JPS61251619A - Nicotin-containing tape preparation - Google Patents

Abstract

PURPOSE:The titled preparation for administrating endermically a fixed amount of nicotin, suppressing a demand for smoking accompanied by reduction in nicotin level in the body without pain, obtained by setting a nicotin-containing high polymer substance layer having adhesion at normal temperature on a substate. CONSTITUTION:In a tape preparation obtained by setting a high polymer substance layer having adhesivity at normal temperature on a substrate, nicotin is added to the high polymer substance layer. Especially (meth)acrylate high polymer substance is preferable as the high polymer substance with resect to stability, releasability of nicotin and adhesiveness. Endermic administration of nicotin makes approximately constant nicotin concentration for a long period, suppresses a demand for smoking and makes smoking and reduction in smoking possible without psychological and physiological pains. Handling is much simpler than an existing nicotin administration method. Successively application of preparations having much lower nicotine content can surely show effects.

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 in response to a smoker's desire without causing discomfort, and for quitting or reducing smoking without psychological or physiological pain.

(b) Prior Art 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 smoking11.

By suppressing habitual smoking by administering nicotine into the body, it is possible to avoid the incorporation into the body of carcinogenic substances produced during cigarette combustion and risk factors such as hydrocyanic acid, carbon oxide, and aldehydes. Can be done.

For this reason, there is a method of administering nicotine into the body and □
Conventionally, the following methods have been proposed.

The first method is to administer nicotine into the body by intravenous or subcutaneous injection (LoM, J
ohnstonw Lancet, 2 (1942) 742
．． * B, RoLucchesi, C, R, 5chus
ter and ^, B, Es1ely, Cl1n
, Pharmacof, Ther., 8 (1967) 89).

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 difthine-containing solution in a plastic single-unit container or multi-dose container, insert this into the nostril, and administer the nicotine solution in the container directly through the nasal mucosa. (Japanese Unexamined Patent Publication No. 135878/1983).

(e) Problems to be Solved by the Invention However, in the first method described above, in addition to pain during injection, the problem of non-uniformity of nicotine concentration in the blood occurs;
Since injections are not commonly used in households, they must be administered by a specialist such as a doctor each time they are given, so there is little chance that they 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 aimed at gradually administering nicotine directly into the body during the day, but in reality, as a result of administering a large amount of nicotine with saliva, the above-mentioned Similar problems arise as with the second method.

Moreover, this method is a temporary administration method that requires frequent application, and the nicotine comes into direct contact with the lining of the esophagus during the day, resulting in unpleasant side effects such as a feeling of sluggishness, heartburn, nausea, and hiccups. There are drawbacks that cause

Furthermore, the fourth method is not sanitary because the container comes into direct contact with the nasal mucous membrane, and is difficult to handle and manage.Like the third method, it has only a temporary effect.
As a result, it is necessary to administer the drug frequently, and in particular, since this method involves inserting the container into the nostril, there are problems such as the inability to handle it in public.

(d) Means for Solving the Problems As a result of intensive studies aimed at solving the above problems, the inventors found that nicotine has excellent transdermal absorption, and that nicotine can be absorbed continuously through the skin. The present invention has been completed based on the discovery that the desire to smoke can be suppressed over a long period of time.

That is, the present invention is a tape preparation in which a polymer material layer exhibiting adhesiveness at room temperature is provided on a carrier, and is characterized in that the polymer material layer contains nicotine.

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; pharmacologically acceptable salts include, for example, nicotine hydrogen tartrate, nicotine tartrate,
Examples include nicotine-fl, R salt, nicotine-fl, nicotine sulfate, and the like.

The polymer substance used in the present invention, which is sticky at room temperature, has a base that has sufficient skin adhesion when applied directly to the skin surface and enables drug release at a desired rate. It is intended to provide.

Examples of this polymeric substance include silicone rubber, polyimprene rubber, polyisobutylene rubber, styrene-butanoene rubber, styrene-isoprene-styrene block copolymer rubber, styrene-butanoene-styrene block copolymer rubber, acrylic rubber, and natural rubber. rubber-based polymer substances such as polyvinyl alkyl ether, polyvinyl alcohol, vinyl-based polymer substances such as polyvinyl acetate, cellulose-based polymer substances such as carboxymethylcellulose, (meth)acrylic acid alkyl ester as a main component, ) Examples include acrylate polymer substances.

Among the above-mentioned polymeric substances, (meth)acrylate-based polymeric substances are particularly preferable in consideration of nicotine decomposition stability, release properties, and skin adhesion, and specifically, for example, (meth)acrylic acid butyl ester, The number of carbon atoms in the alkyl group is 4 or more, such as (meth)acrylic acid pentyl ester, (meth)acrylic acid hexyl ester, (meth)acrylic acid octyl ester, (meth)acrylic acid dodecyl ester, (meth)acrylic acid tetradecyl ester 1
A homopolymer of 4 alkyl (meth)acrylates, or 50 to 99% by weight of these alkyl esters of (meth)acrylate, and a monomer copolymerizable with the ester, such as (meth)acrylate. Acid, methyl (meth)acrylate, ethyl (meth)acrylate, itaconic acid, itaconic anhydride, maleic acid, maleic anhydride, hexamaric acid, crotonic acid, methylaminoethyl (meth)acrylate, (meth)acrylic acid 2-hydroxyethyl ester,
(meth)acrylic acid 2-hydroxypropyl ester,
(meth)methoxyethyl acrylate, (meth)acrylic acid amide, trimethyl (meth)acrylamide, (meth)
Functional monomers such as acrylonitrile, vinyl acetate,
A copolymer consisting of 1 to 50% by weight of a vinyl monomer such as vinyl versatate, vinylpyrrolidone, vinyl chloride, 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 1.
It is preferable to adjust the amount to 0% by weight.

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 is economically disadvantageous, so this is preferable. do not have.

In addition, the method of blending the nicotine and the polymeric substance is as follows:
There are no particular limitations, and examples include the methods described below.

(2) Directly add and mix the nicotine to the solution of the polymeric substance.

(2) Dissolve the nicotine in a solvent such as alcohol or chloroform, and add this solution to the solution of the polymeric substance and mix.

(2) Add various surfactants to the above nicotine and mix this with the solution of the above polymeric substance. The above-mentioned surfactant is added to improve the affinity or solubility of the above-mentioned nicotine to the above-mentioned polymeric substance, and anionic, cationic, or nonionic surfactants may be used if this purpose can be achieved. Any of these surfactants may be used, and examples thereof include sodium lauryl sulfate, sodium laurate, sodium stearate, sodium stearyl sulfate, and polyoxyethylene lauryl ether.

Further, as the carrier used in the present invention, various carriers can be used as long as they have flexibility to the extent that no obvious discomfort is felt when applied to the skin. Specifically, for example, polyolefin, polyester, etc. , 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 laminations thereof. 1 films or sheets, but in particular, in order to increase the water retention capacity of the stratum corneum on the skin surface to which it is applied during application and improve transdermal absorption, it is recommended to use films or sheets that do not have substantially moisture permeability or have the so-called ODT effect. A carrier that can provide a sufficient amount of is preferable.

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 steps 1 to 2 above is applied directly or indirectly to the surface of the carrier, and then dried.

(b) Il with the above ■～■! The prepared nicotine-containing polymer substance is formed into a tape shape, and the tape is applied directly to the surface of the carrier or indirectly via an undercoating 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 thus obtained, it is preferable to protect the surface of the nicotine-containing polymer material layer by covering it 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 material layer, or efficiently releases nicotine onto the skin surface to which it is applied, or keratin softening. It is preferable to add a transdermal absorption auxiliary substance that has a function (so-called loosening).

Specific examples of the above-mentioned percutaneous absorption auxiliary substances include lower alcohols such as ethanol, glycols such as propylene glycol, noethylene glycol, polyethylene glycol, etc., polyhydric alcohols such as glycerin and sorbitol,
salicylic acid, ms, 7lantoin, dimethyl sulfoxide, dimethylacetamide, trimethylformamide,
Examples include diisopropyl anovate, ethyl laurate, lanolin, olive oil, mineral oil, and two or more of these may be added as 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 oral storage, antioxidants such as ascorbic acid, sodium bisulfite, butylhydroxy-7disole, butylhydroxy-toluene, golylic acid, and ethylene-7mine are added. It is preferable to add a chelating agent such as tetraacetic acid or a salt thereof in a proportion of 5 parts by weight or less based on 100 parts by weight of the above-mentioned polymeric substance.

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 layer.
Alternatively, various measures can be taken, such as changing the thickness of the layer or changing the effective application area of the nicotine-containing tape preparation.

In the nicotine-containing tape preparation obtained in this way,
It is possible to gradually reduce the nicotine level in the body over a certain period of time by applying drugs with higher nicotine concentrations to lower concentrations to the living body, thereby making it possible to quit smoking without experiencing psychological pain. .

(e) Effect The nicotine-containing tape preparation of the present invention allows smokers to absorb nicotine transdermally, which greatly affects habitual smoking, so there is no need for a specialist such as a doctor to administer it. It is extremely easy to handle and can be used by any number of people (smokers), and since the nicotine-containing tape preparation is applied directly to the outer skin and the nicotine in the tape preparation is gradually administered into the body through the skin, it can be used by any number of smokers. The nicotine concentration therein remains approximately constant over a long period of time, and as a result, there is no need for frequent administration of the difthine-containing tape formulation.

(f) Examples The present invention will be explained in more detail by examples below.
The present invention is not limited to these in any way, and various applications are possible within the scope of the technical idea.

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

Example 1 A monomer mixture consisting of 30 parts of 2-ethylhexyl (7-acrylate) 5511S, 30 parts of 2-methoxyethyl acrylate, and 15 parts of vinyl acetate was mixed with 0.7-zobisisobutyronitrile.
8 at elevated temperature to 65°C in ethyl acetate in the presence of 2 parts of
After polymerization for one hour, the mixture was further aged for 2 hours at a temperature of 80°C to obtain an acrylic polymer.

Next, for 100 parts of the copolymer solution, 210 parts of Niche and 1 part of Niche were added.
% ethyl alcohol was added and mixed, and the mixture was coated on 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 to obtain a nicotine-containing tape preparation. The amount of nicotine used in this example was set to 400 μs/c2.

The nicotine-containing tape preparation obtained in this way was cut into rectangles (7 x 10 cm2) and applied to the inside of the left arms of 10 non-smokers. 30 minutes after application, the tape preparations containing nicotine were cut into rectangles (7 x 10 cm2). Approximately equal blood nicotine concentrations were achieved and maintained 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 was 40 μm,
After drying at 80°C for 8 minutes, an appropriate amount of 0.5% ethyl alcohol solution of nicotine was applied onto the surface of the polymer material layer, sufficiently impregnated, and then dried to determine the nicotine content. each iooμg/am2.200μg/am
Four types of nicotine-containing tape preparations of 2.300 μg/c112 and 400 μg/an2 were obtained.

For 10 habitual smokers, 4 GO μg/week in the first week.
c112, 300μg/am2 in the second week, 20 in the third week
0 μg/cm2 and 100 μg/am” nicotine in the fourth week (each 7 x 10 cm2 in size).
) was applied continuously every 12 hours, 4 people were able to completely stop smoking, and the other 6 people were able to stop smoking as much as 11 days.
I was able to keep the number of times I smoked to 5 or less. 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 is extremely easy to handle because it is applied to the outer skin and nicotine is administered transdermally, unlike conventional nicotine administration methods. Moreover, since the nicotine concentration remains constant over a long period of time, 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. be.

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

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 than to constantly administer 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 adhesiveness at room temperature, characterized in that the polymer material layer contains nicotine.