Solid Composite Matrix for Prolonged Delivery of Active Agents

Abstract

The invention relates to a composite polymer matrix carrier for prolonged delivery of active substances suitable for controlled release over a sustained period of time. More particularly, the invention relates to a composite polymer matrix carrier comprising at least one thermoplastic polymer, at least one cellulose derivative, and at least one active agent, and the method for manufacturing same. The invention also relates to the use of a cellulose derivative for improving the incorporation of active agents in a thermoplastic polymer matrix.

Claims

1. A composite matrix comprising at least one thermoplastic polymer and at least one cellulose derivative, wherein the cellulose derivative is loaded with at least one active ingredient and represents between 5 to 40% by total weight of said matrix.

2. The matrixaccording toclaim 1, wherein the cellulose derivative is chosen from cellulose esters, cellulose ethers or a mixture thereof.

3. The matrix according to claim 1, wherein the cellulose derivative is chosen from cellulose acetate, carboxymethylcellulose, hydroxypropylmethylcellulose or their mixture.

4. The matrix according to claim 3, wherein the active ingredient represents between 4 and 35% by total weight of the said matrix.

5. The matrix according to claim 1, wherein the active ingredient is an active ingredient of natural or synthetic origin chosen from insecticides, repellents, attractants or essential oils.

6. The matrixaccording to claim 1, wherein the thermoplastic polymer is chosen from polyethylenes (PE), polylactic acids (PLA), thermoplastic polyurethanes (TPU), polyvinyl chlorides (PVC) or Polyesters.

7. The matrix according to wherein the thermoplastic polymer is a low density polyethylene.

8. The matrixaccording to claim 1, wherein the thermoplastic polymer is present in an amount sufficient to reach 100% by total weight of the matrix.

9. The matrixaccording to claim 1, wherein the mixture of thermoplastic polymer and cellulose derivative is a mixture of powders.

10. The matrixaccording to claim 1, wherein the matrix is in the form of a necklace, bracelets, harness, strap or belt.

11. A processfor manufacturing a matrix according to claim 1 comprising: a) mixing the at least one active ingredient with the cellulose derivative in powder form until the at least one active ingredient is fully incorporated into said cellulose derivative. b) adding powdered thermoplastic to the mixture obtained in a); and c) injecting the matrix obtained into a molding or extrusion press .

12. The process according to claim 11, further comprising adding a release agent.

13. A use of at least one cellulose derivative to improve the incorporation of active agents within a thermoplastic matrix according to claim 1 .

14. The use according to claim 13, wherein the cellulose derivative is chosen from cellulose esters, cellulose ethers or a mixture thereof.

15. The useaccording to claim 13, wherein the active ingredient represents between 4 and 35% by total weight of the matrix.

16. The matrix according to claim 4, wherein the active ingredient is an active ingredient of natural or synthetic origin chosen from insecticides, repellents, attractants or essential oils.

17. The matrix according to claim 5, wherein the thermoplastic polymer is chosen from polyethylenes (PE), polylactic acids (PLA), thermoplastic polyurethanes (TPU), polyvinyl chlorides (PVC) or Polyesters.

18. The matrix according to claim 17, wherein the thermoplastic polymer is a low density polyethylene.

19. The matrix according to claim 16, wherein the matrix is in the form of a necklace, bracelets, harness, strap or belt.

20. The matrix according to claim 17, wherein the matrix is in the form of a necklace, bracelets, harness, strap or belt.

Description

[0114] [FIG. 1] shows the results of the study of the influence of the type and of the concentration of the cellulose compound on the salting-out kinetics of the active agent. The release of the active agents is measured by gravimetry. The compositions tested are composition 2 according to the invention, described in example 2, compared with comparative compositions 1 and 10, described in examples 1 and 10, respectively. The curves show that: [0115] composition 1 without cellulose derivative does not allow for release of the active agents over time, and is therefore not suitable for the intended aim of the compositions according to the invention. [0116] composition 10 containing xanthan gum in the form of an active agent vector allows for incorporation and salting-out of the active agents over time, but this composition has been found not to be stable following degradation of the xanthan gum due to the temperature used during the production process, [0117] only composition 2 according to the invention has been found to be stable, making it possible to incorporate the active agents at a percentage of over 5%, and then to release them in a regular manner, over time.

[0118] [FIG. 2] shows the results of the study of the influence of the concentration of the cellulose acetate on the release kinetics of the active agent within compositions 2, 6 and 7 according to the invention. The curves show that the release of the active agents is not proportional to the concentration of acetate used, and allows the three concentrations tested to effectively incorporate and release the active agents.

[0119] [FIG. 3] shows the results of the study of the influence of the concentration of HPMC on the release kinetics of the active agent within compositions 3, 8 and 9 according to the invention. The concentration of HPMC influences the quantity of active agents released, and makes it possible to modulate the release kinetics of the active agent depending on the effect sought.

Example 1 Comparative: Composition 1 Without Cellulose Derivative

[0120] TABLE-US-00001 Composition 1 Concentration (%) Polyethylene (CAS 9002-88-4) 93.86 Geraniol 0.49 Peppermint essential oil 2.37 Thyme satureioides essential oil 0.59 Gylceryl dicaprylate 2.69

[0121] This composition was prepared using the preferred active agents according to the invention, to be integrated into a polyethylene matrix, without adding cellulose derivative, in order to compare this with a composition according to the invention. A number of difficulties were encountered, and various formulation tests had to be carried out in order to manage to obtain a composition in which the active agents could be incorporated. At the end of the various tests, however, it was necessary to use an alternative vector, glyceryl dicaprylate, in order to stabilize the active agents in the LDPE matrix. Moreover, it has not been possible to incorporate, within a composition of this kind, more than 3.45% active agents to maintain a composition which is stable and injectable. However, the aim is to manage to incorporate at least 5% active agents. Moreover, the curve of FIG. 1 shows that the active agents are not released by said formula over time.

[0122] This composition is compared with examples 2 and 10, described below, and the release curves of the active agents over time are shown in FIG. 1.

[0123] Examples 2 to 9 described below are examples of stable compositions according to the invention, which describe compositions that cause the active agents to vary, as well as the cellulose derivative and the concentration thereof.

Example 2: Composition 2 of LDPE Plus 10% Cellulose Acetate

[0124] TABLE-US-00002 Composition 2 Concentration (%) Polyethylene 81.60 Cellulose ester: cellulose acetate 10.00 Geraniol 0.90 Peppermint essential oil 4.40 Thyme satureioides essential oil 1.10 Zinc stearate 2.00

[0125] By virtue of adding the vector cellulose acetate, it was possible to obtain a stable composition comprising 6.4% of the mixture of active agents that are preferred for a repellant composition according to the invention.

[0126] The method for preparing composition 2 is carried out according to the following steps:

[0127] Geraniol and the two essential oils are introduced into a beaker, at ambient temperature, i.e. 25° C. This is stirred gently using a magnetic bar, in order to obtain a homogeneous mixture which constitutes the solution of active agents.

[0128] The cellulose acetate is incorporated, at ambient temperature, while stirring vigorously. The stirring is continued as long as the mixture of active agents is not entirely incorporated into the cellulose acetate powder, and the compound does not appear dry, in order to obtain the “premix.”

[0129] Once the compound is dry, zinc stearate is added, while stirring. Subsequently, PE is added to the cellulose acetate/active agent “premix” obtained previously, in the mixer, while stirring vigorously. This is stirred until all the liquid is entirely absorbed by the polymer. The mixer is emptied, and the compound thus obtained is stored in packaging that is hermetically sealed with respect to air and humidity. The product obtained makes it possible to incorporate the active agents in a stable manner. FIG. 1 clearly shows that composition 2 according to the invention makes it possible to release the active agent, in contrast with composition 1 which does not make it possible to release the active agents, or composition 10 which is unstable.

[0130] The product thus obtained can then be introduced into an injection press in order to mold it to the shape and size obtained. In the present example, the powder laden with active agents is injected, in order to obtain a collar for a dog or cat which can be adjusted to different sizes, such as 35, 60 or 75 cm. Said collar is intended to be worn by a dog or a cat, around the neck, in order to ward off harmful parasites.

Example 3: Composition 3 of LDPE Plus 10% HPMC

[0131] TABLE-US-00003 Composition 3 Concentration (%) Polyethylene 81.60 Cellulose ether: hydroxypropylmethyl cellulose (HPMC) 10.00 Geraniol 0.90 Peppermint essential oil 4.40 Thyme satureioides essential oil 1.10 Zinc stearate 2.00

Example 4: Composition 4 of LDPE Plus 30% Cellulose Acetate

[0132] TABLE-US-00004 Composition 4 Concentration (%) Polyethylene 61.60 Cellulose ester: cellulose acetate 30.00 Geraniol 0.90 Peppermint essential oil 4.40 Thyme satureioides essential oil 1.10 Zinc stearate 2.00

Example 5: Composition 5 of LDPE Plus 30% HPMC

[0133] TABLE-US-00005 Composition 5 Concentration (%) Polyethylene 61.60 Cellulose ether: HPMC 30.00 Geraniol 0.90 Peppermint essential oil 4.40 Thyme satureioides essential oil 1.10 Zinc stearate 2.00

Example 6: Composition 6 of LDPE Plus 5% Cellulose Acetate

[0134] TABLE-US-00006 Composition 6 Concentration (%) Polyethylene 86.60 Cellulose ester: cellulose acetate 5.00 Geraniol 0.90 Peppermint essential oil 4.40 Thyme satureioides essential oil 1.10 Zinc stearate 2.00

Example 7: Composition 7 of LDPE Plus 15% Cellulose Acetate

[0135] TABLE-US-00007 Composition 7 Concentration (%) Polyethylene 76.60 Cellulose ester: cellulose acetate 15.00 Geraniol 0.90 Peppermint essential oil 4.40 Thyme satureioides essential oil 1.10 Zinc stearate 2.00

Example 8: Composition 8 of LDPE Plus 5% HPMC

[0136] TABLE-US-00008 Composition 8 Concentration (%) Polyethylene 86.60 Cellulose ether: HPMC 5.00 Geraniol 0.90 Peppermint essential oil 4.40 Thyme satureioides essential oil 1.10 Zinc stearate 2.00

Example 9: Composition 9 of LDPE Plus 15% HPMC

[0137] TABLE-US-00009 Composition 9 Concentration (%) Polyethylene 76.60 Cellulose ether: HPMC 15.00 Geraniol 0.90 Peppermint essential oil 4.40 Thyme satureioides essential oil 1.10 Zinc stearate 2.00

Example 10: Composition 10 of LDPE Plus Other Polysaccharide

[0138] TABLE-US-00010 Composition 10 Concentration (%) Polyethylene 81.60 Polysaccharide: xanthan gum 10.00 Geraniol 0.90 Peppermint essential oil 4.40 Thyme satureioides essential oil 1.10 Zinc stearate 2.00

[0139] Composition 10 was formed in order to test an alternative polysaccharide to cellulose derivatives, xanthan gum, as a vector of active agents of the composition. The curve of FIG. 1 shows that the active agents could be incorporated at 6.4%, and are salted-out over time. However, the composition is not stable, and cannot be injected. Degradation of the color and the odor is observed, on account of the degradation of the xanthan gum. A lower temperature would be necessary during the injection process in order for the xanthan gum not to degrade, but this temperature would not be sufficient for softening the PE and making the formula injectable. Composition 10 is therefore not in accordance with what the applicant wishes to obtain.

Example 11: Composition 11 OF LDPE Plus 30% HPMC

[0140] TABLE-US-00011 Composition 11 Concentration (%) Polyethylene 59.20 Cellulose ether: HPMC 30.00 Peppermint essential oil 4.40 Cedar essential oil 4.40 Zinc stearate 2.00

Example 12: Composition 12 of LDPE Plus 35% HPMC

[0141] TABLE-US-00012 Composition 12 Concentration (%) Polyethylene 54.20 Cellulose ether: HPMC 35.00 Peppermint essential oil 4.40 Cedar essential oil 4.40 Zinc stearate 2.00

Example 13: Composition 13 of LDPE Plus 40% HPMC

[0142] TABLE-US-00013 Composition 13 Concentration (%) Polyethylene 49.20 Cellulose ether: HPMC 40.00 Peppermint essential oil 4.40 Cedar essential oil 4.40 Zinc stearate 2.00

Example 14: Composition 14 of LDPE Plus 40% Cellulose Acetate

[0143] TABLE-US-00014 Composition 14 Concentration (%) Polyethylene 49.20 Cellulose ester: cellulose acetate 40.00 Peppermint essential oil 4.40 Cedar essential oil 4.40 Zinc stearate 2.00

Example 15: Composition 15 OF PLA Plus 20% Cellulose Acetate

[0144] TABLE-US-00015 Composition 15 Concentration (%) PLA 60 Cellulose ester: cellulose acetate 23.15 Peppermint essential oil 16.85

Example 16: Shows 3 Compositions (16 TO 18) of Matrices Comprising Insecticide Active Agents and Cellulose Acetate According to the Invention

[0145] TABLE-US-00016 Composition 16 Concentration (%) PVC 70 Cellulose ester: cellulose acetate 17.37 Cypermethrine 12.63

TABLE-US-00017 Composition 17 Concentration (%) TPU 60 Cellulose ester: cellulose acetate 25 n-octyl bicyclopehtene dicarboximide 15

TABLE-US-00018 Composition 18 Concentration (%) PLA 70 Cellulose ester: cellulose acetate 15 Diazinon 15