WO2023207835A1 - 一种抗鼻腔过敏凝胶及其制备方法 - Google Patents

一种抗鼻腔过敏凝胶及其制备方法 Download PDF

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WO2023207835A1
WO2023207835A1 PCT/CN2023/090033 CN2023090033W WO2023207835A1 WO 2023207835 A1 WO2023207835 A1 WO 2023207835A1 CN 2023090033 W CN2023090033 W CN 2023090033W WO 2023207835 A1 WO2023207835 A1 WO 2023207835A1
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gel
parts
nasal
formula
nasal allergy
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PCT/CN2023/090033
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English (en)
French (fr)
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蒋士冬
王洪超
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国科瑞诺(中山)生物科技有限公司
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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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K31/722—Chitin, chitosan
    • 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
    • A61K47/08—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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to the technical field of nasal gels, and in particular to an anti-nasal allergy gel and a preparation method thereof.
  • nasal allergies There are two types of nasal allergies. One is the well-known allergic rhinitis. Its symptoms are watery nasal discharge, nasal congestion, and sneezing. In severe cases, people may also have sore nose, itchy nose, eyes, and ears, dizziness, and swelling. Lack of concentration, etc.
  • vasomotor rhinitis which is mainly caused by the imbalance of autonomic nervous system, which makes the parasympathetic nerves strong and causes various symptoms similar to allergic rhinitis. It is not caused by specific antigens, but may be caused by emotional stress, increased pressure, or various other symptoms. Due to physical changes.
  • Allergic rhinitis refers to the release of mediators (mainly histamine) mediated by IgE after atopic individuals are exposed to allergens, and involves the participation of a variety of immune active cells and cytokines. Non-infectious inflammatory diseases of the mucosa.
  • the specific antigen is the substance that causes the body's immune response
  • the atopic individual is the so-called individual difference and allergic constitution
  • the specific antigen and the atopic individual meet.
  • Allergic rhinitis is a global health problem that causes numerous illnesses and workforce losses.
  • Allergic rhinitis does not cause systemic symptoms such as fever, but it can cause irritation in the ears, nose, throat and eyes.
  • Various symptoms of discomfort mainly including recurring nasal itching, sneezing, clear nasal discharge and nasal congestion, which may be accompanied by itchy eyes, itchy throat, and cough. Some of them are related to the season. They tend to occur in spring and autumn, and the symptoms gradually subside after the season.
  • Nasal sugar Corticosteroids and oral antiallergy medications can prevent and relieve symptoms.
  • Allergic rhinitis not only affects the quality of life of patients because of the above-mentioned uncomfortable symptoms caused by repeated attacks, but more importantly, it may also induce allergic conjunctivitis, allergic dermatitis, chronic sinusitis, nasal polyps, secretory otitis media, and in severe cases It may even induce asthma and be life-threatening.
  • allergic rhinitis cannot be completely cured, but through standardized comprehensive prevention and treatment, clinical control can be achieved and maintained and symptoms can be effectively relieved. Therefore, how to prepare a nasal preparation that can effectively prevent and improve the uncomfortable symptoms caused by nasal allergies and does not contain irritating drugs is an urgent technical problem in this field.
  • the purpose of the present invention is to overcome the problems of the prior art and provide an anti-nasal allergy gel and a preparation method thereof.
  • An anti-nasal allergy gel which includes the following components by mass: 0.1 to 2 parts of cellulose; 0.05 to 1 part of chitosan salt or chitosan derivative; 0.1 to 0.2 part of potassium sorbate or sodium sorbate ; 0.8 to 0.9 parts of sea salt; 0.1 to 0.5 parts of xylitol, supplemented by 100 parts of deionized water;
  • Chitosan salt is a substance represented by formula (1):
  • R is Cl - , COO - or HSO 4 -
  • x and n are natural numbers, 0 ⁇ x ⁇ 10 7 , 10 2 ⁇ n ⁇ 10 7 .
  • chitosan derivatives include one or more of the substances represented by formula (2), formula (3), formula (4), formula (5) and formula (6):
  • x and n are natural numbers, 0 ⁇ x ⁇ 10 7 , 10 7 ⁇ n ⁇ 10 7 ;
  • x and n are natural numbers, 0 ⁇ x ⁇ 10 7 , 10 2 ⁇ n ⁇ 10 7 ;
  • x and n are natural numbers, 0 ⁇ x ⁇ 10 7 , 10 2 ⁇ n ⁇ 10 7 ;
  • x and n are natural numbers, 0 ⁇ x ⁇ 10 7 , 0 ⁇ y ⁇ 10 7 , 10 2 ⁇ n ⁇ 10 7 ;
  • x and n are natural numbers, 0 ⁇ x ⁇ 10 7 , 0 ⁇ y ⁇ 10 7 , 10 2 ⁇ n ⁇ 10 7 .
  • the arrangement order of each repeating unit is not exactly in the order marked in the structural formula, but is arranged in an irregular arrangement in the polymer chain.
  • the cellulose is hydroxyethyl cellulose.
  • a preparation method of anti-nasal allergy gel including the following steps:
  • S30 Sterilize the anti-nasal allergy gel mother solution by high pressure or irradiation to obtain the anti-nasal allergy gel.
  • S20 steps also include:
  • steps S20 and S30 the mixture is first heated to between room temperature and 80°C and then stirred to fully dissolve it.
  • the cellulose is hydroxyethyl cellulose.
  • the present invention has the following advantages: the main functional material chitosan salt and its derivatives contained in the anti-nasal allergy gel provided by the present invention is a modified natural polysaccharide with excellent biological properties. Compatible, antibacterial, anti-inflammatory and reparative, non-irritating and non-allergenic. Hydroxyethyl cellulose can be physically cross-linked with chitosan to form a gel, and xylitol is used as a wetting adjuster. Together with sea salt, it is used to provide an isotonic moist environment inside the nasal cavity and better protect the nasal mucosa. Not subject to destruction.
  • This anti-nasal allergy gel can form a film on the surface of the nasal mucosa to form a protective layer, reducing and blocking external irritants such as dust and pathogens from interacting with the nasal cavity.
  • Figure 1 is a graph showing the cytotoxicity test results of the anti-nasal allergy gel of the present invention on mouse fibroblasts (L929).
  • Figure 2 is a three-dimensional fluorescence image of the thin film formed by the anti-nasal allergy gel A prepared in Example 1 isolating the silica beads from the transparent substrate.
  • Figure 3 is a three-dimensional fluorescence image of the film formed by the anti-nasal allergy gel B prepared in Example 2 isolating E. coli from a transparent substrate.
  • Figure 4 is a diagram of the appearance of the mouse nasal cavity in the mouse nasal cavity experiment.
  • Figure 5 is a scanning electron microscope photograph of the nasal mucosa environment of mice without spraying the anti-nasal allergy gel of the present invention (a) and a scanning electron microscope photograph (b) of the nasal mucosa environment of mice sprayed with the anti-nasal allergy gel of the present invention.
  • Figure 6 is a scanning electron microscope photo of the mouse nasal mucosa environment after spraying the anti-nasal allergy gel of the present invention and dripping bacterial solution into the nasal cavity.
  • (b) is an enlarged view of the framed part in (a).
  • An anti-nasal allergy gel the formula is as follows: 0.1 g of hydroxyethyl cellulose, 1 g of chitosan salt of formula (1), 0.2 g of potassium sorbate, 0.9 g of sea salt, 0.5 g of xylitol, 97.3 g of deionized water gram.
  • R is Cl - , COO - or HSO 4 -
  • x and n are natural numbers, 0 ⁇ x ⁇ 10 7 , 10 2 ⁇ n ⁇ 10 7 .
  • a preparation method of anti-nasal allergy gel including the following steps:
  • step S30 Sterilize the mother solution obtained in step S23 by high pressure or irradiation to obtain the anti-nasal allergy gel A.
  • An anti-nasal allergy gel the formula is as follows: 0.2 g of hydroxyethyl cellulose, 0.7 g of chitosan monoguanidine salt of formula (2), 0.2 g of potassium sorbate, 0.9 g of sea salt, 0.4 g of xylitol, deionized Water 97.6 grams.
  • x and n are natural numbers, 0 ⁇ x ⁇ 10 7 , 10 2 ⁇ n ⁇ 10 7 .
  • a preparation method of anti-nasal allergy gel including the following steps:
  • step S30 Sterilize the mother solution obtained in step S23 by high pressure or irradiation to obtain the anti-nasal allergy gel B.
  • An anti-nasal allergy gel the formula is as follows: 0.5 g of hydroxyethyl cellulose, 0.5 g of chitosan biguanide salt of formula (3), 0.15 g of sodium sorbate, 0.85 g of sea salt, 0.2 g of xylitol, deionized water 97.8 grams.
  • x and n are natural numbers, 0 ⁇ x ⁇ 10 7 , 10 2 ⁇ n ⁇ 10 7 ;
  • a preparation method of anti-nasal allergy gel including the following steps:
  • step S30 Sterilize the mother solution obtained in step S23 by high pressure or irradiation to obtain the anti-nasal allergy gel C.
  • An anti-nasal allergy gel with the following formula: 1.0 g of hydroxyethyl cellulose, 0.3 g of carboxymethyl chitosan of formula (4), 0.15 g of sodium sorbate, 0.85 g of sea salt, 0.2 g of xylitol, deionized Water 97.5.
  • x and n are natural numbers, 0 ⁇ x ⁇ 10 7 , 10 2 ⁇ n ⁇ 10 7 ;
  • a preparation method of anti-nasal allergy gel including the following steps:
  • step S30 Sterilize the mother solution obtained in step S23 by high pressure or irradiation to obtain the anti-nasal allergy gel D.
  • An anti-nasal allergy gel the formula is as follows: 1.5 grams of hydroxyethyl cellulose, 0.1 grams of double-modified chitosan derivative of formula (5), 0.15 grams of sodium sorbate, 0.85 grams of sea salt, 0.2 grams of xylitol, 97.2 grams of deionized water.
  • x and n are natural numbers, 0 ⁇ x ⁇ 10 7 , 0 ⁇ y ⁇ 10 7 , 10 2 ⁇ n ⁇ 10 7 ;
  • a preparation method of anti-nasal allergy gel including the following steps:
  • step S30 Sterilize the mother solution obtained in step S23 by high pressure or irradiation to obtain the anti-nasal allergy gel E.
  • An anti-nasal allergy gel the formula is as follows: 2 grams of hydroxyethyl cellulose, 0.05 grams of double-modified chitosan derivative of formula (6), 0.1 grams of sodium sorbate, 0.85 grams of sea salt, 0.1 grams of xylitol, Deionized water 96.9 grams.
  • x and n are natural numbers, 0 ⁇ x ⁇ 10 7 , 0 ⁇ y ⁇ 10 7 , 10 2 ⁇ n ⁇ 10 7 .
  • a preparation method of anti-nasal allergy gel including the following steps:
  • step S30 Sterilize the mother solution obtained in step S23 by high pressure or irradiation to obtain the anti-nasal allergy gel F.
  • Figure 1 shows the cytotoxicity test results of the anti-nasal allergy gel prepared in Examples 1 to 6 of the present invention on mouse fibroblasts (L929). It can be seen from the figure that the test results illustrate that the anti-nasal allergy gel prepared by the present invention has basically no cytotoxicity, and even has a certain promoting effect on cell proliferation, which means that the anti-nasal allergy gel has good biological safety. . Pollen dust barrier simulation experiment
  • the anti-nasal allergy gel prepared in the present invention can form a protective layer after use to reduce and block the contact between pollen dust and nasal mucosa.
  • silica beads to simulate pollen dust.
  • the anti-nasal allergy gel A prepared in Example 1 shown red
  • the silica beads stained with fluorescein shown green
  • the red film formed by this product completely isolates the green silica beads from the substrate, avoiding direct contact between the two. This proves that the protective layer formed by the product of the present invention can reduce the direct contact between dust and nasal mucosa.
  • mice used mice as test animals and Pseudomonas aeruginosa as a typical representative of external irritants such as dust and pathogens to verify that the anti-nasal allergy gel of the present invention can form a protective film in the moist nasal cavity and block allergens. .
  • Photo a in Figure 5 is a scanning electron microscope photo of the nasal mucosa environment of mice that was not sprayed with this product. It can be seen from the picture that the surface of the mouse nasal mucosa is wrinkled. Photo b in Figure 5 shows the environment of the nasal mucosa of mice after spraying the anti-nasal allergy gel A prepared in Example 1 of the present invention into the nasal cavity. Scanning electron microscopy photo, it can be seen in the picture that the wrinkles on the surface of the mouse nasal mucosa have been covered, indicating that this product formed a film on the mouse nasal mucosa surface (the scanning electron microscopy photos of the nasal mucosa of five other mice showed similar results, which are not shown here. display again).
  • Figure 6 is a scanning electron microscope photo of the mouse nasal mucosa environment after spraying the anti-nasal allergy gel A prepared in Example 1 of the present invention and dripping bacterial liquid into the nasal cavity.
  • Pseudomonas aeruginosa in Figure 6b Pointed by the white arrow
  • Figure 6a Pointed by the white arrow
  • the scanning electron microscope photos of the nasal mucosa of five other mice showed similar results and will not be shown here.
  • the anti-nasal allergy gel prepared in the embodiments of the present invention can form a film in the nasal cavity of mice, and can block external irritants such as dust and pathogens represented by Pseudomonas aeruginosa from directly contacting the nasal mucosa. contact, thereby protecting the nasal mucosa.

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Abstract

一种抗鼻腔过敏凝胶，其包括以下质量份的组分：纤维素0.1～2份；壳聚糖盐或壳聚糖衍生物0.05～1份；山梨酸钾或山梨酸钠0.1～0.2份；海盐0.8～0.9份；木糖醇0.1～0.5份，去离子水补足100份；壳聚糖盐为式(1)所示物质，其中R为Cl -、COO -或HSO 4 -，x、n为自然数，0＜x≤107，102≤n≤107。抗鼻腔过敏凝胶可在鼻腔黏膜表面成膜形成保护层，减少并阻隔灰尘、病原体等外来刺激物与鼻腔黏膜直接接触，用于因各种过敏引起的鼻腔不适或易诱发过敏性鼻炎患者的日常保健护理，并且能够有效减少和预防过敏性鼻炎的发病率。

Description

一种抗鼻腔过敏凝胶及其制备方法 技术领域
本发明涉及鼻腔凝胶技术领域，特别是涉及一种抗鼻腔过敏凝胶及其制备方法。
背景技术
鼻腔过敏分两种，一种就是大家所熟知的过敏性鼻炎，它的症状就是水样鼻涕、鼻塞、打喷嚏，严重的人还会有鼻根酸痛、鼻眼耳痒、头晕发胀、注意力不集中等。另外一种就是血管运动性鼻炎，它最主要就是自主神经功能的失调，使得副交感神经旺盛并且造成种种类似过敏性鼻炎的症状，它并非特定抗原所引起，而可能和情绪紧张、压力增加或种种物理变化使然。
统计表明，近些年来过敏性鼻炎的患病率全球呈逐年增加的趋势，我国的过敏性鼻炎患者数量也在逐年攀升，这不仅对人们的身心健康和生活质量具有负面影响，而且对社会经济亦会造成一定的负担，日益成为普通民众关注的健康问题。过敏性鼻炎即变应性鼻炎，是指特应性个体接触变应原后，主要由IgE介导的介质(主要是组胺)释放，并有多种免疫活性细胞和细胞因子等参与的鼻黏膜非感染性炎性疾病。其发生的必要条件有3个：特异性抗原即引起机体免疫反应的物质；特应性个体即所谓个体差异、过敏体质；特异性抗原与特应型个体二者相遇。变应性鼻炎是一个全球性健康问题，可导致许多疾病和劳动力丧失。
过敏性鼻炎不会出现发热等全身症状，但能够引起耳鼻喉及眼睛 的各种不适症状，主要包括反复出现鼻痒、喷嚏、清涕和鼻塞，可伴有眼痒、咽痒、咳嗽，部分与季节有关，春秋季好发，季节过去症状逐渐消退，鼻用糖皮质激素和口服抗过敏药物可预防和缓解症状。
过敏性鼻炎不仅因为反复发作引起病惠的上述不适症状从而影响患者的生活质量，更重要的是还可能诱发过敏性结膜炎、过敏性皮炎、慢性鼻窦炎、鼻息肉、分泌性中耳炎，严重时甚至可能诱发哮喘而危及生命。目前，过敏性鼻炎尚无法完全彻底根治，但通过规范化的综合防治，可以达到并维持临床控制，有效缓解症状。因此，如何制备一种能有效预防和改善鼻腔过敏引起的不适症状且不含刺激类药物的鼻腔制剂是本领域急需解决的技术问题。
发明内容
本发明的目的是克服了现有技术的问题，提供了一种抗鼻腔过敏凝胶及其制备方法。
为了达到上述目的.本发明采用以下方案：
一种抗鼻腔过敏凝胶，其包括以下质量份的组分：纤维素0.1～2份；壳聚糖盐或壳聚糖衍生物0.05～1份；山梨酸钾或山梨酸钠0.1～0.2份；海盐0.8～0.9份；木糖醇0.1～0.5份，去离子水补足100份；
壳聚糖盐为式(1)所示物质：
其中R为Cl-、COO-或HSO4 -，x、n为自然数，0＜x≤107，102≤n ≤107。
进一步的，壳聚糖衍生物包括式(2)、式(3)、式(4)、式(5)和式(6)所示的物质中的一种或多种：
式(2)中，x、n为自然数，0＜x≤107，107≤n≤107；
式(3)中，x、n为自然数，0＜x≤107，102≤n≤107；
式(4)中，x、n为自然数，0＜x≤107，102≤n≤107；
式(5)中，x、n为自然数，0＜x≤107，0＜y≤107，102≤n≤107；
式(6)中，x、n为自然数，0＜x≤107，0＜y≤107，102≤n≤107。
上述式(1)至(6)的分子结构式中，各个重复单元的排列顺序并非是完全按照结构式中所标注的顺序，而是采取无规则的排列方式在高分子链中进行排列组合的。
进一步的，纤维素为羟乙基纤维素。
一种抗鼻腔过敏凝胶的制备方法，包括以下步骤：
S10将以下组成成分按重量份数称取原料：纤维素0.1～2份；壳聚糖盐或壳聚糖衍生物0.05～1份；山梨酸钾或山梨酸钠0.1～0.2份；海盐0.8～0.9份；木糖醇0.1～0.5份，去离子水补足100份；
S20将原料混合后充分搅拌使其完全溶解得到抗鼻腔过敏凝胶母液；
S30将抗鼻腔过敏凝胶母液经高压或辐照灭菌，得到抗鼻腔过敏凝胶。
进一步的，S20步骤还包括：
S21将壳聚糖盐或其衍生物和去离子水混合，通过搅拌使其充分溶解，得第一混合液；
S22将纤维素和去离子水混合，通过搅拌使其充分溶解，得第二混合液；
S23将其余组分和去离子水剩余量混合，并搅拌均匀充分溶解，得第三混合液；
S24将第一混合液、第二混合液和第三混合液混合在一起，搅拌均匀，得抗鼻腔过敏凝胶母液。
进一步的，S20和S30步骤中先将混合物加热至室温～80℃之间再通过搅拌使其充分溶解。
进一步的，纤维素为羟乙基纤维素。
与现有的技术相比，本发明具有如下优点：本发明所提供的抗鼻腔过敏凝胶所含的主要功能材料壳聚糖盐及其衍生物是一种改性天然多糖，具有优良的生物相容性、抗菌性和抗炎促修复性能，且无刺激无致敏性。羟乙基纤维素能与壳聚糖发生物理交联形成凝胶，加上木糖醇作为润湿调整剂，与海盐一起，用于提供鼻腔内部的等渗湿润环境，更好地保护鼻腔黏膜不受破坏。该抗鼻腔过敏凝胶可在鼻腔黏膜表面成膜形成保护层，减少并阻隔灰尘、病原体等外来刺激物与鼻腔 黏膜直接接触，用于因各种过敏引起的鼻腔不适或易诱发过敏性鼻炎患者的日常保健护理，并且能够有效减少和预防过敏性鼻炎的发病率。
附图说明
下面结合附图和具体实施方式对本申请作进一步详细的说明。
图1是本发明的抗鼻腔过敏凝胶对小鼠成纤维细胞(L929)的细胞毒性测试结果图。
图2是实施例1制备的抗鼻腔过敏凝胶A形成的薄膜将二氧化硅小球与透明基底隔离的三维荧光图像。
图3是实施例2制备的抗鼻腔过敏凝胶B形成的薄膜将大肠杆菌与透明基底隔离的三维荧光图像。
图4是小鼠鼻腔实验中小鼠鼻腔外观图。
图5是未喷本发明所述抗鼻腔过敏凝胶的小鼠鼻腔黏膜环境扫描电镜照片a和鼻腔中喷洒本发明所述抗鼻腔过敏凝胶的小鼠鼻腔黏膜环境扫描电镜照片b。
图6是鼻腔中喷洒本发明所述抗鼻腔过敏凝胶并滴加菌液后的小鼠鼻腔黏膜环境扫描电镜照片，(b)为(a)图中框部分的放大图。
具体实施方式
下面结合附图和实施例，对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但不用来限制本发明的范围。
实施例一
一种抗鼻腔过敏凝胶，配方如下：羟乙基纤维素0.1克，式(1)壳聚糖盐1克，山梨酸钾0.2克，海盐0.9克，木糖醇0.5克，去离子水97.3克。
其中R为Cl-、COO-或HSO4 -，x、n为自然数，0＜x≤107，102≤n≤107。
一种抗鼻腔过敏凝胶的制备方法，包括以下步骤：
S10将所述羟乙基纤维素和37.3克去离子水混合，室温下搅拌使其充分溶解，得第一混合液；
S21将式(1)所述壳聚糖盐和30克去离子水混合，然后加热至80℃，搅拌使其充分溶解，得第二混合液；
S22将其余组分和剩余30克去离子水混合，并搅拌均匀充分溶解，得第三混合液；
S23将第一、二、三混合液混合在一起，搅拌均匀，得抗鼻腔过敏凝胶母液；
S30将S23步骤所得母液经高压或辐照灭菌，即可得所述抗鼻腔过敏凝胶A。
实施例二
一种抗鼻腔过敏凝胶，配方如下：羟乙基纤维素0.2克，式(2)壳聚糖单胍盐0.7克，山梨酸钾0.2克，海盐0.9克，木糖醇0.4克，去离子水97.6克。
式(2)中，x、n为自然数，0＜x≤107，102≤n≤107。
一种抗鼻腔过敏凝胶的制备方法，包括以下步骤：
S10将所述羟乙基纤维素和37.6克去离子水混合，然后加热至40℃，并搅拌使其充分溶解，得第一混合液；
S21将式(2)所述壳聚糖盐和30克去离子水混合，70℃下充分搅拌使其溶解，得第二混合液；
S22将其余组分和剩余30克去离子水混合，并搅拌均匀充分溶解，得第三混合液；
S23将第一、二、三混合液混合在一起，搅拌均匀，得抗鼻腔过敏凝胶母液；
S30将S23步骤所得母液经高压或辐照灭菌，即可得所述抗鼻腔过敏凝胶B。
实施例三
一种抗鼻腔过敏凝胶，配方如下：羟乙基纤维素0.5克，式(3)壳聚糖双胍盐0.5克，山梨酸钠0.15克，海盐0.85克，木糖醇0.2克，去离子水97.8克。
式(3)中，x、n为自然数，0＜x≤107，102≤n≤107；
一种抗鼻腔过敏凝胶的制备方法，包括以下步骤：
S10将所述羟乙基纤维素和37.8克去离子水混合，然后加热至50℃，并搅拌使其充分溶解，得第一混合液；
S21将式(1)所述壳聚糖盐和30克去离子水混合，60℃下充分搅拌使其溶解，得第二混合液；
S22将其余组分和剩余30克去离子水混合，并搅拌均匀充分溶解，得第三混合液；
S23将第一、二、三混合液混合在一起，搅拌均匀，得抗鼻腔过敏凝胶母液；
S30将S23步骤所得母液经高压或辐照灭菌，即可得所述抗鼻腔过敏凝胶C。
实施例四
一种抗鼻腔过敏凝胶，配方如下：羟乙基纤维素1.0克，式(4)羧甲基壳聚糖0.3克，山梨酸钠0.15克，海盐0.85克，木糖醇0.2克，去离子水97.5。
式(4)中，x、n为自然数，0＜x≤107，102≤n≤107；
一种抗鼻腔过敏凝胶的制备方法，包括以下步骤：
S10将所述羟乙基纤维素和37.5克去离子水混合，然后加热至60℃，并搅拌使其充分溶解，得第一混合液；
S21将式(4)所述羧甲基壳聚糖和30克去离子水混合，50℃下充分搅拌使其溶解，得第二混合液；
S22将其余组分和剩余30克去离子水混合，并搅拌均匀充分溶解，得第三混合液；
S23将第一、二、三混合液混合在一起，搅拌均匀，得抗鼻腔过敏 凝胶母液；
S30将S23步骤所得母液经高压或辐照灭菌，即可得所述抗鼻腔过敏凝胶D。
实施例五
一种抗鼻腔过敏凝胶，配方如下：羟乙基纤维素1.5克，式(5)双改性壳聚糖衍生物0.1克，山梨酸钠0.15克，海盐0.85克，木糖醇0.2克，去离子水97.2克。
式(5)中，x、n为自然数，0＜x≤107，0＜y≤107，102≤n≤107；
一种抗鼻腔过敏凝胶的制备方法，包括以下步骤：
S10将所述羟乙基纤维素和37.2克去离子水混合，然后加热至70℃，并搅拌使其充分溶解，得第一混合液；
S21将式(5)所述双改性壳聚糖衍生物和30克去离子水混合，40℃下充分搅拌使其溶解，得第二混合液；
S22将其余组分和剩余30克去离子水混合，并搅拌均匀充分溶解，得第三混合液；
S23将第一、二、三混合液混合在一起，搅拌均匀，得抗鼻腔过敏 凝胶母液；
S30将S23步骤所得母液经高压或辐照灭菌，即可得所述抗鼻腔过敏凝胶E。
实施例六
一种抗鼻腔过敏凝胶，配方如下：羟乙基纤维素2克，式(6)双改性壳聚糖衍生物0.05克，山梨酸钠0.1克，海盐0.85克，木糖醇0.1克，去离子水96.9克。
式(6)中，x、n为自然数，0＜x≤107，0＜y≤107，102≤n≤107。
一种抗鼻腔过敏凝胶的制备方法，包括以下步骤：
S10将所述羟乙基纤维素和36.9克去离子水混合，80℃下并搅拌使其充分溶解，得第一混合液；
S21将式(6)所述双改性壳聚糖衍生物和30克去离子水混合，然后室温下充分搅拌使其溶解，得第二混合液；
S22将其余组分和剩余30克去离子水混合，并搅拌均匀充分溶解，得第三混合液；
S23将第一、二、三混合液混合在一起，搅拌均匀，得抗鼻腔过敏 凝胶母液；
S30将S23步骤所得母液经高压或辐照灭菌，即可得所述抗鼻腔过敏凝胶F。
实施例一至六的细胞毒性测试
图1为本发明实施例一至六制备的抗鼻腔过敏凝胶对小鼠成纤维细胞(L929)的细胞毒性测试结果。从图上可以看出该测试结果说明：本发明制备的抗鼻腔过敏凝胶基本没有细胞毒性，甚至对细胞的增殖有一定的促进作用，这说该抗鼻腔过敏凝胶具有良好的生物安全性。花粉类粉尘阻隔模拟实验
为了证实本发明制备的抗鼻腔过敏凝胶使用后能形成保护层减少并阻隔花粉类粉尘与鼻腔黏膜的接触，我们采用二氧化硅小球来模拟花粉类灰尘。首先将被罗丹明B染色的实施例1制备的抗鼻腔过敏凝胶A(显示红色)喷涂透明基底上，待其干燥成膜后，将被荧光素染色的二氧化硅小球(显示绿色)撒至本产品产生的薄膜上；然后采用激光扫描共聚焦显微镜(型号ARsiMP-LSM-Kit-Legend Elite-USX，尼康)观察三维荧光图像。如图2所示，本产品形成的红色薄膜将绿色的二氧化硅小球与基底完全隔离开，避免了二者的直接接触。由此证明本发明所述产品形成的保护层可以减少粉尘与鼻腔黏膜的直接接触。
大肠杆菌类病原体阻隔模拟实验
为了验证本发明所述的抗鼻腔过敏凝胶能够形成保护膜并阻隔病原体 与鼻腔黏膜接触，我们采用大肠杆菌(一种细菌类病原体)进行了模拟实验。首先将被罗丹明染色的实施例2制备的抗鼻腔过敏凝胶B(显示红色)滴至透明基底上，待其千燥成膜后，将染色的大肠杆菌(显示绿色)撒至本产品产生的薄膜上；然后采用激光扫描共聚焦显微镜(型号ARsiMP-LSM-Kit-Legend Elite-USX，尼康)观察三维荧光图像。如图3所示，本产品产生的红色薄膜将绿色的大肠杆菌与基底完全隔离，避免了二者的直接接触。此实验证明了本产品形成的保护层可以减少病原体与鼻腔黏膜的直接接触。
小鼠鼻腔实验
我们以小鼠作为受试动物，以铜绿假单胞菌作为灰尘、病原体等外来刺激物的典型代表，验证本发明所述抗鼻腔过敏凝胶可在湿润的鼻腔内成保护膜并阻隔过敏源。
用按压式喷瓶向6只小鼠鼻腔中分别喷入3次本发明所述实施例一至六制备的抗鼻腔过敏凝胶A-F(每只小鼠鼻腔中喷入一种凝胶产品)，30分钟后向鼻腔中滴入铜绿假单胞菌菌液(菌浓度：1×109CFU/mL)。再待30分钟后，处死小鼠，取鼻腔并固定(鼻腔外观如图4所示)。利用场发射枪环境扫描电镜(仪器型号：Quanta FEG 250；生产厂家：美国FEI公司)观察鼻腔内部黏膜区域的形貌。
图5中照片a为未喷本产品的小鼠鼻腔黏膜环境扫描电镜照片，由图可见，小鼠鼻腔黏膜表面呈褶皱状。图5中照片b为鼻腔中喷洒本发明所述实施例一制备的抗鼻腔过敏凝胶A后小鼠鼻腔黏膜的环境 扫描电镜照片，图中可见小鼠鼻腔黏膜表面的褶皱形貌已被覆盖，说明本产品在小鼠的鼻腔黏膜表面成膜(另外五只小鼠鼻腔黏膜扫描电镜照片显示结果类似，此处不再展示)。
图6为鼻腔中喷洒本发明所述实施例1制备的抗鼻腔过敏凝胶A并滴加菌液后的小鼠鼻腔黏膜环境扫描电镜照片，图中可见，铜绿假单胞菌(图6b中白色箭头所指)位于本产品所成的膜(图6a中白色箭头所指)上方，不与鼻腔黏膜直接接触(另外五只小鼠鼻腔黏膜扫描电镜照片显示结果类似，此处同样不再展示)。
以上试验结果表明，本发明所述实施例制备的抗鼻腔过敏凝胶可在小鼠鼻腔内成膜，并可阻隔以铜绿假单胞菌为代表的灰尘、病原体等外来刺激物与鼻腔黏膜直接接触，从而起到保护鼻腔黏膜的作用。
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，在不脱离本申请技术原理的前提下，还可以做出若干改进和替换，这些改进和替换也应视为本申请的保护范围。

Claims (7)

  1. 一种抗鼻腔过敏凝胶，其特征在于，其包括以下质量份的组分：纤维素0.1～2份；壳聚糖盐或壳聚糖衍生物0.05～1份；山梨酸钾或山梨酸钠0.1～0.2份；海盐0.8～0.9份；木糖醇0.1～0.5份，去离子水补足100份；
    所述壳聚糖盐为式(1)所示物质：
    其中R为Cl-、COO-或HSO4 -，x、n为自然数，0＜x≤107，102≤n≤107。
  2. 根据权利要求1所述的一种抗鼻腔过敏凝胶，其特征在于，所述壳聚糖衍生物包括式(2)、式(3)、式(4)、式(5)和式(6)所示的物质中的一种或多种：
    式(2)中，x、n为自然数，0＜x≤107，102≤n≤107；
    式(3)中，x、n为自然数，0＜x≤107，102≤n≤107；
    式(4)中，x、n为自然数，0＜x≤107，102≤n≤107；
    式(5)中，x、n为自然数，0＜x≤107，0＜y≤107，102≤n≤107；
    式(6)中，x、n为自然数，0＜x≤107，0＜y≤107，102≤n≤107。
  3. 根据权利要求1所述的一种抗鼻腔过敏凝胶，其特征在于，所述纤维素为羟乙基纤维素。
  4. 一种抗鼻腔过敏凝胶的制备方法，其特征在于，包括以下步骤：
    S10将以下组成成分按重量份数称取原料：纤维素0.1～2份；壳聚糖盐或壳聚糖衍生物0.05～1份；山梨酸钾或山梨酸钠0.1～0.2份；海盐0.8～0.9份；木糖醇0.1～0.5份，去离子水补足100份；
    S20将所述原料混合后充分搅拌使其完全溶解得到抗鼻腔过敏凝胶母液；
    S30将所述抗鼻腔过敏凝胶母液经高压或辐照灭菌，得到抗鼻腔过敏凝胶。
  5. 根据权利要求4所述的一种抗鼻腔过敏凝胶的制备方法，其特征在于，所述S20步骤还包括：
    S21将所述壳聚糖盐或其衍生物和所述去离子水混合，通过搅拌使其充分溶解，得第一混合液；
    S22将纤维素和所述去离子水混合，通过搅拌使其充分溶解，得第二混合液；
    S23将其余组分和所述去离子水剩余量混合，并搅拌均匀充分溶解， 得第三混合液；
    S24将所述第一混合液、第二混合液和第三混合液混合在一起，搅拌均匀，得抗鼻腔过敏凝胶母液。
  6. 根据权利要求5所述的一种抗鼻腔过敏凝胶的制备方法，其特征在于，所述S20和S30步骤中先将混合物加热至室温～80℃之间再通过搅拌使其充分溶解。
  7. 根据权利要求5所述的一种抗鼻腔过敏凝胶的制备方法，其特征在于，所述纤维素为羟乙基纤维素。
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