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WO2020253833A1 - Forme posologique orale trans-muqueuse - Google Patents

Forme posologique orale trans-muqueuse Download PDF

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Publication number
WO2020253833A1
WO2020253833A1 PCT/CN2020/097154 CN2020097154W WO2020253833A1 WO 2020253833 A1 WO2020253833 A1 WO 2020253833A1 CN 2020097154 W CN2020097154 W CN 2020097154W WO 2020253833 A1 WO2020253833 A1 WO 2020253833A1
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
layer
pharmaceutical dosage
celexipa
outer layer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2020/097154
Other languages
English (en)
Chinese (zh)
Inventor
田芳
齐默尔曼安妮
贾强
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nycrist Pharmatech Ltd
Seasons Biotechnology Taizhou Co Ltd
Original Assignee
Nycrist Pharmatech Ltd
Seasons Biotechnology Taizhou Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nycrist Pharmatech Ltd, Seasons Biotechnology Taizhou Co Ltd filed Critical Nycrist Pharmatech Ltd
Publication of WO2020253833A1 publication Critical patent/WO2020253833A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • A61K47/30—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
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • D—TEXTILES; PAPER
    • D04—BRAIDING; LACE-MAKING; KNITTING; TRIMMINGS; NON-WOVEN FABRICS
    • D04H—MAKING TEXTILE FABRICS, e.g. FROM FIBRES OR FILAMENTARY MATERIAL; FABRICS MADE BY SUCH PROCESSES OR APPARATUS, e.g. FELTS, NON-WOVEN FABRICS; COTTON-WOOL; WADDING ; NON-WOVEN FABRICS FROM STAPLE FIBRES, FILAMENTS OR YARNS, BONDED WITH AT LEAST ONE WEB-LIKE MATERIAL DURING THEIR CONSOLIDATION
    • D04H1/00—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres
    • D04H1/70—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres
    • D04H1/72—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres the fibres being randomly arranged
    • D04H1/728—Non-woven fabrics formed wholly or mainly of staple fibres or like relatively short fibres characterised by the method of forming fleeces or layers, e.g. reorientation of fibres the fibres being randomly arranged by electro-spinning

Definitions

  • the invention relates to the field of medicine preparation and use. Specifically, the present invention provides an oral drug delivery system with a mucoadhesive membrane, which improves the quality of the drug and the pharmacokinetics of the active substance.
  • Pulmonary arterial hypertension is a disease caused by the narrowing of the small arteries of the lungs, which increases the resistance to blood flow through the lungs. Over time, increased blood pressure can damage the heart and eventually lead to heart failure.
  • Selexipag is an IP receptor agonist used to treat adult patients with PAH.
  • the commercial name of Celexipa immediate-release film-coated tablets approved for marketing is Uptravi.
  • Celacipa is metabolized in the liver to the active metabolite ACT 333679, which is more effective than the parent API and has a plasma concentration that is 3 to 4 times higher than that in human plasma at steady state.
  • Uptravi's dosing schedule is twice a day because of the short half-life of celexipa and its active metabolite, ACT 333679.
  • the half-life of Celexipa is 0.8-2.5 hours, and the half-life of metabolites is 6-13 hours.
  • Celexipa will ionize a lot at pH 6.8 (the pH of saliva).
  • the ionized form has a lower partition coefficient than the non-ionized form, so the oral mucosal tissues are less absorbed (US6264981B1).
  • Patent application WO 2018/162527 A1 discloses an intravenous injection preparation of Celexipa.
  • the lyophilized powder form of Celexipa preparation has a pH of 7-8 and contains the following excipients: glycine, polysorbate 20 and phosphate buffer.
  • the preparation is suitable for cases requiring acute treatment of IP receptor-related diseases. For long-term treatment, such invasive formulations involving skin penetration would be inappropriate.
  • the present invention provides an oral transmucosal pharmaceutical dosage form of selexipag, which comprises a mucosal adhesion layer; the mucosal adhesion layer contains selexipag.
  • the oral transmucosal drug dosage form provided by the present invention can be adhered to the oral mucosa of the human or animal body (such as the mucosa in the cheek, sublingual, gingiva and mouth and jaw) through the mucosal adhesion layer to prevent it from falling off and being swallowed. This achieves oral transmucosal administration, including buccal, sublingual, gingival and oral administration.
  • the effective active metabolite of Celexipa is ACT333679, which is a selective IP receptor agonist. It has the following structural formula:
  • the mucoadhesive layer containing celexipa may have a one-layer or multi-layer structure.
  • the mucoadhesive layer is a layer of adhesive polymer film, which contains Celexipa.
  • the mucosal adhesion layer has a double-layer or multilayer structure, wherein one layer is an adhesive polymer film for adhering to the oral mucosa of the human or animal body, which may or may not contain races.
  • Lexipa In addition, it has one or more polymer films containing Xeloxipa.
  • the pharmaceutical dosage form further has an outer layer.
  • the outer layer may be a water-insoluble or water-soluble outer layer.
  • the outer layer can assist the unidirectional release of active substances, and protect acid and/or enzyme-sensitive active substances such as proteins and peptides from being degraded by acids and/or enzymes in the gastrointestinal tract. Due to the unidirectional release, the local drug concentration at the absorption site will be increased, thus enhancing the absorption effectiveness of active substances with poor oral bioavailability.
  • the outer layer may or may not be removed after Selexipa is released.
  • the pharmaceutical dosage form further includes one or more intermediate layers located in the mucoadhesive layer and the outer layer.
  • the middle layer may contain celexipa or other active pharmaceutical ingredients to achieve controlled release or co-administration of the combination of celexipar and other active pharmaceutical ingredients.
  • the intermediate layer may also be an adhesive layer to connect the mucoadhesive layer and the outer layer (for example, the outer layer is a backing layer).
  • one or more of the mucoadhesive layer and the outer layer and the intermediate layer are in the form of a polymer film.
  • the polymer film may be made of one or more natural and/or synthetic polymers, homopolymers and/or copolymers. Suitable polymers to form the film are polyethylene oxide (PEO), polyvinyl alcohol (PVA), ethyl cellulose (EC), polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), poly Methacrylate, polycaprolactone, polyester and polyamide.
  • the mucoadhesive layer comprises at least one polymer selected from the group consisting of polyacrylic acid, chitosan, pectin, hydroxypropyl cellulose (HPC), hydroxypropyl methyl Cellulose (HPMC), hydroxyethyl cellulose (HEC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene oxide (PEO), sodium carboxymethyl cellulose, polymethacrylate , Poloxamers, alginate, carbomer, hyaluronic acid and polycarbophil.
  • polyacrylic acid chitosan
  • pectin hydroxypropyl cellulose
  • HPMC hydroxypropyl methyl Cellulose
  • HEC hydroxyethyl cellulose
  • PVP polyvinylpyrrolidone
  • PVA polyvinyl alcohol
  • PEO polyethylene oxide
  • Poloxamers alginate, carbomer, hyaluronic acid and polycarbophil.
  • the mucoadhesive layer contains at least one polymer selected from the group consisting of: film hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) or polyethylene oxide ( PEO).
  • HPMC film hydroxypropyl methylcellulose
  • PVP polyvinylpyrrolidone
  • PVA polyvinyl alcohol
  • PEO polyethylene oxide
  • the mucoadhesive layer may additionally include at least one penetration enhancer to improve the penetration of the oral mucosa.
  • the penetration enhancer can be a surfactant (such as sodium lauryl sulfate, polysorbate or chitosan), fatty acids and their derivatives (such as oleic acid), bile salts (such as sodium taurocholate) ) Or polyol (such as propylene glycol or polyethylene glycol).
  • additives such as plasticizers may be added to the mucoadhesive layer to improve the mechanical properties of the film, such as triethyl acetate, tributyl acetate, glycerin, propylene glycol or polyethylene glycol.
  • flavoring and sweetening agents such as peppermint oil, citrus oil, such as lemon, orange or lime, fructose, sorbitol, mannitol, aspartame, can also be added to the mucosal adhesion layer. And sucralose.
  • the outer layer is a water-soluble outer layer. In one aspect of the present invention, the outer layer is a water-insoluble outer layer. In one aspect of the present invention, the outer layer comprises at least one polymer selected from the group consisting of polyamide, ethyl cellulose (EC), cellulose acetate phthalate (CAP), polyacrylonitrile, poly Propylene oxide and polycaprolactone. Preferably, it contains at least one polymer selected from the group consisting of ethyl cellulose (EC), polycaprolactone (PCL), chitosan, polymethacrylate, poly(DL-lactic acid) (PLA) ), poly(lactic acid) co-glycolic acid (PLGA).
  • the water-insoluble outer layer may also contain at least one enzyme inhibitor to inhibit enzymatic degradation.
  • the pharmaceutical dosage form is pH-dependent because oral mucosal permeability is related to pH.
  • the celexipa in the oral transmucosal pharmaceutical dosage form is amorphous celexipa.
  • the celexipa in the oral transmucosal pharmaceutical dosage form is a crystal.
  • Cerexipa in the oral transmucosal pharmaceutical dosage form, Cerexipa can be incorporated into the mucosal adhesion layer or the layered film of the intermediate layer.
  • the polymer used to form the layered film containing the active agent is usually selected based on its ability to regulate the release of the active agent.
  • the release of the active agent from the layer depends on the ability of the polymer carrier to quickly dissolve and therefore deliver the API to the oral mucosal tissues in order to provide the required gradient across the mucosa.
  • the celexipa in the pharmaceutical dosage form is incorporated into the mucoadhesive layer in the form of microstructure and/or nanostructure.
  • the pharmaceutical dosage form of the present invention can be produced, for example, by electrospinning or freeze drying.
  • Celexipa is present in the pharmaceutical dosage form in the form of microstructures and/or nanostructures.
  • the microstructure and/or nanostructure of the Celexipa can be formed by freeze drying or electrospinning.
  • Celexipa is incorporated into the film in the form of micron and/or nanofibers by electrospinning.
  • Electrospinning is an efficient membrane preparation process that can be used to assemble fibrous polymer membranes containing fiber diameters ranging from nanometers to micrometers.
  • the electrostatic process uses a high-voltage electric field to inject current of a certain polarity into the polymer solution/melt, which accelerates the solution/melt toward the collecting surface of the opposite polarity, thereby forming solid fibers.
  • the electrospun fiber matrix has a three-dimensional pore structure with a relatively large surface area. Good fiber formation requires optimization of solution parameters and electrospinning configuration.
  • the control parameters in the electrospinning process affect the drug release pattern from the membrane matrix. In this way, the electrospun membrane matrix can be customized to achieve the desired drug release pattern.
  • Polymers used for electrospinning such as polyaniline, polyacetylene, polypyrrole, etc., together with (one or more) active substances, solvents and auxiliary materials, mixed in the form of solution, suspension, emulsion or melt, can be applied From about 1-30kV voltage to polymer solution, suspension, emulsion or melt form.
  • the active substance can be incorporated by direct dissolution, suspension or in the form of an emulsion.
  • Solvents used to prepare (e.g., by electrospinning or freeze-drying) the solution of the cerexipa pharmaceutical dosage form include water and organic and inorganic solvents.
  • suitable solvents include water or organic solvents, such as ethanol, methanol, dichloromethane, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide or Dimethyl sulfoxide.
  • the solvent is water.
  • a suitable inorganic solvent is an alkaline aqueous solution, such as a sodium hydroxide solution or a buffer solution, which can overcome the problem of low solubility of Celexipa in acidic or neutral pH.
  • a sodium hydroxide solution or a buffer solution which can overcome the problem of low solubility of Celexipa in acidic or neutral pH.
  • Celexipa in the pharmaceutical dosage form exists in the form of its salt.
  • the dosage of celexipa in the oral transmucosal pharmaceutical dosage form is 40-6400 ⁇ g, preferably 100-3200 ⁇ g, more preferably 200-3200 ⁇ g.
  • the oral transmucosal drug dosage form is a buccal dosage form.
  • the oral transmucosal drug dosage form is a sublingual dosage form.
  • the oral transmucosal drug dosage form is a gingival administration dosage form.
  • the oral transmucosal drug dosage form is an oral administration dosage form.
  • the oral transmucosal drug dosage form is a dosage form that is administered once or twice a day.
  • the oral transmucosal drug dosage form provided by the present invention has the characteristic of maintaining an effective plasma active metabolite concentration within 24 hours, the oral transmucosal drug dosage form is suitable for a once-daily administration.
  • the oral transmucosal pharmaceutical dosage form allows Celexipa to exhibit improved bioavailability or improved stability, or have altered pharmacokinetics.
  • the peak time Tmax of the active metabolite ACT333679 of celexipa is greater than 2 hours or longer, such as greater than 4 hours; and/or has an improved residence time, such as ACT333679 during administration After or after the administration is stopped, the plasma concentration remains about 100 ng/ml or higher, for example up to about 500 ng/ml, for up to 24 hours for 2 hours or more.
  • the invention also provides a method for preparing the oral transmucosal pharmaceutical dosage form of Celexipa described above.
  • the method includes the steps of forming a mucosal adhesion layer containing celexipa, which can adhere to the oral mucosa of the human or animal body.
  • the method further includes the step of covering the mucoadhesive layer with a water-soluble outer layer or a water-insoluble outer layer.
  • the method further includes the step of forming one or more intermediate layers between the mucoadhesive layer and the outer layer.
  • the mucoadhesive layer and/or the intermediate layer is incorporated into the mucoadhesive layer and/or the microstructure and/or nanostructure containing celexipa.
  • the intermediate layer is prepared, for example, by electrospinning or freeze-drying.
  • the present invention also provides a method for administering celexipa to humans or animals, which includes the steps of administering the aforementioned pharmaceutical dosage forms to humans or animals.
  • the pharmaceutical dosage form is administered through the mouth.
  • the pharmaceutical dosage form is administered sublingually.
  • the pharmaceutical dosage form is administered through the gums.
  • the pharmaceutical dosage form is administered orally.
  • the pharmaceutical dosage form is administered once or twice a day, preferably once a day.
  • the cerexipa is used to treat pulmonary arterial hypertension (PAH) in humans or animals.
  • PAH pulmonary arterial hypertension
  • the present invention also provides the use of Celexipa in the preparation of a medicament for administration to humans or animals, wherein Celexipa is administered to humans or animals in the pharmaceutical dosage form described above.
  • the Xeloxipa dosage form provided by the present invention delivers Xeloxipa through the oral mucosa in a short period of minutes to 30 minutes, and the active metabolite ACT333679 reaches its peak time after a few hours ( Tmax), and can maintain the concentration of ACT333679 between 100ng/ml and 500ng/ml up to 24 hours.
  • Tmax peak time after a few hours
  • the present invention provides a dosage form of Celexipa that can be delivered to patients within a few minutes, and maintains the level of ACT333679 for 24 hours, which will reduce side effects.
  • the selexipag dosage form provided by the present invention ensures rapid and high absorption through the oral mucosa; the dosage form disintegrates quickly and the dissolution rate of API is high, and the API is absorbed into the mucosa instead of being swallowed.
  • the dosage form avoids the first pass effect, improves the bioavailability, and further reduces side effects.
  • Each formulation was given as a single dose to the same two dogs, and at 0 minutes (before administration) and at 2 minutes, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 12 hours, 24 Blood samples were collected after hours and 48 hours after administration.
  • the drug washout period between the administration of different formulations in the two animals was 4 days.
  • XRPD test was performed using PANalytical X'Pert Empyrean system (PW3040/60) (PANalytical BV, the Netherlands) with CuK ⁇ radiation
  • the divergence slit is 1/4°.
  • Set the X-ray generator to an acceleration voltage of 45kV and a filament emission of 40mA.
  • the sample was scanned between 2 and 40° (2 ⁇ ) using a step size of 0.01313° and a scanning speed of 0.0416o/s.
  • the data was collected using X'Pert Data Collector and observed using X'Pert Data Viewer (PANalytical BV, The Netherlands).
  • the oral adhesive film packaged in an aluminum-plastic packaging bag was subjected to a time-varying physical stability test, and the test condition was a constant temperature and humidity box at 25° C./50% RH.
  • the membranes were tested with XRPD at 1, 3, and 5 months.
  • the formulation is prepared by electrospinning using the nanofiber electrospinning unit from Tong Li Tech.
  • the electrospinning applies process parameters to obtain optimal fiber formation, such as voltage, flow rate, distance from needle tip to collector and collector wheel speed.
  • the API or outer layer is initially spun. Then change the syringe and spray the second layer onto the first layer. After electrospinning, the resulting film is cut into pieces of appropriate size corresponding to the required dose, and each film is packaged in an aluminum-plastic packaging bag, and stored under dry conditions.
  • the prescription formulation B was administered to 2 dogs (2.4 mg/formulation, ⁇ 0.3 mg/kg) by placing the film under the tongue of the beagle for oral mucosal absorption.
  • the prescription formulation C was administered to 2 dogs (2.4 mg/formulation, ⁇ 0.3 mg/kg) by attaching the oral adhesive layer to the cheek and the back layer facing the oral cavity for transmucosal absorption. Place the film in the cheeks for 0.5 hours, and then remove it.
  • the prescription formulation C was administered to 2 dogs (2.4 mg/formulation, ⁇ 0.3 mg/kg) by attaching the oral adhesive layer to the cheek and the back layer facing the oral cavity for transmucosal absorption. Place the film in the cheeks for 0.5 hours, and then remove it.
  • the unit “degrees” of temperature in this text refers to degrees Celsius, that is, degrees Celsius.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Cardiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pulmonology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Hospice & Palliative Care (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Textile Engineering (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une forme posologique orale trans-muqueuse de sélexipag, comprenant une couche d'adhérence aux muqueuses qui peut adhérer à une muqueuse buccale humaine ou animale. La couche d'adhérence aux muqueuses contient du sélexipag. L'invention concerne en outre un procédé de préparation de la forme posologique et un procédé de traitement de maladies l'utilisant. La forme posologique fournie améliore la qualité des médicaments et la pharmacocinétique de substances actives.
PCT/CN2020/097154 2019-06-20 2020-06-19 Forme posologique orale trans-muqueuse Ceased WO2020253833A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910540029.1 2019-06-20
CN201910540029 2019-06-20

Publications (1)

Publication Number Publication Date
WO2020253833A1 true WO2020253833A1 (fr) 2020-12-24

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PCT/CN2020/097154 Ceased WO2020253833A1 (fr) 2019-06-20 2020-06-19 Forme posologique orale trans-muqueuse

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CN (1) CN112107559B (fr)
WO (1) WO2020253833A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022214544A1 (fr) * 2021-04-07 2022-10-13 Københavns Universitet Timbre multicouche

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20250017870A1 (en) * 2021-11-15 2025-01-16 Artience Co., Ltd. Adhesive patch containing selexipag as active ingredient
CN115737605B (zh) * 2022-11-24 2024-11-12 杭州归领医疗器械有限公司 一种夹心结构的粘性持久的口腔溃疡膜及其制备方法

Citations (7)

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Publication number Priority date Publication date Assignee Title
WO2014131376A1 (fr) * 2013-02-26 2014-09-04 Elmarco S.R.O. Nanofibres électrofilées comprenant des agents pharmaceutiquement actifs
EP2646006B1 (fr) * 2010-11-26 2015-02-25 University Of The Witwatersrand, Johannesburg Forme pharmaceutique
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