WO2023025095A1 - 右美托咪定经皮组合物、透皮贴剂及其制备方法和应用 - Google Patents

右美托咪定经皮组合物、透皮贴剂及其制备方法和应用 Download PDF

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WO2023025095A1
WO2023025095A1 PCT/CN2022/113953 CN2022113953W WO2023025095A1 WO 2023025095 A1 WO2023025095 A1 WO 2023025095A1 CN 2022113953 W CN2022113953 W CN 2022113953W WO 2023025095 A1 WO2023025095 A1 WO 2023025095A1
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Prior art keywords
dexmedetomidine
sensitive adhesive
prescription
propylene glycol
parts
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PCT/CN2022/113953
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English (en)
French (fr)
Inventor
刘朋
李柯
吴有斌
林霞
袁靖
吕金良
田峦鸢
李莉娥
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宜昌人福药业有限责任公司
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Priority to CA3227166A priority Critical patent/CA3227166A1/en
Priority to EP22860441.9A priority patent/EP4364729A1/en
Priority to CN202280052393.3A priority patent/CN117750949A/zh
Priority to KR1020247003714A priority patent/KR20240027808A/ko
Publication of WO2023025095A1 publication Critical patent/WO2023025095A1/zh

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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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • 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
    • A61K47/06—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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the application relates to but not limited to the field of pharmaceutical preparations, in particular to a dexmedetomidine transdermal composition, a transdermal patch and a preparation method and application thereof.
  • dexmedetomidine hydrochloride injection is available on the market at home and abroad, and it can only be used under the close supervision of professional medical staff. Sedation, while the half-life of dexmedetomidine is only 2 hours after injection, and the duration of drug effect is short.
  • Prior Art Chinese Patent Application No. CN201480059798.5 discloses a dexmedetomidine transdermal composition.
  • the average dexmedetomidine flow rate of different dexmedetomidine transdermal compositions with application time was tested.
  • the inventors found that the flux of the dexmedetomidine transdermal composition provided by the application was poor, and in some embodiments, the transdermal composition only provided a flux of less than 0.5ug/cm 2 *h, and the transdermal diffusion rate It reaches the maximum at 24h.
  • the application provides dexmedetomidine transdermal composition, transdermal patch, preparation method and application thereof.
  • the product has a better transdermal diffusion rate and good stability, and can achieve a sustained release effect of 2 to 5 days.
  • the application provides a dexmedetomidine transdermal composition
  • the composition includes dexmedetomidine, propylene glycol and metal chelate cross-linking agent;
  • the mass ratio of the propylene glycol to the dexmedetomidine is (4:3)-(8:3).
  • the present application provides a dexmedetomidine transdermal composition, which comprises dexmedetomidine, propylene glycol, a metal chelate crosslinking agent and a pressure-sensitive adhesive;
  • the mass ratio of the propylene glycol to the dexmedetomidine is (4:3)-(8:3).
  • the application provides a dexmedetomidine transdermal patch, wherein the transdermal patch comprises a backing layer, an adhesive layer and an anti-adhesive release film layer in sequence; the adhesive layer It is formed by the dexmedetomidine transdermal composition described in the first aspect or the second aspect.
  • the present application provides a method for preparing the dexmedetomidine transdermal composition described in the second aspect, the preparation method comprising the following steps:
  • the dexmedetomidine solution was mixed with the blank matrix solution, stirred, allowed to stand, and dried.
  • the present application provides the preparation method of the dexmedetomidine transdermal patch described in the third aspect, comprising the following steps:
  • the dexmedetomidine solution is mixed with the blank matrix solution, stirred, and left to stand to obtain the drug-containing matrix solution;
  • the present application provides the application of the above-mentioned dexmedetomidine transdermal composition or dexmedetomidine transdermal patch in the preparation of pharmaceutical preparations for improving sleep disorders.
  • the present application provides a method for improving sleep disorders in individuals, the method comprising administering the above-mentioned dexmedetomidine transdermal composition or dexmedetomidine transdermal patch to the individual in need.
  • the present application provides a dexmedetomidine transdermal composition, which comprises dexmedetomidine, propylene glycol and a metal chelate cross-linking agent.
  • Metal chelate crosslinking agent 0.30-1.25 parts.
  • Metal chelate crosslinking agent 0.30-1.25 parts.
  • Metal chelate crosslinking agent 0.30-0.80 parts.
  • Metal chelate crosslinking agent 0.30-0.80 parts.
  • the mass ratio of propylene glycol to dexmedetomidine in the composition is (4:3)-(8:3).
  • the mass ratio of propylene glycol to dexmedetomidine in the composition is (5:3)-(7:3).
  • the mass ratio of propylene glycol to dexmedetomidine in the composition is 5:3.
  • the metal chelate crosslinking agent is selected from one or more of aluminum acetylacetonate, zirconium acetylacetonate, titanium acetylacetonate and polybutyl titanate .
  • the metal chelate crosslinking agent is aluminum acetylacetonate or polybutyl titanate.
  • the metal chelate crosslinking agent titanium acetylacetonate is (oxy)titanium acetylacetonate or titanium tetraacetylacetonate, or a mixture thereof.
  • the present application provides a dexmedetomidine transdermal composition, which comprises dexmedetomidine, propylene glycol, a metal chelate crosslinking agent and a pressure-sensitive adhesive.
  • the mass ratio of the propylene glycol to the dexmedetomidine is (4:3)-(8:3).
  • the composition comprises 0.72-3.00 parts, 0.72-1.80 parts, 0.72-1.45 parts or 1.00-1.80 parts of dexmedetomidine.
  • the mass ratio of the pressure-sensitive adhesive to the metal chelate crosslinking agent in the composition is (70:1)-(310:1).
  • the mass ratio of propylene glycol to dexmedetomidine in the composition is (4:3)-(8:3).
  • the mass ratio of propylene glycol to dexmedetomidine in the composition is (5:3)-(7:3).
  • the mass ratio of propylene glycol to dexmedetomidine in the composition is 5:3.
  • the mass ratio of the pressure-sensitive adhesive to the metal chelate crosslinking agent in the composition is (70:1)-(160:1), (160:1)- (220:1) or (220:1)-(310:1).
  • the mass ratio of the pressure-sensitive adhesive to the metal chelate crosslinking agent in the composition is (160:1)-(220:1), (160:1)- (210:1), (160:1)-(200:1) or (190:1)-(220:1).
  • the mass ratio of the pressure-sensitive adhesive to the metal chelate crosslinking agent in the composition is 160:1, 170:1, 180:1, 190:1, 200: 1. 210:1 or 220:1.
  • the mass ratio of the pressure-sensitive adhesive to the metal chelate crosslinking agent in the composition is 190:1.
  • the composition comprises 0.30-0.70 part of a metal chelate crosslinking agent.
  • the composition comprises 0.40-0.60 part of a metal chelate crosslinking agent.
  • the composition comprises 0.50 part of a metal chelate crosslinking agent.
  • the metal chelate crosslinking agent is selected from one or more of aluminum acetylacetonate, zirconium acetylacetonate, titanium acetylacetonate and polybutyl titanate .
  • the metal chelate crosslinking agent is aluminum acetylacetonate or polybutyl titanate.
  • the metal chelate crosslinking agent titanium acetylacetonate is (oxygen) titanium acetylacetonate or titanium tetraacetylacetonate, or a mixture thereof.
  • the pressure-sensitive adhesive is selected from acrylate pressure-sensitive adhesives, polyisobutylene pressure-sensitive adhesives, silicone pressure-sensitive adhesives, styrene-isoprene-styrene hot-melt pressure-sensitive adhesives One or more of glue (SIS type) and vinyl acetate copolymer.
  • the acrylate pressure sensitive adhesive is Duro-Tak 387-2510 or DURO-TAK 387-2287.
  • the application provides a dexmedetomidine transdermal patch, which comprises a backing layer, an adhesive layer, and an anti-adhesive release film layer in sequence; the adhesive layer consists of the above-mentioned dexmedetomidine A mididine transdermal composition is formed.
  • the thickness of the adhesive layer is 25 ⁇ m-100 ⁇ m.
  • the present application provides a preparation method of the above-mentioned dexmedetomidine transdermal composition, the preparation method comprising the following steps:
  • the dexmedetomidine solution was mixed with the blank matrix solution, stirred, allowed to stand, and dried.
  • the solvent is selected from one or a mixture of absolute ethanol and n-heptane.
  • the present application provides a method for preparing the above-mentioned dexmedetomidine transdermal patch, the preparation method comprising the following steps:
  • the dexmedetomidine solution is mixed with the blank matrix solution, stirred, and left to stand to obtain the drug-containing matrix solution;
  • the solvent is selected from one or a mixture of absolute ethanol and n-heptane.
  • the present application provides the application of the above-mentioned dexmedetomidine transdermal composition or dexmedetomidine transdermal patch in the preparation of pharmaceutical preparations for improving sleep disorders.
  • the sleep disorder is one or more of perioperative sleep disorder, elderly sleep disorder, and traumatic sleep disorder.
  • the present application provides a method for improving sleep disorders in individuals, the method comprising administering the above-mentioned dexmedetomidine transdermal composition or dexmedetomidine transdermal patch to the individual in need.
  • the sleep disorder is one or more of perioperative sleep disorder, elderly sleep disorder, and traumatic sleep disorder.
  • the present application creatively adds a specific content of propylene glycol to the dexmedetomidine composition, and makes the mass ratio of propylene glycol to the main drug dexmedetomidine be (4:3)-(8:3), and at the same time select metal
  • the chelate cross-linking agent and the pressure-sensitive adhesive are jointly used as the skeleton structure of dexmedetomidine, so that the dexmedetomidine transdermal composition described in the application has a large in vitro diffusivity and stable product quality; Selling dexmedetomidine hydrochloride injection, which is convenient for administration and can achieve sustained release for 2-5 days to ensure the sleep quality of patients after use.
  • Fig. 1 is the preparation schematic diagram of a kind of dexmedetomidine transdermal patch that the application proposes;
  • Fig. 2 is the structural representation of a kind of dexmedetomidine transdermal patch proposed by the present application; Wherein, A: side view of dexmedetomidine transdermal patch; B: top view of dexmedetomidine transdermal patch ;
  • Fig. 3 is the in vitro transdermal diffusion curve of a kind of dexmedetomidine transdermal patch proposed by the application with different thicknesses;
  • Fig. 4 is the crystallization figure of a kind of dexmedetomidine transdermal composition proposed by the present application after storage for 6 months; wherein, A is 10 times imaging, and B is 40 times imaging;
  • Fig. 5 is a line chart of the autonomic activity data of mice applied with a kind of dexmedetomidine transdermal composition proposed by the present application to improve sleep;
  • Fig. 7 is a comparison curve of transdermal diffusion rate per unit area of Example 4, Example 7 and Comparative Example 1 of the present application.
  • NREM sleep non-rapid eye movement sleep, non-rapid eye movement sleep, characterized by slowing down of brain and eye movements, it belongs to the main stage of deep sleep and metabolism.
  • REM sleep rapideye movement sleep, rapid eye movement sleep, characterized by brain activity that has not completely stopped, and belongs to the stage of light sleep and dreaming.
  • the present application provides a dexmedetomidine composition, wherein the calculation method of each component is as follows:
  • Weight percentage X(%) X/(A+B+C+D*d)*100%
  • A is the weight of dexmedetomidine
  • B is the weight of propylene glycol
  • C is the weight of the metal chelate crosslinking agent
  • D is the weight of the pressure-sensitive adhesive
  • d is the corresponding pressure-sensitive adhesive type used in the composition.
  • the present application provides a kind of dexmedetomidine transdermal composition
  • described transdermal composition comprises dexmedetomidine, propylene glycol, metal chelate cross-linking agent and pressure sensitive glue
  • the content of the dexmedetomidine is 0.30-3.00 parts
  • the content ratio of the propylene glycol to the dexmedetomidine is (4:3)-(8:3).
  • the transdermal composition of dexmedetomidine provided by the present application comprises 0.72-1.45 parts or 1.00-1.80 parts of dexmedetomidine; preferably, comprises 0.72 parts of dexmedetomidine -1.00 parts, 1.00-1.45 parts or 1.45-1.80 parts.
  • the transdermal composition of dexmedetomidine provided by the present application comprises 0.72 parts, 1.00 parts, 1.45 parts or 1.80 parts of dexmedetomidine; more preferably, comprises dexmedetomidine Midine 1.00 parts.
  • the content ratio of the propylene glycol to the dexmedetomidine is 4:3, 5:3, 6: 3. 7:3 or 8:3; preferably, the content ratio of propylene glycol to dexmedetomidine is (5:3)-(7:3); more preferably, the content ratio of propylene glycol to dexmedetomidine It is 5:3.
  • the transdermal composition of dexmedetomidine provided by the present application comprises 0.40-8.00 parts, 1.20-4.20 parts, 1.31-2.42 parts, 1.44-2.42 parts, 1.44-1.67 parts of propylene glycol , 1.44-4.20 parts, 1.44-8.00 parts, 1.31-1.67 parts or 1.67-2.42 parts; preferably, 1.20-4.20 parts of propylene glycol are included.
  • the transdermal composition of dexmedetomidine provided by the present application comprises 0.4 parts, 1.2 parts, 1.31 parts, 1.44 parts, 1.67 parts, 2.42 parts, 4.20 parts or 8.00 parts of propylene glycol; Preferably, it contains 1.67 parts of propylene glycol.
  • the mass ratio of the pressure-sensitive adhesive to the metal chelate crosslinking agent is (70:1)- (160:1), (160:1)-(220:1) or (220:1)-(310:1); preferably, the pressure-sensitive adhesive and the metal chelate crosslinking agent
  • the mass ratio is (160:1)-(190:1) or (190:1)-(220:1); more preferably, the mass ratio of the pressure-sensitive adhesive to the metal chelate crosslinking agent It is 190:1.
  • the metal chelate crosslinking agent is selected from aluminum acetylacetonate, zirconium acetylacetonate, titanium acetylacetonate and one or more of polybutyl titanate.
  • the metal chelate crosslinking agent titanium acetylacetonate is selected from (oxygen) titanium acetylacetonate and tetraacetyl One or both of titanium pyruvate.
  • the content range of the metal chelate crosslinking agent is 0.30-1.25 parts, 0.30-0.80 parts, 0.30 parts -0.60 parts, 0.45-0.60 parts, 0.45-0.80 parts, 0.45-1.25 parts or 0.30-0.50 parts; preferably, the content range of the metal chelate crosslinking agent is 0.30-0.80 parts.
  • the content of the metal chelate crosslinking agent is 0.30 parts, 0.45 parts, 0.50 parts, 0.60 parts, 0.80 or 1.25 parts; preferably, the content of the metal chelate crosslinking agent is 0.5 parts.
  • the pressure-sensitive adhesive is selected from the group consisting of acrylate pressure-sensitive adhesive, polyisobutylene pressure-sensitive adhesive, silicone pressure-sensitive adhesive, styrene - one or more of isoprene-styrene hot melt pressure sensitive adhesive (SIS type), vinyl acetate copolymer.
  • the acrylate pressure-sensitive adhesive is one of the following types of pressure-sensitive adhesives: DURO-TAK 387-2287, DURO-TAK 387-2510, DURO-TAK 387-2516, DURO-TAK 87-235A, DURO- TAK 387-2353, DURO-TAK 387-2852, DURO-TAK 387-2051, DURO-TAK 387-2052, DURO-TAK 387-2054, DURO-TAK 87-4287, DURO-TAK 87-6908, and DURO-TAK 87-267.
  • the content ratio of the pressure-sensitive adhesive to the metal chelate crosslinking agent is (70:1) -(310:1), (70:1)-(220:1), (70:1)-(200:1), (110:1)-(310:1), (110:1)-( 220:1), (110:1)-(200:1), (150:1)-(310:1), (150:1)-(220:1), (150:1)-(200:1) 1), (180:1)-(310:1), (180:1)-(220:1) or (180:1)-(200:1).
  • the dexmedetomidine transdermal composition provided by the present application includes 0.72-1.80 parts of dexmedetomidine, 0.30-0.80 parts of metal chelate cross-linking agent, acrylate pressure-sensitive 93.00-99.00 parts of glue and propylene glycol, the content ratio of the propylene glycol to the dexmedetomidine is (4:3)-(8:3).
  • the metal chelate crosslinking agent is polybutyl titanate or aluminum acetylacetonate.
  • the acrylate pressure-sensitive adhesive is Duro-Tak 387-2510 or DURO-TAK 387-2287.
  • the application of the dexmedetomidine transdermal composition provided in the present application in the preparation of a transdermal patch.
  • the dexmedetomidine transdermal patch provided by the present application comprises the dexmedetomidine transdermal composition.
  • the present application provides a dexmedetomidine transdermal patch, and the dexmedetomidine transdermal composition forms an adhesive layer of the transdermal patch.
  • the thickness of the adhesive layer is 25 ⁇ m-100 ⁇ m.
  • the dexmedetomidine transdermal patch provided by the application comprises a backing layer, an anti-adhesive release film layer and a Adhesive layer;
  • the adhesive layer includes 0.72-1.80 parts of dexmedetomidine, 0.30-0.80 parts of polybutyl titanate, 93.00-99.00 parts of acrylate pressure-sensitive adhesive, and propylene glycol; the propylene glycol and the The content ratio of dexmedetomidine is (4:3)-(8:3), and the acrylate pressure-sensitive adhesive is Duro-Tak 387-2510 or DURO-TAK 387-2287.
  • the material of the backing layer is selected from aluminum-polyester film, polyester-polyethylene composite film, polyethylene-aluminum-polyester/ethylene-vinyl acetate composite film, multilayer polyester film and polyester-ethylene composite film.
  • the material of the release film is selected from one or more of siliconized polyester film, fluoropolymer coated polyester film, aluminum foil-silicon grease composite, siliconized aluminum foil and silicon paper.
  • the preparation method of the dexmedetropine transdermal patch provided by the present application comprises the following steps:
  • the solvent comprises absolute ethanol and n-heptane.
  • the present application provides an application of the dexmedetomidine transdermal composition or the dexmedetomidine transdermal patch in improving sleep disorders, and the sleep disorders include perioperative sleep disorders, sleep disorders in the elderly, and traumatic sleep disorders.
  • the dexmedetomidine transdermal composition or the dexmedetomidine transdermal patch provided in the present application can realize a slow release of 2 days to 5 days.
  • the propylene glycol used in this application can play a good solubilizing effect on dexmedetomidine at a relatively low concentration, and can improve the solubility of dexmedetomidine in the framework material, and simultaneously with the raw material drug dexmedetomidine Tomidine has good compatibility;
  • the metal chelate cross-linking agent used in this application and the pressure-sensitive adhesive together serve as the skeleton structure of the transdermal composition of the present application, synergistically adjust the adhesion performance of the transdermal composition, and at the same time provide a drug-loading agent for dexmedetomidine. matrix;
  • the release film used in this application can form a good compatibility relationship with the pressure-sensitive adhesive to ensure that it can be firmly adhered to the surface of the pressure-sensitive adhesive, and can be easily peeled off from the adhesive layer when it is torn off. Erosion of various raw materials and solvents during the preparation and storage of transdermal patches;
  • the backing film used in this application has good flexibility, firm and smooth texture, suitable peel strength, and good compatibility with the raw and auxiliary materials of the transdermal patch of this application;
  • the solvents used in this application include absolute ethanol and n-heptane, which are used to dissolve the bulk drug dexmedetomidine and/or metal chelating agent cross-linking agents, and are non-toxic, non-irritating and have good compatibility with raw materials and auxiliary materials The advantages.
  • FIG 1 The preparation process of the dexmedetomidine transdermal patch of the present application is shown in Figure 1, and the detailed structure of the transdermal patch is shown in Figure 2 (A: side view of the dexmedetomidine transdermal patch; B: right Medetomidine transdermal patch top view);
  • the release film adopts an overlapping method, and forms the current anti-adhesive layer with the punched pockets punched around the patch to further reduce the risk of cold flow.
  • the use or application method of the dexmedetomidine transdermal patch provided by this application is: apply it on the smooth and flat skin surface of the human trunk or upper arm that is not stimulated and unirradiated, and tear it off if the administration is interrupted. Transdermal patches are available.
  • reagents or instruments used in this application can be purchased from the market. Instruments: HS-3 vertical mixing instrument, TB-04D experimental precision coating machine, DGF302-BN electric drying oven, PL-3002-IC electronic balance, KQ-500VDE ultrasonic cleaning machine, MDC-25SX digital display micrometer XMTD-204 Constant temperature magnetic stirrer, Franz transdermal diffusion instrument TK-24BL, GHP-9160 constant temperature incubator, WD-A drug stability tester.
  • Embodiment 1 Study on compatibility and stability of dexmedetomidine and solubilizing agent
  • the above-mentioned experimental samples were prepared into 5 subgroups, namely the control group, high temperature group, high humidity group, light group and accelerated group, and the corresponding conditions are shown in Table 1 below.
  • the sampling time points of high temperature, high humidity, light and acceleration are 0 day, 5 days and 10 days, which are used to investigate the impurity content of the mixture of dexmedetomidine and solubilizer in this application under different conditions.
  • ND means not detected.
  • the maximum single impurity content of the "API + levulinic acid” group is 1.99% and the maximum total impurity content is 5.53% under high temperature conditions; the maximum single impurity content is 0.94% and the maximum total impurity content is 0.94% under light conditions It is 3.35%; under accelerated conditions, the maximum single impurity content is 0.60%, and the maximum total impurity content is 1.85%.
  • the impurity content of the "drug substance + levulinic acid” group exceeded the standard limit. Therefore, the compatibility and stability of the raw materials and auxiliary materials of dexmedetomidine and levulinic acid were poor.
  • the maximum single impurity content of the "API + oleic acid” group is 1.22% under high temperature conditions, and the maximum total impurity content is 4.76%; under light conditions, the maximum single impurity content is 0.64%, and the maximum total impurity content is 2.68%; under accelerated conditions, the maximum single impurity content is 0.88%, and the maximum total impurity content is 2.12%.
  • the impurity content of the "API + oleic acid” group exceeded the standard limit. Therefore, the compatibility and stability of the raw materials and auxiliary materials of dexmedetomidine and oleic acid were poor.
  • the maximum single impurity content of the "API + isopropyl myristate” group is 1.03% under high temperature conditions, and the maximum total impurity content is 3.36%; the maximum single impurity content is 0.72% under light conditions, and the maximum The total impurity content is 4.79%; under accelerated conditions, the maximum single impurity content is 0.72%, and the maximum total impurity content is 4.32%.
  • the impurity content in the group of "crude drug + isopropyl myristate” exceeded the standard limit. Therefore, the compatibility and stability of the raw materials and excipients of dexmedetomidine and isopropyl myristate is poor.
  • the model of the acrylate pressure-sensitive adhesive is Duro-Tak 387-2287, and the solid content is 53.8%.
  • the transdermal patch comprises a backing layer, an adhesive layer and an anti-adhesive release film layer, and the preparation method of the transdermal patch specifically comprises the following steps:
  • Coating Coat the drug-containing matrix after standing overnight on the release film Scotchpak 1022, and adjust the thickness of the coating blade until the thickness of the drug-containing layer of the final transdermal patch is 25 ⁇ m;
  • propylene glycol Different dosages of propylene glycol were selected for formula optimization and screening of propylene glycol. Specifically, the weight ratio of propylene glycol to dexmedetomidine was 3:3, 4:3, 5:3, 6:3, 7:3, 8:3, 9 : 3, and set a blank group at the same time (no propylene glycol is added in prescription 1).
  • the amount of propylene glycol has no significant impact on the related substances of the transdermal patch of this example.
  • Table 8 shows the results of the solubility of dexmedetomidine and the adhesion of the transdermal patch.
  • the sample adhesion performance is weak, when the mass ratio of propylene glycol to dexmedetomidine reaches 4:
  • the adhesion performance of the sample is better; but when the feeding ratio exceeds 8:3, some samples are painful to tear off; when the feeding ratio is in the range of (5:3)-(7:3), this example paste
  • the adhesion performance of the agent on the skin surface is better; when the feeding ratio is 5:3, the adhesion performance of the transdermal patch in this example is the best on the skin surface, and there is no residue and no pain on the skin surface when all the samples are torn off.
  • the model of the acrylate pressure-sensitive adhesive is Duro-Tak 387-2287, and the solid content is 53.8%.
  • the preparation method of prescription 2 is the same as that of prescription 1, except that Scotchpak 9754 backing film is used to compound the drug-containing adhesive layer.
  • prescription 2' (0.07g, about 0.30 parts ), Prescription 2′′ (0.09g, about 0.40 servings), Prescription 2′′’ (0.14g, about 0.60 servings) and Prescription 2′′” (0.16g, about 0.70 servings), adapt to the corresponding prescription acrylate pressure sensitive adhesive Adjustment (in prescription 2'-2"", the dosage of acrylate pressure-sensitive adhesive is 41.33g, 40.91g, 40.49g and 41.37g respectively).
  • the model of the acrylate pressure-sensitive adhesive is Duro-Tak 387-2287; the preparation method is the same as that of prescription 2.
  • prescription 3 ' (0.07g, about 0.30 parts), prescription 3 " (0.09g , about 0.40 parts), prescription 3"' (0.14g, about 0.60 parts) and prescription 3"" (0.16g, about 0.70 parts), the corresponding prescription of acrylic pressure-sensitive adhesive adjustment (prescription 3'-3 In "", the amount of acrylate pressure-sensitive adhesive used is 41.33g, 40.91g, 40.49g and 41.37g respectively).
  • the model of the acrylate pressure-sensitive adhesive is Duro-Tak 387-2287; the preparation method is the same as that of prescription 2.
  • prescription 4 ' (0.07g, about 0.30 parts), prescription 4 " (0.09g , about 0.40 parts), prescription 4"' (0.14g, about 0.60 parts) and prescription 4"" (0.16g, about 0.70 parts), the corresponding prescription of acrylic pressure-sensitive adhesive is adaptively adjusted (prescription 4'-4 In "", the amount of acrylate pressure-sensitive adhesive used is 41.33g, 40.91g, 40.49g and 41.37g respectively).
  • the model of the acrylate pressure-sensitive adhesive is Duro-Tak 387-2287; the preparation method is the same as that of prescription 2.
  • prescription 5' (0.07g, about 0.30 parts), prescription 5 "(0.09g , about 0.40 parts), prescription 5"' (0.14g, about 0.60 parts) and prescription 5"" (0.16g, about 0.70 parts)
  • prescription 5'-5 In “" the amount of acrylate pressure-sensitive adhesive used is 41.33g, 40.91g, 40.49g and 41.37g respectively).
  • the model of the acrylate pressure-sensitive adhesive is Duro-Tak 387-2510, and the solid content is 42.7%.
  • the preparation method of prescription 6 is the same as that of prescription 1, except that Scotchpak 9754 backing film is used to compound the drug-containing adhesive layer.
  • prescription 6' (0.06g, about 0.30 parts), prescription 6" (0.08g , about 0.40 parts), prescription 6"' (0.12g, about 0.60 parts) and prescription 6"" (0.14g, about 0.70 parts), the corresponding prescription of acrylic pressure-sensitive adhesive is adaptively adjusted (prescription 6'-6 In "", the amount of acrylate pressure-sensitive adhesive used is 45.01g, 44.97g, 44.87g and 44.83g respectively).
  • the model of the acrylate pressure-sensitive adhesive is Duro-Tak 387-2510; the preparation method is the same as that of prescription 6.
  • prescription 7' (0.06g, about 0.30 parts), prescription 7" (0.08g , about 0.40 parts), prescription 7"' (0.12g, about 0.60 parts) and prescription 7"" (0.14g, about 0.70 parts), the corresponding prescription of acrylic pressure-sensitive adhesive adjustment (prescription 7'-7 In “", the amount of acrylate pressure-sensitive adhesive used is 45.01g, 44.97g, 44.87g and 44.83g respectively).
  • the model of the acrylate pressure-sensitive adhesive is Duro-Tak387-2510; the preparation method is the same as that of prescription 6.
  • prescription 8' (0.06g, about 0.30 parts), prescription 8" (0.08g , about 0.40 parts), prescription 8"' (0.12g, about 0.60 parts) and prescription 8"" (0.14g, about 0.70 parts), the corresponding prescription of acrylic pressure-sensitive adhesive is adaptively adjusted (prescription 8'-8 In "", the amount of acrylate pressure-sensitive adhesive used is 45.01g, 44.97g, 44.87g and 44.83g respectively).
  • the model of the acrylate pressure-sensitive adhesive is Duro-Tak387-2510; the preparation method is the same as that of prescription 6.
  • prescription 9' (0.06g, about 0.30 parts), prescription 9" (0.08g , about 0.40 parts), prescription 9"' (0.12g, about 0.60 parts) and prescription 9"" (0.14g, about 0.70 parts), the corresponding prescription of acrylic pressure-sensitive adhesive is adaptively adjusted (prescription 9'-9 In "", the amount of acrylate pressure-sensitive adhesive used is 45.01g, 44.97g, 44.87g and 44.83g respectively).
  • the 180°peel strength shows a trend of first decreasing and then increasing, and the holding power shows a sharp increase within a certain range.
  • the content of polybutyl titanate was 0.30 parts, there was a slight pain when the sample was torn off; when the content of polybutyl titanate was 0.70 parts, there was a slight adhesive edge residue when the sample was torn off;
  • the content of butyl ester is in the range of 0.40-0.60 parts, all the samples tested have good adhesive performance, and there is no residue on the adhesive edge.
  • the 180°peel strength shows a trend of decreasing first and then increasing, and the holding power shows a trend of increasing significantly within a certain range.
  • the zirconium acetylacetonate content is in the range of 0.30-0.40 parts, there is a slight pain when the sample is torn off; when the zirconium acetylacetonate content is 0.70 parts, the sample has a slight adhesive edge residue when the When the content of zirconium acid is in the range of 0.50-0.60 parts, all the samples tested have good adhesion performance, and there is no residual trace on the bonding edge.
  • the 180° peel strength first decreases and then increases, and the holding power shows a sharp increase within a certain range.
  • the content of titanium (oxy) acetylacetonate ranges from 0.30 to 0.40 parts, there is a slight pain when the sample is torn off, and when the content of titanium (oxy) acetylacetonate is 0.70 parts, the sample has a slight adhesion Edge residue, when the content of titanium (oxy)acetylacetonate is in the range of 0.50-0.60 parts, all samples tested have good adhesion performance, and there is no residual trace on the bonding edge.
  • the 180°peel strength shows a trend of first decreasing and then increasing, and the holding power shows a sharp increase within a certain range.
  • the polybutyl titanate content is about 0.30 parts, there is slight pain when the sample is torn off;
  • the content of butyl titanate is in the range of about 0.40-0.60 parts, all the samples tested have good adhesion performance, and there is no residue on the adhesive edge.
  • the 180°peel strength first decreases and then increases, and the holding power shows a sharp increase within a certain range.
  • the aluminum acetylacetonate content is in the range of about 0.30-0.40 parts, there is a slight pain when the sample is torn off;
  • the content of aluminum acetylacetonate is in the range of about 0.50-0.60 parts, all the samples tested have good adhesion performance, and there is no residue on the adhesive edge.
  • the zirconium acetylacetonate content is in the range of about 0.30-0.40 parts, there is a slight pain when the sample is torn off; when the zirconium acetylacetonate content is about 0.70 parts, the sample has a slight adhesive edge residue when the When the content of zirconium acetylacetonate is in the range of about 0.50-0.60 parts, all the samples tested have good adhesion performance, and there is no residue on the bonding edge.
  • the 180° peel strength first decreases and then increases, and the holding power shows a sharp increase within a certain range.
  • the titanium (oxygen) acetylacetonate content is in the range of about 0.30-0.40 parts, there is a slight pain when the sample is torn off, and when the titanium (oxygen) acetylacetonate content is about 0.70 parts, the sample is slightly painful Adhesive edge residue, when the content of titanium (oxy)acetylacetonate ranged from about 0.50 to 0.60 parts, all samples were tested with good adhesive performance and no adhesive edge residue.
  • the addition of metal chelate cross-linking agents can improve the adhesive performance of the dexmedetomidine transdermal patch of the present application, which was tested comprehensively by the three tests of holding force, 180° peel strength and in vivo adhesion performance.
  • the amount of metal chelate crosslinking agent used in the transdermal patch of the present application is 0.30-0.70 parts, preferably 0.40-0.60 parts, and more preferably 0.50 parts.
  • the model of the acrylate pressure-sensitive adhesive is Duro-Tak 387-2287, and the solid content is 53.8%.
  • the preparation method of prescription 10 is the same as that of prescription 1, except that the release film Scotchpak9709 is used for coating, and the backing film Scotchpak 9723 is used for lamination.
  • the model of the acrylate pressure-sensitive adhesive is Duro-Tak 387-2510, and the solid content is 42.7%.
  • the preparation method of prescription 11 is the same as that of prescription 1, except that the release film Scotchpak 9709 is used for coating, and the backing film Scotchpak 9723 is used for lamination.
  • the model of the acrylate pressure-sensitive adhesive is Duro-Tak 387-2510, and the solid content is 42.7%.
  • the preparation method of prescription 8 is the same as that of prescription 1, except that the backing film Scotchpak 9745 is compounded on the drug-containing adhesive layer.
  • Embodiment 7 Prescription 13
  • the model of the acrylate pressure-sensitive adhesive is Duro-Tak 387-2510, and the solid content is 42.7%.
  • the preparation method of prescription 9 is the same as that of prescription 1, except that the release film is made of Scotchpak 9709; the backing film is made of Scotchpak 9745; the thickness of the drug-containing layer is adjusted to 50 ⁇ m when coating.
  • Embodiment 8 Prescription 14
  • the model of the acrylate pressure-sensitive adhesive is Duro-Tak 387-2510, and the solid content is 42.7%.
  • the preparation method of prescription 10 is the same as that of prescription 1, except that the release film is made of Scotchpak 9709; the backing film is made of Scotchpak 9745; the thickness of the drug-containing layer is adjusted to 50 ⁇ m when coating.
  • Embodiment 9 Prescription 15
  • the model of the acrylate pressure-sensitive adhesive is Duro-Tak 387-2510, and the solid content is 42.7%.
  • the preparation method of prescription 11 is the same as that of prescription 1, except that the release film is made of Scotchpak 9709; the backing film is made of Scotchpak 9745; the thickness of the drug-containing layer is adjusted to 50 ⁇ m when coating.
  • Embodiment 10 Prescription 16
  • the model of the acrylate pressure-sensitive adhesive is Duro-Tak 387-2510, and the solid content is 42.7%.
  • the preparation method of prescription 12 is the same as that of prescription 1, except that the release film is made of Scotchpak 9709; the backing film is made of Scotchpak 9745; the thickness of the drug-containing layer is adjusted to 50 ⁇ m when coating.
  • Embodiment 11 Prescription 17
  • the model of the acrylate pressure-sensitive adhesive is Duro-Tak 387-2510, and the solid content is 42.7%.
  • the preparation method of prescription 13 is the same as that of prescription 1, except that the release film is made of Scotchpak 9709; the backing film is made of Scotchpak 9745; the thickness of the drug-containing layer is adjusted to 50 ⁇ m when coating.
  • the in vitro transdermal diffusion curves of patches with different thicknesses are shown in Figure 3. From Figure 3, it can be seen that the thickness of the dexmedetomidine skeleton transdermal patch is related to the duration of action, and increasing the thickness of the transdermal patch can prolong the transdermal The duration of action of the patch.
  • the dexmedetomidine penetration patch with a thickness of 25 ⁇ m reached the drug release plateau at 48 hours; the patch with a thickness of 50 ⁇ m reached the drug release plateau at 72 hours; the patch with a thickness of 100 ⁇ m reached the drug release plateau at 120 hours, so , the dexmedetomidine patch formulation of the present application with a thickness of 25 ⁇ m-100 ⁇ m can achieve sustained sustained release for 2 days to 5 days.
  • Skin reaction grades include:
  • Grade 4 erythema, blistering and bullae formation
  • Grade 3 erythema, blistering, no bullae
  • Grade 2 erythema covering the entire patch area; no blistering;
  • Grade 1 Slight erythema covering less than the entire patch area
  • Grade 0 Minimal or no reaction at the patch site
  • mice were placed in the activity instrument for adaptive training, and the activity monitoring within 5 minutes was started after 10 minutes, and the results were recorded as 0-hour activity.
  • the monitoring time is 27h and 30h, and the monitoring method is the same as above.
  • Evaluation indicators Record the number of activities within 5 minutes.
  • the autonomous activity data of the mice is shown in Figure 5.
  • the dexmedetomidine transdermal patch can significantly reduce the activity of the mice, and presents an obvious dose-effect relationship, indicating that dexmedetomidine has a significant Improve sleep medicine effect.
  • the experimental animals were weighed, and randomly grouped according to the body weight, as follows:
  • SD rats (SPF level, male) were placed in a 12h alternating light and dark environment for 7 days (turn off the light at 7:00; turn on the light at 19:00).
  • the animals were anesthetized with Xylazine (i.p., 20mg/kg) combined with xylazine (i.p., 8mg/kg).
  • the brain was fixed with a stereotaxic instrument. Hold the four corners with forceps to fully expose the skull, peel off the periosteum, and wipe it with dry absorbent cotton until the surface is clean.
  • the skull is drilled and electrodes are implanted.
  • the two EMG electrodes were respectively inserted into the neck muscles in parallel, and the two ends were fixed with sutures to prevent their ends from touching each other.
  • the reference electrode is also penetrated into the contralateral neck muscle for fixation.
  • the implant is then placed under the skin, and the surgical wound is sutured and sterilized.
  • the rats were carefully placed in a clean recovery cage, lying on their sides to ensure a smooth airway. Raised in single cages, placed in a shielded recovery room, with 12h automatic light and dark alternation: light off time: 7:00, light on time: 19:00.
  • the animals were given nursing care for 3 days, the surgical incision was treated with cephradine powder locally, gentamicin 4-8mg/kg was subcutaneously administered, and meloxicam 0.1ml/animal was subcutaneously injected for 3 consecutive days, and the experiment was carried out after 7-10 days of recovery. And according to the animal body weight random grouping. After grouping, 24h EEG and EMG were continuously monitored as baseline signals.
  • Raw data were collected by DSI system Ponemah software and analyzed by NeuroScore software.
  • the experimental data are expressed by mean ⁇ standard error (Mean ⁇ S.E.M.), using Graph Pad Prism 7.0 software, and using Two-way ANOVA and One-way ANOVA for statistical analysis, P ⁇ 0.05 means there is a significant difference, P ⁇ 0.01 means There is a very significant difference, P ⁇ 0.001 means there is a very significant difference.
  • A: within 72 hours after patch administration, the cumulative trend graph of Wake time of each group in each time node in the sleep structure of rats; B: within 72 hours after patch administration, the Wake time of each group at each time node Cumulative trend graph of NREM time for each group; C: Cumulative trend graph of REM time for each group at each time node within 72 hours after patch administration; N 8.
  • the awakening time of rats in the drug-containing group within 72 hours gradually decreased, and there was no significant difference between the low-dose group and the normal group in the awakening time within 72 hours; In contrast, the duration of awakening within 72 hours of the rats in the drug-containing patch group was significantly reduced.
  • the slow-wave sleep time of rats in the drug-containing group within 72 hours was gradually prolonged, and there was no significant difference between the low-dose group and the normal group in the slow-wave sleep time within 72 hours; Compared with the model group after operation, the slow-wave sleep time of the rats in the medicated patch group within 72 hours was significantly prolonged.
  • the dexmedetomidine transdermal patch of the present application can effectively prolong the non-rapid eye movement sleep (NREM) time, reduce the rapid eye movement sleep (REM) time of postoperative rats, and can very effectively improve sleep quality.
  • Transdermal patches at high doses have a greater impact on the sleep duration of SD rats, which significantly shortens the proportion of the awake period, which will affect the normal circadian rhythm of animals to a certain extent.
  • Transdermal patches at medium and high doses can After 72 hours, it can continuously and effectively improve the postoperative sleep disorder of rats and promote sleep quality.
  • the low dose group Compared with the low dose (0.88mg/kg), its effect time is longer, but the low dose group can not only significantly improve sleep quality, And it will not change the rhythm of circadian life like the middle and high dose group, the low dose group is basically the same as the total duration of slow wave sleep and the total duration of awakening within 72 hours of the normal group.
  • the model of the acrylate pressure-sensitive adhesive is Duro-Tak 87-2287, and the solid content is 53.8%.
  • the dexmedetomidine transdermal patch of the application comparative example 1 was prepared: by mixing dexmedetomidine and pressure-sensitive adhesive in an organic solvent , followed by mixing to prepare the formulation. Once a homogenous mixture is formed, the solution is cast onto a release liner and dried at 60°C to 80°C for 10 minutes to 90 minutes. The single layer adhesive film was then laminated to a PET backing, cut to size and placed into bags. In this comparative example, levulinic acid was added to the adhesive composition.
  • the solvent contained in the pressure-sensitive adhesive and the organic solvent added during the preparation process are all removed during the drying process.
  • Example 7 Three patches were taken from the patches prepared in Example 7, Example 4 and Comparative Example 1 of the present application, respectively, and the release film layer was removed to conduct an in vitro transdermal diffusion test.
  • the test method was the same as in Example 12.
  • the in vitro transdermal diffusion curves of the three groups of transdermal patches are shown in Fig. 7 .
  • the overall tendency of the diffusion rate of three groups of transdermal patches is that embodiment 7 is better than embodiment 4 and is better than comparative example 1, and the unit area of the dexmedetomidine transdermal patch that embodiment 7 makes The transdermal diffusion rate reached the maximum at 12 hours, which was 1.1 ⁇ g/cm 2 *h, about twice that of Comparative Example 1, and the patch prepared in Comparative Example 1 reached the maximum permeation per unit area at 24 hours. skin diffusion rate.
  • the in vitro diffusion rate of the transdermal patch prepared by the present application is better than that of Reference Document 1.

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Abstract

本申请公开了右美托咪定经皮组合物、透皮贴剂及其制备方法和应用。该组合物包括右美托咪定、丙二醇、金属螯合物类交联剂，或者右美托咪定、丙二醇、金属螯合物类交联剂和压敏胶。另外，本申请通过在右美托咪定经皮组合物中加入丙二醇作增溶剂，能够减少杂质的产生，使得原辅料相容性更好，同时采用金属螯合物类交联剂和压敏胶共同构成本品的骨架结构，使得粘附性能显著提升，患者贴合感更佳。本申请产品稳定性好，无皮肤刺激性，贴敷人体的安全性显著提高，可达到2天-5天的缓释效果。

Description

右美托咪定经皮组合物、透皮贴剂及其制备方法和应用
相关申请
本申请要求2021年8月23日提交的、发明名称为“右美托咪定经皮组合物、透皮贴剂及其制备方法和应用”、申请号为202110969146.7的中国发明专利申请的优先权权益，该中国专利申请的全部内容通过引用并入本文。
技术领域
本申请涉及但不限于药物制剂领域，特别涉及右美托咪定经皮组合物、透皮贴剂及其制备方法和应用。
背景技术
目前国内外上市的右美托咪定仅有盐酸右美托咪定注射液，且只能在专业的医护人员密切监督下使用，临床用于全身麻醉的手术患者气管插管和进行通气时的镇静，而右美托咪定注射后半衰期仅2h，药效持续时间短。
现有技术中国专利申请号CN201480059798.5公开了一种右美托咪定经皮组合物，测试了不同右美托咪定经皮组合物随施加时间变化的平均右美托咪定流量，本发明人发现该申请提供的右美托咪定经皮组合物的流量较差，某些实施方案中经皮组合物仅提供了不到0.5ug/cm 2*h的流量，且透皮扩散速率在第24h才达到最大。
因此，亟需研发一种右美托咪定经皮组合物，该组合物既可以提供较优的经皮扩散速率，储存稳定，且方便患者自主用药，给药次数能明显减少，药物在体内作用时间显著延长。
发明概述
有鉴于此，本申请提供了右美托咪定经皮组合物、透皮贴剂及其制备方 法和应用。该产品具有较优的经皮扩散速率、稳定性好，可达到2天-5天的缓释效果。
以下是对本文详细描述的主题的概述。本概述并非是为了限制本申请的保护范围。
一方面，本申请提供了一种右美托咪定经皮组合物，该组合物包括右美托咪定、丙二醇和金属螯合物类交联剂；
任选地，以重量份计，所述组合物中，
右美托咪定                       0.30-3.00份
丙二醇                           0.40-8.00份
金属螯合物类交联剂               0.30-1.25份；
或者，所述丙二醇与所述右美托咪定的质量比为(4∶3)-(8∶3)。
第二方面，本申请提供了一种右美托咪定经皮组合物，该组合物包括右美托咪定、丙二醇、金属螯合物类交联剂和压敏胶；
任选地，以重量份计，所述组合物中，
Figure PCTCN2022113953-appb-000001
和/或者，所述丙二醇与所述右美托咪定的质量比为(4∶3)-(8∶3)。
第三方面，本申请提供了一种右美托咪定透皮贴剂，其中，所述透皮贴剂依次包含背衬层、胶粘层和防黏离型膜层；所述胶粘层由第一方面或第二方面所述的右美托咪定经皮组合物形成。
第四方面，本申请提供了第二方面所述的右美托咪定经皮组合物的制备方法，所述的制备方法包括如下步骤：
将金属螯合物类交联剂溶解在溶剂中，得到金属螯合物类交联剂溶液；
将压敏胶与金属螯合物类交联剂溶液混合，得到空白基质溶液；
将右美托咪定、丙二醇和溶剂混合，得到右美托咪定溶液；
将右美托咪定溶液与空白基质溶液混合，搅拌，静置，干燥。
第五方面，本申请提供了第三方面所述的右美托咪定透皮贴剂的制备方法，包括如下步骤：
将金属螯合物类交联剂溶解在溶剂中，得到金属螯合物类交联剂溶液；
将压敏胶与金属螯合物类交联剂溶液混合，得到空白基质溶液；
将右美托咪定、丙二醇和溶剂混合，得到右美托咪定溶液；
将右美托咪定溶液与空白基质溶液混合，搅拌，静置，得到含药基质溶液；
将含药基质溶液涂布于防黏离型膜层，干燥，得到胶粘层和防黏离型膜层的复合层；
将背衬层复合于胶粘层上。
第六方面，本申请提供了上述右美托咪定经皮组合物或右美托咪定透皮贴剂在制备改善睡眠障碍药物制剂中的应用。
第七方面，本申请提供了改善个体睡眠障碍的方法，所述方法包括对有相应需要的个体施用上述右美托咪定经皮组合物或右美托咪定透皮贴剂。
第一方面，本申请提供了一种右美托咪定经皮组合物，该组合物包括右美托咪定、丙二醇和金属螯合物类交联剂。
在第一方面的一些实施例方案中，以重量份计，所述组合物中，
右美托咪定                     0.30-3.00份
丙二醇                         0.40-8.00份
金属螯合物类交联剂             0.30-1.25份。
在第一方面的一些实施例方案中，所述组合物中，
右美托咪定                     0.72-3.00份
丙二醇                         1.20-8.00份
金属螯合物类交联剂              0.30-1.25份。
在第一方面的一些实施例方案中，所述组合物中，
右美托咪定                      0.72-1.80份
丙二醇                          1.20-4.20份
金属螯合物类交联剂              0.30-0.80份。
在第一方面的一些实施例方案中，所述组合物中，
右美托咪定                      0.72-1.45份
丙二醇                          1.20-4.20份
金属螯合物类交联剂              0.30-0.80份。
在第一方面的一些实施例方案中，所述组合物中丙二醇与右美托咪定的质量比为(4∶3)-(8∶3)。
在第一方面的一些实施例方案中，所述组合物中丙二醇与右美托咪定的质量比为(5∶3)-(7∶3)。
在第一方面的一些实施例方案中，所述组合物中丙二醇与右美托咪定的质量比为5∶3。
在第一方面的一些实施例方案中，所述金属螯合物类交联剂选自乙酰丙酮酸铝、乙酰丙酮酸锆、乙酰丙酮酸钛和聚钛酸丁酯中的一种或多种。
在第一方面的一些实施例方案中，所述金属螯合物类交联剂为乙酰丙酮酸铝或聚钛酸丁酯。
在第一方面的一些实施例方案中，所述金属螯合物类交联剂乙酰丙酮酸钛为(氧)乙酰丙酮酸钛或四乙酰丙酮酸钛，或者它们的混合物。
第二方面，本申请提供了一种右美托咪定经皮组合物，所述组合物包括右美托咪定、丙二醇、金属螯合物类交联剂和压敏胶。
在第二方面的一些实施例方案中，以重量份计，所述组合物中，
Figure PCTCN2022113953-appb-000002
Figure PCTCN2022113953-appb-000003
在第二方面的一些实施例方案中，所述组合物中，
Figure PCTCN2022113953-appb-000004
所述丙二醇与所述右美托咪定的质量比为(4∶3)-(8∶3)。
在第二方面的一些实施例方案中，所述组合物中，所述组合物包含右美托咪定0.72-3.00份、0.72-1.80份、0.72-1.45份或1.00-1.80份。
在第二方面的一些实施例方案中，所述组合物中压敏胶与金属螯合物类交联剂的质量比为(70∶1)-(310∶1)。
在第二方面的一些实施例方案中，所述组合物中，
Figure PCTCN2022113953-appb-000005
在第二方面的一些实施例方案中，所述组合物中，
Figure PCTCN2022113953-appb-000006
在第二方面的一些实施例方案中，所述组合物中，
Figure PCTCN2022113953-appb-000007
Figure PCTCN2022113953-appb-000008
在第二方面的一些实施例方案中，所述组合物中丙二醇与右美托咪定的质量比为(4∶3)-(8∶3)。
在第二方面的一些实施例方案中，所述组合物中丙二醇与右美托咪定的质量比为(5∶3)-(7∶3)。
在第二方面的一些实施例方案中，所述组合物中丙二醇与右美托咪定的质量比为5∶3。
在第二方面的一些实施例方案中，所述组合物中压敏胶与金属螯合物类交联剂的质量比为(70∶1)-(160∶1)、(160∶1)-(220∶1)或(220∶1)-(310∶1)。
在第二方面的一些实施例方案中，所述组合物中压敏胶与金属螯合物类交联剂的质量比为(160∶1)-(220∶1)、(160∶1)-(210∶1)、(160∶1)-(200∶1)或(190∶1)-(220∶1)。
在第二方面的一些实施例方案中，所述组合物中压敏胶与金属螯合物类交联剂的质量比为160∶1、170∶1、180∶1、190∶1、200∶1、210∶1或220∶1。
在第二方面的一些实施例方案中，所述组合物中压敏胶与金属螯合物类交联剂的质量比为190∶1。
在第二方面的一些实施例方案中，所述组合物包含金属螯合物类交联剂0.30-0.70份。
在第二方面的一些实施例方案中，所述组合物包含金属螯合物类交联剂0.40-0.60份。
在第二方面的一些实施例方案中，所述组合物包含金属螯合物类交联剂0.50份。
在第二方面的一些实施例方案中，所述金属螯合物类交联剂选自乙酰丙酮酸铝、乙酰丙酮酸锆、乙酰丙酮酸钛和聚钛酸丁酯中的一种或多种。
在第二方面的一些实施例方案中，所述金属螯合物类交联剂为乙酰丙酮酸铝或聚钛酸丁酯。
在第二方面的一些实施例方案中，所述金属螯合物类交联剂乙酰丙酮酸 钛为(氧)乙酰丙酮酸钛或四乙酰丙酮酸钛，或者它们的混合物。
在第二方面的一些实施例方案中，所述压敏胶选自丙烯酸酯压敏胶、聚异丁烯压敏胶、硅酮压敏胶、苯乙烯-异戊二烯-苯乙烯热熔压敏胶(SIS型)和乙酸乙烯酯共聚物中的一种或多种。
在第二方面的一些实施例方案中，所述丙烯酸酯压敏胶为Duro-Tak 387-2510或DURO-TAK 387-2287。
第三方面，本申请提供了一种右美托咪定透皮贴剂，所述透皮贴依次包含背衬层、胶粘层和防黏离型膜层；胶粘层由上述右美托咪定经皮组合物形成。
在第三方面的一些实施例方案中，所述胶粘层的厚度为25μm-100μm。
第四方面，本申请提供了上述右美托咪定经皮组合物的制备方法，所述制备方法包括如下步骤：
将金属螯合物类交联剂溶解在溶剂中，得到金属螯合物类交联剂溶液；
将压敏胶与金属螯合物类交联剂溶液混合，得到空白基质溶液；
将右美托咪定、丙二醇和溶剂混合，得到右美托咪定溶液；
将右美托咪定溶液与空白基质溶液混合，搅拌，静置，干燥。
在第四方面的一些实施例方案中，所述溶剂选自无水乙醇和正庚烷中的一种或者两者的混合物。
第五方面，本申请提供了上述右美托咪定透皮贴剂的制备方法，所述制备方法包括如下步骤：
将金属螯合物类交联剂溶解在溶剂中，得到金属螯合物类交联剂溶液；
将压敏胶与金属螯合物类交联剂溶液混合，得到空白基质溶液；
将右美托咪定、丙二醇和溶剂混合，得到右美托咪定溶液；
将右美托咪定溶液与空白基质溶液混合，搅拌，静置，得到含药基质溶液；
将含药基质溶液涂布于防黏离型膜层，干燥，得到胶粘层和防黏离型膜层的复合层；
将背衬层复合于胶粘层上。
在第五方面的一些实施例方案中，所述溶剂选自无水乙醇和正庚烷中的一种或者两者的混合物。
第六方面，本申请提供了上述右美托咪定经皮组合物或右美托咪定透皮贴剂在制备改善睡眠障碍药物制剂中的应用。
在第六方面的一些实施例方案中，所述睡眠障碍为围术期睡眠障碍、老年人睡眠障碍和创伤性睡眠障碍中的一种或多种。
第七方面，本申请提供了改善个体睡眠障碍的方法，所述方法包括对有相应需要的个体施用上述右美托咪定经皮组合物或右美托咪定透皮贴剂。
在第七方面的一些实施例方案中，所述睡眠障碍为围术期睡眠障碍、老年人睡眠障碍和创伤性睡眠障碍中的一种或多种。
本申请通过创造性地在右美托咪定组合物中加入特定含量的丙二醇，并使丙二醇与主药右美托咪定的质量比为(4∶3)-(8∶3)，同时选用金属螯合物类交联剂和压敏胶共同作为右美托咪定的骨架结构，使得本申请所述右美托咪定经皮组合物具有体外扩散率大、产品质量稳定；同时相对于市售盐酸右美托咪定注射液，具有给药方便，并能够实现2天-5天的持续释放，保证患者使用后睡眠质量。
附图概述
附图是用来提供对本申请实施例的进一步理解，并且构成说明书的一部分，与下面的具体实施方式一起用于解释本申请实施例，但并不构成对本申请实施例的限制。
图1为本申请提出的一种右美托咪定透皮贴剂的制备示意图；
图2为本申请提出的一种右美托咪定透皮贴剂的结构示意图；其中，A：右美托咪定透皮贴剂侧视图；B：右美托咪定透皮贴剂俯视图；
图3为本申请提出的一种右美托咪定透皮贴剂不同厚度的体外透皮扩散曲线图；
图4为本申请提出的一种右美托咪定经皮组合物的存放6个月后结晶图；其中，A为10倍成像，B为40倍成像；
图5为本申请提出的一种右美托咪定经皮组合物改善睡眠应用的小鼠自主活动量数据折线图；
图6为本申请提出的一种右美托咪定经皮组合物改善睡眠应用的72h大鼠睡眠-觉醒结构累积时间趋势图；A：贴剂给药后72h内，大鼠睡眠结构中各时间节点内各组别Wake时间累积趋势图；B：贴剂给药后72h内，各时间节点内各组别NREM时间累积趋势图；C：贴剂给药后72h内，各时间节点内各组别REM时间累积趋势图；N＝8。
图7为本申请实施例4、实施例7与对比例1的单位面积透皮扩散速率对比曲线。
详述
在本申请中，部分术语如下定义：
NREM sleep：non-rapideyemovement sleep，非眼球快速运动睡眠，特点是大脑和眼球活动放缓，它属于深度睡眠和新陈代谢的主要阶段。
REM sleep：rapideyemovement sleep，眼球快速运动睡眠，特点是大脑活动尚未完全停止，属于浅睡和做梦的阶段。
在本申请实施方案中，本申请提供的一种右美托咪定组合物，其中各组分计算方法如下：
重量百分比X(％)＝X/(A+B+C+D*d)*100％
其中，A为右美托咪定的重量、B为丙二醇的重量、C为金属螯合物类交联剂的重量、D为压敏胶的重量、d为组合物所用的压敏胶型号对应的固含量；其中X可任选为A、B、C或D*d。
在本申请的实施方案中，本申请提供了一种右美托咪定经皮组合物，所述经皮组合物包括右美托咪定、丙二醇、金属螯合物类交联剂和压敏胶，所述右美托咪定的含量为0.30-3.00份，所述丙二醇与所述右美托咪定的含量比为(4∶3)-(8∶3)。
在本申请的一种实施方案中，本申请提供的右美托咪定的经皮组合物包含右美托咪定0.72-1.45份或1.00-1.80份；优选地，包含右美托咪定0.72-1.00份、1.00-1.45份或1.45-1.80份。
在本申请的一种实施方案中，本申请提供的右美托咪定的经皮组合物包含右美托咪定0.72份、1.00份、1.45份或1.80份；更优选地，包含右美托咪定1.00份。
在本申请的一种实施方案中，本申请提供的右美托咪定的经皮组合物，所述丙二醇与所述右美托咪定的含量比为4∶3、5∶3、6∶3、7∶3或者8∶3；优选地，丙二醇与右美托咪定的含量比为(5∶3)-(7∶3)；更优选地，丙二醇与右美托咪定的含量比为5∶3。
在本申请的一种实施方案中，本申请提供的右美托咪定的经皮组合物包含丙二醇0.40-8.00份、1.20-4.20份、1.31-2.42份、1.44-2.42份、1.44-1.67份、1.44-4.20份、1.44-8.00份、1.31-1.67份或者1.67-2.42份；优选地，包含丙二醇1.20-4.20份。
在本申请的一种实施方案中，本申请提供的右美托咪定的经皮组合物包含丙二醇0.4份、1.2份、1.31份、1.44份、1.67份、2.42份、4.20份或者8.00份；优选地，包含丙二醇1.67份。
在本申请的一种实施方案中，本申请提供的右美托咪定经皮组合物，所述压敏胶与所述金属螯合物类交联剂的质量比为(70∶1)-(160∶1)、(160∶1)-(220∶1)或(220∶1)-(310∶1)；优选地，所述压敏胶与所述金属螯合物类交联剂的质量比为(160∶1)-(190∶1)或(190∶1)-(220∶1)；更优选地，所述压敏胶与所述金属螯合物类交联剂的质量比为190∶1。
在本申请的一种实施方案中，本申请提供的右美托咪定经皮组合物，所述金属螯合物类交联剂选自乙酰丙酮酸铝、乙酰丙酮酸锆、乙酰丙酮酸钛和聚钛酸丁酯中的一种或多种。
在本申请的一种实施方案中，本申请提供的右美托咪定经皮组合物，所述金属螯合物类交联剂乙酰丙酮酸钛选自(氧)乙酰丙酮酸钛和四乙酰丙酮酸钛中的一种或两种。
在本申请的一种实施方案中，本申请提供的右美托咪定的经皮组合物，所述金属螯合物类交联剂的含量范围为0.30-1.25份、0.30-0.80份、0.30-0.60份、0.45-0.60份、0.45-0.80份、0.45-1.25份或者0.30-0.50份；优选地，金属螯合物类交联剂的含量范围为0.30-0.80份。
在本申请的一种实施方案中，本申请提供的右美托咪定的经皮组合物，所述金属螯合物类交联剂的含量为0.30份、0.45份、0.50份、0.60份、0.80份或者1.25份；优选地，金属螯合物类交联剂含量为0.5份。
在本申请的实施方案中，本申请提供的右美托咪定的经皮组合物，所述压敏胶选自丙烯酸酯压敏胶、聚异丁烯压敏胶、硅酮压敏胶、苯乙烯-异戊二烯-苯乙烯热熔压敏胶(SIS型)、乙酸乙烯酯共聚物中的一种或多种。
其中，所述丙烯酸酯压敏胶为下列型号压敏胶中的一种：DURO-TAK 387-2287、DURO-TAK 387-2510、DURO-TAK 387-2516、DURO-TAK 87-235A、DURO-TAK 387-2353、DURO-TAK 387-2852、DURO-TAK 387-2051、DURO-TAK 387-2052、DURO-TAK 387-2054、DURO-TAK 87-4287、DURO-TAK 87-6908和DURO-TAK 87-267。
在本申请的一种实施方案中，本申请提供的右美托咪定的经皮组合物，所述压敏胶与所述金属螯合物类交联剂的含量比为(70∶1)-(310∶1)、(70∶1)-(220∶1)、(70∶1)-(200∶1)、(110∶1)-(310∶1)、(110∶1)-(220∶1)、(110∶1)-(200∶1)、(150∶1)-(310∶1)、(150∶1)-(220∶1)、(150∶1)-(200∶1)、(180∶1)-(310∶1)、(180∶1)-(220∶1)或者(180∶1)-(200∶1)。
在本申请的实施方案中，本申请提供的右美托咪定经皮组合物，包括右美托咪定0.72-1.80份、金属螯合物类交联剂0.30-0.80份、丙烯酸酯压敏胶93.00-99.00份和丙二醇，所述丙二醇与所述右美托咪定的含量比为(4∶3)-(8∶3)。
在本申请的实施方案中，本申请提供的右美托咪定经皮组合物，所述金属螯合物类交联剂为聚钛酸丁酯或乙酰丙酮酸铝。
在本申请的实施方案中，本申请提供的右美托咪定经皮组合物，所述丙烯酸酯压敏胶为Duro-Tak 387-2510或DURO-TAK 387-2287。
在本申请的一种实施方案中，本申请提供的右美托咪定经皮组合物在制备透皮贴剂中的应用。
在本申请的一种实施方案中，本申请提供了的右美托咪定透皮贴剂，包含所述右美托咪定经皮组合物。
在本申请的一种实施方案中，本申请提供的右美托咪定透皮贴剂，所述右美托咪定经皮组合物形成该透皮贴剂的胶粘层。
在本申请的实施方案中，本申请提供的右美托咪定透皮贴剂，所述胶粘层的厚度为25μm-100μm。
在本申请的一种实施方案中，本申请提供的右美托咪定透皮贴剂包含背衬层、防黏离型膜层和设于背衬层和防黏离型膜层之间的胶粘层；所述胶粘层包括右美托咪定0.72-1.80份、聚钛酸丁酯0.30份-0.80份、丙烯酸酯压敏胶93.00份-99.00份，以及丙二醇；所述丙二醇与所述右美托咪定的含量比为(4∶3)-(8∶3)，所述丙烯酸酯压敏胶为Duro-Tak 387-2510或DURO-TAK 387-2287。
其中，所述背衬层的材料选自铝-聚酯膜、聚酯-聚乙烯复合膜、聚乙烯-铝-聚酯/乙烯-乙酸乙烯复合膜、多层聚酯膜和聚酯-乙烯醋酸乙烯复合膜中的一种或多种；
其中，所述离型膜的材料选自硅化聚酯薄膜、氟聚合物涂覆聚酯薄膜、铝箔-硅脂复合物、硅化铝箔和硅纸中的一种或多种。
在本申请的实施方案中，本申请提供的右美托定透皮贴剂的制备方法包括如下步骤：
(a)将金属螯合物类交联剂溶解在溶剂中，得到金属螯合物类交联剂溶液；
(b)将压敏胶，金属螯合物类交联剂溶液进行混合，得到空白基质溶液；
(c)将丙二醇，溶剂，右美托咪定溶解后加入到空白基质溶液中进行混合，得到含药基质溶液；
(d)将含药基质溶液涂布于离型膜，干燥，得到胶粘层和防黏离型膜层的复合层；
(e)将背衬膜复合于胶粘层上，得到右美托咪定透皮贴剂。
其中，所述溶剂包含无水乙醇和正庚烷。
在本申请的实施方案中，本申请提供一种所述右美托咪定经皮组合物或右美托定透皮贴剂在改善睡眠障碍中的应用，所述睡眠障碍包括围术期睡眠障碍、老年人睡眠障碍和创伤性睡眠障碍。
在本申请的实施方案中，本申请提供的所述右美托咪定经皮组合物或右美托定透皮贴剂可实现2天-5天的缓慢释放。
本申请中使用的丙二醇在较低的浓度下即能对右美托咪定起到很好的助溶效果，可以提高右美托咪定在骨架材料中的溶解性，同时与原料药右美托咪定相容性良好；
本申请中使用的金属螯合物类交联剂与压敏胶共同作为本申请经皮组合物的骨架结构，协同调节经皮组合物的粘附性能，同时为右美托咪定提供载药基质；
本申请中使用的离型膜可以与压敏胶组成较好的配伍关系，保证其能牢牢粘附于压敏胶表面，当撕除时也能容易与胶粘层剥离，同时能经受住透皮贴剂制备和储存过程中各种原辅料和溶剂的侵蚀；
本申请中使用的背衬膜具备较好的柔性，质地结实光滑，有适宜的剥离强度，同时与本申请透皮贴剂的原辅料之间存在较好的相容性；
本申请使用的溶剂包括无水乙醇和正庚烷，用于溶解原料药右美托咪定和/或金属螯合剂类交联剂，同时具有无毒、无刺激性和与原辅料相容性好的优点。
本申请右美托咪定透皮贴剂的制备流程如图1所示，透皮贴剂的详细结构如图2所示(A：右美托咪定透皮贴剂侧视图；B：右美托咪定透皮贴剂俯视图)；
其中，离型膜采用交叠的方式，并与贴片周边冲出的冲窝构成当前的防黏层，以进一步减少冷流的风险。
本申请提供的右美托咪定透皮贴剂的使用或施用方法为：将其贴敷于人体躯干或上臂未受刺激及未受照射的光滑平整的皮肤表面，若中断给药，撕去透皮贴剂即可。
本申请中所用试剂或仪器均可由市场购得。仪器：HS-3垂直混合仪器、TB-04D实验用精密涂布机、DGF302-BN电热干燥箱、PL-3002-IC电子天平、KQ-500VDE超声波清洗机、MDC-25SX数显千分尺XMTD-204恒温磁力搅拌器、Franz透皮扩散仪TK-24BL、GHP-9160恒温培养箱、WD-A药物稳定性检查仪。
实施例1右美托咪定与增溶剂相容性稳定性研究
1.样品配制
通过设置“右美托咪定+乙酰丙酸”、“右美托咪定+油酸”、“右美托咪定+月桂氮酮
Figure PCTCN2022113953-appb-000009
”、“右美托咪定+肉豆蔻酸异丙酯”、“右美托咪定+丙二醇”实验组，按照右美托咪定∶增溶剂＝1∶10的比例配制实验样品。
2.原辅料相容性实验
将上述实验样品分别配制5个亚组，分别为对照组、高温组、高湿组、光照组及加速组，相应条件见下表1所示。高温、高湿、光照和加速的取样时间点为0天、5天和10天，用来考察本申请右美托咪定与增溶剂混合物在不同条件下的杂质含量情况。
评价标准：最大未知单杂(％，≤0.5％)总杂(％，≤2.0％)
表1原辅料相容性稳定性研究样品试验条件
样品名称 条件
对照组 /
高温组 60℃
高湿组 25℃/95％RH
光照组 4500±5001x
加速组 40℃/75％RH
3.实验结果
表2右美托咪定与乙酰丙酸的原辅料相容性稳定性实验结果
Figure PCTCN2022113953-appb-000010
Figure PCTCN2022113953-appb-000011
其中，ND表示未检出。
由上表可知，“原料药+乙酰丙酸”组在高温条件下最大单一杂质含量为1.99％，最大总杂质含量为5.53％；在光照条件下最大单一杂质含量为0.94％，最大总杂质含量为3.35％；在加速条件下最大单一杂质含量为0.60％，最大总杂质含量为1.85％。在上述考察条件下，“原料药+乙酰丙酸”组的杂质含量超过标准限度，因此，右美托咪定与乙酰丙酸的原辅料相容性稳定性较差。
表3右美托咪定与油酸的原辅料相容性稳定性实验结果
Figure PCTCN2022113953-appb-000012
由上表可知，“原料药+油酸”组在高温条件下最大单一杂质含量为1.22％，最大总杂质含量为4.76％；在光照条件下最大单一杂质含量为0.64％，最大总杂质含量为2.68％；在加速条件下最大单一杂质含量为0.88％，最大总杂质含量为2.12％。在上述考察条件下，“原料药+油酸”组的杂质含量超过标准限度，因此，右美托咪定与油酸的原辅料相容性稳定性较差。
表4右美托咪定与月桂氮酮
Figure PCTCN2022113953-appb-000013
的原辅料相容性稳定性实验结果
Figure PCTCN2022113953-appb-000014
由上表可知，“原料药+月桂氮酮
Figure PCTCN2022113953-appb-000015
”组在高温条件下最大单一杂质含量为2.21％，最大总杂质含量为4.29％；在光照条件下最大单一杂质含量为0.96％，最大总杂质含量为3.54％；在加速条件下最大单一杂质含量为0.97％，最大总杂质含量为3.86％。在上述考察条件下，“原料药+月桂氮酮
Figure PCTCN2022113953-appb-000016
”组的杂质含量超过标准限度，因此，右美托咪定与月桂氮酮
Figure PCTCN2022113953-appb-000017
的原辅料相容性稳定性较差。
表5右美托咪定与肉豆蔻酸异丙酯的原辅料相容性稳定性实验结果
Figure PCTCN2022113953-appb-000018
由上表可知，“原料药+肉豆蔻酸异丙酯”组在高温条件下最大单一杂质含量为1.03％，最大总杂质含量为3.36％；在光照条件下最大单一杂质含量为0.72％，最大总杂质含量为4.79％；在加速条件下最大单一杂质含量为0.72％，最大总杂质含量为4.32％。在上述考察条件下，“原料药+肉豆蔻酸异丙酯”组的杂质含量超过标准限度，因此，右美托咪定与肉豆蔻酸异丙酯的原辅料相容性稳定性较差。
表6右美托咪定与丙二醇的原辅料相容性稳定性实验结果
Figure PCTCN2022113953-appb-000019
由上表可知，“原料药+丙二醇”组在所有考察条件下最大单杂含量为0.03％，最大总杂质含量为0.05％，因此，右美托咪定与丙二醇的原辅料相容性稳定性非常好。
综上所述，由表2-表6可知，“右美托咪定+乙酰丙酸”、“右美托咪定+油酸”、“右美托咪定+月桂氮酮
Figure PCTCN2022113953-appb-000020
”、“右美托咪定+肉豆蔻酸异丙酯”组在高温和光照的条件下均产生大量杂质，表明上述辅料与原料药右美托咪定的相容性稳定性较差，而“原料药+丙二醇”组在所有考察条件下最大单杂质含量为0.03％，最大总大杂质含量为0.05％，表明该辅料与原料药的相容性稳定性非常好。因此，选择丙二醇作为本申请经皮组合物的增溶剂，在添加后能够减少后续杂质的生成。
实验例2丙二醇用量考察
1.处方1-透皮贴剂
Figure PCTCN2022113953-appb-000021
其中，所述丙烯酸酯压敏胶型号为Duro-Tak 387-2287，固含量为53.8％。
所述透皮贴剂包括背衬层、胶粘层和防黏离型膜层，所述透皮贴剂的制备方法具体包括以下步骤：
(1)乙酰丙酮酸铝溶液的配制：称取乙酰丙酮酸铝0.05g、无水乙醇1.01g和正庚烷1.34g于40mL科学小瓶中，混合均匀，备用；
(2)空白基质的配制：称取丙烯酸酯压敏胶20.12g和配制好的乙酰丙酮酸铝溶液，密封；
(3)混合：将装有空白基质的科学小瓶置于垂直混合仪上，调节转速20rpm，搅拌4h；
(4)含药基质的配制：称取右美托咪定0.08g，加入丙二醇0.16g和无水乙醇2.24g，搅拌至右美托咪定完全溶解，再加入到搅拌4h后的空白基质中，称取无水乙醇0.16g刷洗瓶空瓶，并加至含药基质中混合，密封；
(5)混合：将装有含药基质的科学小瓶置于垂直混合仪上，调节转速20rpm，搅拌6h后停止，静置过夜；
(6)涂布：将静置过夜后的含药基质涂布于离型膜Scotchpak 1022上，调节涂布刀片的厚度至最终透皮贴剂含药层厚度为25μm；
(7)干燥：置于烘箱中，调节温度70℃，20min后取出；
(8)覆膜：将背衬膜Scotchpak 9722复合于含药胶层上；
(9)冲切：冲切成直径(D＝30mm)的圆形贴片，包装。
所有的无水乙醇和正庚烷都将在制备工艺过程中被除去，并且不会出现在最终产品中。
2.实验分组
选用不同用量的丙二醇进行处方优化筛选丙二醇，具体地，丙二醇与右美托咪定投料重量比为3∶3、4∶3、5∶3、6∶3、7∶3、8∶3、9∶3，同时设置空白组(处方1中不添加丙二醇)。
3.有关物质检测
将下列8组样品(n＝6)进行杂质检测，有关物质杂质结果如表7所示。
表7丙二醇用量筛选有关物质杂质结果
组别 丙二醇∶右美托咪定 单杂(％) 总杂(％)
1 0∶3 0.5 0.8
2 3∶3 0.5 0.7
3 4∶3 0.5 0.8
4 5∶3 0.5 0.8
5 6∶3 0.4 0.7
6 7∶3 0.4 0.7
7 8∶3 0.4 0.8
8 9∶3 0.5 0.8
由上表可知，丙二醇的用量对本实例透皮贴剂的有关物质无明显影响。
4.粘附性能测试
将8组样品(n＝6)进行丙二醇用量筛选，将8组样品粘贴于8名志愿者的光滑的手背部皮肤上，30min后剥离，观察是否会有胶体残留于皮肤上以及是否会产生疼痛感，考察本申请透皮贴剂的粘附性能。
粘附性能评分指标：
1：体内粘合性能粘合比较弱；
2：稍有粘合边沿残迹，粘合性能良好；
3：粘合边无残留，粘合性能良好；
4：揭去时疼痛，包括角质化皮肤擦伤。
右美托咪定溶解性及透皮贴剂的粘附性实验结果如表8所示。
表8丙二醇用量筛选试验结果
组别 丙二醇∶右美托咪定 体外粘附性能评价
1 0∶3 1
2 3∶3 1
3 4∶3 2
4 5∶3 3
5 6∶3 3
6 7∶3 3
7 8∶3 4
8 9∶3 4
由上表可知，当透皮贴中不含丙二醇和丙二醇与右美托咪定的投料比为3∶3时，样品粘附性能较弱，当丙二醇与右美托咪定质量比达4∶3及以上时，样品粘附性能较优；但当投料比例超过8∶3时，部分样品撕除时疼痛；当投料比范围为(5∶3)-(7∶3)时，本实例贴剂在皮肤表面的粘附性能更优；当投料比例为5∶3时，本实例透皮贴剂在皮肤表面的粘附性能最佳，全部样品撕除时皮肤表面无残留且无痛感。
实验例3金属螯合物类交联剂用量考察
1.处方配制
①处方2
Figure PCTCN2022113953-appb-000022
其中，所述丙烯酸酯压敏胶型号为Duro-Tak 387-2287，固含量为53.8％。
处方2制备方法同处方1，不同之处在于：采用Scotchpak 9754背衬膜复合于含药胶层上。
保持处方2右美托咪定和丙二醇的用量和含量不变，通过调整金属螯合物类交联剂-聚钛酸丁酯的用量和含量可分别得到处方2′(0.07g，约0.30份)、处方2″(0.09g，约0.40份)、处方2″′(0.14g，约0.60份)和处方2″″(0.16g，约0.70份)，对应处方的丙烯酸酯压敏胶进行适应性调整(处方2′-2″″中，丙烯酸酯压敏胶的用量分别为41.33g、40.91g、40.49g和41.37g)。
②处方3
Figure PCTCN2022113953-appb-000023
其中，所述丙烯酸酯压敏胶型号为Duro-Tak 387-2287；制备方法同处方2。
保持右美托咪定和丙二醇的用量和含量不变，通过调整金属螯合物类交联剂的用量和含量可分别得到处方3′(0.07g，约0.30份)、处方3″(0.09g，约0.40份)、处方3″′(0.14g，约0.60份)和处方3″″(0.16g，约0.70份)，对应处方的丙烯酸酯压敏胶进行适应性调整(处方3′-3″″中，丙烯酸酯压敏胶的用量分别为41.33g、40.91g、40.49g和41.37g)。
③处方4
Figure PCTCN2022113953-appb-000024
Figure PCTCN2022113953-appb-000025
其中，所述丙烯酸酯压敏胶型号为Duro-Tak 387-2287；制备方法同处方2。
保持右美托咪定和丙二醇的用量和含量不变，通过调整金属螯合物类交联剂的用量和含量可分别得到处方4′(0.07g，约0.30份)、处方4″(0.09g，约0.40份)、处方4″′(0.14g，约0.60份)和处方4″″(0.16g，约0.70份)，对应处方的丙烯酸酯压敏胶进行适应性调整(处方4′-4″″中，丙烯酸酯压敏胶的用量分别为41.33g、40.91g、40.49g和41.37g)。
④处方5
Figure PCTCN2022113953-appb-000026
其中，所述丙烯酸酯压敏胶型号为Duro-Tak 387-2287；制备方法同处方2。
保持右美托咪定和丙二醇的用量和含量不变，通过调整金属螯合物类交联剂的用量和含量可分别得到处方5′(0.07g，约0.30份)、处方5″(0.09g，约0.40份)、处方5″′(0.14g，约0.60份)和处方5″″(0.16g，约0.70份)，对应处方的丙烯酸酯压敏胶进行适应性调整(处方5′-5″″中，丙烯酸酯压敏胶的用量分别为41.33g、40.91g、40.49g和41.37g)。
⑤处方6
Figure PCTCN2022113953-appb-000027
Figure PCTCN2022113953-appb-000028
其中，所述丙烯酸酯压敏胶型号为Duro-Tak 387-2510，固含量为42.7％。处方6制备方法同处方1，不同之处在于：采用Scotchpak 9754背衬膜复合于含药胶层上。
保持右美托咪定和丙二醇的用量和含量不变，通过调整金属螯合物类交联剂的用量和含量可分别得到处方6′(0.06g，约0.30份)、处方6″(0.08g，约0.40份)、处方6″′(0.12g，约0.60份)和处方6″″(0.14g，约0.70份)，对应处方的丙烯酸酯压敏胶进行适应性调整(处方6′-6″″中，丙烯酸酯压敏胶的用量分别为45.01g、44.97g、44.87g和44.83g)。
⑥处方7
Figure PCTCN2022113953-appb-000029
其中，所述丙烯酸酯压敏胶型号为Duro-Tak 387-2510；制备方法同处方6。
保持右美托咪定和丙二醇的用量和含量不变，通过调整金属螯合物类交联剂的用量和含量可分别得到处方7′(0.06g，约0.30份)、处方7″(0.08g，约0.40份)、处方7″′(0.12g，约0.60份)和处方7″″(0.14g，约0.70份)，对应处方的丙烯酸酯压敏胶进行适应性调整(处方7′-7″″中，丙烯酸酯压敏胶的用量分别为45.01g、44.97g、44.87g和44.83g)。
⑦处方8
Figure PCTCN2022113953-appb-000030
其中，所述丙烯酸酯压敏胶型号为Duro-Tak387-2510；制备方法同处方6。
保持右美托咪定和丙二醇的用量和含量不变，通过调整金属螯合物类交联剂的用量和含量可分别得到处方8′(0.06g，约0.30份)、处方8″(0.08g，约0.40份)、处方8″′(0.12g，约0.60份)和处方8″″(0.14g，约0.70份)，对应处方的丙烯酸酯压敏胶进行适应性调整(处方8′-8″″中，丙烯酸酯压敏胶的用量分别为45.01g、44.97g、44.87g和44.83g)。
⑧处方9
Figure PCTCN2022113953-appb-000031
其中，所述丙烯酸酯压敏胶型号为Duro-Tak387-2510；制备方法同处方6。
保持右美托咪定和丙二醇的用量和含量不变，通过调整金属螯合物类交联剂的用量和含量可分别得到处方9′(0.06g，约0.30份)、处方9″(0.08g，约0.40份)、处方9″′(0.12g，约0.60份)和处方9″″(0.14g，约0.70份)，对应处方的丙烯酸酯压敏胶进行适应性调整(处方9′-9″″中，丙烯酸酯压敏胶的用量分别为45.01g、44.97g、44.87g和44.83g)。
2.粘附性能测试
依据2020版《中国药典》的《通则0952粘附力测定法》，对处方2-处方9的8组样品(n＝3)进行持粘力、180°剥离强度的测试，并对处方2-处方9的8组样品进行体内粘合性能评价：样品粘贴30min后剥离，评价体内粘附性能，评分指标如下：
评分指标：
1：体内粘合性能粘合比较弱；
2：稍有粘合边沿残迹，粘合性能良好；
3：粘合边无残留，粘合性能良好；
4：揭去时疼痛，包括角质化皮肤擦伤。
按上述操作后的粘附性能测试结果见表9-表16。
3.实验结果
表9处方2-处方2″″的粘附性能测试结果
Figure PCTCN2022113953-appb-000032
由上表可知，随着聚钛酸丁酯用量的增加，180°剥离强度呈现先下降后增加的趋势，持粘力在一定范围内呈现大幅上升趋势。其中，当聚钛酸丁酯含量为0.30份时，样品撕除时有轻微疼痛感；当聚钛酸丁酯含量为0.70份时，样品撕除时稍有粘合边沿残迹；当聚钛酸丁酯含量为范围为0.40-0.60份时，测试所有样品粘合性能良好，且粘合边无残留痕迹。
表10处方3-处方3″″的粘附性能测试结果
Figure PCTCN2022113953-appb-000033
由上表可知，随着乙酰丙酮酸铝用量的增加，180°剥离强度呈现先下降后增加的趋势，持粘力在一定范围内呈现大幅上升趋势。其中，当乙酰丙酮酸铝含量范围为0.30-0.40份时，样品撕除时有轻微疼痛感；当乙酰丙酮酸铝含量为0.70份时，样品撕除时稍有粘合边沿残迹，当乙酰丙酮酸铝含量为范围为0.50-0.60份时，测试所有样品粘合性能良好，且粘合边无残留痕迹。
表11处方4-处方4″″的粘附性能测试结果
Figure PCTCN2022113953-appb-000034
Figure PCTCN2022113953-appb-000035
由上表可知，随着乙酰丙酮酸锆用量的增加，180°剥离强度呈现先下降后增加的趋势，持粘力在一定范围内呈现大幅上升趋势。其中，当乙酰丙酮酸锆含量范围为0.30-0.40份时，样品撕除时有轻微疼痛感，当乙酰丙酮酸锆含量为0.70份时，样品撕除时稍有粘合边沿残迹，当乙酰丙酮酸锆含量为范围为0.50-0.60份时，测试所有样品粘合性能良好，且粘合边无残留痕迹。
表12处方5-处方5″″的粘附性能测试结果
Figure PCTCN2022113953-appb-000036
由上表可知，随着(氧)乙酰丙酮酸钛用量的增加，180°剥离强度呈现先下降后增加的趋势，持粘力在一定范围内呈现大幅上升趋势。其中，当(氧)乙酰丙酮酸钛含量范围为0.30-0.40份时，样品撕除时有轻微疼痛感，当(氧)乙酰丙酮酸钛含量为0.70份时，样品撕除时稍有粘合边沿残迹，当(氧)乙酰丙酮酸钛含量为范围为0.50-0.60份时，测试所有样品粘合性能良好，且粘合边无残留痕迹。
表13处方6-处方6″″的粘附性能测试结果
Figure PCTCN2022113953-appb-000037
由上表可知，随着聚钛酸丁酯用量的增加，180°剥离强度呈现先下降后增加的趋势，持粘力在一定范围内呈现大幅上升趋势。其中，当聚钛酸丁酯含量为约0.30份时，样品撕除时有轻微疼痛感；当聚钛酸丁酯含量为越0.70 份时，样品撕除时稍有粘合边沿残迹；当聚钛酸丁酯含量范围为约0.40-0.60份时，测试所有样品粘合性能良好，且粘合边无残留痕迹。
表14处方7-处方7″″的粘附性能测试结果
Figure PCTCN2022113953-appb-000038
由上表可知，随着乙酰丙酮酸铝用量的增加，180°剥离强度呈现先下降后增加的趋势，持粘力在一定范围内呈现大幅上升趋势。其中，当乙酰丙酮酸铝含量范围为约0.30-0.40份时，样品撕除时有轻微疼痛感；当乙酰丙酮酸铝含量为约0.70份时，样品撕除时稍有粘合边沿残迹，当乙酰丙酮酸铝含量范围为约0.50-0.60份时，测试所有样品粘合性能良好，且粘合边无残留痕迹。
表15处方8-处方8″″的粘附性能测试结果
Figure PCTCN2022113953-appb-000039
由上表可知，随着乙酰丙酮酸锆用量的增加，180°剥离强度呈现先下降后增加的趋势，持粘力在一定范围内呈现大幅上升趋势。其中，当乙酰丙酮酸锆含量范围为约0.30-0.40份时时，样品撕除时有轻微疼痛感，当乙酰丙酮酸锆含量为约0.70份时，样品撕除时稍有粘合边沿残迹，当乙酰丙酮酸锆含量范围为约0.50-0.60份时，测试所有样品粘合性能良好，且粘合边无残留痕迹。
表16处方9-处方9″″的粘附性能测试结果
Figure PCTCN2022113953-appb-000040
由上表可知，随着(氧)乙酰丙酮酸钛用量的增加，180°剥离强度呈现先下降后增加的趋势，持粘力在一定范围内呈现大幅上升趋势。其中，当(氧)乙酰丙酮酸钛含量范围为约0.30-0.40份时，样品撕除时有轻微疼痛感，当(氧)乙酰丙酮酸钛含量为约0.70份时，样品撕除时稍有粘合边沿残迹，当(氧)乙酰丙酮酸钛含量范围为约0.50-0.60份时，测试所有样品粘合性能良好，且粘合边无残留痕迹。
综上所述，加入金属螯合物类交联剂可以改善本申请右美托咪定透皮贴剂的粘附性能，通过持粘力、180°剥离强度以及体内粘附性能三个测试综合评价可知：本申请透皮贴剂的金属螯合物类交联剂用量为0.30-0.70份，优选用量为0.40-0.60份，更优选的用量为0.50份。
实施例4处方10
Figure PCTCN2022113953-appb-000041
其中，所述丙烯酸酯压敏胶型号为Duro-Tak 387-2287，固含量为53.8％。
处方10制备方法同处方1，不同之处在于：涂布采用离型膜Scotchpak9709，覆合采用背衬膜Scotchpak 9723。
实施例5处方11
Figure PCTCN2022113953-appb-000042
其中，所述丙烯酸酯压敏胶型号为Duro-Tak 387-2510，固含量为42.7％。
处方11制备方法同处方1，不同之处在于：涂布采用离型膜Scotchpak 9709，覆合采用背衬膜Scotchpak 9723。
实施例6处方12
Figure PCTCN2022113953-appb-000043
其中，所述丙烯酸酯压敏胶型号为Duro-Tak 387-2510，固含量为42.7％。
处方8制备方法同处方1，不同之处在于：将背衬膜Scotchpak 9745复合于含药胶层上。
实施例7处方13
Figure PCTCN2022113953-appb-000044
Figure PCTCN2022113953-appb-000045
其中，所述丙烯酸酯压敏胶型号为Duro-Tak 387-2510，固含量为42.7％。
处方9制备方法同处方1，不同之处在于：离型膜选用Scotchpak 9709上；背衬膜选用Scotchpak 9745；涂布时调节含药层厚度为50μm。
实施例8处方14
Figure PCTCN2022113953-appb-000046
其中，所述丙烯酸酯压敏胶型号为Duro-Tak 387-2510，固含量为42.7％。
处方10制备方法同处方1，不同之处在于：离型膜选用Scotchpak 9709上；背衬膜选用Scotchpak 9745；涂布时调节含药层厚度为50μm。
实施例9处方15
Figure PCTCN2022113953-appb-000047
其中，所述丙烯酸酯压敏胶型号为Duro-Tak 387-2510，固含量为42.7％。
处方11制备方法同处方1，不同之处在于：离型膜选用Scotchpak 9709上；背衬膜选用Scotchpak 9745；涂布时调节含药层厚度为50μm。
实施例10处方16
Figure PCTCN2022113953-appb-000048
其中，所述丙烯酸酯压敏胶型号为Duro-Tak 387-2510，固含量为42.7％。
处方12制备方法同处方1，不同之处在于：离型膜选用Scotchpak 9709上；背衬膜选用Scotchpak 9745；涂布时调节含药层厚度为50μm。
实施例11处方17
Figure PCTCN2022113953-appb-000049
其中，所述丙烯酸酯压敏胶型号为Duro-Tak 387-2510，固含量为42.7％。
处方13制备方法同处方1，不同之处在于：离型膜选用Scotchpak 9709上；背衬膜选用Scotchpak 9745；涂布时调节含药层厚度为50μm。
实施例11涂布厚度考察
1.方法
采用处方13制备的样品(D＝14mm)，调节含药层厚度为25μm、50μm 和100μm，分为3组。
将制备好的透皮贴剂除去防粘层，贴于猪皮表面，用手指轻压确保猪皮与贴剂粘附的良好性。然后将猪皮贴于装有转子的Franz扩散池和供给室之间，背衬层则与空气相接触，并且用铁夹固定好；用移液管量9mL接收介质进入接收室中，加入磁力搅拌子在恒温(32±0.5℃)、恒速(180r/min)条件下搅拌。在预先拟定的时间点下分别用1mL注射器取样0.8mL，同时补充同温等量的空白接受液。取出的样品立即送往高效液相色谱仪器测定含量。体外透皮扩散结果如下表所示。
2.实验结果
表17不同厚度样品的单位面积累积透过量
Figure PCTCN2022113953-appb-000050
具体的，不同厚度贴剂体外透皮扩散曲线如图3所示，由图3可知右美托咪定骨架型透皮贴剂的厚度与作用时长相关，增加透皮贴剂厚度可延长透皮贴剂作用时长。厚度为25μm的右美托咪定透贴剂在48h时到达药物释放平台期；厚度为50μm的贴剂在72h到达药物释放平台期；厚度为100μm的贴剂在120h到达药物释放平台期，因此，厚度为25μm-100μm的本申请右美托咪定贴剂配方可实现持续缓释2天-5天。
试验例1透皮贴剂皮肤反应测试
评价指标：
皮肤反应等级包括：
等级4：红斑，起泡和大疱形成；
等级3：红斑，起泡，无大疱；
等级2：红斑覆盖全部贴剂区域；没有起泡；
等级1：轻微红斑覆盖小于整个贴剂区域；
等级0：在贴剂部位最小或没有反应；
取本申请处方1-17的样品各2份，分别贴于18只背部脱毛的大鼠24h，结果发现处方1-17的产品均没有皮肤刺激，等级为0。
试验例2制剂稳定性研究
采用上述处方1-处方17的样品(n＝3)圆形贴片通过影响因素试验进行有关物质考察，取平均值，各项杂质含量限度如下，考察结果如下。
表18处方影响因素考察中有关物质的试验结果
Figure PCTCN2022113953-appb-000051
Figure PCTCN2022113953-appb-000052
由上表可知，在高温条件下10天、高温条件下30天以及加速条件下，本申请右美托咪定透皮贴的储存均比较稳定。
试验例3右美托咪定结晶研究
采用处方13制备的样品，观察本申请右美托咪定透皮贴剂长期结晶情况，确认处方中是否会有右美托咪定结晶产生。
样品存放6月后结晶观察结果如图4(A为10倍成像，B为40倍成像)所示，通过偏光显微镜观测结晶状况可知，本申请制备的右美托咪定透皮贴剂在长期存放的6个月内未产生结晶。
试验例4小鼠自主活动量监测
1.方法
小鼠去毛24h后，将小鼠置于活动仪中进行适应性训练，10min后开始进行5min内的活动度监测，结果记录为0h活动度。按表19中小鼠药效学实验方案给予处方13制备的含药贴剂，置于小鼠活动仪中，进行给药后小鼠活动度监测，待后期监测时间到后继续进行小鼠活动度监测，监测时间点分别为1h、3h、6h、8h、12h、24h。
24h监测结束后移除小鼠背部贴剂，继续监测小鼠活动度，监测时间为27h、30h，监测方法同上。
评估指标：记录5min内活动次数。
表19小鼠药效学实验方案
组别 给药剂量(μg/只) 给药途径 动物数量(只)
空白对照组 NA 皮肤给药 8
供试品剂量组1 4.2 皮肤给药 8
组别 给药剂量(μg/只) 给药途径 动物数量(只)
供试品剂量组2 18.5 皮肤给药 8
供试品剂量组3 37.1 皮肤给药 8
供试品剂量组4 53.3 皮肤给药 8
2.实验结果
小鼠自主活动量数据如图5所示，对比空白对照，右美托咪定透皮贴剂可明显减少小鼠活动量，并呈现明显的量效关系，说明右美托咪定具有显著的改善睡眠药效。
试验例5大鼠脑电肌电监测实验
1.分组
给药前，对实验动物称取体重，并根据体重进行随机分组，具体如下：
表20大鼠肌电脑电检测实验分组
Figure PCTCN2022113953-appb-000053
2.万法
将SD大鼠(SPF级别，雄性)置于12h明暗交替环境中适应7天(关灯7：00；开灯：19：00)。实验当天用舒泰(i.p.，20mg/kg)，联合噻拉嗪(i.p.，8mg/kg)麻醉动物，麻醉后，脑立体定位仪固定，头部剪毛与消毒后，剪开头部皮肤，用止血钳夹住四角，充分暴露颅骨，剥离骨膜，干脱脂棉擦净， 直至表面干洁。颅骨钻孔并埋植电极。将2根肌电电极分别平行穿入颈部肌肉内，并用缝合线固定两端，避免其末端相互接触。将参考电极同样穿入对侧颈部肌肉内固定。然后植入子放入皮下，对手术伤口缝合并进行消毒。术后将大鼠小心放入干净恢复笼内，侧卧位，保证呼吸道通畅。单笼饲养，置屏蔽恢复室，12h明暗自动交替：关灯时间：7：00，开灯时间：19：00。手术后给予动物3天护理，手术切口局部给予头孢拉定粉末处理，皮下给予庆大霉素4-8mg/kg，连续3天皮下注射美洛昔康0.1ml/只，恢复7-10天后进行实验，并根据动物体重随机分组。分组后，连续监测24h EEG、EMG作为基线信号。
除Sham组外，对各组大鼠的背部和足底均采取纵长约2em的皮肤以及筋膜切口，然后予以缝合，所有动物造模完毕后，对各组大鼠分别用动物剃毛刀，将给药部位清理干净，并给予对应药物(贴剂位置位于背部并固定在皮肤上，防止贴剂中途脱落引起给药失败)，记录持续72h，监测该时间段内大鼠的EEG与EMG信号，分析术后醒觉(Wake)，浅睡或快动眼睡眠(REM)及深睡或非动眼(NREM)睡眠结构变化。
3.数据分析
原始数据由DSI系统Ponemah软件采集，用NeuroScore软件分析。实验数据由平均值±标准误(Mean±S.E.M.)表示，利用Graph Pad Prism 7.0软件，并采用Two-way ANOVA和One-way ANOVA进行统计分析，P＜0.05表示有显著性差异，P＜0.01表示有非常显著性差异，P＜0.001表示有极显著性差异。
4.实验结果
如图6所示，A：贴剂给药后72h内，大鼠睡眠结构中各时间节点内各组别Wake时间累积趋势图；B：贴剂给药后72h内，各时间节点内各组别NREM时间累积趋势图；C：贴剂给药后72h内，各时间节点内各组别REM时间累积趋势图；N＝8。
图6实验数据显示：
与正常组相比，随着右美托咪定剂量的增加，含药组大鼠72h内的觉醒时间逐渐降低，低剂量组与正常组72h内的觉醒时间无明显差异；与术后模 型组相比，含药贴剂组大鼠72h内的觉醒时长显著降低。
与正常组相比，随着右美托咪定剂量的增加，含药组大鼠72h内的慢波睡眠时间逐渐延长，低剂量组与正常组72h内的慢波睡眠时长无明显差异；与术后模型组相比，含药贴剂组大鼠72h内的慢波睡眠时间显著延长。
总体而言，本申请右美托咪定透皮贴能够有效延长非快速眼动睡眠(NREM)时间，降低术后大鼠的快速眼动睡眠(REM)时间，能够非常有效的改善睡眠质量。高剂量下的透皮贴剂对SD大鼠的睡眠时长影响较大，使得清醒期时长占比明显缩短，一定程度下会影响到动物的正常昼夜生活节律，中高剂量下的透皮贴剂能够在持续72h的情况下持续有效的改善大鼠的术后睡眠障碍，促进睡眠质量，相比于低剂量(0.88mg/kg)其效用时间更长，但低剂量组不仅能够明显改善睡眠质量，而且并不会如中高剂量组一样改变昼夜生活节律，低剂量组基本上与正常组72h内的慢波睡眠总时长和觉醒总时长一致。
对比例1
1.制剂处方
根据对比文件CN201480059798.5中的制剂33制备本申请的对比例，具体处方如下：
右美托咪定                  0.18g
乙酰丙酸                    0.11g
丙烯酸酯压敏胶              32.92g
其中，所述丙烯酸酯压敏胶型号为Duro-Tak 87-2287，固含量为53.8％。
根据对比文件记载的右美托咪定经皮组合物的制备方法制备本申请对比例1的右美托咪定透皮贴：通过将右旋美托咪定和压敏胶在有机溶剂中混合、接着混合来制备制剂。一旦形成均匀混合物，就将所述溶液浇筑在释放衬垫上，并在60℃-80℃下干燥10分钟-90分钟。然后将所述单层粘合剂薄膜层压至PET背衬，切割成所需大小放入袋中。在本对比例中，乙酰丙酸被添加至粘合剂组合物中。
压敏胶中含有的溶剂和制备过程中加入的有机溶剂均在干燥过程中被去 除。
2.体外透皮扩散试验
将本申请实施例7、实施例4以及对比例1所制得的贴剂各取三贴，分别除去离型膜层进行体外透皮扩散实验，试验方法与实施例12相同。
3.实验结果
三组透皮贴剂的体外透皮扩散曲线如图7所示。由图7可知，三组透皮贴剂的扩散速率整体趋势为实施例7优于实施例4优于对比例1，实施例7所制得的右美托咪定透皮贴剂的单位面积透皮扩散速在第12小时达到最大，为1.1μg/cm 2*h，约为对比例1的2倍左右，且对比例1所制得的贴剂在第24h才达到最大的单位面积透皮扩散速率。整体来说，本申请制得的透皮贴剂的体外扩散速率优于对比文件1。
以上所述仅是本申请的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本申请原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本申请的保护范围。

Claims (14)

  1. 一种右美托咪定经皮组合物，其中，所述组合物包括右美托咪定、丙二醇、金属螯合物类交联剂和压敏胶。
  2. 根据权利要求1所述的右美托咪定经皮组合物，其中，以重量份计，所述组合物中，
    Figure PCTCN2022113953-appb-100001
    所述丙二醇与所述右美托咪定的质量比为(4∶3)-(8∶3)。
  3. 根据权利要求2所述的右美托咪定经皮组合物，其中，所述组合物中丙二醇与右美托咪定的质量比为(5∶3)-(7∶3)；或者，所述组合物中丙二醇与右美托咪定的质量比为5∶3。
  4. 根据权利要求2或3所述的右美托咪定经皮组合物，其中，所述压敏胶与所述金属螯合物类交联剂的质量比为(70∶1)-(310∶1)。
  5. 根据权利要求4所述的右美托咪定经皮组合物，其中，所述压敏胶与所述金属螯合物类交联剂的质量比为(70∶1)-(160∶1)、(160∶1)-(220∶1)或(220∶1)-(310∶1)；或者，为(160∶1)-(220∶1)、(160∶1)-(210∶1)、(160∶1)-(200∶1)或(190∶1)-(220∶1)；或者，为160∶1、170∶1、180∶1、190∶1、200∶1、210∶1或220∶1。
  6. 根据权利要求1至5中任一项所述的右美托咪定经皮组合物，其中，所述金属螯合物类交联剂选自乙酰丙酮酸铝、乙酰丙酮酸锆、乙酰丙酮酸钛和聚钛酸丁酯中的一种或多种。
  7. 根据权利要求1至6中任一项所述的右美托咪定经皮组合物，其中，所述压敏胶选自丙烯酸酯压敏胶、聚异丁烯压敏胶、硅酮压敏胶、苯乙烯-异戊二烯-苯乙烯热熔压敏胶、乙酸乙烯酯共聚物中的一种或多种。
  8. 一种右美托咪定透皮贴剂，其中，所述的右美托咪定透皮贴剂依次包 含背衬层、胶粘层和防黏离型膜层；所述胶粘层由权利要求1至7中任一项所述的右美托咪定经皮组合物形成。
  9. 根据权利要求8所述的右美托咪定透皮贴剂，其中，所述胶粘层的厚度为25μm-100μm。
  10. 权利要求8或9所述右美托咪定透皮贴剂的制备方法，包括如下步骤：
    将金属螯合物类交联剂溶解在溶剂中，得到金属螯合物类交联剂溶液；
    将压敏胶与所述金属螯合物类交联剂溶液混合，得到空白基质溶液；
    将右美托咪定、丙二醇和溶剂混合，得到右美托咪定溶液；
    将所述右美托咪定溶液与所述空白基质溶液混合，搅拌，静置，得到含药基质溶液；
    将含药基质溶液涂布于防黏离型膜层，干燥，得到胶粘层和防黏离型膜层的复合层；
    将背衬层复合于胶粘层上。
  11. 权利要求10所述的制备方法，其中，所述的溶剂选自无水乙醇和正庚烷中的一种或者两者的混合物。
  12. 权利要求1至7中任一项所述右美托咪定经皮组合物或权利要求8至9中任一项所述右美托咪定透皮贴剂在制备改善睡眠障碍药物制剂中的应用。
  13. 根据权利要求12所述的应用，其中，所述睡眠障碍为围术期睡眠障碍、老年人睡眠障碍、创伤性睡眠障碍中的一种或多种。
  14. 改善个体睡眠障碍的方法，所述方法包括对有相应需要的个体施用权利要求1至7中任一项所述右美托咪定经皮组合物或权利要求8至9中任一项所述右美托咪定透皮贴剂。
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160310441A1 (en) * 2013-12-18 2016-10-27 Maruishi Pharmaceutical Co., Ltd. Hydrous adhesive patch
CN110585173A (zh) * 2013-10-07 2019-12-20 帝国制药美国公司 右旋美托咪啶经皮递送装置及其使用方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110585173A (zh) * 2013-10-07 2019-12-20 帝国制药美国公司 右旋美托咪啶经皮递送装置及其使用方法
US20160310441A1 (en) * 2013-12-18 2016-10-27 Maruishi Pharmaceutical Co., Ltd. Hydrous adhesive patch

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
LI, XIANFU; LI, MENG; LI, LONG; GAO, JING; ZHANG, HUI; GAO, XIANG; LIU, NAN; CHEN, HONG-GUO; ZHENG, AI-PING: "Compatibility of Raw Material and Excipients in Dexmetomidine Hydrochloride Gel", JOURNAL OF INTERNATIONAL PHARMACEUTICAL RESEARCH, JUNSHI YIXUE KEXUEYUAN * DUWU YAOWU JIANJIUSUO, CN, vol. 46, no. 11, 30 November 2019 (2019-11-30), CN , pages 867 - 872, XP009543753, ISSN: 1674-0440, DOI: 10.13220/j.cnki.jipr.2019.11.010 *
WEI XIAO-CANG, LIU WEI, ZHOU XIAO-SHUN, ZUO XIN-HE, CHEN RU-QUAN, YANG XIANG-LIANG: "Preparation of Thiamazole Hydrogel Patch and its In Vitro Percutaneous Permeability", CHINESE JOURNAL OF HOSPITAL PHARMACY, ZHONGGUO YAO XUEHUI WUHAN FENHUI, WUHAN, CN, vol. 28, no. 05, 31 March 2008 (2008-03-31), CN , pages 348 - 351, XP009543713, ISSN: 1001-5213 *
WU ZHI-FU, DENG DE-HUA, ZHANG YOU-JUAN: "Synthesis and Structure Analysis of Aluminium Glycinate Monohydrate", CHEMICAL WORLD, SHANGHAISHI HUAXUE HUAGONG XUEHUI-WUXI INSTITUTE OF LIGHT INDUSTRY, 214086, CN, no. 2, 31 December 2011 (2011-12-31), CN , pages 92 - 96, XP009543767, ISSN: 0367-6358, DOI: 10.19500/j.cnki.0367-6358.2011.02.008 *
ZHANG XIAO-LING, DENG HONG, ZHANG SHU, LIN HUA-QING: "Preparation of Nestorone Transdermal Patches and Study on the Effect of Different Permeation Enhancer on It", CHINA PHARMACY, ZHONGHUA YIYUAN GUANLI XUEHUI, CN, vol. 24, no. 17, 31 December 2013 (2013-12-31), CN , pages 1587 - 1590, XP009543769, ISSN: 1001-0408, DOI: 10.6039/j.issn.1001-0408.2013.17.19 *

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