HK1066474B - Nicotine-containing film preparation - Google Patents

Description

Nicotine-containing film preparation

Technical Field

The present invention relates to a nicotine-containing film preparation for application to the oral mucosa, which is used as an aid for smoking cessation or smoking continence, and more particularly to a film preparation having a three-layer structure comprising a nicotine-containing drug layer and coating layers provided on both surfaces thereof capable of adhering to the oral mucosa.

Background

As far as formulations involving the administration of nicotine via the oral mucosa are concerned, several formulations are known. For example, tablets for oral or sublingual administration (for example, refer to patent documents 1 and 2), troches (lozenes) (for example, refer to patent documents 3 and 4), hydrocarbon powder bases (for example, refer to patent document 5), troches (troches) (for example, refer to patent document 6: particularly troches in the form of tablets), capsules (for example, refer to patent document 7), saliva dissolving type preparations including patches described in the claims, but any specific patch examples (for example, refer to patent documents 8 and 9), and patches for oral mucosa (for example, refer to patent documents 10, 11, 12, and 13) are not disclosed.

Prior Art

[ patent document 1]

International patent unexamined publication No. 6-502622 (pages 1 and 2)

[ patent document 2]

International patent unexamined publication No. 5-504949 (pages 1 and 2)

[ patent document 3]

International patent unexamined publication No. 9-505553 (pages 1 and 2)

[ patent document 4]

Japanese patent unexamined publication No. 9-286729 (pages 1 and 2)

[ patent document 5]

Japanese patent unexamined publication No. 9-286729 (pages 1 and 2)

[ patent document 6]

International patent unexamined publication No. 2000-504028 (pages 1 and 2)

[ patent document 7]

Japanese patent No. 2602043 (pages 1 and 2)

[ patent document 8]

Japanese patent No. 2958663 (pages 1 and 2)

[ patent document 9]

Japanese patent unexamined publication No. 11-315023 (pages 1 and 2)

[ patent document 10]

Japanese patent unexamined publication No. 3-209626 (pages 1 and 2)

[ patent document 11]

Japanese patent unexamined publication No. 3-209627 (pages 1 and 2)

[ patent document 12]

Japanese patent unexamined publication No. 62-178513 (pages 1 and 2)

[ patent document 13]

Japanese patent unexamined publication No. 63-227522 (pages 1 and 2)

Although careful consideration has been given to conventional nicotine formulations for administration via the oral mucosa, many users perceive certain problems. Moreover, the preparation is easily bitten or swallowed, or its structure is complicated. Therefore, a complicated production method is a problem. In addition, these preparations have drawbacks such as insufficient sustained-release ability, poor reproducibility, or difficulty in controlled release.

When nicotine is absorbed through the oral mucosa, the dissolution time of the film preparation is not particularly limited. However, when it is dissolved too early, the active ingredient is difficult to stay in the oral cavity to cause insufficient absorption. Even if it is acknowledged that the abnormal feeling is alleviated, sticking to the palate for longer than necessary causes a problem that the taste of nicotine itself or the like causes an unpleasant disturbing effect in the case of a diet.

The present invention provides a nicotine film preparation which is easily adhered to mucous membranes, has suitable nicotine sustained-release characteristics and good reproducibility, is rich in flexibility and elasticity, and has no abnormal feeling upon application.

DISCLOSURE OF THE INVENTION

In order to solve the above-mentioned problems, that is, in order to provide a nicotine-containing thin film preparation having a suitable sustained release property and no abnormal feeling upon administration, the present inventors have conducted intensive studies and as a result, found that a thin film preparation having a suitable sustained release property, no abnormal feeling upon administration, and being easily adhered to a mucous membrane can be obtained by combining a coating layer having a prescribed peel strength and solubility with a nicotine-containing layer having a prescribed peel strength and solubility different from those of the coating layer to give a definite thickness, thereby completing the present invention.

That is, the present invention relates to (1) a film formulation of a three-layer structure, comprising: a nicotine-containing layer comprising nicotine and an edible water-soluble polymer, which is applied to Bakelite^TMA 180 degree peel strength of 1g to 30g/20mm when on board, a solubility in water of 3 minutes to 10 minutes; and two coating layers laminated on both sides of the nicotine-containing layer, respectively, the coating layers comprising a water-soluble and non-water-absorbing polysaccharide and/or edible polymer and a softening agent, and the coating layers having 180-degree peel strength of 100g to 500g/20mm, respectively, when applied on a Bakelite plate, and solubility in water of 0.5 to 3 minutes; (2) the film formulation described in (1), wherein a 0.1% aqueous solution of the formulation has a pH of 3 to 9; (3) the film formulation described in (1), wherein the nicotine content in one formulation unit is 0.1mg to 5 mg; (4) the film preparation described in (1), wherein the time required for dissolving one unit of the preparation is 10 to 30 minutes; (5) the film formulation described in (1), wherein the film formulation has a film strength of 2kg to 5kg/20 mm; (6) the thin film formulation described in (1), wherein the thickness of the nicotine-containing layer is 250 μm to 500 μm, the thickness of the coating layer is 5 μm to 30 μm, and the thickness of all three layers is 260 μm to 560 μm; (7) the film formulation described in (1), wherein the coating layer contains a sucrose fatty acid ester; (8) the film formulation described in (1), wherein the nicotine-containing layer comprises polyethylene glycol; (9) the film formulation described in (1), wherein the water-soluble and non-water-absorbing polysaccharide is at least one of the following: water soluble starch, pullulan ether (methyl ether, ethyl ether or propyl ether)Ether) and pullulan ester (acetate or butyrate), the softener being at least one of the following: glycerol, ethylene glycol, propylene glycol, D-sorbitol, maltitol, mannitol and xylitol, the edible water-soluble polymer being at least one of: hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl ethylcellulose (HPEC), Methylcellulose (MC), hydroxyethyl cellulose (HEC), sodium carboxymethylcellulose (CMC Na), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), carboxyvinyl polymer, sodium alginate and sodium acrylate, and the edible polymer is at least one of the following: hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl ethylcellulose (HPEC), Methylcellulose (MC), hydroxyethyl cellulose (HEC), sodium carboxymethylcellulose (CMC Na), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), carboxyvinyl polymer, sodium alginate, sodium acrylate, shellac, Cellulose Acetate Phthalate (CAP), polyvinyl acetate, Eudragit^TMHydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose phthalate (HPMCP).

Japanese patent unexamined publication No. 3-209626 (patent document 10), Japanese patent unexamined publication No. 3-209627 (patent document 11), Japanese patent unexamined publication No. 62-178513 (patent document 12) and Japanese patent unexamined publication No. 63-227522 (patent document 13) have been described above as documents relating to nicotine-containing patches for oral mucosa.

In all the formulations of these inventions water soluble or water swellable polymers were used and there may be no particular problem in terms of adhesion to the mucosa (in experiments the test was performed by adhering the formulation to the beaker wall, which is therefore different from the actual application). However, the time of application of the formulation is considered to be too long and the initial release of the drug is also considered to be insufficient. The film preparation of the present invention is completely dissolved within 10 to 30 minutes, neither abnormal feeling nor uncomfortable feeling is generated, and nicotine is sufficiently absorbed.

Best Mode for Carrying Out The Invention

The present invention is described in more detail below.

In the present invention, the coating layer contains a water-soluble and non-water-absorbent polysaccharide and/or an edible polymer and a softener. The coating layer is mainly composed of pullulan or the like, and water-soluble and non-water-absorbent polysaccharide, so that it acts to protect the surface of the product. The film formulation of the present invention has a thin layer consisting essentially of pullulan on the upper and lower surfaces. Thus, when pressed into the upper jaw, the coating layer dissolves immediately (0.5-3 minutes) due to the moisture of the upper jaw part, and the nicotine-containing layer comes into contact with and adheres to the upper jaw. Therefore, it does not separate immediately. The nicotine-containing layer then dissolves within 10-30 minutes and releases nicotine, which is absorbed through the mucous membranes.

Although the water-soluble and non-water-absorbing polysaccharide used in the present invention includes water-soluble starch, pullulan ether (methyl ether, ethyl ether, or propyl ether), and pullulan ester (acetate or butyrate), pullulan is suitably used. Although the softener includes glycerin, ethylene glycol, propylene glycol, D-sorbitol, maltitol, mannitol, xylitol, and the like, D-sorbitol is suitably used. There is no particular limitation on the edible aqueous polymers, and examples thereof include hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxypropylethyl cellulose (HPEC), Methyl Cellulose (MC), hydroxyethyl cellulose (HEC), sodium carboxymethylcellulose (CMC Na), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), carboxyvinyl polymer, sodium alginate, and the like, but HPC and PVP (particularly, polyvinylpyrrolidone K-90) are suitably used. Edible polymers include water insoluble polymers such as shellac, Cellulose Acetate Phthalate (CAP) and polyvinyl acetate, and water swellable polymers such as Eudragit, hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose phthalate (HPMCP), as well as the edible water soluble polymers described above. While polyethylene glycols include Macrogol300 and Macrogol400, Macrogol400 is suitable. In the present invention, sweeteners and flavors may be used in addition to the above-mentioned components. Examples of the sweetening agent include saccharin, saccharin sodium, aspartame (aspartame), stevioside (stevia), sugar, fructose, and glucose. As the flavoring agent, various flavoring agents can be used.

The nicotine-containing layer of the present invention comprises nicotine and an edible water-soluble polymer.

The nicotine used in the present invention is desirably nicotine having 99% or more of its content. Low grade nicotine is not suitable for use due to its strong irritating properties. The nicotine content in one preparation unit is 0.1-5 mg. There is no particular limitation on the edible water-soluble polymer, the main adhesive ingredient, and examples thereof include hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxypropylethyl cellulose (HPEC), Methyl Cellulose (MC), hydroxyethyl cellulose (HEC), sodium carboxymethylcellulose (CMC Na), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), carboxyvinyl polymer, sodium alginate, and the like. HPC and PVP (especially polyvinylpyrrolidone K-90) are suitable for use. The mixing ratio of the edible water-soluble polymer is 40-90% of the whole preparation. The mixing ratio of the sweetener is preferably 0.2 to 0.8%, the mixing ratio of the water-soluble and non-water-absorbent polysaccharide is preferably 3 to 6%, the mixing ratio of the softener is preferably 0.5 to 2%, and the mixing ratio of the edible polymer is preferably 3 to 6%. Further, the mixing ratio of polyethylene glycol is preferably 1 to 10%.

In the thin film preparation of the present invention, the coating layer is suitably 5 to 30 μm thick, and the nicotine-containing layer is suitably 250-500 μm thick. A suitable thickness as a whole is 260-560 μm. When the coating layer is too thick, the flexibility of the preparation is lost. Although it is easy to dissolve, it sometimes has difficulty in adhering smoothly to the inside of the oral cavity (palate) due to its thickness. On the contrary, when it is too thin, the thickness of the coating tends to be uneven. In extreme cases, it may result in a portion of the formulation being uncoated. In this case, the protection of the nicotine-containing layer is insufficient. When the nicotine-containing layer is too thick, the time required for dissolution is undesirably prolonged. On the contrary, when it is thin, the duration is shortened, thereby possibly causing the beneficial effect of the formulation not to be sufficiently exerted.

The time required for dissolution is not particularly critical for the formulation of the present invention. However, using a material with the properties and thickness as described above allows the formulation of the invention to dissolve in 10-30 minutes. Faster than 10 minutes will result in insufficient absorption of nicotine through the mucosa, while slower than 30 minutes will result in various defects.

The nicotine-containing layer and the coating layer of the film preparation of the invention are applied to Bakelite^TMThe peel strength on the panel was 3-10 minutes and 0.5-3 minutes, respectively. The peel strength applied to Bakelite boards was determined in the following manner. The nicotine-containing layer patch or the coated patch was spread on a PET film having a thickness of 10 μm to prepare a film having a thickness of 100 μm. The film was cut into a size of 2X 5cm to prepare a test piece. One patch of the test piece was uniformly impregnated with 200. mu.ml of purified water and then attached to a Bakelite plate. A roller weighing 850g was applied to the Bakelite board from above to adhere the facing to the Bakelite board. Then, the periphery of the test piece was clamped with a clamp attached to a weight measuring part of the rheometer, and the bench was lowered at a speed of 20 cm/min. Thus, the peel strength of each patch applied to a Bakelite board (model RT-3020D-CW, manufactured by Leotec Co., for the rheometer) was determined.

The peel strength of the nicotine-containing layer when applied on a Bakelite board is suitably from 1 to 30g/20 mm. There are problems in that less than 1g/20mm leads to insufficient compatibility with the coating layer, and more than 30g/20mm leads to production difficulties, separation from the film substrate when spread, and adhesion to the inside of the mouth (palate) even when tentatively used as a product.

Further, the peel strength of the coating layer when applied on a Bakelite board is suitably 100-500g/20 mm. Less than 100g/20mm leads to difficulty in adhesion to the inside of the mouth (upper jaw), while more than 500g/20mm leads to difficulty in production.

The solubility in water was measured according to the following method.

The nicotine-containing layer and the coating layer were separately prepared in the same manner as described above to form a 100- μm film. It was cut into a size of 1.5X 1.5cm to prepare a test piece. The test piece was taken and tested according to the Japanese pharmacopoeia, general test method, elution test method, second method using 900mL of purified water as a test solution with a sinker at 50 rotations. The completion of dissolution was determined visually, and the time required for dissolution was taken as the solubility. The solubility of the nicotine-containing layer in water is suitably from 3 to 10 minutes. Faster than 3 minutes results in no expected nicotine effect, while slower than 10 minutes may result in abnormal sensations in the mouth. Furthermore, the solubility of the coating layer in water is suitably from 0.5 to 3 minutes. Faster than 0.5 minutes or slower than 3 minutes results in difficulty in adhering to the inside of the mouth (palate).

The pH (0.1% aqueous solution) of the film formulation of the invention is suitably from 3 to 9. One tablet of the present formulation was dissolved in 10ml of purified water and measured. When the pH is lower than 3 or higher than 9, irritation to the mucosa easily occurs.

As mentioned above, the time required to dissolve the film formulation of the present invention is suitably from 10 to 30 minutes.

To determine the time required for dissolution, a piece of the formulation of the invention was adhered to the palate of each healthy volunteer (7 volunteers) and the time required for complete dissolution was determined (sensory evaluation).

The strength of the film preparation of the invention is suitably from 2 to 5kg/20 mm.

The film preparation was cut into a size of 2X 5cm (measurement length: 3cm) to prepare a test piece. The periphery (width 2cm) of the test piece was attached to the weight measuring part of the rheometer, and then the test stand was lowered at a speed of 20 cm/min, thereby breaking the film formulation. The required crushing strength at this time was measured. When the strength is less than 2kg/20mm, the expected time required for dissolution is not obtained. The strength of more than 5kg/20mm results in the possibility of cracking of the film.

Examples

Examples and reference examples are given below, but the present invention should not be construed as being limited to these examples.

Example 1

79.5g of pullulan, 20.0g of D-sorbitol and 0.5g of sucrose fatty acid ester were added to an appropriate amount of purified water, and dissolved by stirring to prepare a coating layer solution. Separately, 2.0g of nicotine, 4.0g of titanium dioxide, 8.0g of Macrogol400, 1.0g of 1-menthol, 0.5g of saccharin sodium, 0.1g of a corrigent and 84.4g of hydroxypropyl cellulose (L) were added to an appropriate amount of ethanol and dissolved by stirring to prepare a nicotine-containing layer solution. Then, the coating layer solution was applied to a polyester release film, and dried to form a film having a thickness of about 10 μm. The nicotine-containing layer solution was applied thereon and dried to prepare a film having a thickness of about 330 μm. Finally, the coating layer solution was applied thereto, and dried to form a film having a thickness of about 10 μm. These layers were laminated to produce a film-like product having a total thickness of about 350 μm. It was die-cut into a circular ring shape having a diameter of 12mm, thereby obtaining a nicotine-containing film preparation.

Hereinafter, examples 2 and 3 and comparative examples 1 and 2 were carried out similarly to example 1. Their results are shown in table 1.

TABLE 1

Layer(s)	Name of raw materials		Example 1	Example 2	Example 3	Comparative example 1	Comparative example 2
								Coating layer	Pullulan PI-20		79.5				22.0
D-sorbitol		20.0				75.0
							Sucrose fatty acid ester		0.5				3.0
Layer containing nicotine	Nicotine		2.0	2.0	2.0	2.0								2.0
							Titanium dioxide		4.0		4.0
	PEG 400		8.0	5.0	5.0	10.0								10.0
							HPC-L		84.4	51.0	82.4	38.0	38.0
	PVP K90			40.0
							PVP K30					50.0	50.0
	1-menthol		1.0		1.0
							Saccharin sodium salt		0.5		0.5
	Citric acid			2.0	5.0
							Flavouring agent		0.1		0.1
	Requirement 1	Layer containing nicotine	Peel strength (g/20mm)	5.6	5.0	5.3								35.0	35.0
Solubility (minutes)							5.0	3.8	5.0	2.8	2.8
			Coating layer	Peel strength (g/20mm)	296.7							85.0
Solubility (minutes)		1.5							0.4
						Requirement 2	PH			8.85	6.80	3.56	9.20	9.20
Requirement 3	Nicotine content (mg)		1.0
								Requirement 4	Time required for dissolution (minutes)		21.0	8.0	20.9	9.0	8.0
Requirement 5	Strength (kg/20mm)		2.8	2.6	3.0	1.8	1.7
								Requirement 6	Layer containing nicotine (mum)		350	370	350	390	380
Coating layer (mum)		10

Comparative example 1

The solubility of the nicotine-containing layer is high (2.8 minutes) so that the time required for dissolution is faster than the appropriate time (9.0 minutes), as a result of which problems arise in terms of sustained release. The pH is high, and as a result, irritation to the mucosa occurs. The peel strength is so high that its production is difficult. For example, when applied to a PET film, it is difficult to separate it from the PET film.

Comparative example 2

The peel strength of the coating layer is low, so that its adhesive force is low. Thus, adhesion to the upper jaw becomes difficult. Otherwise similar to comparative example 1.

Effects of the invention

The nicotine film preparation of the present invention has low solubility, has sustained release characteristics, and the peel strength of the nicotine-containing layer and the coating layer is moderate, so that it is easily adhered to the mucous membrane. In addition, the nicotine film preparation of the present invention has a pH of 3 to 9, has no irritation to mucous membranes, is rich in flexibility and elasticity, and has no abnormal feeling upon application.

Industrial applicability

The nicotine film preparation of the present invention is easy to adhere to mucous membranes, has suitable nicotine sustained release characteristics and good reproducibility, is rich in flexibility and elasticity, and has no abnormal feeling upon application. Therefore, the preparation of the present invention can be used as a nicotine-containing film preparation applied to the oral mucosa, and can be used as an aid for quitting or controlling smoking.

Claims (7)

1. A film formulation for oral mucosa of a three-layer structure, the film formulation comprising: a nicotine-containing layer film comprising nicotine and an edible water-soluble polymer, which has a 180 degree peel strength of 1g to 30g/20mm when applied on a Bakelite board, a solubility in water of 3 minutes to 10 minutes, and two coating layer films laminated on both sides of the nicotine-containing layer film, respectively, wherein the edible water-soluble polymer is at least one of the following: hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl ethylcellulose (HPEC), Methylcellulose (MC), hydroxyethyl cellulose (HEC), sodium carboxymethylcellulose (CMC Na), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), carboxyvinyl polymer, sodium alginate and sodium acrylate, the coating film comprises a water-soluble and non-water-absorbing polysaccharide and/or edible polymer and a softening agent, the water-soluble and non-water-absorbing polysaccharide being at least one of the following: water-soluble starch, pullulan ether and pullulan ester, the edible polymer being at least one of the following: hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl ethylcellulose (HPEC), Methylcellulose (MC), hydroxyethyl cellulose (HEC), sodium carboxymethylcellulose (CMC. Na), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), carboxyvinyl polymer, sodium alginate, sodium acrylate, shellac, Cellulose Acetate Phthalate (CAP), polyvinyl acetate, Eudragit, hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose phthalate (HPMCP), the softener is at least one of glycerol, ethylene glycol, propylene glycol, D-sorbitol, maltitol, mannitol and xylitol, and the coating layer films have 180 degree peel strengths of 100g to 500g/20mm, respectively, when applied on Bakelite plates, and a solubility in water of 0.5 to 3 minutes; wherein the mixing ratio of edible water soluble polymer is 40-90% of the whole preparation, the mixing ratio of water soluble and non-water absorbent polysaccharide is 3-6%, the mixing ratio of softener is 0.5-2%, and the mixing ratio of edible polymer is 3-6%; wherein the thickness of the nicotine-containing layer film is 250 μm to 500 μm, the thickness of the coating layer film is 5 μm to 30 μm, and the thickness of all three layers of films is 260 μm to 560 μm; the three-layer film has the film strength of 2kg-5kg/20 mm; and wherein the nicotine content in one unit of the preparation is 0.1mg-5 mg.

2. The film formulation according to claim 1, wherein a 0.1% aqueous solution of said formulation has a pH of 3 to 9.

3. The film formulation according to claim 1, wherein the time required to dissolve one formulation unit is 10 to 30 minutes.

4. The film formulation according to claim 1, wherein said coating layer film contains sucrose fatty acid ester.

5. A film formulation according to claim 1, wherein said nicotine-containing layer film comprises polyethylene glycol.

6. The film formulation according to claim 1, wherein the pullulan ether is pullulan methyl ether, pullulan ethyl ether or pullulan propyl ether.

7. The film formulation according to claim 1, wherein the pullulan ester is pullulan acetate or pullulan butyrate.