HYDROCORTISONE-CONTAINING MUCOADHESIVE BUCCAL NANOFIBER FORMULATIONS FOR ORAL ULCER TREATMENT
Patent Information
- Authority / Receiving Office
- TR · TR
- Patent Type
- Applications
- Current Assignee / Owner
- GAZI UNIVERISTESI
- Filing Date
- 2026-06-01
- Publication Date
- 2026-06-22
Smart Images
Figure 00000009_0000 
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Abstract
Description
1 TARIFF HYDROCORTISONE-CONTAINING MUCOADHESIVE FOR ORAL ULCER TREATMENT BUCCAL NANOFIBER FORMULATIONS Technical Area 5 The invention is a hydrocortisone-containing compound obtained by electrocautery for use in the treatment of oral ulcers. This invention relates to the development of mucoadhesive buccal nanofiber formulations. More specifically, it concerns oral ulcers. Developed for use in local treatment, it contains hydrocortisone and can adhere to the buccal mucosa. and electrospinning-induced nanofiber patches that can form a protective layer over the ulcerated area It is related. 10 State of the Art Oral ulcers can cause pain, inflammation, difficulty eating, difficulty speaking, and discomfort in the mouth. Oral ulcers are common lesions that negatively affect the quality of life of patients. Causes of oral ulcers. This varies from person to person and can be caused by trauma, stress, vitamin deficiencies, cytotoxic treatments, and various other factors. It may be related to systemic factors. Therefore, in the treatment of oral ulcers, symptomatic and 15 Local treatment approaches are preferred. Current topical treatments include gels, creams, ointments, mouthwashes, sprays, films, tablets, and buccal patches. These products contain active ingredients such as anesthetics, antimicrobials, and corticosteroids. These substances can be used. Corticosteroids, especially hydrocortisone and similar anti-inflammatory drugs. agents, 20 for the purpose of relieving local symptoms in painful and inflammatory oral ulcer lesions It is one of the active ingredients that can be used. However, the oral environment is constantly exposed to saliva, along with tongue and cheek movements and mechanical contact. Conventional gels, gargles, sprays, and short-term solutions are used due to conditions such as swallowing and food / liquid intake. Film systems cannot always provide sufficient residence time in the ulcerated area. This situation is ineffective. This makes it difficult for the substance to remain in the target area for a sufficient duration and at a sufficient concentration, frequently 25 This can lead to a decrease in the need for application and patient compliance. The aim in developing mucoadhesive films, tablets, patches, and nanofiber-based systems for buccal application is to... This is because the drug delivery system adheres to the mucosal surface, increasing the local residence time. However, it is known that... active substance-polymer combination in solutions, fiber morphology, mechanical flexibility, mucoadhesion, The desired balance between patient comfort and controlled release characteristics cannot always be achieved. 30 Some systems tend to disperse quickly or be eliminated by saliva, while others are insufficient. It exhibits problems such as adhesion, fragility, low elasticity, or poor patient compliance. Therefore, nano-type adhesives that adhere effectively to the buccal mucosa and can be used in the treatment of oral ulcers are recommended. It has a three-dimensional fiber structure, provides flexible, controlled and extended release, and has a low hydrocortisone content. a protective 35 on the ulcerated area that can balance the solubility property with nanofiber architecture There is a need for a novel local drug delivery system that can form a barrier. 2 Purpose of the Invention The main purpose of the invention is to achieve a more effective application of hydrocortisone, used in the treatment of oral ulcers, at the application site. to ensure long-term retention, to achieve local and controlled release of hydrocortisone, ulcerative The aim is to physically protect the area from the oral environment and to improve patient compliance. Another aim of the invention is to produce porous, homogeneous, preferably bead-free and 5 mm thick fibers using the electrospinning method. to produce nanofibers with diameters in the sub-micron range, thus embedding the active substance within the fiber matrix. By ensuring that it is found in a dispersed or amorphous form, the local solubility of hydrocortisone is reduced, mucosal The aim is to increase its reach and effectiveness in the application area. Another purpose of the invention is to use polyvinylpyrrolidone (PVP) in Eudragit E100, Eudragit L100-55, Eudragit S100, Suitable 10 biocompatible and / or mucoadhesive polymers such as polyvinyl alcohol (PVA) and hyaluronic acid. with their combinations, mechanical strength, flexibility, wettability and suitable for buccal application. The aim is to provide a nanofiber patch platform that possesses mucoadhesion properties. Description of the Invention The invention describes a hydrocortisone-containing compound, produced by electrocautery, for use in the treatment of oral ulcers. This relates to a prepared mucoadhesive buccal nanofiber formulation. This formulation contains buccal 15 It adheres to the mucosa, providing local and controlled release in the application area, and on the ulcerated area. It forms a protective layer and is more effective in the target area compared to conventional topical applications. It offers a drug delivery structure that can remain in place for a long time. The formulation subject to this invention consists of hydrocortisone together with at least one mucoadhesive polymer or mucoadhesive. It contains a polymer combination. In one application, the polymer phase is combined with PVP in Eudragit E100, Eudragit 20. It contains a methacrylic acid-based polymer selected from either L100-55 or Eudragit S100. Another In practice, the polymer phase contains PVA and optionally hyaluronic acid. Hyaluronic acid, In addition to mucoadhesion, keeping the ulcerated area moist and promoting wound healing. It can provide an advantage in that respect. The formulation is produced by combining hydrocortisone with a selected polymer or polymers in a suitable solvent system. 25 dissolving or dispersing it in a solution and subjecting the resulting solution to an electrospinning process This is carried out with Eudragit / PVP based applications. The solvent system is preferably ethanol:N,N- It is a dimethylformamide mixture. A solvent system for PVA and / or hyaluronic acid-based applications. It is preferably a water:ethanol mixture. However, pharmaceutically accepted substances suitable for electrocautery are also available. Other viable solvent systems can also be used. 30 The nanofiber mat obtained by electrospinning exhibits high surface area, porosity, mucoadhesive behavior, and Thanks to its mechanical flexibility properties, it forms a patch that can be applied to the ulcerated area. The patch in question can be single-layered or multi-layered; it can come in different geometric shapes and sizes. It can be cut; it can be offered in single or multiple packs. 35 3 Detailed Description of the Invention Invention-Based Formulation The formulation described in this invention is designed for local application to the oral ulcer area. It is a mucoadhesive buccal nanofiber patch. The formulation can be single-piece, multi-layer, or for localized thickness differences. It can be produced in variants showing these characteristics. Preferably thin, flexible, adaptable to the mucosa, and suitable for application. 5 It exhibits a structure that does not break during this process. The fiber diameter of the nanofiber matrix is preferably less than 1 micron. The fibers are preferably porous, homogeneous, and bead-free. or has a low-bead structure. This structure is characterized by hydrocortisone being dispersed within the fiber matrix or By contributing to its presence in an amorphous state, it enhances the local release of hydrocortisone, which has low solubility. and increases mucosal contact. 10 The amount of hydrocortisone should be 0.1-5% (w / v), preferably 0.5%, based on the formulation solution. The concentrations are between 2% (w / v) and, preferably, around 1% (w / v). These concentrations are relevant to pharmaceutical efficacy and electroconvulsive therapy. Suitability and fiber type can be considered together and modified. Polymer Phase and Auxiliary Components The polymer phase of the formulation subject to the invention has mucoadhesive properties and is suitable for buccal application. 15 It is selected to show the following. In one application, the polymer phase contains PVP and a Eudragit derivative. Eudragit The derivative can be selected from Eudragit E100, Eudragit L100-55 or Eudragit S100. These polymers are used in fiber production. It affects formation, mechanical properties, surface wettability, and controlled release behavior, When used in combination with PVP, they enable the production of nanofiber mats suitable for buccal application. In one application, the amount of Eudragit E100 in a mucoadhesive buccal nanofiber formulation is 20-40% (w / v), 20 The PVP concentration is in the range of 5-20% (w / v), preferably with formulations containing 1% (w / v) hydrocortisone, 30% (w / v) Eudragit contains E100 and 10% (w / v) PVP. In another application, the amount of Eudragit L100-55 in the mucoadhesive buccal nanofiber formulation is 7.5%. (w / v), PVP content is in the range of 5-10% (w / v), preferably the formulation is 1% (w / v) hydrocortisone, Contains 10% (w / v) Eudragit L100-55 and 5% (w / v) PVP. 25 In another application, the mucoadhesive buccal nanofiber formulation Eudragit S100 is used at a concentration of 7.5-15% (w / v). The PVP concentration is in the range of 5-10% (w / v), preferably with a formulation of 1% (w / v) hydrocortisone, 10% (w / v) Contains Eudragit S100 and 5% (w / v) PVP. In another application, the polymer phase contains 5-10% (w / v) PVA. PVA is water-soluble, buccal. It is a polymer suitable for application and capable of exhibiting mucoadhesive properties. Mucoadhesive buccal nanofiber 30 The formulation may also contain 0.1–2% (w / v), preferably approximately 1% (w / v) hyaluronic acid. With PVA The combined use of hyaluronic acid helps keep the ulcerated area moist and creates a healing environment. This can provide an additional advantage in terms of support. PVP can be added to PVA-based formulations when needed. Auxiliary polymers such as these can also be added. The formulation may include plasticizers, pH regulators, stabilizers, and penetration enhancers as needed. regulators, sweeteners, colorings, preservatives, buffering agents or pharmaceuticals 4 It may contain other excipients that are acceptable for buccal administration. The choice is made taking into account suitability, patient compliance, mechanical flexibility, and release profile. In mucoadhesive buccal nanofiber formulations, the nanofiber matrix should be porous, homogeneous, and preferably bead-free. It has a fiber morphology; the fiber diameter of the nanofibers is less than 1 micron. The formulation in question... When applied to the buccal mucosa, it forms a physical protective layer over the ulcerated area. 5 The formulation provides controlled release of hydrocortisone in a pH 6.8 simulated saliva environment. PVP and In formulations containing Eudragit, the in vitro release of hydrocortisone in the first hour is in the range of 35-55%, and in the first 8 hours... The cumulative in vitro release per hour is at least 60%. The developed formulation is in the form of a single-layer or multi-layer buccal patch and is ex vivo. Mucoadhesion is at least 0.10 mJ / cm². 10 The formulation also includes plasticizer, pH regulator, stabilizer, penetration regulator, sweetener, pharmaceuticals selected from coloring agents, preservatives, buffering agents, or combinations thereof. It may contain at least one excipient that can be considered acceptable. Production Method The formulation that is the subject of the invention is preferably produced using the following process steps: 15 a) Hydrocortisone and the selected polymer or polymers in a homogeneous solvent system Dissolving or dispersing in such a way as to form a solution or dispersion; b) The prepared solution should be allowed to stand, if necessary, to remove air bubbles and / or subjected to ultrasonic bath treatment; c) Drawing the solution into a syringe and placing it in the electrocautery device; 20 d) By optimizing the parameters of solution flow rate, applied voltage and needle tip-collector distance. Deposition of nanofibers on an collector; e) Drying the collected nanofiber mat, cutting it into the desired geometric shape and size, and distributing it individually or in groups. packaging. In formulations containing PVP and Eudragit, the ratio of ethanol and N,N-dimethylformamide as the solvent system is 25. A 7:3 volume mixture is used as a solvent in formulations containing PVA and optional hyaluronic acid. The system preferably uses a water:ethanol mixture with a volume ratio of 1:1. Electrospinning can be performed with single-nozzle or multi-nozzle systems. Solution flow rate preferably 0.5-6 ml / hour, applied voltage preferably 5-20 kV and needle tip-collector distance preferably 10- The range is cm. However, the parameters in question depend on the polymer system used, the solution is 30 formulation according to viscosity, conductivity, surface tension and morphological properties of the target fiber It is customizable. A flat and stable aluminum foil-covered surface can be used as a collector. Alternatively, a drum can be used. Fiber orientation is achieved using rotary cylinders, moving belts, or patterned collector surfaces, mats. Thickness, mechanical properties, and surface properties can be controlled. 35 Examples The following example applications are provided to help explain the subject matter of the invention. The examples are not of a nature that would limit the scope of protection. Example 1: Eudragit / PVP-based mucoadhesive nanofiber formulations 5 In Eudragit / PVP-based applications, different Eudragit derivatives and PVP combinations are used with ethanol:DMF. (7:3) solvent system was used. In preliminary studies, Eudragit E100, Eudragit L100-55 and Eudragit S100 has been evaluated at different concentrations; its mechanical suitability for buccal application and Samples exhibiting mucoadhesive properties were loaded with hydrocortisone. Code HC (% w / v) Eudragit E100 (% w / v) Eudragit L100- 55 (% w / v) Eudragit S100 (% w / v) PVP (% w / v) E2-HC 1 30 - - 10 L2-HC 1 - 10 - 5 S2-HC 1 - - 10 5 In the E2-HC sample, fiber formation was achieved with a combination of Eudragit E100 and PVP; in the L2-HC sample... Mechanical flexibility and a balanced release profile were achieved with the Eudragit L100-55 based system; S2-HC In this example, the Eudragit S100-based structure aims to achieve mucoadhesive properties and controlled release. Code Flow rate (ml / hour) Voltage (kV) Distance (mm) E2-HC 1.5 14.5 145 L2-HC 1.75 14.3 122 S2-HC 1 14.5 122 Example 2: PVA and PVA / hyaluronic acid-based mucoadhesive nanofiber formulations In PVA-based applications, polymer solutions are prepared in a distilled water:ethanol (1:1) solvent system. It has been prepared. PVA has been used alone or in combination with hyaluronic acid; also, PVA / PVP has been used. Combinations were also evaluated. Examples containing hydrocortisone are listed below: 20 It has been prepared. Code HC (% w / v) PVA (% w / v) PVP (% w / v) HA (% w / v) P1-HC 1 10 - - PH1-HC 1 10 - 1 PH2-HC 1 5 - 1 Code Flow rate (ml / hour) Voltage (kV) Distance (mm) P1-HC 2 14 150 PH1-HC 2 17 150 PH2-HC 1 17.5 150 6 Example 3: Characterization and performance DSC, FTIR, XRD, SEM, and mechanical imaging were used to characterize the obtained nanofiber formulations. tests, contact angle measurements, ex vivo mucoadhesion studies, and in vitro release studies This has been applied. In Eudragit / PVP-based samples, hydrocortisone is found in nanofibers within a thermal environment. Confirmed by analyses; mechanical and wettability studies show physical suitability for buccal application. 5 It has pointed out the characteristics. Formulation Mucoadhesion (mJ / cm²) HC in the 1st hour release (%) It should pile up at the 8th hour. HC release (%) Technical evaluation E2-HC 0.20±0.05 40.26±19.56 67.71±17.89 Trend towards more prolonged release L2-HC 0.12±0.03 47.87±4.61 91.31±1.39 Mechanical strength and release balanced profile S2-HC 0.14±0.01 47.03±11.08 94.49±3.84 Appropriate mucoadhesive behavior and controlled release In PVA-based samples, P1-HC, PH1-HC, and PH2-HC formulations are suitable for buccal application. They exhibited flexibility and mucoadhesion behavior. In these samples, mucoadhesion was 0.23±0.01, respectively. The values were determined as mJ / cm², 0.14±0.01 mJ / cm² and 0.20±0.02 mJ / cm². PVA and PVA / hyaluronic acid 10 Essential systems, especially those with hydrophilic characteristics and containing hyaluronic acid, are suitable for wound care. It is advantageous because of its potential to support recovery. Advantages and Technical Implications of the Invention • Provides an extended residence time in the buccal mucosa. Enables local and controlled release of hydrocortisone. By providing this, it reduces the frequency of application. 15 • By forming a protective barrier over the ulcerated area, it prevents a direct connection between the oral environment and the ulcerated area. Reduces contact. Adhesion and controlled contact in oral conditions with mucoadhesive polymer combinations. It provides both emission features. • Nano-sized fiber structure, high surface area, and hydrocortisone dispersed / amorphous within the fiber matrix. Its presence in this form supports the local release of low-soluble hydrocortisone. 20 • Suitable for single-step, repeatable, and scalable production using the electrospinning method. Industrial Applicability The invention relates to a mucoadhesive buccal nanofiber formulation, pharmaceutical manufacturing techniques, and electrospinning. It has the potential to be scaled up from the laboratory scale to larger scales using this technology. The formulation was industrially developed as a buccal patch suitable for local application in the treatment of oral ulcers in 25 It is feasible. Explanation of the figures In vitro release studies conducted in Franz diffusion cells: Figure 1. Active ingredient release profile of Eudragit-based E2-HK nanofiber formulation (n=3, Mean±SD) Figure 2. Active ingredient release profile of Eudragit-based L2-HK nanofiber formulation (n=3, Mean±SD) 30
Claims
7 REQUESTS 1. Hydrocortisone-containing, electrocautery-produced for use in the treatment of oral ulcers. It is a mucoadhesive buccal nanofiber formulation; its characteristic is that the said formulation (i) hydrocortisone or a pharmaceutically acceptable derivative of hydrocortisone, (ii) in combination with PVP 5 A methacrylic acid-based product of choice from Eudragit E100, Eudragit L100-55, or Eudragit S100. a mucoadhesive polymer phase containing a polymer or PVA and optionally hyaluronic acid, and (iii) a porous nanofiber that can adhere to the buccal mucosa and form a protective barrier in the ulcerated area This includes a nanofiber matrix; and hydrocortisone is found dispersed within this nanofiber matrix.
2. According to claim 1, the formulation is a mucoadhesive buccal nanofiber; the amount of hydrocortisone in the formulation is 10. Based on the solution, 0.1-5% (w / v), preferably 0.5-2% (w / v), even more preferably approximately 1% (w / v) It is within the range.
3. A mucoadhesive buccal nanofiber formulation according to claim 1 or 2; the said mucoadhesive The polymer phase contains PVP and Eudragit E100.
4. Mucoadhesive buccal nanofiber formulation according to claim 3; Eudragit E100 content 20-40% 15 (w / v), PVP content is in the range of 5-20% (w / v), preferably the formulation is 1% (w / v) hydrocortisone, 30% Contains (w / v) Eudragit E100 and 10% (w / v) PVP.
5. A mucoadhesive buccal nanofiber formulation according to claim 1 or 2; the said mucoadhesive The polymer phase contains PVP and Eudragit L100-55.
6. According to claim 5, the mucoadhesive buccal nanofiber formulation is Eudragit L100-55 in an amount of 7.5-15%. (w / v), PVP content is in the range of 5-10% (w / v), preferably the formulation is 1% (w / v) hydrocortisone, 10% Contains (w / v) Eudragit L100-55 and 5% (w / v) PVP.
7. A mucoadhesive buccal nanofiber formulation according to claim 1 or 2; the said mucoadhesive The polymer phase contains PVP and Eudragit S100.
8. Mucoadhesive buccal nanofiber formulation according to claim 7; Eudragit S100 content 7.5-15% 25 (w / v), PVP content is in the range of 5-10% (w / v), preferably the formulation is 1% (w / v) hydrocortisone, 10% Contains (w / v) Eudragit S100 and 5% (w / v) PVP.
9. A mucoadhesive buccal nanofiber formulation according to claim 1 or 2; the said mucoadhesive The polymer phase contains PVA.
10. Mucoadhesive buccal nanofiber formulation according to claim 9; PVA content 5-10% (w / v) 30 It is within the range.
11. A mucoadhesive buccal nanofiber formulation according to claim 9 or 10; the said formulation It also contains hyaluronic acid. 8 12. Mucoadhesive buccal nanofiber formulation according to claim 11; hyaluronic acid content 0.1-2%. (w / v), preferably in the range of approximately 1% (w / v).
13. A mucoadhesive buccal nanofiber formulation according to any of claims 1-12; the nanofibers The fiber diameter is less than 1 micron.
14. A mucoadhesive buccal nanofiber formulation according to any of claims 1-13; the aforementioned 5 The nanofiber matrix has a porous, homogeneous, and preferably bead-free fiber structure.
15. A mucoadhesive buccal nanofiber formulation according to any of claims 1-14; When the formulation is applied to the buccal mucosa, it forms a physical protective layer over the ulcerated area. It creates.
16. A mucoadhesive buccal nanofiber formulation according to any of claims 1-15; the aforementioned 10 The formulation provides controlled release of hydrocortisone in a pH 6.8 simulated saliva environment.
17. A mucoadhesive buccal nanofiber formulation according to claim 16; containing PVP and Eudragit. In this formulation, the in vitro release of hydrocortisone in the first hour is in the range of 35-55%.
18. A mucoadhesive buccal nanofiber formulation according to claim 16 or 17; containing PVP and Eudragit. The cumulative in vitro release of hydrocortisone in the first 8 hours in this formulation is at least 60%. 15 19. A mucoadhesive buccal nanofiber formulation according to any of claims 1-18; The ex vivo mucoadhesion effect of the formulation is at least 0.10 mJ / cm².
20. A mucoadhesive buccal nanofiber formulation according to any of claims 1-19; The formulation is in the form of a single-layer or multi-layer buccal patch.
21. A mucoadhesive buccal nanofiber formulation according to any of claims 1-20; formulation 20 Also used as a plasticizer, pH regulator, stabilizer, penetration regulator, sweetener, and coloring agent. pharmaceutically accepted preservatives, buffering agents, or combinations thereof. It contains at least one excipient.
22. Method for fabricating mucoadhesive buccal nanofiber formulations according to any of claims 1-21. and the method is (a) hydrocortisone or a pharmaceutically acceptable derivative of hydrocortisone 25 By dissolving or dispersing the mucoadhesive polymer phase in a suitable solvent system, a homogeneous mixture is obtained. (b) preparing the polymer solution or dispersion, electrospinning the said solution or dispersion. (c) forming a nanofiber mat on a collector by subjecting it to the process, drying the resulting nanofiber mat and (d) includes steps to bring the nanofiber mat to the appropriate size and geometry for buccal application.
23. Production method according to claim 22; solvent system 30 in formulations containing PVP and Eudragit. It is a mixture of ethanol and N,N-dimethylformamide, preferably with a volume ratio of 7:
3.
24. Production method according to claim 22; containing PVA and optional hyaluronic acid. In formulations, the solvent system is a water:ethanol mixture with a 1:1 ratio.
25. For the local treatment of aphthous ulcers, aphthous stomatitis, or inflammatory mucosal lesions of the oral cavity. Mucoadhesive buccal nanofiber formulation for use according to any of Claims 1-21. 35