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Stabilised compositions containing hyaluronic acid, their preparation and use
Field of the invention
The invention refers to stabilised composition containing hyaluronic acid, or derivatives thereof commonly used in cosmetic surgery, and a carboxyvinylpolymer capable of greater resistance to demolishing action of the enzymes to which are submitted all the implants made of such materials once applied to patients. State of the art Hyaluronic acid is a polysaccharide naturally present in the human tissues where it is continuously formed. In view of its viscoelastic properties it as been used for a long time in cosmetic surgery to eliminate wrinkles, indentations, scars and similar. Hyaluronic acid is injected for example by means of sterile prefilled syringes, in the subcoutaneous region where the unaesthetic aspect is present and forms a thickness which eliminates the folds caused by wrinkles or scars.
However the hyaluronic acid is submitted to the demolishing action of natural enzymes and after a short time a new application is necessary. In order to overcome such drawback the hyaluronic acid was substituted by its derivatives as esters, salts, cross-linked derivatives but also these products, although allowing a greater permanence of the implant are not satisfactory since their life is always too short.
It is evident the interest in making available compositions containing hyaluronic acids or derivatives thereof, capable of greater resistance to the action of the enzymes and therefore capable of lengthening the time required before a new operation is necessary.
Detailed description of the invention
The present invention provides a means of overcoming of the above said drawbacks thanks to compositions consisting of hyaluronic acid (or derivatives thereof commonly used in the cosmetic surgery and therefore pharmaceutically acceptable) and a carboxyvinylpolymer (Carbomer) of general formula: COOH COOH
I I
H- [CH - CH - CH - CH]n- H (I) I I
OH OH
wherein n is comprised between 50 - 55,000 and having a molecular weight comprised between 10,000 and 10,000,000, preferably 5,000,000 - 6,000,000. Preferably the above said carboxyvinylpolymer is in a concentration of 0.001 % - 5% (quantity calculated as weight in respect of the total weight of the composition) more preferably 0.01 - 0.2%.
Among the hyaluronic acid derivatives used in the aesthetic surgery according to the invention we can cite in particular the esters (for example : methyl-, ethyl-, isopropyl-, butyl-, amyl-, isoamyl-ester), the organic or inorganic salts pharmaceutically acceptable (for example : natrium salt, thethylamine salt or the salts formed with basic aminoacids), cross-linked compounds (for example ethylen-glycole dimethacrylate, glutaric aldehyde, divinylsulphone). The composition according to the invention is prepared according to the methods commonly applied in the art. For example the hyaluronic acid (or the corresponding derivative) is mixed with the suitable quantity of polymer in a suitable mixer.
If the hyaluronic acid derivative used is an ester the mixing is performed in the presence of, for example, p-toluensulphonic acid or ethyl-iodide. The obtained mixture is solved in sterile water in order to obtain the wanted concentration, the solution is filtered using a nylon filter bearing positive charges ; the obtained solution is lyophilised and the solid is dried and solved again, in the appropriated quantity, in sterile water under stirring up to the formation of a viscoelastic transparent gel. The product is packaged in the suitable forms (vials, bottles, sterile prefilled syringes ready to use, preferably in the following quantities : 0.1 , 0.5, 1 , 1.5, 2 ml. Example 1
To 30 g of hyaluronic acid natrium salt 10 g of Carbomer 940 (polymer of Formula (I)) having a PM of about 5,000,000 and the mixture is solved in sterile water (10 3
It) and filtered through a nylon 66 filter (sieve 0.2 microns) up to a total concentration of 0.4%.
The solution is lyophilised to give a dry solid which is solved again in sterile water (1.3%) under stirring up to the formation of a viscoelastic transparent gel having the desired consistency.
The product is packaged in sterile prefilled syringes ready for use of 0.1 , 0.5, 1 ,
1.5, 2 ml.
Following the same procedure compositions wherein the final concentration of polymer is 0.005%, 0.08%, 2% were prepared. Example 2
Following the procedure described in example 1 but replacing the hyaluronic acid natrium salt with hyaluronic acid the corresponding formulation were prepared using the same quantities of polymer given in example 1.
Example 3 Following the procedure described in example 1 but replacing the hyaluronic acid natrium salt with the corresponding thethylamine organic salt the corresponding formulation were prepared using the same quantities of polymer given in example
1.
Example 4 Following the procedure described in example 1 but replacing the hyaluronic acid natrium salt with hyaluronic acid cross-linked with ethylenglycole dimethacrylate the corresponding formulation were prepared using the same quantities of polymer given in example 1.
Example 5 Following the procedure described in example 1 but replacing the hyaluronic acid natrium salt respectively with the methyl-, ethyl-, isopropyl-, butyl-, amyl-, isoamyl- esters of hyaluronic acid in the presence of p-toluensulphonic acid (6%) the corresponding formulation were prepared using the same quantities of polymer given in example 1. Example 6
Compositions analogous to those above described were prepared following the procedure described in example 1- 5 but replacing Carbomer 940 with Carbomer 4
980, 974, P.
Comparative test
A series of enzymatic digestion experiments was performed to compare the different behaviour of the compounds according to the present invention with respect to natrium hyaluronate.
In particular the enzymatic digestion of an aqueous solution of natrium hyaluronate 1.5% was compared to that of the same solution in the presence of
0.08% carboxyvinylpolymer
The enzyme hyaluronidase (type V SIGMA H6254) was used in the tests and the rate of enzymatic reaction was evaluated by kinematics viscosity measurements using a Brookfield RVF apparatus (spindle n° 5 at 10 rpm). The enzymatic degradation was conducted at 26°C and 37°C.
Under the enzyme action at 26°C the hyaluronate solution viscosity falls from
17,000 cps to 1 ,000 cps in 60 minutes, while at 37°C it falls from 15,000 to 7,000 cps in the same period of time.
The solution containing the carboxyvinylpolymer does not show any degradation of the polysaccharide after 60 minutes of contact with the enzyme both at 26°C as at 37°C
The use of the above described compositions in the usual cosmetic surgical applications allowed to obtain very good results, absolutely more satisfactory than those allowed by analogous composition without polymer.
The present invention refers also to a kit containing at least to pre-filled syringes ready for use containing the same or different quantities of a composition according to the invention in order to satisfy different needs.