WO2020259440A1 - Pulvérisation nasale de dexmédétomidine, son procédé de préparation et son utilisation - Google Patents

Pulvérisation nasale de dexmédétomidine, son procédé de préparation et son utilisation Download PDF

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WO2020259440A1
WO2020259440A1 PCT/CN2020/097454 CN2020097454W WO2020259440A1 WO 2020259440 A1 WO2020259440 A1 WO 2020259440A1 CN 2020097454 W CN2020097454 W CN 2020097454W WO 2020259440 A1 WO2020259440 A1 WO 2020259440A1
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dexmedetomidine
nasal spray
preservative
sodium
concentration
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PCT/CN2020/097454
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English (en)
Chinese (zh)
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王万
王震宇
贺钢民
李扬强
石新玥
李佩
侯曙光
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四川普锐特药业有限公司
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Publication of WO2020259440A1 publication Critical patent/WO2020259440A1/fr

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    • 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
    • A61K9/0043—Nose
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/06—Head
    • A61M2210/0618—Nose

Definitions

  • the invention belongs to the technical field of medicine, and specifically relates to a dexmedetomidine nasal spray, and its preparation method and application.
  • Dexmedetomidine dexmedetomidine, (+)-4-[(S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, was developed by Orion Pharma and Abbott in cooperation A non-narcotic ⁇ -2 adrenergic receptor agonist with anti-sympathetic, sedative and analgesic properties. Its structural formula is as follows:
  • dexmedetomidine is currently only approved for marketing in the form of injections.
  • all of the more than ten NMPA approval numbers for dexmedetomidine are injection dosage forms, and the 8 FDA approvals for dexmedetomidine are also injection dosage forms.
  • Contradicting the single marketing authorization injection formulation of dexmedetomidine is the urgent need for clinical application.
  • dexmedetomidine is more selective in the activation of ⁇ -2 adrenergic receptors and has a smaller effective dosage, it has attracted much attention and expectations once it is marketed.
  • dexmedetomidine The characteristics of intranasal administration of dexmedetomidine determine that its requirements for drugs are significantly different from injection administration.
  • the administration of dexmedetomidine injection is usually a one-time administration and is usually used in hospitals. Good storage conditions can ensure its stability by providing a better storage and use environment.
  • nasal spray administration usually requires repeated use of a bottle or can for many times, and it is likely to be used in a variety of environments without good storage conditions.
  • dextromethorphan injection is usually completely sealed and packaged in a glass ampoule for one-time use, which is completely isolated from the outside world.
  • the packaging materials of dexmedetomidine nasal spray also include metering pumps, seals, push buttons and other packaging materials that are in contact with the liquid for a long time, and are semi-open structures.
  • the API concentration of nasal spray is also much higher than that of injection. Under the condition of high concentration of dexmedetomidine, its compatibility with packaging materials needs to be considered again. The above factors will affect the storage stability of dexmedetomidine nasal spray.
  • intranasal administration acts on the nasal mucosa, which also puts forward higher requirements for the irritation of dexmedetomidine drugs.
  • intranasal administration also requires comprehensive consideration of many factors such as bioavailability and absorption stability.
  • Recoo company provides an intranasal dexmedetomidine composition in CN104470516A, which has carried out a more systematic study on the intranasal administration of dexmedetomidine, but its given intranasal dexmedetomidine
  • the formula composition of the mididine composition is still complicated, and the auxiliary materials are used more, and the stability of the composition is still to be discussed.
  • the specific implementation case of Ricoeur CN104470516A mainly uses phenylethanol as a preservative.
  • Phenylethanol has low antibacterial activity, requires a higher concentration, and has the characteristics of being volatile and easily adsorbed by plastics or rubber.
  • phenylethanol is stored in a semi-open device of dexmedetomidine nasal spray for a long time, Due to volatilization or adsorption of packaging materials, the content will be insufficient and the antibacterial effect will be weakened; in addition, the presence of light and oxidants will accelerate the degradation of phenylethanol, thereby reducing the antibacterial effect and increasing the impurity components of the nasal spray.
  • the present invention has done a series of in-depth research on dexmedetomidine nasal spray, and proposes a new type of dexmedetomidine nasal spray, which has fast onset, excellent and stable effect , Good stability, less irritation and high bioavailability of one or more of the technical advantages.
  • CN104470516A the general concept mentions that many kinds of preservatives can be used, and it reveals the problem of precipitation caused by the use of benzalkonium chloride. It further pointed out that a suitable preservative is phenylethanol, which can keep the preservative not precipitated but in the composition solution. Based on this, the core specific implementation example 1 gives the intranasal formulation prescription and preparation method, using phenylethanol as a preservative and adding EDTA-2Na as a stabilizer.
  • the prescription nasal spray formulations using phenylethanol as a preservative have a greater stability problem.
  • the various preservatives mentioned in the general concept of CN104470516A have different performances in the formulation stability of dexmedetomidine nasal spray.
  • potassium sorbate is selected as the preservative
  • the additional addition of EDTA-2Na has an opposite adverse effect on the stability of the nasal spray formulation.
  • the formulations specifically provided in CN104470516A are complicated in composition and do not have cost advantages. At the same time, they have more or less certain aspects in the speed of onset, stability, and bioavailability. insufficient.
  • the basic technical idea of the present invention is to optimize the formulation composition of dexmedetomidine nasal spray, and provide a new formulation of dexmedetomidine nasal spray, which overcomes one of the aforementioned or Two or more technical defects, and then achieve the characteristics of fast onset, strong stability and/or high bioavailability, and do not produce mucosal irritation.
  • the dexmedetomidine nasal spray provided by the present invention comprises a carrier and a therapeutically effective amount of dexmedetomidine or a pharmaceutically acceptable salt, solvate or isomer thereof.
  • the optional concentration of dexmedetomidine in the nasal spray is 0.005% to 1.3%, preferably 0.0125 to 0.7%, more preferably 0.006% to 0.108%.
  • Dexmedetomidine is preferably dexmedetomidine hydrochloride.
  • the preferred concentration of dexmedetomidine hydrochloride in the nasal spray is 0.006% to 1.54%, preferably 0.015 to 0.83%, More preferably, it is 0.007% to 0.13%.
  • Dexmedetomidine nasal spray can release 2.5 ⁇ 650 ⁇ g of dexmedetomidine per press.
  • the spray particle size Dv90 value of dexmedetomidine nasal spray is preferably 50-152.1 ⁇ m, more preferably 52-142 ⁇ m, still more preferably 51-66 ⁇ m, 66-81 ⁇ m, 81-104 ⁇ m or 104-152.1 ⁇ m.
  • the Dv90 value of the spray particle size can be controlled by the amount of thickener added. Controlling the Dv90 value of the spray particle helps to control and obtain a unique drug-time curve, which is suitable for clinical application for specific purposes.
  • the specific preservatives are cationic surfactant preservatives such as benzalkonium chloride, benzalkonium bromide or benzethonium bromide, and paraben preservatives such as methyl paraben and paraben Ethyl, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, isopropyl p-hydroxybenzoate, isobutyl p-hydroxybenzoate, sodium propyl p-hydroxybenzoate or sodium methyl p-hydroxybenzoate, non Aromatic alcohol preservatives such as propylene glycol or chlorobutanol.
  • cationic surfactant preservatives such as benzalkonium chloride, benzalkonium bromide or benzethonium bromide
  • paraben preservatives such as methyl paraben and paraben Ethyl, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, isoprop
  • the preservatives of the dexmedetomidine nasal spray of the present invention can be selected from benzalkonium chloride, benzalkonium bromide, propylene glycol, chlorobutanol, methyl paraben and paraben One or a combination of two or more propyl esters.
  • the concentration can be selected to be 0.002% or more, preferably 0.01% or more, more preferably 0.02% or more, and more preferably 0.01% to 0.2%.
  • the preservative is selected as methyl p-hydroxybenzoate, its concentration can be selected to be 0.01% or more, preferably 0.01% to 0.25%.
  • the concentration can be selected to be 0.01% or more, preferably 0.02% or more, more preferably 0.02% to 0.075%.
  • the concentration can be selected to be 0.05% or more, preferably 0.05% to 30%, more preferably 0.1% to 10%.
  • the preservative is selected as chlorobutanol, its concentration can be selected to be 0.05% or more, preferably 0.05% to 0.75%.
  • the concentrations of the two can be selected to be more than 0.01% and more than 0.01%, and the concentrations of the two are preferably 0.01% to 0.25% and 0.01% to 0.075%, and the two concentrations are more preferably 0.02% to 0.04% and 0.01% to 0.02% in sequence.
  • the concentrations of the two can be selected to be more than 0.1% and more than 0.01%, and the concentrations of the two are preferably 0.1%-10% and 0.01%-0.2%.
  • the type of carrier water may be a pharmaceutically acceptable type, including but not limited to purified water, water for injection, and the like.
  • the single or compound combination of preservatives selected by the present invention can also be used together with antioxidants.
  • the antioxidants can be EDTA-2Na, tert-butyl hydroxyanisole, 2,6-di-tert-butyl-4 -One or a combination of two or more of methylphenol, sodium metabisulfite, potassium metabisulfite, butylated hydroxyanisole, L-ascorbyl palmitate, sodium thiosulfate and vitamin E.
  • the preservative of the present invention can also be selected as potassium sorbate, but when the preservative is selected as potassium sorbate, the formulation should not contain EDTA-2Na.
  • the concentration can be selected from 0.01% to 0.2%.
  • the present invention provides Dexmedetomidine nasal spray also preferably contains a thickener, which is among povidone thickeners, cellulose ether thickeners, mucopolysaccharide thickeners, and polyacrylic thickeners.
  • a thickener which is among povidone thickeners, cellulose ether thickeners, mucopolysaccharide thickeners, and polyacrylic thickeners.
  • One or a combination of two or more, povidone thickener can be PVP K30 or PVP K90
  • cellulose ether thickener can be microcrystalline cellulose-sodium carboxymethyl cellulose composite
  • Hypromellose methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose or hydroxyethyl cellulose
  • mucopolysaccharide thickeners can be sodium hyaluronate or chondroitin sulfate
  • poly The acrylic thickener can be carbomer.
  • the concentration can be selected from 0.1% to 5.0%.
  • the concentration can be selected to be 0.1% to 3.0%.
  • the thickener When the thickener is selected as hypromellose, its concentration can be selected from 0.1% to 5.0%, preferably 0.2% to 1.5%. When sodium hyaluronate is selected as the thickener, its concentration can be selected from 0.01% to 1.0%. When the thickener is selected as carbomer, its concentration can be selected from 0.05% to 1.0%.
  • the dexmedetomidine nasal spray provided by the present invention also preferably contains an osmotic pressure regulator, the osmotic pressure regulator is ionic or non-ionic, and the ionic osmotic pressure regulator includes boric acid, sodium chloride, calcium chloride , Magnesium chloride, zinc chloride or potassium chloride, non-ionic osmotic pressure regulators include anhydrous dextrose, dextrose monohydrate, dextran, glycerol or D-mannitol; the osmotic pressure regulators are preferably boric acid, sodium chloride , Potassium chloride, anhydrous dextrose, dextrose monohydrate, dextran, glycerol and a combination of two or more of D-mannitol, the osmotic pressure regulator is especially preferably sodium chloride or potassium chloride When the osmotic pressure regulator is selected as sodium chloride or potassium chloride, its concentration is preferably 0.7% to 1%.
  • the pH of the dexmedetomidine nasal spray provided by the present invention is preferably 4-7, more preferably 5-6.5.
  • the pH adjusting agent of the dexmedetomidine nasal spray can be an acidulant and/or an alkalinizer, and the acidulant includes hydrochloric acid, phosphoric acid, tartaric acid, citric acid, malic acid, fumaric acid, lactic acid, ascorbic acid and acetic acid.
  • Alkalizing agents include meglumine, trimethylolmethane, sodium phosphate, arginine, lysine, glycine, ammonia, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, ammonium carbonate and borax;
  • the pH adjuster may further preferably be one of hydrochloric acid, phosphoric acid, tartaric acid, citric acid, malic acid, fumaric acid, malic acid, ammonia, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, ammonium carbonate and borax.
  • One or a combination of two or more; the preferred choice of pH adjusting agent is hydrochloric acid and/or sodium hydroxide.
  • the general preparation method of the aforementioned dexmedetomidine nasal spray provided by the present invention is as follows, weigh dexmedetomidine or its pharmaceutically acceptable salt, solvate or its isomers and various excipients (excipients include preservatives) , Osmotic pressure regulator, thickener (add if necessary)), add carrier to dissolve, and optionally adjust pH. On this basis, it is further divided into plastic or glass bottle containers, a metering pump is assembled on the container, and a push button is installed.
  • the present invention also provides its use in the preparation of sedative, analgesic and/or anti-sympathetic products Further application.
  • the said product may be a further compound preparation used in combination with other types of drugs, or a further complex preparation, etc.
  • the percentages refer to percentages by weight.
  • the density of the formulation solution system is approximately converted at 1 g/mL.
  • the concentration of the dexmedetomidine hydrochloride system is 0.24 mg/mL
  • the density of the prescription solution system is approximately converted to 1 g/mL.
  • the weight percentage concentration of the medetomidine system is 0.024%; in the same way, when dexmedetomidine is used at this time, the converted concentration is 0.2 mg/mL, and the weight percentage concentration is 0.02%.
  • the weight conversion coefficient between dexmedetomidine hydrochloride and dexmedetomidine is approximately calculated as 1.1822, and the conversion between them follows the counting retention method of rounding. If there is no special statement or industry customary constraints, the data that needs to be calculated in other similar places in this article also uses the rounding counting retention method.
  • an effective amount generally refers to the amount of an active compound or agent that can cause a biological or medical response.
  • the biological or medical response can be human, animal, system model, tissue, cell in vitro, etc. It is generally obtained by medical researchers, doctors or clinicians in experiments or clinical research.
  • a “biological or medical response” can be the rehabilitation, elimination, alleviation or suppression, or prevention of a disease or symptoms associated with the disease.
  • the “quantity” generally can be determined according to the specific situation of the subject, and a relatively universal range can also be determined for subjects with specific common characteristics.
  • the "effective amount” can also preferably refer to the specific amount described in some specific embodiments or the general range supported by them together.
  • DEX short for dexmedetomidine, that is, dexmedetomidine
  • EDTA-2Na Shorthand for disodium edetate
  • PVP K90 The abbreviation of PVP K90, namely polyvinylpyrrolidone K90, also known as povidone K90, Povidone K90
  • PVP K30 shorthand for PVP K30, namely polyvinylpyrrolidone K30, also known as povidone K30, Povidone K30
  • HEC 250M Short for Hydroxyethylmethyl Cellulose 250M, also abbreviated as HEC-M, that is, hydroxyethyl cellulose 250M
  • HEC 250HX Hydroxyethylmethyl Cellulose 250HX abbreviation, also abbreviated as HEC-H, namely hydroxyethyl cellulose 250HX
  • CL-611 Shorthand for Trade name, produced by FMC BioPolymer company, generic name Microcrystalline Cellulose and Cellulose Gum, Microcrystalline Cellulose and Cellulose Gum
  • RL-591 Shorthand for Trade name, produced by FMC BioPolymer company, generic name Microcrystalline Cellulose and Cellulose Gum, Microcrystalline Cellulose and Cellulose Gum
  • HPMC E50 short for hydroxypropyl methylcellulose E50, namely hypromellose E50, also written as hydroxypropyl methylcellulose E50, hydroxypropyl methylcellulose E50
  • TCB short for trichloro-t-butyl alcohol, also known as 2-Trichloromethyl-2-propanol, Chlorobutanol, namely trichloro-tert-butyl alcohol
  • PE short for Phenylethyl alcohol, namely phenylethanol
  • Methyl ester short for methyl paraben, also known as methyl paraben, Methylparaben
  • Propyl ester short for propyl paraben, also known as propyl paraben, Propylparaben
  • BKB Benzalkonium bromide, also known as Benzalkonlum bromide
  • BKC Benzalkonium chloride, also known as Benzalkonium chloride
  • CBP short for carbopol, namely carbomer
  • PG short for Propylene glycol, namely propylene glycol
  • the embodiments described herein specifically provide a method for preparing and obtaining dexmedetomidine nasal spray.
  • the general method steps are: weighing API (referring to dexmedetomidine or its pharmaceutically acceptable salt, solvent Compounds or isomers) and auxiliary materials (the auxiliary materials include osmotic pressure regulators, preservatives, thickeners and antioxidants, etc., and the auxiliary materials are optionally added depending on the formulation), add an appropriate amount of purified water to dissolve, and use a pH regulator to adjust the system
  • the pH is within the predetermined range of 4-7, and then the carrier water is added to make the volume constant, and the dexmedetomidine nasal spray is obtained evenly. It can be further divided into containers, assembled on the metering pump, and installed on the push button.
  • examples of different active ingredient concentrations are prepared.
  • dexmedetomidine nasal spray provided, dexmedetomidine exists in the form of dexmedetomidine hydrochloride, which is By default, the concentrations are 0.006%, 0.02%, 0.0592%, 0.0593%, 0.108%, 0.01%, 0.03%, 0.04%, 0.05%, 0.07%, 0.1%, 0.2%, 0.4%, 0.7%, 1 % Or 1.3%.
  • the nasal spray includes a liquid medicine part and a device part, and the liquid medicine is preloaded in the device.
  • the device includes a metering drug delivery device, which is composed of a metering pump and a container that cooperate with each other.
  • the material of the container is presented in three embodiments: plastic, low borosilicate glass, and medium borosilicate glass.
  • the metering pump is provided with an actuator. Under the control of the actuator, the nasal spray is delivered by a metered drug delivery device.
  • the quantification of dexmedetomidine per press is 5 ⁇ g, 10 ⁇ g, 15 ⁇ g, 20 ⁇ g, 25 ⁇ g, 30 ⁇ g, 40 ⁇ g, 50 ⁇ g, 60 ⁇ g , 75 ⁇ g, 100 ⁇ g or 125 ⁇ g administration.
  • single or multiple nasal sprays can be administered.
  • the pH of the nasal spray system is 4-7, which can be adjusted by a pH adjusting agent, acidifying agent and/or alkalizing agent.
  • the acidifying agent includes hydrochloric acid, phosphoric acid, tartaric acid, citric acid, and malic acid.
  • alkalizing agents include ammonia, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, ammonium carbonate and borax; pH adjusters can be further preferably hydrochloric acid, phosphoric acid, tartaric acid, citric acid, One or a combination of two or more of malic acid, fumaric acid, malic acid, ammonia, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, ammonium carbonate and borax.
  • the osmotic pressure of the nasal spray can be controlled by the concentration of the osmotic pressure adjusting agent, the osmotic pressure adjusting agent is ionic or non-ionic, and the ionic osmotic pressure adjusting agent includes boric acid and sodium chloride.
  • non-ionic osmotic pressure regulators include anhydrous glucose, dextrose monohydrate, dextran, glycerol or D-mannitol; the osmotic pressure regulator is preferably boric acid , Sodium chloride, potassium chloride, anhydrous dextrose, dextrose monohydrate, dextran, glycerol and D-mannitol one or a combination of two or more.
  • the following is a formulation table of several typical examples.
  • the pH in these typical examples is adjusted by 1N sodium hydroxide and 1N hydrochloric acid.
  • the prescription amount of dexmedetomidine hydrochloride is calculated based on dexmedetomidine, and the conversion coefficient of dexmedetomidine hydrochloride and dexmedetomidine is 1.1822.
  • Degradation rate (1-measured content ⁇ prepared content) ⁇ 100%
  • Degradation rate (1-measured content ⁇ prepared content) ⁇ 100%.
  • Osmotic pressure 10 days at room temperature, 10 days at accelerated (40°C) and 10 days at high temperature (60°C) confirmed that the osmolality of formula 1 is always maintained at 278 ⁇ 286mOsmol/kg.
  • the formulations 1, 4, and 6 using benzalkonium chloride as the preservative are significantly lower than the other formulations.
  • no related substances were detected in 10 days at room temperature and 30 days in accelerated experiment. Although related substances were detected during 30 days at high temperature, they were still in a low range.
  • the related substances of the formula 4 that additionally added hypromellose increased.
  • additional antioxidant EDTA-2Na formula 6 its related substances further increased significantly.
  • formulas 2, 3 and 5 with potassium sorbate as preservative have significantly increased related substances.
  • the prior art discloses that the preservative potassium sorbate is usually used in combination with EDTA-2Na.
  • EDTA-2Na was added (formulation 3)
  • EDTA-2Na and hypromellose were added (formulation 5)
  • the total impurities exceeded 1% after 10 days of acceleration. In further high temperature experiments It even reached 4.33%, which was significantly beyond the controllable level.
  • the preservative is selected as benzalkonium chloride
  • the related substances in the nasal spray preparations have been significantly reduced, and the prescription stability has been significantly improved.
  • Table 1.3 shows that the preservative potassium sorbate degrades significantly under room temperature, accelerated, and high temperature conditions, especially under accelerated and high temperature conditions.
  • Table 1.4 shows that under the same conditions of other variables (such as formula 1 and formula 2, formula 5 and formula 6), even if the investigation time is longer, the degradation rate of the preservative benzalkonium chloride in the formula is lower than that of sorbic acid Potassium. This also confirms from another aspect that the choice of benzalkonium chloride as a preservative has improved the stability of nasal sprays.
  • the dosage is based on dexmedetomidine, and the injection is diluted with saline for use.
  • the measured blood drug concentration was analyzed with Phoenix WinNonlin (v 6.4) as a non-compartmental model, and the results are shown in Table 2.3 below.
  • Histopathological examination The nasopharynx, bronchi, and lungs of all rats in the 30 ⁇ g/kg nasal spray group were examined according to histopathology.
  • the concentration of dexmedetomidine in plasma was determined by the validated LC-MS/MS method and the pharmacokinetic parameters were calculated. The main results are shown in the following table 2.6-Dextetomidine in plasma after single nasal/intravenous injection in rats The pharmacokinetic parameters of Midine (mean):
  • SD rats were infused with dexmedetomidine hydrochloride nasal spray 30 ⁇ g/kg for 7 consecutive days. After the administration, the gross anatomy showed that none of the rats found naked eyes that may be related to dexmedetomidine hydrochloride nasal spray. Abnormal changes.
  • the blood concentration of the dexmedetomidine hydrochloride nasal spray for intranasal administration is slightly lower or is basically equivalent to intravenous administration, the exposure level is also equivalent to that of intravenous administration, the bioavailability is high, and the blood concentration reaches the peak The time is short, and no drug-related toxic reaction is observed within 7 days of administration, which shows the good clinical application prospect of the dexmedetomidine nasal spray of the present invention.
  • Test example 3 Rhesus monkey pharmacokinetic test
  • dexmedetomidine hydrochloride and various auxiliary materials according to the ratio in Table 3.1, add water to dissolve, adjust the pH to the specified value with sodium hydroxide, put them into glass bottles, assemble the metering pump, and install the push button. Get dexmedetomidine nasal spray.
  • the prescription amount of dexmedetomidine hydrochloride is calculated based on dexmedetomidine, and the conversion coefficient of dexmedetomidine hydrochloride and dexmedetomidine is 1.1822.
  • the average spray particle size Dv90 is 52-142 ⁇ m.
  • dexmedetomidine nasal spray (formula 1-A, formula 1-B, and formula 1-C above) and commercially available dexmedetomidine hydrochloride injection (2mL: 200 ⁇ g, Jiangsu Hengrui Pharmaceutical Co., Ltd.)
  • each group of healthy male rhesus monkeys were given the prescribed doses of drugs by intravenous and nasal sprays as shown in Table 3.3.
  • 10min, 15min, 20min, 30min, 45min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, and 10h after administration 1 mL of blood was collected from the vein of the upper extremity for blood concentration detection.
  • the dosage is based on dexmedetomidine, and the injection is diluted with saline for use.
  • the measured blood drug concentration was analyzed by Phoenix WinNonlin (v 6.4) as a non-compartmental model, and the results are shown in Table 3.4 below.
  • the absolute bioavailability of dexmedetomidine hydrochloride nasal spray is 48.3% to 68.6%, that is, the dexmedetomidine hydrochloride nasal spray provided by the present invention has stable and good bioavailability Degree; body exposure (AUC) increases with the increase of dose, and the multiple of exposure increase is slightly higher than the multiple of dose increase.
  • the bioavailability of the nasal spray formula containing thickener is slightly higher than that of the nasal spray formula without thickener (formula 1-A), which is different from Recoo (CN104470516A, an intranasal dexmedetomidine composition) disclosed that "the added viscosity of a thickener will affect the intranasal delivery effect of the drug,..., the use of dexmedetomidine plasma that can cause a decrease Level and therefore omit "under certain conditions” is very different. That is, the use of thickeners (tackifiers) in dexmedetomidine nasal spray is feasible.
  • the spray particle size can be controlled by the amount of hypromellose added. If the spray particle size is too small, it will be absorbed quickly after contact with the nasal mucosa, but it also brings high blood concentration after nasal administration and unnecessary drug exposure and medication risks in the lower respiratory tract. On the other hand, the flow of the liquid medicine will also cause an uncontrollable risk of the loss of the medicine, making it difficult to perform accurate quantitative administration. As described in the present invention, the addition of hypromellose is appropriately increased to enhance the adhesion to the nasal mucosa, reduce the occurrence of flow, and thereby avoid unpredictable drug loss, so as to achieve more accurate quantitative dosing control.
  • the spray particle size value increases, the dissolution of the drug slows down, and the duration of the dissolution of the drug is prolonged. Avoid multiple nasal sprays or a single high-dose nasal spray, which may be accompanied by rapid drug absorption and rapid increase in blood concentration, which will exceed the treatment window in a short time, which will bring medication risks. Furthermore, through the control of the Dv90 value of the spray particle size, the clinical drug effect of stable drug release is obtained, and the bioavailability is improved to a certain extent.
  • Nasal spray and intravenous injection have a similar terminal half-life, indicating that their in vivo pharmacokinetic properties are similar, that is, it is expected to achieve the same effect as intravenous administration under the same exposure in the body, which is good for clinical dosage The control of effects is of great significance.
  • Test example 4 irritation test
  • the prescription amount of dexmedetomidine hydrochloride is calculated based on dexmedetomidine, and the conversion coefficient of dexmedetomidine hydrochloride and dexmedetomidine is 1.1822.
  • the rabbits in each group were in good general condition, normal autonomous activities, clean skin and coat, no abnormal symptoms of breathing and central nervous system, and no local irritation symptoms such as asthma, cough, vomiting, and suffocation.
  • the nasal spray formulated based on formula 1 its 14-day and 28-day antibacterial efficacy meets the standards A and B of the 2015 edition of the Chinese Pharmacopoeia antibacterial efficacy criteria, and has good antibacterial efficacy.
  • Dexmedetomidine hydrochloride (mg) Sodium chloride (mg) Benzalkonium chloride (mg) purified water 240 10800 240 Up to 1200mL
  • the prescription amount of dexmedetomidine hydrochloride is calculated based on dexmedetomidine, and the conversion coefficient of dexmedetomidine hydrochloride and dexmedetomidine is 1.1822.
  • the formula 1 provided by the present invention corresponds to the dexmedetomidine nasal spray at different pH, at room temperature for 10 to 30 days, accelerated 10 Under the experimental conditions of ⁇ 30 days and high temperature of 10 ⁇ 30 days, the content of related substances was extremely low. It further proves the excellent stability of the dexmedetomidine nasal spray of the formula 1 of the present invention, and further proves that the dexmedetomidine nasal spray of the formula 1 of the present invention has a wide range of pH application, at pH 4 ⁇ In the range of 7, good stability can be maintained.
  • Benzalkonium chloride see Table 6.4, based on the overall formula of formula 1 of the present invention, under different preset pH. Under the three experimental conditions of 30 days at room temperature, 30 days at acceleration, and 30 days at high temperature, the content of benzalkonium chloride did not change much and was always stable within the predetermined range. It is further proved that under the environmental conditions of this group, even in a large pH environment deviation, the benzalkonium chloride has good stability.
  • the dexmedetomidine nasal spray provided by the present invention has at least the following technical advantages: First, the present invention is fully aimed at the characteristics of nasal spray administration, and practically provides a suitable dexmedetomidine It is a new nasal spray form with good pharmacokinetic properties. Second, the dexmedetomidine nasal spray of the present invention has a simple formula, but has good stability and antibacterial properties. Third, when the dexmedetomidine nasal spray provided by the present invention uses benzalkonium chloride as the preservative ingredient, the stability of the nasal spray is improved, especially the control of related substances has made significant progress and is unexpected External technical effects.
  • the present invention finds that when the antioxidant EDTA-2Na is combined with potassium sorbate, it adversely affects the stability of the nasal spray.
  • the dexmedetomidine nasal spray formula of the present invention ensures stability and non-irritating nasal administration through the selection of formula types and ratio control. In the pharmacokinetic test of rats and rhesus monkeys, the animals are administered on the same day There were no local or systemic adverse reactions after administration and the acceptance was good. The New Zealand rabbits were given continuous administration for 7 days, and they were generally in good condition. There were no obvious abnormalities in the general anatomical observation of the respiratory tract, oral mucosa, and histopathological examination. Sixth, based on the composition ratio of the present invention, the dexmedetomidine nasal spray of the present invention is applicable to a wide range of pH, and can maintain good stability in the pH range of 4-7.
  • Test Example 7 Further extended research test of preservatives and thickeners
  • the prescription amount of dexmedetomidine hydrochloride is 0.02% based on the free base of dexmedetomidine, and the conversion factor of dexmedetomidine hydrochloride is 1.1822.
  • the prescription amount of dexmedetomidine hydrochloride is 0.02% based on the free base of dexmedetomidine, and the conversion factor of dexmedetomidine hydrochloride is 1.1822.
  • the preparations were prepared in batches of 100ml specifications, and dexmedetomidine hydrochloride and various excipients were weighed out and dissolved in water.
  • the prescriptions containing chlorobutanol, methyl parahydroxybenzoate and methyl parahydroxybenzoate are dissolved in a water bath, adjusted to pH 4.00 ⁇ 6.00, divided into glass bottles according to 10ml each, and assembled with a quantitative pump
  • the prescription preparations DEX-002 ⁇ DEX-020 and DEX-022 to be investigated are obtained.
  • the thickener formulation design in Table 7.3 prepare the prescription in 1000ml batches. Weigh dexmedetomidine hydrochloride and various excipients separately, add water and magnetically stir to dissolve, if necessary, ultrasonic dissolve, that is to get the sample to be tested, of which 900ml of each square sample is used For viscosity measurement, the remaining 100ml is divided into glass bottles according to 10ml each, and a quantitative pump is assembled to obtain a prescription sample to be tested for viscosity and spray performance.
  • the formulations corresponding to the prescriptions in Table 7.1 and Table 7.2 were sampled at high temperature for 10d and 30d respectively, and the related substances and preservative content of the 0d, 10d, and 30d samples were investigated.
  • the phenylethanol prescription (DEX-004) was compared with the existing technology.
  • Benzalkonium chloride samples (DEX-020) were placed together in a colorless vial and placed under light conditions (4500 ⁇ 500lux) for 10d and 30d to further investigate the content of related substances and preservatives.
  • test results of related substances in the light test samples are shown in the following table 7.5:
  • test results of the preservative content of the high temperature test samples are shown in the following table 7.6:
  • chlorobutanol due to the significant decrease in the content of chlorobutanol, considering this reason, such as the use of chlorobutanol as a preservative, the sealing performance of dexmedetomidine nasal spray needs to meet higher standards. , In order to minimize the volatilization loss of the preservative trichlorobutanol. With the support of higher sealing standards and other technical means to reduce the loss of chlorbutamol content, chlorobutanol can also be used as the preservative of this nasal spray.
  • the phenylethanol prescription (DEX-004) detected more impurities at 0d and at 10d and 30d, while the benzalkonium chloride prescription (DEX-020) had no significant increase in impurities under light conditions.
  • the level is significantly better than the prescription of phenylethanol.
  • the viscosity of the prepared samples (DEX-102, 103, 106, 107, 108, 110) was measured with a viscometer 0# rotor, and the viscosity measurement results were recorded as shown in Table 7.7 below.
  • the spray width of the selected thickener formulation is slightly smaller than DEX-108 (blank), and the spray angle is approximately equal to or slightly smaller than DEX-108 (blank).
  • the thickeners selected by the present invention have improved prescription viscosity, better corresponding bioadhesion, reduced loss of nasal drug solution, and improved bioavailability.
  • One theory has been verified by the HPMCE50 prescription (Formulation 1-C) of the pharmacokinetics of rhesus monkeys.
  • the addition of thickeners narrowed the spray width, which is not conducive to the increase of the dosing area. Therefore, the spray width of the prescription for adding thickeners was measured.
  • the antibacterial efficacy test prescription was designed according to the following table 7.10.
  • the prescription amount of dexmedetomidine hydrochloride is 0.02% based on dexmedetomidine, and the conversion coefficient of dexmedetomidine hydrochloride and dexmedetomidine is 1.1822.
  • the bacteria tested in the antibacterial efficacy test were DC, TL, JP, BN and HQ.
  • the results of the antibacterial efficacy test are shown in Table 7.11 below.
  • DC refers to Escherichia coli
  • TL refers to Pseudomonas aeruginosa
  • JP refers to Staphylococcus aureus
  • BN refers to Candida albicans
  • HQ refers to Aspergillus niger.
  • the antibacterial effect may be further improved.
  • the antibacterial efficacy of 14 days and 28 days meets the standards A and B of the antibacterial efficacy judgment standard of the Chinese Pharmacopoeia 2015 edition.
  • the compound of 0.1% propylene glycol and 0.01% benzalkonium chloride (prescription DEX-118) was added, and the antibacterial effect was further improved, which can reach the antibacterial A and B standards of nasal preparations, indicating that the compound propylene glycol , Benzalkonium chloride can achieve excellent antibacterial effect.
  • the prescription DEX-119 (0.02% benzalkonium chloride, 1% PVP K30) with the thickener PVP K30 has excellent antibacterial effect and meets the antibacterial A and B standards of nasal preparations, indicating that PVP K30 as a thickener, not only It can thicken the prescription viscosity and improve the bioadhesion without adversely affecting the antibacterial efficacy of the prescription.
  • a preservative propyl paraben, benzalkonium bromide, or preferably a compound preservative, benzalkonium chloride and propylene glycol, propyl paraben and methyl paraben
  • a preservative of this product it can achieve excellent antibacterial effect.
  • the present invention is not limited to the above-mentioned optional embodiments, and anyone can come to other specific solutions in various forms under the enlightenment of the present invention.
  • the above-mentioned specific embodiments should not be construed as limiting the scope of protection of the present invention, and the scope of protection of the present invention should be defined in the claims, and the description can be used to interpret the claims.

Abstract

La présente invention concerne une pulvérisation nasale de dexmédétomidine. La prescription de base comprend un régulateur de pression osmotique, un agent de conservation, un régulateur de pH, un support et une quantité pharmaceutiquement efficace de dexmédétomidine. La pulvérisation nasale de dexmédétomidine selon la prescription a une stabilité élevée et une large applicabilité de pH, malgré la prescription simple. La pulvérisation nasale a un effet rapide, de bonnes propriétés pharmacocinétiques, ne provoque pas d'irritation de la cavité nasale et réduit également le coût de production.
PCT/CN2020/097454 2019-06-28 2020-06-22 Pulvérisation nasale de dexmédétomidine, son procédé de préparation et son utilisation WO2020259440A1 (fr)

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