KR20190048320A - Varenicline percutaneous drug delivery system - Google Patents

Abstract

Disclosed is a percutaneous drug delivery agent containing varenicline which is a pharmaceutically active compound effective for smoking cessation therapy. In particular, the percutaneous drug delivery agent comprises: (a) a drug-containing adhesive layer containing varenicline as an effective component and a polymer adhesive substrate; (b) a support layer; and (c) a release layer. The percutaneous drug delivery agent of the present invention can dramatically increase the patient′s compliance with drugs.

Description

[0001] Varenicline percutaneous drug delivery system [0002]

The present invention relates to a pharmaceutical composition containing varenicline as an active ingredient in order to improve the compliance of the varenicline used in the smoker's smoking cessation treatment and has no crystal formation even when the drug is contained at a high concentration in the adhesive matrix, The present invention relates to a barrenicin percutaneous absorber capable of stably maintaining a drug without browning of the pressure-sensitive adhesive layer and delivering an effective drug to the body through the skin.

Barreniklin is the first nicotine receptor partial agonist in the world, and is pharmacologically different from conventional nicotine replacement, nicotine replacement, bupropion. The effect of barrenicin on smoking cessation can be attributed to the partial agonist action of the α4β2 nicotinic receptor (stimulating and counteracting). The stimuli lightly stimulate the nicotine receptor, releasing a small amount of dopamine, effectively suppressing the escape symptoms and smoking impulses due to smoking cessation, but it is partially weaker than nicotine. The antagonism is to interfere with the binding of nicotine to nicotinic receptors and weaken its function. As a result, since the release of dopamine by nicotine is suppressed, smoking can not be satisfactory even when smoking.

It is a pharmaceutical advantage to deliver the drug to the body with a parenteral absorbent. For example, percutaneous absorption formulations may be a preferred alternative for patients who have difficulty or discomfort to take oral formulations. Barreniklin's oral medication may cause frequent nausea in some patients, and nausea, sleep disturbances, constipation, high fever, vomiting, and suicidal thoughts may be uncommon. However, the dermal absorbent gradually transfers barrenicin into the body, which is useful for reducing the frequency of nausea. In addition, the barrenicin oral dosage form provides continuous administration of the drug through the skin, as compared to the patient taking the tablets or capsules with water one or two times a day to maintain a therapeutically useful active ingredient in the body's blood levels. , It is estimated that the plasma concentration of Barenicin, which has a half-life of around 33 hours, can continuously increase the body blood concentration of the active ingredient to a therapeutically useful concentration by continuously attaching the patch. Therefore, the percutaneous absorption formulation of barrenicin is a useful formulation for a patient.

As an attempt to develop patches using barrenicin, Japanese Patent No. 5615899 discloses a method of improving the stability of basic drugs using aluminum chloride and ester group-containing bases, but aluminum chloride forms hexahydrate It becomes gelled and dissolves when the amount of water is increased to show acidity. This may change the chemical properties of the base due to moisture and sweat evaporating from the skin, and in the case of sweaty people, the skin may be damaged by acid decomposed with aluminum chloride.

Japanese Patent No. 5537412 discloses a process for producing a polyvinylpyrrolidone by dissolving and neutralizing polyvinyl alcohols such as sodium hydroxide and propylene glycol as a neutralizing agent using a barrenicin tartarate as a neutralizing agent and then adding a rosin, And the solubility of the drug is increased. However, since sodium hydroxide is added in an equivalent amount or more for chemical neutralization, sodium hydroxide may remain in the polymer adhesive base, which may cause skin damage and may cause skin damage The compatibility of the neutralizing agent and the solubilizer with the rubber is low, so homogeneity may become a problem in the adhesive matrix.

Japanese Patent No. 5485135 discloses an adhesive preparation using an acrylic polymer having no carboxyl group as an adhesive base and a pH of the adhesive layer of 7.5 or more. However, it has basically the same technical features as Japanese Patent No. 5537412, and thus it is not preferable because it uses a neutralization reaction for valenylic acid. In addition, a basic adhesive matrix having a pH of 7.5 or more is undesirable because it may damage the skin when considering the pH of the skin is 5.0 to 5.4.

Japanese Patent Application Laid-Open No. 2010-285415 discloses a method of using a polyacrylonitrile and an aluminum laminated sheet as a packaging agent for packaging a percutaneous absorber to inhibit generation of decomposed compounds of barrenicin and prevent discoloration over time. However, even if such a packaging agent is not used, or even when such a packaging agent is removed, it is desirable to ensure the stability of the drug in the adhesive base agent.

Japanese Patent Publication No. 5615899 Japanese Patent Publication No. 5537412 Japanese Patent Publication No. 5485135 Japanese Patent Application Laid-Open No. 2010-285415

Barrenicin is a pale yellow drug having a molecular structure as shown by the following formula (1), and has a pKa (ionization constant) value of 9.2.

[Chemical Formula 1]

When exposed to air in a solid or solution phase, the gel changes, polarity, and molecular structure do not change, so crystals easily precipitate in high-hydrophobicity pressure-sensitive adhesives. Therefore, it is possible to overcome the drawbacks of the above-described techniques, suppress browning of the drug and inhibit crystal formation, and deliver the drug effectively through the skin to the body, thereby improving the convenience of patients and making the transdermal absorbent excellent in stability.

In order to solve the above problems, the inventors of the present invention have found that by using a specific adhesive agent in a drug-containing adhesive layer to inhibit browning and crystal formation of a drug and to use a percutaneous absorption enhancer in a monolytic form, A clean transdermal absorbent was completed.

The barrenicin percutaneous absorber according to the present invention is of the drug release controlled type, has high stability, is easy to store and use, and is easy to manufacture. In addition, the percutaneous absorbent agent according to the present invention can effectively deliver medicines through the transdermal route while greatly improving the patient's compliance with the medicines, and thus can be useful for the treatment of smoking cessation.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a cross-sectional view of a monolithic type percutaneous absorber produced by the present invention, wherein A is a support layer, B is a drug-containing adhesive layer, and C is a release layer.
FIG. 2 is a graph showing the cumulative percutaneous absorption amount of the percutaneous absorbent according to an embodiment of the present invention.

The present invention relates to a percutaneous absorbent comprising barrenicin as an active ingredient.

More particularly, the present invention relates to a monoritic barrenicin percutaneous absorber, which comprises (a) a drug-containing adhesive layer containing barrenicin and an adhesive base (polymeric adhesive base) as an active ingredient; (b) a support layer; And (c) a release layer.

In the present invention, the drug-containing adhesive layer may further contain excipients such as transdermal absorption enhancer and antioxidant in addition to barrenicin and an adhesive base.

In the present invention, it is preferable to use a free base of barrenicin (free base) as an active ingredient. The use of barrenicin free base eliminates the complexity of the process of neutralization reactions, such as acid addition salts, and the risk of skin irritation and damage due to residues of neutralization reactions, and improves transdermal absorption.

In the present invention, barrenicin may be contained in an amount of 3 to 20% by weight, and preferably 5 to 15% by weight based on the total weight of the drug-containing adhesive layer. If the drug content is less than 3% by weight based on the total weight of the drug-containing tackiness, the transdermal drug concentration is weakened due to a weak concentration gradient between the patch and the percutaneous drug. If the content of the drug exceeds 20% by weight, 탆 or less, which is difficult to manufacture, crystals are easily formed, and adhesion to the skin is also lowered.

The pressure-sensitive adhesive to be used in the present invention may be any pressure-sensitive pressure-sensitive adhesive, but it is preferable to use an acrylic pressure-sensitive adhesive.

The acrylic pressure sensitive adhesive in the present invention is a pressure sensitive adhesive composed of an acrylic polymer produced from the synthesis of an acrylic monomer or a vinyl acetate monomer and an acrylic monomer, wherein (i) is free of a functional group, (ii) has a hydroxyl (-OH) , (iii) having a carboxyl (-COOH) group as a functional group, and (iv) having both a hydroxyl group and a carboxyl group (-COOH) as a functional group . It is possible to use a combination of an acrylic pressure-sensitive adhesive having a hydroxyl group (-OH) and an acrylic pressure-sensitive adhesive having a carboxyl group (-COOH), or an acrylic pressure-sensitive adhesive having a carboxyl group (-COOH) Preferably, an acrylic pressure-sensitive adhesive having a carboxyl group (-COOH) and an acrylic pressure-sensitive adhesive having no functional group can be used in combination.

In the present invention, when the pressure-sensitive adhesive is mixed, the ratio of the pressure-sensitive adhesive is important, which is related to the inherent physicochemical properties of each of the pressure-sensitive adhesives. More specifically, when acrylonitrile is mixed with an acrylic pressure-sensitive adhesive to form a drug-containing pressure-sensitive adhesive layer, the acrylic pressure-sensitive adhesive having a hydroxyl group (-OH) has good solubility in the pressure- Non-functional acrylic pressure-sensitive adhesives exhibit transdermal absorption of a suitable drug, but crystals are easily generated in the pressure-sensitive adhesive, and there is a slight change in the viscosity of the pressure-sensitive adhesive having a hydroxyl group (-OH). On the other hand, the acrylic pressure-sensitive adhesive having a carboxyl group (-COOH) is low in transdermal absorption of a drug, but has good solubility of the drug and has no crystallization and no change of drug.

In addition, when using a pressure-sensitive adhesive using a natural or synthetic rubber or an ethylene vinyl acetate (EVA) -based polymer, crystals are easily produced due to high hydrophobicity of the pressure-sensitive adhesive.

To solve this problem, a rosin ester having a carboxyl group or a hydrogeneated rosin ester resin can be used, but a large amount is used to increase the solubility in a pressure sensitive adhesive, thereby lowering the physical properties and lowering the transdermal absorption of the drug.

In the present invention, acrylic pressure-sensitive adhesives having no functional group and hydroxyl group (-OH) may be used in combination with acrylic pressure-sensitive adhesives, When mixed, when the proportion of the pressure-sensitive adhesive having a hydroxyl group (-OH) is increased, crystal formation is suppressed and drug absorption is increased, but a galvanic change occurs at all mixing ratios. Secondly, when the mixed ratio of the adhesive having no functional group and the adhesive having carboxyl group (-COOH) is lowered from a high ratio, the transdermal absorption of the drug increases, If the ratio of the pressure-sensitive adhesive having a carboxyl group (-COOH) is less than 1/3 of that of the pressure-sensitive adhesive without a functional group, crystals precipitate even in a pressure-sensitive adhesive in which two pressure-sensitive adhesives are mixed. Finally, when a pressure-sensitive adhesive having a carboxyl group (-COOH) was mixed with a pressure-sensitive adhesive having a hydroxyl group (-OH), crystal formation did not occur at all mixing ratios. However, as the mixing ratio of a pressure sensitive adhesive having a carboxyl group (-COOH) (-COOH) is more than three times that of a pressure-sensitive adhesive having a hydroxyl group (-OH).

Therefore, it is preferable to use a mixture of a pressure-sensitive adhesive free from a functional group and a pressure-sensitive adhesive having a carboxyl group (-COOH), and the ratio thereof is preferably one third or more of the pressure-sensitive adhesive having a carboxyl group (-COOH).

In the present invention, a transdermal absorption enhancer may be further included to enhance transdermal absorption of the drug. Examples of the transdermal absorption enhancer include fatty acid esters, nonionic surfactants, pyrrolidone derivatives, fatty acids, fatty acid alcohols, fatty acid ethers and polyhydric alcohol esters, preferably fatty acid esters and polyhydric alcohol esters do.

Examples of the transdermal absorption enhancer in the present invention include C _8-18 fatty acid esters such as glycerol lauryl alcohol, oleyl alcohol, myristic acid, isopropyl myristate, Sorbitan monooleate, propylene glycol monolaurate, propylene glycol monooleate, oleoyl macrogolglycerides, oleic acid, lauric acid, It has been found that it can be used in combination with other ingredients such as lauroyl macrogol glyceride, linolenic acid, linoleoyl macrogol glyceride, propylene glycol dicaprylate / caprate, sorbitan monostearate monostearate, sorbitan monooleate, glycerol monooleate, glycerol monooleate, But are not limited to, glycerol monolaurate, propylene glycol monolaurate, propylene glycol monocaprylate, sorbitan monolaurate, lauryl lactate ), PEG-8 caprylic / capric triglycerides, polyoxyethylene sorbitan monolaurate, Corn oil PEG-8 esters ), Corn oil PEG-6 esters and polyhydric alcohol esters, such as triacetin and triethyl citrate, can be used.

Preferably, C _12-18 fatty acid esters include glycerol monooleate, glycerol monolaurate, propylene glycol monolaurate, sorbitan monooleate, sorbitan monolaurate, lauryl pyrrolidone, and polyhydric alcohols , One or two or more selected from the group consisting of triacetin and triethyl citrate can be used.

More preferably, the fatty acid ester of C ₁₈ is glycerol monooleate, sorbitan monooleate, and the ester of C ₁₂ is propylene glycol monolaurate, lauryl pyrrolidone, and polyhydric alcohol, Ethylenediamine, ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid, ethylenediaminetetraacetate, ethylenetetramine,

The transdermal absorption enhancer of the present invention may be used in an amount of 1 to 25% by weight, preferably 5 to 20% by weight, based on the total weight of the drug-containing adhesive layer. If the transdermal absorption enhancer is more than 25% by weight, the transdermal absorption enhancer also acts as a plasticizer of the pressure-sensitive adhesive, which may result in lowering of the physical strength of the transdermal absorbent. In some cases (in the case of containing a large number of hydroxyl groups in the fatty acid ester) Lenny Klein causes a change of brow and can cause user's skin trouble in some cases.

The present invention may further include an antioxidant to inhibit barrenicin degradation and denaturation. Barrenicin may further contain an antioxidant to inhibit browning when it comes into contact with oxygen in a dissolved state in a solution or an adhesive matrix.

Examples of the antioxidant include butyl hydroxy toluene, butyl hydroxy anisole, propyl gallate, ascorbic acid, tocopherol, tocopherol acetate (Tocopherol acetate, ascorbyl palmitate, and the like. Of these, butylhydroxytoluene, tocopherol, and tocopherol acetate are preferably used.

The antioxidant may be used in an amount of 0.1 to 5% by weight, preferably 0.1 to 1% by weight based on the total weight of the drug-containing adhesive layer. When the antioxidant is used in an amount of 5 wt% or more, the antioxidant effect is not further improved.

In the present invention, the support layer is thin, flexible, and does not cause an allergic reaction to the skin, in order to prevent loss of barrenicin from the formulation while it is attached to the skin or during the flow and storage of the product. The supporting layer may be made of a material such as polyethylene terephthalate (PET), polyethylene (PE), polypropylene (PP), ethylene vinyl acetate copolymer (EVA), nylon, cotton, A fabric, a nonwoven fabric or a film, or a combination of two or more fabric and film, a combination of a nonwoven fabric and a film, or a combination of a film and a film. Preferably, a polyethylene terephthalate (PET) material is used to prevent the drug from transferring to the support layer, and a film or a combination of a nonwoven fabric and a film is used to prevent contact with oxygen or oxygen in the air. In addition, an aluminum thin film may be laminated in the middle or aluminum may be deposited on the film surface for shading.

The release layer in the present invention is not particularly limited as long as it protects the drug-containing product during packaging or during distribution and storage of the product, and provides convenience so that it can be easily removed when the product is used. The release layer is made of polyester, polyvinyl chloride, poly As films or papers produced from vinylidene chloride, polyethylene terephthalate, polyethylene, ethylene vinyl acetate and the like, a film laminated with a natural or glazed paper and a polyolefin can be used. The release film is preferably a polyethylene terephthalate film which is coated with a silicone resin or a fluorine resin on the surface contacting the adhesive layer and has excellent long-term stability of the drug. In addition, a film used for the release layer can be laminated with an aluminum thin film in the middle or aluminum can be deposited on the surface of the film for shading.

[Example]

Hereinafter, the present invention will be described in detail in the following examples. It should be noted, however, that the following examples are illustrative of the present invention and that the present invention is not limited to the following examples.

Examples 1 to 8

10% by weight of barrenicin was added to 70 mL vials and dissolved in ethanol, and 90% by weight of an adhesive was added thereto and mixed in a roll mixer for 2 hours to prepare a drug-containing adhesive layer composition. Thereafter, the substrate was allowed to stand for 30 minutes to remove air bubbles. Then, a silicone-treated polyethylene terephthalate peeling film was placed on the coater, and the coated adhesive was dried and coated to a thickness of 30 μm. After drying for 3 minutes in an oven at 80 ° C, the support layer film was laminated, compressed using a pressing roller, and then patched with a 10 cm2 area using a patch cutter. The blending amount according to each example is shown in Table 1 below, and then the physical properties of the patch, the change of color (change of color) and crystal formation were observed and the percutaneous absorption experiment was conducted. Observations and experimental results are also shown in Table 1 below.

Percutaneous absorption experiment

Phosphate buffered saline solution (PBS solution pH = 7.4) was placed in a Franz-type diffusion cell as a receptor. The mixture was maintained at 32 ° C, which is similar to skin temperature, and stirred at a stirring speed of 600 rpm using a magnetic stirrer To remove the dissolved gas in the solution. The patches cut in accordance with the upper donor cell of the Franz-type diffusion mechanism were attached to a percutaneous absorption membrane (Strat-M, Merck KGaA, Darmstadt, Germany) and mounted on a Franz-type diffusion mechanism. After that, the solution of the receptor part was collected at a fixed time and the amount of the new buffer solution was supplemented. The samples were analyzed by high performance liquid chromatography (HPLC). The analysis conditions were as follows.

Analysis condition

Column: C18, 4.6 mm, 5 占 퐉 (Kromasil 100-5C18)

Mobile phase: Methanol: 20 mM KH ₂ PO ₄ (pH 3.0 adjusted with phosphoric acid) = 50:50 (V / V)

Flow rate: 0.8 mL / min

Column temperature: 25 ° C

Injection amount: 20 μl

Detection: UV 237 nm

division Example (% by weight) One 2 3 4 5 6 7 8 Barrenicin 10 10 10 10 10 10 10 10 Duro-Tak ^TM 87-9301 90 Duro-Tak ^TM 87-2516 90 Duro-Tak ^TM 87-2852 90 Duro-Tak ^TM 87-4098 90 Duro-Tak ^TM 87-2287 90 Duro-Tak ^TM 87-2196 90 Duro-Tak ^TM 8027 90 Duro-Tak ^TM 87-2074 90 Appearance Change of course has exist has exist none has exist has exist has exist none has exist Crystal formation Precipitation none none Precipitation none none none none Properties and Adhesion Good Good Good Good Good Good Good Good Percutaneous absorption (㎍ / ㎠ / 24h) 1.54 3.77 1.08 1.84 3.87 1.12 1.10 1.33 Types and Functional Groups of Adhesive Base Raw material name Kinds Functional group Duro-Tak ^TM 87-9301 Acrylate polymer adhesive Non Duro-Tak ^TM 87-2516 Acrylate polymer adhesive -OH Duro-Tak ^TM 87-2852 Acrylate polymer adhesive -COOH Duro-Tak ^TM 87-4098 Acrylic-Vinyl Acetate Polymer Adhesive Non Duro-Tak ^TM 87-2287 Acrylic-Vinyl Acetate Polymer Adhesive -OH Duro-Tak ^TM 87-2196 Acrylic-Vinyl Acetate Polymer Adhesive -COOH Duro-Tak ^TM 8027 Acrylate polymer adhesive -COOH Duro-Tak ^TM 87-2074 Acrylate polymer adhesive -COOH / -OH

As can be seen from the results, the acrylic pressure-sensitive adhesive having a hydroxyl group (-OH) has a higher transdermal absorption than the other pressure-sensitive adhesives but causes a change in appearance. Non-functional acrylic pressure- It is absorbed, but crystals are easily generated in the pressure-sensitive adhesive and it is slightly weaker than the pressure-sensitive adhesive having a hydroxyl group (-OH). On the other hand, the acrylic pressure-sensitive adhesive having a carboxyl group (-COOH) is low in transdermal absorption of a drug, but has good solubility of the drug and has no crystallization and no change of drug. The pressure-sensitive adhesive having both a carboxyl group (-COOH) and a hydroxyl group (-OH) showed a slightly higher transdermal absorption than a pressure-sensitive adhesive having only a carboxyl group (-COOH), but contained a hydroxyl group (-OH) There is a change.

Examples 9 to 23

(10% by weight) was dissolved in ethanol in a 70-mL vial, and each of the pressure-sensitive adhesives was put in a predetermined mixing ratio and mixed in a roll mixer for 2 hours (90% by weight of the pressure-sensitive adhesive mixture) to prepare a drug-containing pressure-sensitive adhesive layer composition. Thereafter, the substrate was allowed to stand for 30 minutes to remove air bubbles. Then, a silicone-treated polyethylene terephthalate peeling film was placed on the coater, and the coated adhesive was dried and coated to a thickness of 30 μm. After drying for 3 minutes in an oven at 80 ° C, the support layer film was laminated, compressed using a pressing roller, and then patched with a 10 cm2 area using a patch cutter. The blending amount according to each example is shown in the following Table 2, and then the physical properties of the patch, the change of color (change of color) and crystal formation were observed and the percutaneous absorption experiment was carried out. Observation and experimental results are shown in Table 2 below.

division Example (% by weight) 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Barrenicin 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 Duro-Tak ^TM 87-9301 67.5 60 45 30 22.5 67.5 60 45 30 22.5 Duro-Tak ^TM 87-2516 22.5 30 45 60 67.5 22.5 30 45 60 67.5 Duro-Tak ^TM 87-2852 22.5 30 45 60 67.5 67.5 60 45 30 22.5 Appearance Change of course has exist has exist has exist has exist has exist none none none none none none has exist has exist has exist has exist Crystal formation has exist none none none none has exist none none none none none none none none none Properties and Adhesion Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good Percutaneous absorption (㎍ / ㎠ / 24h) 1.40 1.45 2.10 2.54 2.73 1.45 1.41 1.32 1.14 1.07 1.18 1.22 1.49 2.46 2.61 Types and Functional Groups of Adhesive Base ※ Please refer to Table 1 for types and functional groups of each adhesive.

When the acrylic pressure-sensitive adhesive having no functional group and the pressure-sensitive adhesive having hydroxyl group (-OH) are used in combination, the crystal formation is suppressed and the drug absorption is increased, but the color change occurs when the proportion of the pressure-sensitive adhesive having a hydroxyl group (-OH) increases.

Secondly, when the mixed ratio of the adhesive having no functional group and the adhesive having carboxyl group (-COOH) is lowered from a high ratio, the transdermal absorption of the drug increases, However, when the pressure-sensitive adhesive having a carboxyl group (-COOH) is lowered to 1/3 or less of the pressure-sensitive adhesive without a functional group, crystals are precipitated even in a pressure-sensitive adhesive using two pressure-sensitive adhesives.

Thirdly, when a pressure-sensitive adhesive having a hydroxyl group (-OH) is mixed with a pressure-sensitive adhesive having a carboxyl group (-COOH), crystal formation has not occurred, but as the mixing ratio of a pressure- The absorption was lowered and all of the changes occurred except for the case where the pressure sensitive adhesive having a carboxyl group (-COOH) was three times or more the pressure sensitive adhesive having a hydroxyl group (-OH).

Examples 24 to 40

The percutaneous absorption enhancer, antioxidant and barrenicin were dissolved in ethanol and dissolved in a 70 mL vial, and the pressure-sensitive adhesive was put in a predetermined ratio in a roll mixer for 2 hours to prepare a drug-containing adhesive layer composition. Thereafter, the substrate was allowed to stand for 30 minutes to remove air bubbles. Then, a silicone-treated polyethylene terephthalate peeling film was placed on the coater, and the coated adhesive was dried and coated to a thickness of 30 μm. After drying for 3 minutes in an oven at 80 ° C, the support layer film was laminated, compressed using a pressing roller, and then patched with a 10 cm2 area using a patch cutter. The compounding amount according to each example is shown in Table 3 below. Then, the physical properties of the patches, the change of browning and crystal formation were observed, and the samples having no abnormality in physical properties, browning and crystal formation were subjected to the percutaneous absorption experiment. Table 3 shows the results.

division Example (% by weight) 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 Barrenicin 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 BHT ¹⁾ 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Duro-Tak ^TM
87-9301 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 Duro-Tak ^TM
87-2852 26.5 26.5 26.5 26.5 26.5 26.5 26.5 26.5 26.5 26.5 26.5 26.5 26.5 26.5 26.5 26.5 26.5 GML ²⁾ 10 GMO ³⁾ 10 SMO ⁴⁾ 10 SML ⁵⁾ 10 LP ⁶⁾ 10 CCT ⁷⁾ 10 LL ⁸⁾ 10 IPM ⁹⁾ 10 PGML ¹⁰⁾ 10 CP8 ¹¹⁾ 10 CP6 ¹²⁾ 10 PGCC ¹³⁾ 10 PGMC ¹⁴⁾ 10 DGME ¹⁵⁾ 10 OA ¹⁶⁾ 10 TA ¹⁷⁾ 10 TC ¹⁸⁾ 10 Appearance Change of course none none none none none none none none none none none none none none none none none decision
produce none none none none none none none none none none none none none none none none none Properties and Adhesion Good Good Good Reduced adhesion Good Good Good adhesive
frailty Good Reduced adhesion Reduced adhesion Good Good Reduced adhesion adhesive
frailty Good Good Percutaneous absorption (㎍ / ㎠ / 24h) 67.9 82.7 85.4 NA 86.3 43.2 56.2 NA 86.7 NA NA 54.8 55.3 NA NA 74.3 70.9 Remarks ※ Please refer to Table 1 for types and functional groups of each adhesive.
1. BHT: butylhydroxytoluene 2. GML: glycerol monolaurate 3. GMO: glycerol monooleate 4. SMO: sorbitan monooleate 5. SML: sorbitan monolaurate 6. LP : Lauryl pyrrolidone
7. CCT: caprylic capric triglyceride, 8. LL: lauryl lactate, 9. IPM: isopropyl myristate, 10. PGML: propylene glycol monolaurate, 11. CP8: corn oil PEG-8 ester , 12. CP6: corn oil PEG-6 ester, 13. PGCC: propylene glycol caprylate / caprate, 14. PGMC: propylene glycol monocaprylate, 15. DGME: diethylene glycol monoethyl ester ), 16. OA: oleic acid, 17. TA: triacetin, 18. TC: triethyl citrate

As shown in the results, the percutaneous absorption enhancer showed a high transdermal absorption effect of glycerol monooleate, sorbitan monooleate, lauryl pyrrolidone, propylene glycol monolaurate, triacetin and triethyl citrate.

Examples 41 to 57

An antioxidant, Barrenicin, was added to the 70 mL vial and dissolved in ethanol. The percutaneous absorption enhancer and the pressure-sensitive adhesive were mixed in the proportions and mixed in a roll mixer for 2 hours to prepare a drug-containing pressure-sensitive adhesive layer. Thereafter, the substrate was allowed to stand for 30 minutes to remove air bubbles. Then, a silicone-treated polyethylene terephthalate peeling film was placed on the coater, and the blended adhesive was coated so as to have a dry thickness of 30 μm after drying. In the case of Example 56, In case of drying, it was coated so as to be 15 mu m after drying. After drying for 3 minutes in an oven at 80 ° C, the support layer film was laminated, compressed using a pressing roller, and then patched with a 10 cm2 area using a patch cutter. The compounding amount according to each example is shown in Table 4 below. Physical properties and crystal formation of the patches were then observed, and a percutaneous absorption experiment was conducted on good samples. Observations and experimental results are also shown in Table 4 and Figure 2 below.

division Example (% by weight) 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 Barrenicin 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 15 20 BHT 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Duro-Tak ^TM
87-9301 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 49.7 46.4 Duro-Tak ^TM
87-2852 26.5 26.5 26.5 26.5 26.5 26.5 26.5 26.5 26.5 26.5 26.5 26.5 26.5 26.5 26.5 24.8 23.1 GMO 5 5 5 5 5 5 5 SMO 5 5 5 5 5 PGML 5 5 5 5 5 5 5 LP 5 5 5 5 5 TA 5 5 5 5 5 TC 5 5 5 5 5 Appearance Change of course none none none none none none none none none none none none none none none none none decision
produce none none none none none none none none none none none none none none none none Create Part Properties and Adhesion Good Good Good Good Good Good Good Good Good Good Good Good Good Good Good adhesiveness
decrease Reduced adhesion Percutaneous absorption (㎍ / ㎠ / 24h) 94.3 109.9 107.5 93.1 91.1 103.2 101.1 92.1 92.3 101.5 95.1 94.8 93.4 91.1 89.7 N / A N / A Remarks ※ Please refer to Table 1 for types and functional groups of each adhesive.
* See Table 3 for abbreviations.

When the percutaneous absorption enhancers used in the previous experiment were mixed, the transdermal absorption was better than that of the single use. Particularly, a mixture of a fatty acid derivative having a lauryl group (C12) and a fatty acid derivative having an oleyl group (C18) And the transdermal absorption was excellent when used.

On the other hand, when the concentration of the drug was increased to 15 wt% to 20 wt%, the thickness of the drug-containing pressure-sensitive adhesive layer was lowered, and the adhesion was considerably lowered.

Examples 58 to 65

An antioxidant, Barrenicin, was added to the 70 mL vial and dissolved in ethanol. The percutaneous absorption enhancer and the pressure-sensitive adhesive were mixed in the proportions and mixed in a roll mixer for 2 hours to prepare a drug-containing pressure-sensitive adhesive layer. Thereafter, the substrate was allowed to stand for 30 minutes to remove the air bubbles. The silicone-treated polyethylene terephthalate peeling film was placed on the coater, and the coated adhesive was coated to a thickness of 30 μm after drying. After drying for 3 minutes in an oven at 80 ° C, And a patch with an area of 10 cm 2 was prepared using a patch cutter. The compounding amount according to each example is shown in Table 4 below. Physical properties and crystal formation of the patches were then observed, and a percutaneous absorption experiment was conducted on good samples. Observations and experimental results are also shown in Table 5 and Figure 3 below.

division Example (% by weight) 58 59 60 61 62 63 64 65 Barrenicin 10 10 10 10 10 10 10 10 BHT 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Duro-Tak ^TM
87-9301 49.7 46.3 43.0 39.7 49.7 46.3 43.0 39.7 Duro-Tak ^TM
87-2852 24.8 23.2 21.5 19.8 24.8 23.2 21.5 19.8 GMO 5 5 5 5 10 15 20 25 PGML 10 15 20 25 5 5 5 5 Appearance Change of course none none has exist has exist none none has exist has exist decision
produce none none none none none none none none Properties and Adhesion Good Bad Bad Bad Good Bad Bad Bad Percutaneous absorption (㎍ / ㎠ / 24h) 121.9 N / A N / A N / A 132.5 N / A N / A N / A Remarks ※ Please refer to Table 1 for types and functional groups of each adhesive.
* See Table 3 for abbreviations.

As can be seen from Table 5, when the ratio of glycerol monooleate mixed with glycerol monooleate, which is a percutaneous absorption enhancer, was high, the transdermal absorption was high and the content of the percutaneous absorption enhancer was increased, (Such as the decrease in the strength of the drug-containing adhesin, the weakening of the shear strength of the adhesive, etc.).

Therefore, the content of the percutaneous absorption enhancer is preferably 20% by weight or less, more preferably 15% by weight or less based on the total weight of the drug-containing adhesive layer.

The cumulative cumulative transdermal absorption of Examples 41 to 55, 58 and 62 is shown graphically in Fig.

Comparative Examples 1 to 6

An antioxidant, Barreniclein, was added to the 70 mL vial and dissolved in methylene chloride. Each raw material was added according to Table 6 and mixed in a roll mixer for 2 hours to prepare a drug-containing adhesive layer. Thereafter, the substrate was allowed to stand for 30 minutes to remove the air bubbles. The silicone-treated polyethylene terephthalate peeling film was placed on the coater, and the coated adhesive was coated to a thickness of 30 μm after drying. After drying for 3 minutes in an oven at 80 ° C, And a patch with an area of 10 cm 2 was prepared using a patch cutter. The physical properties and crystal formation of patches were then observed, and percutaneous absorption experiments were conducted on good samples. Observations and experimental results are also shown in Table 6 below.

division Comparative Example (% by weight) One 2 3 4 5 6 Barrenicin 10 10 10 10 10 10 BHT ¹⁾ 0.5 0.5 0.5 0.5 0.5 0.5 Synthetic rubber ²⁾ 41.5 41.5 Natural rubber ³⁾ 35 35 EVA ⁴⁾ 45.5 45.5 Rosin ester ⁵⁾ 38 44.5 34 Hydrocarbon Resin ⁶⁾ 38 44.5 34 PGML ⁷⁾ 10 10 10 10 10 10 Appearance Change of course has exist has exist has exist has exist has exist has exist Crystal formation none none none produce produce produce Properties and Adhesion Good Good Strength reduction of adhesive Reduced adhesion Reduced adhesion Reduced adhesion Percutaneous absorption (㎍ / ㎠ / 24h) 43.2 31.2 N / A N / A N / A N / A Remarks 1) butylhydroxytoluene
2) First grade natural rubber (RSS # 1)
3) Styrene-isoprene-styrene rubber (Kraton D1161)
4) Ethylene vinyl acetate (EVAFLEX 40W, VA content 40%)
5) Pinecrystal KE-100, Acid value 2 -10
6) Hikorez T1080, Acid value 0.04
7) Propylene glycol monolaurate

In the results of Table 6, all of the pressure sensitive adhesives using natural or synthetic rubber and ethylene vinyl acetate using hydrocarbons were found to undergo curling and crystal formation. In Comparative Example 3 using rosin ester, Adhesives containing rosin ester using natural and synthetic rubbers had good physical properties and properties, but transdermal absorption did not meet expectations.

The barrenicin percutaneous absorber according to the present invention is capable of controlling drug release, has high stability, is easy to store and use, and is easy to manufacture. In addition, the percutaneous absorbent agent according to the present invention can deliver an effective amount of a drug necessary for a patient, while greatly improving the patient's compliance with the medication, and thus can be useful for the treatment of smoking cessation.

Claims (14)

(a) a drug-containing adhesive layer containing barrenicin and a polymeric adhesive base agent as effective ingredients;
(b) a support layer; And
(c) peeling layer
≪ / RTI > The pressure-sensitive adhesive composition according to claim 1, wherein the amount of barrenicin is 3.0 to 20% by weight, the amount of the percutaneous absorption enhancer is 5 to 20% by weight, the amount of the antioxidant is 0.1 to 5% By weight based on the total weight of the composition. The percutaneous absorber according to claim 1 or 2, wherein the polymeric adhesive is an acrylic adhesive. The acrylic pressure sensitive adhesive composition according to claim 1 or 2, wherein the polymeric pressure sensitive adhesive is an acrylic polymeric pressure sensitive adhesive comprising a copolymer of acrylate or vinyl acetate and acrylate, (i) free of a functional group, (ii) (Iii) having a carboxyl (-COOH) group as a functional group, and (iv) having both a hydroxyl group and a carboxyl group (-COOH) as a functional group, Wherein the percutaneous absorber is used. The percutaneous absorber according to claim 4, wherein the polymeric adhesive agent comprises an acrylic adhesive agent having a carboxyl group (-COOH) and an acrylic adhesive agent having no functional group. The composition according to claim 4, wherein the content of the pressure-sensitive adhesive having no carboxyl group (-COOH) is 1/3 or more of the content of the pressure-sensitive adhesive having no carboxyl group (-COOH) . The method of claim 2, wherein the percutaneous absorption enhancer is a percutaneous absorbing agent, characterized in that the C _8-18 aliphatic derivatives. The transdermal absorption enhancer according to claim 2, wherein the transdermal absorption enhancer is selected from the group consisting of glycerol lauryl alcohol, oleyl alcohol, isopropyl myristate, sorbitan monooleate, propylene glycol monolaurate, propylene glycol monooleate, oleoyl macrogol glyceride, Propyleneglycol caprylate / caprate, sorbitan monostearate, sorbitan monooleate, glycerol monooleate, glycerol monolaurate, propylene glycol monolaurate, propylene glycol monolaurate, PEG-8 caprylic / capric triglyceride, polyoxyethylene sorbitan monolaurate, corn oil PEG-8 ester, polyoxyethylene sorbitan monolaurate, sorbitan monolaurate, lauryl lactate, , Corn oil PEG-6 ester, or one or two Percutaneous absorbent characterized by using the above. 9. The composition of claim 8, wherein the percutaneous absorption enhancer is selected from the group consisting of glycerol monooleate, glycerol monolaurate, propylene glycol monolaurate, sorbitan monooleate, sorbitan monolaurate, lauryl pyrrolidone, triacetin, Wherein the percutaneous absorption agent is one or more selected from the group consisting of a surfactant and a surfactant. The percutaneous absorption enhancer according to claim 2, wherein the percutaneous absorption enhancer is 5 to 20% by weight based on the total weight of the drug-containing adhesive layer. The composition according to claim 2, wherein the antioxidant is one or more compounds selected from the group consisting of butylhydroxytoluene, butylhydroxyanisole, propyl gallate, ascorburic acid, tocopherol, tocopherol acetate and ascorbyl palmitate Is used as the absorbent. The method of claim 1, wherein the support layer is made of a material such as polyethylene terephthalate (PET), polyethylene (PE), polypropylene (PP), ethylene vinyl acetate copolymer (EVA), nylon, cotton, A combination of two or more woven fabrics and films, a combination of a nonwoven fabric and a film, and a combination of a film and a film are used in order to prevent contact of water vapor in oxygen and air A film or a combination of a nonwoven fabric and a film is used. The method according to claim 1, wherein the release layer comprises at least one of a polyester film, a polyvinyl chloride film, a polyvinylidene chloride film, a polyethylene terephthalate (PET) film, a polyethylene (PE) film, a polyethylene / / EVA composite material is a release layer surface-treated as silicon or fluorine treatment agent. The percutaneous absorber according to claim 12 or 13, wherein an aluminum thin film is laminated in the middle for further shielding or aluminum is deposited on the surface of the film.

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