Patent Application
20070264315
The invention will be better understood and other characteristics and advantages thereof will become more clearly apparent from the following explanatory description referring to the Figures, in which:
In the different features of the invention, the paste of the invention is a biocompatible paste and the water used for its preparation is advantageously prepurified water as conventionally used in products that are to be brought into contact with a wound.
As essential components, this paste contains natural kaolin, a humectant selected from the group comprising propylene glycol, glycerol, polyethylene glycol, sorbitol and mixtures thereof, and a hydrogelling agent selected from the group consisting of an anhydrous colloidal silica, a cellulose, carboxymethyl cellulose, guar gum, xanthan gum and mixtures thereof.
In the presence of water introduced in a sufficient amount to substantially saturate the kaolin and form a hydrogel by virtue of the presence of the hydrogelling agent, these three essential constituents make it possible to obtain a composition in the form of a paste whose rheological properties and adhesive (tack) properties are suitable for achieving the effect of a dressing on the oral mucosae or the skin when this paste is applied.
Those skilled in the art will of course understand that the proportions of the essential constituents and that of the water present in the composition can vary according to the nature of the two constituents represented by the hydrogelling agent and the hydrating agent.
The kaolin contains at least 80% by weight and advantageously at least 95% by weight of kaolinite and acts as a fluid absorber in the paste of the invention. It has the general properties of the clays known in medicine and cosmetics, but, in particular, in combination with the hydrogelling agent and the humectant, it gives the paste of the invention the desired texture and theological behavior.
The (preferably purified) water is introduced in a sufficient amount to give a paste of the desired viscosity, texture and appearance.
The humectant makes it possible on the one hand to obtain the visual appearance of the product and to prevent the paste from drying out during storage.
In particular, in cooperation with the other two essential constituents of the invention represented by the hydrogelling agent and the kaolin, the humectant makes it possible to obtain the desired texture and rheological behavior of the paste. The hydrogelling agent additionally gives the paste properties of adhesion to the skin or the oral mucosae.
The hydrogelling agent is preferably an anhydrous colloidal silica and particularly preferably one with a specific surface area in the order of 200 m2/g. An example of such an anhydrous colloidal silica is the product marketed under the mark Aérosil® 200 by Degussa.
In one particularly advantageous variant, the humectant is propylene glycol.
As explained above, the proportions of the essential constituents vary according to their nature.
However, in one particularly advantageous variant of the invention, in the case where the hydrogelling agent is anhydrous colloidal silica, the paste comprises the following proportions by weight of essential constituents and water:
By virtue of the presence of the kaolin, the paste of the invention as defined above already possesses valuable hemostatic properties.
However, it will often be advantageous to add to this paste an astringent, which contributes to stopping the bleeding more rapidly through its tissue retracting action, and/or a vasoconstrictor, which also contributes to stopping the bleeding more rapidly through its constricting action on the blood vessels.
This astringent will advantageously be selected from the group comprising iron or aluminum chlorides and sulfates, potassium aluminum sulfate and mixtures thereof.
Preferably, the astringent will be aluminum chloride and will be present in the composition in a concentration advantageously of between 5 and 25% by weight, preferably of about 15% by weight, based on the total weight of the paste.
Finally, a vasoconstrictor, e.g. adrenaline, may also be introduced into the paste of the invention.
As explained above, the value of the compositions of the invention is their ability to form a dressing when applied to the skin or the oral mucosae. This imposes very specific rheological and adhesive properties on the paste, which are advantageously as follows:
This rheofluidifying behavior is characterized by a yield stress of between 110 and 140 Pa, measured at 23° C., and a viscosity of between 60 and 90 Pa·s, measured at a shear rate of 5 s−1 and a temperature of 23° C.
Thus the paste of the invention preferably has a rheofluidifying behavior at 23° C. This means that the viscosity of the paste according to the invention drops when a stress is applied. Thus, at rest, the paste of the invention has a viscosity of between 3000 and 4500 Pa·s, measured at 23° C. This viscosity enables it to remain in place, even on non-horizontal substrates, without flowing.
However, when applying a low stress, such as a stress corresponding to a mixing action with a spatula, the viscosity of the paste drops, enabling it to be applied to and smoothed over the skin or the oral mucosae without any effort.
This behavior also enables it to be applied to the application site with a syringe by simply using manual force, without exerting excessive pressure.
This constitutes an advantage for the compositions of the invention, which will advantageously be packaged in syringes, particularly those with disposable tips, especially for use by dentists.
The paste of the invention has a thixotropic behavior; in other words, even after manual agitation or the application of pressure to eject it from the syringe, it recovers its original viscosity once the agitation or the application of pressure has stopped.
Furthermore, the paste of the invention adheres to the skin and also to the oral mucosae, which are a moist environment at 37° C., without the application of pressure to hold it in place.
This adhesive property corresponds to an adhesive (tack) strength of between 0.3 and 0.7 N, measured at 23° C. and ambient humidity.
When measured at 37° C. and 90% relative humidity in order to simulate the humidity and temperature conditions of the mouth, the adhesive properties of the paste of the invention remain excellent.
Preferably, the adhesive (tack) strength of the paste of the invention is between 0.5 and 0.6 N.
As regards the rheofluidifying behavior of the paste, this is characterized by a yield stress of between 110 and 140 Pa, measured at 23° C., and a viscosity of between 60 and 90 Pa·s, measured at a shear rate of 5 s−1 and a temperature of 23° C.
Thus, by virtue of its theological behavior, advantageously enabling it to flow easily under a low stress, the paste of the invention can be packaged in a syringe, allowing the product to be applied in a precise and localized manner and to be kept aseptic.
Of course, the paste of the invention is biologically compatible.
The paste of the invention can be used to stop the skin from bleeding and also to stop the oral mucosae from bleeding, so it is particularly suitable for use by dentists when they are operating. In fact, the paste of the invention may be applied with a syringe or with a spatula, without exerting pressure.
Once in place, its adhesive properties are such that it adheres to the oral mucosae and stops the bleeding without having to be held by the application of pressure.
Finally, the paste of the invention advantageously contains a colorant. The presence of the colorant is of particular value in dental applications because it will enable the dentist to locate the wound more easily during the intervention.
It is for this reason that a blue colorant will preferably be chosen in dental applications.
The paste of the invention will also advantageously comprise a flavoring.
Both the colorant and the flavoring will advantageously be selected from food-grade products.
Of course, those skilled in the art will readily understand that the amounts and concentrations of the colorants and/or flavorings, and in general of the products used in the pastes of the invention, will have to be determined so as not to modify the rheological and adhesive properties of the composition.
One particularly preferred paste according to the invention comprises between 0.03 and 0.1% of food-grade blue colorant and/or between 0.5 and 2% of food-grade flavoring, in percentages by weight based on the total weight of the paste.
Preferably, if present, the colorant must be of food grade and present in the paste of the invention in a percentage by weight of 0.05%, based on the total weight of the paste.
The use of a blue colorant is particularly advantageous, especially on the mucosae.
If present in the paste according to the invention, the food-grade flavoring is preferably present in a concentration of 1% by weight, based on the total weight of the paste.
As explained above, the paste of the invention preferably contains a blue colorant so that the dentist can precisely locate the application site of the paste. Once bleeding has stopped, the paste of the invention is removed simply by rinsing with water, no rubbing being necessary. Here again, the blue coloration will enable the dentist to assess visually that all the paste has been removed.
He will then be able to continue treatment as required.
As indicated above, by virtue of their composition and their ability to adhere to the skin or the oral mucosae, the pastes of the invention can advantageously be used as a dressing and very particularly as a hemostatic dressing.
To provide a better understanding of the invention, several embodiments thereof will now be described by way of purely illustrative and non-limiting Examples.
A paste according to the preferred embodiment of the invention is obtained by the following process. This process is carried out at room temperature.
38 g of water are weighed out.
10 g of this water are taken and 0.05 g of food-grade blue colorant is dissolved therein to give a first solution.
15 g of aluminum chloride are then dissolved in the remainder of the water.
When the aluminum chloride has completely dissolved, 3 g of propylene glycol and 1 g of flood-grade strawberry flavoring are added.
This solution is homogenized to give a second solution.
The first solution containing the food-grade blue colorant is then introduced into the second solution and the whole is homogenized.
The pH of the resulting solution is 2.
4.05 g of Aérosil® 200 are added to this solution and the product is mixed to give a gel.
38.9 g of commercial kaolin containing at least 95% by weight of kaolinite are added gradually to this gel.
When all the kaolin has been incorporated, mixing is continued in order to homogenize the product.
In this Example, which is the particularly preferred embodiment of the invention, the aluminum chloride is used as an astringent,
Rheological Behavior
The theological behavior of the paste obtained in this Example was measured using a flow test in which the sample of paste is stressed at a given rate of strain (shear rate) and the corresponding stress is measured for increasing rate of strain values.
The following procedure is used:
Equipment: AR 1000 rheometer from TA Instruments
Data processing software: Rheology Advantage Data Analysis V5.1.42
Type of test: flow with measurements at equilibrium, the following applying to each point:
validation by three concordant samplings (tolerance: 5%)
sampling period: 10 s
maximum measurement time per point: 1 minute
Number of points: 50, with linear distribution
Range of shear rates: 0.05-5 s−1
Temperature: 23° C., controlled by Pelletier Plate (precision: 0.1° C.)
Measuring geometry: 25 mm anodized aluminum plate
Air gap: 1200 μm
Product deposited with a spoon
Manual descent to 1500 μm
Automatic descent to 1250 μm
Cleaning of surplus sample
Automatic descent to 1200 μm
The results obtained are presented in
This drop in viscosity is very marked up to 2 s−1, after which a kind of plateau is observed, the viscosity decreasing at a much slower rate.
The Figure also shows the presence of a vertical asymptote for shear rates close to zero. This means that the viscosity is infinite for a zero shear rate. In other words, the paste has a very high flow resistance when at rest. This property enables the paste to “sit” and not to flow when it is subjected to shear stresses below a value known as the yield stress.
The behavior of the product can be represented by the Hershel-Bulkley equation:
μ=σs/γ0+β(γ0)n−1
where σs (yield stress), β and n are constant.
The yield stresses over 5 tests were obtained by performing an extrapolation calculation centered more on the low shear rates. As regards the viscosity at 5 s−1, this was measured using the processing software.
The yield stress values and the viscosity values obtained, measured at 5 s−1, are collated in Table I below:
To demonstrate the stability of this rheological behavior and evaluate the effect of sedimentation of the paste, some of the paste obtained in Example 1 was centrifuged and the bottom part of the centrifuged sample was collected. This bottom part is subjected to the same flow test as described above.
The curves shown in
If the curves obtained in
Table II below collates the yield stress values and the corresponding viscosities obtained in the paste of the invention after centrifugation.
It is seen that sedimentation has a slight influence on the paste, which is found to be slightly thickened.
This results in a slightly higher yield stress in the order of 160 Pa instead of 120, but there is no distinct variation of the plateau viscosity, which remains of the same order of magnitude.
Thixotropic Behavior
The thixotropic behavior of the paste obtained in this Example was also demonstrated.
This thixotropic behavior was evaluated on the uncentrifuged sample obtained in Example 1.
The thixotropic character of the paste of the invention, i.e. its capacity to recover its initial viscosity (viscosity at rest) after being stressed, was demonstrated using the following test carried out at 23° C.:
shear at a very low shear rate (0.05 s−1) for 5 minutes after sampling every 10 seconds
shear at 5 s−1 for 30 seconds with sampling every 2 seconds
repeat of step 1
measuring geometry: 25 mm aluminum plate
air gap: 1200 μm
This test makes it possible to visualize the recovery of the viscosity after shear by comparing the viscosity obtained at equilibrium during the first step with that measured during the third step.
The results obtained are presented in
It is seen in the third step that the fluid tends to recover its initial viscosity after stress, this reversibility being characteristic of thixotropy.
Two types of test were carried out to demonstrate the adhesive properties of the paste obtained in the Example of the invention.
Firstly, a test was carried out at 23° C. and ambient humidity.
These tests are based on FINAT standard test method no. 9 with the following exceptions:
ambient humidity
sample adhesive coated on fixed substrate (aluminum plate)
contact area: 25 mm×25 mm
sensor: 5 N+0.025 N
the paper used has a basis weight of 80 g/m2.
These tests correspond to loop tack tests.
The loop tack test consists in bringing a strip of paper into contact with a sample and measuring the force required to detach the paper, i.e. the tack strength. The contact area is 625 mm2 (i.e. 25 mm×25 mm).
This test does not involve push contact; in other words, the loop is simply placed on the surface to be studied, in contrast to the needle tack tests, where a maintenance pressure is applied during contact.
Although the name of this test refers to the concept of tack, it actually measures stickiness, a term employed e.g. to describe jam or soft chocolate.
The measured adhesive (tack) strengths (in N) are collated in Table III below:
The curve representing the behavior of the paste obtained in Example 1 is shown in
In the case of the paste of the invention, the “loop tack” test does not enable the adhesive strength to be measured because the measured value is of the same order as the measurement noise. It can therefore be said that, in the case of simple contact, without pressure, the paste of the invention exhibits adhesive properties. The rupture pattern observed with the paste of the invention confirms this conclusion. In fact, a deposit of paste of the invention remains on the loop after detachment. It will be noted that the measured value of the tack strength cannot be associated with this inevitable excess weight of the loop, since the curve returns to zero (measurement noise after the detachment peak).
Furthermore, it should be emphasized that there is a correlation between the cohesion of the paste of the invention and its adhesion to a surface.
The tack strength is defined as the force required to separate a material that possesses instantaneous adhesion, i.e. contact adhesion, from a surface that is to be stuck to said material. Now, the rupture is cohesive, meaning that the adhesion of the paste of the invention is greater than the cohesion. The term stickiness is used under these conditions.
However, this low cohesion in no way detracts from the intended application, since the paste of the invention is used in thin layers on the skin or the gum.
The yield stress is then sufficiently large to prevent the bulk of the product from flowing under the effect of gravity or flowing blood.
“Loop tack” tests were also carried out in a controlled atmosphere, simulating the conditions found in the mouth.
These tests are also based on FINAT standard test method no. 9 with the following values:
temperature: 37° C.
humidity: 90%
adhesive (sample) coated on the borosilicate glass sample holder of the system
contact area: 25 mm×40 mm
sensor: 5 N±0.025 N
The paper used has a basis weight of 80 g/m2.
The tack strengths measured on the sample paste are collated in Table IV below:
The values obtained under these conditions differ from those obtained at 23° C. and ambient humidity.
In fact, the high humidity of the environment causes the paste of the invention to absorb water and become filled with water. However, the same type of rupture continues to be observed, meaning that, under these conditions, the paste of the invention still makes it possible to obtain adhesion on the gum without applying pressure.
Furthermore, if it is considered that, at the moment of coating on the wound, the ambient humidity of the mouth ultimately has only a small influence on the behavior of the paste, since it does not have the time to acclimatize to the humidity conditions of the mouth during this short phase.
Measurement of the Contact Angles
The adhesive properties of the paste of the invention were also demonstrated by contact angle measurements.
The object of these measurements is to measure the contact angles formed by drops of reference liquid of controlled volume (in this case two microliters) deposited on the surface of a given substrate (in this case the paste of Example 1). The angles are measured on the right and left of the drop for better precision, two seconds after the drop has been deposited.
The reference liquids used are water and isotonic solution, which gives results similar to those obtained in the case of the saliva and blood bathing the gum.
The paste of Example 1 was coated on a microscope slide until a satisfactory surface evenness was obtained. About 1 g of this paste was used to give a film having a thickness of about 1 mm and a surface area of 10 cm2, corresponding to a basis weight of about 1 kg of paste per m2 of slide.
The contact angle is measured on at least 5 samples of the reference liquids with the paste of Example 1.
Measurement of the contact angle makes it possible to visualize the spreading of the reference liquids over the paste obtained in Example 1, i.e. the affinity of these liquids for the paste of Example 1. These measurements give an idea of the affinity of the paste of Example 1 for the liquids in contact with the gum, such as saliva and blood.
In the case of a very weak interaction between the sample and the substrate (paste of Example 1), the measured contact angle will be high, since the sample attempts to minimize its contact area with the substrate (paste of Example 1).
In the opposite case, the sample will spread very well over the substrate (paste of Example 1) and the angle will be very small.
The values of the angles measured using the paste of the invention obtained in Example 1 as substrate, and drops of water and/or drops of saline solution, are presented in Table V below.
It is therefore seen that the drops have a fairly small contact angle, showing that the paste obtained in Example 1 will indeed wet the surface of the gum when it comes into contact therewith.
Tests of Tolerance and Anti-Bleeding Efficacy
Tolerance and biocompatibility tests were performed by applying the paste of the invention obtained in Example 1 to injured hamster cheeks.
These tests showed the perfect tolerance and biocompatibility of the paste of the invention.
They also showed that the paste of the invention obtained in Example 1 makes it possible to stop bleeding by application for about 2 minutes.
As the paste of the invention does not dry out, even several hours after application, it is removed after these 2 minutes by simply washing with water, without the need for rubbing.
A process for the production of a paste according to the invention that does not contain aluminum chloride is given below.
This process is carried out at room temperature.
45.55 g of water are weighed out.
10 g of this water are taken and 0.05 g of food-grade blue colorant is dissolved therein to give a first solution.
3 g of propylene glycol and 1 g of food-grade strawberry flavoring are dissolved in the remainder of the water and the solution is homogenized. The first solution containing the colorant is then added to this solution and the whole is homogenized. This addition of acid gives a pH comparable to that of the composition of Example 1.
0.4 g of tartaric acid crystals is added and the whole is mixed and homogenized.
The pH of the resulting solution is 2.
4.05 g of Aérosil 200 are then added and the whole is mixed to give a gel.
46 g of kaolin are added gradually to this gel. When all the kaolin has been incorporated, mixing is continued in order to homogenize the product.
The results in terms of theological behavior, viscosity, thixotropy, contact angles and tolerance are similar to the results obtained with the paste according to Example 1.
It is thus seen that the paste of the invention exhibits a stickiness which allows adhesion without pressure when used as a mechanical dressing on a skin or gum wound; this is a great asset to guaranteeing the painless nature of the operation and the cleanliness of the wound after treatment, since no appreciable pressure will have been exerted on the wound.
Furthermore, the paste of the invention is removed very easily and painlessly.
Of course, the invention is in no way limited to the preferred embodiments, which have been given solely by way of illustration and without implying a limitation.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0651678 | May 2006 | FR | national |
| PCT/FR07/50938 | Mar 2007 | FR | national |
