FIELD OF APPLICATION OF THE INVENTION

The present invention relates to compositions for the delivery of active ingredients into and through the skin and other tissues. More particularly, but not exclusively, this invention relates to compositions in a gel form to be applied to cutaneous damaged tissue in order to accelerate the repair and regeneration of said damaged tissue.

BACKGROUND TO THE INVENTION

The human skin is the largest organ of the body, and is further comprised of multiple layers and tissue that serves to guard important muscles, bones, ligament and organs within the body. The protective or barrier-like function of the skin is effective as each layer serves a particular purpose, where some important examples include protecting the body from harsh environmental conditions, dehydration, pathogens and harmful chemicals. While the skin has a low permeability, some foreign substances are still capable of penetrating the skin, which could result in damage to both cutaneous (visible skin) and subcutaneous (under the skin) tissue. In addition, the infliction of sufficient external force, external trauma or pressure to the skin can also result in damage to both cutaneous tissue and subcutaneous tissue.

Even though the skin has limited permeability, there has been a keen interest in developing techniques and products that painlessly penetrate the skin and deliver drugs or other active compounds into the human body. A typical example is what is commonly referred to as a “nicotine patch”, which is a transdermal patch that delivers nicotine into the body through the skin. US 4920989 A was granted and discloses a method and apparatus for the nicotine patch by which a transdermal patch can help an individual to reduce their incidence of tobacco smoking. US 8404661 B2 discloses a wound-healing pharmaceutical composition to be administered as a foam in order to treat a wound in a biological tissue, and said pharmaceutical composition contains a combination of glycine, proline and sodium hyaluronate. There are several compositions available in the art that are used as topical medications. The majority of these compositions assist with the process of wound healing and reduce the spread of infection or, in some instances, reduce the formation of scar tissue.

The characteristics sought after when selecting an ideal wound dressing material would be to accelerate wound healing, while reducing the loss of protein, electrolytes and fluid from the wound, and further to minimize pain and infection of the wound. Typically, the effectiveness of a wound dressing material is assessed by looking at the amount of drainage, depth of damage, presence of infection and location of the wound. However, a suitable wound dressing will only be effective if a patient also supplements the healing process by means of nutrition and systemic antibiotics ¹ .

A disadvantage of the prior art is that most compositions do not exhibit any effective regenerative properties, while the only compositions that have been shown to exhibit some regenerative properties comprise stem cells in some shape or form. An example of the benefits of stem cell therapy was disclosed in WO 2011/101760, which describes a regenerative bio-material comprised of mesenchymal stem cells and other

Sarabahi. S. (2012), Recent advances in topical wound care. Indian J Plast Surg , 45: 379-387. cells that can be used in combination with skin or hair care products to encourage skin growth.

Extracting these stem cells is considered by many to be an unethical procedure. Furthermore, extraction of the stem cells can also be a costly and difficult process accompanied by high rejection rates.

A further disadvantage of the prior art is that there is no cost-effective chemical composition, ointment or therapeutic method available that is capable of producing the effective regeneration of damaged tissue.

While a plurality of pharmaceutical compositions to treat cutaneous and subcutaneous are known in the art, it is clear that there exists a present need for a composition that does not simply assist with the formation of scar tissue, but also provides for the regeneration of tissue.

OBJECT OF THE INVENTION

Accordingly, it is an object of the present invention to provide a chemical composition that can be applied to the skin and provide for the regeneration of damaged tissue. It is a further object of the present invention to provide a chemical composition that seeks to, at least partially, overcome or less the above disadvantages and/or will be use a useful alternative to stem cell therapy. SUMMARY OF THE INVENTION

According to a first aspect thereof, the present invention provides for a gel composition, the gel composition including:

- A vitamin;

- A hydrochloride amino acid salt;

- A moisturizer; and

- A cellulose ether.

The vitamin may be selected from a group that includes niacinamide, niacin, nicotinamide riboside and a combination of any one or more thereof.

In an embodiment of the invention, the gel composition may include the vitamin and optionally one or more antibiotic agents, antimicrobic agent, natural additive or a combination of two or more thereof.

The antibiotic agent may be selected from a group that includes aminocyclitols, aminoglycosides, aminoglycosides, fosfomycins, glycopeptides, lincosamides, lipopeptides, macrocyclic macrolides, nitrofurans, nitroimidazoles, oxazolidinones, phenicols, pseudomonic acid, quinolones, fluoroquinolone, fusidanes, streptogramins, tetracyclines, glycyclines, aminomethylcycline and a combination of one or more thereof. The antimicrobic agent may be selected from a group that includes folate pathway inhibitors, nitrofurans, thiazolide and a combination of any one or more thereof.

The natural additive may be selected from a group that includes Curcuma longa, Vitamin E, Honey, Sea cucumber, Ocimum sanctum, Baphia nitida, Aloe barbadensis, lllicium verum, Citrus aurantium, Cinnamomum zeylanicum, Juniperus communis, Cananga odorata, eucalypt, mint, rosemary, lavender, pine, clove volatile oils, Commiphora guidotti Chiov. ex. Guid., Copaifera officinalis, Pentaclethra macroloba, Rosa damascena petals, Malva sylvestris, Solanum nigrum leaves, Calophyllum inophyllum, Rosa damascena petals, Calophyllum inophyllum, Calophyllum inophyllum, Blumea balsamifera, Struthanthus vulgaris, H. speciosa leaves Gomes, Casearia sylvestris, Achyrocline satureioides, Matricaria recutita, Melia azedarach, Mirabilis jalapa, Hypericum perforatum, Echium italicum, Echium vulgare, Echium angustifolium, Archillea coarctata Poir., Aegilemma kotschyi Boiss., Archillea lycaonica Boiss., Heldr. (AL) (genus Achillea L), Rumex abyssinicus Jacq (Polygonaceae), Combretum mucronatum, Salvadora persica, Calotropis procera, Moringa oleifera, Polygonum aviculare, Porophyllum ruderale, Allium ascalonicum Linn., Rubus ellipticus, Musa sapientum, Propolis, Baccharis dracunculifolia, Aloe vera, Calendula officinalis, Glucosamine, Methyl sulphonyl methane (MSM), epigallocatechin-3-gallate, Ganoderma lucidum, Tremella fuciformis, Lentinula edodes, Coriolus versicolor, Fomitopsis officinalis, Cordyceps sinensis, Boletus edulis, Auricularia polytricha, Camellia sinensis and a combination of any one or more thereof.

The hydrochloride amino acid salt may be selected from a group that includes alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine and a combination of one or more thereof.

The moisturizer may be selected from a group that includes dexpanthenol, panthothenol, dimethicone, beeswax, castor oil, cetyl alcohol, cetearyl alcohol, cocoa butter, hyaluronic acid, glycerine, isopropyl myristate, isopropyl palmitate, lanolin, liquid mineral oil, paraffin, petrolatum, polyethylene glycols, shea butter, silicone oils, stearic acid, stearyl alcohol and a combination of one or more thereof.

The cellulose ether may be selected from a group that includes sodium carboxymethyl cellulose, diethylaminoethyl cellulose, ethulose, ethyl cellulose, ethyl methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, Hypromellose, chitosan, flax seed powder, psyllium, methyl cellulose and a combination of one or more thereof.

The gel composition may include:

- 1 .0 % - 10 % of the vitamin;

- 0.25 % - 20 % of the moisturizer;

- 1 .0 % - 15 % of the hydrochloride amino acid salt; and

- 0.5% - 10 % of the ether.

The gel composition may include:

3 % - 10 % of the vitamin; 3 % - 20 % of the moisturizer;

- 3 % - 7.5% of the hydrochloride amino acid salt; and

- 3% - 5 % of the ether.

The gel composition may be used in the regeneration of damaged tissue.

The method of regenerating damaged tissue by administering to the patient a dosage of the gel composition, substantially as showed herein above.

The use of the gel composition in the manufacture of a medicament to regenerate damaged tissue.

In a further embodiment, the gel composition may be shaped by the process of 3D printing, which includes:

- loading the 3D printer with heated gel composition;

- providing the instrument with instructions to print a wound dressing for a specific body part; or

- providing the instrument with instructions to print directly on the skin of a patient.

The process of 3D printing may be used to print the gel composition directly onto the skin.

In a further embodiment, the gel composition may be used for cosmetic skin growth and cosmetic skin rejuvenation. In a further embodiment, the gel composition may be used as a growth medium for new skin.

The above and other characteristics, features and advantages of the present invention will become apparent from the following detailed description, taken in conjunction with the accompanying examples. This description is given for the sake of example only, without limiting the scope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates the visible observation of wound healing of a patient’s finger over 50 days.

Figure 2 illustrates the visible observation of wound healing of a patient’s burn injury over 17 days.

Figure 3 illustrates the visible observation of wound healing of patient’s burn injury over 10 days.

Table 1 gives the components and their relative quantities used to make up the composition in Example 1 .

Table 2 gives the components and their relative quantities used to make up the composition in Example 2.

Table 3 gives the components and their relative quantities used to make up the composition in Example 3.

Table 4 gives the components and their relative quantities used to make up the composition in Example 4. DETAILED DESCRIPTION OF THE INVENTION

A non-limiting example of a preferred embodiment of the invention is described in more detail below.

The present invention provides a novel wound gel composition that includes a vitamin, hydrochloride amino acid salt, moisturizer, cellulose ether, aromatic alcohol and water. This list is, however, not comprehensive and a person skilled in the art could foresee the addition of other compounds that are typically utilized in the state of the art.

Nicotinic acid and niacinamide (also referred to as nicotinamide) are B3 vitamins that can be converted into each other within an organism. Niacinamide also plays an important role in the facilitation of hydrogen transfer through it being a component of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Through topical application, Niacinamide reduces transepidermal water loss, increases DNA repair, increases protein synthesis and can also result in some anti-inflammatory effects. ^{2 3}

Dexpanthenol is a stable alcoholic analogue of pantothenic acid, which is a member of the B complex vitamins that is known to be well absorbed through the skin. Topical dexpanthenol can also act like a moisturizer that also exhibits some barrier improving and wound-healing properties. This has led to this compound finding application in its incorporation in creams, emollient, drops, gels, lotions, oils, ointments, solutions and sprays. Overall, dexpanthenol has been shown to reduce erythema and result in a more elastic and solid tissue regeneration in burn patients,

² Gehring, W. (2004), Nicotinic acid/niacinamide and the skin. Journal of Cosmetic Dermatology, 3: 88-93.

³ Chen, A. C. and Damian, D. L. (2014), Nicotinamide and the skin. Australasian Journal of Dermatology, 55: 169-175. patients showing risks for hypertrophic or keloid scars and patients that are likely to develop psychological distress in case hypertrophic or keloid scars occur. ⁴

Arginine is a basic amino acid involved in various cellular processes. In general, amino acids are involved in protein synthesis and cell signalling through the production of nitric oxide. These properties of amino acids and, more particularly, arginine have been shown to improve the healing process of wounds and tissue repair. ⁵ A combination of nitric oxide (NO) synthesis and arginine can accelerate and improve wound healing, where arginine typically plays a critical role in cellular physiology. Furthermore, arginine is directly involved in the production of both NO and cell proliferation in order to facilitate and improve wound healing. ⁵ The bioactive molecule NO also plays a specialized role in various cellular activities, where one important example related to the wound-healing process includes its impact on the cellular responses that are produced by wound healing. ⁶ Results have also shown that NO production is suppressed in wounds that are affected by diabetes or steroid treatment, for which topical application of a NO-containing therapeutics may alleviate such a deficiency and thereby improve wound healing. ⁷

Sodium carboxymethyl cellulose is another material of natural origin that can be used to improve film-forming properties. These favourable properties result from the presence of microfibrillar fibres of partially substituted carboxymethylcellulose that ensure optimal pH, swelling and mechanical properties. ⁸

⁴ Proksch E., de Bony R., Trapp S. and Boudon S. (2017), Topical use of dexpanthenol: a 70th anniversary article, Journal of Dermatological Treatment, 28, 766-773

⁵ Witte, M. B. and Barbul, A. (2003), Arginine physiology and its implication for wound healing. Wound Repair and Regeneration, 11, 419-423.

⁶ Isenberg, J.S., Ridnour, L.A., Espey, M.G., Wink, D.A. and Roberts, D.A. (2005), Nitric oxide in wound-healing. Microsurgery, 25, 442-451.

⁷ Shabani, M., Pulfer, S.K., Bulgrin, J.P. and Smith, D.J. (1996), Enhancement of wound repair with a topically applied nitric oxide-releasing polymer. Wound Repair and Regeneration, 4, 353-362.

⁸ Tenorova, K., Masteikova, R. , Kostelanska, K. and Vetchy, D. (2019), Film wound dressing containing dexpanthenol - preparation and evaluation. Ceska Siov Farm, 68. 27-33. Hyaluronic acid is a naturally occurring polyanionic, polysaccharide that is present in the intercellular matrix of most vertebrate connective tissues. Hyaluronic acid has found various clinical applications, which include: supplementing joint fluid in arthritis; use as a surgical aid in eye surgery; and to facilitate the healing and regeneration of surgical wounds. ⁹

Sodium benzoate and Potassium sorbate are generally used as preservatives that can be added to a range of goods that include personal care and medical products. ¹⁰ _’ ¹¹

The incorporation of various compounds that exhibit wound-healing properties and the further possibility of such a composition leading to gel formation has various benefits. Hydrogels are 3D, hydrophilic and polymeric networks that are capable of absorbing large amounts of water or biological fluids. These properties are similar to natural living tissue and thereby are effective means to dress wounds, but there are also various challenges as hydrogels often exhibit low mechanical strength and fragility. ¹²

EXAMPLES

The following are given by way of illustration and should not be construed to limit the scope of the present invention. The three different phases specified in each table were mixed in order to yield a gel-like composition. However, Example 4 was

⁹ Brown, M. and Jones, S. (2005), Hyaluronic acid: a unique topical vehicle for the localized delivery of drugs to the skin. Journal of the European Academy of Dermatology and Venereology, 19: 308-318.

¹⁰ Zengin N., YUzba§ioglu D., Llnal F., Yilmaz S. and Aksoy H. (2011), The evaluation of the genotoxicity of two food preservatives: Sodium benzoate and potassium benzoate. Food Chem Toxicology, 49. 763 - 769.

¹¹ Pylypiw H. and Grether M. T. (2000), Rapid high-performance liquid chromatography method for the analysis of sodium benzoate and potassium sorbate in foods. Journal of Chromatography A, 883, 299-304.

¹² Avlia-Salas, F ; Marican, A.; Pinochet, S ; Garreho, G ; Valdes, O ; Venegas, B ; Donoso, W ; Gabrera-Barjas, G ; Vijayakumar, S.; Duran-Lara, E.F. (2019), Film Dressings Based on Hydrogels: Simultaneous and Sustained-Release of Bioactive Compounds with Wound Healing Properties. Pharmaceutics, 11, 447 found to be the only gel composition that effectively improves the wound healing process.

Example 1

The individual components required to prepare the gel composition is given in Table 1.

Table 1 : Gel composition of Example 1

Weight g per

Raw materials: 100ml:

Dexpanthenol 2.0

Water 35.7

Sodium CMC 4.0

Glycerine _ 15.0

Potassium sorbate 0.2

Sodium benzoate 0.1

Water 43.0

Example 2

The individual components required to prepare the gel composition is given in Table 2. Table 2: Gel composition of Example 2 n . . . Weight g per

Raw materials: 100ml·

Dexpanthenol 3.5

Water _ 35.7

Sodium CMC 5.0

Glycerine 15.0

Potassium sorbate 0.2

Sodium benzoate 0.1

Water 41.0

Example 3

Table 3: Gel composition of Example 3

Weight g per

Raw materials: 100ml:

Hyaluronic acid 2.0 Sodium CMC 6.0 Glycerine 20.0

Benzyl alcohol 1.0

Dexpanthenol 5.0

Water 80.0

Example 4:

The individual components required to prepare the gel composition is given in Table 4. Table 4: Composition of a preferred formulation

Weight g per

Raw materials: 100ml:

Niacinamide 6.0 Dexpanthenol 5.0 Arginine hydrochloride 5.0

Hyaluronic acid 2.0 Sodium CMC 6.0

The gel Glycerine 20.0 composition Phase 3 given in Table 4 Benzyl alcohol 1.0 was found to Water 90.0 be the only gel composition that exhibits efficient and improved wound-healing properties. The method of preparation makes use of quantities that are measured as the gram (g) mass per 100 ml_ and all g-values therefore simply correspond to the g/1 OOmL value. The method of preparation can be described as follows:

- Step 1 : 1 .0 g benzyl alcohol and 90 g water are added to a stainless-steel mixing vessel and mixed until a homogenous solution is observed;

- Step 2: 6.0 g niacinamide, 5.0 g dexpanthenol and 5.0 g arginine hydrochloride are added and mixed with the contents in the stainless-steel mixing vessel until fully dissolved;

- Step 3: In a separate container, 20.0 g of glycerine is firstly weighed and then mixed with 2.0 g hyaluronic acid and 6.0 g sodium carboxymethyl cellulose to wet the powders with glycerine to prevent clumping when water is added and gelled. - Step 4: The contents of the contain in step 3 are added to the stainless-steel mixing vessel and mixed at a low speed until the formation of a solution gel can be observed:

- Step 5: The low-speed mixing is continued until the powder content has completely undergone gel formation, and so as to avoid bubble formation and oxygenation; and

- Step 6: Transfer of gel content to suitably-sized containers.

Patient Wound Test:

Figures 1 - 3 illustrate the effects of the wound gel as prepared according to the synthesis and composition set out for Example 1 . More particularly, Figure 1 shows how an open wound on a patient’s finger heals over 50 days by daily applying the Gel of Example 1 to the target area (wound). Figure 2 shows how a burn wound on the chest area of a patient was healed by daily applying the Gel of Example 1 to the target area over a period of 17 days. Figure 3 shows how a burn wound on patient’s hand healed after applying the Gel of Example 1 to the target burn wound area.