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WO2024037043A1 - 用于口腔粘膜的包含尼古丁的薄膜组合物 - Google Patents

用于口腔粘膜的包含尼古丁的薄膜组合物 Download PDF

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Publication number
WO2024037043A1
WO2024037043A1 PCT/CN2023/091557 CN2023091557W WO2024037043A1 WO 2024037043 A1 WO2024037043 A1 WO 2024037043A1 CN 2023091557 W CN2023091557 W CN 2023091557W WO 2024037043 A1 WO2024037043 A1 WO 2024037043A1
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Prior art keywords
film composition
nicotine
film
oral mucosa
range
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English (en)
French (fr)
Inventor
孙搴慧
容辉
张寒
沙丽丽
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Shenzhen Huabao Collaborative Innovation Technology Research Institute CoLtd
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Shenzhen Huabao Collaborative Innovation Technology Research Institute CoLtd
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Priority to PCT/CN2023/091557 priority Critical patent/WO2024037043A1/zh
Publication of WO2024037043A1 publication Critical patent/WO2024037043A1/zh
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/465—Nicotine; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—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
    • A61K47/32—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
    • 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
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse

Definitions

  • the invention belongs to the technical field of oral films, and specifically relates to a nicotine-containing film composition for oral mucosa, which maximizes the absorption of nicotine active substances through the oral mucosa without entering the stomach, thereby reducing the user's exposure to nicotine. desire.
  • nicotine-addicted tobacco users must overcome their cravings for nicotine, thereby reducing the need to use tobacco products.
  • Certain nicotine replacement therapies have been developed to help habitual tobacco users quit smoking. These nicotine replacement therapies attempt to temporarily replace some of the nicotine in the blood of habitual users who quit smoking when they quit smoking.
  • Nicotine replacement therapies have been developed and are available in a variety of product forms. Such nicotine replacement products include, for example, nicotine-containing lozenges and nicotine-containing lollipops.
  • Such nicotine replacement products include, for example, nicotine-containing lozenges and nicotine-containing lollipops.
  • the above dosage forms have an obvious foreign body sensation in the mouth and are easy to swallow. Nicotine will react when mixed with gastric acid, irritating the stomach and causing vomiting and stomach cramps. The nicotine entering the stomach will be affected by gastric acid. After destruction, it will not be able to bring physiological satisfaction to consumers.
  • the present invention provides a nicotine-containing film composition for oral mucosa containing nicotine salts and a nicotine-containing film composition for oral mucosa.
  • the nicotine-containing film composition for the oral mucosa is placed on the oral mucosa, such as under the tongue or between the upper lip and upper gums of the oral cavity, without foreign body sensation and does not hinder speech.
  • a first technical solution is a nicotine-containing film composition for oral mucosa, wherein each nicotine-containing film composition for oral mucosa contains: (i) nicotine salt as an active ingredient, (ii) A film-forming matrix of a film-forming agent, (iii) a plasticizer, and (iv) a pharmaceutically acceptable auxiliary agent.
  • the pharmaceutically acceptable auxiliary agents include: coloring agents, flavoring agents, sweeteners, Taste masking agents, emulsifiers, fillers, enhancers, pH adjusters, preservatives and/or antioxidants.
  • each nicotine-containing film composition for oral mucosa contains: in the range of about 5% w/w to about 15% w/w (e.g., 5% w/w, 9% w/w, 12% w/w or 15% w/w) nicotine salt, from about 55% w/w to about 80% w/ based on the total weight of solute in the film composition
  • a film-forming matrix within a w range e.g., 55% w/w, 60% w/w, 70% w/w, or 80% w/w
  • about 10% w based on the total weight of solutes in the film composition /w to about 30% w/w e.g., 10% w/w, 15% w/w, 20% w/w, or 30% w/w
  • a plasticizer based on the solute in the film composition
  • Pharmaceutically acceptable in the range of about 5% w/w to about 15% w/w e.g., 5% w/w,
  • each nicotine-containing film composition for oral mucosa contains: in the range of about 5% w/w to about 15% w/w (e.g., 5% w/w, 9% w/w, 12% w/w or 15% w/w) nicotine salt, from about 55% w/w to about 80% w/ based on the total weight of solute in the film composition
  • a film-forming matrix within a w range e.g., 55% w/w, 60% w/w, 70% w/w, or 80% w/w
  • about 10% w based on the total weight of solutes in the film composition /w to about 30% w/w e.g., 10% w/w, 15% w/w, 20% w/w, or 30% w/w
  • a plasticizer based on the solute in the film composition
  • Pharmaceutically acceptable in the range of about 5% w/w to about 15% w/w e.g., 5% w/w,
  • the nicotine salt is selected from one or more of tartaric acid-nicotine salt, citric acid-nicotine salt, benzoic acid-nicotine salt, and resin acid-nicotine salt.
  • the prior art usually uses a film-forming agent containing monovalent cations (such as sodium alginate) as a nicotine film agent.
  • a film-forming agent containing monovalent cations such as sodium alginate
  • the alginate film-forming agent is a hydrophilic agent with very strong hydration ability.
  • the water-based gelling agent and excessive flexibility cause the nicotine-containing film composition for oral mucosa containing an alginate film-forming agent to easily shrink, as shown in Figure 1 .
  • the present invention creatively proposes that the film-forming matrix be selected from gelatin, carbomer, guar gum, xanthan gum, pullulan, arabic gum, polyvinyl alcohol, pectin or a blend thereof
  • the film-forming matrix not only has a slow disintegration speed, but also has good adhesion after absorbing water.
  • a nicotine-containing film for oral mucosa containing the film-forming matrix provided by the invention The composition has good stiffness and is not easy to shrink, as shown in Figure 2.
  • the plasticizer is selected from one or more of glycerol, sorbitol, and polyethylene glycol.
  • the pharmaceutically acceptable auxiliary agent is selected from one of (a) water-soluble flavors, (b) sweeteners, (c) preservatives, (d) color additives, and (e) fillers. or more.
  • the water-soluble flavor is selected from one of strawberry flavor, mint flavor, blueberry flavor, citrus flavor and other flavors.
  • the sweetener is selected from one or more of xylose, sucrose, maltose, fructose, glucose, mannitol, sucralose, aspartame and acesulfame potassium.
  • the preservative is paraben, which is suitable for use in the alkaline environment of the present invention.
  • the filler is selected from one or more types of acetate starch and starch.
  • the present invention uses one or more of acetate starch and starch as fillers, which can not only prevent the film composition from adhesion, but also improve the taste of the film composition.
  • the surfactant is selected from one or more types of polysorbate 80 and soybean lecithin.
  • the absorption enhancer is selected from menthol.
  • the weight ratio of the plasticizer to the film-forming matrix ranges from about 1:3 to about 1:6.
  • the nicotine-containing film composition for oral mucosa provided by the present invention is optimized through a large number of screening of plasticizers and thickeners.
  • the ratio of the compound plasticizer to the film-forming matrix can greatly extend its performance in the oral cavity.
  • the release time, disintegration index is stable, and it is not easy to dissolve.
  • the nicotine-containing film composition used on the oral mucosa can be more long-lasting, efficient, and quick-acting, and can achieve low dosage, low side effects, and low toxicity.
  • each nicotine-containing film composition for oral mucosa is an independent single-layer film, and each nicotine-containing film composition for oral mucosa has a surface area of about 0.5 cm 2 to about 15 cm 2 .
  • each nicotine-containing film composition for oral mucosa has a thickness of about 0.01 mm to about 1 mm.
  • each nicotine-containing film composition for oral mucosa has a weight per unit area of about 0.01 to 2 g/cm 2 .
  • the pH value of the preparation liquid of nicotine film is usually set to 9.5-13, but the applicant found that at a pH value of 9.5-13, the acidic nicotine salt state in the nicotine-containing film composition for oral mucosa changes. It is very unstable and easily precipitates nicotine. Nicotine is an unpleasant, bitter, clear oily liquid with strong volatility. It is easily oxidized into a light yellow liquid in the air and under light, and its content and color are extremely unstable. , Nicotine evaporates and is lost as storage time increases.
  • the present invention creatively proposes that the pH value of the casting liquid before film formation is 6.5-9.0, and is adjusted with sodium bicarbonate, sodium bicarbonate and citric acid to improve the nicotine-containing pH value for oral mucosa.
  • the stability of the film composition makes it safer and more convenient to transport, store and use.
  • the oral mucosa in contact with the film composition is in a local pH value of 6.5 to 9.0.
  • nicotine salts Free form of nicotine exists, and free nicotine is more easily swallowed by consumers. It is absorbed by the mucous membrane in the cavity and achieves physiological satisfaction efficiently.
  • each nicotine-containing film composition for oral mucosa before forming is 20 to 95%, and the moisture content after film formation is 8 to 12%.
  • the second technical solution is a disintegrable oral film with high mucoadhesion to the oral mucosa, which contains the aforementioned nicotine-containing film composition for oral mucosa.
  • the third technical solution is a disintegrable oral film applied to the oral cavity and adhered between the upper lip and upper gums of the oral cavity, which contains the aforementioned nicotine-containing film composition for oral mucosa.
  • the present invention has the following beneficial effects:
  • the nicotine-containing film composition for oral mucosa containing nicotine salt of the present invention is applied to the oral cavity and adheres to the mucosal surface, for example, under the tongue or between the upper lip and upper gums of the oral cavity. Since the present invention adopts a film dosage form, no The foreign body sensation does not hinder chewing, swallowing, drinking, speaking, etc. Secondly, since the present invention uses a film-forming matrix with a slow disintegration speed through formula adjustment, the nicotine-containing film composition for oral mucosa has high mucoadhesion to the oral mucosa, preventing the nicotine salts released from it from being swallowed.
  • the nicotine-containing film composition for oral mucosa will slowly release nicotine salt and be absorbed into the blood circulation through oral epithelial cells, rapidly increasing its serum concentration and achieving a certain physiological satisfaction.
  • the present invention prolongs the release time of the nicotine-containing film composition for oral mucosa in the oral cavity, exceeding the 2-hour action time of the general oral mucosa.
  • the disintegration index is stable and difficult to dissolve. It is used in the oral cavity.
  • the mucosal nicotine-containing film composition is more long-lasting, efficient, and quick-acting, and can achieve low dosage, low side effects, and low toxicity.
  • Figure 1 is an appearance view of a nicotine-containing film composition for oral mucosa prepared in Comparative Example 2 of the present application;
  • Figure 2 is an appearance view of the nicotine-containing film composition for oral mucosa prepared in Example 1 of the present application.
  • test methods described in the following examples are all conventional methods unless otherwise stated; the reagents, materials, instruments and equipment, etc., can be obtained from commercial sources unless otherwise stated.
  • the casting liquid on a solid plane to form a wet film with a thickness of, for example, 0.5-5mm, such as 2-5mm, such as 3-5mm, and put the wet film into a hot air box at 50°C to dry until the moisture content is ⁇ 20 % to obtain a nicotine-containing film composition for oral mucosa.
  • the dry or semi-dry film so obtained can be divided, for example by cutting or punching, into suitably sized dosage units containing 2 ⁇ 0.2 mg of nicotine per 1 cm 2 .
  • the beaker contains artificial saliva solution with a temperature of 37 ⁇ 1°C. Adjust the water level so that the screen is 15mm below the liquid surface when the hanging basket rises. Take a sample of the example with a size of 1cm 2 (nicotine per 1cm 2 2 ⁇ 0.2 mg) and the samples of the comparative example were placed in the glass tubes of the above-mentioned hanging baskets, added with baffles, started the disintegration instrument for inspection, and recorded the moment when disintegration began.
  • Comparative Example 1 added less film-forming matrix and a small amount of plasticizer, but failed to form an effective sustained-release film. It began to disintegrate at the 13th second, and the cumulative disintegration amount stabilized at 99.90% after the 4th hour. The sustained-release time Far inferior to Embodiment 2 of the present invention.
  • Comparative Example 2 uses sodium alginate as the film-forming matrix.
  • Alginic acid is usually used as a disintegrant for immediate-release tablets. Although a plasticizer was added, it failed to form an effective sustained-release film and began to disintegrate at the 8th second. Most of it disintegrated within the first hour, and the cumulative disintegration amount stabilized at 99.90% after the 4th hour, and the sustained release time was also far inferior to Example 2 of the present invention.
  • Comparative Example 3 did not add plasticizer, and it began to disintegrate within 10 seconds and was basically completely disintegrated after 1 hour.
  • Comparative Example 4 added excess plasticizer, and most of it disintegrated within the first hour. After the fourth hour, the cumulative disintegration amount stabilized at 99.90%, and the sustained release time was also far inferior to that of Example 2 of the present invention.
  • Comparative Example 5 added a small amount of plasticizer, and it began to disintegrate within 14 seconds, and most of it disintegrated within the first hour. After the fourth hour, the cumulative disintegration amount stabilized at 99.90%, and the sustained release time was also far inferior to that of the present invention.
  • Example 2
  • Comparative Example 6 added less film-forming matrix. It began to disintegrate within 20 seconds, and most of it disintegrated within the first hour. After the fourth hour, the cumulative disintegration amount stabilized at 99.90%, and the sustained release time was also far inferior. Embodiment 2 of the present invention.
  • Comparative Example 7 The filler added in Comparative Example 7 was excessive, and it began to disintegrate within 20 seconds, and most of it disintegrated within the first hour. After the fourth hour, the cumulative disintegration amount stabilized at 99.90%, and the sustained release time was also far less than this. Invention embodiments 2.
  • the film composition containing nicotine for oral mucosa can be slowly released for at least 8 hours, thereby maintaining a stable blood drug concentration, reduced side effects, excellent safety, reduced dosage times, convenient taking, and improved user compliance.
  • the products of each embodiment and each comparative example were tested, and the oral mucosa of pigs was selected to test the mucoadhesive properties of the nicotine-containing film composition for oral mucosa. Take the same area of the nicotine-containing film composition for oral mucosa and apply it on the pig oral mucosa. After leaving it for 2 minutes, rinse the nicotine-containing film composition for oral mucosa with the same flow rate of purified water (5 ml per minute). Film composition, test the peeling time of the film composition containing nicotine for oral mucosa, and record it as the washout resistance time. This test can characterize the adhesion ability of a nicotine-containing film composition for oral mucosa to the mucosa, and the test results are shown in Table 3.
  • the present invention uses nicotine salt as an active ingredient and uses washout resistance time and in vitro disintegration time as comprehensive indicators to formulate a nicotine-containing film composition for oral mucosa.
  • the composition and ratio of the formula were investigated and optimized, and the optimal prescription of nicotine oral film was determined.
  • the nicotine oral film prepared by the invention has a uniform and complete appearance, consistent thickness, stable properties, easy use and carrying, and strong adhesion.
  • the mucoadhesive ability of Examples 1-15 is extremely strong, which allows the mucoadhesive material to stably cover the oral mucosa. Due to the high mucoadhesion and slow The disintegration rate of the nicotine active substance is basically absorbed at the adhesion points in the oral cavity. Because the nicotine active substance is absorbed through the oral mucosa, the amount of swallowed nicotine active substance can be minimized, effectively preventing nicotine from entering the stomach. .

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Abstract

本发明属于口腔膜剂技术领域，具体涉及一种用于口腔粘膜的包含尼古丁的薄膜组合物。其中，每个用于口腔粘膜的包含尼古丁的薄膜组合物包含：(i)作为活性成分的尼古丁盐，(ii)作为膜形成剂的成膜基质，(iii)增塑剂，和(iv)药学上可接受的助剂。使通过口腔粘膜实现对尼古丁活性物质的吸收最大化，而不进入胃部，减轻了用户对尼古丁的渴望。

Description

用于口腔粘膜的包含尼古丁的薄膜组合物 技术领域
本发明属于口腔膜剂技术领域，具体涉及一种用于口腔粘膜的包含尼古丁的薄膜组合物，通过口腔粘膜实现对尼古丁活性物质的吸收最大化，而不进入胃部，从而减轻了用户对尼古丁的渴望。
背景技术
为了成功戒烟，使用尼古丁上瘾的烟草使用者必须克服对尼古丁的渴望，从而减少了使用烟草制品的需求。已经开发出某些尼古丁替代疗法来帮助习惯烟草使用者戒烟。这些尼古丁替代疗法试图临时替代血液中的某些尼古丁，这些习惯性使用者是在习惯性使用者戒烟时退出的。
已经开发出尼古丁替代疗法，并以多种产品形式提供。这样的尼古丁替代产品包括例如含尼古丁的锭剂和含尼古丁的棒棒糖。然而，上述剂型在口腔中的异物感明显，而且容易被吞咽，尼古丁与胃酸混合后会发生反应，对胃部有刺激作用，会引起呕吐和胃部痉挛，进入胃部的烟碱受到胃酸的破坏后，也无法给消费者带来生理满足感。
于是，急需开发出一种产品，保证尼古丁盐只被口腔上皮细胞吸收而不进入胃部。
发明内容
为了实现上述保证尼古丁盐只被口腔上皮细胞吸收而不进入胃部的目标，本发明提供了一种用于口腔粘膜的包含尼古丁盐的用于口腔粘膜的包含尼古丁的薄膜组合物和具有对口腔粘膜的高粘膜粘附性的可崩解口腔膜，该用于口腔粘膜的包含尼古丁的薄膜组合物置于口腔粘膜上，如舌下或口腔上唇和上牙龈之间，无异物感，不妨碍讲话，不会误吞，并从用于口腔粘膜的包含尼古丁的薄膜组合物中释放尼古丁盐到口腔粘膜中，通过口腔粘膜实现对尼古丁活性物质的吸收最大化，而不进入胃部，从而减轻了用户对尼古丁的渴望。
为达到上述目的，本发明提供如下技术方案：
第一技术方案，一种用于口腔粘膜的包含尼古丁的薄膜组合物，其中，每个用于口腔粘膜的包含尼古丁的薄膜组合物包含：(i)作为活性成分的尼古丁盐，(ii)作为膜形成剂的成膜基质，(iii)增塑剂，和(iv)药学上可接受的助剂。
作为优选方案，所述药学上可接受的助剂包含：着色剂、调味剂、甜味剂、 掩味剂、乳化剂、填充剂、增强剂、pH值调节剂、防腐剂和/或抗氧化剂。
作为优选方案，每个用于口腔粘膜的包含尼古丁的薄膜组合物包含：基于所述薄膜组合物中溶质总重量的在约5％w/w至约15％w/w范围内(例如5％w/w、9％w/w、12％w/w或15％w/w)的尼古丁盐，基于所述薄膜组合物中溶质总重量的在约55％w/w至约80％w/w范围内(例如55％w/w、60％w/w、70％w/w或80％w/w)的成膜基质，基于所述薄膜组合物中溶质总重量的在约10％w/w至约30％w/w范围内(例如10％w/w、15％w/w、20％w/w或30％w/w)的增塑剂，基于所述薄膜组合物中溶质总重量的在约5％w/w至约15％w/w范围内(例如5％w/w、9％w/w、12％w/w或15％w/w)的药学上可接受的助剂，基于所述薄膜组合物中溶质总重量的在0％w/w至约10％w/w范围内(例如0％w/w、4％w/w、6％w/w或10％w/w)的表面活性剂。
作为优选方案，每个用于口腔粘膜的包含尼古丁的薄膜组合物包含：基于所述薄膜组合物中溶质总重量的在约5％w/w至约15％w/w范围内(例如5％w/w、9％w/w、12％w/w或15％w/w)的尼古丁盐，基于所述薄膜组合物中溶质总重量的在约55％w/w至约80％w/w范围内(例如55％w/w、60％w/w、70％w/w或80％w/w)的成膜基质，基于所述薄膜组合物中溶质总重量的在约10％w/w至约30％w/w范围内(例如10％w/w、15％w/w、20％w/w或30％w/w)的增塑剂，基于所述薄膜组合物中溶质总重量的在约5％w/w至约15％w/w范围内(例如5％w/w、9％w/w、12％w/w或15％w/w)的药学上可接受的助剂，基于所述薄膜组合物中溶质总重量的在0％w/w至约10％w/w范围内(例如0％w/w、4％w/w、6％w/w或10％w/w)的表面活性剂，基于所述薄膜组合物中溶质总重量的在0％w/w至约1％w/w范围内的吸收促进剂(例如0％w/w、0.2％w/w、0.4％w/w、0.6％w/w、0.8％w/w或1％w/w)。
作为优选方案，所述尼古丁盐选自酒石酸-尼古丁盐、柠檬酸-尼古丁盐、苯甲酸-尼古丁盐、树脂酸-尼古丁盐中的一种或多种。
现有技术通常采用包含一价阳离子的(如海藻酸钠)作为尼古丁膜剂的成膜剂，然而，申请人通过大量的试验发现，藻酸盐成膜剂是一种水合能力非常强的亲水性凝胶剂、柔韧度过高，导致含有藻酸盐成膜剂的用于口腔粘膜的包含尼古丁的薄膜组合物易皱缩，如图1所示。为解决现有技术的缺陷，本发明创造性地提出成膜基质选自明胶、卡波姆、瓜尔胶、黄原胶、普鲁兰多糖、阿拉伯胶、聚乙烯醇、果胶或其共混物中的一种或多种，上述成膜基质不仅崩解速度慢，而且其吸水后拥有良好的粘附性，同时，包含本发明提供的成膜基质的用于口腔粘膜的包含尼古丁的薄膜组合物硬挺性好，不易皱缩，如图2所示。
作为优选方案，所述增塑剂选自甘油、山梨醇、聚乙二醇中的一种或多种。
作为优选方案，所述药学上可接受的助剂选自(a)水溶性香精、(b)甜味剂、(c)防腐剂、(d)颜色添加剂、(e)填充剂中的一种或多种。
作为优选方案，所述水溶性香精选自草莓香精、薄荷香精、蓝莓香精、柑橘香精等口味中的一种。
作为优选方案，所述甜味剂选自木糖、蔗糖、麦芽糖、果糖、葡萄糖、甘露醇、三氯蔗糖、阿斯巴甜和安赛蜜中的一种或多种。
作为优选方案，所述防腐剂选用尼泊金酯，尼泊金酯适用于本发明的偏碱性环境中。
作为优选方案，所述填充剂选自醋酸酯淀粉、淀粉中的一种或多种。本发明采用醋酸酯淀粉、淀粉中的一种或多种作为填充剂，不仅可以起到防止薄膜组合物粘连的效果，还能够提升薄膜组合物的口感。
作为优选方案，所述表面活性剂选自聚山梨酯80、豆磷脂中的一种或多种。
作为优选方案，所述吸收促进剂选自薄荷醇。
作为优选方案，所述增塑剂与所述成膜基质的重量比在约1:3至约1:6的范围内。本发明提供的用于口腔粘膜的包含尼古丁的薄膜组合物通过对增塑剂、增稠剂的大量筛选优化，复配增塑剂与成膜基质的比例可以极大的延长其在口腔中的释放时间，崩解指标稳定，不易溶解，使用于口腔粘膜的包含尼古丁的薄膜组合物更能长效、高效、速效，更能达到剂量低，副作用低、毒性低。
作为优选方案，每个用于口腔粘膜的包含尼古丁的薄膜组合物为独立的单层薄膜，每个用于口腔粘膜的包含尼古丁的薄膜组合物具有约0.5cm2至约15cm2的表面积。
作为优选方案，每个用于口腔粘膜的包含尼古丁的薄膜组合物具有约0.01mm至约1mm的厚度。
作为优选方案，每个用于口腔粘膜的包含尼古丁的薄膜组合物具有约0.01至2g/cm2的单位面积重量。
现有技术通常将尼古丁膜剂的制备液pH值设为9.5-13，但申请人发现，在pH值9.5-13下，用于口腔粘膜的包含尼古丁的薄膜组合物中的酸性尼古丁盐状态变得很不稳定，容易析出尼古丁，而尼古丁是一种难闻、味苦、澄清的油质液体，挥发性强，在空气中及光照下极易氧化成淡黄色液体，含量和颜色极不稳定，尼古丁随储存时间增加而挥发损失。为解决现有技术的缺陷，本发明创造性地提出在成膜前的铸膜液pH值为6.5～9.0，用碳酸氢钠、碳酸氢钠和柠檬酸调节，提高用于口腔粘膜的包含尼古丁的薄膜组合物的稳定性，在运输、保存、使用上更为安全便捷，同时，与该薄膜组合物接触的口腔粘膜处于局部的pH值6.5～9.0中，在弱碱性环境中，尼古丁盐以游离形式存在，游离态的尼古丁更容易被消费者口 腔中的粘膜所吸收，高效达到生理满足。
作为优选方案，每个用于口腔粘膜的包含尼古丁的薄膜组合物在成型之前的铸膜液水分含量为20～95％，成膜后的水分含量为8～12％。
第二技术方案，一种具有对口腔粘膜的高粘膜粘附性的可崩解口腔膜，其中，包含前述的用于口腔粘膜的包含尼古丁的薄膜组合物。
第三技术方案，一种应用于口腔并粘附在口腔上唇和上牙龈之间的可崩解口腔膜，其中，包含前述的用于口腔粘膜的包含尼古丁的薄膜组合物。
与现有技术相比，本发明具有以下有益效果：
将本发明包含尼古丁盐的用于口腔粘膜的包含尼古丁的薄膜组合物应用于口腔并粘附在粘膜表面，例如，舌下或口腔上唇和上牙龈之间，由于本发明采用了薄膜剂型，无异物感，不妨碍咀嚼、吞咽、喝水，说话等。其次，由于本发明通过配方调整，采用崩解速度慢的成膜基质，用于口腔粘膜的包含尼古丁的薄膜组合物具有对口腔粘膜的高粘膜粘附性，防止其释放出的尼古丁盐被吞咽，使通过口腔粘膜实现对尼古丁活性物质的吸收最大化，所以吞咽的尼古丁活性物质的量可以减至最少，不进入胃部，避免对胃部的刺激作用，并提高消费者的生理满足感。此外，用于口腔粘膜的包含尼古丁的薄膜组合物会缓慢释放尼古丁盐，及经口腔上皮细胞吸收进入血液循环，快速增加其血清浓度，达到一定的生理满足感。本发明通过配方调整，延长了用于口腔粘膜的包含尼古丁的薄膜组合物在口腔中的释放时间，超过了一般口腔粘附膜2小时的作用时间，崩解指标稳定，不易溶解，使用于口腔粘膜的包含尼古丁的薄膜组合物更能长效、高效、速效，更能达到剂量低，副作用低、毒性低。
附图说明
图1是本申请对比例2制得的用于口腔粘膜的包含尼古丁的薄膜组合物的外观图；
图2是本申请实施例1制得的用于口腔粘膜的包含尼古丁的薄膜组合物的外观图。
具体实施方式
为了更加清楚地呈现本发明的技术特点及有益效果，将结合下述实施例及附图具体阐述。本领域技术人员应理解，下述实施例仅用于说明本发明，而不以任何方式限制本发明。
下述实施例中所述试验方法，如无特殊说明，均为常规方法；所述试剂、材料、仪器和设备等，如无特殊说明，均可从商业途径获得。
除非另外定义，本发明使用的技术术语或者科学术语应当为本发明所属领域内具有一般技能的人士所理解的通常意义。
本公开使用的所有术语(包括技术术语或者科学术语)与本公开所属领域的普通技术人员理解的含义相同，除非另外特别定义。还应当理解，在诸如通用词典中定义的术语应当被理解为具有与它们在相关技术的上下文中的含义相一致的含义，而不应用理想化或极度形式化的意义来解释，除非本文有明确地这样定义。
对于相关领域普通技术人员已知的技术、方法和设备可能不作为详细讨论，但在适当情况下，所述技术、方法和设备应当被视为说明书的一部分。
<实施例和对比例的制备>
按表1称取各组分后，将称量的尼古丁盐加入去离子水中，混合15-30分钟，并且通过加入碳酸钠将pH值调节到8-9，得到澄清溶液后升高温度至45℃，将称量的成膜基质加入该澄清溶液中并混合45-120分钟，得到混合溶液。将称量的其它组分加入到该混合溶液中并混合15-20分钟，得到混合铸膜液。
将该铸膜液分布于固体平面上作为具有例如0.5-5mm，又例如2-5mm，例如3-5mm的厚度的湿薄膜，将湿薄膜放入50℃的热风箱中干燥至含水量≤20％，得到用于口腔粘膜的包含尼古丁的薄膜组合物。在薄膜至少部分干燥后，可将如此得到的干薄膜或半干薄膜通过例如切割或冲压分成合适大小的剂量单位，其中每1cm2含尼古丁2±0.2mg。
表1.实施例和对比例的配方(基于溶质总质量的w/w％)



<实施例和对比例的体外测试>
I.体外崩解实验
按照崩解时限检查法(中国药典2010年版二部附录XA)，将吊篮通过上端的不锈钢轴悬挂于金属支架上，浸入1000ml烧杯中，并调节吊篮位置使其下降时筛网距离烧杯底部25mm，烧杯内盛有温度为37±1℃的人工唾液溶液，调节水位高度使吊篮上升时筛网在液面下15mm处，取大小为1cm2的实施例的样品(每1cm2含尼古丁2±0.2mg)和对比例的样品，分别置于上述吊篮的玻璃管中，加挡板，启动崩解仪进行检查，记录开始崩解的时刻。同时在第30秒、第10分钟、第30分钟、第1小时、第4小时、第6小时取1mL人工唾液溶液样品。在每次取样后，用新鲜人工唾液溶液补充取出的人工唾液体积(1mL)。通过对所采集的样品进行HPLC分析，测定尼古丁累计释放(％)，测试结果如表2所示。
表2

由表2数据可看出：
对比例1加入较少成膜基质和少量增塑剂，未能形成有效的缓释薄膜，在第13秒开始崩解，且在第4小时后累计崩解量稳定在99.90％，缓释时间远不如本发明实施例2。
对比例2采用海藻酸钠作为成膜基质，海藻酸通常用作速释片的崩解剂，虽然加入了增塑剂，但未能形成有效的缓释薄膜，在第8秒开始崩解，在第1小时内大部分崩解，在第4小时后累计崩解量稳定在99.90％，缓释时间也远不如本发明实施例2。
对比例3未添加增塑剂，其在10秒内开始崩解，在1小时后基本崩解完全。
对比例4添加过量增塑剂，在第1小时内大部分崩解，在第4小时后累计崩解量稳定在99.90％，缓释时间也远不如本发明实施例2。
对比例5添加少量增塑剂，其在14秒内开始崩解，在第1小时内大部分崩解，在第4小时后累计崩解量稳定在99.90％，缓释时间也远不如本发明实施例2。
对比例6添加的成膜基质较少，其在20秒内开始崩解，在第1小时内大部分崩解，在第4小时后累计崩解量稳定在99.90％，缓释时间也远不如本发明实施例2。
对比例7添加的填充剂过量，其在20秒内开始崩解，在第1小时内绝大部分崩解，在第4小时后累计崩解量稳定在99.90％，缓释时间也远不如本发明实施例 2。
对比例8添加的表面活性剂过量，其在12秒内开始崩解，在第4小时内绝大部分崩解，在第4小时后累计崩解量稳定在99.90％，缓释时间也远不如本发明实施例2。
从实施例1-15的数据可以看出，本申请通过配方调整，加入成膜基质以及增塑剂，使得用于口腔粘膜的包含尼古丁的薄膜组合物可至少缓慢释放8小时，从而保持平稳的血药浓度，降低副作用，具有优良的安全性，减少服用次数，服用方便，提高了用户顺应性。
II.耐冲刷实验
取各实施例和各对比例的产物进行测试，选取猪口腔黏膜测试用于口腔粘膜的包含尼古丁的薄膜组合物的黏膜粘附性能。取相同面积的用于口腔粘膜的包含尼古丁的薄膜组合物贴敷在猪口腔黏膜上，静置2分钟后，用相同流速的纯净水(每分钟5毫升)冲刷用于口腔粘膜的包含尼古丁的薄膜组合物，测试用于口腔粘膜的包含尼古丁的薄膜组合物剥落的时间，记为耐冲刷时间。该测试可以表征用于口腔粘膜的包含尼古丁的薄膜组合物对黏膜的粘附能力，测试结果如表3所示。
表3耐冲刷时间
由表3数据可知，对比例1-8耐冲刷时间均远低于实施例1-15，即对比例1-8的黏膜粘附能力远不如本申请1-15。本发明以尼古丁盐为活性成分，以耐冲刷时间、体外崩解时间为综合指标，对用于口腔粘膜的包含尼古丁的薄膜组合物的配 方组成和配比进行了考察和优化，确定了尼古丁口腔膜剂的最佳处方。本发明制得的尼古丁口腔膜剂外观均匀完整，厚度一致，性质稳定，使用及携带方便，黏附力强。结合上文耐冲刷性能的分析可得，实施例1-15的黏膜粘附能力极强，这就使得该黏膜粘附材料可以稳定地覆盖在口腔粘膜上，由于高的粘膜粘附性和缓慢的崩解速率，尼古丁活性物质基本上在口腔内的粘附点被吸收，因为尼古丁活性物质是通过口腔粘膜吸收的，所以吞咽的尼古丁活性物质的量可以减至最少，有效避免尼古丁进入胃部。
虽然在上文已经结合某些说明性实施方案对本发明进行了描述，但是应当理解，可以采用其它类似实施方案，或者可以对所述实施方案进行变通和添加以用于实施本发明的相同功能而不偏离本发明。此外，因为可以将本发明的各种实施方案进行组合以提供所需特性，所以所有所公开的实施方案不一定是二选一的。本领域普通技术人员可以在不脱离本发明宗旨和范围的情况下进行变化。因此，本发明不应当限于任何单个说明性实施方案，而是在宽度和范围上都应根据所附权利要求书的叙述来进行解释。

Claims (16)

  1. 一种用于口腔粘膜的包含尼古丁的薄膜组合物，其中，每个用于口腔粘膜的包含尼古丁的薄膜组合物包含：
    (i)作为活性成分的尼古丁盐，(ii)作为膜形成剂的成膜基质，(iii)增塑剂，和(iv)药学上可接受的助剂。
  2. 根据权利要求1所述的薄膜组合物，其中，每个用于口腔粘膜的包含尼古丁的薄膜组合物包含：
    基于所述薄膜组合物中溶质总重量的在约5％w/w至约15％w/w范围内的尼古丁盐，基于所述薄膜组合物中溶质总重量的在约55％w/w至约80％w/w范围内的成膜基质，基于所述薄膜组合物中溶质总重量的在约10％w/w至约30％w/w范围内的增塑剂，基于所述薄膜组合物中溶质总重量的在约5％w/w至约15％w/w范围内的药学上可接受的助剂，基于所述薄膜组合物中溶质总重量的在0％w/w至约10％w/w范围内的表面活性剂。
  3. 根据权利要求1所述的薄膜组合物，其中，每个用于口腔粘膜的包含尼古丁的薄膜组合物包含：基于所述薄膜组合物中溶质总重量的在约5％w/w至约15％w/w范围内的尼古丁盐，基于所述薄膜组合物中溶质总重量的在约55％w/w至约80％w/w范围内的成膜基质，基于所述薄膜组合物中溶质总重量的在约10％w/w至约30％w/w范围内的增塑剂，基于所述薄膜组合物中溶质总重量的在约5％w/w至约15％w/w范围内的药学上可接受的助剂，基于所述薄膜组合物中溶质总重量的在0％w/w至约10％w/w范围内的表面活性剂，基于所述薄膜组合物中溶质总重量的在0％w/w至约1％w/w范围内的吸收促进剂。
  4. 根据权利要求1至3中任一项所述的薄膜组合物，其中，所述尼古丁盐选自酒石酸-尼古丁盐、柠檬酸-尼古丁盐、苯甲酸-尼古丁盐、树脂酸-尼古丁盐中的一种或多种。
  5. 根据权利要求1至3中任一项所述的薄膜组合物，其中，所述成膜基质选自明胶、卡波姆、瓜尔胶、黄原胶、普鲁兰多糖、阿拉伯胶、海藻酸钠、聚乙烯醇、果胶或其共混物中的一种或多种。
  6. 根据权利要求1至3中任一项所述的薄膜组合物，其中，所述增塑剂选自甘油、山梨醇、聚乙二醇中的一种或多种。
  7. 根据权利要求1至3中任一项所述的薄膜组合物，其中，所述药学上可接受的助剂选自(a)水溶性香精、(b)甜味剂、(c)防腐剂、(d)颜色添加剂、(e)填充剂中的一种或多种；
    所述水溶性香精选自草莓香精、薄荷香精、蓝莓香精、柑橘香精等口味中的 一种；
    所述甜味剂选自木糖、蔗糖、麦芽糖、果糖、葡萄糖、甘露醇、三氯蔗糖、阿斯巴甜和安赛蜜中的一种或多种；
    所述防腐剂选用尼泊金酯；
    所述填充剂选自醋酸酯淀粉、淀粉中的一种或多种。
  8. 根据权利要求2至3中任一项所述的薄膜组合物，其中，所述表面活性剂选自聚山梨酯80、豆磷脂中的一种或多种。
  9. 根据权利要求3所述的薄膜组合物，其中，所述吸收促进剂选自薄荷醇。
  10. 根据权利要求2至3中任一项所述的薄膜组合物，其中，所述增塑剂与所述成膜基质的重量比在约1:3至约1:6的范围内。
  11. 根据权利要求1至3中任一项所述的薄膜组合物，其中，每个用于口腔粘膜的包含尼古丁的薄膜组合物具有约0.5cm2至约15cm2的表面积。
  12. 根据权利要求1至3中任一项所述的薄膜组合物，其中，每个用于口腔粘膜的包含尼古丁的薄膜组合物具有约0.01至2g/cm2的单位面积重量。
  13. 根据权利要求1至3中任一项所述的薄膜组合物，其中，每个用于口腔粘膜的包含尼古丁的薄膜组合物具有约0.01mm至约1mm的厚度。
  14. 根据权利要求1至3中任一项所述的薄膜组合物，其中，每个用于口腔粘膜的包含尼古丁的薄膜组合物在成型之前的铸膜液水分含量为20～95％，成膜后的水分为8～20％；和/或
    成膜前的铸膜液pH值为6.5～9.0，用碳酸氢钠、碳酸氢钠和柠檬酸调节。
  15. 根据权利要求1至3中任一项所述的薄膜组合物，其中，所述薄膜组合物为具有对口腔粘膜的高粘膜粘附性的可崩解口腔膜。
  16. 根据权利要求1至3中任一项所述的薄膜组合物，其中，所述薄膜组合物应用于口腔并粘附在口腔上唇和上牙龈之间。
PCT/CN2023/091557 2023-04-28 2023-04-28 用于口腔粘膜的包含尼古丁的薄膜组合物 Pending WO2024037043A1 (zh)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060198873A1 (en) * 2003-07-24 2006-09-07 Chan Shing Y Orally dissolving films
CN101384249A (zh) * 2006-02-17 2009-03-11 诺瓦提斯公司 可崩解口腔膜剂
US20090095313A1 (en) * 2007-10-11 2009-04-16 Fuisz Richard C Smokeless Tobacco Product, Smokeless Tobacco Product in the Form of a Sheet, Extrudable Tobacco Composition, Method for Manufacturing a Smokeless Tobacco Product, Method for Delivering Super Bioavailable Nicotine Contained in Tobacco to a User, and Packaged Smokeless Tobacco Product Sheet
CN101795710A (zh) * 2007-05-16 2010-08-04 麦克内尔股份公司 用氨基酸缓冲的口服尼古丁制剂
US20110200670A1 (en) * 2010-02-18 2011-08-18 Jatin Thakkar Nicotine Containing Soft Gelatin Pastilles
US20150096572A1 (en) * 2012-03-27 2015-04-09 Nicoccino Ab Nicotine formulation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060198873A1 (en) * 2003-07-24 2006-09-07 Chan Shing Y Orally dissolving films
CN101384249A (zh) * 2006-02-17 2009-03-11 诺瓦提斯公司 可崩解口腔膜剂
CN101795710A (zh) * 2007-05-16 2010-08-04 麦克内尔股份公司 用氨基酸缓冲的口服尼古丁制剂
US20090095313A1 (en) * 2007-10-11 2009-04-16 Fuisz Richard C Smokeless Tobacco Product, Smokeless Tobacco Product in the Form of a Sheet, Extrudable Tobacco Composition, Method for Manufacturing a Smokeless Tobacco Product, Method for Delivering Super Bioavailable Nicotine Contained in Tobacco to a User, and Packaged Smokeless Tobacco Product Sheet
US20110200670A1 (en) * 2010-02-18 2011-08-18 Jatin Thakkar Nicotine Containing Soft Gelatin Pastilles
US20150096572A1 (en) * 2012-03-27 2015-04-09 Nicoccino Ab Nicotine formulation

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