Dressing enabling the controlled and prolonged release of metformin

Abstract

The subject matter of the present invention is, according to a first aspect, a dressing comprising an interface layer, characterised in that said interface layer comprises a weave coated with an elastomeric matrix comprising metformin, the salts and the complexes thereof. The subject matter of the invention is also a dressing comprising metformin, characterised in that the percentage of metformin released after 72 hours is between 40 and 100% of the quantity of metformin inserted in the dressing. Moreover, the subject matter of the invention is a method for producing said dressing as well as the use thereof for healing a wound.

Claims

1. A dressing comprising an interface layer comprising an elastomeric matrix, said matrix comprising metformin, the salts and the complexes thereof, wherein the metformin has a particle size defined by 75 μm<d50<300 μm and 195 μm<d90<600 μm.

2. The dressing according to claim 1, wherein the elastomeric matrix comprises an elastomer chosen from triblock sequenced polymers of the ABA type comprising two terminal A styrene blocks and a central sequence B which is a saturated olefin such as for example ethylene-butylene or ethylene-propylene.

3. The dressing according to claim 1, wherein the elastomeric matrix comprises at least one elastomer, said elastomer being a poly(styrene-(-ethylene-butylene-)-styrene) triblock sequenced polymer.

4. The dressing according to claim 1, wherein the metformin has a particle size defined by 75 μm<d50<200 μm and 75 μm<d90<510 μm.

5. The dressing according to claim 1, wherein the elastomeric matrix comprises a plasticiser and/or a hydrocolloid.

6. The dressing according to claim 1, wherein the plasticiser is a mixture of mineral oil.

7. The dressing according to claim 1, wherein the elastomeric matrix comprises at least one releasing agent chosen from the copolymer of the salt of 2-methyl-2[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid and of 2-hydroxyethyl ester of propenoic acid or of the mixture of 2-octyl-1-dodecanol, D-xylopyranoside, 2-octyldodecyl and polyethyleneglycol 30 dipolyhydroxystearate.

8. The dressing according to claim 1, wherein the elastomeric matrix consists substantially: 0.5 to 15%, in relation to the total weight of the matrix, of metformin having a particle size defined by 75 μm<d50<300 μm and 195 μm<d90<600 μm, the salts or the complexes thereof; 2 to 15%, in relation to the total weight of the matrix, of at least one elastomeric polymer; 1 to 25%, in relation to the total weight of the matrix, of at least one hydrocolloid; 45 to 95%, in relation to the total weight of the matrix, of at least one plasticiser; 0.05 to 1%, in relation to the total weight of the matrix, of at least one agent antioxidant; 0.01 to 10%, in relation to the total weight of the matrix, of a releasing agent chosen from the copolymer of the salt of 2-methyl-2[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid and of 2-hydroxyethyl ester of propenoic acid or the mixture of 2-octyl-1-dodecanol, D-xylopyranoside, 2-octyldodecyl and polyethyleneglycol 30 dipolyhydroxystearate.

9. The dressing according to claim 1, wherein the elastomeric matrix consists substantially: 0.5 to 15%, in relation to the total weight of the matrix, of metformin having a particle size defined by 75 μm<d50<300 μm and 195 μm<d90<600 μm, the salts or the complexes thereof; 2 to 15%, in relation to the total weight of the matrix, of at least one elastomeric polymer; 1 to 25%, in relation to the total weight of the matrix, of at least one hydrocolloid compound; 45 to 95%, in relation to the total weight of the matrix, of at least one plasticiser; 0.01 to 10%, in relation to the total weight of the matrix, of a releasing agent chosen from the copolymer of the salt of 2-methyl-2[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid and of 2-hydroxyethyl ester of propenoic acid or the mixture of 2-octyl-1-dodecanol, D-xylopyranoside, 2-octyldodecyl and polyethyleneglycol 30 dipolyhydroxystearate.

10. The dressing according to claim 1, wherein the percentage of metformin released after 72 hours is between 40 and 100% of the quantity of metformin inserted in the dressing.

11. A method of producing the dressing according to claim 1 comprising: i. preparing an interface layer formed from an elastomeric matrix by: a. preparing an elastomeric matrix by dispersion of the metformin having a particle size defined by 75 μm<d50<300 μm and 195 μm<d90<600 μm, the salts and the complexes thereof in an elastomer, b. coating of a weave with the elastomeric matrix prepared in the step i or the hot casting of said matrix, ii. optionally the covering of the interface layer with at least one absorbent layer iii. optionally the maintaining of the interface layer and of the possible absorbent layer by a strip or an adhesive support intended to be fastened onto the peripheral zones of healthy skin far from the wound.

12. A method of healing a wound in a subject having a wound comprising contacting the wound with the dressing of claim 1.

Description

FIGURES

(1) FIG. 1 is a graphical representation of the non-cumulative ideal dissolution profile and evaluated in mg/cm.sup.2 of released active principle

(2) FIG. 2 is a graphical representation of the cumulative dissolution profiles, evaluated in mg/cm.sup.2 of active principle released from dressings described from the example 1 to the example 7.

(3) FIG. 3 is a graphical representation of the non-cumulative dissolution profiles, evaluated in mg/cm.sup.2 of active principle released from dressings described from the example 1 and to the example 7.

(4) FIG. 4 is a graphical representation of the cumulative dissolution profiles, evaluated in μg/cm.sup.2 of active principle released from dressings described from the example 8 to the example 12.

(5) FIG. 5 is a graphical representation of the non-cumulative dissolution profiles, evaluated in μg/cm.sup.2 of active principle released from dressings described from the example 8 to the example 12.

(6) FIG. 6 is a graphical representation of the cumulative dissolution profiles, evaluated in μg/cm.sup.2 of active principle released from dressings described from the example 13 to the example 16.

(7) FIG. 7 is a graphical representation of the non-cumulative dissolution profiles, evaluated in μg/cm.sup.2 of active principle released from dressings described from the example 13 to the example 16.

(8) FIG. 8 is a graphical representation of the cumulative dissolution profiles, evaluated in μg/cm.sup.2 of active principle released from dressings described from the example 17 to the example 20.

(9) FIG. 9 is a graphical representation of the non-cumulative dissolution profiles, evaluated in μg/cm.sup.2 of active principle released from dressings described from the example 17 to the example 20.

(10) FIG. 10 is a graphical representation of the cumulative dissolution profiles, evaluated in μg/cm.sup.2 of released active principle from dressings described in the examples 21 and 22.

(11) FIG. 11 is a graphical representation of the non-cumulative dissolution profiles, evaluated in μg/cm.sup.2 of released active principle from dressings described in the examples 21 and 22.

(12) The following examples show, in a non-limiting way, the invention that is the subject matter of the present application.

(13) Generally, the various exemplified dressings were prepared according to the following method:

(14) The carboxymethylcellulose and the metformin are pre-mixed and screened at 315 μm.

(15) The vaseline and half of the oil are introduced into a mixer at a temperature setting of 115° C., at a speed from 75 to 120 rotations per minute (rpm), then the carboxymethylcellulose powders and screened metformin are introduced. This is mixed for 15 minutes.

(16) The temperature setting is increased to 150° C. Then half of the oil, the elastomer and the antioxidant are introduced. This is mixed for 40 minutes (until a smooth and homogeneous mixture is obtained). The releasing agent is introduced 15 minutes before the end.

(17) Then the tank of the mixer is emptied.

(18) Interface dressings comprised of a weave (or marquisette) (weave 601 marketed by the company MDB TEXINOV) coated with elastomeric matrix were elaborated using elastomeric matrices of the examples 1 to 21.

(19) The example 22 was carried out by hot casting of the composition described in table 23 on an etched plate forming the imprint of a net or grid with a square mesh that has the following dimensions: 200×200 mm, lugs of 1×1 mm, grooves d=600 μm, 1=1.6 mm. This moulding is followed by a demoulding. The elastomeric matrix thus obtained does not have any support weave and forms a self-supported interface layer.

(20) Method for Measuring the Cumulative and Non-Cumulative Release of Metformin:

(21) Equipment

(22) Luna SCX column 5 μm-100 Å-100 mm×4.6 mm, ref. Phenomenex 00D-4398-E0,

(23) HPLC system provided with a UV detector, a sample changer and a column over,

(24) Reagents

(25) Ammonium dihydrogen phosphate for analysis. For example: ref. VWR 21305.290 or equivalent,

(26) Low UV acetonitrile for analysis. For example: ref. VWR 20048.290 or equivalent,

(27) Sodium chloride for analysis. For example: ref. VWR 27810.295 or equivalent,

(28) Purified water, HPLC quality.

(29) Reference Substance

(30) Metformin hydrochloride for secondary reference stored in a closed bottle stored in drying oven.

(31) Solutions/Samples to be Prepared

(32) Phase Mobile

(33) The phase mobile is a solution of ammonium dihydrogen phosphate at 17 g/L to which are added 2% acetonitrile.

(34) Test Solutions

(35) Preliminary precaution: the physiological serum used during the analysis will be thermostatically controlled beforehand at 32° C.

(36) Cut a sample of 5 cm×5 cm at the centre of the dressing (weigh the sample),

(37) Introduce the sample into a hermetic jar,

(38) Add 10.0 mL of physiological serum,

(39) Stir at 120 strokes/minutes at 32° C. for 72 h,

(40) Take 1 sampling per jar at 4 h, 7 h, 24 h, 48 h and 72 h:

(41) At each one of these points, recover the supernatant,

(42) Place 10.0 mL of physiological serum in each jar,

(43) Stir again until the next sampling point.

(44) Assay the test solution by HPLC-UV.

(45) Operating Conditions

(46) TABLE-US-00001 TABLE 1 Chromatographic conditions Column Luna SCX - 5 μm - 100 mm × 4.6 mm Phase mobile Ammonium dihydrogen phosphate at 17 g/L + 2% of acetonitrile Flow rate 1.2 mL/min Temperature of the sample Non-refrigerated and not temperature changer monitored Temperature of the column 35° C. oven Mode Isocratic Injection volume 10 μL Detection UV set to 232 nm Retention time of the Approximately 6 minutes metformin peak Analysis time 10 minutes

(47) Calculations/Expression of Results

(48) Determination of the quantity of metformin released over time (either as a %, or in μg/cm.sup.2).

(49) Listing of HPLC data

(50) The test solutions analysed are quantified in relation to the calibration line. The results obtained from the calculator are given in μg/mL and are listed in table 2. The identification of the various tests is also indicated as follows:

(51) Surface of the sample: S (cm.sup.2)

(52) Weight of the weave: G (g/m.sup.2)

(53) Metformin content in the matrix: T (%)

(54) Initial volume: V (mL)

(55) TABLE-US-00002 TABLE 2 DRY raw results (μg/mL) Total Coated Sample mass mass no. Reference (g) (g) 4 h 7 h 24 h 48 h 72 h Pst X EXXXX m a b c d e

(56) With:

(57) a, b, c, d, e=HPLC raw results corresponding to the concentration of the test solutions injected respectively at 4 h, 7 h, 24 h, 48 h and 72 h (expressed in μg/mL to the nearest 10.sup.−4)

(58) Coated mass:

(59) $\mathrm{Coated}\mathrm{mass}=\left[\mathrm{total}\mathrm{mass}-\left(\frac{S}{10000}\times G\right)\right]$$S=\mathrm{surface}\mathrm{of}\mathrm{the}\mathrm{sample}\left({\mathrm{cm}}^2\right)$$G=\mathrm{weight}\mathrm{of}\mathrm{the}\mathrm{weave}\left(g/{\mathrm{cm}}^2\right).\mathrm{In}\mathrm{the}\mathrm{case}\mathrm{of}\mathrm{these}\mathrm{dressings},\mathrm{the}\mathrm{weight}G\mathrm{of}\mathrm{the}\mathrm{weave}\mathrm{is}28g/m^2.$

(60) Calculations of the Results of Cumulative Release

(61) The cumulative release results at each sampling point are expressed in μg/cm.sup.2 and as a percentage (%).

(62) TABLE-US-00003 TABLE 3 Sample Cumulative release of metformin in μg/cm.sup.2 no. Reference 0 4 h 7 h 24 h 48 h 72 h Pst X EXXXX 0.00 A B C D E μg/cm.sup.2 μg/cm.sup.2 μg/cm.sup.2 μg/cm.sup.2 μg/cm.sup.2

(63) TABLE-US-00004 TABLE 4 Sample Cumulative release of metformin in % no. Reference 0 h 4 h 7 h 24 h 48 h 72 h Pst X EXXXX 0.00 A % B % C % D % E %

(64) With:

(65) A μg/cm.sup.2, B μg/cm.sup.2, C μg/cm.sup.2, D μg/cm.sup.2 and E μg/cm.sup.2 which respectively designate the cumulative release at 4 h, 7 h, 24 h, 48 h and 72 h in μg/cm.sup.2 (to the nearest 10.sup.−2).

(66) A %, B %, C %, D % and E % which respectively designate the cumulative release at 4 h, 7 h, 24 h, 48 h and 72 h in % (to the nearest 10.sup.−′).

(67) TABLE-US-00005 TABLE 5 Expression of the results in μg/cm.sup.2 Cumulative release in μg/cm.sup.2 Time Symbol Calculation formula  4 h A μg/cm.sup.2 $\frac{a\times V}{S}$  7 h B μg/cm.sup.2 $\frac{b\times V}{S}+A\mathrm{.Math.g}\text{/}{\mathrm{cm}}^2$ 24 h C μg/cm.sup.2 $\frac{c\times V}{S}+B\mathrm{.Math.g}\text{/}{\mathrm{cm}}^2$ 48 h D μg/cm.sup.2 $\frac{d\times V}{S}+C\mathrm{.Math.g}\text{/}{\mathrm{cm}}^2$ 72 h E μg/cm.sup.2 $\frac{e\times V}{S}+D\mathrm{.Math.g}\text{/}{\mathrm{cm}}^2$

(68) TABLE-US-00006 TABLE 6 Expression of the results in % Cumulative release in % Time Symbol Calculation formula  4 h A % $\frac{a\times V}{\frac{T}{100}\times \mathrm{coated}\mathrm{mass}\times 1000000}\times 100$  7 h B % $\frac{b\times V}{\frac{T}{100}\times \mathrm{coated}\mathrm{mass}\times 1000000}\times 100+A\%$ 24 h C % $\frac{c\times V}{\frac{T}{100}\times \mathrm{coated}\mathrm{mass}\times 1000000}\times 100+B\%$ 48 h D % 0$\frac{d\times V}{\frac{T}{100}\times \mathrm{coated}\mathrm{mass}\times 1000000}\times 100+C\%$ 72 h E % $\frac{e\times V}{\frac{T}{100}\times \mathrm{coated}\mathrm{mass}\times 1000000}\times 100+D\%$

(69) Calculations of the Non-Cumulative Release Results:

(70) It is sufficient to use the cumulative release results and to subtract the value obtained at time t from the value obtained at time t−1.

(71) Cumulative Release Results:

(72) TABLE-US-00007 TABLE 7 Sample Cumulative release of metformin in μg/cm.sup.2 no. Reference 0 4 h 7 h 24 h 48 h 72 h Pst X EXXXX 0.00 A B C D E μg/cm.sup.2 μg/cm.sup.2 μg/cm.sup.2 μg/cm.sup.2 μg/cm.sup.2

(73) TABLE-US-00008 TABLE 8 Sample Cumulative release of metformin in % no. Reference 0 h 4 h 7 h 24 h 48 h 72 h Pst X EXXXX 0.00 A % B % C % D % E %
Use of these Results to Express the Non-Cumulative Release:

(74) TABLE-US-00009 TABLE 9 Sample Non-cumulative release of metformin in μg/cm.sup.2 no. Reference 0 4 h 7 h 24 h 48 h 72 h Pst X EXXXX 0.00 A B C D E μg/cm.sup.2 μg/cm.sup.2- μg/cm.sup.2- μg/cm.sup.2- μg/cm.sup.2- A B C D μg/cm.sup.2 μg/cm.sup.2 μg/cm.sup.2 μg/cm.sup.2

(75) TABLE-US-00010 TABLE 10 Sample Non-cumulative release of metformin in % no. Reference 0 h 4 h 7 h 24 h 48 h 72 h Pst X EXXXX 0.00 A % B %-A % C %-B % D %-C % E %-D %
List of the Results

(76) All of the results will be listed in summary tables such as those described hereinabove, the release kinetics of the metformin is then plotted as a function of time (expressed in hours).

Examples 1 to 7

(77) TABLE-US-00011 TABLE 11 Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 % by % by % by % by % by % by % by Commercial ref weight weight weight weight weight weight weight SEBS (Kraton G1654 ES 6 6 6 6 6 6 6 from Kraton Polymer) White mineral oil 64.88 64.88 64.88 64.88 64.88 64.88 64.88 (Ondina 919 from Shell) Pentacrythitol Tetrakis3- 0.12 0.12 0.12 0.12 0.12 0.12 0.12 (3,5-di-tert-butyl-4- hydroxyphenyl)propionate (Irganox 1010 from BASF) Vaseline (Vaseline Codex A 5 5 5 5 5 5 5 from Synteal) Sodium carboxymethyl 14 14 14 14 14 14 14 cellulose (CMC Blanose 7H4XF from Aschland) Metformin from Fukang 5 5 5 5 5 5 5 copolymer of the salt of 2- 5 methyl-2[(1-oxo-2- propenyl)amino]-1- propanesulfonic acid and of 2-hydroxyethyl ester of propenoic acid (Sepinov EMT 10 from SEPPIC) Polyacrylate crosspolymer-6 5 (Sepimax Zen from SEPPIC) octyldodecanol, octyldodecyl 5 xyloside and PEG30 dipolyhydroxystearate (Easynov from SEPPIC) Polysorbate 80 (Montanox 20 5 from SEPPIC) Sorbitan Laurate (Montane 20 5 from SEPPIC) Acrylic Acid Polymer Sodium 5 Salt, Additives (Aquakeep from Sumitomo Seika Chemicals) Polyethylene glycol 300 5

(78) TABLE-US-00012 TABLE 12 Average cumulative release of metformin in mg/cm.sup.2 Average cumulative release in mg/cm.sup.2 Examples 0 h 7 h 24 h 72 h Example 1 0 0.23 0.34 0.41 Example 2 0 0.31 0.40 0.44 Example 3 0 0.20 0.29 0.36 Example 4 0 0.48 0.59 0.62 Example 5 0 0.51 0.59 0.61 Example 6 0 0.34 0.43 0.47 Example 7 0 0.43 0.52 0.56

(79) TABLE-US-00013 TABLE 13 Average non-cumulative release of metformin in mg/cm.sup.2 Average non-cumulative release in mg/cm.sup.2 Examples 0 h 7 h 24 h 72 h Example 1 0 0.23 0.11 0.07 Example 2 0 0.31 0.08 0.05 Example 3 0 0.20 0.09 0.06 Example 4 0 0.48 0.10 0.03 Example 5 0 0.51 0.09 0.02 Example 6 0 0.34 0.09 0.04 Example 7 0 0.43 0.09 0.04

(80) FIG. 2 is a graphical representation of the cumulative release of examples 1 to 7.

(81) FIG. 3 is a graphical representation of the non-cumulative release of examples 1 to 7.

(82) The releasing agents that have the best kinetics and the best quantity released are SEPINOV EMT10® and Easynov®. They indeed allow for the best compromise between a release profile with a bolus and a slow and continuous release of the metformin, and a high total quantity of metformin released.

Examples 8 to 12

(83) TABLE-US-00014 TABLE 14 Ex. 8 Ex. 9 Ex. 10 Ex. 11 Ex. 12 % by % by % by % by % by Commercial ref. weight weight weight weight weight White mineral oil 69.947 69.847 69.447 68.947 67.947 (Puretol 9P from Petro Canada) SEBS (Kraton G1651 E 4.931 4.931 4.931 4.931 4.931 from Kraton Polymer) Pentacrythitol Tetrakis3- 0.123 0.123 0.123 0.123 0.123 (3,5-di-tert-butyl-4- hydroxyphenyl)- propionate (Irganox 1010 from BASF) Vaseline (Vaseline 5 5 5 5 5 Codex A from Synteal) Sodium carboxymethyl 14.999 14.999 14.999 14.999 14.999 cellulose (CMC Blanose 7H4XF from Aschland) Metformin from IPCA 5 5 5 5 5 copolymer of the salt of 0 0.1 0.5 1 2 2-methyl-2[(1-oxo-2- propenyl)amino]-1- propanesulfonic acid and of 2- hydroxyethyl ester of propenoic acid (Sepinov EMT 10 from SEPPIC)

(84) TABLE-US-00015 TABLE 15 Average cumulative release of metformin in μg/cm.sup.2 Average cumulative release (μg/cm.sup.2) Examples 0 h 4 h 7 h 24 h 48 h 72 h Example 8 0.00 104 135 231 347 421 Example 9 0.00 151.68 186.17 283.13 397.41 465.75 Example 10 0.00 190.99 222.75 310.92 408.81 466.56 Example 11 0.00 215.04 248.29 340.07 439.00 493.46 Example 12 0.00 296.27 343.33 436.13 511.43 549.99

(85) TABLE-US-00016 TABLE 16 Average non-cumulative release of metformin in μg/cm.sup.2 Average non-cumulative release (μg/cm.sup.2) Examples 0 h 4 h 7 h 24 h 48 h 72 h Example 8 0.00 104 31 96 116 74 Example 9 0.00 151.68 34.49 96.96 114.28 68.33 Example 10 0.00 190.99 31.76 88.17 97.89 57.75 Example 11 0.00 215.04 33.25 91.77 98.94 54.45 Example 12 0.00 296.27 47.07 92.80 75.29 38.56

(86) FIG. 4 is a graphical representation of the cumulative release of examples 8 to 12.

(87) FIG. 5 is a graphical representation of the non-cumulative release of examples 8 to 12.

(88) The rate of releasing agent, here Sepinov EMT 10, has an influence on the quantity of metformin released in 72 h. Indeed, the higher the rate of Sepinov EMT 10 is, the higher the quantity of metformin released is. This correlation is not however proportional. The non-cumulative results show that the quantity released at each sampling (4 h, 7 h, 24 h, 48 h, 72 h) depends on the rate of Sepinov EMT 10 contained in the matrix.

(89) Thus, a rate of 2% of Sepinov EMT 10 will generate a more substantial release of metformin at 4 h while a lower rate of Sepinov EMT 10 (0.1%) will allow for a more progressive release over time.

(90) Thus, the formulations at 0.1%; 0.5% and 1% of Sepinov EMT 10 (examples 9, 10 and 11) terminate their kinetics at 72 h with a similar released quantity but a profile that is somewhat different. In the framework of this application, a formulation that does not have a “flash” release is therefore preferred (excessive release at 4 h), and that has a most progressive release possible of metformin. The formulation that does not contain any releasing agent (example 8) has a progressive release profile but the quantity of metformin released is not as substantial that in the presence of a releasing agent, said quantity released could be insufficient in certain applications wherein a more substantial quantity of metformin should be released all throughout the use of the dressing.

Examples 13 to 16

(91) TABLE-US-00017 TABLE 17 Ex. 13 Ex. 14 Ex. 15 Ex. 16 % by % by % by % by Commercial ref. weight weight weight weight White mineral oil (Puretol 9P from Petro Canada) 68 White naphthenic oil (Pionier 2076P from 71.74 66.74 68 Hansen&Rosenthal) SEBS (Kraton G1651 E from Kraton Polymer).sup.(1) 4.9 4.9 SEBS (Kraton G1654 ES from Kraton Polymer).sup.(1) 6.34 6.34 Pentacrythitol Tetrakis3-(3,5-di-tert-butyl-4- 0.12 0.12 0.12 0.12 hydroxyphenyl)propionate (Irganox 1010 from BASF) Vaseline (Vaseline Codex A from Synteal) 5 5 5 Sodium carboxymethyl cellulose (CMC Blanose 7H4XF 14.8 14.8 15 15 from Aschland) Metformin from Fukang 5 5 5 5 copolymer of the salt of 2-methyl-2[(1-oxo-2- 2 2 2 2 propenyl)amino]-1-propanesulfonic acid and of 2- hydroxyethyl ester of propenoic acid (Sepinov EMT 10 from SEPPIC) .sup.(1)As the viscosities of the two Kraton are different, Kraton G1651 E was introduced in order to obtain a similar viscosity for the formulations of examples 15 and 16.

(92) TABLE-US-00018 TABLE 18 Average cumulative release (μg/cm.sup.2) Example 0 h 4 h 7 h 24 h 48 h 72 h Example 13 0 481 563 647 711 748 Example 14 0 472 560 645 717 756 Example 15 0 357 420 509 594 641 Example 16 0 343 398 495 597 666

(93) TABLE-US-00019 TABLE 19 Average non-cumulative release (μg/cm.sup.2) Example 0 h 4 h 7 h 24 h 48 h 72 h Example 13 0 481 82 84 64 37 Example 14 0 472 88 84 72 39 Example 15 0 357 63 89 85 48 Example 16 0 343 55 97 102 69

(94) FIG. 6 is a graphical representation of the cumulative release of examples 13 to 16.

(95) FIG. 7 is a graphical representation of the non-cumulative release of examples 13 to 16.

(96) The models of examples 13 to 16 tested have a similar release profile. However, the release values obtained make it possible to distinguish the models of examples 13 and 14 from the models of examples 15 and 16. Indeed, at 72 h, the models of examples 13 and 14 release approximately 86% of metformin. The presence or not of vaseline therefore has no impact on the release. The models of examples 15 and 16, however release approximately 75% of metformin at 72 h without revealing any impact in the change of oil (Puretol vs. Pionier) on the released quantities of metformin.

(97) The difference between the models resides in the grade of Kraton used (G1654® for the models of examples 13 and 14 vs. G1651® for the models of examples 15 and 16).

(98) The results obtained show a more progressive release (better release profile) by using Kraton G1651®.

Examples 17 to 20

(99) TABLE-US-00020 TABLE 20 Ex. 17 Ex. 18 Ex. 19 Ex. 20 % by % by % by % by Commercial ref. weight weight weight weight SEBS (Kraton G1654 ES from Kraton Polymer) 6 6 6.34 6.34 White mineral oil (Ondina 919 from Shell) 72.88 72.88 White naphthenic oil (Pionier 2076P from 71.74 71.74 Hansen&Rosenthal) Pentacrythitol Tetrakis3-(3,5-di-tert-butyl-4- 0.12 0.12 0.12 0.12 hydroxyphenyl)propionate (Irganox 1010 from BASF) Sodium carboxymethyl cellulose (CMC Blanose 14 14 14.8 14.8 7H4XF from Aschland) copolymer of the salt of 2-methyl-2[(1-oxo-2- 2 2 2 2 propenyl)amino]-1-propanesulfonic acid and of 2- hydroxyethyl ester of propenoic acid (Sepinov EMT 10 from SEPPIC) Metformin from Fukang 5 Metformin from Wanbury 5 Metformin from Weifa 5 Metformin from IPCA 5

(100) The metformins tested in the examples 17 to 20 are distinguished by their particle size as explained in the following table:

(101) TABLE-US-00021 Example Population d50 (μm) d90 (μm) Example 17 Unimodal 125 264 (Metformin from Fukang) Example 18 Bimodal 443 1123 Example 19 Unimodal 75 195 Example 20 Unimodal 182 509

(102) TABLE-US-00022 TABLE 21 Average cumulative release (μg/cm.sup.2) Example 0 h 4 h 7 h 24 h 48 h 72 h Example 17 0.00 504.59 586.15 650.49 688.83 708.24 Example 18 0.00 370.59 442.28 504.08 535.39 553.83 Example 19 0.00 315.27 379.15 455.69 503.16 532.00 Example 20 0.00 500.08 587.71 662.05 706.56 730.12

(103) TABLE-US-00023 TABLE 22 Average non-cumulative release (μg/cm2) Example 0 h 4 h 7 h 24 h 48 h 72 h Example 17 0.00 504.59 81.56 64.34 38.34 19.41 Example 18 0.00 370.59 71.69 61.80 31.31 18.44 Example 19 0.00 315.27 63.88 76.54 47.47 28.84 Example 20 0.00 500.08 87.63 74.34 44.51 23.56

(104) FIG. 8 is a graphical representation of the cumulative release of examples 17 to 20.

(105) FIG. 9 is a graphical representation of the non-cumulative release of examples 17 to 20.

Examples 21 and 22

(106) TABLE-US-00024 TABLE 23 Ex. 21 Ex. 22 % by % by Commercial ref. weight weight SEBS (Kraton G1654 ES from Kraton Polymer) 5.7 5.7 SEBS (Kraton G1650 E from Kraton Polymer) 2.6 2.6 White mineral oil (Ondina 919 from Shell) 57 57 Pentacrythitol Tetrakis3-(3,5-di-tert-butyl-4- 0.2 0.2 hydroxyphenyl)propionate (Irganox 1010 from BASF) Sodium carboxymethyl cellulose (CMC Blanose 14 14 7H4XF from Aschland) Vaseline-mixture of paraffin, liquid paraffin and wax 13.5 13.5 (Vaseline Codex A from Synteal) copolymer of the salt of 2-methyl-2[(1-oxo-2- 2 2 propenyl)amino]-1-propanesulfonic acid and of 2- hydroxyethyl ester of propenoic acid (Sepinov EMT 10 from SEPPIC) Metformin from Fukang 5 5

(107) TABLE-US-00025 TABLE 24 Average cumulative release (μg/cm.sup.2) Example 0 h 4 h 7 h 24 h 48 h 72 h Example 21 0.00 524.28 598.51 642.15 664.97 675.08 Example 22 0.00 563.24 688.07 900.24 1096.63 1254.29

(108) TABLE-US-00026 TABLE 25 Average non-cumulative release (μg/cm.sup.2) Example 0 h 4 h 7 h 24 h 48 h 72 h Example 21 0.00 524.28 74.23 43.64 22.83 10.11 Example 22 0.00 563.24 124.83 212.17 196.39 157.67

(109) The most interesting releases were obtained with the examples 17, 19, 20 and 22. Indeed, the cumulative release curve (FIG. 8) shows that, although releasing a sufficient quantity of metformin, the example 18 has a progression in the release of metformin that is not as high as that of the other examples. The non-cumulative release curve shows that after 10 h, the curve of the example 18 is that which releases the least amount of metformin.

(110) The example 22 revealed an unexpected release: indeed, when the elastomeric matrix is used in a self-supporting interface dressing, the release of metformin is improved with respect to the same matrix coated on one weave.

(111) Furthermore, surprisingly and unexpectedly, the samples of metformin having a particle size of small dimension are those for which the dissolution was the slowest. Yet, usually, the smaller the particle size is, the faster the dissolution is.

(112) The best results were obtained with a metformin of which the particle size has a unimodal distribution. Preferably the particle size is d50<200 μm, d90<510 μm.