Flexibility measurements of injectable gels

Abstract

A process for evaluating rheological characteristics of an injectable gel including measuring the flexibility, wherein the flexibility is evaluated by measuring the strain at the crossover point of the amplitude sweep. The process may include subjecting an injectable gel to oscillating mechanical stresses to determine G′ and G″ as a function of strain (γ) in an amplitude sweep, determining the crossover point as the point at which G′ and G″ have the same value, determining the strain γ.sub.cross at the crossover point, and determining the flexibility of the injectable gel as γ.sub.cross or proportional to γ.sub.cross. Further, a method of comparison of dermal fillers by measuring their flexibility and a method of evaluation of dermal filler behavior in human skin by measuring the flexibility.

Claims

1. A process for evaluating flexibility of an injectable gel, the process comprising: subjecting the injectable gel to oscillating mechanical stresses to determine elastic modulus (G′) and viscous modulus (G″) of the injectable gel as a function of strain (γ) in an amplitude sweep of the injectable gel; determining the strain (γ.sub.cross) at a crossover point of the amplitude sweep of the injectable gel, wherein the crossover point of the amplitude sweep is where G′ and G″ have the same value; determining the flexibility of the injectable gel as the strain γ.sub.cross at the crossover point; and comparing the flexibility of the injectable gel with a flexibility value of a reference gel, wherein flexibility of the injectable gel higher than the flexibility value of the reference gel indicates that the injectable gel is more suitable than the reference gel for being implanted at facial regions that are subjected to movement.

2. The process according to claim 1, wherein the amplitude sweep is performed by increasing deformation of the injectable gel until a change in both G′ and G″ are observed.

3. The process according to claim 1, wherein determining the strain (γ.sub.cross) at the crossover point of the amplitude sweep of the injectable gel is performed by plotting G′ and G″ as a function of the strain (γ) and selecting the crossover point as the point where the plot of G′ and the plot of G″ intersect.

4. The process according to claim 3, wherein plotting G′ and G″ as a function of the strain (γ) comprises performing a frequency sweep at a fixed strain before performing the amplitude sweep.

5. The process according to claim 1, wherein the flexibility of the injectable gel is measured in percentage (%).

6. The process according to claim 1, wherein the amplitude sweep is performed at a frequency of between 0.5 Hz-1.5 Hz.

7. The process according to claim 1, wherein the injectable gel is a dermal filler comprising crosslinked hyaluronic acid.

8. A method of comparing suitability of injectable gels as dermal fillers, the method comprising: evaluating the flexibility of a plurality of injectable gels that are candidate dermal fillers according to the method of claim 1; comparing the evaluated flexibility between or among the plurality of injectable gels; and selecting a dermal filler from the plurality of injectable gels as a dermal filler suitable for injection based on the comparison.

9. The method according to claim 8, wherein the injectable gel having the highest flexibility value of the plurality of injectable gels is selected as the dermal filler suitable for injection in the facial area.

10. The process according to claim 1, wherein determining the strain (γ.sub.cross) at the crossover point of the amplitude sweep of the injectable gel, wherein the crossover point of the amplitude sweep is where G′ and G″ have the same value, comprises receiving input data of G′ and G″ as a function of the strain γ of the injectable gel.

11. The process according to claim 10, further comprising displaying the flexibility of the injectable gel on a computer screen.

12. The process of claim 10, wherein the process is performed using a device in communication with computer-executable components run on a processing unit included within the device.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows an example of an amplitude sweep showing uncertain yield points.

(2) FIG. 2 shows an amplitude sweep with the crossover point.

(3) FIG. 3 shows an amplitude sweep results for Defyne (FIG. 3a) and Refyne (FIG. 3b).

(4) FIG. 4 shows flexibility values for a number of dermal fillers.

(5) FIG. 5 shows OBT products with fewer (FIG. 5a) and more (FIG. 5b) crosslinking points, while in a relaxed state.

(6) FIG. 6 shows OBT products with fewer (FIG. 6a) and more (FIG. 6b) crosslinking points, while in a stretched state.

DETAILED DESCRIPTION OF THE INVENTION

(7) The present invention relates to a process to characterize an injectable gel, and more preferably a dermal filler gel, by measuring a new parameter, the flexibility.

(8) The flexibility of the gel is measured and in the below description and examples denoted as XStrain. The higher the value is, the higher the flexibility of the gel. This new parameter can be used to characterize different dermal fillers and their different behaviors in skin after injection.

(9) To verify if a difference in flexibility could be detected using a scientific test methodology, rheology was employed. For the first time, the filler flexibility can be measured. As evaluated from the cross-over point between G′ and G″ in the amplitude sweep results, a difference in flexibility was evident from the difference in the deformation (strain, γ) at which the cross-over point occurred. The flexibility value obtained is here denoted XStrain. The value of XStrain demonstrates how much deformation the tested material can withstand before changing from a solid-like to a liquid-like behavior, i.e. going from basically reversible to basically irreversible deformation. The XStrain measured can be considered a flexibility index of a material.

(10) The firmness of a product, measured as G′ using rheometry, is performed under nearly static conditions. The deformations used in these measurements are very small, in order to keep within the linear viscoelastic region (LVR), the region where the stress changes linearly with deformation. These measurements are normally performed as a frequency sweep. In order to determine a suitable level of deformation to use in the frequency sweep, an amplitude sweep is performed, where the amount of deformation is increased until a change in the results is observed, indicating the end of the LVR. A level of deformation where the measured firmness is stable is chosen for the frequency sweep. However, the data from the amplitude sweep can be further evaluated. When the edge of the LVR is reached, it means that the deformation is so large that the material can no longer retain its original shape, and starts behaving more like a liquid than a solid. In rheology, this point is often referred to as the yield point. A typical example of a material having a noticeable yield point is tomato ketchup, which moves frustratingly little until the bottle is shaken enough, resulting in the delivered portion of ketchup being larger than intended.

(11) Though there is a consensus on what the yield point is, the definition on where in the amplitude sweep this can be found may vary. Generally, as soon as there is a change in the signal, e.g. in the level of G′, this would indicate the endpoint of the LVR. Since there is always some noise in the signal, the change has to be of a certain magnitude in order to be correctly detected. When analyzing very soft samples giving a weaker signal, a larger deviation has to be allowed in order not to incorrectly detect noise as the end of the LVR (FIG. 1).

(12) An endpoint that is much easier to pinpoint exactly is the cross-over point, where G′ and G″ intersect (FIG. 2). Though this point may be considered to overestimate the yield point, its exactness and simplicity is a huge advantage. The inventors have found that at this cross-over point, the strain can be evaluated as a measure of flexibility. A material with a large XStrain can stand a large deformation before yielding, and can therefore be considered to be more stretchable, or flexible. The cross-over strain value may be considered a flexibility index for the material.

(13) Flexibility values can be in the range of 0.1% to 20000% according to the type of dermal filler requested use.

(14) In a specific embodiment, when dermal filler are injected into the face to correct age related effects, the flexibility parameter gives the ability to natural animation without the implant showing under the skin. Being more of less flexible, the dermal filler hydrogel follows the movement of the face and gives the ability to preserve the natural expressions of the face.

EXPERIMENTAL EXAMPLES

(15) The following non-limiting examples will further illustrate the present invention. In these examples, the flexibility of different dermal fillers comprising hyaluronic acid was determined. The following examples are describing how flexibility can be measured through evaluation of the cross-over point from the amplitude sweep and help to characterize dermal filler products.

Example 1: Measurement of Flexibility

(16) a) Injectable Gels

(17) The Optimal Balance Technology (OBT) products from Galderma are dermal filler differing in the amount of crosslinker used. This results in materials with different rheological properties. There is a need to understand their behavior by characterizing their rheological properties, through this measurement of the new parameter: flexibility. The OBT family of dermal filler products has previously been found to cover a large span of G′ values as measured from a frequency sweep at small deformations. The purpose of this study was to investigate evaluation of the cross-over point in the amplitude sweep as a measure of flexibility for the OBT family of products. This measurement can characterize dermal fillers and explain their differentiating features and behavior in the skin.

(18) b) Test Methods

(19) The rheology measurement was performed in a sequence including a relaxation time of 30 min, a frequency sweep from 10 to 0.1 Hz at 0.1% strain, followed by an amplitude sweep from 0.1 to 10000% (0.001 to 100) strain at 1 Hz. The gap was 1 mm using a PP25 measuring system at 25° C. The frequency sweep was evaluated for G′, G″ at 0.1 Hz. The amplitude sweep was first evaluated at 0.1% strain in order to verify that the applied frequency sweep strain was within the linear viscoelastic range. Secondly the strain was evaluated at the crossover point of the amplitude sweep, i.e. the point where G′ and G″ have the same value (FIG. 3).

(20) c) Test Results

(21) Each product of the OBT range (Table 1) was analyzed for the xStrain value derived from the amplitude sweep (FIG. 4).

(22) TABLE-US-00001 TABLE 1 List of analyzed products and test results: Product xStrain (%) Restylane Defyne 761 Restylane Volyme 908 Restylane Kysse 930 Restylane Refyne 1442 Restylane Fynesse 2221

(23) d) Discussion

(24) Since the different products in the OBT family are crosslinked in exactly the same way, differing only in the amount of crosslinker used, it can be assumed that the main difference in the crosslinking structure is the distance between crosslinking points (FIG. 5). From this follows that when the material is subjected to mechanical stress, the material with a larger distance between the crosslinking points will allow more deformation before the HA chains are fully stretched (FIG. 6). This material will be perceived as more flexible, elastic or compliant, compared to a material with smaller distance between crosslinking points. Materials with larger distance between the crosslinking points—everything else equal—will tend to be more flexible, and will also tend to be softer. It must be pointed out, however, that the firmness derived from the small-deformation frequency sweep is a completely different property from the flexibility derived from the large-deformation amplitude sweep. Just because a material is soft, it does not necessarily have to be flexible. Each property has to be measured separately.

(25) The person skilled in the art realizes that the present invention by no means is limited to the preferred embodiments described above. On the contrary, many modifications and variations are possible within the scope of the appended claims. Additionally, variations to the disclosed embodiments can be understood and effected by the skilled person in practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims. In the claims, the word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measured cannot be used to advantage.