Transdermal solvent system and methods of use

Abstract

Described herein are transdermal solvent systems comprising at least one active agent in solution in a base solution, the base solution comprising at least one fatty acid ester compound, at least one monoterpene compound and a co-solvent in the form of DMSO or DMI and at least one plant oil. The base solution was found to be highly versatile and provide superior or at least comparable skin penetration efficacy and active agent compatibility. Methods of treatment, uses of the solvent system and methods of manufacture are also described.

Claims

1. A base solution formulated to carry, in solution, at least one active agent and to deliver the at least one active agent via transdermal administration, the base solution comprising: 10-20% by weight of at least one fatty acid ester compound; 1-14.99% by weight of at least one monoterpene compound; 8-25% by weight dimethylsulfoxide (DMSO) and/or dimethyl isosorbide (DMI); 0.75-5% by weight of at least one plant oil; 0.1-25% by weight of at least one amphiphilic compound; 5-20% by weight at least one compound with emollient and/or humectant properties; 5-10% by weight at least one compound that acts as a wetting agent and/or emulsifier; and at least one ethylene glycol ether compound as a diluent added to volume q.s.

2. The base solution as claimed in claim 1, wherein the base solution is anhydrous.

3. The base solution as claimed in claim 1, wherein the at least one plant oil is selected from: chamomile oil, frangipani oil, lilac oil, sage oil, seabuckthorn oil, and combinations thereof.

4. The base solution as claimed in claim 1, wherein the at least one amphiphilic compound is lecithin.

5. The base solution as claimed in claim 1, wherein viscosity of the base solution is less than or equal to 5000 cP.

6. The base solution as claimed in claim 1, wherein the base solution further comprises at least one excipient selected from compounds with: emollient and/or humectant activity, diluents, surfactants/wetting agents, and anti-oxidants.

7. The base solution of claim 1, wherein the at least one active agent is fully dissolved in the base solution.

8. The base solution as claimed in claim 1, wherein the at least one fatty acid ester compound is selected from: isopropyl myristate, isopropyl palmitate, octyl dodecyl myristate, ethylhexyl stearate, glyceryl stearate, myristil myristate, stearyl stearate, cholesteryl isostearate, and combinations thereof.

9. The base solution as claimed in claim 1, wherein the at least one monoterpene compound is selected from: camphor, eucalyptol, D-limonene, P-cymem, citranellol, and combinations thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) Further aspects of the transdermal solvent systems and methods of use will become apparent from the following Examples that are given by way of example only and with reference to the accompanying drawings in which:

(2) FIG. 1 illustrates Scanning Electron Microscope (SEM) images showing a cross section of cattle skin. The left side images (ECLPS) represent cattle skin penetrated by commercial product, and the right side images (INN) represent cattle skin penetrated by the solvent system of Example 1;

(3) FIG. 2 illustrates a graph of the amount of Vitamin B12 drug permeation (ng) over time when treated with the solvent system of Example 1; and

(4) FIG. 3 illustrates a graph of the amount of selenium permeation (mg) over time when treated with the solvent system of Example 5.

WORKING EXAMPLES

(5) The above described solvent systems, methods of treatment and uses thereof are now described by reference to specific examples.

Example 1

(6) A vitamin B12 containing solvent system is described below in Table 1:

(7) TABLE-US-00001 TABLE 1 Example Solvent System Amount Function Compound (w/v) Fatty acid ester Isopropyl myristate   10-13% Monoterpene D-limonene   1-5% Co-solvent, stabiliser Dimethyl sulfoxide (DMSO) or   10-20% dimethyl isosorbide (DMI) Plant oil/penetration Seabuckthorn oil 0.75-5% enhancer Amphiphilic compound/ Soya lecithin  0.1-0.25% Penetration assisting agent Surfactant/wetting agent Polysorbate 80  2.5-7.5% Active agent (vitamin) Cyanocobalamin (Vit B12)  0.1-1% Humectant/emollient Propylene glycol   5-15% Diluent Diethylene glycol monoethyl To volume ether (DGME) q.s.

Example 2

(8) The solvent system of Example 1 was compared with a commercially available dual anthelmintic pour-on solution to compare active agent transdermal penetration of the Example 1 solvent system (irrespective of active agent) through cattle skin against that of the art product.

(9) Post administration and sufficient time to transfer the active agent(s), tissue biopsies were taken and tested.

(10) This trial was done to test the transdermal properties of the solvent system and how that compared to known art products.

(11) FIG. 1 illustrates four cross-section cattle skin images of the biopsied tissue samples observed using Scanning Electron Microscope (SEM) images. The upper images are SEM images taken at 10× magnification and the lower images are taken at 40× magnification. The left side images (marked ECLPS) represent cattle skin penetrated by the art commercial product, and the right side images (INN) represent cattle skin penetrated by the solvent system of Example 1.

(12) The images show the stratum corneum layer of the epidermis resting on extracellular matrix (ECM) of the dermis underneath. Both compartments are connected by the basement membrane (BM).

(13) As can be seen, particularly in the lower 40× magnified images, the solvent system of Example 1 penetrates through cattle skin significantly deeper (distance X′ in FIG. 1) than the art referenced commercial product (distance X in FIG. 1). Further, the solvent system tissue sample shows that the system and agent do not concentrate in the epidermal layer, but spread symmetrically through whole volume of the skin to which it is applied (see the width of the image and common depth of penetration visible through the 40× sample (right and bottom side FIG. 1).

(14) These biopsy results support the inventor's finding that the solvent system enhances transdermal delivery of active agents.

Example 3

(15) The trial completed in Example 2 was further verified in respect of the solvent system of Example 1 transferring the active agent to the animal in vivo by measuring the concentration of vitamin B12 in the animal over time. Samples of blood were taken hourly post administration to look for an increase attributable to the solvent system of Example 1 having been effectively moved across the skin barrier.

(16) FIG. 2 shows the results where the x axis illustrates the time intervals and the y axis shows the measured level of vitamin B12 permeate (ng). As shown in FIG. 2, the level of vitamin B12 (termed drug permeate in FIG. 2) shows a significant change and increase over time which can only be attributable to the transfer across the skin barrier from the solvent system of Example 1.

(17) As may be appreciated, transfer of vitamin B12 represents a particularly challenging scenario. Vitamin B12 is a relatively large molecule and vitamin B12 has considerable bioavailability within the skin. It might be expected that transfer would be poor to the bloodstream as a result with the skin blocking the larger molecules of vitamin B12 and/or the skin absorbing the B12 and not having it transfer through into the bloodstream. This example clearly shows the benefits of the solvent system in allowing effective transfer even for challenging active agents.

Example 4

(18) A further example of a solvent system is described below in Table 2, this time for transdermal delivery of two compounds with anthelmintic activity having opposing chemical properties i.e. levamisole is water soluble or hydrophilic while eprinomectin is poorly water insoluble and hydrophobic.

(19) TABLE-US-00002 TABLE 2 Example Solvent System Amount Function Compound (w/v) Fatty acid ester Isopropyl myristate  10-20% Monoterpene D-limonene   1-5% Co-solvent, stabiliser Dimethyl sulfoxide (DMSO) or  15-25% dimethyl isosorbide (DMI) Plant oil/penetration Seabuckthorn oil   1-3% enhancer Amphiphilic compound/ Soya lecithin 0.1-0.5% Penetration assisting agent Surfactant/wetting agent Polysorbate 80 2.5-5% Active agent 1 Eprinomectin   1-3% Active agent 2 Levamisole Base  15-30% Antioxidant BHT 0.1-1% Humectant/emollient Propylene glycol   5-15% Diluent Diethylene glycol monoethyl To volume ether (DGME) q.s.

Example 5

(20) A further example of a solvent system is described below in Table 3, this time for transdermal delivery of an anti-fungal spray composition for treating ringworms:

(21) TABLE-US-00003 TABLE 3 Example Solvent System Amount Function Compound (w/v) Fatty acid ester Isopropyl myristate  10-15% Monoterpene D-limonene  10-14.99% Co-solvent, stabiliser Dimethyl sulfoxide (DMSO) or   8-12% dimethyl isosorbide (DMI) Plant oil/penetration Sage oil   1-2% enhancer Amphiphilic compound/ Soya lecithin 0.1-0.5% Penetration assisting agent Surfactant/wetting agent EO/PO block copolymer   5-10% Active agent Imidazole 0.1-0.5% Agent solvent (added to Water   5-15% the active agent before mixing with the base solution) Humectant/emollient Sorbitol   5-7.5% Diluent Diethylene glycol monoethyl To volume ether (DGME) q.s.

Example 6

(22) A further example of a solvent system is described below in Table 4, this time for transdermal delivery of an anti-inflammatory transdermal formulation:

(23) TABLE-US-00004 TABLE 4 Example Solvent System Amount Function Compound (w/v) Fatty acid ester Isopropyl palmitate   10-15% Monoterpene Menthol  1.5-7.5% Co-solvent, stabiliser Dimethyl sulfoxide (DMSO) or   10-20% dimethyl isosorbide (DMI) Plant oil/penetration Frangipani oil   1-5% enhancer Amphiphilic compound/ Soya lecithin 0.25-0.5% Penetration assisting agent Surfactant/wetting agent Polysorbate 80   5-10% Active agent Meloxicam  0.2-0.25% Agent solvent (added to Water   8-12% the active agent before mixing with the base solution) Humectant/emollient Propylene glycol   10-15% Diluent Diethylene glycol monobutyl To volume ether (DGME) q.s.

Example 7

(24) A further example of a solvent system is described below in Table 5, this time for transdermal delivery of a selenium supplement:

(25) TABLE-US-00005 TABLE 5 Example Solvent System Amount Function Compound (w/v) Fatty acid ester Isopropyl myristate   15-20% Monoterpene D-limonene   4-10% Co-solvent, stabiliser Dimethyl sulfoxide (DMSO) or   8-15% dimethyl isosorbide (DMI) Plant oil/penetration Lilac oil 0.75-1.5% enhancer Amphiphilic compound/ Soya lecithin  0.1-0.5% Penetration assisting agent Surfactant/wetting agent Polysorbate 80   5-10% Active agent Sodium selenate   2-5% Agent solvent (added to Water   10-15% the active agent before mixing with the base solution) Humectant/emollient Glycerine   5-7.5% Diluent Diethylene glycol monoethyl To volume ether (DGME) q.s.

Example 8

(26) A further trial to test the solvent system efficacy was completed. In this example the solvent system described in Example 7 above was administered to a cattle and blood samples then taken hourly post administration and the level of selenium permeate measured.

(27) FIG. 3 shows the results where the amount of selenium measured as drug permeated (mg) on the y axis of the graph over time increased steadily over time clearly showing transdermal transfer occurred.

Example 9

(28) The efficacy of the solvent system was further tested using the solvent system of Example 4 above.

(29) The solvent system was administered at the calculated dose to the backs of sheep as two separate spots of approximately 20 ml each at the back of the neck and about the rump of the animal (3 groups, n=55 sheep).

(30) The trial was set at a challenging level with no cleaning or special pre-treatment of the wool or skin such as trimming completed prior to administration of the solvent system. The sheep had not been sheared prior to treatment and represented a difficult challenge for transdermal delivery due to the long wool coating (more than 3 inches long), dirt and sebum oil/wax/grease layer on the animal skin, mainly being lanolin.

(31) Measurements of egg were completed from samples taken were taken pre-treatment and on 10 days of post treatment.

(32) Results are shown in Table 6 below of the faecal egg count (FEC) (measured in eggs per gram) before administration and 10 days post administration:

(33) TABLE-US-00006 TABLE 6 Faecal Egg Count (FEC) test of dual anthelmintic formulation Total EPG Total EPG after 10 FEC Sheep Groups on day 0 days post treatment Reduction % Group 1 112  8.5 95.9% Group 2 259  15.11 96.8% Group 3 175  13.6 95.8% No Treatment 476 878.9  0.0%

(34) As can be seen from the above table, the results were highly positive with over 95% FEC reduction of the parasite infection from the solvent solution in sheep. These results support the inventors findings that the solvent system provides for excellent transdermal transfer of active agents.

Example 10

(35) The solvent system described in Example 4, Table 2 was subjected to stability testing in accelerated aging storage conditions of 40° C. for 12 months and the results are provided in Table 7 below:

(36) TABLE-US-00007 TABLE 7 Tests of stability of dual anthelmintic solvent system Concentration Concentration Initial after after Active concentration 6 months 12 months Eprinomectin  16.5 g/L  15.8 g/L 14.6 g/L Levamisole 27.15 g/L 25.45 g/L 24.1 g/L

(37) As seen from the above, the concentration of both active ingredients post accelerated aging was less than 15% from the initial formulated concentrations. These results are well within accepted variations and demonstrate active agent stability in the solvent system.

Example 11

(38) The solvent system of Example 4 was tested on sheep directly after shearing (applied directly on the skin) and compared with sheep having wool of 60 mm and over 100 mm long. The trial was completed to test how effective the solvent system is at moving through wool and still achieving the desired efficacy. The results are shown below in Table 8:

(39) TABLE-US-00008 TABLE 8 FEC reading on Sheep of Varying Wool Length Wool length FEC Reduction: Off Shear 99.1% 60 mm 97.5% Over 100 mm 99.6%

(40) As seen from the results above, the presence of wool or not appears to make no difference to the efficacy of the solvent system with the FEC reduction near identical in the trailed animals and irrespective of wool length. These findings support the inventors findings that woolly animals may be treated suing the solvent system with no loss in efficacy and without need to pre-treat the site of administration.

Example 12

(41) To investigate whether there were any adverse effects of the solvent system on the skin of treated animals, a trial was conducted in Roxburgh, Otago (South Island, New Zealand). A base solution (without actives) and the solvent solution of Example 4 (with active) were applied to the skin of sheep using a standard applicator gun.

(42) The animals were observed by a veterinarian daily for any signs of skin irritation, skin redness, swelling at the place of application, along with any wool loss.

(43) It was found that in the case of both the base solution and the solvent system, i.e. without or with actives, there were no significant side effects noticed. Furthermore, any minor effects that were observed had disappeared by day 3 post application.

Example 13

(44) The simplicity of the method of manufacture of the base solution and solvent systems is demonstrated using the solvent system described in Example 1, Table 1.

(45) The method of manufacture involves a simple process of mixing and dissolving. In this example, to manufacture 1000 L of 0.5% vitamin B12 solvent system: To a mixing vessel, the following compounds are added in no particular order comprising 130 kg of isopropyl myristate, 10 kg D-limonene, 200 kg of dimethyl sulfoxide or dimethyl isosorbide, 10 kg of seabuckthorn oil, 50 kg of polysorbate 80, 100 kg of propylene glycol, 1 kg of soya lecithin and 100 kg of diethylene glycol monoethyl ether. Shortly thereafter, 5 kg of vitamin B12 is added to the solution and the mixture is brought up to volume with the remaining amount of diethylene glycol monoethyl ether.

(46) No intense mixing is required and not heating or cooling is required.

Example 14

(47) The method of manufacture is further demonstrated using the formulation in Example 4, Table 2.

(48) In this example, the following compounds are mixed together in a mixing vessel added in no particular order: 130 kg of isopropyl myristate, 10 kg D-limonene, 200 kg of Dimethyl sulfoxide, 100 kg of Propylene glycol, 1 kg of Seabuckthorn oil, 1 kg of Lecithin, 100 kg of Diethylene glycol monoethyl ether; 1 kg of BHT and 27 kg of Levamisole Base; and 16.5 kg of Eprinomectin;

(49) The above solution is mixed until all the solids are dissolved; Polysorbate 80 is then added and the solution is brought to volume with diethylene glycol monoethyl ether.

(50) As noted above, the above manufacturing process does not require any specific conditions, such as heating, high shear agitation or any another mixing vessels.

Example 15

(51) A further example of a solvent system is described below in Table 6, this time for transdermal delivery of a dual anthelmintic solution:

(52) TABLE-US-00009 TABLE 6 Example Solvent System Amount Function Compound (w/v) Fatty acid ester Octyl dodecyl nyristate  10-20% Monoterpene Camphor   1-5% Co-solvent, stabiliser Dimethyl sulfoxide (DMSO) or  15-25% dimethyl isosorbide (DMI) Plant oil/penetration Chamomile oil   1-3% enhancer Amphiphilic compound/ Hydrogenated lysolecithin 0.1-0.5% Penetration assisting agent Surfactant/wetting agent Polysorbate 80 2.5-5% Active agent 1 Eprinomectin   1-3% Active agent 2 Levamisole Base  15-30% Antioxidant BHT 0.1-1% Humectant/emollient Propylene glycol   5-15% Diluent Diethylene glycol monoethyl To volume ether (DGME) q.s.

Example 16

(53) A further example of a solvent system is described below in Table 7, this time for transdermal delivery of a vitamin B12 solution:

(54) TABLE-US-00010 TABLE 7 Example Solvent System Amount Function Compound (w/v) Fatty acid ester Glyceryl stearate   15-20% Monoterpene Pinene   4-10% Co-solvent, stabiliser Dimethyl sulfoxide (DMSO) or   8-15% dimethyl isosorbide (DMI) Plant oil/penetration Oregano oil 0.75-1.5% enhancer Amphiphilic compound/ Soya lecithin  0.1-0.5% Penetration assisting agent Surfactant/wetting agent Antarox L64   5-10% Active agent Vit B12   2-5% Agent solvent (added to Ethanol   10-15% the active agent before mixing with the base solution) Humectant/emollient Sorbitol   5-7.5% Diluent Diethylene glycol monoethyl To volume ether (DGME) q.s.

(55) Aspects of the solvent systems, methods of treatment and uses thereof have been described by way of example only and it should be appreciated that modifications and additions may be made thereto without departing from the scope of the claims herein.