Method for producing novel nanofiber medical textile material with transdermal drug release properties

Abstract

The present invention relates to the production of a medical textile material having a nanofiber surface with transdermal drug release properties and coated with an azithromycin active substance by using a needle-type electrospinning method and an ultrasonic spray pyrolysis (USP) technique. A nanofiber medical textile material production method is disclosed, which comprises the steps of: preparing a polymer solution containing PVP (polyvinylpyrrolidone) at a concentration of 12 wt% and GEL (gelatin) at a concentration of 0.72 wt%; determining solution properties such as conductivity, viscosity and surface tension, producing nanofibers from the prepared polymer solution under optimum process parameters by means of an atmosphere-controlled horizontal needle-type fiber spinning (electrospinning) device, obtaining PVP / GEL nanofibers after the fiber spinning process, coating the obtained nanofibers (PVP / GEL nanofibers) with a drug active substance as a thin film by means of the USP (ultrasonic spray pyrolysis) method, and crosslinking the two polymers in two steps in order to facilitate the final application process of the drug release material, which can provide fast and slow release and maintain its stability in an aqueous environment by forming a sandwich structure.

Description

TECHNICAL FIELD

[0001] The present invention relates to the production of medical textile materials with nanofiber surfaces having transdermal drug release properties using needle-type electrospinning method and ultrasonic spray pyrolysis (USP) technique.

[0002] The present invention more particularly relates to a method for the manufacture of a medical textile capable of transdermal drug release, said method comprising obtaining a nanofiber structure by using polyvinylpyrrolidone (PVP) and gelatin (GEL) polymer combination needle-type electrospinning method, process of adding AZI (azithromycin) active substance with drug load to the nanofiber by ultrasonic spray pyrolysis (USP) method. BACKGROUND

[0003] Today, some inconveniences are encountered in the systemic administration of the drugs used. Especially for antibiotics, high oral doses are required and resistance can develop against various bacteria. Over time, due to this high dose, the resistance of bacteria to antibiotics makes treatment impossible.

[0004] With transdermal administration, this situation is eliminated and the patient can be given as much dose as he needs without the need for high doses. In the evaluation of the prior art, transdermal drugs used commercially such as Durogesic, Exelon and Nicotinell are encountered.

[0005] Transdermal therapeutic systems or transdermal patches deliver drugs to the body through the skin by absorption. One of the advantages thereof is the immediate visual confirmation of the administration when the patch is applied to the skin. In addition, the formulation is designed to be able to control the drug absorption rate, which helps to maintain the drug blood concentration over a longer period of time.

[0006] With controlled release drug delivery systems, the plasma level of the drug can be kept constant for the desired time. Thus, the patient avoids taking the drug too frequently and treatment can be provided at very low doses. Since treatment can be provided in this way at low doses, its side effects and toxic effects are reduced or completely eliminated. With these systems, the frequency of taking the medication by the patient is reduced, the risk of forgetting to take the medication is eliminated, and the medication at night is eliminated. This is an important parameter especially for psychiatric patients, children and the elderly. In this case, the quality of life of the patient improves and patient care becomes easier.

[0007] In the prior art, different methods are used in the production of transdermal drug delivery systems. The present invention relates to the production of nanofiber-containing medical textile materials with transdermal drug release properties by using electrospinning method and ultrasonic spray pyrolysis (USP) method, and aims to provide an alternative solution to the problem encountered in the prior art.

[0008] In the state of the art, there are many studies in the literature about the production of nanofiber by electrospinning method. However, the difference in process steps in the electrospinning method in this method and the combination of polyvinylpyrrolidone (PVP) and gelatin (GEL) polymers are both new features of the invention. In addition, drug loading on the nanofiber and the addition of AZI active substance are not found by USP method.

[0009] For example, in the state of the art, the publication given in the title of "Nano Fiber Production by Roller Electro Spinning Method" at https: / / www.researchgate.net / publication / 259479847_Silindirli_Elektro_Lif_Cekim_Yontemi_ile_Nano_Lif_Uretimi" is given. However, in the invention, which is the subject of this patent application, horizontal electrospinning method technology is utilized. In roller electrospinning method, a roller rotating at a certain speed is used as a fiber spinning device. In the production method, which is the subject of this application, a single nozzle is used and the Taylor cone, which has an important role in fiber drawing, is one. In the roller electrospinning method, dozens of Taylor cones are formed simultaneously along the roller. In addition, a voltage higher than 80 kV is used in the roller electrospinning method, but a voltage of 25-30 kV is sufficient in needle electrospinning. As explained, the working principles of these two technologies are also completely different from each other.

[0010] The invention relates to the production of a medical textile having a nanofiber surface by using electrospinning method. By this method, nanofiber production can be made with many known polymer raw materials. The USP (ultrasonic spray pyrolysis) method, which is another technology used in the invention, is widely present in the literature related to thin film coating of inorganic materials on non-porous surfaces such as glass, metal and thin film. However, with the help of the invention, unlike the literature, the drug active substance is coated on the nanofiber surface having high porosity in thin film layer by ultrasonic spray pyrolysis (USP) method. In the invention, a new type of medical textile is produced for the first time in terms of both technology (process steps of the production method and coating of active drug substance as a thin film layer) and the use of azithromycin drug active substance.

[0011] In addition, the inventor, after conducting research, surprisingly obtained superior characterization properties of the nanofiber medical fabric material with transdermal drug release produced by the new method he / she developed. Detailed characterization studies of the nanofiber surface have also been completed and are given within the scope of the specification. SUMMARY

[0012] The purpose of the present invention is to develop a nanofiber structure having a high specific surface area (m 2 / g) and a drug-loaded extremely fine fiber diameter, and having a high loading capacity, a high porosity, and an open pore structure. A product having superior properties has been developed compared to a thin film structure. The average specific surface area of a conventional fiber is 0.2 m 2 / g, while the average specific surface area of a nanofiber is 200 m 2 / g. While the linear density of a conventional fiber is on average 1-30 dtex, the linear density of a nanofiber is about 0.0001 dtex. The diameter of a conventional fiber is about 10-40 μm, but the average fiber diameter of a nanofiber is about 0.2 μm.

[0013] Another feature of the present invention is that, since the produced nanofiber biomaterial has a transdermal drug delivery property, other advantages of a drug compared to a systemic drug form (use of a low dose, ease of patient care, etc.) are also utilized.

[0014] In the present invention, a nanofiber medical textile surface having an azithromycin release characteristic was developed as a model drug. In the application of the present invention, film coating of a broad-spectrum lipophilic antibiotic on a nanofiber was performed in different sandwich structures, and then the release behavior of the drug from the surface was measured. In the production of a nanofiber, an optimization study was performed in terms of the properties of a polymer solution and process parameters. Then, a detailed characterization study of the model drug coated nanofiber surface was performed. According to the results of the study, it can be concluded that the nanofiber material has an industrial level of production, and has important application potential in biomedical applications.

[0015] An important advantage of the present invention is that it has been clearly seen that no adverse reactions occur during the application of the production method of the present invention, and that the material components (polymer, active substance, etc.) do not interact with each other. In other words, the drug coating process on a nanofiber has been successfully and safely performed by this production method (coating with USP).

[0016] Another advantage of the present invention is that both an immediate release drug release system and a controlled release drug release system can be prepared using this method.

[0017] In addition, while the transdermal products used commercially (Duro-tak 100 meg / hour, Duro-tak 75 meg / hour, Duro-tak 50 meg / hour, Duro-tak 25 meg / hour, Exelon 13.3 mg / 24 hours, Exelon 9.5 mg / 24 hours, Nicotinell 14 mg / 24 hours, 7 mg / 24 hours, etc.) are of a film structure, the material of the present invention is composed of fibers with high porosity and very small fiber diameter.

[0018] The present invention is essentially a production method of a PVP / GEL-based drug-loaded nanofiber medical textile surface that can provide transdermal drug delivery in a burst or controlled release manner, and the production method comprises the following process steps;

[0019] a) preparing a polymer solution containing PVP (polyvinylpyrrolidone) at a concentration of 12 wt% and GEL (gelatin) at a concentration of 0.72 wt%,

[0020] b) producing nanofibers from the prepared polymer solution with an atmosphere-controlled horizontal needle electrospinning device,

[0021] c) performing a crosslinking process in two steps to maintain the stability of the produced material in an aqueous environment, since both polymers are water-soluble,

[0022] d) obtaining PVP / GEL nanofibers,

[0023] e) coating a model drug as a film onto the PVP / GEL nanofibers by using the USP (ultrasonic spray pyrolysis) method. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 : SEM images of AZI-coated PVP / GEL nanofibers with sample code USP 0.1 (x5000 and x20000)

[0025] Figure 2 : SEM images of AZI-coated PVP / GEL nanofibers with sample code USP 0.3 (x5000 and x20000)

[0026] Figure 3 : SEM images of AZI-coated PVP / GEL nanofibers with sample code USP 0.5 (x5000 and x20000)

[0027] Figure 4 : SEM images of AZI-coated PVP / GEL nanofibers with sample code USP 0.7 (x5000 and x20000)

[0028] Figure 5: SEM image of AZI coated PVP / GEL nanofibers (x5000 and x20000) at sample code USP 0.9

[0029] Figure 6 : SEM image of USP O (without drug active (AZI)) nanofibers (x5000 and x20000)

[0030] Figure 7 : Histogram of PVP / GEL (USP O) nanofibers

[0031] Figure 8 : FT-IR spectra of AZI, PVP, GEL and nanofibers

[0032] Figure 9 : TGA curves of powdered AZI, PVP and GEL

[0033] Figure 10 : TGA curves of PVP / GEL based nanofibers coated with AZI at different concentrations by USP method

[0034] Figure 11 : DSC curves of powdered AZI, PVP and GEL

[0035] Figure 12 : DSC curves of PVP / GEL based nanofibers coated with AZI at different concentrations by USP method

[0036] Figure 13 : XRD diffractograms of pure AZI, PVP, GEL and PVP / GEL nanofibers coated with AZI at different concentrations

[0037] Figure 14 : Cumulative release profile of PVP / GEL nanofibers coated with AZI at different concentrations

[0038] Figure 15-A : Cross-sectional SEM image (x500) of nanomesh structure in sandwich structure

[0039] Figure 15-B : Surface SEM image (x500) of nanomesh structure in sandwich structure

[0040] Figure 16 : Cumulative drug release profile of sandwich structure

[0041] Figure 17 : Post-release SEM image of AZI coated nanofiber surface at sample code USP 0.1 (x10000)

[0042] Figure 18: Post-release SEM image of the surface of the nanofiber coated with AZI for sample code USP 0.3 (x 10,000)

[0043] Figure 19 : Post-release SEM image of the surface of the nanofiber coated with AZI for sample code USP 0.5 (x 10,000)

[0044] Figure 20 : Post-release SEM image of the surface of the nanofiber coated with AZI for sample code USP 0.7 (x 10,000)

[0045] Figure 21 : Post-release SEM image of the surface of the nanofiber coated with AZI for sample code USP 0.9 (x 10,000)

[0046] Figure 22 : SEM image of the sandwich structure after release study for sample USP 0.7-5 (x 5,000)

[0047] Figure 23 : SEM image of the sandwich structure after release study for sample USP 0.7-15 (x 5,000)

[0048] Figure 24 : SEM image of the sandwich structure after release study for sample USP 0.7-30 (x 5,000)

[0049] Figure 25 : SEM image of the sandwich structure after release study for sample USP 0.7-45 (x 5,000)

[0050] Figure 26 : SEM image of the sandwich structure after release study for sample USP 0.7-60 (x 5,000) DETAILED DESCRIPTION

[0051] In the research of the present invention, the surface of nanofiber-based medical textile with transdermal drug release properties was developed. Considering the 'green electrospinning' approach, polyvinylpyrrolidone (PVP) and gelatin polymer were used as raw materials and, due to the production of medical surfaces, ultrapure water and acetic acid were used as solvents. For this purpose, the drug release behavior of nanofibers was investigated by selecting the ultrasonic spray pyrolysis (USP) method for coating the lipophilic antibiotic (azithromycin) as a model drug on the surface of nanofibers. First, the polymer solution concentration optimization (polymer concentration, drug concentration, etc.) was performed, and then the solution properties such as the conductivity, surface tension and viscosity of the polymer solution were analyzed. In the production of drug-loaded nanofibers, the electrospinning method was used to complete the optimization studies (such as voltage, distance between electrodes, solution feed rate and humidity), and nanofibers with the best properties were produced under the best process. Then, another method - ultrasonic spray pyrolysis method was used to perform optimization studies (under conditions such as temperature, nozzle frequency and distance), and PVP / GEL-based nanofibers were coated with AZI on their surfaces. After the completion of the material production, the characterization studies of drug-loaded nanofibers were performed by SEM, FTIR, XRD, DSC, TGA, etc. Finally, the drug release behavior of the developed AZI-loaded nanofibers was analyzed by crosslinking them, and their release profiles were compared.

[0052] In the production method that is the subject of the present invention; the aim is to prepare drug-loaded PVP / GEL-based nanofiber medical textile surfaces with the best properties, to determine their drug release performance, and to investigate their usability in transdermal drug delivery. For this purpose, first, the polymer solution was prepared. As a result of the optimization studies within the scope of the research, a polymer solution with a PVP concentration of 12 wt% and a GEL concentration of 0.72 wt% was prepared. Then, the solution properties such as conductivity, viscosity and surface tension were measured. After characterizing the polymer solution properties, nanofiber production was performed using an atmosphere-controlled horizontal needle-type electrospinning device. Matsusada Precision Inc. (Nagutsu, Japan) was used as the power supplier and New Era Pump Systems (Farmingdale, New York, USA) was used as the solution feed pump in the device.

[0053] During the fiber spinning, all the solutions were produced under the same process parameters at the same time. The produced nanofibers were collected on aluminum foil. The best process parameters applied during the fiber spinning are given in Table 1.

[0054] Table 1: Electrospinning process parameters

[0055]

[0056] The production method of PVP / GEL based drug-loaded nanofiber medical textile surfaces that can be provided for transdermal administration in a burst or controlled release manner, which is the subject of the present invention, basically comprises the following process steps;

[0057] a) Preparation of a polymer solution containing PVP (Polyvinylpyrrolidone) at a concentration of 12 wt% and GEL (Gelatin) at a concentration of 0.72 wt%,

[0058] b) Production of nanofibers from the prepared polymer solution with an atmosphere-controlled horizontal needle type fiber spinning (electrospinning) device,

[0059] c) Crosslinking treatment is performed in two steps to maintain the stability of the produced material in aqueous environments, since both polymers are water-soluble,

[0060] d) PVP / GEL nanofibers are obtained,

[0061] e) The active pharmaceutical substance is coated as a thin film on the obtained PVP / GEL nanofibers by the USP (Ultrasonic Spray Pyrolysis) method.

[0062] Two-step crosslinking treatment is performed on the nanofiber surface obtained after the electrospinning process. Crosslinking treatment is performed to maintain the stability of the nanomesh in aqueous environments and to increase its stability. In this study, these polymers are crosslinked in two steps, since both polymers (PVP and GEL) used are water-soluble. The first step of the crosslinking treatment is the crosslinking of the PVP polymer. The PVP polymer is thermally crosslinked. As a result of the optimization studies performed for the above-mentioned purposes, the optimum temperature is determined as 180°C and the optimum time is determined as 4 hours. In the second step, the GEL polymer is crosslinked. The GEL polymer is chemically crosslinked for this purpose, for which glutaraldehyde crosslinking agent is used. After the optimization studies, it is determined that the nanomesh is crosslinked in glutaraldehyde vapor for 24 hours at room temperature. When the literature is analyzed, no studies are found that crosslink by using these two polymers together.

[0063] After crosslinking, the nanomesh is coated with the drug using the USP technique. The coating process details are as follows:

[0064] The most important process step of the method of the present invention is the thin film coating of the AZI active substance on the PVP / GEL nanofiber by using the USP method. This process is carried out in the Energy Technology Laboratory of the Suleyman Demirel University Innovation Technology Application and Research Center with the Sono-Tek brand FlexiCoat model USP device.

[0065] AZI was first dissolved in chloroform for use in the USP method. During this process, n-hexane was used as an anti-solvent to prevent the chloroform from dissolving the nanofiber surface and causing damage to it. The ratio of chloroform / n-hexane in the solution was kept constant at 1 / 5, and the AZI concentration was adjusted to 0.3 mg / mL. Then, optimization studies were performed on the USP to determine process parameters such as substrate temperature, solution flow rate, forming gas pressure, nozzle frequency, and distance. As a result of the optimization studies, the process parameters are given in Table 2.

[0066] Table 2: Process parameters of the USP method

[0067]

[0068] In the next step, the thin film coating process was performed on the PVP / GEL (USP0) nanofiber with the appropriate amount of AZI / chloroform / n-hexane solution. In Table 3, the codes of the samples produced by this method and the amount of AZI / chloroform / n-hexane solution are given. In the studies that are the subject of the present invention, the amount of coated AZI / chloroform / n-hexane solution was between 942 and 8460 μL.

[0069] Table 3: Sample codes and solution amounts used in the USP method

[0070]

[0071] After the production of the drug-loaded nanofiber surface, detailed characterization studies were performed.

[0072] In Figures 1-2 In 3-4-5, SEM images of PVP / GEL nanofibers coated with different ratios of AZI by the USP technique are provided. When the SEM images were analyzed, first of all, as the coating amount increased, the AZI drug active was clearly visible on the surface of the nanomesh. As expected, the deformation of the surface increased as the coating time increased. In general, the nanofibers had a fine and uniform structure. Figure 7 The histogram curve illustrating the fiber diameter distribution of the USP0 (PVP / GEL) nanofiber is given.

[0073] According to the Figure 7 The average fiber diameter was 196.44 nm, and the standard deviation was 36.15 nm. The fiber diameter uniformity coefficient was 1.0335, the fiber diameter distribution was uniform, and the normal distribution curve was unimodal. While the thinnest fiber in the nanomesh structure was 128 nm, the thickest fiber measured was 324 nm.

[0074] Figure 8 The FT-IR analysis performed on the coated nanofiber surface and the pure nanofiber surface is given in.

[0075] When the spectra are analyzed in detail; the spectral peak seen at a wavelength of 3434 cm -1 in the PVP spectrum is the O-H stretching peak of the hydroxyl group. The alcohol O-H stretching vibration seen at about 3600 cm -1 is masked by the broad O-H peak of water molecules absorbed onto the PVP polymer. When the spectra of the nanofibers coated by the USP technique are examined in detail, the O-H stretching peak of the hydroxyl group seen at a wavelength of 3434 cm -1 in the PVP spectrum is at 3446 cm -1 in the USP 0 sample, at 3446 cm -1 in the USP 0.1 sample, at 3446 cm -1 in the USP 0.3 sample, at 3446 cm -1 in the USP 0.5 sample, at 3447 cm -1 in the USP 0.7 sample, and at 3445 cm -1 in the USP 0.9 sample. The presence of the isomeric molecule and the carbonyl group in the pyrrolidone ring of the PVP is identified by the sharp spectral peak at 1654 cm -1 which is the signature of the C=O stretching. Here, the vibration frequency of the carbonyl stretching is very sensitive to the hydrogen bonding with water molecules. Thus, as the concentration of the absorbed water increases, this spectral peak can shift from 1680 cm -1 to 1652 cm -1 . The C-N stretching observed at a wavelength of 1499 cm -1 in the PVP spectrum is at a wavelength of 1494 cm -1 , 1495 cm -1 , 1494 cm -1 , 1495 cm -1 , 1495 cm -1 and 1495 cm -1 in the nanofiber samples of USP 0, USP 0.1, USP 0.3, USP 0.5, USP 0.7 and USP 0.9, respectively. In addition, the spectral peak appearing at a wavelength of 1460 cm -1 in the PVP spectrum can be attributed to the C-H distortion deformation of the CH2 group, and this spectral peak is detected at a wavelength of 1460 cm -1 and 1462 cm -1 in all nanofiber samples. Furthermore, in the spectra of all nanofiber samples, the CH2 fold is also seen at 1165 cm -1 , the C-C ring is seen at 837 cm -1 in the fingerprint region, and the C-C ring is seen at 583 cm -1The N-C=0 bending peak. Generally, the presence of heteroatoms and carbonyl in the pyrrolidone ring sufficiently reduces the symmetry. Therefore, in the IR spectra of both PVP and PVP-based nanofibers, most of the vibrational modes exist with different intensities.

[0076] The characteristic amide-I (C=0 stretching), amide-II (N-H bending and C-H stretching) and amide-III (C-N stretching) peaks, which are clearly visible in the GEL spectrum at 1656 cm -1 , 1516 cm -1 and 1232 cm -1 wavelength, respectively, are missing their intensities in the spectra of nanofibers around these wavelengths. It is believed that the reason for missing their intensities is due to the use of low concentration during the production of nanofibers. In addition, a weak peak is observed in the GEL spectrum at a wavelength of 720 cm -1 . This can be attributed to -CH2- rocking vibrations seen in samples having 4 or more consecutive CH2groups, as in the amino acid lysine, which is an important component of gelatin.

[0077] The OH stretching peaks seen in the AZI spectrum at 3495 cm -1 and 3562 cm -1 wavelength are attributed to water molecules tightly bound in the AZI lattice. In addition, other researchers have shown that the doublet seen around 3500 cm -1 near wavelength in the nanofiber spectra can be explained by the transformation of AZI from crystalline to amorphous morphology. In the DSC and XRD analyses carried out within the scope of the study, it has been determined that AZI is transformed from crystalline to amorphous morphology. In addition, in the AZI spectrum, the group peak of the OH group bending is also seen around 1458 cm -1 wavelength. The C-O ether stretching peak seen in the AZI spectrum at a wavelength of 1188 cm -1 increases from USP 0.1 to USP 0.9 in the nanofiber spectra (except for the USP 0 sample), and appears at wavelengths of 1169 cm -1 , 1170 cm -1 and 1171 cm -1 . In addition, the symmetrical aliphatic ether peak detected in the AZI spectrum at 1051 cm -1 is around 1078 cm -1 wavelength in the spectra of nanofibers, and not in cm -1The exception is the USP0 sample, which is near the cm⁻¹ wavelength. This is likely attributed to van der Waals forces formed between the AZI and the carrier, i.e., the polymer. Based on FT-IR spectroscopy, undesirable chemical interactions not typically observed between the drug and the polymer were identified, and the fundamental characteristic peaks of the AZI and the polymer were clearly seen in the nanofiber spectrum.

[0078] Thermodynamic analysis (TGA) was performed to determine the thermal stability of the model drug AZI, PVP, and GEL polymers used in the study, as well as the produced nanofibers. Figure 9 The images include TGA thermograms of AZI active pharmaceutical ingredients in powder form, as well as PVP and GEL polymers.

[0079] When detailed inspection Figure 9 At that time, AZI, PVP, and GEL could be clearly observed to exhibit step-by-step degradation. Due to the high hydrophilicity of the PVP and GEL polymers, at temperatures reaching 100°C, their weight losses were 11.40% and 11.52%, respectively, attributed to water molecules. The PVP polymer also showed significant degradation at 354.60°C (t0) and 478.10°C (t2). f The degradation occurred between 221.73 °C and 469.76 °C, leaving a 5.72% residue at 600 °C. Similarly, the GEL polymer degraded between 221.73 °C and 469.76 °C, with a weight loss of 63.14%, resulting in a sample mass of 25.34 wt% at the final temperature. Here, the GEL polymer rapidly achieved a 44.38 wt% loss at 352.10 °C, while the remaining 18.76 wt% loss continued slowly until 600 °C. The 5.17 wt% loss of AZI between 25 and 120 °C indicates the transition of AZI from its dihydrate form to its anhydrous AZI form. This observed 5.17 wt% loss corresponds to a stoichiometric loss of two water molecules.

[0080] The degradation temperature of AZI begins at 216.56℃, similar to that of GEL polymers, and continues to 472.30℃. Meanwhile, at the final temperature of 600℃, it loses 91.46% of its mass and leaves very little residue, such as 3.37% (Table 4).

[0081] Table 4: Thermal degradation temperature and residual amount of PVP, GEL and AZI

[0082]

[0083] Figure 10 The paper provides TGA thermograms of PVP / GEL nanofibers coated with AZI at different concentrations using USP technology.

[0084] according to Figure 10Due to the water molecules in its structure, weight loss was observed in all nanofiber samples between 25-100 °C. Generally, the temperature at which the nanofibers started to degrade was between 306.9 °C and 354.1 °C. Similarly, the temperatures at which the mass loss ended were very close to each other and all samples ended at around 469 °C. The amount of residue left by the samples varied between 0.010 mg and 0.383 mg. From the thermograms, it was observed that the degradation temperature of the nanofibers was higher than the degradation temperatures of AZI and the polymers (PVP and GEL). As shown by the FT-IR analysis, this situation can be attributed to the formation of some weak bonds (Van der Waals forces) between the polymer and the active substance. Thus, this indicates that the AZI active substance has been successfully added to the structure of the PVP / GEL nanofibers.

[0085] Finally, it can be said that the thermal stability of the AZI pharmaceutical active substance increased with the production of nanofibers, since the degradation temperature of PVP is about 158 °C higher than that of AZI, and the degradation temperature of the nanofibers is higher than that of PVP.

[0086] DSC thermograms show the change in heat flow within the sample as the temperature is raised. In addition, these thermograms indicate the degradation of the drug and polymer and the endotherm below 100 °C, i.e. dehydration. DSC and XRD analyses were performed to determine the physical state of the active substance AZI and the molecular composition in the fibers within the study range.

[0087] Figure 11 DSC thermograms of the common AZI, PVP and GEL powders are provided in Table 1.

[0088] PVP is an amorphous polymer and exhibits a considerable endotherm due to dehydration, extending from 29.73 °C to 137.57 °C, reaching its maximum at 78.90 °C. Due to the hygroscopic and amorphous nature of PVP, this observed peak is expected and is due to the water loss of the sample. As the material becomes amorphous, the peak indicating the melting point (t m ) can disappear. PVP polymers are known to be mainly amorphous. In addition, PVP polymers are polymers that can exist in glass or rubber form. Thus, the corresponding t m peak is quite small. As shown in the DSC thermogram of PVP, a small endotherm extending between 174.39-190.25 °C was observed, with a peak at 182.51 °C belonging to the t m point.

[0089] A very small endothermic transition, called softening temperature of GEL polymer, was detected in the thermogram of pure GEL in powder form at 49.10°C. Then, an endothermic peak was observed, which started at 111.58°C, reached a peak at 120.30°C and ended at 130.28°C. At this temperature, the triple helix structure of GEL melts and forms a randomly distributed structure. The obtained value of 17.68 J / g of transition enthalpy (ΔH) indicates the energy required to rearrange the hydrogen bonds, amide bonds and van der Waals interactions into a random conformation that helps to maintain the triple helix structure. This is common for solid GEL which always contains some water (usually 10-15%). In addition, a small endothermic peak appeared at about 213°C (called decomposition temperature of common GEL polymer powder) as known from the literature. This peak is in agreement with the TGA results.

[0090] In the DSC thermogram of AZI, a sharp endothermic peak was observed between 112.92-131.52°C corresponding to the melting point. As reported in the literature, this broad endothermic peak reached a peak at 125.74°C and the reason for the broadness of the peak is due to the separation of the crystalline water from its structure during melting. The melting temperature of this peak was determined to be 88.53 J / g. In the literature, different researchers reported that AZI samples showed variable thermal behavior with one or two DSC endotherms, while the USP reference standard indicated that it has a single DSC endotherm.

[0091] In Figure 12 , the DSC thermograms of PVP / GEL nanofibers coated with AZI at different rates using USP technique were provided.

[0092] When the DSC thermogram of the nanofiber was examined in detail, it can be clearly seen that AZI, which is the pharmaceutical active, does not show any melting peak. This indicates that AZI is no longer in the form of a crystalline material, but is transformed into an amorphous form. This indicates that AZI has good compatibility with the polymer solution, good dispersion occurs when the drug and polymer solution are mixed, and high quality fibers are produced at the end of the electrospinning process. The SEM images obtained confirm this conclusion.

[0093] The endothermic peaks of the nanofibers coated with thin films having different concentrations of AZI active vary between about 83°C and 96°C, while in the thermogram of PVP / GEL nanofibers containing no AZI, an endothermic peak is detected at around 62°C. It was thus determined that coating AZI on the surface of the nanofiber using USP technique causes an average 20-25°C shift in the endothermic of the nanofiber.

[0094] In Figure 13XRD patterns of pure AZI, PVP, GEL and PVP / GEL nanofibers coated with AZI at different concentrations using USP technique are provided.

[0095] According to Figure 13 In the XRD diffractogram of pure AZI dihydrate sample, due to its crystal structure, sharp peaks of different intensities appeared at 2 theta diffraction angles 8.16°, 9.50°, 10.09°, 11.41°, 12.19°, 13.24°, 15.19°, 16.59°, 17.68°, 18.91°, 19.99°, 21.10°, 24.19°, 26.30°, 28.42°, 30.53°. In addition, due to its crystal structure, AZI dihydrate has a complex XRD diffractogram with many diffraction peaks, while AZI monohydrate shows an amorphous structure. The diffractogram of PVP polymer reveals a highly amorphous structure, as expected and known from literature. In the spectrum, there are only two characteristic broad humps at 12.86° and 21.37° between the Bragg angles of 10° and 25°. These broad humps are attributed to the amorphous nature of the polymer, revealing that the molecular orientation of the polymer is irregular and complex. Similarly, in the X-ray spectrum of the common GEL polymer powder, there are typical GEL XRD structural patterns originating from the alpha-helix and triple helix structures at 14.36° and 20.45°.

[0096] Under X-ray diffraction of nanofibers, broad and diffuse hump peaks appeared in all samples. These hump peaks are attributed to the amorphous polymer in the nanofiber structure and appear at around 13° in all diffractograms of nanofibers. There are almost no characteristic peaks of AZI in the diffractogram of electrospun nanofibers. This clearly indicates that AZI is no longer in the form of a crystalline material, but has been completely converted into an amorphous form.

[0097] DSC and XRD data of USP coated nanofibers prove that the drug molecules are in an amorphous form in the PVP / GEL nanofiber matrix. The XRD, DSC results obtained in this research phase overlap with each other and with the previous studies involving electrospun nanofibers, and the SEM images taken for morphological observations.

[0098] From the graphs, the analysis results are given in detail above, first, the form, chemical and thermal properties of the material obtained by analysis were measured and analyzed in detail. As a result of these analyses, it can be clearly seen that no adverse reactions occurred during production and the material components (polymer, active substance, etc.) did not interact with each other. In other words, the drug coating process on the nanofiber was successfully performed by this production method (coating with USP). In addition, by this method, immediate release and long-term release drug release systems can be prepared. In addition, while the transdermal products used commercially (DuoDerm 100 mcg / hour, DuoDerm 75 mcg / hour, DuoDerm 50 mcg / hour, DuoDerm 25 mcg / hour, Estrasorb 13.3 mg / 24 hours, Estrasorb 9.5 mg / 24 hours, Nicotinell 14 mg / 24 hours, 7 mg / 24 hours, etc.) are in the form of a film, the material of the present application is composed of fibers having nanometer-sized pores and diameters. With the aid of this material, the superior properties of nanofibers such as high specific surface area (the average specific surface area of conventional fibers is 0.2 m 2 / g, while the average specific surface area of nanofibers is 20 m 2 / g), nanometer-sized fiber diameter (the diameter of conventional fibers is approximately 10-40 μm, while the average fiber diameter of nanofibers is approximately 0.2 μm), high porosity, adjustable pore size and open pore structure, high loading capacity, high linear density (the linear density of conventional fibers is on average 1-30 dtex, while the linear density of nanofibers is approximately 0.0001 dtex) are utilized.

[0099] In addition, the drug release behavior and performance of the medical textile material produced by the production method of the present application are supported by comparative data.

[0100] In Table 5, the diameter, weight, thickness information and loading effect values measured before the release study of the nanomesh coated with different amounts of AZI by the USP method are provided.

[0101] Table 5: Diameter, weight, thickness and loading effect values of the nanomesh coated with USP

[0102]

[0103] Figure 14 The cumulative release profile of the nanofiber surface coated with different amounts of AZI by the USP method is shown.

[0104] In the USP technique, model drug AZI was coated on the surface of nanofibers. Thus, when the drug-loaded nanofibers were brought to the dissolution medium, they diffused very fast and the loaded drug was released as expected suddenly. It was observed that the surface released very fast in general, but the AZI concentration had no effect on the release. All samples released all of the loaded AZI in the first 30 minutes. It can be clearly seen that the drug delivery system prepared by this method is also very suitable for drugs that require fast release.

[0105] Laminate structures were created to obtain systems that can release more slowly using the USP method. For this purpose, five different pure PVP / GEL nanofibers produced for 1 hour were coated with USP to contain 0.7% of AZI, which was best selected in the previous release studies. Then, PVP / GEL nanofiber production was performed on these coated surfaces for 5-60 minutes (5, 15, 30, 45 and 60 minutes were studied in the examples). The release profiles of these laminate structures were investigated. In Figures 15A-B, cross-sectional and surface SEM images of the laminate structure, each layer of which was produced for 60 minutes (USP0.7-60), are provided.

[0106] The diameters, thicknesses, weights and loading effect values of the laminate structures are given in Table 6.

[0107] Table 6. Diameters, weights, thicknesses and loading effect values of the laminate structures

[0108]

[0109] When the release profiles of the laminate structures were examined, Figure 16 it can be clearly shown that the nanofiber laminate structures have been successfully obtained. It is also revealed in the cross-sectional images that the very small amount of bead-like structures seen on the surface. In the surface images, it is again revealed that the nanofibers are very thin and smooth. In Figure 16 the release profiles of these laminate structures are provided.

[0110] When Table 6 and Figure 16 it can be seen that the release time is also prolonged as the thickness of the laminate structure formed increases. Since in these structures, the drug is only located in the middle layer. There is no drug on the surface and near the surface of the laminate structure. Thus, the drug molecules cannot diffuse to the dissolution medium quickly. It was determined that when the nanofibers were produced for a short time (such as 5 minutes) on the drug layer coated with USP, the release time increased from 30 minutes to 2 hours, while when produced for 1 hour, the release time was prolonged to 2 days. While the S0.7 sample, which did not form a laminate structure, released 80% of the loaded drug in the first 30 minutes, it released 22.15% when the laminate was formed for 5 minutes and only 9.38% when the laminate structure was formed for 60 minutes.

[0111] In the release studies with USP, with this method, it has been shown that it is possible to prepare a drug delivery system that can not only be used in situations where immediate release is required, but also to create a long-term release system by capturing the drug molecules in the middle of the sandwich structure. As a result of the release studies with this method, it has been seen that by using the same method, the same polymer concentration and the same amount of drug, it is possible to create a drug delivery system that can both release immediately and release slowly. Creating a system with the desired release characteristics with a single method gives an advantage to the method.

[0112] When the surfaces Figures 17-18 -19-20-21 were examined, it was seen that the fiber structure on the surface was highly deformed compared to the conventional electrospinning method. The reason for this is considered to be due to the coating process being carried out directly on the surface and the images being taken from these surfaces. However, it is noteworthy that as the coating amount increases, the surface tends to maintain its porous structure. Considering that there is a 9-fold difference between the lowest and highest concentrations and the release times are very close to each other, this situation is considered to occur due to the fact that there is not enough time for the pores coated with AZI to empty as the high concentration AZI molecules enter the dissolution medium during the uptake, and since the release time is also fast, there is not enough time for swelling.

[0113] In Figures 22-23 -24-25-26, post-release SEM images of the sandwich structure are provided. From the SEM images given, it can be observed that the pores in the sandwich structure are significantly smaller or have disappeared. It is concluded that the reason for such deformation of the nanofiber and porous structure is due to the considerable swelling of the fibers over the long release period.

Claims

1. A method for preparing PVP / GEL based drug loaded nanofibrous medical textile surface capable of providing transdermal drug delivery in either burst or controlled manner, characterized by comprising the following process steps: a) Preparation of a polymer solution containing PVP (Polyvinylpyrrolidone) at a concentration of 12 wt% and GEL (Gelatin) at a concentration of 0.72 wt%, b) Production of nanofibers from the prepared polymer solution with an atmosphere controlled electrospinning device, c) Crosslinking treatment in two steps to maintain the stability of the produced material in an aqueous environment, since both polymers are water-soluble, d) Obtaining PVP / GEL nanofibers, e) Coating of the obtained PVP / GEL nanofibers with a pharmaceutically active substance as a thin film by ultrasonic spray pyrolysis.

2. A process for the preparation of PVP / GEL based drug loaded nanofibrous medical textile surface for transdermal drug delivery in burst or controlled manner as claimed in claim 1, wherein comprising the following process steps: In step b) nanofibers are produced by the fiber spinning method at a voltage of 26.4 kV, a feed rate of 0.3 mL / h, a distance between the electrodes of 17.0 cm, a needle diameter of 0.8 mm, a humidity of 33 ± 2%, and a temperature of 23.5 ± 1 °C for 60 minutes.

3. A process for the preparation of PVP / GEL based drug loaded nanofibrous medical textile surface for transdermal drug delivery in burst or controlled manner as claimed in claim 1, wherein comprising the following process steps: In step e) the active substance is coated on the nanofibers at a substrate temperature of 100 °C, a flow rate of 1 mL / min, a nozzle frequency of 85 kHz, a distance between the nozzle and the substrate of 13 cm, and a forming nitrogen pressure of 1 kPA.

4. A process for the preparation of PVP / GEL based drug loaded nanofibrous medical textile surface for transdermal drug delivery in burst or controlled manner as claimed in claim 1, wherein The crosslinking step given in step c) comprises the following process steps: - The PVP polymer is first crosslinked at 180 °C for 4 hours, - The GEL polymer is then chemically crosslinked with glutaraldehyde crosslinking agent.

5. A process for the preparation of PVP / GEL based drug loaded nanofibrous medical textile surface for transdermal drug delivery in burst or controlled manner as claimed in claim 1, wherein comprising the following process steps in order to provide a slow release system for the ultrasonic spray pyrolysis in step e): - The pharmaceutically active substance of the drug is first dissolved in chloroform, - During the process, n-hexane is added as an anti-solvent to prevent the chloroform from dissolving the surface of the nanofibers, - The ratio of chloroform: n-hexane in the solution is adjusted to 1:5, - The concentration of the pharmaceutically active substance is adjusted to 0.3 mg / mL.

6. A method of preparing PVP / GEL based drug loaded nanofibrous medical textile surface for transdermal drug delivery in burst or controlled manner as claimed in claim 5, wherein the said method comprises of: The amount of the coated AZI / chloroform / n-hexane solution is between 942 and 8460 µL.

7. A method of preparing PVP / GEL based drug loaded nanofibrous medical textile surface for transdermal drug delivery in burst or controlled manner as claimed in claim 1 or 5 or 6, wherein the said method comprises of: The nanomesh coated with ultrasonic spray pyrolysis has a diameter of 51-52 mm, a thickness of the nanomesh of 332.3-374.3 µm, and a weight of the nanomesh between 45.2-43.5 mg.

8. A process for the preparation of PVP / GEL based drug loaded nanofibrous medical textile surface for transdermal drug delivery in burst or controlled manner as claimed in claim 2 or 3, wherein the process comprises of comprising the following process steps in order to provide a slow release system: - The PVP / GEL nanofibers produced for 1 hour (60 minutes) are coated with AZI at 0.7% by ultrasonic spray pyrolysis, and - A sandwich structure of PVP / GEL nanofibers is further produced on these coated surfaces for 5-60 minutes.

9. A method of preparing PVP / GEL based drug loaded nanofibrous medical textile surface for transdermal drug delivery in burst or controlled manner as claimed in claim 1 or 5 or 6, wherein the said method comprises of: The nanomesh coated with ultrasonic spray pyrolysis has a diameter of 51-52 mm, a thickness of the nanomesh of 311.2-719.8 µm, and a weight of the nanomesh between 45.2-43.5 mg.

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