A biphasic hydrogel formulation and methods of production and use thereof

Abstract

The present invention provides a biphasic formulation, comprising a liquid layer on the outside and an elastic hydrogel wherein the water formed on the surface of the elastic gel is physically cooling the skin by evaporating and to give a first boost of the active ingredients directly when placing on the skin of humans or animals. The biphasic formulation according to the present invention may be arranged in a hydrogel patch which creates an environment that relieves or promotes the healing process for the treatment of insect bites, sunburn, erythema, pruritus, acne, dry skin or callus. In accordance with the present invention, there is provided a biphasic hydrogel composition, comprising 6% or less PVA, physical crosslinking, glycerol as humectant and the use of water impermeable packaging to reach equilibrium of the syneresis and preserve the moisture of the gel during long-term storage.

Claims

1. A dermal device comprising a biphasic hydrogel with one liquid layer and one elastic hydrogel layer, wherein the biphasic hydrogel comprises a monopolymeric formulation, and wherein the dermal device is arranged to provide syneresis of at least 10% within 2 weeks.

2. The dermal device according to claim 1, wherein the biphasic hydrogel is physically crosslinked.

3. The dermal device according to claim 1, wherein the dermal device comprises a monopolymeric formulation with a gel forming polymer concentration of maximum 10 wt %, preferably maximum 6 wt %.

4. The dermal device according to claim 1, wherein the dermal device comprises polyvinyl alcohol (PVA).

5. The dermal device according to claim 1, wherein the dermal device also comprises one or more skin humectants, essential oils, plasticizers, antipruritic agents, local anesthetics, debriding agents or cooling agents, or a combination thereof.

6. The dermal device according to claim 1, wherein the dermal device also comprises a basic or acidic agent providing a pH adjustment to a value that is lower or higher than the normal dermal pH.

7. The dermal device according to claim 6, wherein the basic or acidic agent ensures to maintain a pH in the dermal device below 3 or above 7.5.

8. The dermal device according to claim 6, wherein the dermal device comprises acetic acid.

9. The dermal device according to claim 1, wherein the level of syneresis of at least 10% within 2 weeks is determined by measuring the weight difference of the gel phase at day 0 and day 14.

10. The dermal device according to claim 1, wherein the biphasic hydrogel and thus dermal device is elastic with an elongation to break of at least 100% and the force required to elongate the dermal device 50% is less than 0.5 N.

11. The dermal device according to claim 1, said dermal device providing a cooling effect caused by water evaporation suitable for relieving pruritus and wherein the dermal device also functions as a physical barrier providing protection against scratching.

12. The dermal device according to claim 1, said dermal device intended as an aid for relieve of itching from insect bites, and said dermal device comprising polyvinyl alcohol (PVA) in the monopolymeric formulation and in a concentration of maximum 10 wt %, said dermal device also comprising acetic acid in a concentration of 1-3 wt %.

13. The dermal device according to claim 1, wherein the elastic hydrogel layer has a non-flat surface to increase the specific surface area thereof and/or to retain a liquid layer against the skin of the user.

14. The dermal device according to claim 1, wherein the non-flat surface comprises surface holes, is fluted or comprises surface extensions to increase the specific surface area and/or to retain a liquid layer against the skin of the user.

15. The dermal device according to claim 1, wherein the biphasic hydrogel is self-supportive and sticks to the surface of a skin without the need for adhesives.

16. The dermal device according to claim 1, wherein the dermal device is packed in a barrier material having a cavity for accommodation of the hydrogel to preserve the moisture until use and to retain liquid that is creeping out from the hydrogel during syneresis, and wherein the equilibrium between the gel and liquid form is preserved by packaging the dermal device in a protective barrier until use.

17. A method for the production of a dermal device according to claim 1, said method comprising providing a water-soluble gel forming polymer and water as a solvent; dissolving the gel forming polymer in water during mixing and heating; optionally, adding one or more excipients; mixing to obtain a homogenous solution; and physically crosslinking and thus solidifying the homogenous solution to a hydrogel and storing the hydrogel in a package until syneresis has occurred to create a biphasic hydrogel.

18. The method according to claim 17, wherein the monopolymeric formulation is provided with a gel forming polymer concentration in a range of 3-6 wt % and is dissolved in 60-97 wt % water.

19. The method according to claim 17 or 18, wherein the step of filling is performed before or after the crosslinking step, into a barrier material having a cavity for accommodation of the hydrogel to preserve the moisture until use and to retain liquid that is creeping out from the hydrogel during syneresis.

20. The method according to claim 17, wherein the step of physically crosslinking the hydrogel comprises repeating freezing and thawing cycles or applying gamma radiation.

21. The method according to claim 17, wherein said method also comprises a step of affecting the elastic hydrogel layer to provide a non-flat surface thereof and to increase the specific surface area and/or to enabling to retain a liquid layer against the skin of the user.

Description

DESCRIPTION OF THE DRAWINGS

[0054] FIG. 1 shows one example of a biphasic hydrogel according to the present invention, where the figure shows a section of the solid gel with a liquid layer surrounding the gel.

[0055] FIGS. 2a and 2b show a circular hydrogel according to the present invention, suitably with a thickness of 0.5 to 3 mm. This is one possible example of a shape, but other may of course be used.

[0056] FIGS. 3a and 3b shows a hydrogel with ridges, creating an increased surface area.

[0057] FIGS. 4a and 4b shows a hydrogel with circular perforations, thereby creating pores to retain the exudate and to allow for evaporation.

[0058] The hydrogel according to the present invention may be packaged in different ways. In FIGS. 5a and 5b two different alternatives are shown. In FIG. 5a there is shown a tear open package and in FIG. 5b there is shown a corresponding peel off alternative. Many other package alternatives are possible according to the present invention.

[0059] FIG. 6 shows s a graph of the syneresis rate that is slowing down after 14 days. Freshly prepared patches were weighed before packaging in a barrier package. Patches were then taken out of the package and weighed after 1 day, 2 days, 4 days, 11 days and 30 days. Excess fluid was removed before weighing. The amount of syneresis was calculated by subtracting the weight recorded after storage from the weight that was recorded at day 0.

[0060] FIG. 7 shows a comparative example referring to syneresis.

[0061] FIG. 8 shows a comparative example referring to elongation to rupture.

EXAMPLES

Example 1: Preparation of PVA Solution

[0062] The PVA solution was prepared by dissolving 4-10% wt of PVA in water while heating at 90° C. and gentle stirring until dissolved, (2-6 hours). A preferred PVA average molecular weight range was chosen which resulted in a viscosity of 20-35 mpa of a 4% aqueous solution at 20° C. and which was 97-100% hydrolysed. The PVA used in the experiments was purchased from Cururay Poval and Merck.

Example 2: Preparation of Acidic Gel for Alleviation Pruritus Caused by Insect Bites or Rashes

[0063] A gel intended to alleviate insect bites was prepared by adding glycerol (0-10%) and acetic acid (1-3%) to the PVA solution prepared in example 1 and was physically crosslinked and packaged as in example 7-9 below. Before arriving to this solution, a large number of natural gels evaluated (alginate, gelatin, carrageenan, xanthan and locust bean gum) were evaluated. It was discovered that these polymers did not result in an acceptable hydrogel at acidic pH. When the gel was placed on itching insect bites, the gel had a soothing effect, alleviated pruritus and formed a physical barrier to protect the skin from being scratched thereby protecting the skin from infection and damage caused by scratching the skin.

Example 3: Advantage of Syneresis

[0064] In one experiment, the water loss from gel patches prepared as described in experiment 2 was determined. It was unexpectedly observed that an equilibrium occurred already after 10 days, when about 25% of the liquid had been creeping out of the gel. The hydrogel then remained stable inside the package, during at least 6 months. The liquid phase forming on the outside of the patch is advantageous since it instantly humidifies the skin and results in a cooling/soothing sensation when placed on the skin due to the evaporation of water. The surface layer also ensures that the gel patch does not stick to the package but easily slips out.

Example 4: Preparation of Hydrogel to Sooth Acne or Other Irritated Skin Conditions

[0065] Calamine lotion (2-10%) and/or tee-tree oil (0.1-1%) and/or glycerol and/or vitamin A, was added to the PVA solution prepared in example 1, and packaged and crosslinked as in example 7-9 below. The calamine lotion used in these experiments were purchased from ACO hud AB (“soothing cooling balm”) The ferric oxide in the calamine lotion resulted in an appealing light opaque pink color, the patches were moist and slippery and gave a cooling and soothing effect when placed on irritated skin.

Example 5: Preparation of a Hydrogel to Remove or Soften Callus or Warts

[0066] Glycerol (2-10%) and keratolytic agents such as 0.1 to 2% wt of a suitable protease, or 0.5-to 3% of an acid such as acetic acid or salicylic acid was added to the PVA solution prepared in example 1 and crosslinked and packaged as in example 6-8 below. A gel prepared as described in this example, containing glycerol as humectant and trypsin as the keratolytic enzyme was found to be comfortable to wear and softened the skin.

Example 6: Packaging Hydrogel after Freeze/Thaw

[0067] The solution was prepared as in example 1, 4, or 5 and dispensed in to molds of the desired shape. The molds were exposed to repeated freezing and thawing of 6 to 12 hours for 2 to 5 times (2-5×6-12 hours) until the gel was sufficiently solidified (Force to break >0.1 and <3 N). The crosslinked and solidified hydrogel patches were removed from the molds and packed in aluminum pouches or plastic pouches and sealed (FIGS. 3a and 3b).

Example 7: Filling in Blisters Before Freeze/Thaw

[0068] PVA solutions were prepared as in example 1, 4, or 5 and dispensed into cavities in blister packages prepared in the desired shape, while in liquid form, sealed and then exposed to freeze-thawing cycles until solidified.

Example 8: Filling in Sachets Before Freeze/Thaw

[0069] PVA solutions were prepared as in example 1, 4, or 5 and dispensed into pouches of the desired form that were sealed manually or in a vertical or horizontal form/fill/seal machine, and then exposed to freeze-thawing cycles until solidified.

Example 9: Protecting the Applied Gel with a Nonwoven Layer

[0070] In one example the hydrogels are combined with pre-cut pieces of thin breathable non-woven material with adhesive. A material from 3M art #1776 was found to be suitable to protect and keep the patch in place while still allowing for water to evaporate

Example 10: Preparation of a Stable, Elastic Hydrogel Patch with a Syneresis at Equilibrium of at Least 20%

[0071] The desired amount of syneresis and elasticity is reached by using a PVA polymer that is >97% hydrolyzed with a molecular weight range of 90 000-100 000 g/mol, keeping the final PVA concentration in the formulation below 8%, temperature cycling a maximum of 4 times, and packaging in a sachet or blister with a sufficiently high water barrier. The result is a highly elastic gel with a 10-20% syneresis after 2 weeks, that will be elastic and moist for at least 6 months.

Comparative Experiments

[0072] The following materials were used to conduct a comparative trial of a PVA gel according to the present invention, with other gels (Table 1):

TABLE-US-00001 TABLE 1 Composition of gels used for comparing syneresis and elongation to break Agar 1 Agar 2 Agar 3 Agar 4 PVA Gel* (Agar (Agar (Agar (Agar Material (GX.sup.+) LBX.sup.+) LBX) XC) XC.sup.+) PVA 6% — — — Agar — 0.9% 0.9% 0.6% 0.6% Glycerol 7.5%.sup.   15%  15%  10%  10% Acetic Acid 2% .sup. 2% — — .sup. 2% Locust Bean Gum — 0.1% 0.1% — Xhantan Gum 0.1% 0.1% 0.1% 0.1% Konjac Mannan 0.3% 0.3% *According to the present invention Agar, locust bean gum, konjac mannan and xanthan are first dispersed in glycerol, water is added while stirring, heated until clear.

[0073] The following methods were used to compare syneresis:

3 g gels are molded in 3 cm diameter silicone forms. PVA gels were temperature cycled 3 times and agar gels were left to settle overnight. The solidified gels were weighed and packaged in high barrier sachets (PET/PE/ALU/PE);

[0074] After 1, 3, 8, 13, 20 and 48 days, excess liquid shaken off and the gels were weighed. Syneresis was calculated by the following formula: (Initial weight−weight after storage)*100/Initial weight

[0075] Syneresis equilibrium was evaluated over time and the results are shown in FIG. 7. Here it is seen that a gel according to the present invention has a high syneresis in comparison to the known agar gels.

[0076] Furthermore, a manual elongation to break test was also performed. The following procedure was performed:

[0077] 1) Gels are cut in to 4×1 cm strips;

[0078] 2) Clamps are attached in both ends with 2 cm gel strip in between* *The polysacharide gels are too brittle to be held by the clamp so they are handheld instead

[0079] 3) Gels are pulled apart along a steel ruler; and

[0080] 4) The % elongation at the time when the gel breaks are noted;

[0081] The results are presented in FIG. 8 where it is clear that the gel according to the present invention has a much higher elongation to break (rupture) than known agar gels.

[0082] Furthermore, the elasticity of a PVA hydrogel according to the present invention was also compared with 3 different polysaccharide gels, by measuring the force required to rupture the gel.

Method and Material of the Elasticity Trials

Gel Preparation for the Elasticity Trials

[0083] Gels with the dimensions 2.2 cm diameter and 1.2 mm height were prepared as follows: The polysaccharides were dispersed in glycerol, water added and then heated to 90° C. 4 ml of each gel was pipetted in a 6-well plate while still warm. Left to gel over-night. The recipes were taken from WO0101950A1, pre-formed gel sheet, with the exception that agarose was replaced with agar and that no preservatives were added (see table 2 below).

TABLE-US-00002 TABLE 2 Composition of gels used for compression testing Gel 4:1 and 4:2 Gel 1 Gel 2 Gel 3 (acc. to present Material (E.G.1) (E.G.6) (E.G.8) invention) * PVA 6% Acetic Acid 2% Agar Agar 0.9% 0.4% — — Locust Bean Gum 0.1% — 0.5% — Xhantan gum 0.1% 0.1% 0.5% — Konjac Mannan 0.2% 0.2% — — Glycerol 99.5%  15%  10%  10% 7.5%.sup.  *4 ml was pipetted per well. Gel 4:1 was temperature cycled twice and Gel 4:2 was temperature cycled three times

Compressive Rupture Test

[0084] Compressive rupture was measured manually by placing the gels between two glass petri-dishes. The dish was place on a scale and weights were added on top until breakage could be seen.

Result of the Rupture Test

[0085] The PVA gels according to the present invention could not be ruptured within the capacity of the scale and the result for both PVA gels is therefor set to >33N. They were compressed >90% but did not break and sprung back to their original form, when pressure was released.

Gel 1 required 3.8 N to break and Gel 2 1.4N. Gel 3 could not be measured since it did not hold together. The results are presented below in table 3.

TABLE-US-00003 TABLE 3 Rupture tests of known gels in comparison to gels according to the present invention Gel S1 (N) S2 (N) mean 1 4 3.5 3.8 2 1.5 1.2 1.4 3 Could not Could not Could not measure measure measure 4:1 according to the >33 >33 >33 present invention 4:2 according to the >33 >33 >33 present invention

[0086] As may be seen, the polysaccharide gels are brittle and breaks easily. Force to rupture is at least 10 times lower compared to the PVA gels according to the present invention.

[0087] Based on the above, according to yet another specific embodiment of the present invention, the biphasic hydrogel and thus dermal device is elastic with an elongation to break of at least 100% and the force required to elongate the dermal device 50% is less than 0.5 N. This is of interest so that the dermal device adjusts to irregularities of the skin surface where it is attached. Moreover, this is also a clear difference of the dermal device and hydrogel according to the present invention when comparing to known hydrogels.