KR20110012727A - Nicotine transdermal delivery patch - Google Patents

Abstract

PURPOSE: A nicotine patch which is used for smoking cessation is provided to reduce loss of volatile nicotine. CONSTITUTION: A nicotine patch for transdermal delivery contains nicotine or pharmaceutically acceptable salt thereof; an acrylate polymer as an adhesive ingredient; starch; and a matrix layer containing soluble polymer. The starch is a mixture of hydrolysate and modified starch. The modified starch is hydroxy propyl starch, hydroxy propyl phosphoric acid distarch or mixture thereof. The soluble polymer is pectin. The patch further comprises a backing layer having aluminum deposition polyester film and a release liner having siliconized polyester terphthalate.

Description

Nicotine transdermal delivery patch

The present invention relates to a nicotine patch for transdermal delivery containing nicotine as an active ingredient.

The skin acts to protect the body from foreign substances, so most substances are very difficult to pass through the skin. However, it is moderately fat-soluble and low molecular weight substances can penetrate the skin. Recently, much attention has been focused on the administration of drugs through the skin, and various products such as nitroglycerin patches, scopolamine patches, nicotine patches, etc. have been marketed as patch formulations for transdermal administration.

The patch delivers drugs through the skin to avoid drug instability in the gastrointestinal tract and the effects of food, which can occur during oral administration, and is easy to use, resulting in high patient compliance and very easy removal when side effects occur. There is this.

On the other hand, regular administration of nicotine has not only helped to quit smoking, but also has been shown to be effective in treating schizophrenia and reducing pain after surgery. In particular, when nicotine is administered to patients who want to quit smoking, it is clinically found to be effective in reducing nicotine dependence and habitual smoking rate.

Nicotine patches for the administration of nicotine can be largely divided into a reservoir type and a matrix type. Nicotine patches of the reservoir type disclosed in U.S. Patent No. 5,364,630 and the like have the advantage that they can be used even at high doses of the drug, while the structure is complicated, the manufacturing process is complicated, and the drug is absorbed into the body when the membrane of the drug reservoir is damaged. There is a risk that over-adsorption of the drug may occur because is not controlled. The matrix type patch mentioned in US Pat. No. 5,603,947 and the like is controlled by the release of the drug by the physical properties, content, etc. of the polymer constituting the matrix, and the drug delivery rate decreases as the drug present on the surface of the matrix disappears. Such a matrix type patch has to satisfy various aspects such as release control, securing adhesiveness, and ensuring stability in a single structure, but has an advantage of being easy and simple to manufacture.

One of the nicotine patches available on the market, Nicotinell TTS ™ (Cico-Geigy) is a non-woven fabric coated with an oil-based acrylic adhesive on an aluminum-deposited polyester film and impregnated with nicotine on it and a skin adhesion control with drug release control. The layers are laminated. It has excellent adhesive properties and no skin irritation, but has a disadvantage of poor skin adhesion, low initial drug release rate, and complex manufacturing.

Another commercially available nicotine patch, Nicoderm ™ (Nicoderm), combines acrylic adhesives and nicotine on aluminum-deposited polyester films, coats them to form a drug layer, and controls high-density polyethylene to control drug release. A ethylene (HPDE) film was used, and a polyisobutylene rubber-based adhesive was transfer-coated as a skin adhesion layer.

In preparing such nicotine patches, it is difficult to apply a manufacturing process that includes a drying step because nicotine is very volatile and because nicotine acts as a powerful plasticizer or solvent for polymers and plastic films commonly used in patch products. It is not easy to manufacture. In order to solve this problem, some prior art adopts a patch having a complex system structure, but these nicotine patches have a considerable level of thickness and have a problem in that manufacturing is complicated.

For example, US Pat. Nos. 4,915,950, 5,603,947, and the like, in order to avoid the coating step and the drying step, have the problem of requiring the presence of an absorbent net or absorbent paper. There is also a method of supplying nicotine in the form of liquid or concentrated concentrates, but this type of system requires a significant amount of raw material for production and often has a thicker, less attractive appearance. In addition, hot-melt processes can be used to avoid the use of solvents and to omit the drying step. However, this process brings significant limitations, in particular to the choice of polymers and auxiliaries.

That is, compared with patches having other active ingredients such as estrogen, currently available nicotine patches are abnormally thick and not soft due to the above reason, and thus there is a problem in that the feeling of adhesion is not good.

It is an object of the present invention to provide a nicotine transdermal delivery patch that is excellent in nicotine release rate, has improved manufacturing stability, is simple to manufacture, has excellent skin adhesion, and is small in size and has little inconvenience of adhesion.

In order to achieve the above object, the present invention is an active ingredient nicotine or a pharmaceutically acceptable salt thereof; Acrylate polymers as adhesive components; Starch; And a matrix layer containing a water soluble polymer.

The present invention disperses nicotine or a pharmaceutically acceptable salt thereof as an active ingredient in an acrylate-based polymer matrix layer, which is an adhesive, and includes a specific starch and a water-soluble polymer therein, thereby producing a very high production yield and simple manufacturing. It has good nicotine release rate, good skin adhesion, and can be manufactured in a small size, providing a nicotine transdermal delivery patch with good patient compliance.

That is, the present invention provides a nicotine patch of the matrix type, wherein the drug-containing mattress layer of the patch according to the present invention contains nicotine or a pharmaceutically acceptable salt thereof as an active ingredient. In view of mobility in the drug-containing matrix layer, ease of preparation and the like, it is preferable to use nicotine in the free base form. However, salt forms such as nicotine tartaric acid salts can also be used, and such salt forms are not excluded from the scope of the present invention.

Nicotine, which is the active ingredient, is uniformly dispersed in the matrix layer, preferably 0.005-0.1% by weight, and more preferably 0.01-0.06% by weight, based on the total weight of the matrix layer in the matrix. If nicotine is contained in the matrix layer in excess of the above range, there is a concern that the amount of nicotine released by the patch application for 24 hours may be excessive. If the content of nicotine is less than the above range, the amount of nicotine absorbed may be too small. have.

The nicotine containing matrix layer of the present invention is the main component of which the polymer, which is an adhesive, constitutes the matrix. The adhesive is preferably an acrylate polymer in view of the release of nicotine, skin adhesion, and the like, and the acrylate polymer DURO-TAK® 87-2051, 87-2052, 87-2054, 87-2287, 87 -2353, 87-2510, 87-2516, 87-2525, 87-2825, 87-200A, 87-202A, 87-207A, 87-2074, 87-2100, 87-2194, 87-2196, 87-235A , 87-2677, 87-2852, 87-2979, 87-4098, 87-4287, 87-502A, 87-503A, 87-504A, 87-900A, 87-901A, 87-9088, 87-9301, etc. Can be used, in particular DURO-TAK® 87-2196 and 87-9301.

Such an adhesive is preferably 60-95% by weight relative to the total weight of the matrix layer, particularly preferably 80-90% by weight in consideration of the production yield of nicotine patches, the release of nicotine, skin adhesion and the like.

The nicotine containing adhesive matrix layer according to the present invention comprises starch and a water soluble polymer, which is believed to play a role in controlling the release of nicotine. When the matrix layer contains a volatile substance such as nicotine, a crosslinking agent or the like is used to prevent volatilization, but a matrix using a crosslinking agent or the like may have a large release variation depending on the degree of crosslinking. In addition, since conventional crosslinking agents are used after being dissolved in an organic solvent, the possibility of remaining of the solvent may be pointed out as a problem. Especially when the drug contained is a drug that is not hydrophobic, such as nicotine, it is common to use a dispersant and / or stabilizer to ensure the dispersion stability of the drug in solution. In the matrix layer according to the present invention, nicotine may be stably dispersed due to the addition of starch and water-soluble polymers.

Preferably, the starch included in the matrix layer is a mixture of hydrolyzate of starch starch and modified starch. The hydrolyzate of waxy starch may improve the skin adhesion by giving a soft feeling throughout the matrix, and waxy starch hydrolyzate and modified starch are thought to form an appropriate network in the matrix to capture nicotine in the matrix and release it at an appropriate rate .

In the present invention, the hydrolyzate of waxy starch means that it is obtained by hydrolyzing (eg, acid treatment, enzyme treatment, or heat treatment) of waxy starch having an amylopectin content of 90% by weight or more.

Waxy starch containing more than 90% by weight of amylopectin may be used in waxy corn starch, glutinous rice starch, waxy maize starch, etc. In addition, genetically engineered amylopectin content of corn, tachioka, potato, rice, wheat, sweet potato, etc. Alternatively, waxy starch may be obtained by treating common corn starch, rice starch, wheat starch, sweet potato starch, potato starch, tapioca starch and the like.

Waxed starch hydrolyzate in the present invention can be obtained by, for example, acidic or enzymatically treated waxy starch, the viscosity of 10% by weight aqueous solution of waxy starch is 500-5000 cps (for example, form B at 40 ℃) It is preferable to use the hydrolyzed waxy starch until the Brookfield viscometer is used, and more preferably to use the hydrolyzed waxy starch hydrolyzate until 2000-3000 cps.

Acid treatment can be carried out by organic or inorganic acid treatment. More specifically, the waxy starch may be hydrolyzed by treating organic acids such as acetic acid, formic acid, citric acid, malic acid, or inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and the like. Enzyme treatment can be carried out by enzymes such as alpha amylase, heat resistant alpha amylase, fluranase, iso amylase, glucoamylase, beta amylase and the like.

In addition, waxy starch obtained by using an acid-treated or enzymatically processed waxy starch hydrolyzate, or an acid-treated or enzymatically processed waxy starch, is used to enhance aging stability. Hydrolysates may also be used.

The content of the waxy starch hydrolyzate in the matrix is preferably 1-10% by weight, more preferably 2-6% by weight based on the total weight of the matrix.

The matrix layer according to the invention also comprises modified starch. Modified starch is typically modified through one or more denaturation reactions, such as oxidation reactions, esterification reactions, etherification reactions, crosslinking reactions, superoxide reactions, phosphorylation reactions, octenylsuccinylation reactions, hydroxyethylation reactions, alphaation reactions, and the like. Starch modified by. These modified starches include hydroxypropyl starch, hydroxypropyl phosphate starch, oxide starch, octenyl succinyl sodium starch, octenyl succinyl starch, starch oxide starch, acetyladipic acid starch, acetyl phosphate starch, octenyl succinic acid Sodium starch, starch phosphate, monophosphate starch, phosphate starch, starch acetate, etc. may be used, but considering the ease of preparation of nicotine patches and the release of nicotine, hydroxypropyl starch, hydroxypropyl phosphate starch or these It is preferable that it is a mixture of these, and it is more preferable that it is hydroxypropyl starch.

The content of the modified starch in the matrix is preferably 3-10% by weight, more preferably 5-9% by weight relative to the total weight of the matrix.

The nicotine-containing mattress layer according to the present invention also includes a water-soluble polymer, and this water-soluble polymer not only plays a role in controlling the dispersibility of nicotine, the release property of nicotine, etc., but also prevents starch from agglomerating to produce a patch or It also prevents nicotine release during storage. As the water-soluble polymer, pullulan, gelatin, pectin, hydroxypropylmethylcellulose, alginic acid, sodium alginate, carrageenan, arabic gum, guar gum, locust bean gum, xanthan gum, gellan gum, agar and the like may be used alone or in combination. . As the water-soluble polymer, pullulan, gelatin and pectin are preferable, and pectin is more preferable.

Such a water-soluble polymer is preferably included in the matrix at 0.05-10% by weight relative to the total weight of the matrix, more preferably 1-5% by weight.

The nicotine containing matrix layer according to the present invention may comprise other ingredients such as skin penetration promoters for promoting skin penetration of nicotine, plasticizers for improving the flexibility of the matrix.

For example, as a plasticizer, sorbitol, maltitol, xylitol, glycerin, polyethylene glycol, propylene glycol, hydrogenated syrup, syrup, triacetin, glycerol oleate, sucrose fatty acid ester, medium chain fatty acid, and the like may be used. Fatty acids such as oleic acid and linoleic acid; Surfactants such as tween; Alcohols such as ethanol; Glycols such as propylene glycol; Terpenes such as menthol may be used, but are not limited thereto.

The nicotine containing matrix layer according to the present invention may be provided as a patch having a backing layer on top and a release liner on the bottom, the support layer being, for example, an aluminum deposited polyester film, the release layer being an example. For example, siliconized polyester terphthalate may be used, but is not limited thereto.

The patch according to the invention may also comprise another adhesive layer for the purpose of controlling the release of nicotine, improving skin adhesion, etc., between the drug containing matrix layer and the release layer.

The invention also

(S1) nicotine or a pharmaceutically acceptable salt thereof as an active ingredient; Acrylate polymers (preferably Duro-Tak® 87-9301 or 87-2196) as adhesive components; Starch (preferably a mixture of hydrolyzate of hydroxystarch and hydroxypropyl starch); And preparing a solution or suspension containing the water soluble polymer (preferably pectin),

(S2) applying the solution or suspension to the peeling film or support film,

(S3) drying the applied solution or suspension at 40 ~ 80 ℃, and

(S4) a step of laminating the dried film on a supporting film or a peeling film

It provides a method for producing a nicotine transdermal delivery patch, characterized in that it comprises.

The method for producing a nicotine transdermal delivery patch according to the present invention is not only very simple to manufacture, but also can produce a nicotine patch having a high yield and excellent nicotine release properties.

The nicotine transdermal delivery patch of the present invention is simple to manufacture, has low nicotine loss during the manufacturing process, has excellent nicotine release rate, good skin adhesion, and can be manufactured in a small size, thus increasing patient compliance.

Hereinafter, examples and the like will be described in detail to help understand the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the invention should not be construed as limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

Example 1 Preparation of Nicotine Transdermal Delivery Patch

As the film used for the adhesive layer, a functional group-free acrylate polymer solution, Duro-Tag ™ 87-9301 (National Starch & Chemical, USA) was used.

2 g of hydroxypropyl starch (Avebe Co., Ltd., hydrolyzate of waxy starch, 10 mg of waxy starch (about 2700 cps of 10 wt% aqueous solution), 10 mg of nicotine, 62 g of DuroTac 87-9301 as dry matter. 5 g of Kreation D8) and 1.5 g of pectin were added and dissolved to prepare a homogeneous nicotine containing solution. The prepared solution was applied on a polyester peeling film (3M company, USA) using a lab coater dryer (Mathis, Switzerland) and dried at 60 ° C. at a fan speed of 100 rpm for about 30 minutes. The dried film was again laminated onto an aluminized polyester film (3M, USA) to produce transdermal delivery patches containing nicotine.

Example 2 Preparation of Nicotine Transdermal Delivery Patch

A nicotine patch for transdermal delivery was prepared in the same manner as in Example 1, except that 20 mg of nicotine was added instead of 10 mg of nicotine.

Experimental Example 1 Measurement of Nicotine Loading Content

The content of nicotine per unit area (cm ² ) contained in the nicotine patches prepared in Examples 1 and 2 was measured by conventional HPLC methods. The results are shown in FIG.

As shown in FIG. 2, the nicotine content per unit area of the nicotine patch prepared in Example 1 was 714.37 μg / cm 2, and the nicotine content per unit area of the nicotine patch of Example 2 was 1603.183 μg / cm 2. The nicotine content per unit area of commercially-available nicotine transdermal delivery formulation Nicostop ™ was 1900 μg / cm 2.

Considering the approximate patch area obtained in Example 2 and the nicotine content per unit area of the nicotine patch, the nicotine yield of the patch compared to the nicotine administered is considered to be quite high, which is achieved without loss of nicotine through the preparation method according to the present invention. It shows that nicotine patches can be prepared simply in high yield. As described above, the nicotine patch according to the present invention was not only easy to manufacture but also stably produced a highly volatile nicotine patch.

Experimental Example 2 Nicotine Release Experiment of Nicotine Patch

Drug permeation experimental diffusion device (Franzov) was charged with 5.4 mL of PBS pH 7 to maintain the temperature at 37 ℃, and stirred at a speed of 400 rpm. Thereafter, the peeling layers of the patches prepared in Examples 1 and 2 were removed and pasted on a membrane (Spectra / Por Dialysis Membrane, MWCO: 3500) in In vitro release tests were performed. The surface area in contact with PBS at this time was 0.64 cm 2. A commercially available Nicostop ™ patch was used as a comparative example. Over time, PBS was taken hourly to evaluate the diffusion amount of nicotine by HPLC method. The results are shown in Fig.

As shown in FIG. 3, the amount of nicotine released from the nicotine patch of Example 2 according to the present invention was superior to that of commercially available Nicostop ™. In particular, considering the fact that the amount of nicotine loading of Example 2 was less than that of the comparative example, it can be predicted that the nicotine transdermal delivery ability of the nicotine patch of the present invention will be very excellent. In addition, the cumulative release amount after 24 hours was 1294.59 ㎍ / ㎠ in Example 2 and 850.50 ㎍ / ㎠ in the case of Nicostop ™, considering the conventional use of nicotine patch to attach once daily nicotine patch according to the present invention compared to the content The 24 hour utilization rate (approximately 80.8% vs. 44.8%) is significantly improved.

1 is a cross-sectional view of nicotine transdermal delivery patches in accordance with the present invention.

FIG. 2 is a graph showing nicotine content per unit area of Nicostop ™ used as a nicotine transdermal delivery patch and comparative experiment group in accordance with one embodiment of the present invention.

3 is a graph showing nicotine transdermal delivery patches and nicotine release over time from Nicoscotop ™ according to the present invention.

Claims (10)

Nicotine or a pharmaceutically acceptable salt thereof as an active ingredient; Acrylate polymer as an adhesive component; Starch; And a matrix layer containing a water soluble polymer. 2. The nicotine transdermal delivery patch of claim 1, wherein the starch is a mixture of hydrolyzate of starch starch and modified starch. The hydrolyzate of waxy starch is a hydrolyzate of waxy starch having an amylopectin content of 90% by weight or more, and the viscosity of the 10% by weight aqueous solution is 500-5000 cps at 40 ° C. Nicotine transdermal delivery patch. The method of claim 2, wherein the modified starch is hydroxypropyl starch, hydroxypropyl phosphate starch, oxide starch, octenyl succinyl sodium starch, octenyl succinyl starch, starch oxide starch, acetyladipic acid starch, acetyl phosphate Nicotine transdermal delivery patch, characterized in that any one or more selected from the group consisting of starch, sodium octenyl pumpkin starch, starch phosphate, starch monophosphate, starch phosphate starch and starch acetate. 5. The nicotine transdermal delivery patch according to claim 4, wherein the modified starch is hydroxypropyl starch, hydroxypropyl phosphate starch or a mixture thereof. The method of claim 1, wherein the water-soluble polymer is selected from the group consisting of pullulan, gelatin, pectin, hydroxypropylmethylcellulose, alginic acid, sodium alginate, carrageenan, gum arabic, guar gum, locust bean gum, xanthan gum, gellan gum and agar. Nicotine transdermal delivery patch, characterized in that at least one selected. 7. The nicotine transdermal delivery patch according to claim 6, wherein the water soluble polymer is pectin. 2. The nicotine transdermal delivery patch of claim 1, wherein the adhesive component is provided from Duro-Tak 87-9301, 87-2196 or a mixture thereof. The method of claim 1, wherein the patch further comprises a backing layer consisting of an aluminum deposited polyester film and a release liner consisting of siliconized polyester terphthalate. Nicotine transdermal delivery patch. (S1) nicotine or a pharmaceutically acceptable salt thereof as an active ingredient; Acrylate polymer as an adhesive component; Hydrolyzate of waxy starch; Hydroxypropyl starch, hydroxypropyl phosphate starch or mixtures thereof; And preparing a solution or suspension containing pectin, (S2) applying the solution or suspension to the peeling film or support film, (S3) drying the applied solution or suspension at 40 ~ 80 ℃, and (S4) a step of laminating the dried film on a supporting film or a peeling film A method for producing a nicotine transdermal delivery patch, comprising:

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