WO2022027970A1 - 黏膜下注射的配方及其用途 - Google Patents

黏膜下注射的配方及其用途 Download PDF

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WO2022027970A1
WO2022027970A1 PCT/CN2021/081096 CN2021081096W WO2022027970A1 WO 2022027970 A1 WO2022027970 A1 WO 2022027970A1 CN 2021081096 W CN2021081096 W CN 2021081096W WO 2022027970 A1 WO2022027970 A1 WO 2022027970A1
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formulation
oligosaccharide
degraded
divalent cation
submucosal injection
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PCT/CN2021/081096
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English (en)
French (fr)
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林志强
黄俊尧
魏宏恩
李慧芳
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大员生医股份有限公司
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Priority to CN202180000780.8A priority Critical patent/CN114286673A/zh
Publication of WO2022027970A1 publication Critical patent/WO2022027970A1/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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/721—Dextrans
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/723—Xanthans
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/734—Alginic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/0033—Xanthan, i.e. D-glucose, D-mannose and D-glucuronic acid units, saubstituted with acetate and pyruvate, with a main chain of (beta-1,4)-D-glucose units; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0084—Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0087—Glucomannans or galactomannans; Tara or tara gum, i.e. D-mannose and D-galactose units, e.g. from Cesalpinia spinosa; Tamarind gum, i.e. D-galactose, D-glucose and D-xylose units, e.g. from Tamarindus indica; Gum Arabic, i.e. L-arabinose, L-rhamnose, D-galactose and D-glucuronic acid units, e.g. from Acacia Senegal or Acacia Seyal; Derivatives thereof
    • C08B37/0096—Guar, guar gum, guar flour, guaran, i.e. (beta-1,4) linked D-mannose units in the main chain branched with D-galactose units in (alpha-1,6), e.g. from Cyamopsis Tetragonolobus; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles

Definitions

  • the present invention relates to a formulation for submucosal injection, and more particularly to a pseudoplastic submucosal injection formulation and a preparation method thereof.
  • Endoscopic resection is a useful treatment for mucosal lesions and early-stage cancers of the gastrointestinal tract. It usually includes endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD).
  • EMR endoscopic mucosal resection
  • ESD endoscopic submucosal dissection
  • the conventional standard method for performing EMR or ESD is to inject submucosal injections into the mucosal layer to elevate or protrude the lesion, thereby creating a lift to improve the efficiency of lesion resection.
  • Physiological saline, glycerin, hyaluronic acid, glucose solution, hydroxypropyl methylcellulose, etc. are common submucosal injections.
  • existing submucosal injections also include two-dose injection solutions, one of which contains polysaccharide and the other that contains divalent cations.
  • the two solutions are injected into the lesion separately, so that the polysaccharide and divalent cation are cross-linked at the lesion and form an insoluble colloid. If the two solutions are mixed before injection, the gel will block the endoscope needle and make the injection impossible.
  • An object of the present invention is to provide a submucosal injection with the following properties: (1) durable mucosal lift; (2) safe and non-toxic; (3) easy to obtain raw materials; (4) easy to inject; Organization is non-destructive.
  • One object of the present invention is to provide a pseudoplastic submucosal injection with low injection pressure and high tissue lifting efficiency.
  • One embodiment of the present invention provides a formulation for submucosal injection, comprising: divalent cations and oligosaccharides.
  • divalent cations When the divalent cation is in contact with the oligosaccharide, the viscosity of the formulation is greater than 1000 cP, and the injection pressure of the formulation falls within the range of 2.5-4 kgf.
  • the oligosaccharide in the formulation is obtained by exposing polysaccharide powder to radiation, thermal energy, ultrasound, or ultraviolet light.
  • the oligosaccharide in the formulation is prepared by exposing the polysaccharide powder to gamma ( ⁇ ) rays at 25-100 kGy, heat energy at 160-200° C., UV-C light at 100-280 nm, or 20- 60kHz ultrasound.
  • the divalent cation in the formulation comprises calcium (Ca 2+ ), magnesium (Mg 2+ ), iron (Fe 2+ ), copper (Cu 2+ ), barium (Ba 2+ ) + ), and at least one divalent cation in the group consisting of zinc (Zn 2+ ) divalent ions.
  • the concentration of the divalent cation in the formulation falls within the range of 0.1-0.5% w/v.
  • the oligosaccharide in the formulation is selected from the group consisting of degraded sodium alginate, degraded xanthan gum, degraded polydextrose (dextran), degraded welan gum , at least one of the group consisting of degraded gellan gum and degraded diutan gum.
  • the concentration of the oligosaccharide in the formulation falls within the range of 0.5-2% w/v.
  • the formulation is premixed and provided as a single solution.
  • the divalent cation and the oligosaccharide in the formulation are packaged separately, and the oligosaccharide is provided in powder form.
  • the formulation further comprises a physiologically acceptable excipient.
  • Another embodiment of the present invention provides a method of preparing the aforementioned formulation for submucosal injection.
  • the method includes the following steps: providing a divalent cation solution; providing an oligosaccharide powder; and mixing the oligosaccharide with the solution to obtain the formula.
  • Yet another embodiment of the present invention provides the use of the aforementioned formulation for the preparation of a medicament for submucosal elevating.
  • the formulation for submucosal injection according to the embodiment of the present invention is not only easy to use, but also has low injection pressure and excellent mucosal lifting ability.
  • 1 is a histogram showing the effect of divalent cation concentration and radiation dose on the injection pressure of a formulation according to an embodiment of the present invention
  • 2A is a micrograph showing droplets formed by formulations of embodiments of the present invention.
  • Figure 2B is a photographic view showing a side view of the droplet in Figure 2A;
  • Figure 3 is a graph showing the change in mucosal height as a function of time for formulations of embodiments of the present invention.
  • 4A and 4B are photographic diagrams showing a side view and a perspective view of a formulation-lifted submucosa according to an embodiment of the present invention.
  • the formulation for submucosal injection comprises divalent cations and oligosaccharides.
  • the formulation may premix the divalent cation and the oligosaccharide and provide a single solution; or may package the divalent cation and the oligosaccharide separately, wherein the divalent cation is in solution (eg, divalent cation) cationic solution) and the oligosaccharide is provided in powder form (eg, oligosaccharide powder).
  • the divalent cation may include calcium (Ca 2+ ), magnesium (Mg 2+ ), iron (Fe 2+ ), copper (Cu 2+ ), barium (Ba 2+ ) and zinc (Zn 2+ ) At least one divalent cation in the group consisting of divalent ions; in other words, the divalent cation may include Ca 2+ , Mg 2+ , Fe 2+ , Cu 2+ , Ba 2+ , Zn 2+ or its any combination.
  • the oligosaccharide may comprise selected from degraded sodium alginate, degraded xanthan gum, degraded polydextrose (dextran), degraded welan gum, degraded gellan At least one of the group consisting of gellan gum and degraded diutan gum; in other words, the oligosaccharide may include degraded sodium alginate, degraded xanthan gum, degraded polydextrose , degraded welan gum, degraded gellan gum, degraded Dingyou gum, or any combination thereof.
  • the concentration of divalent cations in the formulation or in the divalent cation solution may fall within the range of 0.1 to 0.5% w/v.
  • the formulation or the divalent cation solution may further comprise at least one physiologically acceptable divalent cationic excipient (eg, mannitol). Additionally, colorants (eg, Brilliant Blue FCF) can also be added to the formulation to facilitate visualization of the injection site.
  • the concentration of oligosaccharides in the formulation may fall in the range of 0.5-2% w/v.
  • the formulation or the oligosaccharide powder may further comprise at least one physiologically acceptable excipient (eg, sorbitol, sucrose, lactose, maltose and trehalose).
  • the oligosaccharide or oligosaccharide powder in the formulation can be obtained from the degradation of the polysaccharide; specifically, the oligosaccharide in the formulation can be obtained by exposing the powdered polysaccharide to radiation, thermal energy, ultrasound or ultraviolet (UV) light or oligosaccharide powder.
  • polysaccharide powder can be treated in an atmospheric environment at a dose of 25 to 100 kGy using gamma ( ⁇ ) rays generated by a radiation source containing 60 Co.
  • the polysaccharide powder can also be heated in an oven at 160-200°C for 2-6 hours in an atmospheric environment, or exposed to UV-C light at 100-280 nm for 1-30 minutes, or It is suspended in ethanol or other organic solvent and ultrasonic waves are applied at a frequency of 20-60 kHz for 20-200 minutes.
  • the formulation when the formulation is provided as a single solution, the formulation is a pseudoplastic homogeneous non-Newtonian fluid with a viscosity greater than 1000 cP and an injection pressure in the range of 2.5-4 kgf.
  • the formulation when the formulation is provided in a two-dose form, the formulation will form the aforementioned pseudoplastic homogeneous non-Newtonian fluid after mixing the divalent cation solution with the oligosaccharide powder.
  • the aforementioned formulation is for the preparation of a medicament for elevating mucosa.
  • a method of preparing the aforementioned formulation for submucosal injection comprises the steps of: providing a divalent cation solution containing the aforementioned divalent cation; providing the aforementioned oligosaccharide powder; and combining the oligosaccharide powder with the aforementioned oligosaccharide powder The divalent cation solution is mixed to obtain the formulation for submucosal injection.
  • Formulations 1 to 5 0.01 to 0.03 grams (g) of calcium lactate (as shown in Table 1 below), 0.2 grams of mannitol, and 0.002 grams of Edible Blue No. 1 in deionized water (dH 2 O) Mix and add deionized water until the total volume reaches 10 milliliters (mL) to make a divalent cation solution.
  • 0.8 g of oligosaccharide powder was slowly added to 10 ml of divalent cation solution, and stirred at room temperature for 15 minutes, thereby obtaining formulations 1 to 5 for submucosal injection.
  • Calcium lactate (g) Calcium lactate concentration (%w/v) 1 0.01 0.1% 2 0.015 0.15% 3 0.02 0.2% 4 0.025 0.25% 5 0.03 0.3%
  • Formulations 6 to 8 Mix 0.025 g of calcium lactate, 0.2 g of mannitol, and 0.002 g of edible blue No. 1 in deionized water, and then add deionized water until the total volume reaches 10 ml to obtain a divalent cationic solution.
  • 0.8 g of oligosaccharide powder was slowly added to 10 ml of divalent cation solution and stirred at room temperature for 15 minutes, thereby obtaining formulations 6-8 for submucosal injection.
  • Formulations 9-14 Mix 0.01-0.025 grams of calcium lactate (as shown in Table 3 below), 0.2 grams of mannitol, and 0.002 grams of Edible Blue No. 1 in deionized water, and then add deionized water until the total The volume was brought to 10 ml, and a divalent cation solution was prepared. Mix 0.1 g of degraded sodium alginate, 0.25 g of sucrose, and 0.45 g of sorbitol to obtain oligosaccharide powder; wherein, degraded sodium alginate is obtained by exposing the sodium alginate powder to gamma rays of 25-53 kGy (details are as follows) shown in Table 3). 0.8 g of oligosaccharide powder was slowly added to 10 ml of divalent cation solution and stirred at room temperature for 15 minutes, thereby obtaining formulations 9-14 for submucosal injection.
  • Viscosity testing was carried out at 25°C using a rotational viscometer (Brookfield, DVE), sample cell model SC4-13R(P), spindle model SC4-18.
  • Injection pressure was measured using a syringe consisting of a 23G endoscopic long needle (160mm) attached to a 3ml syringe barrel. The measurement is performed by fixing a syringe filled with the formulation to be tested to a texture analyzer (JISC, JSH-1000), which pushes the piston of the syringe at a constant rate of 60 mm/min, and the formulation to be tested is removed from the test formulation at 25°C. The force required to expel the long needle of the endoscope is defined as the injection pressure.
  • the diffusivity test uses a dropper to place a drop of the formulation on the filter paper and observe the change in drop shape after 5 minutes.
  • the submucosa lifting capacity test will be performed by injecting 5 ml of the formula into the submucosal mucosa of porcine colon samples and measuring the elevation of the mucosa before and after needle withdrawal.
  • the pseudoplastic formulation has the characteristics of high viscosity (over 1000cP) but low injection pressure (2.5-4kgf). Therefore, when the injection pressure is greater than 2.5kgf, it means that the formula begins to appear pseudoplastic.
  • Figure 1 when formulas 9 to 14 were tested, it was found that in order to obtain a formula with an injection pressure greater than 2.5 kgf, a higher dose of ⁇ -ray irradiation was required to degrade the polysaccharide, and the lactic acid in the divalent cation solution had to be increased. calcium concentration.
  • the divalent cation solution needs to contain at least 0.25% w/v calcium lactate; similarly, when the ⁇ -ray irradiation dose to sodium alginate is less than 32kGy, The desired calcium lactate concentration is at least 0.1% w/v.
  • formula 8 is less likely to spread, and obviously has a better lifting effect.
  • formulations 1-4 could maintain the lift for at least 30 minutes, showing excellent mucosal lift ability.
  • Embodiments of the present invention disclose a pseudoplastic formulation in which the divalent cation and oligosaccharide may be premixed and provided as a single solution; or the divalent cation solution and oligosaccharide powder may be separated packaged in two-dose form.
  • the invention is suitable for submucosal injection and lifting, and provides an effective and easy-to-operate solution for endoscopic resection.

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Abstract

提供一种黏膜下注射的配方及其用途，该配方包含：二价阳离子以及寡糖，该寡糖是通过将多糖粉末暴露于辐射、热能、超音波、或紫外线而获得。该配方可作为单一溶液提供；或可将该二价阳离子及该寡糖分开包装，且该二价阳离子以溶液形式提供，而该寡糖以粉末形式提供。该二价阳离子可为0.1～0.5％w/v的钙、镁、铁、铜、钡、锌二价离子或其任意组合。该寡糖可为0.5～2％w/v的降解海藻酸钠、降解黄原胶、降解聚葡萄糖、降解威兰胶、降解结兰胶、以及降解定优胶或其混合物。当该二价阳离子与该寡糖接触时，该配方的黏度大于1000cP，且该配方的注射压力落在2.5～4kgf的范围内。

Description

黏膜下注射的配方及其用途 技术领域
本申请案主张于2020年8月6日提申的美国临时专利申请案第63/061810号的优先权，将该案的全部内容以引用的方式并入本文中。
本发明涉及黏膜下注射的配方，更具体地涉及假塑性黏膜下注射剂型及其制备方法。
背景技术
内视镜切除手术是用于治疗黏膜病变及胃肠道早期癌症的有用的治疗手段。其通常包括内视镜黏膜切除术(EMR)及内视镜黏膜下剥离术(ESD)。进行EMR或ESD的常规标准方法是将黏膜下注射剂注射至黏膜层，使病灶抬起或突起，从而形成抬升以提高病灶切除效率。生理食盐水、甘油、玻尿酸、葡萄糖液、羟丙基甲基纤维素等为常见的黏膜下注射剂。
然而，由于将生理食盐水注射至组织后容易扩散，尤其加上切除时的挤压，抬升部位会在短时间内变形并消失。因此，需要重复注射生理食盐水以维持抬升。
此外，现有的黏膜下注射剂还包括两剂式的注射溶液，其中一剂包含多糖，而另一剂包含二价阳离子。临床使用时，将该两种溶液分别地注射至病灶处，从而使多糖和二价阳离子于病灶处交联并形成不可溶的胶体。若在注射之前就将两溶液混合，则胶体会阻塞内视镜注射针，导致注射无法进行。
发明内容
本发明的一目的在于提供一种黏膜下注射剂，具有下列性质：(1)持久的黏膜抬升；(2)安全无毒性；(3)原料容易取得；(4)易于注射；及(5)对于组织无破坏性。
本发明的一目的在于提供一种假塑性黏膜下注射剂，其注射压力低且组织抬升效率高。
本发明的一实施方式提供一种黏膜下注射的配方，包含：二价阳离子及寡糖。当该二价阳离子与该寡糖接触时，该配方的黏度大于1000cP，且该配方的注射压力落在2.5～4kgf的范围内。
在一实施方式中，该配方中的该寡糖是通过将多糖粉末暴露于辐射、热能、超音波、或紫外线而得。
在一实施方式中，该配方中的该寡糖是通过将多糖粉末暴露于25～100kGy的伽马(γ)射线、160～200℃的热能、100～280nm的UV-C光、或20～60kHz的超音波而得。
在一实施方式中，该配方中的该二价阳离子包含选自于钙(Ca 2+)、镁(Mg 2+)、铁(Fe 2+)、铜(Cu 2+)、钡(Ba 2+)、及锌(Zn 2+)二价离子所构成的群组中的至少一种二价阳离子。
在一实施方式中，该配方中的该二价阳离子的浓度落在0.1～0.5％w/v的范围内。
在一实施方式中，该配方中的该寡糖包含选自于降解海藻酸钠(sodium alginate)、降解黄原胶(xanthan gum)、降解聚葡萄糖(dextran)、降解威兰胶(welan gum)、降解结兰胶(gellan gum)、以及降解定优胶(diutan gum)所构成的群组中的至少一种。
在一实施方式中，该配方中的该寡糖的浓度落在0.5～2％w/v的范围内。
在该实施方式中，该配方预混合并以单一溶液形式提供。
在一实施方式中，该配方中的该二价阳离子及该寡糖分别包装，且该寡糖是以粉末形式提供。
在一实施方式中，该配方进一步包含生理上可接受的赋形剂。
本发明的另一实施方式提供制备前述黏膜下注射的配方的方法。该方法包括以下步骤：提供一二价阳离子溶液；提供一寡糖粉末；将该寡糖与该溶液混合而得到该配方。
本发明的再另一个实施方式提供使用前述配方制备使黏膜下抬升的药物的用途。
根据本发明的实施方式的黏膜下注射的配方，不但容易使用，且具有低注 射压力及优异的黏膜抬升能力。
为了使本发明所属领域中具有公知常识者能够更明确得知本发明的上述内容及其他目的、特征及益处，于下方描述理想的实施方式及附图的详细说明。
附图说明
图1为表示本发明的实施方式的二价阳离子浓度及辐射量对于配方的注射压力的影响的直方图；
图2A为表示本发明的实施方式的配方所形成的液滴的显微图；
图2B为表示图2A中的液滴的侧视图的照片图；
图3为表示本发明的实施方式的配方抬升的黏膜高度随时间变化的曲线图；及
图4A及图4B为表示本发明的实施方式的配方抬升的黏膜下层的侧视图及透视图的照片图。
具体实施方式
下述将参照以下实施例而更详细说明本发明。需注意地，本说明书中对于本发明的理想实施例进行详细描述的目的仅在于作为例示及说明，并未旨在详尽或限制于所公开的精确形式。
根据本发明的实施方式，黏膜下注射的配方包含二价阳离子以及寡糖。该配方可将该二价阳离子和该寡糖预混合，以单一溶液的形式提供；或可将该二价阳离子和该寡糖分开包装，其中，该二价阳离子以溶液形式(例如，二价阳离子溶液)提供，该寡糖以粉末形式(例如，寡糖粉末)提供。
该二价阳离子可包括选自于钙(Ca 2+)、镁(Mg 2+)、铁(Fe 2+)、铜(Cu 2+)、钡(Ba 2+)及锌(Zn 2+)二价离子所构成的群组中的至少一种二价阳离子；换言之，该二价阳离子可包括Ca 2+、Mg 2+、Fe 2+、Cu 2+、Ba 2+、Zn 2+或其任意的组合。该寡糖可包括选自于降解的海藻酸钠(sodium alginate)、降解的黄原胶(xanthan gum)、降解的聚葡萄糖(dextran)、降解的威兰胶(welan gum)、降解的结兰胶(gellan gum)、以及降解的定优胶(diutan gum)所构成的群组中的至少一种；换言之，该寡糖可包括 降解的海藻酸钠、降解的黄原胶、降解的聚葡萄糖、降解的威兰胶、降解的结兰胶、降解的定优胶，或其任意的组合。
在该实施方案中，该配方或该二价阳离子溶液中的二价阳离子的浓度可落在0.1～0.5％w/v的范围内。该配方或该二价阳离子溶液可进一步包含至少一种生理上可接受的二价阳离子赋形剂(例如，甘露醇)。此外，也可将着色剂(例如，食用蓝色一号(Brilliant Blue FCF))添加至配方中，以促进注射部位的可视化。
该配方中的寡糖的浓度可落在0.5～2％w/v的范围内。该配方或该寡糖粉末还可进一步包含至少一种生理上可接受的赋形剂(例如，山梨醇、蔗糖、乳糖、麦芽糖及海藻糖)。
该配方中的寡糖或寡糖粉末可从多糖的降解中获得；具体而言，可通过将粉末状的多糖暴露于辐射、热能、超音波或紫外线(UV)中而获得配方中的寡糖或寡糖粉末。例如，可利用含 60Co的辐射源所产生的伽马(γ)射线，以25～100kGy的剂量、在大气环境下处理多糖粉末。在一些实施方案中，也可在大气环境下，将多糖粉末以160-200℃的烘箱加热2～6小时，或将其暴露于100～280nm的UV-C光下1～30分钟，或将其悬浮在乙醇或其他有机溶剂中以20-60kHz的频率施加超音波20～200分钟。
在该实施方案中，当配方是以单一溶液的形式提供时，该配方为一种具有假塑性的均质非牛顿流体，其黏度大于1000cP且注射压力落在2.5～4kgf的范围内。而当配方是以两剂式的形式提供时，该配方会在二价阳离子溶液与寡糖粉末混合后，形成上述的假塑性均质非牛顿流体。
根据本发明的另一实施方案，前述配方是用于制备使黏膜抬升的药物。
根据本发明的再另一实施方案，制备前述黏膜下注射的配方的方法包括下述步骤：提供含有前述二价阳离子的二价阳离子溶液；提供前述寡糖粉末；以及将该寡糖粉末与该二价阳离子溶液混合而获得该黏膜下注射的配方。
例一：材料制备
配方1～5：将0.01～0.03克(g)的乳酸钙(详如下表1所示)、0.2克的甘露醇、及0.002克的食用蓝色一号在去离子水(dH 2O)中混合，再添加去离子水直到总体积达到10毫升(mL)，而制得二价阳离子溶液。将0.1克降解海藻酸钠、0.25克 蔗糖、及0.45克山梨醇混合，而制得寡糖粉末；其中，降解海藻酸钠是由将海藻酸钠粉末暴露于37kGy的伽马(γ)射线而得。将0.8克的寡糖粉末缓慢添加到10毫升的二价阳离子溶液中，并在室温搅拌15分钟，从而得到黏膜下注射的配方1～5。
表1
配方 乳酸钙(g) 乳酸钙浓度(％w/v)
1 0.01 0.1％
2 0.015 0.15％
3 0.02 0.2％
4 0.025 0.25％
5 0.03 0.3％
配方6～8：将0.025克的乳酸钙、0.2克的甘露醇、及0.002克的食用蓝色一号在去离子水中混合，再添加去离子水直到总体积达到10毫升，而制得二价阳离子溶液。将0.1克降解海藻酸钠、0.25克蔗糖、及0.45克山梨醇混合，而制得寡糖粉末；其中，降解海藻酸钠是由将海藻酸钠粉末暴露于25～53kGy的γ射线(详如下表2所示)而得。将0.8克的寡糖粉末缓慢添加到10毫升的二价阳离子溶液中，并在室温搅拌15分钟，从而得到黏膜下注射的配方6～8。
表2
配方 乳酸钙(g) γ射线剂量(kGy)
4 0.01 37
6 0.015 25
7 0.02 32
8 0.025 53
配方9～14：将0.01～0.025克的乳酸钙(详如下表3所示)、0.2克的甘露醇、及0.002克的食用蓝色一号在去离子水中混合，再添加去离子水直到总体积达到10毫升，而制得二价阳离子溶液。将0.1克降解海藻酸钠、0.25克蔗糖、及 0.45克山梨醇混合，而制得寡糖粉末；其中，降解海藻酸钠是由将海藻酸钠粉末暴露于25～53kGy的γ射线(详如下表3所示)而得。将0.8克的寡糖粉末缓慢添加到10毫升的二价阳离子溶液中，并在室温搅拌15分钟，从而得到黏膜下注射的配方9～14。
表3
Figure PCTCN2021081096-appb-000001
例二：分析方法
黏度测试使用旋转黏度仪(Brookfield，DVE)，样品槽型号SC4-13R(P)，转轴型号SC4-18，在25℃下进行测量。
注射压力使用注射器测量，该注射器包括连接3毫升注射针筒的23G内视镜长针(160mm)。测量的方式为，将填充有待测配方的注射器固定到质地分析仪(JISC，JSH-1000)，该分析仪以60mm/min的恒定速率推动注射器的活塞，在25℃下将待测配方从内视镜长针排出所需的力，定义为注射压力。
扩散性试验使用滴管将一滴配方放在滤纸上，在5分钟后观察液滴形状的变化。
黏膜下层抬升能力试验将通过将5毫升的配方注射到猪结肠样本的黏膜下，并在拔针前后分别测量黏膜的抬升高度。
例三：效果评估
I.二价阳离子浓度对配方的黏度及注射压力的影响
如表4所示，配方1～5的黏度及注射压力随配方中乳酸钙的浓度而增加。值得注意的是，如配方4及5的测试结果所示，当含有至少0.25％的乳酸钙的二价阳离子溶液与经37kGy的γ射线照射过的寡糖粉末混合时，配方黏度显著 增加(超过1000cP)，但其注射压力仅保持稳定的增长，并没有随着黏度的变化以同样的倍数增加。换言之，当配方中含有特定浓度的乳酸钙时，注射压力的增加与黏度的增加不成比例。此观察结果表明，配方4与配方5具有假塑性(pseudoplastic behavior)，即所谓的非牛顿流体中的剪稀化(shear thinning)现象。
表4
Figure PCTCN2021081096-appb-000002
II.辐射剂量对配方的黏度及注射压力的影响
如表5所示，配方4及6-8的注射压力随着γ射线剂量的增加而降低，且三种配方皆处于高黏度状态。此结果表明，在与含有0.25％w/v的乳酸钙的二价阳离子溶液混合之前，该寡糖粉末需暴露于至少32kGy的γ射线，所得的配方才会表现出假塑性。
表5
配方 γ射线(kGy) 黏度(cP) 注射压力(kgf)
6 25 >1000 6.03
7 32 >1000 3.15
4 37 >1000 2.89
8 53 >1000 2.67
III.二价阳离子浓度与辐射剂量的相关性及其对配方的注射压力的影响
如上所述，具假塑性的配方，具有黏度高(超过1000cP)但注射压力低(2.5～4kgf)的特性。因此，当注射压力大于2.5kgf时，表示配方开始出现假塑性。如图1所示，对配方9～14进行检验时发现，为了获得注射压力大于2.5kgf的配方，须以较高剂量的γ射线进行照射来降解多糖，并且须提高二价阳离子溶液中的乳酸钙浓度。例如，当对海藻酸钠的γ射线照射剂量大于32kGy时，该二价阳离子溶液需含有至少0.25％w/v的乳酸钙；同理，当对海藻酸钠的γ射线照射剂量小于32kGy时，所需的乳酸钙浓度为至少0.1％w/v。
IV.配方的扩散性
如图2A～2B所示，配方8与玻尿酸及生理食盐水相比，较不易扩散，显然具有更佳的抬升效果。
V.黏膜抬升能力
如图3及图4A～4B所示，配方1-4可维持至少30分钟的抬升，表现出优异的黏膜抬升能力。
本发明的实施方式揭露一种具有假塑性的配方，该配方可将其中的二价阳离子和寡糖预混合，以单一溶液的形式提供；或可将其中的二价阳离子溶液及寡糖粉末分开包装，以两剂式的形式提供。本发明适用于黏膜下注射及抬升，为内视镜切除手术提供了一种有效且易于操作的解决方案。
虽将最实际及理想的实施方式以术语记载来说明本发明，只是应当理解地，本发明未受限于所公开的实施方式。反之，本发明旨在涵盖所有包括在权利要求的精神及范围内的各种修改及同等置换，其应与最宽泛的解释相一致，从而涵盖所有修改和置换。

Claims (10)

  1. 一种黏膜下注射的配方，其特征在于，包含：
    二价阳离子；以及
    寡糖，是通过将多糖粉末暴露于辐射、热能、超音波、或紫外线而获得；
    其中，当该二价阳离子与该寡糖接触时，该配方的黏度大于1000cP，且该配方的注射压力落在2.5～4kgf的范围内。
  2. 根据权利要求1所述的黏膜下注射的配方，其特征在于，该寡糖是通过将该多糖粉末暴露于25～100kGy的伽马(γ)射线、160～200℃的热能、100～280nm的UV-C光、或20～60kHz的超音波而获得。
  3. 根据权利要求1所述的黏膜下注射的配方，其特征在于，该二价阳离子包含选自于钙(Ca 2+)、镁(Mg 2+)、铁(Fe 2+)、铜(Cu 2+)、钡(Ba 2+)、及锌(Zn 2+)二价离子所构成的群组中的至少一种二价阳离子。
  4. 根据权利要求1所述的黏膜下注射的配方，其特征在于，该配方中的二价阳离子的浓度落在0.1～0.5％w/v的范围内。
  5. 根据权利要求1所述的黏膜下注射的配方，其特征在于，该寡糖包含选自于降解海藻酸钠、降解黄原胶、降解聚葡萄糖、降解威兰胶、降解结兰胶、以及降解定优胶所构成的群组中的至少一种。
  6. 根据权利要求1所述的黏膜下注射的配方，其特征在于，该配方中的寡糖的浓度落在0.5～2％w/v的范围内。
  7. 根据权利要求1所述的黏膜下注射的配方，其特征在于，该二价阳离子和该寡糖分别包装，且该寡糖为粉末形式。
  8. 根据权利要求1所述的黏膜下注射的配方，其特征在于，该二价阳离子和该寡糖预混合并以单一溶液形式提供。
  9. 根据权利要求1所述的黏膜下注射的配方，其特征在于，进一步包含一生理上可接受的赋形剂。
  10. 一种使用权利要求1至9中任一项所述的黏膜下注射的配方制备使黏膜抬升的药物的用途。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20000012173A (ko) * 1999-03-26 2000-03-06 김공수 저분자다당류및올리고당의제조방법
CN106456789A (zh) * 2013-10-07 2017-02-22 波士顿科学国际有限公司 可注射组合物
TW201825080A (zh) * 2017-01-09 2018-07-16 林錫璋 可供內視鏡治療術應用的即溶乾燥粉末
CN109789219A (zh) * 2016-07-21 2019-05-21 波士顿科学国际有限公司 可注射组合物
CN109952117A (zh) * 2016-09-21 2019-06-28 雀巢皮肤健康公司 具有二价锌阳离子的透明质酸凝胶
CN111246842A (zh) * 2017-09-25 2020-06-05 京都府公立大学法人 用于粘膜下注射的两剂型局部注射溶液

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103957954A (zh) * 2011-11-25 2014-07-30 日本制药株式会社 粘膜下隆起剂
US10179190B2 (en) * 2015-05-29 2019-01-15 Boston Scientific Scimed, Inc. Compositions and methods for treatment of tissue
KR101884467B1 (ko) * 2017-06-12 2018-08-02 한국맥널티 주식회사 알긴산 또는 그 약학적으로 허용되는 염과 콜로이드성 다당류를 함유하는 액상 조성물
EP3821920A4 (en) * 2018-07-13 2022-03-02 T-ACE Medical Co., Ltd. SUIT FOR ENDOSCOPIC SURGERY

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20000012173A (ko) * 1999-03-26 2000-03-06 김공수 저분자다당류및올리고당의제조방법
CN106456789A (zh) * 2013-10-07 2017-02-22 波士顿科学国际有限公司 可注射组合物
CN109789219A (zh) * 2016-07-21 2019-05-21 波士顿科学国际有限公司 可注射组合物
CN109952117A (zh) * 2016-09-21 2019-06-28 雀巢皮肤健康公司 具有二价锌阳离子的透明质酸凝胶
TW201825080A (zh) * 2017-01-09 2018-07-16 林錫璋 可供內視鏡治療術應用的即溶乾燥粉末
CN111246842A (zh) * 2017-09-25 2020-06-05 京都府公立大学法人 用于粘膜下注射的两剂型局部注射溶液

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