Technical Field of the Invention

The present invention relates to buccal film formulations developed for use in various conditions such as buccal infection, wound, etc. The invention also relates to a method used in the preparation of the buccal film formulations of the invention and to buccal film formulations according to the invention for use in the treatment of buccal wounds and/or infections.

State of the Art of the Invention

Spray/mouthwash drug forms are generally used in the treatment of buccal/intraoral infection and/or wounds. One of the therapeutic agents frequently used in the treatment of these disorders is benzydamine or pharmaceutically acceptable salt thereof (BZD), such as benzydamine hydrochloride. BZD is a nonsteroidal anti-inflammatory agent with local anesthetic and analgesic effects. Another therapeutic agent used for similar purposes is chlorhexidine, a broad-spectrum antiseptic with bacteriostatic and bactericidal effects, or a pharmaceutically acceptable salt thereof such as gluconate/acetate/diacetate (CHG). These two active substances are produced in the pharmaceutical industry in combination or in the form of spray/mouthwash containing a single agent and are used in treatment. However, sprays and mouthwashes are in liquid form and their residence time in the mouth is limited. Such formulations are rapidly moving away from the area intended to act with natural factors such as the continuity of saliva secretion in the oral environment, intraoral mobility, speech, etc. They require a high number of applications due to the low residence time of these drug forms and their bioavailability may be low. Spray/mouthwashes may need to be used every 1.5-3 hours depending on the state and course of the disease.

Thermosensitive in situ gels have been developed to increase the residence time of the drug in intraoral/buccal region wounds and/or infections in recent years. Heat-sensitive formulations are systems that are liquid at room temperature and can gel at body temperature. These systems begin to dilute rapidly with intraoral mobility and saliva secretion and dissipate in the mouth with decreased viscosity even though they have a longer residence time in the mouth than liquid formulations such as fluid and mouthwash. It is aimed to develop new formulations that will increase the residence time in buccal infections in order to overcome these problems.

Object of the invention

The object of the invention is to develop formulations that remain in the mouth for longer periods of time for use in the treatment of buccal wounds and/or infections.

Another object of the invention is to develop formulations that will require less application frequency in the treatment of buccal wounds and/or infections.

Another object of the invention is to increase the bioavailability of agents known to be used in the treatment of buccal wounds and/or infections with a new formulation.

Brief Description of the Invention

The present invention relates to a buccal film formulation comprising as an active substance chlorhexidine or the pharmaceutically acceptable salt thereof (CHG) and benzydamine or a pharmaceutically acceptable salt thereof (BZD) and at least one bioadhesive polymer suitable for use in the treatment of buccal wounds and/or infections.

The buccal film formulations prepared in this way provide efficacy in the treatment of buccal wounds and/or infections by containing both active substances and ensure that the active substances remain in the mouth for a longer time because they are formulated in the form of buccal film formulation. CHG prevents the growth of bacteria with its antiseptic effect whereas BZD relieves pain with its analgesic and local anesthetic effect. The wounds and/or infections in the mouth are allowed to contact chlorhexidine or a pharmaceutically acceptable salt (CHG) and benzydamine or a pharmaceutically acceptable salt (BZD) for a longer period of time in this way. The bioavailability of the agents in the formulation is also increased in this way. Detailed Description of The Invention

The present invention relates to a buccal film formulation comprising as an active substance chlorhexidine or the pharmaceutically acceptable salt thereof (CHG) and benzydamine or a pharmaceutically acceptable salt thereof (BZD) and at least one bioadhesive polymer suitable for use in the treatment of buccal wounds and/or infections, as mentioned above.

The bioadhesive polymer may be selected from the group consisting of chitosan, hydroxypropyl methyl cellulose, hydroxy propyl cellulose, sodium alginate, gelatin, guar gum, cellulose ester derivatives, poly(acrylic) acid or pharmaceutically acceptable derivatives thereof, such as salts, esters, solvates or double or triple combinations thereof in a preferred embodiment of the invention.

More than one, for example two, bioadhesive polymers are used in the buccal film formulation according to the invention in a preferred embodiment of the invention. If more than one, e.g. two, bioadhesive polymers are used, they may be selected from two different bioadhesive polymers in the aforementioned group.

As the bioadhesive polymer in the buccal film formulation according to the invention, chitosan, the pharmaceutically acceptable derivative of chitosan, preferably a salt thereof, for example chitosan lactate or chitosan acetate or chitosan hydrochloride or chitosan glutamate or chitosan ascorbate or chitosan citrate is used in one embodiment of the invention. The chitosan salt can be directly commercially available in this manner or can be obtained and used by treating the chitosan with lactic acid or acetic acid or hydrochloric acid or glutamic acid or ascorbic acid or citric acid during the production of the buccal film formulation.

Two different bioadhesive polymers are used as bioadhesive polymers in the pharmaceutical formulation according to the invention in one embodiment of the invention. As the bioadhesive polymer, chitosan or a pharmaceutically acceptable salt thereof, for example chitosan lactate or chitosan acetate or chitosan hydrochloride or chitosan glutamate or chitosan ascorbate or chitosan citrate and cellulose ester derivatives or preferably hydroxypropyl methyl cellulose (HPMC) and/or hydroxypropyl cellulose (HPC) are used in a particularly preferred embodiment of the invention. Chitosan lactate or chitosan acetate or chitosan hydrochloride or chitosan glutamate or chitosan ascorbate or chitosan citrate and hydroxypropyl methyl cellulose or hydroxypropyl cellulose are used as the bioadhesive polymer in a particularly preferred embodiment of the invention.

Chitosan or a pharmaceutically acceptable derivative and hydroxy propyl methyl cellulose (HPMC) are used as the bioadhesive polymer and the amount of HPMC with chitosan or its derivative is in the range of 1 : 1 to 1 :2 in one embodiment of the invention. It is concluded that the film formulations prepared in this way are more durable buccal films at buccal pH.

The buccal film formulation according to the invention may be in the form of a film having a suitable size for use in the mouth or in the form of a solution for preparing the film form.

There is a bioadhesive polymer in an amount of 0.1-20% according to the total weight of the formulation in the buccal formulation according to the invention. The total amount of the bioadhesive polymer is between 0.1-20% according to the total weight of the formulation if two or more bioadhesive polymers are used in the formulation. The formulation according to the invention may contain at least one, optionally two or more bioadhesive polymers as mentioned above.

The formulations according to the invention may further comprise different pharmaceutically acceptable excipients, such as solvents, flavorings, sweeteners, buffering agents, plasticizer agents.

Plasticizer, sweetener and optionally solvent are used in addition to bioadhesive polymers in the buccal formulation according to the invention in a preferred embodiment of the invention.

Said plasticizer agent may be selected from glycerin, propylene glycol, or poly(ethylene)glycol (PEG) polyethylene glycol (PEG400) preferably having a molecular weight of 400 or PEG200, or PEG300, or PEG500.

The plasticizer agent in the formulation according to the invention can be used in an amount of 0.1-30% according to the total weight of the formulation. The sweetening agent mentioned herein may be selected from the group consisting of saccharin, aspartame, acesulfame K, inulin, isomalt, dextrose, fructose, galactose, maltitol, sorbitol, trehalose, xylitol, mannitol, sucrose, glucose, stevia, alitame.

The sweetening agent in the formulation according to the invention can be used in an amount of 0.02-0.1% according to the total weight of the formulation.

The chlorhexidine or the pharmaceutically acceptable salt thereof, preferably chlorhexidine gluconate, which is the active substance in the buccal formulation according to the invention, can be used in an amount of 0.1-1% according to the total weight of the formulation.

Benzydamine hydrochloride, which is the active substance in the buccal formulation according to the invention, can be used in an amount of 0.1-1% according to the total weight of the formulation.

In a preferred embodiment of the invention, the buccal film formulation according to the invention, before drying, in the form of a solution, comprises the following by weight, according to the total weight of the formulation:

• 0.1-1% chlorhexidine or equivalent amount of the pharmaceutically acceptable chlorhexidine derivative, preferably the chlorhexidine salt, particularly preferably the chlorhexidine gluconate

• 0.1-1% benzydamine or equivalent amount of pharmaceutically acceptable benzydamine derivative, preferably benzydamine salt, particularly preferably benzydamine hydrochloride

• 0.02-0.1% sweetening agent, preferably 0.02-0.1% sweetening agent selected from the group consisting of saccharin, aspartame, acesulfame K, inulin, isomalt, dextrose, fructose, galactose, maltitol, sorbitol, trehalose, xylitol, mannitol, sucrose, glucose, stevia, alitame or double or triple combinations thereof,

• 0.1-30% plasticizer agent, preferably 0.1-30% plasticizer agent selected from glycerin, propylene glycol, or poly(ethylene)glycol (PEG), polyethylene glycol (PEG400) preferably having a molecular weight of 400 or PEG200, or PEG300, or PEG500 or double, triple combinations thereof, • at least one bioadhesive polymer in an amount of 0.1-20%, preferably two bioadhesive polymers in an amount of 0.1-20%, particularly preferably a first bioadhesive polymer selected from chitosan derivatives that are pharmaceutically acceptable, for example chitosan lactate or chitosan acetate or chitosan hydrochloride or chitosan glutamate or chitosan ascorbate or chitosan citrate and a second bioadhesive polymer selected from hydroxypropyl methyl cellulose or hydroxypropyl cellulose, in an amount of 0.1-20%,

• and water as a solvent in an amount such that the total is 100% by weight.

In another aspect, film formulation in a suitable size for buccal use according to the invention comprises the following by weight, according to the total weight of the formulation:

• 1-15% chi orhexi dine or equivalent amount of pharmaceutically acceptable chi orhexi dine salt, particularly preferably chlorhexidine gluconate

• 1-15% benzydamine or equivalent amount of pharmaceutically acceptable benzydamine salt, especially benzydamine hydrochloride

• And in addition, the sweetening agent, preferably a sweetening agent selected from the group consisting of saccharin, aspartame, acesulfame K, inulin, isomalt, dextrose, fructose, galactose, maltitol, sorbitol, trehalose, xylitol, mannitol, sucrose, glucose, stevia, alitame or double or triple combinations thereof,

• Plasticizer agent, preferably selected from glycerin, propylene glycol, or poly (ethylene)glycol (PEG), preferably polyethylene glycol (PEG400) preferably having a molecular weight of 400 or PEG200, or PEG300, or PEG500 or double, triple combinations thereof,

• At least one bioadhesive polymer, preferably two bioadhesive polymers, particularly preferably a first bioadhesive polymer selected from chitosan derivatives that are pharmaceutically acceptable, for example chitosan lactate or chitosan acetate or chitosan hydrochloride or chitosan glutamate or chitosan ascorbate or chitosan citrate and a second bioadhesive polymer selected from hydroxypropyl methyl cellulose or hydroxypropyl cellulose.

In another aspect, the present invention relates to a method for preparing buccal formulations according to the invention, said method comprising the steps of: a. Preparation of chitosan salt solution by treating with lactic acid or acetic acid or hydrochloric acid or glutamic acid or ascorbic acid or citric acid; and lyophilization, b. If another bioadhesive agent is optionally used, dissolving the second bioadhesive agent in a solvent, preferably water, c. Mixing the chitosan salt obtained in step a) by adding to the solution prepared in step b), d. Mixing by adding sweetening agent and plasticizer agent to the mixture obtained in step c), e. Mixing by adding benzydamine salt and chlorhexidine salt to the mixture obtained in step d), f. drying the mixture obtained in step e) at a temperature of 20-60°C by pouring into a dish such as petri dishes or a suitable surface, and g. optionally cutting the film formulation obtained in step f) to a size suitable for buccal use.

The mixture obtained in step e) is kept for approximately 10-24 hours at room temperature to remove air bubbles in the mixture before pouring into the petri surface in step f). It is aimed to obtain a film form with a more homogeneous distribution and without bubbles by performing this step even though it is possible to obtain the formulation in the film structure without performing this step.

The mixing process in step c) of the method according to the invention aims to dissolve the chitosan salt in the solution. Therefore, the stirring process is carried out until the chitosan salt is completely dissolved, for example, it is stirred for 10-14 hours.

The expression “suitable size for buccal use” used within the scope of the application describes films in 1*1 cm ² , 1.5* 1.5 cm ² or 2*2 cm ² sizes.

The invention discloses buccal film formulations according to the invention for use as a drug in the treatment of buccal wounds and/or infections in another aspect.

Applicability to Industry

A more effective buccal film formulation has been developed in the treatment of buccal wounds and/or infections compared to the types of formulations existing in the state of the art thanks to the invention. The invention concerns both end-users in the health sector and drug developers in this respect.

Examples

Example 1 : Buccal film formulation according to the invention

Buccal film formulations containing chlorhexidine gluconate and benzydamine hydrochloride (w/w):

Chlorhexidine gluconate (0.1-1%)

Benzydamine HC1 (0.1-1%)

1. Bioadhesive polymer 0.1-10% (Chitosan salt) and/or 2. Bioadhesive polymer 0.1-10% (HPMC and derivatives)

Plasticizer 0.1-30% (Glycerin/Propylene glycol/PEG 400)

Sufficient amount of distilled water (enough to complete the solution to 100%) (qs 100)

Sweeting agent 0.02-0.1% (saccharin etc.)

Example 2: Method of preparing the buccal film formulation according to the invention

-Since chitosan is not soluble in water, it is dissolved with organic acids (lactic acid/acetic acid/hydrochloric acid/glutamic acid/ascorbic acid/citric acid etc.) and its salts are prepared by lyophilization method after the dialysis process.

-Afterward, firstly, HPMC will be dissolved in water (2 hours - room temperature - 500 rpm).

-Afterward, the lyophilized chitosan salt is added to the solution and dissolved by stirring at 500 rpm at room temperature for 12 hours.

-Sweeting agent and plasticizer (Glycerin/Propylene glycol/PEG 400) will be added and homogenized by mixing for 2 hours.

-Finally, the active substances benzydamine hydrochloride and chlorhexidine gluconate are added and stirred at room temperature for 2 hours.

-It is kept at room temperature for 12 hours to remove air bubbles.

-Homogeneous solution without air bubbles is poured into the petri dish.

-It is dried at -50°C for 10-16 hours. -The obtained film is cut in 1*1 cm ² sizes