Technical Field of the Invention

The invention relates to a biocompatible and biodegradable polymer composite film having properties of adhesion and healing on wet surfaces comprising hydroxypropyl methylcellulose, film-forming agent, carrier and lubricant.

State of the Art

Due to wound treatment research in the world, great importance is given to the application of materials with healing properties on the skin. The purpose of using these care products with healing properties is to contribute to the healing process by covering the damaged areas, protecting the tissues from external factors, and activating cell production with various healing agents if their structure is appropriate. It has been observed from the studies that these applications will be effective if ideal environmental conditions are provided in the healing process.

Nowadays, the provision of an environment humid enough to allow the regeneration of damaged tissues is the basis of modern wound dressings. Studies have shown that a humid environment increases the vitality of the tissues in the dressings that provide wound healing and the effectiveness of the factors that play a significant role in healing. Nowadays, polymers are used in many fields by improving their properties. Polymers occupy a large area in our daily lives and play a significant role in the fields of food and cosmetics; wound healing, drug delivery systems, and designing wound dressings in the field of health. However, the deficiencies and different reactions occur in the body lacking of accepting the materials used for wound healing. In this respect, structures made of biocompatible and biodegradable materials are preferred. In this case, composite structures are required to form polymer films with different properties. The combination of materials with different properties to show superior properties forms the basis of these composite structures. Many films are synthesised to perform healing on the skin. However, the synthesised polymer films do not show sufficient adhesion on wet ground. Besides, these polymer films cannot release and do not fragmentize in the desired amount. Therefore, they show different negative effects on the body [1 ].

Hydroxypropyl methylcellulose is the propylene glycol ether of methyl cellulose. It is formed by bonding anhydrous glucose groups together with either bond or forming compositions with polymeric structure. Hypromellose molecular weights are determined by the percentage and viscosity of hydroxyl groups and the percentage of hydroxypropyl groups. They contain methoxyl group and hydroxypropyl groups in a certain proportion. Hydroxypropyl methylcellulose is a type of non-ionic cellulose ether, a white powder which acts as a thickener, incrassative, binder, film-former, lubricant, protective colloid, greasing agent, emulsifier, suspension, and water retention aid. Depending on its numerous properties, HPMC (Hydroxypropyl Methylcellulose) is often used in place of many other low-density additives, making it an incredibly productive and efficient additive in the fields of adhesives, building/construction chemicals, foods, household products or pharmaceuticals [2],

Polyethylene glycol (PEG) is a polyether compound derived from petroleum with many fields of application ranging from industrial production to pharmaceuticals. Depending on its molecular weight, PEG is also known as polyethylene oxide (PEG) or polyoxyethylene (POE). The PEG structure is usually expressed as H-(O-CH2-CH2) n-OH. Polyethylene glycol, or PEG as it is often abbreviated, is an organic compound widely used in many different industries. It is actually a name given to form a polymer or oligomer side by side by opening the ethylene oxide. Therefore, it is also called polyethylene oxide. PEG is a hydrophilic molecule soluble in water, methanol, ethanol, acetonitrile, benzene and dichloromethane. Polyethylene Glycol has different applications depending on the length of the molecule. PEG is widely used in the medical industry. It is used together with auxiliary electrolytes, especially for the treatment of constipation and for cleansing the intestines before procedures such as colonoscopy. It is also used as an excipient in all COVID-19 vaccines. Because PEG has low toxicity, this material is an ideal lubricant coating material for many aqueous and non-aqueous surfaces. Due to its hydrophilic property, PEG is a suitable substance for reactions and experiments under high osmotic pressure. It is used as a protective coating material on many surface areas, including wood which is the reason why it is widely preferred especially for historical items. Thanks to its hydrophilic property, PEG dries without deteriorating its properties when applied to wet wood, also being applied to prevent shrinkage in freshly cut wood. PEG is also the main ingredient in many personal care products and used as a dispersant in kinds of toothpaste and as a filler in foods and beverages. Low molecular weight samples are used as lubricants in inks and some printing machine tips [3].

Starch, farina or amidone is a complex carbohydrate, insoluble in water found in plants to store excess glucose. In industrial field, it is used in glue, paper and textile production. Starch is used as an incrassative in the food industry and as a liquid thickener in cooking. It is a tasteless and odourless powder obtained mainly from cereals and potatoes. By its very nature, starch consists of two different molecules, amylose and amylopectin. Amylose is a linear polymer that forms a colloidal dispersion in hot water and has an excellent film-forming ability [4],

In the state of the art, the article by R. B. Bodini et al. about the effect of starch and hydroxypropyl methylcellulose polymers on the properties of orally fragmentized films describes different formulations of pregelatinized starch (% S) and hydroxypropyl methylcellulose (% HPMC) based orodispersible films, considering the advantages of orodispersible films as alternative pharmaceutical dosage forms. HPMC and starch are used to determine the best formulation for orodispersible films. Sorbitol was used as a plasticiser and resulted as Sorbitol-used films are more easily fragmentized than films without sorbitol. Since sorbitol is easily fragmentized, it does not support a structure that can release.

In the state of the art, patent application W02021015241 A1 relates to a mucosal adhesive film that, regardless of the solubility thereof, exhibits a persistent adhesiveness for wet surfaces such as mucous membranes and is capable of longterm adhesion. The mucosal adhesive film is provided with at least two layers of an adhesive layer and a support layer; the adhesive layer contains a first compound and a second compound, wherein the first compound is formed from at least one acrylic water-soluble mucosal adhesive polymer and the second compound is at least one water-insoluble compound selected from the group consisting of cellulosic compounds. The mucosal adhesive film prepared in this patent application cannot release and does not fragmentize the desired amount.

In said technique, polymer films, which are intended to heal the skin, do not show sufficient adhesion on wet ground or cannot release in the desired amount. Besides, the non-fragmentation of these films has negative effects on the body. Wound dressings or films that are currently used and have healing properties are wanted to be expelled by the living structure over time or must be removed from the area used after a certain period of use. Since the materials used in the formulations or composite films in the present art are not accepted by the body or show reactions in the body, the synthesised polymer films do not show sufficient adhesion on wet ground, and these polymer films cannot release and do not fragmentize in the desired amount, it has become necessary to make an improvement in the related field.

Brief Description and Aim of the Invention

The invention discloses a biocompatible and biodegradable polymer composite film having properties of adhesion and healing on wet surfaces, comprising 1 % hydroxypropyl methylcellulose (HPMC), 4.03% film-forming agent, 1.84% carrier, 0.1 1 % lubricant, 1 .59% natural healing agent and 91 .43% solvent by weight.

The most important aim of the invention is to synthesise biocompatible and biodegradable polymer composite films having properties of adhesion and healing properties on wet surfaces. The main structures used in the synthesis of polymer composite film having high tissue healing properties are hydroxypropyl methylcellulose (HPMC), starch, and polyethylene glycol (PEG), wherein; the composite film with healing properties is synthesised by using 1 % hydroxypropyl methylcellulose (HPMC), 4.03% film-forming agent, 1 .84% carrier, 0.1 1% lubricant, 1 .59% natural healing agent and 91.43% solvent by weight. Besides, HPMC has the property of forming a transparent flexible film and has high adhesion strength, therefore a polymer composite film that is adhesive on wet surfaces is provided.

Another aim of the invention is to synthesise a biocompatible and biodegradable polymer composite film which can maintain the humid environment, dissolve without leaving residue in intra-oral applications when necessary, and release as well. Polymer groups having properties of dissolving easily in water and forming a strong elastic film are used in the invention. HPMC is a cellulose derivative having properties of transparent flexible film formation, high adhesion strength, compatibility with water- soluble components, good biodegradability, and easy removal without enzymes. Besides, biocompatible starch, which is the main component of many herbal products, is used in the invention. With its properties of being natural and facilitating fragmentation in the mouth, starch provides biodegradable properties to the polymer composite film that is the subject of the invention. Biocompatible and biodegradable polymer composite film is provided in the invention by using 1 % hydroxypropyl methylcellulose (HPMC), 4,03% film-forming agent, 1 ,84% carrier, 0,1 1 % lubricant, 1 ,59% natural healing agent, and 91 ,43% solvent by weight.

Another aim of the invention is to provide a low-cost polymer composite film. The solution casting method, which is the method of obtaining polymer films, does not require any special equipment and accordingly, polymer composite film is produced at a low cost.

A low-cost, biocompatible and biodegradable polymer composite film having properties of adhesion and healing on wet surfaces is provided with the invention.

Description of Figures

Figure 1 is the 1 mm SEM (Scanning Electron Microscope) image of the polymer composite film.

Figure 2 is the 100 pm SEM (Scanning Electron Microscope) image of the polymer composite film.

Detailed Description of the Invention

The invention relates to a biocompatible and biodegradable polymer composite film having properties of adhesion and healing on wet surfaces comprising hydroxypropyl methylcellulose, film-forming agent, carrier and lubricant. The polymer composite film that is the subject of the invention comprises 1 % hydroxypropyl methylcellulose (HPMC), 4.03% film-forming agent, 1.84% carrier, 0.1 1 % lubricant, 1.59% natural healing agent, and 91 .43% solvent by weight per volume.

The invention is a polymer composite film with healing properties in living structures. This film is capable of maintaining the required humid environment, leaving no residue for use in intra-oral applications when necessary, and releasing the healing components as well. The main component in the polymer composite film is HPMC (hydroxypropyl methylcellulose) and starch. HPMC is a water-soluble polymer with a film-forming property. Since it can be used in foods, cosmetics, pharmaceuticals and similar areas, it is preferred as an agent with the film-forming property. Besides, it forms a homogeneous structure with the components doped into it compared to other polymers that can be used for film formation. In the invention that is the subject of the application, there is a single-layer film, which can be dissolved in water; accordingly, this is a film that adheres and oscillates. While the film that is the subject of the invention shows adhesive properties on a wet surface, the healing agent doped into it can oscillate over a certain period.

The component used as a lubricant in the polymer composite film that is the subject of the invention is PEG (polyethylene glycol), a polymer with low toxicity and used as a lubricant for various surfaces in aqueous and non-aqueous environments. It also shows viscosity increasing, flexible, water-soluble and humidifying properties. Besides, it has a high solubility in many organic solvents. PEG is used in the structure of the polymer composite film that is the subject of the invention as it is a biodegradable product having strong hydroscopic properties, showing anti -electrostatic and lubricating properties. PVA, which is also non-toxic and can be used in various fields such as wound dressings, drug delivery systems and artificial organs due to its excellent biocompatibility, adjustable physical properties, and high swelling properties in aqueous solutions, can be used instead of PEG. Likewise, PVP, which is a biocompatible, water-soluble, binder in drug formulations, dispersing agent, film plasticiser, anti-irritant, anti-toxic agent, viscosity adjuster and used as a carrier in controlled releases, can be used instead of PEG.

As a film-forming agent, the biocompatible starch, which is the main component of many herbal products, is also used in the invention. At the same time, since starch can be chemically, physically, and enzymatically modified to improve its properties and functionality, it is used as the main component of the biocompatible and biodegradable film obtained together with HPMC. The film-forming ability of starch is utilised herein. Besides, maltodextrin, which is a tasteless and easily digestible carbonate derived from natural corn starch, can be used instead of starch.

Since the natural components selected as healing agents are in the oil phase and the general structure is in the water phase, a carrier system is required for the homogeneous doping of natural healing agents into the structure. In this case, glycerol is used both as a carrier system and as a humidifier in the polymer structure. In addition, collagen, albumin, chitosan, and alginate can be used as an alternative in polymer composite film structures. Hyaluronic acid used in polymer composite structures is preferred as it is biocompatible and biodegradable, it is a natural anionic polymer such as healing and hydrophilic characters in tissues, and it is an acid that enables cell production in the skin connective tissue and keeps the tissues moisturized.

In the polymer composite film that is the subject of the invention, the main structure is a homogeneous solution of HPMC and starch. Since the solution obtained using the solution casting method is viscous, it is poured on a flat surface. The drying method is 2-3 days at room conditions. In the obtained main structure, ethyl alcohol is preferred as it shows cross-linking properties and is a product showing antibacterial properties. The production method of the polymer composite film that is the subject of the invention comprises the process steps of: i. dissolution of 1 .00% HPMC component by mass in 10 mL of water at about 90°C, ii. dissolution of 4.03% starch component by mass in 60 mL of water at about 60°C in a separate beaker, iii. mixing the obtained HPMC and starch solutions at 50-60°C, iv. adding 0.1 1 % lubricant by mass to the mixture and continuing the mixing process, v. adding 1 ,84% carrier by mass and 1 ,59% natural healing agent by mass into the solution by mixing and continuing the mixing until the solution becomes homogeneous, vi. obtaining the polymer composite film by pouring the obtained homogeneous solution on the surface and drying the poured solution.

The production method is based on the processes of pouring water or alcohol-water mixtures of priority materials, polymers, and some other materials into a mould, drying them, and bringing them to the required size. The material used in the method is dissolved in a solvent, other auxiliary substances are added if necessary, and water is usually used as a solvent. The mixing process is continued in the range of 50-60 °C due to the increased solubility of H PMC with hot water. The surface required for casting the obtained solutions may be glass, plastic or Teflon. The drying process of the cast solution is carried out at room temperature. The drying method was evaluated as 2-3 days under room conditions. SEM (Scanning Electron Microscope) analysis was performed for the doping of natural healing agents into the polymer composite film, and since no agglomeration was observed, it was determined that homogeneous doping of natural healing agents was appropriate. Said SEM image is shown in Figure 1. Besides, 4 cm ² sections were taken from the synthesised biocompatible and biodegradable polymer composite films, the sections were subjected to a swelling test by soaking in water, and the fragmentation times were determined. As a result of the test conducted, it was determined that the synthesised films started to fragmentize in the 6 ^th minute on average. In addition, it was determined that the polymer composite films doped with Thymus vulgaris fragmentized in the least time (2 minutes), and the polymer composite films doped with Eugenia caryophyllata fragmentized in the longest time (22 minutes). Then, swelling kinetics practices were carried out, and fragmentation times were supported by k _s (swelling rate constant) values. The k _s values of the synthesised films are given in the table below.

The polymer composite film fragmentizes spontaneously and dissolves completely for a length of time after wetting. Natural healing agents used in polymer composite structures were selected as hyaluronic acid, propolis, cannabis oil, black mulberry essence, Hypericum perforatum, Boragoofficinalis, Thymus vulgaris, Eugenia caryophyllata or Lavandula angustifolia. These films, which can be supported with glycerol, which is prepared with biocompatible and biodegradable materials; vegetable oils with healing properties supported with polymers such as PEG, PVA or PVP; and hyaluronic acid that contributes to cellular regeneration, are suitable for use in the field of health as composite structures that will provide ease of use on the damaged skin tissues. In addition, the solution casting method, which is the method of obtaining polymer films, does not require any special equipment and accordingly, they are produced at lower cost. At the same time, since the adhesion problem of biocompatible polymer composite films to wet surfaces is eliminated with this practice, it is also possible to use them as films that can release natural healing substances doped with natural ingredients in oral wounds and gum diseases. Since the obtained polymer composite structures are biocompatible, it is possible to use them in the field of agriculture when they are supported with different bioactive agents to be immobilised in them. To grow high-quality surplus crops, each plant needs to receive the right amount of nutrients throughout the growing season. Therefore, fertilisation is usually applied. At this stage, it is possible to use fertilisers and/or pesticides immobilised in the biocompatible polymer that is the subject of the invention together while the plant is introduced into the soil as a seed or seedling. The composite, which has high water solubility and biodegradability, dissolves with the irrigation process and releases without harming the soil and plant. Thus, the application of fertilisers and/or pesticides will be realised in situ and practically. Fertiliser and pesticide will be applied to the plant with the controlled release by planting the plant once and without the need for a second process.

REFERENCES

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Carboxymethylcellulose Hydrogels in Relation to Cross-Linking, pH, and Charge Density. Macromolecules, 33(20), 7475-7480. https://doi.Org/10.1021/ma0007029

[2] O. (2022, January 29). Hidroksi Propl'l Metil Seluloz (Hipromelloz). O Kimya A.§. https://okimya.com.tr/jel-kivam-verici-kimyasallar/hidroksi- propil-metil-seluloz- hipromelloz/

[3] Bailey, F. E., & Koleske, J. V. (2000). Polyethylene glycol. Ullmann’s Encyclopedia of Industrial Chemistry. https://d0i.0rg/l 0.1002/14356007. a21_579

[4] Roy L. Whistler; James N. BeMiller; Eugene F. Paschall, eds. (2012). Starch:

Chemistry and Technology. Academic Press, p. 220. “Starch has variable density depending on botanical origin, prior treatment, and method of measurement”.