[go: up one dir, main page]

WO2025140529A1 - Composition de quétiapine de type solution pour administration transnasale et son utilisation - Google Patents

Composition de quétiapine de type solution pour administration transnasale et son utilisation Download PDF

Info

Publication number
WO2025140529A1
WO2025140529A1 PCT/CN2024/143117 CN2024143117W WO2025140529A1 WO 2025140529 A1 WO2025140529 A1 WO 2025140529A1 CN 2024143117 W CN2024143117 W CN 2024143117W WO 2025140529 A1 WO2025140529 A1 WO 2025140529A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
mass percentage
quetiapine
combination
cyclodextrin
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.)
Pending
Application number
PCT/CN2024/143117
Other languages
English (en)
Chinese (zh)
Inventor
韩淼
张文龙
王万
石新玥
张宾
王震宇
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.)
Chengdu Sibeibo Pharmaceutical Technology Co Ltd
Original Assignee
Chengdu Sibeibo Pharmaceutical Technology 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 Chengdu Sibeibo Pharmaceutical Technology Co Ltd filed Critical Chengdu Sibeibo Pharmaceutical Technology Co Ltd
Publication of WO2025140529A1 publication Critical patent/WO2025140529A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • 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
    • 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
    • A61K47/16—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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the invention belongs to the technical field of pharmaceutical preparations, in particular to the field of quetiapine pharmaceutical preparations, and specifically to a novel composition for nasal administration and application thereof.
  • Quetiapine is a new atypical drug for the treatment of psychiatric disorders.
  • the mechanism of action of quetiapine may be to exert its therapeutic effect by antagonizing central D2 receptors and 5-HT2A receptors.
  • AstraZeneca promoted the first launch of quetiapine tablets in the United States.
  • the current approved indications for tablets involve "schizophrenia, bipolar depression, bipolar I mania or mixed symptoms", and the listed specifications of tablets are 25mg, 50mg, 100mg, 200mg, 300mg, and 400mg.
  • quetiapine sustained-release tablets were first launched in the United States.
  • the current approved indications involve "schizophrenia, bipolar depression, bipolar I mania or mixed symptoms, and adjuvant treatment of major depressive disorder", and the listed specifications of sustained-release tablets are 50mg, 150mg, 200mg, 300mg, and 400mg.
  • the quetiapine tablets and sustained-release tablets that have been on the market are both oral preparations, which have common clinical defects of oral preparations such as poor compliance, the existence of first-pass effect leading to slow dissolution, absorption and onset of action, and lower bioavailability. Especially for patients with mental illnesses who are the target of their application, these defects often become unacceptable in the clinical application of the drug.
  • Indian patent applications represented by IN202211053155A provide a nanoemulsion that dissolves quetiapine in an oil phase and then prepares an oil-in-water nanoemulsion.
  • the nanoemulsion is designed to be delivered to the brain through the nasal olfactory pathway to avoid metabolism caused by the first-pass effect of the liver and improve bioavailability.
  • the "Bioavailability and biodistribution studies" section in the patent shows that compared with oral preparations, the C max and AUC 0-480 of the provided nanoemulsion after nasal administration are significantly improved (Table.11).
  • the primary purpose of the present invention is to provide an improved form of quetiapine, which should have a rapid peak or onset time compared to the marketed oral dosage form, and is easy to use and has strong patient compliance.
  • the novel improved form should also have a high bioavailability to avoid the problem of low bioavailability of oral preparations, which requires large doses and brings clinical safety risks.
  • the present invention provides the following technical solutions after extensive attempts:
  • a composition for nasal administration of quetiapine comprising quetiapine or a pharmaceutically acceptable salt thereof, wherein the composition is a solution. That is, the improved form provided by the present invention is a "solution-type nasal administration composition".
  • the present invention formulates quetiapine into a solution type and simultaneously administers it via the nose, which can significantly shorten the peak onset time, such as a significant shortening of Tmax .
  • formulating quetiapine into a solution type and simultaneously administering it via the nose can also take into account the achievement of significantly improved bioavailability, which is not available in conventional improvements.
  • the mass percentage of quetiapine in the composition is 0.22-11.7% or 4.3-11.7% based on the free base.
  • quetiapine is dissolved in the composition in the form of a fumarate, and the mass percentage of quetiapine fumarate in the composition is 0.25-13.4%, 0.25-5%, 0.25-1.7%, 5-13.4%, 5-9.7%, 5-7%, 0.25%, 1.7%, 5%, 5.2%, 6%, 6.5%, 6.6%, 6.7%, 7%, 8.2%, 9.5%, 9.7%, 13%, 13.3% or 13.4%.
  • the solution-type quetiapine nasal administration composition further includes a solubilizer, a cosolvent, a viscosity enhancer, a stabilizer, a preservative, a pH adjuster, and a pH buffer, or a combination of two or more thereof.
  • the solubilizer may optionally include a combination of one or more of benzyl alcohol, DMA, cyclodextrin, and a surfactant
  • the cyclodextrin may optionally include a combination of one or more of ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, and sulfobutyl- ⁇ -cyclodextrin
  • the surfactant may optionally include a combination of one or more of Tween, Span, carbomer, and polyethylene glycol-15 hydroxystearate.
  • Cosolvents may optionally include saturated alcohols
  • saturated alcohols may optionally include a combination of one or more of propylene glycol, ethanol, and glycerol.
  • Viscosifiers may optionally include a combination of one or more of polyethylene glycol, pectin, cellulose, polyethylene hydrocarbon, and polyacrylic acid.
  • Stabilizers may optionally include edetate, and edetate may optionally include EDTA-2Na and/or EDTA-2K.
  • Preservatives may include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, potassium sorbate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, isopropyl parahydroxybenzoate, isobutyl parahydroxybenzoate, sodium propyl parahydroxybenzoate and/or sodium methyl parahydroxybenzoate.
  • pH regulators may include one or more combinations of citric acid, hydrochloric acid, sodium hydroxide, potassium hydroxide and meglumine.
  • pH buffers may include one or more combinations of citrate buffers, phosphate buffers and acetate buffers.
  • the solution-type quetiapine nasal administration composition further comprises a solubilizer, a cosolvent, a viscosity enhancer and water, wherein the solubilizer is benzyl alcohol, and the mass percentage of benzyl alcohol in the composition can be selected to be 1-10%, 1-9.3%, 5-9.3%, 1%, 3.2%, 5%, 7.5% or 9.3%.
  • the cosolvent is one or a combination of two or more of propylene glycol, ethanol and glycerol, preferably propylene glycol; wherein: the mass percentage of propylene glycol in the composition can be selected as 0-12%, 4.6-12%, 6-12%, 4.6%, 4.7%, 5%, 6%, 10%, 11% or 12%, the mass percentage of ethanol in the composition can be selected as 0-20%, 6-20%, 0-19.8%, 18.3-19.8%, 6%, 10%, 18.3%, 18.5% or 19.8%, and the mass percentage of glycerol in the composition can be selected as 0-5%, 0-3%, 0-2.5%, 0-2.2% or 2.2%.
  • the viscosity enhancer is polyethylene glycol, preferably PEG3350 or PEG400; wherein: the mass percentage of PEG3350 in the composition can be selected as 0-20%, 2.5%-15%, 5-15%, 2.5%, 4.6%, 4.7%, 5%, 15% or 20%, and the mass percentage of PEG400 in the composition can be selected as 0-15%, 10% or 15%.
  • the solution-type quetiapine nasal administration composition further comprises a stabilizer, a preservative, a pH regulator and a pH buffer, one or a combination of two or more thereof.
  • the stabilizer is EDTA-2Na
  • the mass percentage of EDTA-2Na in the composition can be selected as 0-0.1% or 0.05%.
  • the preservative is benzalkonium chloride, and the mass percentage of benzalkonium chloride in the composition can be selected as 0-0.02% or 0.02%.
  • the pH regulator is a combination of one or more of citric acid, hydrochloric acid, sodium hydroxide and meglumine, and the pH value of the pH regulator adjusting the composition is 4.1-6.0, 4.5-6.0, 5.0-6.0, 4.1, 4.5, 4.9, 5.0, 5.1, 5.3 or 6.0.
  • the pH buffer is a citrate buffer, a phosphate buffer or an acetate buffer.
  • the second object of the present invention is to increase the saturated solubility concentration of quetiapine in the solution-type quetiapine composition for nasal administration based on the solution-type quetiapine composition for nasal administration provided by the primary object above.
  • the single dosing volume during nasal administration cannot be too high. If the dosing volume is too high, the excess liquid medicine cannot be adsorbed by the nasal mucosa, and will flow out of the nasal cavity or even enter the throat through the nasopharynx. It cannot be absorbed and takes effect, and brings uncomfortable dosing feelings and unnecessary side effects.
  • the single dosing volume of nasal spray is usually no more than 200 ⁇ L, and it is generally best to keep it no more than 100 ⁇ L. When delivered in a "solution type" with such a small dosing volume, the active ingredient of the drug needs to have a higher solubility concentration to ensure the dosage.
  • quetiapine is a drug with a low saturated solubility concentration.
  • the saturated solubility concentration of quetiapine fumarate in water is only 4.0mg/ml. Therefore, in order to ensure the dosage and reduce the number of sprays to reduce nasal irritation, it is very necessary to use means to increase the saturated solubility concentration of quetiapine.
  • a composition for nasal administration with improved solubility concentration of quetiapine comprises quetiapine or a pharmaceutically acceptable salt thereof.
  • the composition is a solution and further comprises a solubilizer.
  • the solubilizer can optionally comprise one or a combination of two or more of benzyl alcohol, DMA, cyclodextrin and a surfactant, preferably benzyl alcohol or DMA.
  • the present invention has found in further research and exploration that for the poorly soluble quetiapine, it is relatively easy to increase the saturated solubility concentration of quetiapine to about 20 mg/mL by using a common solubilization method. However, on this basis, it becomes increasingly difficult to further increase the saturated solubility concentration of quetiapine, especially to increase it to more than 50 mg/mL. In order to deliver therapeutic dose drugs under a smaller administration volume, it is advantageous or even necessary to increase the drug concentration to more than 50 mg/mL. In the extensive testing of the present invention, it is surprisingly found that the use of solubilizing agent benzyl alcohol or DMA is very beneficial for increasing the saturated solubility concentration of quetiapine to a higher concentration of more than 50 mg/mL.
  • benzyl alcohol is also an inactive ingredient excipient included in the "FDA Drug Inactive Ingredient Database” and allowed to be applicable to the nasal spray administration route, and its irritation and safety of the nasal route have been recognized by regulatory verification), and is very suitable as a solubilizing agent for the solution-type quetiapine nasal administration composition provided by the present invention.
  • benzyl alcohol is widely used as a preservative and disinfectant in the industry, and in the solution-type quetiapine nasal composition of the present invention, the addition of benzyl alcohol unexpectedly has a significant and beneficial help to the improvement of the saturated solubility concentration of quetiapine. Therefore, benzyl alcohol is used as the most preferred solubilizing agent for the solution-type quetiapine nasal administration composition provided by the present invention.
  • the solubilizer in the solution-type nasal administration composition for increasing the solubility concentration of quetiapine does not contain other types of solubilizers that are more irritating to the nasal cavity than benzyl alcohol; as several specific options: the solubilizer in the composition may only contain benzyl alcohol, or the solubilizer in the composition may only contain benzyl alcohol and cyclodextrin, or the solubilizer in the composition may only contain benzyl alcohol and a surfactant, or the solubilizer in the composition may only contain benzyl alcohol, cyclodextrin and a surfactant.
  • the mass percentage of benzyl alcohol in the composition can be 1-10%, 3.2-10%, 5-10%, 5-9.3%, 5-7.5%, 1%, 3.2%, 5%, 7.5%, 9.3% or 10%.
  • the amount of quetiapine added in the composition can fluctuate within ⁇ 20% of the amount of quetiapine added, that is, preferably, the mass ratio of benzyl alcohol to quetiapine in the composition is 1:0.8-1.2.
  • the solution-type nasal administration composition for improving the dissolution concentration of quetiapine of the present invention also includes a cosolvent, which can optionally include a saturated alcohol, and the saturated alcohol can optionally include one or more combinations of propylene glycol, ethanol and glycerol, and the saturated alcohol is preferably propylene glycol, or a combination of propylene glycol and ethanol.
  • a cosolvent such as propylene glycol, can promote the dissolution of poorly soluble drugs, which is helpful for further improving the saturated dissolution concentration of quetiapine in the provided composition.
  • the mass percentage of propylene glycol in the composition can be selected as 0-12%, 4.6-12%, 6-12%, 4.6%, 4.7%, 5%, 6%, 10%, 11% or 12%.
  • the mass percentage of ethanol in the composition can be selected as 0-20%, 6-20%, 0-19.8%, 18.3-19.8%, 6%, 10%, 18.3%, 18.5% or 19.8%.
  • the mass percentage of glycerol in the composition can be selected as 0-5%, 0-3%, 0-2.5%, 0-2.2% or 2.2%.
  • the solution-type nasal administration composition for improving the solubility concentration of quetiapine of the present invention further includes a surfactant and/or polyethylene glycol, preferably also includes one or more combinations of Tween, PEG3350 and PEG400, and Tween includes Tween 80 or Tween 20.
  • Tween includes Tween 80 or Tween 20.
  • the addition of these additional substances can further stabilize the solution system, especially inhibit the accidental precipitation of quetiapine under high or low temperature conditions.
  • the mass percentage of PEG3350 in the composition can be selected as 0-20%, 2.5%-15%, 5-15%, 2.5%, 4.6%, 4.7%, 5%, 15% or 20%.
  • the mass percentage of PEG400 in the composition can be selected as 0-15%, 10% or 15%.
  • the mass percentage of Tween in the composition can be selected as 0-1.5%, 0.5%, 1%, 1.4% or 1.5%.
  • the solution-type nasal administration composition for improving the dissolution concentration of quetiapine of the present invention further comprises cyclodextrin, which comprises one or a combination of two or more of ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and sulfobutyl- ⁇ -cyclodextrin, and the mass percentage of cyclodextrin in the composition can be selected as 0-10%, 1-5% or 5%.
  • Cyclodextrin has a certain improvement on the saturated dissolution concentration of the quetiapine solution composition, but when used alone, it is not as effective as benzyl alcohol or DMA.
  • the dissolution concentration of quetiapine in the composition is 4.3-11.7% by mass as a free base.
  • the dissolution concentration of quetiapine free base is 5.6-11.7% by mass.
  • quetiapine is preferably dissolved in the composition in the form of fumarate, and the mass percentage of quetiapine fumarate in the composition is 5-13.4%, 5-9.7%, 5-7%, 5%, 5.2%, 6%, 6.5%, 6.6%, 6.7%, 7%, 8.2%, 9.5%, 9.7%, 13%, 13.3% or 13.4%.
  • the higher active ingredient concentration is particularly suitable for nasal spray administration, which can significantly reduce the number of nasal sprays during single treatment, thereby reducing frequent stimulation of the nasal cavity and alleviating clinical medication discomfort and side effects such as sneezing and tingling.
  • the solution-type nasal administration composition for increasing the solubility concentration of quetiapine of the present invention is an aqueous solution, which further includes water and one or a combination of two or more of a viscosity enhancer, a stabilizer, a preservative, a pH adjuster and a pH buffer.
  • a viscosity enhancer e.g., a viscosity enhancer, a stabilizer, a preservative, a pH adjuster and a pH buffer.
  • the optional excipients described in the second object of the present invention of "viscosity enhancer, stabilizer, preservative, pH adjuster and pH buffer" can be selected in any combination with reference to the corresponding excipient types and amounts mentioned anywhere in the primary object of the present invention.
  • the third object of the present invention is to further provide a composition with good chemical stability based on the solution-type quetiapine composition for nasal administration provided by the first and second objects above.
  • a stable composition for nasal administration which is a solution comprising water and the following components:
  • the mass percentage of quetiapine in the composition is 4.3-11.7% based on the free base.
  • quetiapine is preferably dissolved in the composition in the form of fumarate, and the mass percentage of quetiapine fumarate in the composition is 0.25-13.4%, 0.25-5%, 0.25-1.7%, 5-13.4%, 5-9.7%, 5-7%, 0.25%, 1.7%, 5%, 5.2%, 6%, 6.5%, 6.6%, 6.7%, 7%, 8.2%, 9.5%, 9.7%, 13%, 13.3% or 13.4%.
  • the solubilizer in the stable solution-type quetiapine nasal administration composition includes one or a combination of two or more of benzyl alcohol, cyclodextrin, Tween and polyethylene glycol-15 hydroxystearate, cyclodextrin may include hydroxypropyl- ⁇ -cyclodextrin, and Tween may include Tween 80 and/or Tween 20.
  • the mass percentage of benzyl alcohol in the composition may be 1-10%, 1-9.3%, 5-9.3%, 1%, 3.2%, 5%, 7.5% or 9.3%
  • the mass percentage of cyclodextrin in the composition may be 0-5% or 5%
  • the mass percentage of Tween in the composition may be 0-1.4%, 1% or 1.4%
  • the mass percentage of polyethylene glycol-15 hydroxystearate in the composition may be 0-3%, 1.5% or 3%.
  • the cosolvent in the stable solution-type quetiapine nasal administration composition includes one or a combination of two or more of propylene glycol, ethanol and glycerol.
  • the mass percentage of propylene glycol in the composition can be selected as 0-12%, 4.6-12%, 6-12%, 4.6%, 4.7%, 6%, 11% or 12%
  • the mass percentage of ethanol in the composition can be selected as 0-20%, 0-19.8%, 18.3-19.8%, 18.3%, 18.5% or 19.8%
  • the mass percentage of glycerol in the composition can be selected as 0-5%, 0-3%, 0-2.5%, 0-2.2% or 2.2%.
  • the viscosity enhancer in the stable solution-type quetiapine nasal administration composition includes polyethylene glycol and/or pectin, and the polyethylene glycol may include PEG3350 and/or PEG400.
  • the mass percentage of PEG3350 in the composition may be 0-5%, 2.5%-5%, 2.5%, 4.6%, 4.7% or 5%
  • the mass percentage of PEG400 in the composition may be 0-15% or 15%
  • the mass percentage of pectin in the composition may be 0-1% or 0.7%.
  • the stable solution-type quetiapine nasal composition further comprises any one or a combination of two or more of the following components:
  • the stabilizer in the stable solution-type quetiapine nasal administration composition includes edetate, which includes disodium edetate and/or dipotassium edetate, and the mass percentage of disodium edetate in the composition can be 0-0.1% or 0.05%.
  • the preservative includes benzalkonium chloride, and the mass percentage of benzalkonium chloride in the composition can be 0-0.02% or 0.02%.
  • the pH adjuster in the stable solution-type quetiapine nasal composition includes one or a combination of two or more of sodium hydroxide, potassium hydroxide, meglumine, citric acid and hydrochloric acid, and the amount of the pH adjuster added can be selected to adjust the pH of the composition to 4.1-6.0, 4.5-6.0, 5.0-6.0, 4.1, 4.5, 4.9, 5.0, 5.1, 5.3 or 6.0.
  • the mass percentage of meglumine in the stable solution-type quetiapine nasal composition can be 0-0.5%, 0.02%, 0.25% or 0.5%
  • the citric acid can be 1M citric acid solution.
  • the stable solution-type quetiapine nasal composition may or may not be added with a pH buffer, and the pH buffer may optionally include one or a combination of two or more of a citrate buffer, a phosphate buffer, and an acetate buffer.
  • the stable solution-type quetiapine nasal administration composition consists only of quetiapine fumarate, a solubilizer, a cosolvent, a viscosity enhancer and water, and does not contain other unspecified components except for the pharmaceutically acceptable impurity content
  • the solubilizer is benzyl alcohol
  • the cosolvent is one or a combination of two or more of propylene glycol, ethanol and glycerol, in particular propylene glycol
  • the viscosity enhancer is PEG3350 and/or PEG400.
  • the composition may also be optionally added with or without one or a combination of two or more of benzalkonium chloride, a pH adjuster and a pH buffer.
  • the present invention also provides a quetiapine nasal spray, which comprises any of the above-mentioned quetiapine solution-type nasal composition described in the present invention and a quantitative nasal spray device for delivering the composition into the nasal cavity, and the volume of the composition delivered by each spray of the quantitative nasal spray device can be selected as 25-200 ⁇ L, 50-150 ⁇ L, 25 ⁇ L, 50 ⁇ L, 75 ⁇ L, 100 ⁇ L, 125 ⁇ L, 150 ⁇ L, 175 ⁇ L or 200 ⁇ L.
  • the present invention also provides the use of any of the aforementioned solution-type quetiapine nasal administration compositions of the present invention or the aforementioned quetiapine nasal spray of the present invention in the preparation of drugs for treating mental illnesses.
  • Figure 2 shows the total movement distance of the experimental rats in Example A, Example 2, 60-150 minutes after the start of the test.
  • the data are expressed as Mean ⁇ SEM, and one-way ANOVA was used (comparison of test substance A with test substance D, * indicates p ⁇ 0.05).
  • the density of the solution composition is approximately converted to 1 g/mL.
  • the balance means adding the corresponding components to 100%.
  • Example A Animal study on the pharmacokinetic and pharmacodynamic properties of the solution-type nasal administration composition of the present invention
  • Example 1 In vivo pharmacokinetic study in beagle dogs
  • the purpose of this experimental study is to evaluate and compare the pharmacokinetic characteristics of the solution-type nasal administration composition of the present invention, oral tablets, and injections after administration to beagle dogs.
  • test substances A and B are as follows:
  • Group C quetiapine fumarate tablets were purchased from Hunan Dongting Pharmaceutical Co., Ltd. through ordinary commercial channels.
  • the injection in group D was prepared by dissolving quetiapine fumarate in normal saline.
  • mice in each group were randomly divided into 4 groups. Except for one group that was randomly given intravenous injection of test substance D, the other three groups were given test substances A, B, and C in rotation in each cycle for cross-administration. The administration was given for three cycles in total, with a 7-day washout period before changing the test substance in each cycle.
  • the dosage of the oral group and the intravenous injection group was set at 25 mg/piece, and the dosage of the nasal spray group was set at 27.75 mg/piece.
  • the dosage was corrected to the same dosage for calculation of pharmacokinetic parameters.
  • C oral group before administration (0h), 25min, 45min, 1h, 1.5h, 2h, 4h, 6h, 8h, and 12h after administration.
  • test substances A, B, C or D were given test substances A, B, C or D in different ways while the animals were awake.
  • methamphetamine modeling was performed (intraperitoneal injection).
  • the methamphetamine dosage was 3 mg/kg to induce hyperactivity in the animals.
  • the animals were placed in an observation box after drug administration and observed and recorded for 90 minutes.
  • the distance (meters) the animals moved in the observation box was counted every 5 minutes, and abnormal phenomena such as toxic reactions or deaths of animals during the experiment were recorded in a timely manner.
  • the saturated solubility concentration is higher at a moderately lower pH, and the optimal pH for the solution type is 4.5-6.5. Even if the pH value is controlled at a lower level, the saturated solubility concentration of quetiapine fumarate is still at a low level, which cannot meet the needs of nasal delivery of solution-type preparations.
  • the present invention further tested the following prescription solvents, and the saturated solubility concentration of quetiapine fumarate was as follows:
  • test process and results show that the above preparations have a certain improvement in the saturated solubility concentration of quetiapine fumarate, but the improvement is still limited and still difficult to meet the needs of nasal delivery solution preparations. It also shows that different types of buffer salts have no obvious effect on the saturated solubility concentration, but have a certain effect on the dissolution rate, and citric acid buffer is relatively better.
  • test process and results show that the addition of DMA significantly increases the saturated solubility concentration of quetiapine fumarate, making it suitable for nasal spray administration.
  • An active ingredient concentration greater than 50 mg/mL for nasal spray administration can significantly reduce the frequency of administration and thus reduce the corresponding nasal irritation.
  • Example C Chemical stability study of the solution-type nasal composition of the present invention
  • the above prescription was tested for 30 days at long-term (25°C, 75% RH) and accelerated (40°C, 75% RH).
  • the test and analysis data are as follows:
  • the above prescription was tested for 24 days at long-term (25°C, 75% RH) and accelerated (40°C, 75% RH).
  • the test and analysis data are as follows:

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Neurology (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention se rapporte au domaine technique des préparations pharmaceutiques, et concerne une nouvelle composition de quétiapine de type solution pour administration transnasale. Dans la composition selon l'invention, la quétiapine est complètement dissoute dans celle-ci sous la forme d'une solution et administrée par voie transnasale. Par rapport à des formes posologiques orales commercialisées, la préparation transnasale de type solution de quétiapine selon l'invention présente des profils pharmacocinétiques et pharmacodynamiques particulièrement utiles. Par rapport à d'autres formes de nanoémulsion transnasale divulguées, la composition de la présente invention présente encore des profils pharmacocinétiques et pharmacodynamiques surprenants, présente de bonnes perspectives d'application clinique, et devrait répondre à des besoins cliniques non satisfaits. Sur cette base, la présente invention concerne en outre une nouvelle solution technique de concentration de dissolution à saturation élevée améliorée et une nouvelle solution technique de stabilité chimique satisfaisante améliorée pour préparer la préparation transnasale de type solution de quétiapine.
PCT/CN2024/143117 2023-12-29 2024-12-27 Composition de quétiapine de type solution pour administration transnasale et son utilisation Pending WO2025140529A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202311871438 2023-12-29
CN202311871438.2 2023-12-29

Publications (1)

Publication Number Publication Date
WO2025140529A1 true WO2025140529A1 (fr) 2025-07-03

Family

ID=96216847

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/143117 Pending WO2025140529A1 (fr) 2023-12-29 2024-12-27 Composition de quétiapine de type solution pour administration transnasale et son utilisation

Country Status (1)

Country Link
WO (1) WO2025140529A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1880725A1 (fr) * 2006-07-13 2008-01-23 Neuraxpharm Arzneimittel GmbH u. Co. KG Formulation liquide comprenant du clozapine, du quétiapine, d'un sel de quétiapine et/ou de l'olanzapine pour administration orale
EP1880724A1 (fr) * 2006-07-13 2008-01-23 Neuraxpharm Arzneimittel GmbH u. Co. KG Formulation liquide comprenant du clozapine, du quétiapine, d'un sel de quétiapine at/ou de l'olanzapine pour administration orale
CN102552128A (zh) * 2012-02-28 2012-07-11 陆荣政 一种富马酸喹硫平注射液及其制备方法
US20200290999A1 (en) * 2017-10-06 2020-09-17 Leyden Technologies B.V. Stable solutions of multicyclic antidepressants
US20210121477A1 (en) * 2019-10-29 2021-04-29 OWP Pharmaceuticals, Inc. Quetiapine oral liquid suspension and use thereof
IN202211053155A (fr) * 2022-09-16 2022-09-23

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1880725A1 (fr) * 2006-07-13 2008-01-23 Neuraxpharm Arzneimittel GmbH u. Co. KG Formulation liquide comprenant du clozapine, du quétiapine, d'un sel de quétiapine et/ou de l'olanzapine pour administration orale
EP1880724A1 (fr) * 2006-07-13 2008-01-23 Neuraxpharm Arzneimittel GmbH u. Co. KG Formulation liquide comprenant du clozapine, du quétiapine, d'un sel de quétiapine at/ou de l'olanzapine pour administration orale
CN102552128A (zh) * 2012-02-28 2012-07-11 陆荣政 一种富马酸喹硫平注射液及其制备方法
US20200290999A1 (en) * 2017-10-06 2020-09-17 Leyden Technologies B.V. Stable solutions of multicyclic antidepressants
US20210121477A1 (en) * 2019-10-29 2021-04-29 OWP Pharmaceuticals, Inc. Quetiapine oral liquid suspension and use thereof
IN202211053155A (fr) * 2022-09-16 2022-09-23

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MITHILA, B. ET AL.: "Quetiapine Nanoemulsion for Intranasal Drug Delivery: Evaluation of Brain-Targeting Efficiency", AAPS PHARMSCITECH, vol. 18, no. 3, 20 May 2016 (2016-05-20), XP036201343, ISSN: 1530-9932, DOI: 10.1208/s12249-016-0552-9 *

Similar Documents

Publication Publication Date Title
JP5683719B2 (ja) ベポタスチン組成物
CA2460140C (fr) Compositions de traitement d'un rhume simple
EP2522365B1 (fr) Compositions comprenant de l'azélastine et leurs procédés d'utilisation
JPWO2007086493A1 (ja) 経鼻投与用薬剤
US20220339124A1 (en) Intranasal pharmaceutical compositions of cyclobenzaprine
US12324811B2 (en) Intranasal formulation
WO2025140529A1 (fr) Composition de quétiapine de type solution pour administration transnasale et son utilisation
WO2024109652A1 (fr) Utilisation d'un composé de gallate de (-)-épigallocatéchine
US20220370445A1 (en) Methods for administering (r)-n-[4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)phenyl]acetamide
US20250228836A1 (en) Bilastine composition for once-daily parenteral administration
WO2025068591A1 (fr) Formulations intranasales pour traiter l'apnée obstructive du sommeil
AU2002329578B2 (en) Compositions for treatment of common cold
KR20160090312A (ko) 조산 조건의 치료에서 사용을 위한 용량 단위의 조합
WO2025036183A1 (fr) Préparation pour administration du nez au cerveau de nimodipine, son procédé de préparation et son utilisation
JP2008273867A (ja) 経粘膜投与用製剤
EA037259B1 (ru) Применение фармацевтической композиции с фиксированной дозой, содержащей мометазон и азеластин, для лечения аллергического ринита и способ лечения аллергического ринита
AU2002329578A1 (en) Compositions for treatment of common cold
HK1092064A (en) Compositions comprising ipatropium and xylometazoline for treatment of the common cold
HK1067984B (en) Compositions comprising ipatropium and xylometazoline for treatment of the common cold

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24911449

Country of ref document: EP

Kind code of ref document: A1