EP4543421A1

EP4543421A1 - Rapidly dissolving and orodispersible nanofibers loaded with risperidone produced by electrospinning method

Info

Publication number: EP4543421A1
Application number: EP23827639.8A
Authority: EP
Inventors: Fusun Acarturk; Mehmet BIRER; Yasin TURANLI
Original assignee: Gazi Universitesi
Current assignee: Gazi Universitesi
Priority date: 2022-06-21
Filing date: 2023-06-20
Publication date: 2025-04-30

Abstract

Rapidly dissolving and orodispersible nanofibers loaded with risperidone are in the form of a film containing polyethylene oxide of different molecular weights and xylitol and/or vinylpyrrolidone-vinyl acetate copolymer as a dispersant. Since risperidone is prepared by dissolving in the polymer solution, it is homogeneously loaded in the nanofibers and this nanofiber film is orodispersible in less than 30 seconds when taken orally and all risperidone is released in less than 15 minutes.

Description

RAPIDLY DISSOLVING AND ORODISPERSIBLE NANOFIBERS LOADED WITH RISPERIDONE PRODUCED BY ELECTROSPINNING METHOD

Technical Field

The invention relates to rapidly dissolving and orodispersible risperidone-loaded nanofibers prepared by electrospinning technology.

State of the Art

Schizophrenia is clinically manifested by a cluster of findings and symptoms which include characteristic thought and perception disorders, motor anomalies, cognitive impairments, avolition, apathy, restricted emotional expression, and communication difficulties. Positive symptoms known as extremism or distortion in ordinary functions include delusions, hallucinations, speech impairments, and behavioral problems. Negative symptoms which are defined as a decrease or loss of normal functions manifest itself in the form of a reduction in emotional reactions, alogia, avolition, and social withdrawal.

Drug administration is a main element of treatment in schizophrenia and other psychotic disorders. It is reported that 50-60% of patients with schizophrenia deny that they have an illness. Two-thirds of the cases have to be re-hospitalized due to complete or partial non-compliance with treatment. Within 1 year after the first hospitalization, relapse is seen in 40% of the patients due to non-compliance with treatment. Treatment compliance problems increase hospital readmission, morbidity, and mortality. Hospital readmission leads to occupational and family problems, and in connection with these, the patient's quality of life decreases. In psychotic disorders, maintenance treatment to be arranged after the attack is known to reduce the risk of relapse. The compliance problem, which is usually more common during maintenance treatment, adversely affects the prognosis by causing exacerbations in the early period of the disease. However, non-compliance with treatment is an important problem that is frequently encountered in clinical practice and may require re-hospitalization. Treatment of schizophrenia is a process in which the patient has low compliance and rejection to use drugs is frequently encountered in patients. Risperidone is an antipsychotic agent used in the treatment of schizophrenia. Conventional film-coated tablets containing risperidone, rapidly dissolving and orodispersible tablets, solutions, and injectable preparations are available.

Description of the Drawings:

Fig. 1 . The results of the dispersion test of nanofiber formulations (s: seconds)

Fig. 2. In vitro release profiles of the formulations

Fig. 3. Conclusions on the mechanical strength of the formulations

Fig. 3a. Tensile Strength (MPa)

Fig. 3b. Elongation at Break (%)

Fig. 4. SEM images of the formulations

Fig. 5. Scheme of the electrospinning method

Description of the References

The reference numbers in Fig. 5 are described below.

1 . High Voltage Power Supply

2. Syringe Pump

3. Solvent Mixture: Ethanol 6.5 mL, Distilled water 3 mL, Acetic acid 0.5 mL

4. Risperidone, Polymer (PEO), Dispersant (Xylitol or Kollidon VA64)

5. Collector Turntable

6. Formulation Obtained in the form of Nanofiber

Description of the Invention

The invention is a risperidone-containing drug formulation that can be used in the treatment of schizophrenia to elimination positive and negative symptoms, especially in cases where it is difficult to achieve patient compliance. When preparing the formulations, they are designed to contain polyethylene oxide polymer which is biocompatible and not harmful to health, with xylitol or vinylpyrrolidone-vinyl acetate copolymer as dispersant and risperidone as an antipsychotic agent. Through the rapidly dissolving and orodispersible composition in the form of a nanofiber, the film is disintegrated in the salivary fluid in a short time and the transition to the stomach is provided when the patients placed the formulation into their mouths. Thus, it is ensured that the patient uses the drug. While using tablets, behaviors such as holding the drug in the mouth without swallowing it and then removing it at the first opportunity are frequently encountered in schizophrenia patients. The invention can prevent this drawback with its features, and it can help in the providing of patient compliance and treatment effectiveness in schizophrenia patients, especially in the first stages of treatment.

Electrospinning technology is used in the production of the formulation of the present invention. The formulation containing polyethylene oxide polymer as the polymer, vinylpyrrolidone-vinyl acetate copolymer 6:4 or xylitol as the dispersant, risperidone as the active ingredient to be loaded will increase patient compliance and treatment efficacy. It is possible to achieve high treatment efficacy and patient compliance with the oral film which is orodispersible in less than 30 seconds with the risperidone-loaded formulation of the present invention. Since risperidone is prepared by dissolving in polymer solution, it is homogeneously loaded in nanofibers.lt is orodispersible in less than 30 seconds and all risperidone is released in less than 15 minutes when this nanofiber film is taken orally.

The formulation of the present invention includes polyethylene oxide (PEO) with a molecular weight of 100000 to 600000 as a polymer. The amount of polyethylene oxide used in the formulation according to the molecular weight can be calculated by the formula (X (%w/v) = 15 * 100000/Mol weight) in percentage weight/volume. Polyethylene oxide polymer with a molecular weight of 100000, 200000, 300000, 400000, 500000, or 600000 g/mol can be used in the formulations of the present invention.

The formulation of the present invention contains xylitol or vinylpyrrolidone-vinyl acetate copolymer 6:4 (Kollidon VA64) as a dispersant. The vinylpyrrolidone-vinyl acetate copolymer contains 1 -vinyl-2-pyrrolidone and vinyl acetate in a 6:4 weight ratio. Copovidone is known as Copolyvidone, VP/VAc copolymer 60/40 Kollidon® VA 64 (BASF).

A mixture of 65:30:5 Ethanol :distilled water:acetic acid is used as a solvent.

In an embodiment, the nanofiber is obtained from a solution of 15% Polyethylene oxide (PEO, Molecular weight: 100000), 15% Xylitol, and 3% Risperidone in a ratio of 65:30:5 in Ethanol :Distilled water:Acetic acid by electrospinning method. In another embodiment, the nanofiber is obtained from a solution of 7.5% Polyethylene oxide (PEO, Molecular weight: 200000), 7.5% Xylitol, and 1.5% Risperidone in a ratio of 65:30:5 in EthanokDistilled water:Acetic acid by electrospinning method.

In another embodiment, the nanofiber is obtained from a solution of 2.5% Polyethylene oxide (PEO, Molecular weight: 600000), 2.5% Xylitol, and 0.5% Risperidone in a ratio of 65:30:5 in EthanokDistilled water:Acetic acid by electrospinning method.

In another embodiment, the nanofiber is obtained from a solution of 15% Polyethylene oxide (PEO, Molecular weight: 100000), 15% Kollidon VA 64, and 3% Risperidone in a ratio of 65:30:5 in EthanokDistilled water:Acetic acid by electrospinning method.

In another embodiment, the nanofiber is obtained from a solution of 7.5% Polyethylene oxide (PEO, Molecular weight: 200000), 7.5% Kollidon VA 64, and 1.5% Risperidone in a ratio of 65:30:5 in EthanokDistilled water:Acetic acid by electrospinning method.

In another embodiment, the nanofiber is obtained from a solution of 2.5% Polyethylene oxide (PEO, Molecular weight: 600000), 2.5% Kollidon VA 64, and 0.5% Risperidone in a ratio of 65:30:5 in EthanokDistilled water:Acetic acid by electrospinning method.

The invention has the potential to provide an alternative to the existing orodispersible risperidone-loaded tablets, which are costly and are not manufactured in our country and are not imported. The invention can replace high-cost products. It is clear that the developed formulation contributes to the economy with high added value.

Examples:

F1 FORMULATION

It is the nanofiber that is produced from the polymer solution prepared by dissolving 15% Polyethylene Oxide (PEO) (1500 mg) (Molecular weight: 100000), 15% Xylitol (1500 mg), and 3% Risperidone (300 mg) as an active ingredient in a 65:30:5 ratio in Ethanokdistilled water:acetic acid solvent mixture (Total 10 mL) by electrospinning method. F2 FORMULATION

It is the nanofiber that is produced from the polymer solution prepared by dissolving 7.5% Polyethylene Oxide (PEO) (750 mg) (Molecular weight: 200000), 7.5% Xylitol (750 mg) and 1.5% Risperidone (150 mg) as an active ingredient in a 65:30:5 ratio in Ethanokdistilled water:acetic acid solvent mixture (Total 10 mL) by electrospinning method.

F3 FORMULATION

It is the nanofiber that is produced from the polymer solution prepared by dissolving 2.5% Polyethylene Oxide (PEO) (250 mg) (Molecular weight: 600000), 2.5% Xylitol (250 mg) and 0.5% Risperidone (50 mg) as an active ingredient in a 65:30:5 ratio in Ethanokdistilled water:acetic acid solvent mixture (Total 10 mL) by electrospinning method.

F4 FORMULATION

It is the nanofiber that is produced from the polymer solution prepared by dissolving 15% Polyethylene Oxide (PEO) (1500 mg) (Molecular weight: 100000), 15% Kollidon VA 64 (1500 mg), and 3% Risperidone (300 mg) as an active ingredient in a 65:30:5 ratio in Ethanokdistilled water:acetic acid solvent mixture (Total 10 mL) by electrospinning method.

F5 FORMULATION

It is the nanofiber that is produced from the polymer solution prepared by dissolving 7.5% Polyethylene Oxide (PEO) (750 mg) (Molecular weight: 200000), 7.5% Kollidon VA 64 (750 mg), and 1.5% Risperidone (150 mg) as an active ingredient in a 65:30:5 ratio in Ethanokdistilled water:acetic acid solvent mixture (Total 10 mL) by electrospinning method.

F6 FORMULATION

It is the nanofiber that is produced from the polymer solution prepared by dissolving 2.5% Polyethylene Oxide (PEO) (250 mg) (Molecular weight: 600000), 2.5% Kollidon VA 64 (250 mg), and 0.5% Risperidone (50 mg) as an active ingredient in a 65:30:5 ratio in Ethanol :distilled water:acetic acid solvent mixture (Total 10 mL) by electrospinning method.

The following characterization studies have been conducted on the formulations:

1 ) CHARACTERIZATION STUDIES OF POLYMER SOLUTIONS

The prepared polymer solutions were evaluated by measuring viscosity, surface tension, and conductivity values (Table 1). According to the data, polymer solutions can have a conductivity of 200 to 400 pS/cm, viscosity of 400 to 1400 cPs, and surface tension of 25 to 33 mN/m.

Table 1 . The measurement results for conductivity, viscosity, and surface tension of the polymer solutions

2) AVERAGE FIBER DIAMETERS OF NANOFIBERS

The process parameters and average fiber diameters of nanofibers obtained by the electrospinning method are shown in Table 2. According to the data, the average fiber diameter can be from 400 to 1200 nm.

Table 2. Electrospinning method’s process parameters and average fiber diameters of nanofibers

3) DISPERSION TEST

11 mg samples of nanofiber formulations were prepared and dispersion tests were carried out in a simulated oral environment. The results for this test are shown in Fig. 1 . All of the tested formulations dispersed within 5 seconds.

The simulated oral environment is prepared by soaking the double-layer filter paper placed in the petri dish with 10 mL of simulated oral fluid or distilled water.

Simulated oral fluid content with pH 6.8 is as follows:

Na₂HPO₄. 1.19 g

KH₂PO₄. 0.095 g

NaCI . 4 g

Distilled water . Qs . 500 mL.

4) DIFFERENTIAL SCANNING CALORIMETRY (DSC) ANALYSES

It was carried out to examine whether there is an incompatibility between the excipients used in the formulation and the active ingredient and no incompatibility was detected.

5) FOURIER TRANSFORM INFRARED ANALYSIS (FT-IR)

FT-IR test of the active ingredient risperidone, excipients, and formulations was carried out and the results were found to be appropriate.

6) IN VITRO DISSOLUTION RATE STUDIES In vitro release studies of the formulations in the artificial gastric environment with pH 1 .2 were carried out.

The results of this study are shown in Fig. 2. 7) MECHANICAL STRENGTH TESTS OF NANOFIBER FORMULATIONS

Texture Analyzer device was used to investigate the mechanical strength of the nanofiber formulations (Fig. 3). 8) SCANNING ELECTRON MICROSCOPY (SEM) IMAGES OF THE NANOFIBERS

SEM images of the nanofibers are shown in Fig. 4.

Claims

CLAIMS An oral film formulation in the form of orodispersible nanofiber, wherein the formulation comprises:

• risperidone,

• polyethylene oxide polymer with a molecular weight of 100000 to 600000 g/mol, and

• a xylitol or vinylpyrrolidone-vinyl acetate copolymer. An oral film formulation in the form of orodispersible nanofiber according to Claim 1 , wherein the formulation comprises:

• risperidone,

• xylitol. An oral film formulation in the form of orodispersible nanofiber according to Claim 1 , wherein the formulation comprises:

• risperidone,

• a vinylpyrrolidone-vinyl acetate copolymer. An oral film formulation in the form of orodispersible nanofiber according to any one of the Claims 1 to 3, wherein the nanofiber is produced by the electrospinning method from a solution of

• 3% w/v risperidone,

• 15% w/v polyethylene oxide polymer with a molecular weight of 100000 g/mol, and

• 15% w/v xylitol in 65:30:5 v/v/v in Ethanol :Distilled water:Acetic acid. An oral film formulation in the form of orodispersible nanofiber according to any one of the Claims 1 to 3, wherein the nanofiber is produced by the electrospinning method from a solution of

• 1 .5% w/v risperidone,

• 7.5% w/v polyethylene oxide polymer with a molecular weight of 200000 g/mol, and

7.5% w/v xylitol in 65:30:5 v/v/v in Ethanol :Distilled water:Acetic acid. An oral film formulation in the form of orodispersible nanofiber according to any one of the Claims 1 to 3, wherein the nanofiber is produced by the electrospinning method from a solution of

• 0.5% w/v risperidone,

• 2.5% w/v polyethylene oxide polymer with a molecular weight of 600000 g/mol, and

• 2.5% w/v xylitol in 65:30:5 v/v/v in Ethanol :Distilled water:Acetic acid. An oral film formulation in the form of orodispersible nanofiber according to any one of the Claims 1 to 3, wherein the nanofiber is produced by the electrospinning method from a solution of

• 3% w/v risperidone,

• 15% w/v Kollidon VA 64 in 65:30:5 v/v/v in EthanokDistilled water:Acetic acid. An oral film formulation in the form of orodispersible nanofiber according to any one of the Claims 1 to 3, wherein the nanofiber is produced by the electrospinning method from a solution of

• 1 .5% w/v risperidone,

• 7.5% w/v Kollidon VA 64 in 65:30:5 v/v/v in EthanokDistilled water:Acetic acid. An oral film formulation in the form of orodispersible nanofiber according to any one of the Claims 1 to 3, wherein the nanofiber is produced by the electrospinning method from a solution of

• 0.5% w/v risperidone,

• 2.5% w/v Kollidon VA 64 in 65:30:5 v/v/v in EthanokDistilled water:Acetic acid. An oral film formulation in the form of orodispersible nanofiber according to any of the previous claims, wherein the formulation is dispersed within 30 seconds in the simulated oral environment. An oral film formulation in the form of orodispersible nanofiber according to any of the previous claims, wherein the formulation is prepared by an electrospinning method. A method for preparing the oral film formulation in the form of orodispersible nanofiber, wherein the method comprises the following steps:

• dissolving risperidone, polyethylene-oxide polymer with a molecular weight of 100000 to 600000 g/mol, and xylitol or vinylpyrrolidone-vinyl acetate copolymer 6:4 as a dispersant in a mixture of Ethanokdistilled water:acetic acid (65:30:5 v/v/v), and

• obtaining the nanofibers by the electrospinning method. An oral film formulation in the form of orodispersible nanofiber comprising risperidone, polyethylene oxide polymer, xylitol, and/or vinylpyrrolidone-vinyl acetate copolymer for use in the treatment of schizophrenia.