WO2020010616A1 - 用于内镜手术的组合 - Google Patents

用于内镜手术的组合 Download PDF

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WO2020010616A1
WO2020010616A1 PCT/CN2018/095644 CN2018095644W WO2020010616A1 WO 2020010616 A1 WO2020010616 A1 WO 2020010616A1 CN 2018095644 W CN2018095644 W CN 2018095644W WO 2020010616 A1 WO2020010616 A1 WO 2020010616A1
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French (fr)
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林锡璋
陈志鸿
康瑞文
曾中柏
康文宣
林诠胜
何启铭
温芝宁
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0031—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0042—Materials resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions

Definitions

  • the present invention relates to a combination or composition for endoscopy, particularly a lyophilized powder for endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD).
  • EMR endoscopic mucosal resection
  • ESD endoscopic submucosal dissection
  • Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) offer new options for minimally invasive treatment of gastrointestinal adenomas and early cancers involving the lowest risk of lymph node metastasis.
  • EMR Endoscopic mucosal resection
  • ESD endoscopic submucosal dissection
  • the use of submucosal injection solutions is indispensable for the success of these endoscopic resection or dissection techniques (Drug Design, Development and Therapy 2008: 2131-138).
  • saline (NS) solutions were often used as submucosal injection solutions.
  • Other submucosal injections have also been developed, such as hypertonic saline solution, glycerol, dextrose water (DW), hyaluronic acid (HA), fibrinogen mixture (FM), and hydroxypropyl methylcellulose (HPMC) ) (Drug Design, Development and Therapy 2008: 2131-138).
  • hypertonic saline solution glycerol, dextrose water (DW), hyaluronic acid (HA), fibrinogen mixture (FM), and hydroxypropyl methylcellulose (HPMC)
  • DW dextrose water
  • HA hyaluronic acid
  • FM fibrinogen mixture
  • HPMC hydroxypropyl methylcellulose
  • the aforementioned injection solution having a relatively high viscosity makes the injection process difficult, for example, it is difficult to flow a viscous solution through an injection device.
  • hydrogel has been reported to be unstable during storage, easily decomposed in the presence of water, and not as stable as desired when used in vivo. These disadvantages are not conducive to its use as a drug delivery vehicle or in other organisms. Uses in medical applications.
  • the present invention provides a combination for endoscopic surgery, which can be used for tissue lift or tissue elevation, especially for mucosal lift.
  • the combination of the present invention is an instant powder, which can be used as an injection solution after rehydration.
  • the combination of the present invention is an injection solution, it can be used as a solution for mucosal elevation in endoscopic surgery.
  • One aspect of the invention provides a combination comprising: a first composition comprising an anionic polysaccharide and a solubilizing agent; and a second composition comprising a cationic crosslinking agent, wherein the first composition and the second combination
  • the contents are stored in separate containers.
  • the first composition and the second composition are in the form of lyophilized powder and stored in separate containers.
  • the anionic polysaccharide is sodium alginate.
  • the solubilizing agent is selected from the group consisting of sucrose and sorbitol.
  • the content of sodium alginate is about 5 to about 15 parts by weight, specifically 5, 6, 7, 8, 9, 10, 11, 15, 13, 14, or 15 parts by weight.
  • the content of sucrose is about 25 to about 35 parts by weight, specifically 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 parts by weight.
  • the content of sorbitol is about 60 to about 65 parts by weight, specifically 60, 61, 62, 63, 64 or 65 parts by weight.
  • the content of sodium alginate is about 12.5 parts by weight
  • the content of sucrose is about 25 parts by weight
  • sorbose The content of the alcohol is about 62.5 parts by weight.
  • the cationic crosslinking agent is selected from the group consisting of calcium lactate and mannitol.
  • the content of calcium lactate is about 50 to about 70 parts by weight, specifically 50, 51, 52, 53 , 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 or 70 parts by weight.
  • the content of mannitol is about 30 to about 50 parts by weight, specifically 30, 31, 32, 33 , 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 parts by weight.
  • the content of calcium lactate is about 67 parts by weight, and the content of mannitol is about 33 parts by weight.
  • Another aspect of the invention provides a combination comprising: a first composition comprising an anionic polysaccharide and a solubilizing agent; and a second composition comprising a cationic crosslinking agent, wherein the first composition and the second composition It is in the form of a solution and stored in a separate container.
  • the content of sodium alginate is about 0.4 to about 1.2 parts by weight; the content of sucrose is about 2.0 to about 2.8 weight. And the content of sorbitol is about 3.5 to about 5.2 parts by weight; and based on the total amount of the second composition solution being 100 parts by weight, the content of calcium lactate is about 3.0 to about 4.2 parts by weight; and manna The alcohol content is about 1.8 to about 3.0 parts by weight.
  • the content of sodium alginate is about 1 part by weight; the content of sucrose is about 2 parts by weight; and sorbitol And the content of calcium lactate is about 4 parts by weight based on the total amount of the second composition solution being 100 parts by weight; and the content of mannitol is about 2 parts by weight.
  • Another aspect of the present invention provides a method for preparing an injection solution for endoscopic surgery, comprising: providing a first composition as described herein; providing a second composition as described herein; and mixing The first composition and the second composition to obtain an injection solution.
  • Another aspect of the present invention provides a method for performing endoscopic surgery, which comprises injecting the first composition and the second composition in the form of a solution into a target tissue of a patient, respectively, wherein the first composition and the second combination are The object is crosslinked in the patient's target tissue, preferably forming a hydrogel as a cushion.
  • Another aspect of the present invention provides a combination comprising a first composition and a second composition, wherein: the first composition comprises:
  • the second composition includes:
  • first composition and the second composition are stored in separate containers.
  • the second composition further comprises: (IIb) mannitol.
  • the content of sodium alginate is about 5 to about 15 parts by weight based on the total amount of the dry powder of the first composition being 100 parts by weight; the content of sucrose is about 25 to about 35 parts by weight And the content of sorbitol is about 60 to about 65 parts by weight; and based on the total amount of the second composition being 100 parts by weight, the content of calcium lactate is about 50 to about 70 parts by weight; and mannitol The content is about 30 to about 50 parts by weight.
  • the content of sodium alginate is about 12.5 parts by weight; the content of sucrose is about 25.0 parts by weight; and sorbitol And the content of calcium lactate is about 67 parts by weight based on the total amount of the second composition being 100 parts by weight; and the content of mannitol is about 33 parts by weight.
  • the first composition and the second composition are in the form of a lyophilized powder.
  • the first composition and the second composition are in the form of a solution.
  • the rehydration ratio (solid: water) of the first composition is 0.01: 1, 0.02: 1, 0.03: 1, 0.04: 1, 0.05: 1, 0.06: 1, 0.07: 1 0.08: 1, 0.09: 1, 0.1: 1, and preferably 0.08: 1.
  • the rehydration ratio (solid: water) of the second composition is 0.01: 1, 0.02: 1, 0.03: 1, 0.04: 1, 0.05: 1, 0.06: 1, 0.07: 1 0.08: 1, 0.09: 1, 0.1: 1, and preferably 0.06: 1.
  • the content of sodium alginate is about 0.4 to about 1.2 parts by weight; the content of sucrose is about 2.0 to about 2.8 parts by weight; and the content of sorbitol is about 3.5 to about 5.2 parts by weight; and based on 100 parts by weight of the total amount of the second composition solution, the content of calcium lactate is about 3.0 to about 4.2 parts by weight; And the content of mannitol is about 1.8 to about 3.0 parts by weight.
  • the content of sodium alginate is about 1 part by weight; the content of sucrose is about 2 parts by weight; and sorbus
  • the content of sugar alcohol is about 5 parts by weight; and the content of calcium lactate is about 4 parts by weight based on the total amount of the second composition solution being 100 parts by weight; and the content of mannitol is about 2 parts by weight.
  • Another aspect of the invention provides the use of a combination as described herein in the manufacture of a medicament for endoscopic surgical mucosal elevation.
  • the medicament is used for endoscopic polypectomy, endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD).
  • EMR endoscopic mucosal resection
  • ESD endoscopic submucosal dissection
  • Figures 1 (A) to (C) show the continuous process of rehydration of the lyophilized powder of the first composition of the present invention.
  • Figures 2 (A) to (C) show the continuous process of rehydration of the lyophilized powder of the second composition of the present invention.
  • Figures 3 (A) to (C) show the hydrogel produced after mixing the first composition and the second composition of the present invention.
  • Figures 4 (A) to (D) show the combination of the present invention for endoscopic submucosal dissection ESD procedure.
  • a range is expressed herein as "about” one particular value and / or “about” another particular value.
  • embodiments include a range from one particular value and / or to another particular value.
  • a numerical value is expressed as an approximate value, by using the word "about”, it should be understood that the specific value forms another embodiment.
  • the endpoints of each range are important to and independent of the other endpoint.
  • the term "about” means ⁇ 30%, preferably ⁇ 20%, more preferably ⁇ 10%, and even more preferably ⁇ 5%.
  • first refers to different units (eg, a first composition, a second composition).
  • second refers to different units (eg, a first composition, a second composition).
  • the use of these terms here does not necessarily imply the order of one unit before another, but merely provides a mechanism to distinguish specific units.
  • composition refers to a mixture of one or more compounds, elements or molecules.
  • the composition can be in the form of a solution, tablet, powder, lyophilized powder, pellets, beads, granules, microspheres, capsules, pills, and the like.
  • compositions capable of being administered simultaneously, separately or sequentially.
  • delayed administration of the second composition does not result in the loss of the combined benefits.
  • lyophilization refers to a drying process by freezing a substance dissolved in water to below 0 ° C. Then use a vacuum pump to lower the surrounding pressure to sublimate the frozen water in the material.
  • substitution refers to the conversion of a pharmaceutical composition in a solid form into a liquid state by adding a solvent.
  • solvent is a substance that dissolves a solute that causes a solution.
  • Suitable solvents include, but are not limited to, saline or water for injection (WFI).
  • WFI water for injection
  • the solvent may include a suitable buffer solution (eg, phosphate, histidine, acetate, citrate, succinate, etc.).
  • pharmaceutically acceptable carrier refers to solvents, diluents, binders, adhesives, adjuvants, excipients, receptors, stabilizers, analogs, flavoring agents, sweeteners, emulsifiers and Preservatives, which are well known in the art, are used in the manufacture of pharmaceutical compositions.
  • pharmaceutically acceptable carriers include, but are not limited to, water, saline, buffers, inert and non-toxic solids.
  • Solubilizers can be glycerol, propylene glycol, sorbitol, sucrose, glucose polyethylene glycol, alpha-hydroxy acids, cyclodextrins (e.g., ⁇ -cyclodextrin, gamma-cyclodextrin), cyclodextrin derivatives (e.g., Sulfobutyl or hydroxypropyl ether), bile acids, bile acid derivatives, sterol derivatives, alcohols.
  • the solubilizer according to the present invention is preferably selected from the group consisting of sorbitol and sucrose, and more preferably contains sorbitol and sucrose.
  • the cationic crosslinking agent may be calcium sulfate (CaSO 4 ) and calcium carbonate (CaCO 3 ), calcium lactate or mannitol.
  • the solubilizer according to the present invention preferably contains calcium lactate or mannitol, and more preferably contains calcium lactate and mannitol.
  • the antifreeze may be sugar, sugar alcohol and mixtures thereof, wherein the sugar may be selected from lactose, maltose, sucrose, trehalose and combinations thereof, and wherein the sugar alcohol may be selected from mannitol, sorbitol, maltitol, xylitol , Lactitol and combinations thereof.
  • the content of the antifreeze is 1 to 20 parts by weight based on 100 parts by weight of the total amount of the combination.
  • the solubilizer according to the invention is preferably mannitol.
  • the first composition and the second composition according to the present invention are crosslinked at the target tissue, preferably to form hydrogel.
  • the method of forming hydrogel from alginate includes ionic crosslinking, covalent crosslinking and thermal gel. (Prog Polym Sci. 2012 January; 37 (1): 106-126).
  • Ionic cross-linking refers to the use of ionic cross-linking agents, such as divalent cations (ie, Ca 2+ ) that are bound only to the guluronic acid block of the alginate chain, because of the structure of the guluronic acid block High degree of coordination of divalent ions is allowed.
  • divalent cations ie, Ca 2+
  • Covalent crosslinking refers to the use of poly (ethylene glycol) (PEG), poly (aldehyde guluronic acid) (PAG), poly (acrylamide-co-hydrazide) (PAH), adipic acid dihydrazide (AAD) Formation of PEG gel, PAG / PAH gel or PAG / AAD gel.
  • PEG poly (ethylene glycol)
  • PAG poly (aldehyde guluronic acid)
  • PAH poly (acrylamide-co-hydrazide)
  • AAD adipic acid dihydrazide
  • Thermal gelation refers to the use of poly (N-isopropylacrylamide) (PNIPAAm) hydrogel, which exhibits adjustable swelling properties in response to temperature changes.
  • PNIPAAm poly(N-isopropylacrylamide)
  • the composition of the invention may be packaged in ampoules, vials, bottles, prefilled syringes or similar containers.
  • the first composition and the second composition of the present invention are stored in separate containers.
  • the composition of the invention is packaged in liquid form in a 5 ml or 10 ml pre-filled syringe, or in a 10 ml, 20 ml or 50 ml ampoule / ampule.
  • the composition of the invention is applied by means of an endoscopic injection needle, preferably in a room temperature environment.
  • the first composition and the second composition are freeze-dried by a freeze-vacuum dryer (Lyophilization) treatment to make them into a porous powder with a large contact area. Just add the right amount of water for injection and it will dissolve immediately for injection. In addition, frozen crystal treatment can make it difficult to oxidize, no degradation and deterioration, and increase its shelf life.
  • the first composition and the second composition are separately mixed with injectable water, and after being fully dissolved, they become the first composition solution and the second composition solution, respectively, and can be used in endoscopic therapy.
  • Example 1 Preparation of a first composition and a second composition
  • the method for preparing the first composition includes a step of preparing a solution and a lyophilization step.
  • pre-lyophilizing pre-lyophilizing the product at -40 ° C for 5 hours to freeze and compact the product
  • the lyophilized powder of the obtained first composition can be easily rehydrated with a solvent within 1 minute, and the lyophilized powder of the obtained second composition can be easily rehydrated with a solvent within 10 seconds.
  • the rehydration ratio of the first composition is 0.08: 1 (solid: water), and the rehydration ratio of the second composition is 0.06: 1 (solid: water).
  • the first composition and the second composition are rehydrated.
  • the composition ratio is as follows:
  • Fig. 1 (A) and Fig. 2 (A) show a state where the powder is completely dry
  • Fig. 1 (B) and Fig. 2 (B) show a state where the powder is dissolved
  • Fig. 1 (C) and Fig. 2 (C) show that the powder is completely Dissolved state.
  • the first composition takes about 1 minute from Figure 1 (A) ⁇ Figure 1 (B) ⁇ Figure 1 (C). It takes about 5 to 10 seconds for the second composition from FIG. 2 (A) ⁇ FIG. 2 (B) ⁇ FIG. 2 (C).
  • Example 2 Use of the combination of the invention during endoscopic surgery
  • the first composition and the second composition according to Example 1 were prepared as a lyophilized powder.
  • the user applies the first composition or the second composition, and then rinses the remaining solution in the endoscope injection needle with about 1 ml of physiological saline, and then applies another composition to prevent cross-linking in the catheter. reaction.
  • simultaneous injections can be made via two separate needle cannulas; or simultaneous injections can be made from two different diameters of one needle.
  • Figures 4 (A) to (D) are photographs of the combination of the present invention for endoscopic submucosal dissection (ESD).
  • Fig. 4 (A) relates to the target tissue (injury) before injection
  • Fig. 4 (B) relates to the formation of a cushion from the bulge after injection
  • Fig. 4 (C) is an endoscopic submucosal dissection of the bulged area.
  • Fig. 4 (D) Complete endoscopic submucosal dissection.
  • the combined submucosal injection of the present invention provides a highly submucosal liquid cushion for safe and effective EMR.
  • the hydrogel formed by cross-linking the first composition and the second composition is mainly used for human tissues by utilizing the "physical properties" of the ingredients, rather than using pharmacological, immune or metabolic machines. Therefore, the solution for endoscopic submucosal dissection of the present invention belongs to medical equipment.
  • the cushion formed by the solution for endoscopic submucosal dissection of the present invention has the advantage of low diffusion in the tissue around the lesion.

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Abstract

用于内镜手术的组合或组合物，是用于内镜粘膜切除术或内镜粘膜下剥离术的冻干粉末，包含第一组合物及第二组合物，第一组合物包含海藻酸钠及选自蔗糖和山梨糖醇所组成的群；且第二组合物包含乳酸钙；其中第一组合物及第二组合物存放于分开的容器中。

Description

用于内镜手术的组合 技术领域
本发明涉及用于内镜手术(endoscopy)的组合或组合物，特别是用于内镜粘膜切除术(EMR)或内镜粘膜下剥离术(ESD)的冻干粉末(lyophilized powder)。
背景技术
针对微创治疗胃肠腺瘤和涉及淋巴结转移风险最小的早期癌症而言，内镜粘膜切除术(EMR)和内镜粘膜下剥离术(ESD)提供了新的选择。使用粘膜下注射溶液对于这些内镜切除或剥离技术的成功是不可缺少的(Drug Design，Development and Therapy 2008：2 131-138)。
过去，生理盐水(NS)溶液常用作粘膜下注射溶液。其他粘膜下注射液亦已被开发出来，如高渗盐溶液，甘油，右旋糖水(DW)，透明质酸(HA)，纤维蛋白原混合物(FM)，羟丙基甲基纤维素(HPMC)(Drug Design，Development and Therapy 2008：2131-138)。这些注射溶液在高浓度注射到目标组织时具有高粘度，可在EMR和ESD手术中形成垫层(cushion)，也借着粘稠的特性减少注射流出离开病灶区域。
然而，前述具有较高粘度的注射溶液对注射过程造成困难，例如难以使粘稠溶液流过注射装置。此外，已经报道的水胶(hydrogel)在保存时不稳定，容易在水的存在下产生分解，并且在体内使用时不如所希望的那样稳定，这些缺点不利于其作为药物递送载体或在其他生物医学应用中的用途。
因此，需要提供一种用于内镜手术的新颖组合物(composition)或组合(combination)，其能够易于获得，保存期长，容易注射并且能够提供高且持久的粘膜下垫层。
发明内容
本发明提供用于内镜手术的组合，可用于组织提升(tissue lift)或组织升高(tissue elevation)，特别是粘膜抬升。
优选的，本发明的组合为速溶粉末，经复水后，可作为注射液使用。
优选的，本发明的组合若为注射液，可作为内镜手术粘膜抬升用的溶液。
本发明的一个方面提供一种组合，其包含：包含阴离子多醣和增溶剂的第一组合物；和 包含阳离子交联剂的第二组合物，其中所述第一组合物和所述第二组合物存放于分开的容器中，优选的，所述第一组合物和所述第二组合物是呈冻干粉末形式并储存在分开的容器中。
在本发明的优选实施方案中，阴离子多醣是海藻酸钠(sodium alginate)。
在本发明的优选实施方案中，增溶剂选自蔗糖(sucrose)及山梨糖醇(sorbitol)所组成的群。
在本发明的另一个优选实施方案中，以所述第一组合物干粉的总量是100重量份计，海藻酸钠的含量是约5至约15重量份，具体为5、6、7、8、9、10、11、15、13、14或15重量份。
在本发明的另一个优选实施方案中，以所述第一组合物干粉的总量是100重量份计，蔗糖的含量是约25至约35重量份，具体为25、26、27、28、29、30、31、32、33、34或35重量份。
在本发明的另一个优选实施方案中，以所述第一组合物干粉的总量是100重量份计，山梨糖醇的含量是约60至约65重量份，具体为60、61、62、63、64或65重量份。
在本发明进一步优选的实施方案中，以所述第一组合物干粉的总量是100重量份计，海藻酸钠的含量是约12.5重量份，蔗糖的含量是约25重量份，且山梨糖醇的含量是约62.5重量份。
在本发明的优选实施方案中，所述阳离子交联剂选自乳酸钙(calcium lactate)及甘露醇(mannitol)所组成的群。
在本发明的另一个优选实施方案中，以所述第二组合物干粉的总量是100重量份计，乳酸钙的含量是约50至约70重量份，具体为50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69或70重量份。
在本发明的另一个优选实施方案中，以所述第二组合物干粉的总量是100重量份计，甘露醇的含量是约30至约50重量份，具体为30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50重量份。
在本发明的另一个优选实施方案中，以所述第二组合物干粉的总量是100重量份计，乳酸钙的含量是约67重量份，且甘露醇的含量是约33重量份。
本发明的另一个方面提供一种组合，其包含：包含阴离子多醣和增溶剂的第一组合物；和包含阳离子交联剂的第二组合物，其中所述第一组合物和第二组合物呈溶液形式并储存在分开的容器中。
在本发明的优选实施方案中，以所述第一组合物溶液的总量为100重量份计，海藻酸钠的含量是约0.4至约1.2重量份；蔗糖的含量是约2.0至约2.8重量份；及山梨糖醇的含量是约 3.5至约5.2重量份；且以所述第二组合物溶液的总量为100重量份计，乳酸钙的含量是约3.0至约4.2重量份；及甘露醇的含量是约1.8至约3.0重量份。
在本发明的优选实施方案中，以所述第一组合物溶液的总量为100重量份计，海藻酸钠的含量是约1重量份；蔗糖的含量是约2重量份；及山梨糖醇的含量是约5重量份；且以所述第二组合物溶液的总量为100重量份计，乳酸钙的含量是约4重量份；及甘露醇的含量是约2重量份。
本发明的另一方面提供一种用于制备用于内镜手术的注射溶液的方法，其包括：提供如本文所述的第一组合物；提供如本文所述的第二组合物；并混合第一组合物和第二组合物来获得注射溶液。
本发明的另一方面提供一种执行内镜手术的方法，其包括将溶液形式的所述第一组合物及第二组合物分别注射到患者的目标组织，其中第一组合物和第二组合物在患者的目标组织交联，优选是形成水胶以作为垫层。
本发明的另一方面提供一种组合，其包含第一组合物及第二组合物，其中：所述第一组合物包含：
(Ia)海藻酸钠；及
(Ib)选自蔗糖及山梨糖醇所组成的群；且
所述第二组合物包含：
(IIa)乳酸钙；
其中所述第一组合物及第二组合物存放于分开的容器中。
在本发明的优选实施方案中，所述第二组合物进一步包含：(IIb)甘露醇。
在本发明的优选实施方案中，以所述第一组合物干粉的总量是100重量份计，海藻酸钠的含量是约5至约15重量份；蔗糖的含量是约25至约35重量份；及山梨糖醇的含量是约60至约65重量份；且以所述第二组合物的总量是100重量份计，乳酸钙的含量是约50至约70重量份；及甘露醇的含量是约30至约50重量份。
在本发明的优选实施方案中，以所述第一组合物干粉的总量是100重量份计，海藻酸钠的含量是约12.5重量份；蔗糖的含量是约25.0重量份；及山梨糖醇的含量是约62.5重量份；且以所述第二组合物的总量是100重量份计，乳酸钙的含量是约67重量份；及甘露醇的含量是约33重量份。
在本发明的优选实施方案中，其中所述第一组合物及第二组合物呈冻干粉末形式。
在本发明的优选实施方案中，其中所述第一组合物及第二组合物呈溶液形式。
在本发明的优选实施方案中，第一组合物的复水比例(固体∶水)是0.01∶1、0.02∶1、 0.03∶1、0.04∶1、0.05∶1、0.06∶1、0.07∶1、0.08∶1、0.09∶1、0.1∶1，优选为0.08∶1。
在本发明的优选实施方案中，第二组合物的复水比例(固体∶水)是0.01∶1、0.02∶1、0.03∶1、0.04∶1、0.05∶1、0.06∶1、0.07∶1、0.08∶1、0.09∶1、0.1∶1，优选为0.06∶1。
在本发明的优选实施方案中，其中，以所述第一组合物溶液的总量为100重量份计，海藻酸钠的含量是约0.4至约1.2重量份；蔗糖的含量是约2.0至约2.8重量份；及山梨糖醇的含量是约3.5至约5.2重量份；且以所述第二组合物溶液的总量为100重量份计，乳酸钙的含量是约3.0至约4.2重量份；及甘露醇的含量是约1.8至约3.0重量份。
在本发明的优选实施方案中，其中，以所述第一组合物溶液的总量为100重量份计，海藻酸钠的含量是约1重量份；蔗糖的含量是约2重量份；及山梨糖醇的含量是约5重量份；且以所述第二组合物溶液的总量为100重量份计，乳酸钙的含量是约4重量份；及甘露醇的含量是约2重量份。
本发明的另一方面提供如本文所述的组合在制造用于内镜手术粘膜抬升的药物中的用途。
在本发明的优选实施方案中，所述药物用于内镜息肉切除术，内镜粘膜切除术(EMR)或内镜粘膜下剥离术(ESD)。
本发明详细描述于以下部分中。本发明的其他特征、目的及优点可轻易在本发明的详细描述及申请专利范围中发现。
附图说明
图1(A)至(C)展示本发明第一组合物冻干粉末复水连续过程。
图2(A)至(C)展示本发明第二组合物冻干粉末复水连续过程。
图3(A)至(C)展示本发明的第一组合物和第二组合物的混合后所产生的水胶。
图4(A)至(D)展示本发明的组合用于内镜粘膜下剥离术ESD手术过程。
具体实施方式
除非本文另外定义，在本发明中使用的科学及技术术语应具有本领域技术人员通常所理解的意义。术语的意义及范畴应为明确的；然而，若存在任何潜在不明确性，则本文所提供的定义优先于任何词典或外来定义。
除非另外指明，否则如根据本发明所利用，以下术语应理解为具有以下意义。
除非上下文另有要求，否则单数术语应包括复数，复数术语应包括单数。例如，术语“一”定义为一个或多于一个。
权利要求中的术语“或”用于表示“和/或”，除非明确指出仅指代替代或者替代是相互排斥的。
通常，范围在本文中表述为从“大约”一个特定值和/或“大约”另一特定值。当表达这样的范围时，实施例包括从一个特定值和/或到另一个特定值的范围。类似地，当数值被表示为近似值时，通过使用单词“约”，应该理解，该特定值形成另一个实施例。将进一步理解的是，每个范围的端点对于和独立于另一端点都是重要的。术语“约”是指±30％，优选±20％，更优选±10％，甚至更优选±5％。
术语“第一”，“第二”等表示不同的单元(例如，第一组合物，第二组合物)。这里使用这些术语不一定意味着一单元先于另一个单元的顺序，而仅提供区分特定单元的机制。
术语“组合物(composition)”是指一或多种化合物，元素或分子的混合物。该组合物可为溶液，片剂，粉末，冻干粉末，小球，珠粒，颗粒，微球体，胶囊，丸剂等形式。
术语“组合(combination)”是指一或多个组合物的组合，所述一或多个组合物能够同时，分开或顺序投与。在分开或顺序投与的情况下，延迟施用第二组合物不会导致失去组合作用的益处。
术语“冻干(lyophilization)”是指通过将溶解于水中的物质冷冻至低于0℃的干燥过程。然后使用真空泵降低周围压力，以使材料中的冷冻水升华。
术语“复水(reconstitution)”是指通过添加溶剂将固体形式的药物组合物转化成液体状态。
术语“溶剂”是溶解导致溶液的溶质的物质。合适的溶剂包括但不限于盐水或注射用水(WFI)。溶剂可以包含合适的缓冲溶液(例如磷酸盐，组氨酸，乙酸盐，柠檬酸盐，琥珀酸盐等)。
术语“药学上可接受的载体”是指溶剂，稀释剂，粘合剂，粘合剂，佐剂，赋形剂，受体，稳定剂，类似物，调味剂，甜味剂，乳化剂和/或防腐剂，其为本领域众所周知，用于制造药物组合物。药学上可接受的载体的实例包括但不限于水，盐水，缓冲液，惰性和无毒固体。
增溶剂
增溶剂可为甘油，丙二醇，山梨糖醇，蔗糖，葡萄糖聚乙二醇，α-羟基酸，环糊精(例如β-环糊精，γ-环糊精)，环糊精衍生物(例如磺丁基或羟丙基醚)，胆汁酸，胆汁酸衍生物，甾醇衍生物，醇。根据本发明的增溶剂优选是选自由山梨糖醇及蔗糖所组成的群，更优选是包含山梨糖醇及蔗糖。
阳离子交联剂
阳离子交联剂可为硫酸钙(CaSO 4)和碳酸钙(CaCO 3)，乳酸钙或甘露醇。根据本发 明的增溶剂优选是包含乳酸钙或甘露醇，更优选是包含乳酸钙及甘露醇。
防冻剂
防冻剂可为醣，醣醇及其混合物，其中糖可以选自乳糖，麦芽糖，蔗糖，海藻糖及其组合，并且其中可以选择糖醇选自甘露醇，山梨糖醇，麦芽糖醇，木糖醇，乳糖醇及其组合。基于以所述组合的总量是100重量份计，防冻剂的含量是1至20重量份。根据本发明的增溶剂优选是甘露醇。
交联
根据本发明的所述第一组合物及第二组合物是在目标组织交联，优选为形成水胶，由藻酸盐形成水胶的方法包括离子交联，共价交联和热凝胶化(Prog Polym Sci.2012 January；37(1)：106-126)。
离子交联是指使用离子交联剂，例如仅与藻酸盐链的古洛糖醛酸盐嵌段结合的二价阳离子(即Ca 2+)，因为古洛糖醛酸盐嵌段的结构允许高二价离子的配位度。
共价交联是指使用聚(乙二醇)(PEG)，聚(醛古洛糖醛酸)(PAG)，聚(丙烯酰胺-共-酰肼)(PAH)，己二酸二酰肼(AAD)形成PEG凝胶，PAG/PAH凝胶或PAG/AAD凝胶。
热凝胶化是指使用聚(N-异丙基丙烯酰胺)(PNIPAAm)水胶，其响应于温度变化显示出可调整的溶胀性能。
容器
本发明组合物可以包装于安瓿瓶、小瓶、瓶、预充注射器或其类似容器。本发明的所述第一组合物及第二组合物存放于分开的容器中。例如，本发明组合物以液体形式包装在5毫升或10毫升预充注射器中，或者包装在10毫升、20毫升或50毫升安瓿瓶(ampoule/ampule)中。发明组合物通过内镜注射针的方法施用，优选地在室温环境施打。
于本发明的一优选实施例中，所述第一组合物及第二组合物是经冷冻真空干燥机将其冻晶干燥(Lyophilization)处理，使其成为具多孔性、接触面积大的粉末，只需加入适量的注射用水，即可立即溶解供注射；此外，冻晶处理可使其不易氧化、无降解变质的状况、可增加其保存期限。使用时，将所述第一组合物与第二组合物分别与可注射用水混合，充分溶解后分别成为第一组合物溶液与第二组合物溶液，可使用于内视镜治疗术。注射时，因所述第一组合物溶液与所述第二组合物溶液在注射管并不互相接触或交联，故不形成胶状物质，避免先前技术中造成注射管堵塞的问题。现已大体上描述本发明，经由参考如下实例可更容易理解本发明，这些实例提供用于制造本发明的组合及用于内镜治疗术的例示性方案。这些实例仅出于说明的目的提供，且不意欲以任何方式限制本发明的范畴。已尽力确保所用数值(例 如，量、温度等)的准确性，但当然应允许一定实验误差及偏差。
实例
实例1：制备第一组合物和第二组合物
Figure PCTCN2018095644-appb-000001
第一组合物的制备方法包括制备溶液的步骤和冻干步骤。
将上表的成分称量并放入装满10毫升注射用水的容器中，搅拌直到溶解，过滤和灭菌溶液，随后将溶液放入液体储罐中，分包装，部分塞住，冻干，加盖和包装。冻干步骤如下：
1)预冷冻干燥(pre-lyophilizing)：在-40℃下将产物预冻干5小时以使产品冷冻并压实；
2)初步干燥(primary drying)：在产品预冷冻干燥后，启动真空泵抽空至真空度达到20Pa，将产品温度升至-30℃并保持5小时；和将产品温度升至-20℃并保持5小时；将产品温度升至-10℃并保持10小时；将产品温度升至0℃并保持10小时；将产品温度升至10℃并保持10小时；将产品温度升至-20℃并保持10小时；
3)二次干燥(secondary drying)：将产品逐渐加热到25℃的温度，并保持5小时。
所得到的第一组合物的冻干粉末可以容易地在1分钟内用溶剂复水，且所得到的第二组合物的冻干粉末可以容易地在10秒内用溶剂复水。第一组合物的复水比例是0.08∶1(固体∶水)、第二组合物的复水比例是0.06∶1(固体∶水)，第一组合物及第二组合物经复水后的成分比例如下：
Figure PCTCN2018095644-appb-000002
在图1及图2的速溶粉末溶解范例中，将10毫升的生理盐水各加入第一组合物及第二组合 物，充分摇晃即可溶解均匀。图1(A)与图2(A)为粉末完全干燥的状态、图1(B)与图2(B)为粉末溶解中的状态、图1(C)与图2(C)为粉末完全溶解的状态。第一组合物由图1(A)→图1(B)→图1(C)，共需约1分钟的时间。第二组合物由图2(A)→图2(B)→图2(C)，共需约5至10秒的时间。
于图3(A)至(C)中，将图1(C)的第一组合物溶液及图2(C)的第二组合物溶液混合后，于10秒内，即可见交联反应产生的水胶。
实例2：在内镜手术过程中使用本发明的组合
制备根据实施例1的第一组合物和第二组合物作为冻干粉末。在注射期间，使用者先施打第一组合物或第二组合物，再使用约1毫升生理盐水冲洗内镜注射针管内残留溶液，最后才施打另一组合物以防止导管内的交联反应。
或者，可经由分别的两支针管同时注射；或者由一支针的两个不同的管径同时注射。
图4(A)至(D)为本发明的组合用于内镜粘膜下剥离术(ESD)过程的照片。图4(A)涉及注射前的靶组织(损伤)，图4(B)涉及注射后从隆起形成垫层，图4(C)为对隆起区域进行内镜粘膜下剥离术，图4(D)完成内镜粘膜下剥离术。如图4(B)所示，本发明组合的粘膜下注射为安全有效的EMR提供了高粘膜下液体垫层。
通过交联第一组合物和第二组合物形成的水胶主要是利用各成分「物理特性」，而不以药理，免疫或代谢机制作用于人体组织。因此，本发明用于内镜粘膜下剥离术的溶液属于医疗器材。
另外，本发明用于内镜粘膜下剥离术的溶液所形成的垫层在病灶周围的组织中具有低扩散的优点。
本领域技术人员能想到如以上说明性实例中所阐述的本发明的诸多修改及变化。因此，只有在所附的权利要求书中所记载的限制可用于局限本发明。

Claims (11)

  1. 一种组合(combination)的用途，其用于制备供内镜手术粘膜抬升用的药物，其中所述组合包含第一组合物(composition)及第二组合物，其中：
    所述第一组合物包含：
    (Ia)海藻酸钠(sodium alginate)；及
    (Ib)选自蔗糖(sucrose)及山梨糖醇(sorbitol)所组成的群；且
    所述第二组合物包含：
    (IIa)乳酸钙(calcium lactate)；
    其中所述第一组合物及第二组合物存放于分开的容器中。
  2. 如权利要求1所述的用途，其中所述第二组合物进一步包含：(IIb)甘露醇(mannitol)。
  3. 如权利要求1或2所述的用途，其中：
    以所述第一组合物的总量是100重量份计，海藻酸钠的含量是5至15重量份；蔗糖的含量是25至35重量份；及山梨糖醇的含量是60至65重量份；且
    以所述第二组合物的总量是100重量份计，乳酸钙的含量是50至70重量份；及甘露醇的含量是30至50重量份。
  4. 如权利要求3所述的用途，其中，其中：
    以所述第一组合物的总量是100重量份计，海藻酸钠的含量是约12.5重量份；蔗糖的含量是约25.0重量份；及山梨糖醇的含量是约62.5重量份；且
    以所述第二组合物的总量是100重量份计，乳酸钙的含量是约67重量份；及甘露醇的含量是约33重量份。
  5. 如权利要求1或2所述的用途，其中所述第一组合物及第二组合物呈冻干粉末(lyophilized powder)形式。
  6. 如权利要求1或2所述的用途，其中所述第一组合物及第二组合物呈溶液形式。
  7. 如权利要求6所述的用途，其中：
    以所述第一组合物溶液的总量为100重量份计，海藻酸钠的含量是0.4至1.2重量份；蔗糖的含量是2.0至2.8重量份；及山梨糖醇的含量是3.5至5.2重量份；且
    以所述第二组合物溶液的总量为100重量份计，乳酸钙的含量是3.0至4.2重量份；及甘露醇的含量是1.8至3.0重量份。
  8. 如权利要求7所述的用途，其中：
    以所述第一组合物溶液的总量为100重量份计，海藻酸钠的含量是约1重量份；蔗糖的 含量是约2重量份；及山梨糖醇的含量是约5重量份；且
    以所述第二组合物溶液的总量为100重量份计，乳酸钙的含量是约4重量份；及甘露醇的含量是约2重量份。
  9. 如权利要求1或2所述的用途，其中所述内镜治疗术选自由内镜瘜肉切除术、内镜粘膜切除术及内镜粘膜下剥离术所组成的群。
  10. 如权利要求9所述的用途，其中所述药物中的第一组合物及第二组合物于欲实施内镜治疗术的组织的粘膜下混合。
  11. 如权利要求10所述的用途，其中所述混和会导致第一组合物中的海藻酸钠与第二组合物产生交联反应。
PCT/CN2018/095644 2018-07-13 2018-07-13 用于内镜手术的组合 Ceased WO2020010616A1 (zh)

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