Polymer support for the distribution of a naturally crystalline substance and production method

Abstract

The invention relates to the implementation of a method for loading, without a vehicle, a naturally crystalline substance solubilized by a solvent mixture in a lipophilic medium in a mixture of granulated polymers, for forming, without a plasticizer, a polymer support for the long-term controlled distribution of the naturally crystalline substance in the stable solubilized state, without permanent crystallization on the surface of said support. Said substance according to the invention can be insecticides and pesticides of the group of pyrethroids (e.g. deltamethrin), formamidines (e.g. amitraz) and carbamates (e.g. propoxur), or the mixture thereof, or cosmetics of the group of alkaloids (e.g. caffeine), or medicaments (e.g. ibuprofen). The permanent non-crystallization state on the surface of the polymer support is only ensured when said substance is solubilized in the solvent mixture consisting of an oxygenated solvent of dibasic esters of methylenic fatty acids and an oxygenated methylenic cosolvent in an active lipophilic solution incorporated into a polymer mixture consisting of a polyether block amide (PEBA) and a thermoplastic polyurethane elastomer (TPU). Said support can be shaped as a collar, as an ear tag for animals, a band, a patch, a tag, a polymer block or any other device for the distribution of the active substances. It is shaped by any one of the plastic processing techniques known by a person skilled in the art. It is advantageous in that it is loaded with a quantity of active substance of between 30% and 50% less than the previous devices for at least the same active efficiency.

Claims

1. A vehicle-free method of loading a naturally crystalline substance solubilized by a solvent mixture in a lipophilic medium into a mixture of polymer granules for forming a plasticizer-free polymer support for long-term controlled release of the naturally crystalline substance in a stable solubilized state, wherein said method ensures the permanent non-crystallization on a surface of said polymer support, said method comprising the steps of: a) preparation of said solvent mixture which comprises an oxygenated solvent of dibasic esters of methylenic fatty acids and an oxygenated methylenic cosolvent; b) solubilization of said naturally crystalline substance in said solvent mixture of step a) to obtain a stable solution of said naturally crystalline substance; c) addition of a vegetable oil in said stable solution of step b) to obtain an active lipophilic solution; d) incorporation of said active lipophilic solution obtained in step c) into a mixture of polymer granules comprising a polyether block amide (PEBA) and a thermoplastic polyurethane elastomer (TPU) to form a polymer mixture loaded with said naturally crystalline substance in said stable solubilized state; e) forming of said polymer support loaded with said naturally crystalline substance in a stable solubilized state by shaping said mixture of polymer granules loaded with said naturally crystalline substance obtained in d).

2. The method according to claim 1, wherein a ratio of the two components of the solvent mixture in the order solvent/cosolvent varies between 38/62 and 90/10.

3. The method according to claim 1, wherein a concentration threshold of the naturally crystalline substance is increased by solubilizing in said solvent mixture at a temperature between room temperature and 45 C.

4. The method according to claim 1, wherein a ratio of the polymer mixture comprising PEBA/TPU varies between 80/20 and 40/60.

5. The method according to claim 1, wherein said solubilized naturally crystalline substance is selected from the group consisting of an insecticide a pesticide, a cosmetic, and a drug.

6. The method according to claim 1, wherein said technical additives comprise coloring agents and/or structure polymers.

7. The method according to claim 1, wherein a ratio of incorporation of said naturally crystalline substance varies between 0.25% and 20% by weight of the support.

8. A polymer support for long-term controlled release of a naturally crystalline substance in a stable solubilized state, wherein a permanent non-crystallization state on a surface of said polymer support is only assured when said naturally crystalline substance is solubilized in a solvent mixture composed of an oxygenated solvent of dibasic esters of methylenic fatty acids and an oxygenated methylenic cosolvent forming an active lipophilic solution by adding a vegetable oil, this active lipophilic solution being incorporated into a mixture of polymer granules composed of a polyether block amide (PEBA) and a thermoplastic polyurethane elastomer (TPU), wherein said polymer support is obtained by molding said mixture of polymer granules loaded with said crystalline substance.

9. The polymer support of claim 8, wherein a ratio of the two components of the solvent mixture in the order solvent/cosolvent varies between 38/62 and 90/10.

10. The polymer support of claim 8, wherein the ratio of the polymer mixture in the order PEBA/TPU varies between 80/20 and 40/60.

11. The polymer support of claim 8, further comprising a technical additive.

12. The polymer support of claim 8, wherein said polymer support has a storage capacity between 0.25% and 20% by weight of a naturally crystalline substance with respect to the total weight of the said support.

13. The polymer support of claim 8, wherein said polymer support is in the shape of a collar, a medallion, an ear tag for animals, a bracelet, a patch, a pack, or a block.

14. The method of claim 1, further comprising addition of a technical additive to said polymer mixture loaded with said naturally crystalline substance.

15. The method of claim 2, wherein said wherein the ratio of the two components of the solvent mixture in the order solvent/cosolvent varies between 45/55 and 75/25.

16. The method of claim 4, wherein said ratio of the polymer mixture in the order PEBA/TPU varies between 55/45 and 45/55.

17. The method of claim 5, wherein said insecticide or pesticide is selected from the group consisting of a pyrethroid, a formamidine and a carbamate, or a combination thereof.

18. The method of claim 5, wherein said cosmetic is an alkaloid.

19. The polymer support of claim 9, wherein said ratio of the two components of the solvent mixture in the order solvent/cosolvent varies between 45/55 and 75/25.

20. The polymer support of claim 10, wherein the ratio of the polymer mixture in the order PEBA/TPU varies between 55/45 and 45/55.

Description

EXAMPLES

Example 1: Elaboration of an Anti-Ectoparasitic Polymer Medallion with Deltamethrin

(1) The following inputs are available:

(2) Oxygenated solvent of dibasic esters of methylenic fatty acids marketed by DOW HALTERMANN under the registered trademark ESTASOL.

(3) Oxygenated methylenic solvent which is dimethyl isosorbide (DMI) marketed by CRODA under the registered trademark ARLASOLVE DMI.

(4) Deltamethrin in powder form marketed by SIGMA ALDRICH under the registered trademark FULKA.

(5) Refined coconut oil marketed by OLVEA.

(6) Polymer granules of polyether block amide (PEBA) marketed by ARKEMA under the registered trademark PEBAX 2533 SA 01.

(7) Polymer granules of ether-based thermoplastic polyurethane (TPU) marketed by GAZECHIM under the registered trademark PEARLTHANE D15N70.

(8) Pearly white colouring agent which is a masterbatch marketed by ELIAN.

(9) The elaboration of an anti-ectoparasitic polymer medallion with Deltamethrin proceeds in three steps.

(10) Step 1: Preparation of the Active Solution

(11) Preparation of the solvent mixture ESTASOL/ARLASOLVE DMI according to a ratio of 75%/25%

(12) Solubilisation of the Deltamethrin in the solvent mixture according to a ratio Deltamethrin/solvent mixture of 12.6%/87.4%;

(13) Addition of refined coconut oil according to an active ratio solvent mixture/coconut oil of 75%/25%.

(14) Procedure:

(15) In a 1 liter beaker, the following products are successively introduce with stirring:

(16) 600 g ESTASOL

(17) 200 g ARLASOLVE DMI

(18) And then introduce by sprinkling while still stirring:

(19) 115 g Deltamethrin

(20) After completely dissolving, pour while still stirring:

(21) 300 g refined coconut oil.

(22) After 30 min, a stable, limpid active solution is obtained.

(23) Step 2: Incorporation of the Active Solution into the Polymer Granules of PEBAX 2533 SA 01/PEARLTHANE D15N70

(24) Procedure:

(25) Preheat the DRAIS horizontal mixer having a volume of 20 liters, to 95 C.;

(26) While stirring at 80 rpm, add 1843 g granules PEBAX and 1843 g granules PEARLTHANE D15N70, that is, a ratio of 50%/50%;

(27) Let mix until the real temperature of the granules is 80 C.;

(28) Still stirring, add drop by drop 1215 g of active solution to the mixer, that is, a ratio of active solution/polymer of 25%/75%;

(29) Let the active solution incorporate into the polymer granules for approximately 30 minutes until they become dry and unsticky;

(30) Lower the mixer temperature to 20 C. and the stirring speed to 50 rpm;

(31) Still stirring, add 100 g of pearly white colouring agent;

(32) Stop stirring after 20 minutes;

(33) The resulting polymer granules loaded with the coloured active substance is collected.

(34) Step 3: Forming by Injection-Molding in the Medallion to be Fastened to a Collar

(35) A SANDRETTO series 8 injection press developing a pressure capacity of 90 ton mould is available.

(36) The steel mould mounted on the said press has four imprints-moulds in the shape of a medallion.

(37) The temperature chart of the sheath from the hopper to the nozzle is as follows: 105 C., 125 C., 125 C., 25%.

(38) The medallions loaded with Deltamethrin obtained weigh approximately 10 g and contain 2.4% Deltamethrin, that is, 40% less than the devices of the prior art. They have a main oval body equipped with a tab on one of the sides and a pass-through on the other.

(39) The medallions loaded with Deltamethrin obtained are packaged and stored at room temperature for 12 months. No recrystallization of the Deltamethrin is observed at the medallion surface, proof that the Deltamethrin has remained in the solubilised state.

(40) The medallion is fastened and mounted on a dog collar placing it in intimate contact with the fur, that is, directly with the animal skin.

(41) The said medallion allows effectively fighting against ectoparasites of all kinds for a long period, that is, up to several months.

Example 2: Comparative Study of Releasing Deltamethrin in Olive Oil from a Support According to the Invention and from a Commercially Available Support

(42) Use of olive oil is known to determine the quantity of a solubilized non-volatile active substance released in a lipophilic composition. The choice of olive oil is justified by the fact that its composition is close to the structure of the lipid layer of the animal epidermis.

(43) In fact, this experimental model which allows evaluating the quantity of Deltamethrin released from the medallion loaded with Deltamethrin obtained according to the method of the invention, as well as from a commercially available collar, the SCALIBOR loaded with Deltamethrin.

(44) Procedure:

(45) Three medallions loaded with 4% Deltamethrin and each weighing approximately 10 g are placed in a 120 mm dia crystallizing dish in which 200 milliliters of olive oil are poured. The medium is stirred at 250 rpm using a magnetized bar placed in each crystallizing dish.

(46) In parallel, the same protocol is performed with SCALIBOR with 4% Deltamethrin each weighing approximately 25 g. Stirring is made at 250 rpm.

(47) A standard solution at 40 mg/L Deltamethrin whose purity is known is realized under the same conditions using olive oil.

(48) Protocol:

(49) The released Deltamethrin quantity is determined by High Pressure Liquid Chromatography (HPLC). To do this, a PROVIDER ICS chromatograph equipped with a pump model 2250 and a column PRONTOSIL 120-5-C18 sized 250 mm3.0 mm is available. A mobile phase of acetonitrile/water (85/15) is worked with and the detector's wavelength is adjusted to 275 nm.

(50) 5 milliliters samples of each solution are taken to start the chromatography and then completed with 5 milliliters of fresh olive oil after each sampling.

(51) Samples are taken at times T0, T1, T2, T3, T7, T10, T17, T31, T45, T59, and T73. The time unit is a day. After each sampling, each sample is analysed by HPLC to determine the Deltamethrin quantity released in the olive oil.

(52) The obtained results are shown on the graphic in FIG. 1 in terms of Deltamethrin release kinetics in percentage in olive oil.

(53) By referring to FIG. 1, it discloses that 65% more Deltamethrin is released by the support according to the invention than that released by the commercially available collar. This proves a clearly operational superiority with respect to the Deltamethrin quantity released by both devices.

Example 3: Elaboration of a Caffeine Patch to Fight Against Human Orange Skin

(54) Thanks to its hydrophilic property, it is well known that caffeine is generally formulated in cream or in gel. Moreover, the largest number of caffeine-based products available on the market are creams.

(55) In addition to the inputs given in example 1, other inputs are available as follows: Anhydrous caffeine in powder marketed by INTERAXION MULTIFLEX G00A41 elastomer marketed by DOW CORNING.
The elaboration of a caffeine patch according to the invention proceeds in three steps.
Step 1: Preparation of the Active Solution

(56) The preparation of the active solution passes by the solubilisation of the caffeine in the solvent mixture according to a ratio oxygenated solvent of dibasic esters of methylenic fatty acids/oxygenated methylenic solvent of 3/5.

(57) Procedure:

(58) In a 1 liter beaker, the following are successively added under stirring:

(59) 150 g ESTASOL;

(60) 250 g ARLASOLVE DMI;

(61) 25 g caffeine;

(62) 100 g refined coconut oil.

(63) All is stirred for 20 minutes until the active solution becomes limpid. The said active solution is stable, that is, the caffeine does not recrystallise.

(64) Step 2: Incorporation of the Active Solution into the Polymer Mixture PEBAX/PEARLTHANE D15N70 according to a ratio of 1/2

(65) Procedure:

(66) Preheat the DRAIS horizontal mixer having a volume of 20 liters, to 95 C.;

(67) Introduce 1000 g of PEBAX granules and 2000 g of PEARLTHANE D15N70 granules in it;

(68) Stir at 80 rpm until the real temperature of the polymer granules reaches 90 C.;

(69) Still stirring, add drop by drop 525 g of active solution to the mixer;

(70) Let the active solution incorporate for at least 15 min into the polymer granules until they become dry and unsticky;

(71) Lower the temperature to 20 C., and stir at 50 rpm;

(72) Still stirring at 50 rpm, add 100 g of pearly white colouring agent;

(73) Still stirring at 50 rpm, add 500 g of MULTIFLEX G00A41;

(74) Stop stirring after 5 minutes;

(75) The resulting polymer granules loaded with the lipophilic caffeine solution are collected.

(76) Step 3: Forming a Patch Intended to be Applied to the Thighs.

(77) The same equipment is available as in example 1. The mounted moulds have four imprints-moulds in the shape of a parallelogram 7 centimeters long, 4 centimeters wide and 2 millimeters deep.

(78) The injection temperature chart from the hopper to the nozzle is as follows: 105 C., 125 C., 125 C., 25%.

(79) The obtained patches with 0.6% caffeine and a slimming effect are very flexible. MULTIFLEX G00A41 brings the essential flexibility to the said patches. They can be applied directly to the skin at the level of the thighs to fight against orange skin. The said patches can be associated with a panty for a more intimate application against the skin.