JPH0583523B2 - - Google Patents

Description

[Detailed Description of the Invention] (a) Industrial Application Field The present invention relates to a nicotine-containing tape preparation that is applied to the outer skin and allows nicotine to be absorbed transdermally. The present invention relates to a nicotine-containing tape preparation for transdermally administering a certain amount of nicotine without causing discomfort to smokers in response to their desires, and for quitting or reducing smoking without psychological or physiological pain.

(b) Conventional technology It is well known that nicotine contained in cigarettes greatly influences habitual smoking. Therefore, it has been proposed that one method of reducing smoking is to administer nicotine to the body in a form other than smoking. By suppressing habitual smoking by administering nicotine into the body, it is possible to prevent the uptake into the body of carcinogenic substances produced during cigarette combustion, as well as risk factors such as prussic acid, carbon monoxide, and aldehydes. It can be avoided.

For this reason, the following methods have been proposed as methods for administering nicotine into living bodies.

The first method is to administer nicotine into the body by intravenous or subcutaneous injection (LM Johnston, Lancet, 2 (1942) 742., B.
R. Lucc hesi, CR Schuster and ABEmely,
Clin.Pharmacol.Ther., 8 (1967) 789).

The second method is to administer nicotine into a living body using an oral capsule.

The third method is to administer nicotine directly into the body through the mouth using nicotine-containing chewing gum.

The fourth method is to place an aqueous nicotine-containing solution in a plastic single-dose container or multi-dose container, insert this into the nostril, and administer the nicotine solution in the container directly through the nasal mucosa ( Tokukai Akira
59-135878).

A fifth method has been proposed in which nicotine is administered transdermally by applying a 30% aqueous solution to the healthy skin on the inside of the forearm (Chem.
Abstr.vol.101, 105621k (1984)).

(c) Problems to be Solved by the Invention However, in the first method mentioned above, in addition to pain during injection, the problem of non-uniformity of nicotine concentration in the blood arises, and injections cannot be carried out at home etc. However, since the drug is not widely used and is not widely used, it must be administered by a specialist such as a doctor each time it is administered, so there is little chance that it will be accepted as a smoking cessation law.

Next, the second method cannot be expected to be effective because most of the nicotine is metabolized and removed from the blood when it passes through the liver.

In addition, the third method mentioned above is intended to gradually administer nicotine directly into the living body from the mouth, but in reality, as a result of swallowing a large amount of nicotine along with the sleeping fluid, the third method mentioned above does not occur. The same problem as the second method arises.

Moreover, this method is a temporary administration method that requires frequent application, and the nicotine comes into direct contact with the inside of the mouth and the lining of the esophagus, resulting in unpleasant sensations such as bad taste, heartburn, nausea, and burning sensation. It has the disadvantage of causing side effects.

Furthermore, the fourth method is not sanitary because the container comes into direct contact with the nasal mucosa, and is difficult to handle and manage.Like the third method, it has only a temporary effect, resulting in frequent In particular, since this method involves inserting a container into the nostril, there were problems such as the inability to handle it in public.

Furthermore, the fifth method uses water as an essential ingredient, but in the case of formulations that use water in this way,
The following problems arise.

That is, first of all, in formulations that use water, variations in the water content in the formulation will cause variations in the transdermal absorption of nicotine, so it is necessary to strictly control the moisture in the formulation by drying, etc. There is, but
In this way, it is extremely difficult to control the moisture content in the formulation by drying or the like.

In addition, when a preparation using water is applied to the skin, it dries immediately and the percutaneous absorption of nicotine decreases rapidly, so after applying the preparation to the skin, immediately cover the application area with a non-porous synthetic resin film. It was necessary to cover it, which caused problems such as extremely poor handling.

Furthermore, even if a formulation using water is applied to the skin and the area of application is immediately covered with a nonporous synthetic resin film, the water concentration in the formulation decreases over time and the amount of nicotine administered transdermally decreases. As a result, it is difficult to maintain the required nicotine concentration over a long period of time, resulting in problems such as frequent administration of the formulation, which is extremely cumbersome.

(d) Means for Solving the Problems As a result of intensive studies aimed at solving the above problems, the present inventors have previously recognized that the presence of water is essential for transdermal administration of nicotine. This is common sense, and no nicotine formulation has been found that does not contain substantial water. However, when nicotine is contained in a polymer material layer that does not contain substantially water and this is applied to the skin, a surprising result is obtained. It has become clear that nicotine can be absorbed transdermally from such a polymeric material layer, and nicotine in such a polymeric material layer has excellent transdermal absorption, and nicotine can be absorbed continuously through the skin. The present invention has been completed based on the discovery that it is absorbed through the skin and suppresses the desire for smoking over a long period of time.

That is, the present invention provides a tape preparation comprising a polymer material layer on a carrier that exhibits tackiness at room temperature and does not contain substantially water, in which nicotine is contained in the polymer material layer. This is a characteristic feature.

Nicotine that can be used in the present invention is not particularly limited, and includes natural or synthetic nicotine or pharmacologically acceptable salts thereof (hereinafter referred to as nicotines), but especially nicotine in cigarettes. Natural nicotine, as present, is preferred.

In addition, pharmacologically acceptable salts include, for example, nicotine hydrogen tartrate, nicotine tartrate,
Examples include nicotine monohydrochloride, nicotine dihydrochloride, nicotine sulfate, and the like.

The polymeric substance used in the present invention, which exhibits adhesiveness at room temperature and contains substantially no water, has sufficient skin adhesion when applied directly to the skin surface and prevents drug release. The purpose is to provide a base that allows for the desired speed.

Examples of this polymeric material include silicone rubber, polyisoprene rubber, polyisobutylene rubber, styrene-butadiene rubber, styrene-isoprene-styrene block copolymer rubber, styrene-butadiene-styrene block copolymer rubber, acrylic rubber, natural Rubber-based polymer substances such as rubber, vinyl-based polymer substances such as polyvinyl alkyl ether, polyvinyl alcohol, and polyvinyl acetate, cellulose-based polymer substances such as carboxymethyl cellulose, and (meth)acrylic acid alkyl esters ( Examples include meth)acrylate polymer substances.

Among the above-mentioned polymeric substances, considering the stability against decomposition of nicotine, release properties, and skin adhesion,
Particularly preferred are (meth)acrylate-based polymer substances, such as butyl (meth)acrylate, pentyl (meth)acrylate, hexyl (meth)acrylate, octyl (meth)acrylate, Homopolymers of (meth)acrylic acid alkyl esters in which the alkyl group has 4 to 14 carbon atoms, such as (meth)acrylic acid dodecyl ester and (meth)acrylic acid tetradecyl ester, or these (meth)acrylic acids 50 to 99% by weight of an alkyl ester and a monomer copolymerizable with the ester, such as (meth)acrylic acid, methyl (meth)acrylate, ethyl (meth)acrylate, itaconic acid, itaconic anhydride, maleic acid. , maleic anhydride, fumaric acid, crotonic acid, methylaminoethyl (meth)acrylate, 2-hydroxyethyl (meth)acrylate,
Functional monomers such as (meth)acrylic acid 2-hydroxypropyl ester, (meth)acrylic acid methoxyethyl ester, (meth)acrylic acid amide, dimethyl (meth)acrylamide, (meth)acrylonitrile, vinyl acetate, vinyl versatate, vinyl A copolymer containing 1 to 50% by weight of a vinyl monomer such as pyrrolidone, vinyl chloride, or vinyl propionate, or a monomer such as styrene can be used.

The blending ratio of the above nicotine and the above polymer substance varies depending on the polymer substance used and the type of nicotine, but usually the proportion of nicotine in the mixture of both is 2 to 10% by weight. It is preferable to do so.

If the proportion of nicotine is less than this range, the desired effect cannot be obtained, while if it is greater than this range, the transdermal absorption of nicotine may be excessive or it may be economically disadvantageous, which is not preferable.

The method of blending the nicotine and the polymeric substance is not particularly limited, and examples include the methods described below.

The nicotine compound is directly added to the solution of the polymeric substance and mixed.

The nicotine compound is dissolved in a solvent such as alcohol or chloroform, and this solution is added to the solution of the polymeric substance and mixed.

Various surfactants are added to the above nicotine,
This is mixed with the solution of the polymeric substance. The above-mentioned surfactant is also added to improve the affinity or solubility of the above-mentioned nicotine to the above-mentioned polymeric substance, and anionic, cationic, and nonionic surfactants can be used as long as they can achieve this purpose. Any type of surfactant may be used, and examples thereof include sodium lauryl sulfate, sodium laurate, sodium stearate, sodium stearyl sulfate, polyoxyethylene lauryl ether, and the like.

Further, as the carrier used in the present invention, various carriers can be used as long as they are flexible enough not to cause a noticeable discomfort when applied to the skin. Specifically, for example, polyolefin, polyester, Films or sheets of various plastics such as polyurethane, polyvinyl alcohol, polyvinylidene chloride, polyamide, foamable sheets or films made of rubber and/or synthetic resins, nonwoven fabrics, woven fabrics, papers, metal foils, or laminated films of these. Examples include sheets, but in order to increase the water retention capacity of the stratum corneum on the skin surface to which it is applied during patch use and improve transdermal absorption, it is recommended to use sheets that have virtually no moisture permeability or so-called
A carrier that provides a sufficient ODT effect is preferred.

For producing the nicotine-containing tape preparation of the present invention, there are, for example, the methods described below.

(a) The solution of the nicotine-containing polymeric substance prepared in the above steps is applied to the surface of the carrier directly or indirectly via an undercoat member, and then dried.

(b) The nicotine-containing polymeric substance prepared in the above steps is formed into a tape shape, and the tape is attached to the surface of the carrier directly or indirectly via an undercoat member.

(c) A layer of the polymeric substance is formed on the surface of the carrier, and a solution of the nicotine-containing polymeric substance is applied to the surface of the layer.

In the nicotine-containing tape preparation thus obtained, it is preferable to protect the surface of the nicotine-containing polymer by covering the surface of the nicotine-containing polymer with a release film such as polyethylene terephthalate that has been subjected to release treatment.

The nicotine-containing tape preparation of the present invention improves the solubility and diffusion mobility of nicotine in the nicotine-containing polymer layer, or efficiently releases nicotine onto the skin surface to which it is applied, or has keratin softening properties. It is preferable to add a transdermal absorption auxiliary substance that has a function (so-called loosening) or the like.

Specific examples of the above-mentioned transdermal absorption aids include lower alcohols such as ethanol, glycols such as propylene glycol, diethylene glycol, and polyethylene glycol, polyhydric alcohols such as glycerin and sorbitol, salicylic acid, urea,
Examples include allantoin, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, diisopropyl adipate, ethyl laurate, lanolin, olive oil, mineral oil, and two or more of these may be added if desired.

The addition ratio is appropriately determined in consideration of the balance between skin adhesion and cohesive force, but it is preferably 30 parts by weight or less based on 100 parts by weight of the above-mentioned polymeric substance.

In addition, in the present invention, in order to suppress the decomposition of nicotine during storage over time, antioxidants such as ascorbic acid, sodium bisulfite, butylated hydroxyanisole, butylated hydroxytoluene, polyphosphoric acid, ethylenediaminetetraacetic acid, or the like are added. Add a chelating agent such as a salt to the above-mentioned polymeric substance 100
It is preferable to add at a ratio of 5 parts by weight or less to parts by weight.

A preferred embodiment of the combination of the nicotine-containing tape preparations of the present invention is one in which one dosage form is composed of multiple types of nicotine-containing tape preparations in which the nicotine content in each nicotine-containing tape preparation is varied. It is.

That is, nicotine-containing tape preparations are formed by gradually reducing the amount of nicotine contained in one dosage unit in order to eliminate dependence on nicotine by reducing the amount of nicotine administered into the body at regular intervals. It is preferable to combine them.

Specific methods for changing the amount of nicotine in a nicotine-containing tape preparation for one dose include, for example, changing the concentration of nicotine in the nicotine-containing polymer material layer, or changing the thickness of the layer, or Various means can be adopted, such as changing the effective application area of the tape formulation containing the tape.

In the nicotine-containing tape preparations obtained in this way, tapes containing nicotine from high to low concentrations are applied to the living body in order to gradually lower the nicotine level in the living body at regular intervals, thereby causing psychological effects. It is possible to quit smoking without feeling any pain.

(e) Effect The nicotine-containing tape preparation of the present invention is a preparation in which nicotine is contained in a polymeric material layer that exhibits adhesiveness at room temperature and does not substantially contain water, and is provided on a carrier. It is attached to the outer skin of the skin and allows smokers to absorb nicotine through the skin, which has a large effect on habitual smoking, so there is no need for a doctor or other specialist to administer it, and it is extremely easy to handle and can be used by many people ( Furthermore, since the nicotine-containing tape preparation is applied directly to the outer skin and the nicotine contained in the tape preparation is gradually administered into the body through the skin, the nicotine concentration in the blood can be maintained for a long time. As a result, it is not necessary to frequently administer the nicotine-containing tape preparation.

(f) Examples The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited to these in any way and various applications can be made within the scope of the technical idea.

In addition, parts in the examples mean parts by weight.

Example 1 A monomer mixture consisting of 55 parts of 2-ethylhexyl acrylate, 30 parts of 2-methoxyethyl acrylate, and 15 parts of vinyl acetate was heated at 65°C in ethyl acetate in the presence of 0.2 part of azobisisobutyronitrile.
After increasing the temperature to 80℃ and polymerizing for 8 hours, the temperature was further increased to 80℃.
The mixture was aged for 2 hours under the following conditions to obtain an acrylic polymer.

Next, 10 parts of nicotine was added to 100 parts of the copolymer solution.
Add and mix 25 parts by weight of ethyl alcohol solution,
The thickness after drying on one side of the polyethylene film
After applying it to a thickness of 40 μm, it was dried at 80° C. for 8 minutes to obtain a nicotine-containing tape preparation. The amount of nicotine used in this example was set to 400 μg/cm ² .

The nicotine-containing tape preparation thus obtained was cut into rectangles (7 x 10 cm ² ) and applied to the inside of the left arms of 10 non-smokers.
Blood nicotine concentrations approximately equivalent to those obtained when smoking a cigarette were reached in minutes and sustained for approximately 12 hours.

Example 2 The copolymer solution of Example 1 above was applied to one side of a polyethylene film so that the thickness after drying would be 40 μm, and then dried at 80°C for 8 minutes. After applying an appropriate amount of 0.5% nicotine ethyl alcohol solution to thoroughly impregnate it, dry it to determine the nicotine content.
100μg/cm ² 200μg/cm ² , 300μg/cm ² , 400μg/
Four nicotine-containing tape formulations of cm ² were obtained.

400μ in the first week for 10 habitual smokers
g/cm ² , 300μg/cm ² in the second week, 200μ in the third week
After continuous application of tape preparations (each measuring 7 x 10 cm ² ) containing 100 μg/cm ² of nicotine every 12 hours during the fourth week, four participants completely stopped smoking ^. is possible, and the other 6 people are also 1/5 of the normal size.
I was able to reduce the number of times I smoked. It was also confirmed that the effect of quitting smoking or reducing smoking persists even after the end of the adhesion test.

(g) Effects of the Invention The nicotine-containing tape preparation of the present invention has the above-mentioned structure, and unlike conventional nicotine administration methods, it is sticky at room temperature and contains nicotine in a polymer layer that does not contain substantially water. This product contains nicotine on a carrier and is applied to the outer skin to administer nicotine transdermally, making it extremely easy to handle and providing nicotine over a long period of time. Since the concentration remains constant, the desire to smoke for a long time is suppressed without frequent use, and as a result, it becomes possible to quit smoking or reduce smoking without psychological or physiological pain.

In addition, if the carrier in the nicotine-containing tape preparation is formed of a material that does not have substantially moisture permeability, nicotine can be absorbed transdermally into the body more efficiently due to the so-called CDT effect.

In addition, when applying nicotine-containing tape preparations to the skin, it is more reliable to apply tapes with lower nicotine content sequentially over a fixed period of time compared to always administering a fixed amount of nicotine. It is possible to achieve therapeutic effects.

Claims (1)

[Claims] 1. A nicotine-containing tape preparation comprising a polymer material layer on a carrier that exhibits tackiness at room temperature and does not contain substantially water, characterized in that the polymer material layer contains nicotine. Tape formulation.