WO2021122707A1

WO2021122707A1 - Oxygen generating composition

Info

Publication number: WO2021122707A1
Application number: PCT/EP2020/086369
Authority: WO
Inventors: Karol Lorent; Pascal VANDENBUSSCHE; Sergey Morozov; Jessica LINK
Original assignee: Solvay Sa
Priority date: 2019-12-19
Filing date: 2020-12-16
Publication date: 2021-06-24

Abstract

The present invention relates to an oxygen releasing composition comprising a solid peroxide and a citric acid/citrate buffer. It also relates to a process for releasing oxygen in water, said process comprising contacting a solid peroxide with water to obtain an aqueous phase and buffering the pH of said aqueous phase with a citric acid/citrate buffer.

Description

Oxygen generating composition

This application claims priority to European application No. 19217866.3 filed on December 19, 2019, the whole content of this application being incorporated herein by reference for all purposes.

The present invention relates to an oxygen generating composition and to a process for releasing oxygen in water.

An increasing number of people are suffering from chronic wounds, for instance diabetic patients. The problem with this type of wounds is that the concerned tissues are generally depleted in oxygen i.e. they are hypoxic tissues (tissues in ischemia) which need to be provided with oxygen for the healing process to be completed.

Among the solutions to this problem, are worth mentioning:

- GHT (Global Hyperbaric Therapy)

- THT (Topical Hyperbaric Therapy)

- 02 or Oxygen Breathing

- NATROX® and EPIFLOW® (Pumping system delivering 02 over a wound)

- Granulox ® (haemoglobin spray)

- Gels, wound dressings or implants comprising oxygen generating compounds or devices.

WO 2008/124126 relates to a method of treating hypoxic tissue in vivo comprising contacting the hypoxic tissue with a composition comprising a biodegradable polymer and an inorganic peroxide incorporated into the polymer, preferably in solid form. In some embodiments, the composition is in the form of a sheet material, and the contacting step is carried out by contacting the sheet material to the tissue. In some embodiments, the composition is in the form of injectable micro-particles, and the contacting step is carried out by injecting the micro-particles into the tissue. In some embodiments, the composition is in the form of a spray, and the contacting step is carried out by spraying the composition onto the tissue. In some embodiments, the composition is in the form of a surgical or paramedical aid, and the contacting step is carried out by contacting the aid to the tissue. As far as topical applications are concerned, the spray alternative offers the advantage of covering the wound with a uniform and thin layer of the composition, of not requiring contacting the wound; and the fact that the composition is easy to apply in outdoor or other “uncomfortable” conditions, and this even by non-skilled people.

The compositions disclosed in WO 2008/124126, which are mainly based on sodium percarbonate (SPC) dispersed in poly(lactide-co-glycolide) (PLGA), offer the advantage of being gentle (not aggressive) towards the treated tissues.

However, they suffer from the drawback that they include several non- active ingredients like a biodegradable polymer matrix and a liquid carrier. These ingredients increase the cost and weight of the spray devices through which the compositions are delivered. Besides, they tend to decrease the activity of the compositions which actually slowly releases oxygen.

Oxygen releasing compositions based on calcium peroxide have been reported also in the frame of wound care/healing. EP 2450114 for instance describes a gel comprising up to 60wt% of an oxidant release agent that may be calcium peroxide, and that may be used in wound care. However, when in contact with a wound, calcium peroxide will produce calcium hydroxide that will hence generate a highly aggressive basic medium if present in high quantities. US 2017/0368223 discloses a skin-friendly absorbent structure comprising oxygen providing units (like calcium peroxide) and pH regulating units, and which has a pH between 4 and 7 after absorbing liquids. This document mentions solid acids like citric acid as pH regulating units; however, it does not deal with the problem of pH evolution and oxygen release over time. The Applicant found out however that the pH evolves over time and can become too basic (hence, too aggressive) before the end of use of the structure.

The present invention aims at solving these problems by providing an oxygen releasing composition for wound healing having increased efficiency, favourable economics and weight and size savings, and being mild (gentle) to the wound tissues.

To this end, the present invention concerns an oxygen releasing composition comprising a solid peroxide and a citric acid/citrate buffer.

The idea behind the present invention is to use an acid in order to control the pH (reduce it in order to make it skin friendly) and to favour the generation of hydrogen peroxide (which decomposes to generate oxygen) when the composition of the invention is contacted with the moist of the wound. However, acidification tends to lower the kinetics of hydrogen peroxide decomposition (generating the oxygen feeding the hypoxic tissue) so that in fact, there is a narrow ideal pH range that should be maintained during the entire wound healing process. The Applicant has found that such a continuous and reliable pH control can be achieved by using a citric acid/citrate buffer.

The composition according to the invention comprises a solid peroxide generally as solid particles the granulometry of which (determined by laser diffraction spectroscopy) - and eventually other properties - can be adapted to be sprayed i.e. to form an aerosol. To this end, its particles are preferably substantially spherical, preferably with an average diameter between 1 to 100 pm, preferably between 2 to 50 pm and even more preferably, between 3 to 30 pm.

In another embodiment, the solid particles of the composition are embedded in granules, tablets or films, eventually with a binder so that they can be directly applied on the wound or integrated into the wound dressing. The binder should be an organic binder, as they are usually soluble in water, such as polymers (cellulose or cellulose derivatives, starch, lignin derivatives, sucrose, polyacrylates, polyethylene glycol, polyvinyl alcohol, polyurethane, polyester, polyvinylpyrrolidone) or glues (epoxy resins, waxes and wax emulsions, paraffins, dextrins, casein glue or gelatin). Biodegradable polymers can also be used, such as for instance those mentioned in EP2155235, namely poly(lactide)s, poly(glycolide)s, poly(lactide-coglycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, poly(caprolactone), polycarbonates, polyesteramides, polyanhydrides, poly(amino acid)s, poly( ortho ester)s, polycyanoacrylates, polyamides, polyacetals, poly( ether ester)s, copolymers of polyethylene glycol) and poly(ortho ester)s, poly(dioxanone)s, poly(alkylene alkylate)s, biodegradable polyurethanes, as well as blends and copolymers thereof.

In still another embodiment, the solid particles can be inserted into a solid device of any kind, for instance a thin bag or envelope (like a “tea bag”) to prevent any contact between the wound and the particles, for instance by inserting it under a wound dressing or to be integrated into a wound dressing. This kind of dressing has the advantage of not leaving residual particles on the wound that might irritate the skin or remain in the wound. The particles could be separated from the wound with an envelope made of one or two different membranes. One in contact with the wound, which should be an oxygen and water permeable membrane to insure the transfer of oxygen directly to the wound. This membrane could be made of paper, filter, cotton, hydrophilic polymers (for example polyamide, polyurethane, acrylic polymers, polyethylene glycol, polyvinyl alcohol or biopolymers) or micro-porous water and oxygen permeable polymer membranes with pores preferably smaller than the size of the particles (made of hydrophilic PVDF, cellulose, PTFE, PSU for example). The membrane on the top of the envelope preferably should be a water and oxygen impermeable to localize the oxygen near the wound and could be made of PVDC, PET, fluorinated polymers such as PVDF, PTFE or their copolymers for example.

These membranes can be sealed for example by thermo-sealing, or by using chemical adhesives.

The particles can also be dispersed in a cream. In this case it is preferable to use a dispersive phase (like water), a vegetable oil (like coconut, olive, corn, almond, hazelnut or argan oil), mineral (vaseline or paraffin) or synthetic silicon oil, an emulsifier (surfactants like mono/di/tri-stearates, sorbitan ester, sodium lauryl sulfate, or oleates; or polymers such as arabic gum, cellulose derivatives, alginate or carraghenates), a thickening agent (usually stearates, natural or synthetic polysaccharides or gelatines) and/or an emollient (for example a polyol such as glycerol, propylene glycol, caprylil glycerol, polymeric polyols (like polydextrose ), glyceryl triacetate, lactic acid, triglycerides or vaseline).

Finally, it is also possible to disperse the particles in a gel and more particularly in a hydrogel or a cryogel. Gels are developed using different possible water-soluble polymers like gelatin-based polymers, polysaccharides (for example cellulose, alginate, guar, xanthan, carrageenan, agarose, chitosan, gellan gum), polyvinyl alcohol, polyacrylic acids, polyamides, polyethylene oxide, polyurethanes, acrylate polymers or polyethers.

Hence, in one aspect of the invention, if the solid particles are not used as such, they can be embedded in granules, tablets, films, in a cream, a polymer gel or a cryogel.

The solid peroxide preferably is an inorganic peroxide, more preferably an alkaline metal peroxide (like sodium, potassium or lithium peroxide) or an alkaline earth metal peroxide (like calcium, magnesium, barium, zinc or strontium peroxide), or a mixture thereof. It more preferably is calcium or magnesium peroxide, most preferably calcium peroxide which has superior oxygen release and beneficial counter ions for cicatrisation purpose. A mixture of Ca, Mg and Zn peroxide might also be used for cicatrisation purposes.

If the solid peroxide is calcium peroxide (Ca02), the composition of the invention generally also comprises calcium hydroxide (Ca(OH)2) since most commercial grades of Ca02 contain Ca(OH)2, generally in an amount of at least 20wt% and even up to 40wt%. This is due to the way Ca02 is manufactured (starting from Ca(OH)2 and hydrogen peroxide).

Alternatively, the solid peroxide may be an organic peroxide like urea peroxide. The present invention uses a buffer i.e. molecules that donate or accept protons to resist changes in pH as acids or bases are added to an aqueous solution. A buffer consists of a weak acid and its conjugate base, or a weak base and its conjugate acid. In the present invention, the buffer comprises citric acid and a citrate. Citrate is a salt of citric acid with an alkaline or alkaline earth metals like Na, K, Ca or Mg.

The citrate according to the invention is preferably calcium (Ca) citrate, especially when the solid peroxide is calcium peroxide.

When using the commercial grade Ixper® 75C (which contains about 75wt% of Ca02), good results were obtained with the following formulation: 26.0 wt% Ixper®75C, 47.2 wt% citric acid and 26.8 wt% calcium citrate (please see the results in the Examples below). This formulation gives a good pH range (between 5 and 8) and leads to the best oxygen release over time. It corresponds to the following molar composition: 37.3 mol% citric acid, 41.1 mol% Ca02,

13.3 mol% Ca(OH)2 and 8.2 mol% calcium citrate. From Applicant’s experience, it seems that the best results are obtained with a molar ratio citric acid:solid peroxide between 0.70 and 0.95, preferably between 0.8 and 0.94 and even more preferably between 0.90 and 0.92, especially when said solid peroxide is calcium peroxide.

The role of citrate is to form a buffer with citric acid. The amount of citrate is calculated so that the pH of the buffer ranges from 7.7 to 7.8. Due to the lack of solubility of the calcium citrate (only about 1 g/1 at room temperature), this pH is generally not reached before 24h. However, the fact of using a highly soluble salt (like sodium citrate) with limited amounts of liquid available to dilute is likely to create a situation of exposing wounds to highly hypertonic conditions which can result in swelling, irritation, pain induction and impeded healing.

Calcium citrate containing compositions in contrast to sodium citrate containing compositions generate only slightly soluble calcium citrate as a final product ensuring limited effect on the liquid osmolarity. This was proven by tests on mice.

In some embodiments, a metal may be added to the composition in order to catalyse hydrogen peroxide decomposition. Suitable metals for use in this embodiment of the invention are those that catalyse hydrogen peroxide decomposition like Cu, Mn, Mo, Ag, Fe, Ti, Zn, V, Co, Zr and Nb. These metal(s) may be added as salts or oxides for example. Iron and Copper give good results in practice and Silver might bring an additional advantage in terms of disinfection. More than one metal may be used. In a preferred embodiment, the metal is iron, copper, titanium or silver or a mixture thereof, either in insoluble solid micro-particulate form, or as soluble salts. A mixture of mineral salts of metals (oligo-elements) is preferred.

In case the composition of the invention is solid, it may also comprise other ingredients but preferably not in a high amount (except as far as an alkaline or alkaline earth hydroxide (like calcium hydroxide) is concerned; see above); for instance, the composition may comprise anti caking agents, desiccants, inorganic coatings, surface levellers, cratering reducers, anti-electrostatic agents and enzymes (for example catalase) - which all preferably are biocompatible, and preferably in an amount of from 0 to 25wt%, preferably 0.05 to 10wt%, more preferably 0.5 to 5wt%. In particular, the solid composition according to this embodiment of the invention does not comprise a polymer matrix i.e. it contains less than 50wt% polymer, preferably less than 20wt% polymer, particularly less than 5wt% polymer or even is devoid of any polymer (biodegradable or not).

The solid composition according to this embodiment of the invention can be sprayed by any device suitable to generate a solid aerosol i.e. a suspension of fine solid particles in air or an inert gas like nitrogen for instance.

The pH of the composition when contacted with water (i.e. moisture of the wound) is preferably close to the physiological pH i.e. close to 7.5. In practice, it is generally sufficient to have a pH between 4 and 9, more preferably between 5 and 8. This pH range can generally be reached and maintained over a long period of time (for instance at least one day and even up to 4 days or more) by adapting the respective amounts of the ingredients of the composition. In the above mentioned embodiment related to the use of commercial IXPER® grades and Ca citrate, it is namely the quantity of citric acid, the amount of Ca02 (knowing that for instance the pH of Ca02 in contact with water is at around 12), of Ca(OH)2 (the case being) and of Ca citrate.

Besides wound healing, other applications of the oxygen generating composition of the invention are the following: disinfection and odour removal for textiles; armpits, feet or shoe spray for odour control / disinfection; stem cells therapy; and any other application implying contact with the skin or cells from a human or an animal.

The present invention also concerns contacting a wound with a composition as described above. A first embodiment concerns a method for treating a wound said method comprising spraying a layer of the composition as described above onto said wound.

In this embodiment, the composition of the invention is preferably sprayed as a layer having a thickness between 0.1 to 5 mm, more preferably between 0.5 to 3 mm, most preferably 0.75 to 2 mm.

In another embodiment of the present invention, the composition is suspended in a highly viscous hydrophilic matrix (glycerol for instance; or ethylene glycol or any other biocompatible excipient) and the suspension so obtained is applied on a wound. This suspension preferably has a viscosity between 0.5 to 1000 Pa.s, more preferably between 3 to to 500 Pa.s and even more preferably between 5 to 100 Pa.s and hence, typically has the viscosity of a cream.

In yet another embodiment, a wound dressing can be applied on a layer of the composition of the invention that has been sprayed, applied or otherwise applied onto the wound (for instance being inserted in a kind of envelope like a “tea bag”), preferably a wound dressing that is able to maintain a moisture level at an optimal point in the vicinity of the wound. For instance, if the wound is dry, the wound dressing will preferably comprise a hydrogel. And if the wound is super exudative, the wound dressing will preferably be super absorbent. The present invention also concerns a process for releasing oxygen in water, said process comprising contacting a solid peroxide with water to obtain an aqueous phase and buffering the pH of said aqueous phase with a citric acid/citrate buffer.

In the process of the invention, water may be added on purpose (through any aqueous liquid in fact) or it can come from the environment, for instance from ambient humidity, humidity emitted by the body of a living being (like sweat, wound exudate or lymphatic liquid) etc.

In processes involving a living being, the amount of water is generally low and is generally slowly released. In practice, the amount of solid peroxide and citric acid/citrate buffer used in these processes is calculated in view of the amount of water that will be in contact with them i.e. locally released by the living being.

In the process of the invention, the solid peroxide is preferably a metal peroxide, more preferably Ca02 and the citrate is preferably Ca citrate. In a first embodiment, the citric acid/citrate buffer is mixed with the solid peroxide prior to its contact with water.

In a second embodiment, citric acid is mixed with the solid peroxide and optionally with a metal hydroxide prior to its contact with water and the citrate is generated in situ by reaction of citric acid with a decomposition product of the solid peroxide and optionally with the metal hydroxide.

The second embodiment might be preferred when using a commercial grade of Ca02 also containing Ca(OH)2 in a sufficient amount (like an IXPER® product for instance).

In the process of the invention, the pH is buffered i.e. it is maintained in a desired range over a given period of time, preferably of at least one day

(preferably at least 2 and even more preferably up till 4 days) by using the citric acid/citrate buffer. Preferably, at least for processes involving a living being, said desired range is between 4 and 9, more preferably between 5 and 8.

Hence, in a preferred embodiment of the invention, the pH is maintained in a desired range over a period of at least one day, said desired range being between 4 and 9, more preferably between 5 and 8.

In practice, the pH will generally evolve over time as the solid peroxide will progressively decompose. Preferably, the pH will vary from a minimum value of 4.0 to 6.0 (preferably from 5.0 to 5.5) at the beginning of the process, to a maximum value of 6.1 to 8.0 (preferably 7.5 to 8.0) at the end of the process, and this preferably over the above given period of time. In a preferred embodiment, this pH evolution takes place over a period of at least one day, preferably at least two days, even more preferably at least three or even four days. Preferably, substantially all the solid peroxide has decomposed at the end of the process. In this embodiment, “substantially” means that at least 80wt% of the peroxide’s available oxygen will be released, preferably at least 90wt% of it, even more preferably at least 95wt% of it. It is namely so that from an economical point of view, it is advantageous to consume all the available oxygen. But from a comfort point of view, oxygen release may not be too quick namely because in the case of Ca02, the Ca(OH)2 released by the decomposition in contact with water reacts with the citric acid in a very exothermic reaction.

In the process of the invention, the molar ratio citric acid: solid peroxide is preferably between 0.70 and 0.95, more preferably between 0.8 and 0.94 and even more preferably between 0.90 and 0.92. Additionally or alternatively, in the process of the invention, the amount of citrate is calculated so that the pH of the buffer ranges from 7.7 to 7.8. Due to the lack of solubility in water of the calcium citrate (only about 1 g/1 at room temperature), this pH is generally not reached before 24h.

Should the disclosure of any patents, patent applications, and publications which are incorporated herein by reference conflict with the description of the present application to the extent that it may render a term unclear, the present description shall take precedence.

Example

Reagents used: - Calcium peroxide (Ca0₂) : IXPER® 75C (SOLVAY)

- Citric acid: Citric acid monohydrate, reagent grade > 98% (SIGMA- ALDRICH)

- Calcium citrate: Calcium citrate tetrahydrate, 99% (SIGMA- ALDRICH) Equipments used:

- Cryo-grinder: Dangoumill 300 (PROLABO)

- pH measurement: 913 pH Meter (METROHM)

- pH electrode: Solitrode with pt 1000 temperature probe (METROHM)

Test description: a) Sample preparation:

The IXPER®75C, the citric acid and the calcium citrate respectively according the following mass ratio 26%:47.2%:26.8% were placed in the cryo- grinder. The solid mix recovered was dried in a vacuum oven at 40°C during 30 minutes. b) Oxygen release measurement:

The principle used was to measure over time the volume of water that was displaced in a water column due to the decomposition of the calcium peroxide that releases oxygen. The water column was hermetically connected to a cell inside which the sample was located and which was heated at 37°C in an oil bath. The reaction was triggered by addition of demineralized water to the solid. c) pH measurement:

The pH of the aqueous solution in contact with the sample heated at 37°C was measured over time. Results obtained:

A. pH Evolution over time:

Sample Ref. (Amount)

22-h.l (g) 0.05024

22-h.2 (g) 0.05023

22-h.3 (g) 0.05055

Table 1.

The results obtained are shown in Table 1 above and illustrated in Figure 1 attached (average pH evolution over time).

B. 02 release:

Sample characteristics mass (g) 0.6397

IXPER (wt%) 26 mass IXPER (g) 0.1663

Theoretical available oxygen (mL) 21 Table 2

The results obtained are shown in Table 2 above and in Figure 2 attached.

Claims

1. An oxygen releasing composition comprising a solid peroxide and a citric acid/citrate buffer.

2. The composition of claim 1, wherein the solid peroxide is an inorganic peroxide, preferably an alkaline metal peroxide or an alkaline earth metal peroxide.

3. The composition of claim 2, wherein the solid peroxide is calcium peroxide, said composition also preferably comprising calcium hydroxide.

4. The composition according to any of the preceding claims, wherein the citrate is calcium citrate.

5. The composition according to any of the preceding claims, said composition having a molar ratio citric acid: solid peroxide between 0.70 and 0.95, preferably between 0.8 and 0.94 and even more preferably between 0.90 and 0.92.

6. The composition according to any of the preceding claims, the pH of which when contacted with water is between 4 and 9, preferably between 5 and 8

7. The composition according to any of the preceding claims, said composition being inserted into a solid device, preferably a thin bag or envelope.

8. The composition according to any of claims 1 to 6, said composition being embedded in granules, tablets, films, in a cream, a polymer gel or a cryogel.

9. A process for releasing oxygen in water, said process comprising contacting a solid peroxide with water to obtain an aqueous phase and buffering the pH of said aqueous phase with a citric acid/citrate buffer.

10. The process according to claim 9, wherein the solid peroxide is a metal peroxide, preferably calcium peroxide, and the citrate is calcium citrate.

11. The process according to claim 9 or 10, wherein citric acid is mixed with the solid peroxide and optionally with a metal hydroxide prior to its contact with water and the citrate is generated in situ by reaction of citric acid with a decomposition product of the solid peroxide and optionally with the metal hydroxide.

12. The process according to any of claims 9 to 11, wherein the pH is maintained in a desired range over a period of at least one day, said desired range being between 4 and 9, more preferably between 5 and 8.

13. The process according to claim 12, wherein the pH varies from a minimum value of 4.0 to 6.0 at the beginning of the process, to a maximum value of 6.1 to 8.0 at the end of the process.

14. The process according to any of claims 9 to 13, wherein substantially all the solid peroxide is decomposed at the end of the process.

15. The process according to any of claims 9 to 14, wherein the molar ratio of the citric acid used versus the solid peroxide used is between 0.70 and

0.95 and wherein the amount of citrate used is sufficient to control pH.