WO2018076856A1 - 一种丁香酚口腔溃疡膜及其制备方法 - Google Patents

一种丁香酚口腔溃疡膜及其制备方法 Download PDF

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WO2018076856A1
WO2018076856A1 PCT/CN2017/095141 CN2017095141W WO2018076856A1 WO 2018076856 A1 WO2018076856 A1 WO 2018076856A1 CN 2017095141 W CN2017095141 W CN 2017095141W WO 2018076856 A1 WO2018076856 A1 WO 2018076856A1
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eugenol
oral ulcer
parts
film
oral
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PCT/CN2017/095141
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English (en)
French (fr)
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杜卓
刘飞蝶
朱春霞
张丽华
邝婉容
谭淑仪
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佛山科学技术学院
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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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • 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
    • 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

Definitions

  • the invention relates to the field of medical instruments, in particular to an eugenol oral ulcer film; the invention also relates to a preparation method of an eugenol oral ulcer film.
  • Oral ulcer is a common oral disease in life, which occurs mostly in the oral mucosa and is characterized by local damage of the oral mucosa. Because it will recur after healing, it is also known as recurrent oral ulcer in the clinic. It is also called aphthous ulcer.
  • the disease can occur in people of different ages, races, and regions, and the prevalence can be as high as 20% in the general population. It is the most common oral mucosal disease in the clinic.
  • the first illness lasts for a long time. After that, the duration of each episode is slowly shortened.
  • the internal pain and pain during the illness greatly affect the patient's oral activities such as chewing and swallowing, which brings various pains and inconveniences to the patient. Especially for the quality of life of patients with frequent attacks.
  • eugenol is 4-allyl 2-methoxyphenol, which is an organic acid phenol, which is widely present in aromatic oils such as clove oil, cinnamon leaves, skin oil, and camphor oil.
  • Eugenol has a wide range of pharmacological effects, mainly antibacterial, anti-inflammatory, antipyretic and analgesic effects.
  • eugenol is a volatile oil, which is extremely difficult to dissolve in water, has poor stability, and is easily lost in the production and storage of traditional preparations, affecting the efficacy.
  • eugenol as an active ingredient for relieving oral ulcers mainly includes:
  • Chinese patent CN 104800261 A discloses a clove compound mouthwash comprising tea polyphenol, eugenol and notoginseng extract, and the invention combines various components together, in addition to the function of cleaning the mouth with different mouthwashes, It has the effect of treating or preventing oral diseases such as periodontitis, dental caries, bad breath and oral ulcers, whitening, healthy teeth, clearing away heat and swelling, and preventing cancer.
  • oral diseases such as periodontitis, dental caries, bad breath and oral ulcers, whitening, healthy teeth, clearing away heat and swelling, and preventing cancer.
  • the Chinese patent CN1820737A is an anti-inflammatory and analgesic Ding Peng sputum preparation and preparation method for preparing a Ding Peng gargle containing clove basil oil (the main component is eugenol) and borax.
  • clove basil oil the main component is eugenol
  • borax the main component is eugenol
  • the above-mentioned mouthwash or gargle prepared by using eugenol to inhibit pathogenic bacteria and fungi can play an anti-inflammatory effect and relieve pain, but the contact time of mouthwash or gargle with the oral cavity is short. The effect time is slower, and it is urgent to provide a new type of product that can solve the technical problem of poor stability of eugenol in the preparation, and at the same time, can effectively protect the oral ulcer wound and act rapidly in the lesion.
  • the technical problem to be solved by the invention is to provide a eugenol oral ulcer film and a preparation method thereof, which can protect the oral ulcer wound for a long time, prevent secondary infection, and quickly act in the lesion site, and have antibacterial, anti-inflammatory, anesthetic analgesia and promotion. The healing effect.
  • the present invention provides an eugenol oral ulcer film comprising the following raw materials in parts by weight:
  • the following raw materials are prepared by weight:
  • the present invention also provides a method for preparing an eugenol oral ulcer film, comprising the following steps:
  • Step 1 Weigh 0.2-0.6 parts of eugenol, 0.2-5.5 parts of polyvinyl alcohol, 0.01-3.5 parts of sodium carboxymethylcellulose, 0-1 parts of glycerin and 10-100 parts of distilled water by weight;
  • Step 2 mixing polyvinyl alcohol and sodium carboxymethyl cellulose and adding to distilled water for 20-30 hours to fully swell to obtain a colloidal material;
  • Step 3 The colloidal material is heated in a water bath condition of 85-95 ° C for 20-40 minutes and stirred and mixed, and allowed to stand for 30 minutes;
  • Step 4 adding glycerin and eugenol to the colloidal material in the heat preservation, slowly stirring and mixing, and standing to obtain a mixed solution;
  • Step 5 The mixed solution is laid flat on a glass container, placed horizontally, sealed and dried, stripped, and punched to obtain the eugenol oral ulcer film.
  • the colloidal material is kept at 30-35 ° C for 30 minutes while standing.
  • the laminated glass container is placed in an oven and dried at a temperature of 35-45 ° C, and the drying time is 2.5- 4 hours.
  • the glass container after filming is dried at room temperature and the wind speed is 5-15 m/s, and the drying time is 12-18. hour.
  • the thickness of the eugenol oral ulcer film is 0.5 ⁇ 0.02 mm.
  • the eugenol oral ulcer film is die-cut into a size of 1.5 cm ⁇ 1.5 cm.
  • the invention combines eugenol with polyvinyl alcohol and sodium carboxymethyl cellulose to form a film, which has the advantages of good film forming property, smooth surface, uniform thickness, color and good softness, and is applied to oral ulcer wounds and skin followability. Well, the application is comfortable to use and not easy to fall off.
  • the active ingredient eugenol in the membrane can quickly act on the lesion, relieve pain, anti-inflammatory and antibacterial, promote the formation of granulation tissue and the healing of the ulcer sore surface, and the eugenol can be stably retained during the preparation and storage of the membrane.
  • polyvinyl alcohol, sodium carboxymethyl cellulose, glycerin and distilled water are all pharmaceutical grade excipients, which have excellent biocompatibility. And degradability, the product is safe and reliable.
  • the present invention provides a eugenol oral ulcer film comprising the following raw materials by weight:
  • Eugenol is chemically known as 4-allyl 2-methoxyphenol and is an organic acid phenol which is widely found in aromatic oils such as clove oil, cinnamon leaves, skin oil, and camphor oil. Because of its structure containing an aromatic ring, the polar group phenolic hydroxyl group on the aromatic ring can bind to the active groups of some enzymes of bacteria, destroying the normal metabolic function of bacteria to affect the normal growth of bacteria. Therefore, eugenol has the functions of sterilization, anti-inflammatory, etc., and can significantly inhibit Staphylococcus, Candida albicans, Streptococcus, mold and Escherichia coli.
  • eugenol also blocks the transmission of neurotransmitters in the wound surface to rapidly relieve pain at the lesion, and can also inhibit the activity of cyclooxygenase and reduce the formation of inflammatory mediators while producing local anesthesia. So as to quickly eliminate the symptoms of congestion and swelling in the ulcer, to promote the formation of granulation tissue and the healing of ulcer sores.
  • the above new pharmacological and physiological findings have made eugenol more and more widely used in stomatology.
  • eugenol is a volatile oil, which is extremely difficult to dissolve in water, has poor stability, and is easily lost in the production and storage of traditional preparations, affecting the efficacy.
  • the existing patent uses mouthwash or gargle prepared by eugenol to inhibit pathogenic bacteria and fungi, although it can play an anti-inflammatory effect and relieve pain, but the contact time of mouthwash or gargle with the oral cavity is short. The effect time is slower.
  • the present invention combines eugenol with polyvinyl alcohol and sodium carboxymethyl cellulose to form a film, which has the advantages of good film forming property, smooth surface, uniform thickness, color, and good flexibility, and is attached to an oral ulcer wound.
  • the skin has good followability, and the application is comfortable to use and not easy to fall off.
  • both polyvinyl alcohol and sodium carboxymethyl cellulose are film-forming materials, and are degradable polymer materials with high adhesion and biosafety. Polyvinyl alcohol and sodium carboxymethyl cellulose are combined. It can be used to improve the film forming properties and adhesion properties of the film.
  • the active ingredient eugenol in the membrane can quickly act on the lesion, relieve pain, anti-inflammatory and antibacterial, promote the formation of granulation tissue and the healing of the ulcer sore surface, and the eugenol can be stably retained during the preparation and storage of the membrane.
  • polyvinyl alcohol, sodium carboxymethyl cellulose, glycerin and distilled water are all pharmaceutical grade excipients, which have excellent biocompatibility. And degradability, the product is safe and reliable.
  • the eugenol oral ulcer film of the present invention comprises the following raw materials in parts by weight:
  • the proportion of eugenol may be 0.2, 0.3, 0.4, 0.5 or 0.6, but not limited thereto;
  • the ratio of the number of parts selectable is 1.5, 2.1, 2.7, 3.5 or 5.0, but is not limited thereto;
  • the proportion of sodium carboxymethyl cellulose may be selected from 0.3, 0.9, 1.5, 2.0 or 3.2, but is not limited thereto.
  • the ratio of the glycerin may be 0, 0.5 or 1.0, but is not limited thereto; the ratio of the distilled water may be 20, 30, 40, 46, 52 or 70, but is not limited thereto.
  • the present invention also provides a method for preparing an eugenol oral ulcer film, comprising the following steps:
  • Step 1 Weigh 0.2-0.6 parts of eugenol, 0.2-5.5 parts of polyvinyl alcohol, 0.01-3.5 parts of sodium carboxymethylcellulose, 0-1 parts of glycerin, and 10-100 parts of distilled water by weight, and use.
  • Step 2 Polyvinyl alcohol and sodium carboxymethylcellulose are mixed and added to distilled water for 20-30 hours to sufficiently swell to obtain a colloidal material.
  • a preferred technical solution of the present invention is to swell polyvinyl alcohol and sodium carboxymethyl cellulose soaked in distilled water at a constant temperature of 20-25 ° C; another feasible technical solution of the present invention is to change the temperature according to room temperature and at room temperature. 25 ° C is the reference temperature, and the amount of distilled water added is appropriately increased. Specifically, the amount of distilled water added to the formulation is increased by 1-3 ml for every 5 ° C reduction in room temperature.
  • Step 3 The colloidal material is heated under a water bath condition of 85-95 ° C for 20-40 minutes, stirred and mixed, and allowed to stand for 30 minutes.
  • the colloidal material When the colloidal material is heated in a water bath and stirred uniformly, a large amount of bubbles are generated, which reduces the smoothness of the film.
  • the mixed polymer material heated by the water bath is allowed to stand in a constant temperature water bath at 30-35 ° C for 30 minutes, thereby eliminating bubbles and avoiding the problem that the mixed material is cooled too fast and is not easy to be filmed.
  • Step 4 Glycerol and eugenol are added to the colloidal material in the heat preservation, and slowly stirred and mixed, and allowed to stand to obtain a mixed solution.
  • the eugenol is heated and volatile, so in order to avoid the volatilization of eugenol during the preparation process, firstly, when adding eugenol, the temperature of the mixed film-forming material should not be too high, and the suitable holding temperature is 30-35 ° C, slowly stirring to avoid a large amount of Bubbles and let stand for 30 minutes to remove air bubbles.
  • Step 5 The mixed solution is laid flat on a glass container, placed horizontally, sealed and dried, stripped, and punched to obtain the eugenol oral ulcer film.
  • the defoamed mixed solution is poured into a glass container. Since the mixed solution is kept for 30 minutes, the fluidity is good, and it is easy to be flattened in a glass container, and the film thickness is uniform.
  • the preparation method of the present invention is to avoid direct exposure to the air and reduce the content of the main drug, and should be dried in a sealed environment.
  • the preferred technical solution is to place the filmed glass container in an oven. In the case of drying at a temperature of 35-45 ° C, the drying time is 2.5-4 hours; a better technical solution is to dry the glass container after filming at room temperature and a wind speed of 5-15 m / s, The drying time is 12-18 hours.
  • the film thickness after film formation is 0.5 ⁇ 0.02 mm, and is punched into an appropriate size as needed.
  • the present invention blasts the eugenol oral ulcer film into a size of 1.5 cm ⁇ 1.5 cm.
  • Formulation 0.5 g of eugenol, 2.1 g of polyvinyl alcohol, 0.9 g of sodium carboxymethylcellulose, 0.5 g of glycerin, and 46 ml of distilled water.
  • Step 1 Weigh 0.2-0.6 parts of eugenol, 0.2-5.5 parts of polyvinyl alcohol, 0.01-3.5 parts of sodium carboxymethylcellulose, 0-1 parts of glycerin and 10-100 parts of distilled water by weight;
  • Step 2 mixing polyvinyl alcohol and sodium carboxymethyl cellulose and adding to distilled water for 20-30 hours to fully swell to obtain a colloidal material;
  • Step 3 The colloidal material is heated in a water bath condition of 85-95 ° C for 20-40 minutes and stirred and mixed, and allowed to stand at 30-35 ° C for 30 minutes;
  • Step 4 adding glycerin and eugenol to the colloidal material in the heat preservation, slowly stirring and mixing, and standing to obtain a mixed solution;
  • Step 5 The mixed solution is laid flat on a glass container, placed horizontally, sealed and dried at a wind speed of 5-15 m/s, stripped, and punched to obtain a eugenol oral ulcer film, which is an experimental sample.
  • weight difference (single piece weight - average weight) / average weight x 100%.
  • the dissolution time of the eugenol oral ulcer film is shown in Table 2. The results showed that the average adherent dissolution time of the eugenol oral ulcer film was 68.2 min, and the average dissolution time was 139.7 s.
  • Table 2 Record record of dissolution time of eugenol oral ulcer film
  • the dissolution time of the phenolic oral ulcer film can be found that the dissolution time of the eugenol oral ulcer film is about one hour, which is in line with the drug demand for oral administration.
  • the dissolution time of the stirred eugenol oral ulcer film is shorter, suggesting that the eugenol oral ulcer film should be used when the patient should talk less to avoid chewing or swallowing action, and the eugenol oral ulcer film is not suitable for oral administration.
  • the eugenol oral ulcer film obtained by the preparation method of the invention has a smooth surface, uniform thickness and color, and good flexibility.
  • the results of the film quality evaluation test showed that the prepared eugenol oral ulcer film was evaluated in terms of weight difference, simulated oral dissolution time, main drug content in the film, product stability and recovery rate.
  • the 50 volunteers with oral ulcers were observed, including 28 males and 22 females, aged between 15 and 45 years, with a course of 1 to 30 days.

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Abstract

本发明公开了一种丁香酚口腔溃疡膜，包括以下按重量份计的原料制成：0.2-0.6份丁香酚、0.2-5.5份聚乙烯醇、0.01-3.5份羧甲基纤维素钠、0-1份甘油以及10-100份蒸馏水。本发明还公开了一种丁香酚口腔溃疡膜的制备方法。采用本发明，可长效保护口腔溃疡创面，防止继发感染，在病灶部位迅速作用，具有抗菌消炎、麻醉镇痛，促进愈合的功效。

Description

一种丁香酚口腔溃疡膜及其制备方法 技术领域
本发明涉及一种医疗器械领域，尤其涉及一种丁香酚口腔溃疡膜；本发明还涉及一种丁香酚口腔溃疡膜的制备方法。
背景技术
口腔溃疡是一种生活中常见的口腔类疾病，多发生在口腔黏膜处，以口腔黏膜局部损伤为表现形式。因为其治愈后会反复发作在临床上也被成为复发性口腔溃疡，民间也称其为口疮。这种疾病在不同年龄层、不同种族、不同地区的人都可能发生，患病率在一般人群中可高达20％，是临床上最常见的口腔黏膜疾病。第一次患病持续时间长，此后每次发作病程时间慢慢缩短，患病时口腔内部刺激疼痛感极大程度上影响病人咀嚼、吞咽等口腔活动给患者带来各种痛苦和不便。尤其对频繁发作的患者生活质量产生较大影响。临床上根据溃疡表现的大小，深浅及数目不同又分为轻型口腔溃疡、口炎型溃疡及坏死性黏膜周围炎。其治疗原则是消除致病因素，改善饮食习惯，提高抵抗力等缓解局部症状，促进溃疡。
丁香酚的化学名称为4－烯丙基2－甲氧基苯酚，是有机酸酚类，广泛存在于丁香油、肉桂叶、皮油、樟脑油等芳香油中。丁香酚具有广泛的药理作用，主要有抗菌消炎、解热镇痛的作用。然而丁香酚属于挥发油类，极难溶于水，稳定性差，易于在传统制剂的生产和储藏过程中散失、影响药效。现有技术中以丁香酚作为有效成分用于缓解口腔溃疡的产品主要有：
中国专利CN 104800261 A公开了一种丁香复方漱口水，包含茶多酚、丁香酚和三七提取物，本发明将多种成分结合到一起，除具有不同漱口水的清洁口腔的功能外，还具有治疗或预防牙周炎、龋齿、口臭、口腔溃疡等口腔疾病，增白、健齿、清热消肿、预防癌症的功效。
另外，中国专利CN1820737A一种消炎止痛的丁鹏含漱液的处方及制备方法制备一种以丁香罗勒油(主要成分为丁香酚)、硼砂为主要的丁鹏含漱液，可 广泛用于急慢性牙髓炎、牙周炎、牙龈溢脓、红肿，空腔炎，有良好的止痛作用。
然而，上述利用丁香酚对致病细菌和真菌有抑制作用制得的漱口水或含漱液虽然可起消炎作用，缓解疼痛，但是漱口水或含漱液这些产品与口腔的接触时间短，起效时间较慢，亟需提供一种新型的产品可解决丁香酚在制剂中稳定性差的技术问题，同时能长效保护口腔溃疡创面，在病灶部位迅速作用。
发明内容
本发明所要解决的技术问题在于，提供一种丁香酚口腔溃疡膜及其制备方法，可长效保护口腔溃疡创面，防止继发感染，在病灶部位迅速作用，具有抗菌消炎、麻醉镇痛，促进愈合的功效。
为了解决上述技术问题，本发明提供了一种丁香酚口腔溃疡膜，包括以下按重量份计的原料制成：
Figure PCTCN2017095141-appb-000001
作为所述丁香酚口腔溃疡膜的优选技术方案，包括以下按重量份计的原料制成：
Figure PCTCN2017095141-appb-000002
相应地，本发明还提供一种丁香酚口腔溃疡膜的制备方法，包括以下步骤：
步骤1：按重量份计称取0.2-0.6份丁香酚、0.2-5.5份聚乙烯醇、0.01-3.5份羧甲基纤维素钠、0-1份甘油以及10-100份蒸馏水，待用；
步骤2：将聚乙烯醇和羧甲基纤维素钠混合并加入蒸馏水浸泡20-30小时使其充分溶胀，得到胶体材料；
步骤3：将所述胶体材料在85-95℃水浴条件下加热20-40分钟并搅拌混匀，保温静置30分钟；
步骤4：将甘油和丁香酚加入到保温中的胶体材料中，并缓慢搅拌混匀，静置，得到混合溶液；
步骤5：将混合溶液铺平在玻璃容器上，水平放置，密封干燥，脱膜，冲切后即得所述丁香酚口腔溃疡膜。
作为所述丁香酚口腔溃疡膜的制备方法的优选技术方案，所述步骤3中，静置时胶体材料在30-35℃下保温30分钟。
作为所述丁香酚口腔溃疡膜的制备方法的优选技术方案，所述步骤5中，铺膜后的玻璃容器放置在烘箱中，在温度为35-45℃条件下进行干燥，干燥时间为2.5-4小时。
作为所述丁香酚口腔溃疡膜的制备方法的优选技术方案，所述步骤5中，铺膜后的玻璃容器在室温，风速为5-15m/s的条件下进行干燥，干燥时间为12-18小时。
作为所述丁香酚口腔溃疡膜的制备方法的优选技术方案，所述丁香酚口腔溃疡膜的厚度为0.5±0.02mm。
作为所述丁香酚口腔溃疡膜的制备方法的优选技术方案，所述丁香酚口腔溃疡膜冲切成1.5cm×1.5cm的尺寸。
实施本发明实施例，具有如下有益效果：
本发明将丁香酚结合聚乙烯醇和羧甲基纤维素钠将其制成膜，具有成膜性好，表面光滑，厚度、颜色均匀，柔软性好的优点，贴于口腔溃疡创面，皮肤追随性好，敷贴使用舒适，不易脱落。同时，膜中的活性成分丁香酚能迅速作用于病灶，缓解疼痛，消炎抗菌，促进肉芽组织生成及溃疡疮面的愈合，而且所述膜剂在制备和储藏过程中，丁香酚能稳定存留在膜剂中，不会出现明显的挥发散失，产品效果的稳定性得到了保证；聚乙烯醇、羧甲基纤维素钠、甘油和蒸馏水皆为药用级辅料，具有极佳的生物相容性和可降解性，产品安全可靠。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚，下面将对本发明作进一步地详细描述。
本发明提供一种丁香酚口腔溃疡膜，包括以下按重量份计的原料制成：
Figure PCTCN2017095141-appb-000003
丁香酚(Eugenol)化学名称为4－烯丙基2－甲氧基苯酚，是有机酸酚类，广泛存在于丁香油、肉桂叶、皮油、樟脑油等芳香油中。因其结构中含有芳香环，芳香环上的极性基团酚羟基，能与细菌的某些酶的活性基团结合，破坏细菌正常的代谢功能以影响细菌的正常生长。所以丁香酚具有杀菌、消炎等作用，能明显抑制葡萄球菌、白色念珠菌、链球菌、霉菌及大肠杆菌等。随着现代医学的发展，研究发现丁香酚还具有阻断创面神经末梢递质传递，以迅速缓解病损处疼痛，在产生局麻作用同时也可抑制环氧化酶活性并减少炎症介质的形成，从而迅速消除溃疡处的充血肿胀症状，达到促进肉芽组织生成及溃疡疮面的愈合。以上药理和生理新发现使得丁香酚在口腔医学中的应用越来越广泛。
然而丁香酚属于挥发油类，极难溶于水，稳定性差，易于在传统制剂的生产和储藏过程中散失、影响药效。现有专利利用丁香酚对致病细菌和真菌有抑制作用制得的漱口水或含漱液虽然可起消炎作用，缓解疼痛，但是漱口水或含漱液这些产品与口腔的接触时间短，起效时间较慢。
为此，本发明将丁香酚结合聚乙烯醇和羧甲基纤维素钠将其制成膜，具有成膜性好，表面光滑，厚度、颜色均匀，柔软性好的优点，贴于口腔溃疡创面，皮肤追随性好，敷贴使用舒适，不易脱落。需要说明的是，聚乙烯醇和羧甲基纤维素钠这两者都是成膜材料，是具有粘附性、生物安全性高的可降解高分子材料，聚乙烯醇和羧甲基纤维素钠配合起来使用，有利于提高膜剂的成膜性能和粘附性能。同时，膜中的活性成分丁香酚能迅速作用于病灶，缓解疼痛，消炎抗菌，促进肉芽组织生成及溃疡疮面的愈合，而且所述膜剂在制备和储藏过程中，丁香酚能稳定存留在膜剂中，不会出现明显的挥发散失，产品效果的稳定性得到了保证；聚乙烯醇、羧甲基纤维素钠、甘油和蒸馏水皆为药用级辅料，具有极佳的生物相容性和可降解性，产品安全可靠。
优选地，本发明一种丁香酚口腔溃疡膜，包括以下按重量份计的原料制成：
Figure PCTCN2017095141-appb-000004
需要说明的是，本发明所述丁香酚口腔溃疡膜，按重量份计丁香酚的配比可选择的份数为0.2、0.3、0.4、0.5或0.6，但不限于此；聚乙烯醇的配比可选择的份数为1.5、2.1、2.7、3.5或5.0，但不限于此；羧甲基纤维素钠的配比可选择的份数为0.3、0.9、1.5、2.0或3.2，但不限于此；甘油的配比可选择的份数为0、0.5或1.0，但不限于此；蒸馏水的配比可选择的份数为20、30、40、46、52或70，但不限于此.
相应地，本发明还提供一种丁香酚口腔溃疡膜的制备方法，包括以下步骤：
步骤1：按重量份计称取0.2-0.6份丁香酚、0.2-5.5份聚乙烯醇、0.01-3.5份羧甲基纤维素钠、0-1份甘油以及10-100份蒸馏水，待用。
步骤2：将聚乙烯醇和羧甲基纤维素钠混合并加入蒸馏水浸泡20-30小时使其充分溶胀，得到胶体材料。
由于溶胀过程中环境温度对于溶胀度有较大的影响，低温条件下，若按照室温20℃下的聚乙烯醇和羧甲基纤维素钠与蒸馏水的配比，聚乙烯醇和羧甲基纤维素钠溶胀不完全，铺膜困难。本发明优选的技术方案是将浸泡在蒸馏水中的聚乙烯醇和羧甲基纤维素钠置于恒温20-25℃下进行溶胀；本发明另一可行的技术方案是根据室温的变化，并以室温25℃为参照温度，适量增加蒸馏水的添加量。具体为，室温每降低5℃，配方中蒸馏水的添加量增加1-3ml。
步骤3：将所述胶体材料在85-95℃水浴条件下加热20-40分钟并搅拌混匀，保温静置30分钟。
将胶体材料进行水浴加热并搅拌均匀的过程中有大量气泡产生，降低了膜的光滑性。本发明所述制备方法将水浴加热之后的混合高分子材料在30-35℃恒温水浴箱中静置30分钟，既排除了气泡，又避免了混合材料冷却过快不易铺膜的问题。
步骤4：将甘油和丁香酚加入到保温中的胶体材料中，并缓慢搅拌混匀，静置，得到混合溶液。
丁香酚受热易挥发，因此在制备过程中为了避免丁香酚受热挥发，首先在加入丁香酚时要保证混合成膜材料温度不宜过高，适宜的保温温度为30-35℃，缓慢搅拌避免产生大量气泡，并静置30分钟排除气泡。
步骤5：将混合溶液铺平在玻璃容器上，水平放置，密封干燥，脱膜，冲切后即得所述丁香酚口腔溃疡膜。
将去泡后的混合溶液倒入玻璃容器上，由于该混合溶液经过30分钟的保温，其流动性较好，易在玻璃容器中铺平，成膜厚度均匀。
需要说明的是，本发明所述制备方法为避免直接暴露在空气中，使主药含量降低，应在密封环境下进行干燥，其中较佳的技术方案为将铺膜后的玻璃容器放置在烘箱中，在温度为35-45℃条件下进行干燥，干燥时间为2.5-4小时；更佳的技术方案为铺膜后的玻璃容器在室温，风速为5-15m/s的条件下进行干燥，干燥时间为12-18小时。
成膜后的膜厚为0.5±0.02mm，并根据需要冲切成适当的尺寸，优选地，本发明将所述丁香酚口腔溃疡膜冲切成1.5cm×1.5cm的尺寸。
下面通过几个实验对所述丁香酚口腔溃疡膜进行质量评价：
1、实验样品：
配方：丁香酚0.5g，聚乙烯醇2.1g，羧甲基纤维素钠0.9g，甘油0.5g，加入蒸馏水46ml。
制备方法：
步骤1：按重量份计称取0.2-0.6份丁香酚、0.2-5.5份聚乙烯醇、0.01-3.5份羧甲基纤维素钠、0-1份甘油以及10-100份蒸馏水，待用；
步骤2：将聚乙烯醇和羧甲基纤维素钠混合并加入蒸馏水浸泡20-30小时使其充分溶胀，得到胶体材料；
步骤3：将所述胶体材料在85-95℃水浴条件下加热20-40分钟并搅拌混匀，30-35℃下保温静置30分钟；
步骤4：将甘油和丁香酚加入到保温中的胶体材料中，并缓慢搅拌混匀，静置，得到混合溶液；
步骤5：将混合溶液铺平在玻璃容器上，水平放置，在风速为5-15m/s的条件下密封干燥，脱膜，冲切后得到丁香酚口腔溃疡膜，即为实验样品。
2、实验方法
2.1重量差异度测定
取实验样品丁香酚口腔溃疡膜20片，精密称定20片膜剂总重量，求出每片的平均重量。再分别精密称定每片重量，求重量差异度。
公式如下：重量差异度＝(单片重量－平均重量)/平均重量×100％。
2.2溶解时间测定
取实验样品丁香酚口腔溃疡膜6片，均匀贴于盛有200ml蒸馏水(37℃)500ml烧杯壁上距离水面3cm。记下完全溶解的时间，并求出贴壁的平均溶解时间。
另取丁香酚口腔溃疡膜6片置于同样实验条件下，并用玻璃棒缓慢搅拌模拟肠道蠕动和口腔吞咽咀嚼情况，再记下其完全溶解的时间，并求出搅拌条件下平均溶解时间。
2.3含量测定
2.3.1制备标准曲线
精密称取0.9988g丁香酚标准样于洁净干燥的小烧杯中，加80％(V/V)稀释后，移入100ml容量瓶中，再加80％(V/V)乙醇稀释至刻线，摇匀制成①号溶液。吸取①号溶液10ml于100ml容量瓶中，再用80％(V/V)乙醇稀释至刻线。摇匀制成浓度为0.9838mg/ml的丁香酚对照品储备液。精密吸取丁香酚对照品贮备液1.5，2.0，2.5，3.0，3.5，4.0ml分别放至100ml容量瓶中，加80％(V/V)乙醇稀释至刻度，使成浓度分别为14.76，19.68，24.60，29.51，34.43，39.35μg/ml的系列对照品溶液，以80％(V/V)乙醇为空白对照，在281.0nm波长处测定吸光度(A)。以浓度(C)为横坐标，以吸光度(A)为纵坐标，绘制标准曲线，求出回归方程与相关系数。
2.3.2精密度实验
取14.76，29.51，39.35μg/ml三个浓度的对照品溶液各5份，以80％(V/V)乙醇为空白，在281.0nm处测定紫外吸收波长，求日内RSD值。
2.3.3样品溶液稳定性实验
取最优处方制备的丁香酚口腔溃疡膜1片剪碎后置于烧杯中加80％(V/V)乙醇搅拌至膜剂完全溶解，再将溶液移至50ml容量瓶中，加80％(V/V)乙醇定容至刻度摇匀，过滤，并弃去初滤液，然后移取续滤液10ml于25ml容量瓶中，定容至刻度，摇匀制成样品液，取样品液5份，于间隔时间为0，2，4，8， 12h时测定吸光度。
2.3.4重复性实验与含量测定。
取最优处方制备的丁香酚口腔溃疡膜6片，精密称定每片重量后剪碎，并分别将各片置于烧杯中加80％(V/V)乙醇搅拌至膜剂完全溶解，再将溶液移至50ml容量瓶中，加80％(V/V)乙醇定容至刻度摇匀，制成6份溶液。过滤，并弃去初滤液，然后移取续滤液10ml于25ml容量瓶中，定容至刻度，摇匀制成样品液。以80％(V/V)乙醇为空白对照，在波长281.0nm处测定样品液的吸光度，并代入回归方程，计算得出丁香酚口腔溃疡膜剂的平均含量与RSD值。
2.3.5加样回收率实验
向4.3.4方法制备的已知含量的样品液，加入已知含量的丁香酚对照品储备液0.5ml，并通过紫外分光光度计进行含量测定，根据公式回收率(％)＝(实测含量-样品含量)/加入标准品含量×100％。计算回收率和相对RSD值。
3、测定结果
3.1重量差异度测定结果
丁香酚口腔溃疡膜的重量差异度测定结果见表1，结果表明丁香酚口腔溃疡膜每片重量差异度均在±10％之内，符合中国药典(2010年版)有关膜剂的要求。
表1丁香酚口腔溃疡膜重量差异度测定结果
Figure PCTCN2017095141-appb-000005
3.2溶解时间测定结果
丁香酚口腔溃疡膜的溶解时间见表2，结果显示丁香酚口腔溃疡膜的平均贴壁溶解时间为68.2min，搅拌平均溶解时间为139.7s。
表2丁香酚口腔溃疡膜溶解时间测定结果记录表
Figure PCTCN2017095141-appb-000006
香酚口腔溃疡膜的溶解时间实验可发现，丁香酚口腔溃疡膜的贴壁溶解时间为一个小时左右，符合口腔给药的用药需求。而搅拌丁香酚口腔溃疡膜的溶解时间较短，提示丁香酚口腔溃疡膜是使用时患者应该少说话尽量避免咀嚼或吞咽动作，另外该丁香酚口腔溃疡膜不宜口服胃肠道给药。
3.3标准曲线测定结果
丁香酚溶液通过紫外分光光度计测定制作的标准曲线见图1，并计算得出回归方程：A＝0.018C-0.1448，相关系数r＝0.9991，由图可知丁香酚溶液的标准曲线方程在14.76～39.35μg/ml范围内线性关系良好。
3.4精密度实验结果
精密度实验结果见表3，日内RSD分别为：0.04％、0.07％、0.09％(n＝5)，精密度良好。
表3精密度试验结果
Figure PCTCN2017095141-appb-000007
3.5样品溶液稳定性实验测定结果
丁香酚口腔溃疡膜样品溶液稳定性测定结果见表4，结果表明样品溶液的吸光度在8小时内基本不变。
表4丁香酚口腔溃疡膜样品溶液稳定性的测定结果记录表
Figure PCTCN2017095141-appb-000008
Figure PCTCN2017095141-appb-000009
3.6重复性实验与含量测定结果
丁香酚口腔溃疡膜的重复性实验与含量测定结果见表5，结果表明，丁香酚口腔溃疡膜中丁香酚平均含量为98.02mg/g，RSD＝4.4％，重复性良好。
表5重复性测试与含量测定结果
Figure PCTCN2017095141-appb-000010
3.7回收率实验结果
丁香酚口腔溃疡膜的回收率测定结果见表6，结果表明，平均回收率为98.8％，RSD＝0.914％，丁香酚口腔溃疡膜剂回收率良好。
表6回收率实验结果
Figure PCTCN2017095141-appb-000011
由上述实验可知，采用本发明所述制备方法得到的丁香酚口腔溃疡膜表面光滑，厚度、颜色均匀一致，柔软性好。通过膜剂质量评价试验结果表明，制备出的丁香酚口腔溃疡膜在重量差异度评价，模拟口腔溶解时间，膜剂中主药含量、产品稳定性、回收率均较理想。
以下为本发明所述丁香酚口腔溃疡膜初步临床试验
(1)试验对象
以患有口腔溃疡的50名自愿者为观察对象，其中，男性28名，女性22名，年龄在15～45岁之间，病程1～30天。
(2)使用方法
采用温水漱口后再将丁香酚口腔溃疡膜贴于溃疡创面，每天1～3片。
(3)疗效判定
显效：敷贴后疼痛及红肿明显消退或消失，溃疡于2日内愈合，且愈合时间较以往明显缩短；
有效：经治疗后疼痛，红肿反应减轻，但摄入刺激性食物任感不适，溃疡于4日内愈合；
无效：用药后疼痛缓解，5日内溃疡不愈合。
(4)治疗结果
经临床应用50例，显效26例，显效率52％，有效21例，有效率42.0％，无效3例，总有效率94％。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。

Claims (8)

  1. 一种丁香酚口腔溃疡膜，其特征在于，包括以下按重量份计的原料制成：
    Figure PCTCN2017095141-appb-100001
  2. 如权利要求1所述丁香酚口腔溃疡膜，其特征在于，包括以下按重量份计的原料制成：
    Figure PCTCN2017095141-appb-100002
  3. 一种丁香酚口腔溃疡膜的制备方法，其特征在于，包括以下步骤：
    步骤1：按重量份计称取0.2-0.6份丁香酚、0.2-5.5份聚乙烯醇、0.01-3.5份羧甲基纤维素钠、0-1份甘油以及10-100份蒸馏水，待用；
    步骤2：将聚乙烯醇和羧甲基纤维素钠混合并加入蒸馏水浸泡20-30小时使其充分溶胀，得到胶体材料；
    步骤3：将所述胶体材料在85-95℃水浴条件下加热20-40分钟并搅拌混匀，保温静置30分钟；
    步骤4：将甘油和丁香酚加入到保温中的胶体材料中，并缓慢搅拌混匀，静置，得到混合溶液；
    步骤5：将混合溶液铺平在玻璃容器上，水平放置，密封干燥，脱膜，冲切后即得所述丁香酚口腔溃疡膜。
  4. 如权利要求3所述丁香酚口腔溃疡膜的制备方法，其特征在于，所述步 骤3中，静置时胶体材料在30-35℃下保温30分钟。
  5. 如权利要求3所述丁香酚口腔溃疡膜的制备方法，其特征在于，所述步骤5中，铺膜后的玻璃容器放置在烘箱中，在温度为35-45℃条件下进行干燥，干燥时间为2.5-4小时。
  6. 如权利要求3所述丁香酚口腔溃疡膜的制备方法，其特征在于，铺膜后的玻璃容器在室温，风速为5-15m/s的条件下进行干燥，干燥时间为12-18小时。
  7. 如权利要求3所述丁香酚口腔溃疡膜的制备方法，其特征在于，所述丁香酚口腔溃疡膜的厚度为0.5±0.02mm。
  8. 如权利要求3所述丁香酚口腔溃疡膜的制备方法，其特征在于，所述丁香酚口腔溃疡膜冲切成1.5cm×1.5cm的尺寸。
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