WO2024037043A1

WO2024037043A1 - Nicotine-containing film composition for oral mucosa

Info

Publication number: WO2024037043A1
Application number: PCT/CN2023/091557
Authority: WO
Inventors: 孙搴慧; 容辉; 张寒; 沙丽丽
Original assignee: 深圳华宝协同创新技术研究院有限公司
Priority date: 2023-04-28
Filing date: 2023-04-28
Publication date: 2024-02-22

Abstract

The present invention belongs to the technical field of oral film agents, and specifically relates to a nicotine-containing film composition for the oral mucosa. In particular, each nicotine-containing film composition for the oral mucosa comprises: (i) a nicotine salt as an active ingredient; (ii) a film-forming substrate as a film forming agent; (iii) a plasticizer; and (iv) a pharmaceutically acceptable adjuvant. The absorption of nicotine active substances is maximized by means of the oral mucosa without entering the stomach, so that the desire of the user for nicotine is reduced.

Description

Nicotine-containing film composition for oral mucosa

Technical field

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.

Background technique

To successfully quit smoking, 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. However, 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.

Therefore, there is an urgent need to develop a product that ensures that nicotine salt is only absorbed by oral epithelial cells without entering the stomach.

Contents of the invention

In order to achieve the above-mentioned goal of ensuring that nicotine salts are only absorbed by oral epithelial cells without entering the stomach, the present invention provides a nicotine-containing film composition for oral mucosa containing nicotine salts and a nicotine-containing film composition for oral mucosa. A disintegrable oral film with high mucoadhesion for the 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. , will not be accidentally swallowed, and releases nicotine salts from the nicotine-containing film composition for oral mucosa into the oral mucosa, maximizing the absorption of nicotine active substances through the oral mucosa without entering the stomach, thereby alleviating User's craving for nicotine.

In order to achieve the above objects, the present invention provides the following technical solutions:

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.

As a preferred embodiment, the pharmaceutically acceptable auxiliary agents include: coloring agents, flavoring agents, sweeteners, Taste masking agents, emulsifiers, fillers, enhancers, pH adjusters, preservatives and/or antioxidants.

Preferably, 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) of 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) of 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, 9% w/w, 12% w/w, or 15% w/w) of the total weight additives in the range of 0% w/w to about 10% w/w based on the total weight of solute in the film composition (for example, 0% w/w, 4% w/w, 6% w/w or 10% w/w) surfactant.

Preferably, 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) of 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) of 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, 9% w/w, 12% w/w, or 15% w/w) of the total weight additives in the range of 0% w/w to about 10% w/w based on the total weight of solute in the film composition (for example, 0% w/w, 4% w/w, 6% w/w or 10% w/w) of surfactant, an absorption enhancer in the range of 0% w/w to about 1% w/w based on the total weight of solute in the film composition (e.g., 0% w/w, 0.2 % w/w, 0.4% w/w, 0.6% w/w, 0.8% w/w or 1% w/w).

As a preferred embodiment, 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. However, the applicant found through a large number of experiments that 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 . In order to solve the deficiencies of the prior art, 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 One or more of the substances, the film-forming matrix not only has a slow disintegration speed, but also has good adhesion after absorbing water. At the same time, 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.

As a preferred embodiment, the plasticizer is selected from one or more of glycerol, sorbitol, and polyethylene glycol.

As a preferred embodiment, 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.

As a preferred embodiment, the water-soluble flavor is selected from one of strawberry flavor, mint flavor, blueberry flavor, citrus flavor and other flavors.

As a preferred embodiment, the sweetener is selected from one or more of xylose, sucrose, maltose, fructose, glucose, mannitol, sucralose, aspartame and acesulfame potassium.

As a preferred embodiment, the preservative is paraben, which is suitable for use in the alkaline environment of the present invention.

As a preferred embodiment, 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.

As a preferred embodiment, the surfactant is selected from one or more types of polysorbate 80 and soybean lecithin.

As a preferred embodiment, the absorption enhancer is selected from menthol.

As a preferred embodiment, 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.

As a preferred embodiment, 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 .

Preferably, each nicotine-containing film composition for oral mucosa has a thickness of about 0.01 mm to about 1 mm.

As a preferred embodiment, each nicotine-containing film composition for oral mucosa has a weight per unit area of about 0.01 to 2 g/cm ² .

In the prior art, 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. In order to solve the deficiencies of the existing technology, 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. At the same time, the oral mucosa in contact with the film composition is in a local pH value of 6.5 to 9.0. In a weakly alkaline environment, 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.

As a preferred embodiment, the moisture content of 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.

Compared with the prior art, 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. , to maximize the absorption of nicotine active substances through the oral mucosa, so the amount of swallowed nicotine active substances can be minimized, not entering the stomach, avoiding stomach irritation, and improving consumers' physiological satisfaction. In addition, 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. Through formula adjustment, 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.

Description of drawings

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.

Detailed ways

In order to present the technical features and beneficial effects of the present invention more clearly, the technical features and beneficial effects of the present invention will be described in detail with reference to the following embodiments and drawings. Those skilled in the art should understand that the following examples are only used to illustrate the present invention and do not limit the present invention in any way.

The 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.

Unless otherwise defined, technical terms or scientific terms used in the present invention shall have the usual meaning understood by a person with ordinary skill in the field to which the present invention belongs.

All terms (including technical terms or scientific terms) used in this disclosure have the same meanings as understood by one of ordinary skill in the art to which this disclosure belongs, unless otherwise specifically defined. It should also be understood that terms defined in, for example, general dictionaries should be understood to have meanings consistent with their meanings in the context of the relevant technology and should not be interpreted in an idealized or highly formalized sense, unless expressly stated herein. Ground is defined this way.

Techniques, methods and devices known to those of ordinary skill in the relevant art may not be discussed in detail, but where appropriate, such techniques, methods and devices should be considered a part of the specification.

After weighing each component according to Table 1, add the weighed nicotine salt to deionized water, mix for 15-30 minutes, and adjust the pH value to 8-9 by adding sodium carbonate. After obtaining a clear solution, raise the temperature to 45 ℃, add the weighed film-forming matrix into the clear solution and mix for 45-120 minutes to obtain a mixed solution. Add weighed other components into the mixed solution and mix for 15-20 minutes to obtain a mixed casting solution.

Distribute 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. After the film has been at least partially dried, 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 .

Table 1. Formulations of Examples and Comparative Examples (w/w% based on total mass of solute)

I. In vitro disintegration test

According to the disintegration time limit inspection method (Chinese Pharmacopoeia 2010 Edition, Part II, Appendix 25mm, 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. At the same time, take 1 mL artificial saliva solution samples at the 30th second, 10th minute, 30th minute, 1st hour, 4th hour, and 6th hour. After each sampling, the removed artificial saliva volume (1 mL) was replenished with fresh artificial saliva solution. By performing HPLC analysis on the collected samples, the cumulative nicotine release (%) was determined. The test results are shown in Table 2.

Table 2

It can be seen from the data in Table 2:

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.

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 surfactant added in Comparative Example 8 was excessive, and it began to disintegrate within 12 seconds, and most of it disintegrated within the 4th hour. After the 4th hour, the cumulative disintegration amount stabilized at 99.90%, and the sustained release time was also far inferior. Embodiment 2 of the present invention.

It can be seen from the data of Examples 1-15 that by adjusting the formula and adding a film-forming matrix and a plasticizer, 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.

II. Erosion resistance test

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.

Table 3 Erosion resistance time

It can be seen from the data in Table 3 that the erosion resistance time of Comparative Examples 1-8 is much lower than that of Example 1-15, that is, the mucoadhesion ability of Comparative Examples 1-8 is far inferior to that of 1-15 of the present application. 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. Combined with the above analysis of the erosion resistance, it can be seen that 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. .

Although the present invention has been described above in connection with certain illustrative embodiments, it is to be understood that other similar embodiments may be employed, or variations and additions may be made to the described embodiments for carrying out the same functions of the present invention. without departing from the invention. Furthermore, because various embodiments of the invention may be combined to provide desired characteristics, all disclosed embodiments are not necessarily alternatives. Those of ordinary skill in the art can make changes without departing from the spirit and scope of the invention. Therefore, the present invention should not be limited to any single illustrative embodiment, but rather will be construed in breadth and scope in accordance with the recitation of the appended claims.

Claims

A nicotine-containing film composition for oral mucosa, wherein each nicotine-containing film composition for oral mucosa includes:

(i) nicotine salt as active ingredient, (ii) film-forming matrix as film-forming agent, (iii) plasticizer, and (iv) pharmaceutically acceptable auxiliaries.
The film composition of claim 1, wherein each nicotine-containing film composition for oral mucosa comprises:

Nicotine salts in the range of about 5% w/w to about 15% w/w, based on the total weight of solutes in the film composition, and in the range of about 55% w/w to about 15% w/w, based on the total weight of solutes in the film composition. Film-forming matrix in the range of about 80% w/w, based on the total weight of solutes in the film composition Plasticizer in the range of about 10% w/w to about 30% w/w, based on the film composition A pharmaceutically acceptable auxiliary agent in the range of from about 5% w/w to about 15% w/w based on the total weight of solutes in the film composition and in the range of from 0% w/w to about Surfactants in the 10% w/w range.
The film composition of claim 1, wherein each nicotine-containing film composition for oral mucosa contains: from about 5% w/w to about 15% based on the total weight of solutes in the film composition. Nicotine salt in the range of w/w, film-forming matrix in the range of about 55% w/w to about 80% w/w, based on the total weight of solute in the film composition Plasticizer in the range of about 10% w/w to about 30% w/w by weight, based on the total weight of solutes in the film composition in the range of about 5% w/w to about 15% w/w A pharmaceutically acceptable adjuvant in the range of 0% w/w to about 10% w/w of a surfactant, based on the total weight of solutes in the film composition of absorption enhancers in the range of 0% w/w to about 1% w/w.
The film composition according to any one of claims 1 to 3, wherein the nicotine salt is selected from one of tartaric acid-nicotine salt, citric acid-nicotine salt, benzoic acid-nicotine salt, and resin acid-nicotine salt. Kind or variety.
The film composition according to any one of claims 1 to 3, wherein the film-forming matrix is selected from the group consisting of gelatin, carbomer, guar gum, xanthan gum, pullulan, gum arabic, and alginic acid. One or more of sodium, polyvinyl alcohol, pectin or blends thereof.
The film composition according to any one of claims 1 to 3, wherein the plasticizer is selected from one or more of glycerol, sorbitol, and polyethylene glycol.
The film composition according to any one of claims 1 to 3, wherein the pharmaceutically acceptable auxiliary agent is selected from the group consisting of (a) water-soluble flavors, (b) sweeteners, (c) preservatives, (d) One or more of color additives and (e) fillers;

The water-soluble flavor is selected from strawberry flavor, mint flavor, blueberry flavor, citrus flavor and other flavors. A sort of;

The sweetener is selected from one or more types of xylose, sucrose, maltose, fructose, glucose, mannitol, sucralose, aspartame and acesulfame potassium;

The preservative is paraben;

The filler is selected from one or more types of acetate starch and starch.
The film composition according to any one of claims 2 to 3, wherein the surfactant is selected from one or more of polysorbate 80 and soybean lecithin.
The film composition of claim 3, wherein the absorption enhancer is selected from menthol.
The film composition of any one of claims 2 to 3, wherein the weight ratio of the plasticizer to the film-forming matrix ranges from about 1:3 to about 1:6.
The film composition according to any one of claims 1 to 3, wherein each nicotine-containing film composition for oral mucosa has a surface area of about 0.5 cm 2 to about 15 cm 2 .
The film composition according to any one of claims 1 to 3, wherein each nicotine-containing film composition for oral mucosa has a weight per unit area of about 0.01 to 2 g/cm 2 .
The film composition according to any one of claims 1 to 3, wherein each nicotine-containing film composition for oral mucosa has a thickness of about 0.01 mm to about 1 mm.
The film composition according to any one of claims 1 to 3, wherein the moisture content of the casting liquid before forming each nicotine-containing film composition for oral mucosa is 20 to 95%. The moisture content is 8~20%; and/or

The pH value of the casting solution before film formation is 6.5 to 9.0, which is adjusted with sodium bicarbonate, sodium bicarbonate and citric acid.
The film composition according to any one of claims 1 to 3, wherein the film composition is a disintegrable oral film having high mucoadhesion to oral mucosa.
The film composition according to any one of claims 1 to 3, wherein the film composition is applied to the oral cavity and adheres between the upper lip and upper gums of the oral cavity.