~ ~ ~ ,-~-i r~l N N
V- N

Q

O
Q ca d0'. p ~ O
_+~~O~pO_ O U' O Z I 1 O n +~ ~ ~p r~ N
t=p ~ M O N
+-' d' O t0 (~

M N u1 +~

O U
N C

V f0 Q

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The attached Figure shows the following curve:
Tan.delta = f (stressing frequency) for each of the four hydrogels prepared according to Examples 1 to 4.
The rheological behavior of the hydrogeis of the invention s (Examples 3 and 4) is different from that of the hydrogel of the prior art (Example 1).
Furthermore, the hydrogels of the invention are monophase and thus very different from the hydrogel of Example 2 (biphase).

Claims (16)

1. Process for the crosslinking of at least one polymer selected from polysaccharides and derivatives thereof, which is carried out in an aqueous solvent by the action of an effective and non-excessive amount of at least one crosslinking agent, characterized in that it is carried out on a mixture containing at least one low-molecular weight polymer and at least one high-molecular weight polymer.
2. Process according to claim 1, characterized in that said mixture contains a single polymer with at least two different molecular weights, at least one being low and at least one being high, and advantageously with two different molecular weights, one low and one high.
3. Process according to claim 1 or 2, characterized in that said polymer is a hyaluronic acid salt.
4. Process according to claim 3, characterized in that said hyaluronic acid salt is selected from the sodium salt, the potassium salt and mixtures thereof, and advantageously consists of the sodium salt.
5. Process according to any one of claims 1 to 4, characterized in that said mixture contains:
- at least one hyaluronic acid salt of low molecular weight m, where m <= 9.9.10 5 Da, advantageously 10 4 Da <= m <= 9.9.10 5 Da; and - at least one hyaluronic acid salt of high molecular weight M, where M >= 10 6 Da, advantageously 10 6 Da <= M <= 10 8 Da, and very advantageously 1.1.10 6 Da<=M<=5.10 6Da, said low-molecular weight and high-molecular weight salts advantageously being of the same nature and very advantageously consisting of sodium hyaluronate.
6. Process according to claim 5, characterized in that said mixture has an intrinsic viscosity of less than 1900 ml/g.
7. Process according to claim 5 or 6, characterized in that said mixture contains more than 50% by weight, advantageously more than 70% by weight, of at least one hyaluronic acid salt of low molecular weight m, and less than 50% by weight, advantageously less than 30% by weight, of at least one hyaluronic acid salt of high molecular weight M.
8. Process according to any one of claims 5 to 7, characterized in that said mixture contains at least 5% by weight of at least one high-molecular weight hyaluronic acid salt.
9. Process according to any one of claims 5 to 8, characterized in that said mixture contains about 90% by weight of the sodium salt of hyaluronic acid having a molecular weight of about 3.10 5 Da, and about 10% by weight of the sodium salt of hyaluronic acid having a molecular weight of about 3.10 6 Da.
10. Process according to any one of claims 1 to 9, characterized in that said crosslinking agent is selected from bifunctional crosslinking agents and mixtures thereof, is advantageously selected from epichlorohydrin, divinyl sulfone, 1,4-bis(2,3-epoxypropoxy)butane, 1,2-bis(2,3-epoxypropoxy) ethylene, 1-(2,3-epoxypropyl)-2,3-epoxycyclohexane, aldehydes such as formaldehyde, glutaraldehyde and crotonaldehyde, and mixtures thereof, and very advantageously consists of 1,4-bis(2,3-epoxypropoxy)butane.
11. Process according to any one of claims 1 to 10, characterized in that said effective and non-excessive amount of at least one crosslinking agent is such that the degree of crosslinking, defined by the ratio: 100 x (total number of reactive groups in said crosslinking agent/total number of disaccharide units in the polymer molecules present), is theoretically between 0.5 and 70%, advantageously between 4 and 50%.
12. Process for the preparation of an injectable monophase hydrogel of at least one crosslinked polymer selected from polysaccharides and derivatives thereof, characterized in that it comprises:
- the crosslinking of a mixture according to any one of claims 1 to 11; and - the formulation of said crosslinked mixture, neutralized if necessary, into a solution buffered to a pH of between 6.5 and 7.5, advantageously of between 7 and 7.4 and very advantageously of between 7.1 and 7.3.
13. Process according to claim 12, characterized in that it comprises:
- the crosslinking of a mixture according to any one of claims 3 to 11; and - the formulation of said crosslinked mixture, neutralized, into a solution buffered to a pH of between 7.1 and 7.3, at a concentration of between 10 and 40 mg/g, advantageously of between 20 and 30 mg/g.
14. Crosslinked polymer obtainable after a crosslinking process according to any one of claims 1 to 11 has been carried out.
15. Injectable monophase hydrogel obtainable after a preparative process according to claim 12 or 13 has been carried out.
16. Injectable monophase hydrogel according to claim 15, containing low-molecular weight sodium hyaluronate and high-molecular weight sodium hyaluronate in crosslinked form.
CA2521961A 2003-04-10 2004-04-08 Crosslinking of low-molecular weight and high-molecular weight polysaccharides; preparation of injectable monophase hydrogels; polysaccharides and hydrogels obtained Expired - Lifetime CA2521961C (en)

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