TR201407775A2 - Mucoadhesive buccal film formulation. - Google Patents

Abstract

The present invention provides a composition in the form of a mucoadhesive film comprising nystatin, at least one corticosteroid, and at least one polymer selected from hydroxyethyl cellulose and xanthan gum with at least one local anesthetic. The composition of the present invention is effective in the treatment of oral diseases such as oral candidiasis and aphthae.

Description

specification Technical Field of the Invention The present invention is used in oral diseases, especially in the treatment of oral candidiasis or canker sores. relates to mucoadhesive film compositions suitable for use. The present invention is more specifically buccal route containing nystatin, hydrocortisone and at least one local anesthetic relates to mucoadhesive film formulations to be applied. Invention, especially xanthan gum of active substance release by using HEC mucoadhesive polymers with Film formulations that provide healing and are effective in the diseases mentioned above It is related to.

Background of the Invention In patients with candidiasis, HIV/AIDS infection, suppression of the immune system and cancer most common opportunist due to the use of antitumoral drugs in patients infections [Feigal, D.W., Katz, MH., GreenSpan, D., Westenhouse) J.) Winkelstei'n, W., Lang, W., Samuel, M., Buchbinder, S.P., Hessol, N.A., Liffson, AR. (J 991) The prevalence of oral lesi'ons in HIV-infected homosexual and bisexual men: three San Francisco epidemi'ologi'cal cohorts. AIDS, 5, 519-525.]. Most of these infections most of them are Candida albicans. These infections can be systemic as well as also seen locally. Oral candidiasis is a locally common candida is an infection. Aphthous ulcer, another disease seen in the mouth, is also known as "aphthous ulcer". It is called painful ulcer formation in the mouth. Classic wound of the mouth, inside the mouth on the mucous layer, it is seen as red oval scars.

Antifungal drugs are used to treat these infections. Oral in conventional therapy The most frequently used and most preferred antifungals are amphotericin B and fluconazole. Pharmacodynami'cs Qfifluconazole, itraconazole, and amphoterici'n B against Candida albi'cans. Diagnostic Microbiology and Infecti'ous Disease, 36, 13-18]. However, some Studies have shown that resistance to these drugs has developed. In addition, systemic antifungal agents route of administration exposes patients to toxicity. Again, in recent years Some studies have shown that local antifungal therapy for oral candidiasis is better than systemic therapy. states that it provides effective healing [Sudhakar, Y., Kuotsu, K., Bandyopadhyay, WHITE. (2006). Buccal bioadhesive drug delivery - A promising option for orally less efficient drugs. J Contr Rel, 114, 15-40.]. Therefore, in the present study, the polygenic macrolide group Nystatin, which is an antifungal and can only be applied locally, is used. Nystatin, cell It acts on permeability and transport functions by binding to its membranes, The daily dose for topical use is 2-4 mg/kg. Nystatin only fungus in the mouth It is used in infections, there is no absorption in the stomach. Therefore, nystatin lozenges or Oral suspension forms are available. However, the retention time of these formulations is low. This creates a disadvantage in treatment. Bioadhesive dosage for solving this problem Forms of the drug are developed and the active substance stays longer in the buccal area. can be provided. In this context, lidocaine, one of the mucoadhesive films presented according to the invention, is the first Active substance release of 70% in half an hour and up to 30% of hydrocortisone in the first half hour and the release for both active substances continued for 8 hours and It is seen that it reaches the range of 90-100% at the end. For oral candidiasis, pain and treatment of inflammatory symptoms in the first half hour and that this treatment lasts for 8 hours It is very important in terms of patient compliance. Because the patient is primarily suffering from pain. will want the feeling of pain to decrease and the pain factor to disappear. antifungal agent On the other hand, nystatin, which is used as nystatin, shows a more controlled release and nystatin is added to the first half hour. Its release is 20%, and it shows a release of around 50% at the end of the 8th hour. in the first half hour The amount of release is well above the MIC value, at the same time, the antimicrobial made in films. The activity test also showed that nystatin films showed very strong antifungal properties. proves.

In recent years, many adhesive tablets, gels, patches and polymeric films have been produced. bioadhesive mucosal dosage forms have been developed [Perioli, L., Ambrogi', V., Angeli'ci', F. and arc. (2004). Development of mucoadhesive patches for buccal administration of ibuprofen.

J Contr Rel, 99, 73-82.]. The properties expected from buccal drug delivery systems are flexible and good. They have bioadhesive properties and in this way, the drug can be absorbed in the oral cavity for the desired time. is to ensure that it remains. In addition, the drug of mucoadhesive buccal systems is controlled and predictably releasing the needed therapeutic response release eudragi't buccal patches. Int. J. Pharm, I 78, 1 1-22.]. Controlled drug release in recent years technologies are becoming more and more important. Among the advantages of these systems is that the frequency of dosing decrease in patient compliance, decrease in side effects, lasting effect and reducing the cost of treatment [Wise, D.L. (Ed). (2000). Handbook of Pharmaceutical Controlled Release Technology. New York: Marcel Dekker Inc., 465-466.].

In the application area of nystatin, which has a strong antifungal activity against Candida albi'cans The low residence time necessitates the need to design new formulations for this active ingredient. has given birth. In order for the treatment with nystatin to be successful, concentration is greater than the minimum inhibitory concentration (MIC) required. In recent years, the understanding of the effectiveness of controlled release systems and It is thought that this problem can be overcome with the use of mucoadhesive polymers. This In this context, various mucoadhesive buccal nystatins prepared with bioadhesive polymers formulations are available in the literature. However, these studies reveal both physical form and formulations that will provide effective treatment in oral diseases such as does not offer. In addition, existing formulations in the state of the art The limited anti-inflammatory and anesthetic properties are another disadvantage. is doing. In this context, one of the objects of the invention is to have at least one besides nystatin. is the presentation of oral film formulations containing corticosteroids.

However, another difficulty encountered in such formulations is that, apart from nystatin, additional active due to drug-drug interactions and cross-reactions that occur when In the disease process of the patient, which is already progressing with severe symptoms, the pain and irritation become worse. is the increase. The pain and irritation in question is associated with the self-induced pain and irritation of the disease. should not be mixed. Because the incompatibility and cross-reactions presented by drugs Additional pain and irritation manifest over time. Therefore, another aim of the invention is Oral film containing at least one local anesthetic alongside nystatin and a corticosteroid presenting the formulations.

Another problem detected in such multi-active oral film formulations The problem is that different release profiles are desired for each of the active substances used. Therefore, the problems experienced in adjusting their release profiles in a single formulation are difficulties. Therefore, another object of the invention is to achieve the desired release profile. oral film formulations with suitable combinations of multiple active substances exhibiting is the submission.

The formulation of the present invention is intended to provide a solution to the above-mentioned problems. together with nystatin, which has an antifungal effect for oral infections. a corticosteroid to relieve inflammation, and the best medicine to relieve pain and irritation It is in the form of a film formulation containing a little local anesthetic. In the form of the film in question formulations, due to the mucoadhesive film feature to be applied via the buccal route. fills a gap needed in the prior art. Thus, antifungal therapy At the same time, other symptoms caused by fungal infection should be treated. is intended to be. The use of three active substances in this study has been reported in the literature. This is one of the differences compared to other studies with a single active substance containing nystatin.

In addition, xanthan, which is one of the mucoadhesive polymers, is a new approach in the present invention. New formulations have been developed using gum and HEC. These polymers are three different obtaining formulations with the best release profile when it comes to the active substance. is considered effective.

Brief Description of Figures Figure 1 shows the dissolution profile of nystatin in the oven-dried formulations presented according to the invention. shows.

Figure 2 shows hydrocortisone acetate in the oven-dried formulations presented according to the invention. shows the dissolution profile.

Figure 3 shows the dissolution profile of lidocaine in the oven-dried formulations presented according to the invention. shows.

Figure 4 is the dissolution of nystatin in the lyophilizer dried formulations presented according to the invention. shows your profile.

Figure 5 shows hydrocortisone in lyophilizer dried formulations presented according to the invention. shows the dissolution profile of acetate.

Figure 6 shows the dissolution of lidocaine in the lyophilizer dried formulations presented according to the invention. shows your profile.

Figure 7 is the % swelling graph of the oven dried films presented according to the invention.

Figure 8 is the % swelling graph of the lyophilizer dried films presented according to the invention.

Figure 9 is the % inatric erosion graph of the oven dried films presented according to the invention.

Figure 10 shows the % matrix erosion of films dried in the lyophilizer presented according to the invention. is the graph.

Figure 11, the polymer mixture presented according to the invention (Hydroxyethyl cellulose-shantan gum) containing The comparison of the films is the erosion graph.

Figure 12, containing polymer blend (Hydroxyethyl cellulose:Xanthan gum) presented according to the invention is the comparative swelling graph of the films.

Detailed Description of the Invention In the present invention; mouth infections, especially fungal infections such as aphthae It occurs together with nystatin, which has an antifungal effect, to be used in infections. at least one corticosteroid to relieve inflammation and pain relief mucoadhesive film containing at least one local anesthetic to be applied by the buccal route formulations are presented. Thanks to the substance in 3 different pharmacological groups used While providing antifungal treatment, it is also possible to avoid other infections caused by fungal infection. It is also intended to treat symptoms. offered under the invention the advantageous effects of formulations especially in the treatment of oral candidiasis and presence has not been detected. A new method is also used in the preparation of mucoadhesive film formulations. As an approach, xanthan gum and HEC, which are mucoadhesive polymers, were used and The effects of polymer type and ratio on drug release were evaluated in vitro. has been evaluated.

The corticosteroid mentioned within the scope of the invention is anti-inflammatory well known in the art. are compounds of the type with properties of hydrocortisone acetate, preferably hydrocortisone acetate, according to the invention. is used. Again, the above-mentioned local anesthetic is available in the known art. any local anesthetic acting transdermally. Within the scope of the invention, lidocaine free base or its HC] salt may be used. Lidocaine HCl is well soluble in water but free Since the base form is hydrophobic, it does not dissolve well in water. The inventors thereby release in the oral cavity using free base and salt forms, or mixtures thereof They found that the profile can be adjusted as desired. At this point forinulation, for example may contain lidocaine free base, its HCl salt, or a mixture of both.

The following specification is combined with hydrocortisone and lidocaine in preferred embodiments. have been illustrated but should not be construed as limited thereto.

Mucoadhesive film formulations adhere to the mucosa, resulting in localized localized drug release. it provides. Mucoadhesive polymers used in their preparation do not cause mucoadhesion. is active. Mucoadhesive film formulations contain mucoadhesive substance(s) are matrix systems within polymer/polymers. In these systems, the active substance is either dissolved or It is contained in the polymer film, either as a suspension or in suspension, and the release of the drug(s) from the system. Its speed is mainly based on polymer type, molecular weight, viscosity, concentration and active substance- controls the polymer ratio. Drug release from these systems, diffusion of the drug and/or polymer occurs by the erosion mechanism.

Hydrophilic polymers can be used in mucoadhesive film formulations. But polymer to be used in film formulations as explained in the following specification If xanthan gum and HEC were chosen as the Other disadvantages of polymers in the technique are eliminated.

Xanthan gum (CAS No: 11138-66-2), pure carbohydrate with Xanthomonas campestri's It is a high molecular weight polysaccharide formed by culture fermentation. hot or It dissolves in cold water and gives visually turbid solutions at neutral pH. In hot glycerin Viscosities are stable in the range.

Hydroxyethylcellulose (HEC), (CAS No: 9004-62-0), Light tawny or cream It is a whiteish powder, odorless and tasteless. It may contain appropriate anti-caking agents. Density 0.6 g/mL, pH951 is between 6-8.5. Gives clear, colorless solution in hot or cold water. pH 2 Between 12 and 12, the viscosity is stable. Suspension or Viscosity Provider, Binder or used as a filmmaker (Handbook of Pharmaceutical Excipients, 6th Ed.).

Nystatin, one of the active ingredients, has both fungistatic and fungicidal effects. Clinically mucocutaneous, such as C. albicans, C. parapsilosis, C. krusei' and C. tropicali's in topical use It has a broad spectrum in the treatment of Candida infections [Kurijîlm, T., Williams, DW., Bagg, J. (2005). In vitro susceptibility of oral Candida to seven antifungal agents.

Oral Microbiol [mmunol, 20(6), 349-53). Nystatin for skin, mucous membrane, gastrointestinal absorption from organs is negligible [Bennett, J.E. (1993).

Antimicrobial agents.' antifungal agents. In Gilaman, AG., Nies, A.S. (Ed), The pharmacological basi's of therapeutic'cs. New York: McGraw-Hi'll; 1 1 65-81.]. Nystatin, yellow or slightly brownish, hygroscopic powder. Practically in water and alcohol insoluble, freely soluble in dimethylformamide and dimethyl sulfoxide. lightly in methanol soluble [Ph. EUR. 7.0]. The pH of the %Tluk aqueous solution is between 6.0-8.0 [USP 37]. LogP Lidocaine is one of the most preferred substances in superficial anesthesia. white or white It is a near crystalline powder. It is highly soluble in water, freely soluble in ethanol. 5 mg/ml carbon dioxide free pH of its solution in water is between 4.0-5.5 [ Ph. EUR. 7.0]. Local anesthetics, sensory and motor functions are blocked by reversibly binding to voltage-gated sodium channels Hydrocortisone Acetate is in the form of white or almost white crystalline powder. Bitter and bitter odorless [Florey, K. Hydrocortisone. In K. Florey (Ed. ), Analytical Profiles of Drug Substance. Vol. 12., American Pharmaceutz'cal Association, 277-324.]. practically in water insoluble. Slightly soluble in anhydrous ethanol and methylene chloride [Ph. EUR. 7.5]. adrenal It is the most important of the natural glucocorticoids secreted from the cortex. allergic conjunctivitis, alopecia, anterior segment inflammation, atopic dermatitis, insect bites and stings, bursitis, skin inflamation, Crohn's disease, dermatitis herpetiformis, discoid lupus erythematosus, exfoliative dermatitis, endophralmitis, epicondylitis, erythema multiforme, granuloma annulare, Graves' ophthalmopathy, gouty arthritis, hemorrhoids, iritis, juvenile rheumatoid arthritis, pruritus (pruritus), keratitis, contact dermatitis and many other diseases are used in the treatment.

Mucoadhesion, mucoadhesive hydrophilic effect of pharmaceutical formulations containing active compound As a result of its fusion with polymers, it increases the region-specific drug release. This The reason for the formulation to adhere to the biological surface is localized drug release. Active` The release of the compound close to the site of action provides a significant increase in the pharmaceutical effect. Pharmacokinet, 40 (2), 77-84.].

Mucoadhesive buccal film intended to be presented within the scope of the present invention Xanthan gum and HEC were used as polymers in the formulations. Choice The active ingredient (nystatin, hydrocortisone acetate, lidocaine HCl), water and ethyl alcohol as solvents, improve the elasticity of the formulations and the film. Propylene glycol (PG) as a plasticizer and surfactant to regulate its properties (Tween 80, Cremophor RH 40, Ascorbic palmitate) can be used. In this context In the mucoadhesive films presented according to the invention, the effect of lidocaine and hydrocortisone in the first hours It is intended to show the effect and continue for 8 hours. In this way, oral For candidiasis, the pain and inflammatory symptoms should be treated in the first half hour and this It is very important that the treatment lasts for 8 hours in terms of patient compliance.

Nystatin, which is used as an antifungal agent, shows controlled release and If the amount of release per hour is above the MIC value, the release continues to increase. are some of the most powerful features of the invention. At the same time, antimicrobial made in films The activity test also showed that nystatin films showed very strong antifungal properties. confirms. Mucoadhesive films have the desired release profile as well as physicochemical and It should also provide properties such as mechanical properties, swelling and erosion properties. three active Presenting all these elements at the same time in a system where there is a substance presents various difficulties. is doing.

The inventors used a triple combination of nystatin, hydrocortisone acetate and lidocaine HCl. diseases in the mouth if it is arranged as a film formulation, It has shown that it can be effective especially in the treatment of oral candidiasis and aphtha type diseases. it is in the dump. But as will be appreciated by those skilled in the art, such a film formulation will be able to find different application areas related to the mouth. For example, dental Use of mucoadhesive films presented according to the invention in the treatment of diseases and disorders will be possible.

The inventors describe the composition of HEC polymers with xanthan gum in a combination of three active ingredients. When used together, mucoadhesive film forms can be used for improved film formation and found to have erosional properties. HEC in preferred embodiments: The xanthan ratio can be 1:10 to 10:1 by weight. But the best results are 1:] to 1:2 obtained between the rates. All of the polymers or polymer mixtures used its ratio in the composition may be between 1 and 5% by weight.

In preferred embodiments of the invention, the film formulation contains at least one surfactant. contains. Surprisingly, the inventors found a release profile of water-insoluble nystatin. found to be improved by the use of surfactant. The main active ingredient Although nystatin is not soluble in water, thanks to the use of surfactant It was found that the resolution was increased. In matrix-structured polymer systems, water is absorbed. Release occurs when it diffuses out following its diffusion. Water diffuses into the matrix structure Despite the fact that the active substance does not dissolve in water, sufficient effectiveness cannot be achieved. causes. The solubility of the surfactant active substance added to the formulation has increased. For this purpose, Tween 80, ascorbic palmitate and Cremophor RH 40 is preferred. However, within the scope of the invention, Cremophor RH 40 and More successful results were obtained with Tween 80.

In also preferred embodiments, mucoadhesive film formulations contain at least one plasticizer. contains the agent. The inventors unexpectedly found flexibility in the formulation of PG. found that it increased the release of the active substance as well as giving it. This effect is particularly It has been observed that it becomes more pronounced with the use of PG at a rate of 6-10% by weight. Meet below this rate, the use of plasticizers is not sufficient, and above He noticed that the physical properties of the film form were damaged by the formation of the layer.

The drying method used in the production of the mucoadhesive film forms presented according to the invention It also has an effect on the release profile and physico-chemical properties of the formulation. has been found. The drying method used in preferred embodiments of the invention is in the oven. drying or lyophilization. However, the inventors unexpectedly dried in an oven. Both the Minimum Inhibition Concentration (MIC) suspension and bioadhesion and found that it is advantageous over lyophilization in terms of film flexibility. Examples Pre-Formulation Studies: In the preformulation studies, various polymers and their concentrations (chitosan (%) The use of different concentrations (6% and 10%) of the plasticizing agent (PG) The effect on the release of active substance from the formulations was investigated. Moreover It was decided to add surfactant to the formulations. Invention preferred Cremophor RH 40 (RH 40) and Tween 80 (TW) as surfactants were selected and the concentrations of these surfactants in the formulations were determined.

Surfactant in all formulations except formulations prepared with chitosan. The active substance release of the use of the drug was found to be significant (p<0.05) as arttird1g1. chitosan The visual properties of the formulations prepared with with chitosan polymer because it is too low to provide pharmacological activity. work is not continued. With the decided polymer and surfactant percentages final formulations have been prepared. The parameters discussed in these studies and the obtained the results are given below.

2.5% and 3% (w/w) for HEC in terms of buccal films, 2.8% and 3% for xanthan gum concentrations are used. Gel-forming medium for HEC and xanthan gum 25±2°C and the holding period is arranged as 24 hours. Providing flexibility of buccal films Propylene glycol (PG) was chosen as the plasticizer. Made without the addition of active ingredient In polymer selection studies, when the flexibility of the formed films is examined visually, The formulations were kept in an oven (40±2°C) for 24 hours and for 60 hours in an incubator. It was determined that the drying was optimum.

Film containing active ingredients under optimized conditions based on the above studies formulations are presented in Table 1 below.

Table 1. Film formulations containing active ingredients (%, w/w) Formulation Nisrtati Hydrocortisone Lidocaine Hiîreîgisgft" Kzsaaiilzn Filim“ RH 40 “gen allîliiil Manufacturing method: The polymers used in the specified formulations are HEC and Xanthan gum, in distilled water It was weighed at the specified concentrations and left to swell. Then water in a separate beaker Lidocaine HCl was dissolved in the remaining part of the amount. Calculated again in a separate beaker By taking a large amount of alcohol, nystatin and hydrocortisone acetate were dissolved. same phase The solubility of the active substances was increased with the addition of surfactant. Adding PG to the alcohol phase While aiming the flexibility of the formulation, at the same time, the added active ingredients the resolution has been increased. First, the water phase was slowly added to the inflated polymer. Weather It was mixed homogeneously, paying attention to the absence of bubbles. Later alcohol phase It was added slowly, and then mixed, taking care not to have air bubbles.

The prepared formulations were poured into Petri dishes with a diameter of 9.8 cm. Each formulation It was dried by two different methods (oven and lyophilization). 40 °C ± in oven drying process 0.5 temperature is preferred.

Salim Tests: Among the prepared mucoadhesive buccal film formulations, nystatin, lidocaine HCl and in the European Pharmacopeia (EP) to detect the dissolution of hydrocortisone acetate. It was worked with the tool specified in the “Dissolution test monograph for films (2.9.4)” given. Infinite dilution for nystatin, lidocaine HCl and hydrocortisone acetate in dissolution experiments Ethyl alcohol-saliva medium (pH 6.75) (1: l) mixture (900 ml) as the medium providing (sink condition) used. The temperature of the system was set to 37±0.5°C and the rotation speed of the pallet was set to 50 cycles/min. 5 Mucoadhesive buccal film placed on a watch glass of cm diameter formulations were covered with 125 µm stainless steel wire, and this assembly was 900 After being placed in the ml beaker, the active substances are determined depending on time. The release from the formulations was examined. HPLC method was used for analysis. This In the method, a C18 (reverse phase) column with a particle size of 150><4.6 mm and a particle size of 5 µm used. Methanol/0.1 M NagHPO4 is mixed at a ratio of 60:40 as the mobile phase and diluted. The pH was adjusted to 4.5 with phosphoric acid. Room with a flow rate of 1.0 nil/minute with the gradient method temperature was analyzed. 230 nm was chosen as the detection wavelength. [Pendella, M., Kahsay, G., Baekelandt, 1., Van Schepdael, A., Adams, E. (2011). simultaneous determination ol lidocaine hydrochloride, hydrocortisone and nystatin in a pharmaceutical preparation by RP-LC. J Pharmaceut Biomed, 56, 641-644.] Visual, inspection, thickness, weight, effective on the prepared buccal film formulations. with the determination of the amount of substance, the dissolution rate of the active substance and the matrix-erosion test. Physical durability, elasticity and bioadhesion strength tests were carried out.

In the tests made; Formulations made with HEC and Xanthan gum are homogeneous. and flexibility were found to be good. HEC° formulations have a brighter appearance. xanthan gum formulations have a more opaque appearance. Oven dried films It was measured with a caliper and their thickness was between 0.039 - 0.095 mm and dried in a lyophilizer. The films were found to be between 0.060 - 1.198 mm. Oven-dried films It was found to be between 0.1784 g. Effective from films dried in an oven and lyophilizer The graphs of the dissolution rate profiles of the substances are presented in Figure 1-6.

The results of the release studies were evaluated statistically and the film The release profiles of the active substances from the formulations were investigated. oven dried when the nystatin release of the films is examined, the release amounts follow the order; F9, F10 > significant difference between formulations (F1-F4) and formulations with xanthan (FS-F12) observed (p<0.05). This is because the different polymer structure does not affect the in vitro release profile of the drug. is the effect. When the release profile of formulations prepared with xanthan is examined, nystatin The amount of release was significantly (p<0.05) higher than the formulations with HEC at the end of the 8th hour. appears to be too much. Diffusion-controlled (Fickian) according to kinetic studies conforms to the release mechanism. The in vitro release rate is higher in xanthan formulations. slower than xanthan swelling and delayed release of the active substance. may be thought to originate. Due to the hydrophilic nature of HEC, swelling and gel Both polymer and diffusion controlled release (non-Fickian) is performing. The role of rapid gelling of the polymer in the release mechanism nystatin release is accelerated in the first hours in formulations containing HEC. it has been seen.

When the formulations with HEC are evaluated within themselves, the active substance release profile rank; F1, F3 > F2, F4. This is because HECSII formulations contain polymers. It is the decrease in the amount of release when the concentration increases. Plasticizers in these formulations No effect of substance concentration on active substance release was observed. All HEC It is seen that the nystatin release from the formulations continues to increase for 8 hours.

When the cumulative nystatin release amounts from xanthan formulations were compared, the best It appears to be in the form. From xanthan formulations to nystatin release profiles in every time slot specified between F9 and F10 and F5, F6, F7 and F8. no significant difference is observed (p>0.05). However, between the Fll and Fl2 formulations . While there is no significant difference until the 5th and 8th hours, there is a significant difference between the 5th and 8th hours. (p<0.05). In xanthan formulations, the release amount of PG, which is a plasticizer, increased with increasing concentration (F9, FIO, F] 1, F12). PG concentration is less Nystatin release rate, PG concentration in formulations with xanthan (F5, F6, F7, F8) was found to be less than the higher ones. Surfactant to xanthan formulations When the effect of substance type on nystatin release is examined; F5, F6, F7 with low PG ratio Among the release profiles of formulations coded F8 and F8, surfactant type nystatin It is thought that there is no effect on the release. On the other hand, those with high PG concentration The nystatin release of surfactant addition in F9, F10, F11 and F12 coded formulations. effect has been found. As a surfactant, from formulations containing RH 40 It was determined that nystatin release was higher than Tween 80”1i formulations. This Based on the results, it was determined that the polymer concentration of nystatin in formulations with xanthan Although it did not affect the release profile of the drug, PG did not have a major effect on the release profile of the drug. Depending on the PG concentration, the surfactant type also affects the nystatin release. It is believed that it affects.

Hydrocortisone 60% from the F2 and F4 formulations, which are film formulations dried in the oven While the release of hydrocortisone from formulations other than this, the release of hydrocortisone is around 80%. found around. When these data are evaluated statistically, high concentration of HEC in oven-dried film formulations. It is thought that it reduces hydrocortisone release significantly (p<0.05).

When the lidocaine HCl release from the film formulations dried in the oven is evaluated there is no significant difference between formulations (p>0.05). According to these data polymer type and percentage, plasticizer concentration and surfactant type. shows that it has no effect on lidocaine HC] release. From all formulations and reached its maximum peak value at the end of the 3rd hour. Lidocaine from all formulations it continues. It was the first time that lidocaine HCF showed high solubility in artificial saliva. cause a rapid and high concentration release profile starting from hours has been. The reason for this is that the increase in water-soluble content decreases the dissolution rate from the films. because it increases acceleration. Pain symptoms of oral candidiasis occur in the first half hour. It is very important for the patient to be treated and to continue this treatment for 8 hours. is important. In addition, optimization of the duration of the anesthetic effect Lidocaine salt and base can be done by changing the ratio. Because the solubility of salt and base of lidocaine is different. This optimization will be carried out.

When the nystatin release profile of the film formulations dried in the lyophilizer is examined, Significant in terms of release profile and amount (p<0.05) according to the formulations dried in the oven. differences have been identified. Cumulative nystatin release amounts from all formulations Ranking of formulations showing the best nystatin release profile compared to F12 > F4 Of the formulations with F12 and F11, HEC, F4 and F3 show the highest nystatin release.

When we consider the statistical evaluations, it is seen that the formulations of F 3, F4, F 1 1, F 12 showed the highest nystatin release. From these results, both xanthan increase in the amount of plasticizer in both formulations with HEC It can be interpreted that it significantly increased the amount of nystatin release. Of the reasons for this One of them is that the plasticizing agent increases the solubility of the active substances in the medium. can be explained. Nystatin release when HEC formulations are evaluated on their own were found as F4>F3>F2,Fl respectively. PG ratio is 10% in F4 and F3 formulations, F2 and 6% in F1 formulations. Here is the plasticizer It is seen that an increase in the amount of nystatin significantly increases the release of nystatin. Moreover, Nystatin release of polymer concentration in formulations containing low amount of PG While it has no effect on the polymer in formulations containing high amount of PG increase in concentration increases the amount of release (F4>F3, p<0.05). hydrophilic The increase in drug release in polymers (such as HEC) is accompanied by an increase in polymer concentration. is proportional. Another reason for this is the drying of the high-concentration polymer in the lyophilizer. formation of more porous structures during the process and diffusion of water during release can be considered as excessive. Xanthan formulations differ among themselves. evaluated according to the amount of nystatin release F12 > Fll > F9 > F7, F8, F10 > F6 > It can be sorted as F5. Plasticizer of all formulations (except the FIO formulation) It is seen that 10% of the rate has a major effect on nystatin release. This containing Tween 80 in formulations with both PG ratios (6% and 10%), except It was found that forinulations showed higher nystatin saline than those containing RH 40. has been made. As a result, the release of the amount of plasticizer and the type of surfactant arguably had an effect on it.

Hydrocortisone release from film formulations dried in lyophilizer was statistically between formulations except for the difference between F7 and F12 when evaluated. there is no significant difference (p>0.05). Except for F7, all formulations are 70% and shows saline on it. The F7 formulation has the least hydrocortisone release. has realized. When the lidocaine release is evaluated statistically, the film There is no significant difference between formulations]. Lidocaine release 100% around and reached its peak value at the 3rd hour. This is because lidocaine HCl is artificial saliva. It is considered to show high solubility in the medium' because it dissolves in water. The increase in the content increases the acceleration of the dissolution rate from the films.

Inflatable and Erosion Test: % hydration and % matrix of prepared mucoadhesive buccal film formulations Frames with a side length of 1 cm from the films prepared to detect erosion cut into pieces and weighed precisely. into wire cages prepared in the same dimensions. watch glasses were prepared to be placed. Film formulations, swelling amounts and They were kept at 37 C7 in artificial saliva medium (pH 6.75) to determine the erosion they have grown. At 24 minutes and 24 hours, the samples were carefully removed from the environment and excess water was wiped onto a towel. impregnated and weighed. Then, with the help of the formulas given below, the swelling amounts of the films and matrix erosion %” were calculated [Martin, L., Wilson, C.G., Koosha, F., Uchegbu, l.F. (2003) Sustained buccal delivery of the hydrophobic drug denbufylline using physically cross-linked palmitoyl glycol chitosan hydrogels. Eur J Pharm Biopharm, 55, 35-45]. Experiment It was repeated 3 times.

Swelling test findings of buccal films dried in oven and lyophilizer are shown in Figures 7 and 8 and Matrix erosion test findings are also given in Figures 9 and 10. dried in lyophilizer Of the films, F1, F2, F3, F4 were completely eroded at the 45th minute.

In polymeric films, the swelling rate is important as it correlates with the mucoadhesive strength.

However, excessive swelling usually results in reduced mucoadhesion and/or retention time.

When the film starts to absorb water, swelling and binding begins, adhesion occurs. But in the end It reaches the excessive swelling point and the polymer molecules at this interface It causes separation and degradation and thus reduces adhesion. oven dried Formulations with HEC (F1-F4) were over 70% hydrated in the first 5 minutes, 60. 88,872 hydrated. 85% of all HEC°1i formulations after 6 hours It was observed that it was hydrated around and above. Looking at the profile of the inflatables (Figure 7) It was observed that the HEC71i formulations swelled very quickly in the first minutes and it was 6 hours. It is observed that this swelling continues with very small increases throughout. Increase in HEC content did not make a significant difference in the swelling rate. In xanthan formulation, swelling 5. It was found around 60% per minute and was higher for 6 hours compared to formulations with HEC. a controlled swelling occurred, at the end of the 6th hour the swelling rate was around 80% and above has been found. Formulations with HEC dried in a lyophilizer are 94% in the first 5 minutes. It is hydrated and completely eroded at 60 minutes. Xanthan formulations were first . Over 72% hydrated per minute, around 90% hydrated at the end of the 6th hour has been observed. These results showed higher water uptake than xanthan, as expected by HEC. It shows you have the capacity. This is because the solubility of HECI in water is higher. that is high. When comparing matrix erosion studies and swelling studies, erosion and swelling results are compatible with each other. High swell index in this direction formulations show high matrix erosion. This is because the water The influx weakens the polymer network integrity, the structural strength of the swollen matrix It may be highly affected and erosion may occur by losing the gel layer. This In parallel, matrix erosion studies on buccal film formulations confirms the result. With HEC in film formulations dried in an oven It is seen that the erosion values of the formulations (F1, F2, F3, F4) are higher.

Among the film formulations dried in a lyophilizer, formulations with HEC were taken at 45 minutes. completely eroded. These data show that the formulations prepared with xanthan shows better erosion properties. Inflatable capacity especially two It's important for a reason. Most importantly, the absorption of water by the film is It provides better bioadhesion in the mucosa. Second, diffusion and erosion is that it helps drug release with its mechanism. The buccal inucosa of the film after its implementation, respectively; diffusion of water molecules into the polymer, hydration, swelling, separation of the film from the tissue and erosion of the polymer occurs. adhesion hydration increases with the increase of hydration, but due to separation at the polymer/tissue interface, At a certain point, there is a sudden decrease in adhesion. Excessive hydration, slippery, sticky Causes non-mucilage formation so that adhesive strength is reduced or adhesion is completely disappears. This is also due to the adhesive at the interface of the mucus and bioadhesive systems. It is the result of dilution of functional groups required for interaction. into the matrix The diffusion of water causes a thin layer to dissolve on the surface of the matrix. You are the matrix With swelling, the drug molecule diffuses out of the matrix. How much watery into the matrix the more the medium diffuses, the more the drug molecule diffuses out of the matrix. However, inflatables character is highly dependent on the structure and composition of the film. Also in water The increase of insoluble drug molecules increases the water absorption by the dosage form. Erosion It has been observed that the increase in the ratio of non-ionic polymers (such as HEC) is more and It is thought that it may be directly proportional to the increase in the swelling rate.

Determination of Physical Strength and Elasticity Physical durability and strength of the prepared mucoadhesive buccal film formulations. Texture analyzer (TA.XT Plus Stable Micro systems, UK) was used. Evaluations were made according to the literature [Jones, D.S., Woolfson, AD., Djokic, J., Coulter, W.A. (1996). Development and inechanical characterization of bioadhesive semi-solid, polymeric systems containing tetracycline for the treatment of The films cut in length should be prepared with a distance of 1.5 cm between the two clamps of the device. fastened. The upper gripper of the device moves upwards at a constant speed according to the parameters given below. The test was repeated 3 times for each formulation and the average values were taken and the standard deviations were calculated.

Test Parameters Loading cell : 5 kg Test mode : Tension Speed before test: 1.0 mm/s Test speed: 0.5 mm/sec Post-test speed: 10 mm/sec Target mode : Distance Distance : 100 mm Force required to start the test: 2g Apparatus used for the test: A/TG tensile grips Using the formulas given below, the breaking force and elongation distance of the formulations was calculated and the breaking force per cm2 and the % elasticity values were calculated.

Breaking force (N) obtained from the force-distance graph Breaking Force (N/cm2) = The area of the film used in the test (cm2) The amount of elongation of the film (cm)* Elasticity (%) = X 100 Length of pre-test film (cm) Physical Strength and Elasticity of buccal films dried in oven and lyophilizer Detection findings are given in Table 2.

Table 2: Findings of Physical Strength and Elasticity Determination Tear resistance Elasticity Formulation (N' cm2) (arrow) SD in the Oven SD in the Lyophilizer SD in the Oven SD in the Lyophilizer Determination of Bioadhesion Force The adhesion strength of the prepared mucoadhesive buccal film formulations to the skin is shown below. TA-XT2 model Texture analyzer (TA.XT Plus Stable) with given test parameters Measured using Microsystems, UK). In this test, the adhesion of the formulations to the mucosa A membrane filter was used to detect it. Bioadhesion of film formulations For the determination of the strength, the formulation was attached to the probe of the analyzer with bidirectional tape.

The membrane was cut and placed in the device. The system was placed in the salivary medium at 37±0.5°C. and contacting the probe to which the film is attached with the membrane according to the parameters given below provided. After being kept in contact for 180 seconds, the probe moves upwards at a constant speed. withdrew. The bioadhesion heat was calculated from the force-distance graph obtained. test each It was repeated 3 times for the formulation and standard deviations were determined by taking the mean values. calculated.

Test Parameters Test mode : Adhesion Probe :P0.5 perspex Speed of the probe before the test: 1.0 mm/second Speed of the probe during the test: 1.0 mm/second Speed of the probe after the test: 5.0 mm/second Return distance of the probe: 50.0 mm Contact time between the film and the mucosa: 180 seconds Initial contact force of the film and the mucosa: 1.0 N During the contact of the film with the mucosa applied force : 0.5 N Appliance used for testing: A/MUC Test appliance The area under the force-distance curve (AUCi_2) gives the job of bioadhesion. one The following formula was used to calculate the bioadhesion work per cmzs.

Biodesion heat (ml/cm2) = ................. 7t.r2 : The area of the transdermal formulation in contact with the mucosa Bioadhesion study findings of buccal films dried in oven and lyophilizer Table It is given in 3.

Table 3: Results of Determination of Bioadhesion Strength BIOADDESIGN HEAT (MJ/CMZ) FORMULATION SD In Oven SD In Lyophilizer Dried Dried In vitro bioadhesion, elasticity and resistance to rupture in selected buccal film formulations. Resistance tests were also carried out. The elasticity of the formulations dried in the oven is in the lyotilizer. significantly (p<0.05) higher than the dried formulations. both in the oven formulations containing HEC from both dried and lyophilized films Significantly (p<0.05) higher elasticity than formulations containing xanthan gum they have shown. Xanthan with formulations containing HEC in oven-dried formulations When the gum-containing formulations are compared, the elasticity difference is between 6 and 3.5 times, The difference varies between 11 and 2 times in those dried in a lyophilizer. Also plasticizer the presence of the agent (PG) was found in both the oven-dried formulations and, as expected, It increased the elasticity of formulations dried in the lyotylizer (F9>F5, F10>F6, F11>F7, F12>F8). Generally, in addition of plasticizers to polymeric systems. The glass transition temperature is reduced, so they become softer and more flexible. But oven dried While there was no significant difference in film elasticity between HECali formulations, There is a significant (p<0.05) difference in formulations dried in a lyophilizer (F3, F4>F1, F2; F3>Fl, F4>F2). Especially in formulations dried in lyophilizer, polymer It was observed that the elasticity decreased as the concentration increased. Also surfactant It is thought that the type may have an effect on elasticity. Movie featuring Tween 80 formulations showed higher elasticity than those containing Cremophor RH 40.

In the films dried in the lyophilizer, both the type of polymer and plasticizer and the polymer While the effect of the concentration is visible, the polymer type and plasticizer in the oven-dried films agent concentration was the determining parameter on elasticity. decided When the rupture forces of buccal film formulations are evaluated, Dried film formulations are more durable than oven-dried formulations. it has been seen. Likewise, the films dried in both the lyophilizer and the oven Formulations containing xanthan gum are more resistant to breakage than formulations containing HEC. showed high resistance. In both oven-dried formulations and lyophilizer When the PG concentration increases in the dried formulations, a large percentage of the formulations In most cases, resistance to rupture has decreased. Effect of plasticizer on tensile strength has been studied by many researchers. Hyppola et al. [ Hyppola, R., Husson, I., Sundholm, F. (1996). Evaluation of physical properties of plasticized ethyl cellulose films that it is important to obtain the required tensile strength, shrinkage with the plasticizing agent They observed a change in strength. Mucoadhesive agent in studies also It is stated that the increase in concentration is not proportional to the tensile strength.

In our study, the tensile strength of the polymer concentration and the surfactant type has no effect on film formulations dried in an oven or lyophilizer. Moreover Bioadhesiveness testing was also performed on these formulations. Film dried in the lyotilizer when the bioadhesiveness of the formulations was compared to the formulations dried in the oven. It was observed that it was significantly low (p<0.05). Oven-dried formulations The bioadhesiveness of formulations containing HEC was compared to formulations containing xanthan gum. significantly (p<0.05) higher than the formulations dried in the lyophilizer. The bioadhesiveness of HEC-containing formulations is generally higher than that of xanthan zains. has been found. In a study, it was found that hydrogels containing xanthan gum had a low mucoadhesion, but safety, gel durability, sustained release properties and can be applied to the buccal area because of its good feeling in the mouth. In both types of polyiner (xanthan gum and HEC), PG in formulations dried by both drying methods The presence of the concentration caused a decrease in bioadhesion. Both drying In the method, the increase of both polymer concentrations increased the bioadhesion. in the oven formulations containing Tween 80, formulations containing Cremophor RH 40 It exhibits less bioadhesion than formulations. dried in lyophilizer It was found that the type of surfactant in formulations had no effect on bioadhesion. has been seen. The buccal area is soft, relatively immobile and bioadhesive for accessibility. It is very suitable for the system. The most important advantage of bioadhesive systems is the calc in the oral cavity. It is the increase in the duration and the localization of the drug molecules in a particulate sense.

According to the findings obtained, the antifungal activity of all film formulations was demonstrated in vitro. Antimicrobial activity test was also performed to measure it (Table 4).

In this test, the diameter of the disc at which the film sections kill the fungal cells planted in the medium. is measured. This Measurement is a criterion for assessing antifungal efficacy. disc diameters the remaining formulations containing HEC (F1, F2, F3, F4) from the dried film formulations While it differs significantly with the formulation containing xanthan, there is no significant difference within each other. they do not differ. HEC-containing formulations were significantly xanthan-containing. shows significantly less efficacy compared to formulations. dried in lyophilizer Ranking of the disc diameters of the formulations in the antifungal activity test formulations containing HEC significantly compared to formulations with xanthan. showed less disc diameter. However, xanthan containing high concentration of PG formulations (Fll and F12) reduced disc diameter similar to formulations containing HEC and the difference was not significant. Xanthan formulations are similar, except for Fll and F12. and shows close results. Formulations with HECl have similar results in themselves. they have shown. Among the formulations dried in the lyophilizer, in general, the ones dried in the oven Less disc diameter was obtained compared to the formulations.

Table 4: Antifungal Activity Test Results Antimicrobial Activity .. Oven Dried Formulation . .

Difference (mm) Difference (mm) As a result of the findings obtained at the end of the study, when the release kinetics were examined, xanthan It is seen that the gum is more suitable for controlled release and erosion findings are observed in the buccal film. It is considered to be optimum for formulations. For formulations containing HEC, Elasticity and bioadhesion findings were observed to be the most appropriate. These results In order to obtain optimum physical and kinetic findings in line with HEC and xanthan Zainki is intended to be used as a mixture. Tested formulations are in Table 5 is listed.

Table 5. Film prepared using a mixture of hydroxyethylcellulose:xanthan gum coding of formulations (%, w/w) Hydroxy ethyl cellulose: . .

Hydroxy . .

... . . . . . xanthan . Xanthan Propylene RH Tween Ethyl Formulation Nystatin Hydrocortisone Lidocaine gum ethyl gum glycol 40 80 alcohol cellulose 0.5 0.4 0.8 2 0.5 0.4 0.8 2 0.5 0.4 0.8 - 6 0.5 0.4 0.8 - 6 0.5 0.4 0.8 6 0.5 0.4 0.8 6 0.5 0.4 0.8 - 6 Film containing HEC:Xanthan mixture prepared for the purpose mentioned above within the scope of the invention formulations were subjected to erosion and swelling tests. These formulations are in the text It was prepared according to the reported film preparation method. In these tests, only HEC or films prepared with Xanthan polymers were also used. presented in Figure 11 As can be seen in erosion tests, formulations with HEC differ from formulations with Xanthan. is subject to further erosion. Interestingly, however, the ratio of HECszantan by weight is 1:] and 1:2 mixtures are less erosive than formulations using HEC and xanthan alone. he has tried. Least eroded mixture with a HEC2Xanthan ratio of 1:2 by weight formulation.

Mixtures with a HEC2Xanthan ratio of 2:1, 321 and 4:1 by weight are proportional to the HEC ratio in the content. somehow more eroded. But these formulations alone are HEC less erosion than the use of xanthan alone, more erosion than formulations using xanthan alone they have been.

Considering the swelling data given in Figure 12, the most consistent with the erosion data It is a formulation with a good swelling HECszantan ratio of 1:2. Its HECszantan ratio is 121. formulation follows.

Claims (16)

REQUESTS 1. Composition in the form of a mucoadhesive film comprising nystatin, at least one drug of a corticosteroid nature, and at least one local anesthetic, together with at least one polymer selected from hydroxyethyl cellulose and xanthan gum. 2. Composition offered according to claim, characterized in that the anesthetic substance in question is Iidocaine HCl salt and/or free base. 3. It is the composition offered according to the request, and its feature is that the drug with corticosteroid composition is hydrocortisone acetate. 4. It is the composition offered according to the request, characterized in that the composition also contains a plasticizer agent. 5. Composition according to claim 4, characterized in that said plasticizing agent is propylene glycol. 6. The composition presented according to claim Si, characterized in that the ratio of propylene glycol is in the range of 6 to 10% based on the total weight of the composition. 7. Composition presented according to claim, characterized in that the composition also contains a surfactant. 8. Composition according to claim 7, characterized in that said surfactant is selected from among Tween 80, ascorbic palmitate and Cremophor RH 40. 9. The composition offered according to claim 1, characterized in that the composition contains a mixture of hydroxyethylcellulose and xanthan gum as polymer. 10. The composition according to claim 9, characterized in that the ratio of Hydroxyethylcellulose:Xanthan gum is 1:10 to 1021 by weight. 11. The composition offered according to claim 10, characterized in that the ratio of Hydroxyethylcellulose:Xanthan gum is 121 to 122 by weight. 12. A composition according to any one of the preceding claims, characterized in that the total polymer content in the composition is 1 to 5% by weight. 13. The composition offered according to claim 12, characterized in that the total polymer content in the composition is 2.5 to 3% by weight. 14. A composition according to any of the preceding claims, characterized in that said composition is dried in an oven or by lyophilization. 15. It is the composition offered according to claim 14, characterized in that the composition is dried in an oven. 16. The composition according to claim 1 for use in the treatment of oral candidiasis and aphthae.