WO2023249595A1 - Rapidly dissolving and orodispersible nanofibers loaded with risperidone produced by electrospinning method - Google Patents
Rapidly dissolving and orodispersible nanofibers loaded with risperidone produced by electrospinning method Download PDFInfo
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- WO2023249595A1 WO2023249595A1 PCT/TR2023/050594 TR2023050594W WO2023249595A1 WO 2023249595 A1 WO2023249595 A1 WO 2023249595A1 TR 2023050594 W TR2023050594 W TR 2023050594W WO 2023249595 A1 WO2023249595 A1 WO 2023249595A1
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- Prior art keywords
- risperidone
- nanofiber
- orodispersible
- polyethylene oxide
- molecular weight
- Prior art date
Links
- 239000002121 nanofiber Substances 0.000 title claims abstract description 51
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 229960001534 risperidone Drugs 0.000 title claims abstract description 40
- 238000000034 method Methods 0.000 title claims description 30
- 238000001523 electrospinning Methods 0.000 title claims description 27
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 43
- 229920000642 polymer Polymers 0.000 claims abstract description 29
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims abstract description 18
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims abstract description 18
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims abstract description 18
- 229960002675 xylitol Drugs 0.000 claims abstract description 18
- 235000010447 xylitol Nutrition 0.000 claims abstract description 18
- 239000000811 xylitol Substances 0.000 claims abstract description 18
- 229920001577 copolymer Polymers 0.000 claims abstract description 10
- 239000002270 dispersing agent Substances 0.000 claims abstract description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 63
- 239000000203 mixture Substances 0.000 claims description 50
- 238000009472 formulation Methods 0.000 claims description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 13
- 229920003083 Kollidon® VA64 Polymers 0.000 claims description 12
- 239000012153 distilled water Substances 0.000 claims description 9
- 201000000980 schizophrenia Diseases 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 description 9
- 239000011877 solvent mixture Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 6
- 239000000835 fiber Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 206010002942 Apathy Diseases 0.000 description 3
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 2
- 239000000164 antipsychotic agent Substances 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 238000011418 maintenance treatment Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000001878 scanning electron micrograph Methods 0.000 description 2
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- 208000027534 Emotional disease Diseases 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 208000020114 Schizophrenia and other psychotic disease Diseases 0.000 description 1
- 206010041243 Social avoidant behaviour Diseases 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 201000007201 aphasia Diseases 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 231100000871 behavioral problem Toxicity 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 208000013407 communication difficulty Diseases 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 231100000868 delusion Toxicity 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000004626 scanning electron microscopy Methods 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
Definitions
- the invention relates to rapidly dissolving and orodispersible risperidone-loaded nanofibers prepared by electrospinning technology.
- 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.
- 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.
- Fig. 1 The results of the dispersion test of nanofiber formulations (s: seconds)
- 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.
- 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.
- xylitol or vinylpyrrolidone-vinyl acetate copolymer as dispersant and risperidone as an antipsychotic agent.
- 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.
- 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.
- 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).
- 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.
- 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.
- 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.
- PEO Polyethylene oxide
- Xylitol 2.5%
- Risperidone 0.5%
- 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.
- PEO Polyethylene oxide
- Kollidon VA 64 Molecular weight: 100000
- Risperidone 3% Risperidone in a ratio of 65:30:5 in EthanokDistilled water:Acetic acid by electrospinning method.
- 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.
- PEO Polyethylene oxide
- Kollidon VA 64 7.5%
- Risperidone 1.5%
- 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.
- PEO Polyethylene oxide
- Kollidon VA 64 2.5%
- Risperidone 0.5%
- 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.
- 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.
- PEO Polyethylene Oxide
- Xylitol Xylitol
- Risperidone 300 mg
- nanofiber 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.
- PEO Polyethylene Oxide
- Xylitol 750 mg
- Risperidone 150 mg
- nanofiber 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.
- PEO Polyethylene Oxide
- Xylitol 250 mg
- Risperidone 50 mg
- nanofiber 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.
- PEO Polyethylene Oxide
- Kollidon VA 64 (1500 mg
- Risperidone 300 mg
- nanofiber 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.
- PEO Polyethylene Oxide
- Kollidon VA 64 750 mg
- Risperidone 150 mg
- nanofiber 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.
- PEO Polyethylene Oxide
- Kollidon VA 64 250 mg
- Risperidone 50 mg
- 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.
- 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.
- Electrospinning method s process parameters and average fiber diameters of nanofibers
- 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:
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,
• polyethylene oxide polymer with a molecular weight of 100000 to 600000 g/mol, and
• xylitol. An oral film formulation in the form of orodispersible nanofiber according to Claim 1 , wherein the formulation comprises:
• risperidone,
• polyethylene oxide polymer with a molecular weight of 100000 to 600000 g/mol, and
• 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 polyethylene oxide polymer with a molecular weight of 100000 g/mol, and
• 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 polyethylene oxide polymer with a molecular weight of 200000 g/mol, and
• 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 polyethylene oxide polymer with a molecular weight of 600000 g/mol, and
• 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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2022/010312 TR2022010312A2 (en) | 2022-06-21 | RAPIDLY DISSOLVABLE RISPERIDONE LOADED NANOFIBERS PRODUCED BY ELECTROSTRUCTION METHOD. | |
| TR2022010312 | 2022-06-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2023249595A1 true WO2023249595A1 (en) | 2023-12-28 |
Family
ID=89380384
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2023/050594 WO2023249595A1 (en) | 2022-06-21 | 2023-06-20 | Rapidly dissolving and orodispersible nanofibers loaded with risperidone produced by electrospinning method |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2023249595A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3295932A2 (en) * | 2016-09-15 | 2018-03-21 | Zentiva K.S. | Stable odf composition containing hardly soluble therapeutic agent |
| EP3494970A2 (en) * | 2017-12-05 | 2019-06-12 | Zentiva K.S. | Hardly soluble therapeutic agents belonging to bcs class ii or iv suspended in the liquid formulation and/or in the final nanofibrous structure |
-
2023
- 2023-06-20 WO PCT/TR2023/050594 patent/WO2023249595A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3295932A2 (en) * | 2016-09-15 | 2018-03-21 | Zentiva K.S. | Stable odf composition containing hardly soluble therapeutic agent |
| EP3494970A2 (en) * | 2017-12-05 | 2019-06-12 | Zentiva K.S. | Hardly soluble therapeutic agents belonging to bcs class ii or iv suspended in the liquid formulation and/or in the final nanofibrous structure |
Non-Patent Citations (1)
| Title |
|---|
| BAHRAINIAN SARA, ABBASPOUR MOHAMMADREZA, KOUCHAK MARYAM, TAGHAVI MOGHADAM POORIA: "A Review on Fast Dissolving Systems: From Tablets to Nanofibers", JUNDISHAPUR JOURNAL OF NATURAL PHARMACEUTICAL PRODUCTS, IRAN, ISLAMIC REPUBLIC OF, vol. 12, no. 2, Iran, Islamic Republic of , pages e34267, XP093125980, ISSN: 1735-7780, DOI: 10.5812/jjnpp.34267 * |
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