KR20210105596A - Transdermal drug delivery system comprising granisetron - Google Patents

Abstract

The present invention relates to a transdermal absorption preparation containing granisetron. The transdermal absorption preparation containing granisetron according to the present invention not only exhibits a high granisetron transdermal absorption rate, but also has no skin irritation upon attachment. In addition, by effectively suppressing nausea and vomiting, which may occur due to the side effects of anticancer drugs administered to cancer patients, through continuous drug delivery through the skin (transdermal), it is possible to reduce patient discomfort and increase compliance.

Description

Transdermal drug delivery system comprising granisetron

The present invention relates to a transdermally absorbable preparation containing granisetron as an active ingredient, and more particularly, to an antiemetic transdermally absorbable preparation containing granisetron having excellent transdermal absorption and hypoallergenicity. .

Side effects such as nausea and vomiting occurring during chemotherapy in cancer patients can lead to reduced food intake, dehydration, and deterioration of nutritional status. This can weaken cancer patients and cause poor adherence to chemotherapy, weakening the resistance to cancer and reducing the therapeutic effect.

Drugs that can suppress nausea and vomiting, such as ondansetron, granisetron, and tropisetron, which are antagonists of the 5-hydroxytrptamine3 (5-HT3) receptor It is known that antiemetics can suppress vomiting, which may appear as a side effect of anticancer drugs when administered in combination during chemotherapy.

Antiemetics, which oppose the 5-HT3 receptor, are currently administered intravenously, orally, or rectally. Among them, granisetron is a colorless drug having a molecular structure as shown in Formula 1 below, and is currently mostly administered through intravenous injection or oral administration, but in the case of intravenous injection, only under the supervision of a doctor. It can be carried out, and there is a problem that not only can reduce patient compliance due to the discomfort caused by repeated administration and avoidance of injection, but also cause bacterial infection if the preparation is not carefully handled. In addition to the disadvantage of having to administer frequently (up to four times a day), there may be a problem in that it is difficult to administer to patients who are experiencing severe nausea and vomiting.

[Formula 1]

Accordingly, there is a need for the development of a parenteral drug delivery system capable of maintaining a constant plasma concentration of an antiemetic agent for a long period of time. When the formulation is applied to granisetron, it is possible to maintain a constant blood concentration of the drug, as well as to solve the problems of drug administration through intravenous, oral, etc.

As a prior art for transdermal absorbent containing granisetron, Korean Patent No. 10-2005-0116365 discloses transdermal absorption comprising only acrylic adhesive containing granisetron and non-acidic hydroxyl moiety. In Korea Patent No. 10-2005-0116365, a pressure-sensitive adhesive in which granisetron and an acrylate polymer having a hydroxyl group and an acrylate polymer without a functional group are mixed in a ratio of 20-90:10-80 Transdermal absorption preparations containing

However, the acrylate polymer having a hydroxyl group applied in Korean Patent No. 10-2005-0116365 has a good skin absorption rate of the drug, but lacks the cohesive force of the adhesive itself, causing slippage when the transdermal absorbent is applied to the affected area (cold). flow) may occur, and the acrylate polymer without a functional group applied in Korean Patent No. 10-2005-0116365 has good cohesiveness of the adhesive itself, but the transdermal absorption rate of the drug is lower than that of the acrylate polymer having a hydroxyl group. there is a problem.

Korean Patent Publication No. 10-2005-0116365 Korean Patent Publication No. 10-2009-0076434

It is an object of the present invention to provide a transdermally absorbable preparation containing granisetron that does not have problems such as skin irritation and has a high transdermal absorption rate by mixing an acrylate polymer without a functional group and a transdermal absorption promoter in order to solve the conventional problems.

Specifically, an object of the present invention is to provide a transdermally absorbable preparation comprising a drug-containing layer containing granisetron as an active ingredient, wherein the drug-containing layer further comprises a transdermal absorption accelerator and an adhesive, wherein the adhesive has no functional group. It is to provide a transdermally absorbable preparation comprising an acrylate-based polymer.

In order to solve the above problems, a transdermally absorbable preparation containing granisetron of the present invention was developed.

The inventors of the present invention research and develop granisetron transdermal absorption preparation capable of suppressing nausea and vomiting that may appear due to the side effects of anticancer drugs administered to cancer patients. When an acrylate polymer adhesive without an accelerator and a functional group is included, it can be effectively inhibited through continuous drug delivery through the skin to reduce patient discomfort and increase compliance, while exhibiting a high transdermal absorption rate of granisetron as well as the skin upon attachment. The present invention was completed by finding that there was no irritation.

Hereinafter, the present invention will be described in detail.

Transdermal absorption preparation containing granisetron

An object of the present invention is to provide a transdermally absorbable preparation comprising a drug-containing layer containing granisetron as an active ingredient, wherein the drug-containing layer further comprises a transdermal absorption accelerator and an adhesive, wherein the adhesive is an acrylate-based adhesive without a functional group. It is to provide a transdermally absorbable preparation comprising a polymer.

In the present invention, granisetron may be directly prepared by a conventionally known manufacturing method, or purchased from the market may be used.

In the present invention, the content of granisetron may be 1 to 25% by weight of the entire drug-containing layer, more preferably 1 to 6% by weight of the entire drug-containing layer, but is not limited thereto.

In the present invention, the term "drug-containing layer" refers to a matrix type of a main component included in the transdermal absorption preparation of the present invention, which includes pharmacologically active granisetron, a transdermal absorption enhancer, and an adhesive. .

In the present invention, the average thickness of the drug-containing layer may be 20 ~ 140㎛, preferably 80 ~ 120㎛ may be, but is not limited thereto.

In the present invention, the term "transdermally absorbable preparation" refers to a preparation that is absorbed through the skin (skin), and is composed of a support layer, a drug-containing layer, and a release layer.

In the present invention, the term "support layer" means to prevent the drug from being lost from the preparation during storage and distribution of the transdermally absorbed preparation or while it is attached to the skin.

In this case, in the case of the support layer, a thin, flexible, and non-irritating layer is used. As the support layer, for example, a material such as polyethylene terephthalate (PET), polyethylene (PE), polypropylene (PP), ethylene vinyl acetate copolymer (EVA), nylon (Nylon), etc. may be used, and a film of such material may be used alone, or a laminated film in which two or more films are combined may be used. In addition, when using a film in which two or more films are laminated, an aluminum deposition film may be used for light blocking and moisture proofing.

In the present invention, the term "peel layer" means to protect the drug-containing product while the transdermally absorbable preparation is packaged as a product, stored or distributed, and to provide convenience so that it can be easily removed when using the product.

At this time, as the release layer, for example, a film made from polyester, polyvinyl chloride, polyvinylidene chloride, polyethylene terephthalate, polyethylene, ethylene vinyl acetate, etc. Film can be used. The release layer is coated with a silicone resin or a fluororesin on the surface to which the adhesive layer touches, and it is preferable to use a polyethylene terephthalate film having excellent long-term stability of the drug.

In the present invention, the term "transdermal absorption promoter" means that it is possible to enhance the skin absorption rate of granisetron and the solubility of the drug in the transdermal absorption agent during the storage period.

In the present invention, the transdermal absorption enhancer is any one or more fatty acid esters selected from the group consisting of glycerol monooleate, propylene glycol monooleate and sorbitan monolaurate; Any one or more propanediols selected from the group consisting of 2-amino-2-methyl-1,3-propanediol, 3-amino-1,2-propanediol and 2-amino-1,3-propanediol ; any one or more glycerides selected from the group consisting of caprylocaproyl macrogol-8 glyceride and caprylocaproyl polyoxyl-8 glyceride; And any one or more glycols selected from the group consisting of diethylene glycol monoethyl ether and propylene glycol dicaprylocaprate; may be one or two or more selected from the group consisting of, but is not limited thereto.

Also, preferably, the fatty acid esters may be propylene glycol monooleate and glycerol monooleate, and the propanediols may be 2-amino-2-methyl-1,3-propanediol, and glycerides. may be caprylocaproyl macrogol-8 glyceride, and the glycols may be diethylene glycol monoethyl ether, propylene glycol dicaprylocaprate, and propylene glycol monocaprylate, but is not limited thereto.

In the present invention, the transdermal absorption enhancer may be used in combination of two or more transdermal absorption enhancers, specifically, propylene glycol monooleate (fatty acid esters) and 2-amino-2-methyl-1,3-propanediol (propanediols), propylene glycol monooleate (fatty acid esters) and diethylene glycol monoethyl ether (glycols), propylene glycol monooleate (fatty acid esters) and propylene glycol dicaprylocaprate ( glycols), propylene glycol monooleate (fatty acid esters) and propylene glycol monocaprylate (glycols), propylene glycol monooleate (fatty acid esters) and glycerol monoolet (fatty acid esters) may be a combination of propylene glycol monooleate (fatty acid esters) and caprylocaproyl macrogol-8 glyceride (glycerides), more preferably propylene glycol monooleate (fatty acid esters) and Caprylocaproyl macrogol-8 glyceride (glycerides) may be used in combination, but is not limited thereto.

For example, when the transdermal absorption enhancer is used in combination with propylene glycol monooleate (fatty acid esters) and 2-amino-2-methyl-1,3-propanediol (propanediols), 0.5 to 1.5: 0.5 It may be mixed in a weight ratio of ~ 1.5, but is not limited thereto.

In addition, when the transdermal absorption accelerator is used in combination with propylene glycol monooleate (fatty acid esters) and diethylene glycol monoethyl ether (glycols), it may be mixed in a weight ratio of 1 to 5: 1, more specifically, 2 to 3.5: may be mixed in a weight ratio of 1, but is not limited thereto.

In addition, when the transdermal absorption promoter is used in combination with propylene glycol monooleate (fatty acid esters) and propylene glycol dicaprylocaprate (glycols), it may be mixed in a weight ratio of 1 to 5: 1, more specifically 2 to 3.5: may be mixed in a weight ratio of 1, but is not limited thereto.

In addition, when the transdermal absorption promoter is used in combination with propylene glycol monooleate (fatty acid esters) and propylene glycol monocaprylate (glycols), it may be mixed in a weight ratio of 1 to 5: 1, more specifically, 2 to 3.5: may be mixed in a weight ratio of 1, but is not limited thereto.

In addition, when the transdermal absorption enhancer is used in combination with propylene glycol monooleate (fatty acid esters) and glycerol monoolet (fatty acid esters), it may be mixed in a weight ratio of 1 to 5: 1, more specifically 2 ~ 3.5: may be mixed in a weight ratio of 1, but is not limited thereto.

In addition, when the transdermal absorption enhancer is used in combination with propylene glycol monooleate (fatty acid esters) and caprylocaproyl macrogol-8 glyceride (glycerides), it can be mixed in a weight ratio of 1 to 5: 1, , more specifically 1 to 3.5: may be mixed in a weight ratio of 1, but is not limited thereto.

In the present invention, when the two or more transdermal absorption promoters are combined, propylene glycol monooleate (fatty acid esters) is a transdermal absorption promoter that is necessarily combined, and by including it as a base, there is an advantage that can improve the transdermal permeability. .

In the present invention, the content of the transdermal absorption enhancer may be 0.1 to 25% by weight of the total drug-containing layer, preferably 0.1 to 10% by weight, but is not limited thereto.

In the present invention, when the content of the transdermal absorption enhancer is less than 0.1% by weight of the total drug-containing layer, the expected transdermal permeability cannot be obtained, and when it exceeds 25% by weight, the transdermal absorption of the drug is no longer improved, and the transdermal Since the absorption enhancer also acts as a plasticizer of the pressure-sensitive adhesive, the physical strength of the transdermal absorption enhancer may be reduced, and in some cases, skin irritation may be caused to the user.

In the present invention, the term “adhesive” means that the transdermal absorption agent can function as a carrier for skin adhesion and granisetron and a transdermal absorption accelerator.

In the present invention, the pressure-sensitive adhesive includes an acrylate-based polymer without a functional group, and is characterized in that the acrylate-based polymer having a functional group is excluded.

Specifically, there is a problem in that the cohesive force of the pressure-sensitive adhesive itself is lowered depending on the content of the transdermal absorption accelerator, so that when the skin is attached to the skin, a cold flow may occur.

In the present invention, the term "functional group" means a common atomic group that causes the characteristic in acrylate-based polymers having the same chemical properties, for example, OH group, COOH group, and the like.

An acrylate polymer without a functional group usable as an adhesive in the present invention is Durotak 87-9301 (Acrylate copolymer) obtained through the synthesis of a vinyl acetate-based monomer and an acrylic monomer, or Duro-Tak 87-900A obtained through the synthesis of an acrylic monomer. and Duro-Tak 87-4098.

As the polymer that can be used as an adhesive for the transdermal absorption agent, an acrylate polymer having a hydroxyl group and an acrylate polymer having no functional group can be used. However, the acrylate polymer having a hydroxyl group has a good skin permeability of the drug, but lacks the cohesive force of the adhesive itself, so there is a problem that cold flow may occur when the formulation is applied to the affected area. Although the acrylate polymer has good cohesiveness of the adhesive itself, there is a problem that the skin permeability of the drug is lower than that of the acrylate polymer having a hydroxyl group.

Therefore, the inventors of the present invention confirmed that by selecting an acrylate polymer without a functional group and mixing and using a transdermal absorption accelerator, the effect of synergizing transdermal absorption and improving skin irritation were obtained.

In the present invention, the content of the acrylate-based polymer without a functional group may be 70 to 99.9% by weight of the entire drug-containing layer, preferably 84 to 89% by weight, but is not limited thereto.

In the present invention, the transdermally absorbable preparation may be used for the prevention or treatment of vomiting caused by chemotherapy or post-operative nausea and vomiting, but is not limited thereto.

In the present invention, the transdermally absorbable preparation may be in the form of a patch, but is not limited thereto.

In the present invention, the term “patch agent” refers to an adhesive containing granisetron, which is used by attaching it to a site necessary for the granisetron to slowly penetrate into the human body. It can be included in the range that does not impair the characteristics of the patch posted on

The granisetron may be used in a therapeutically effective amount, and in the case of a patch, the granisetron may be in the range of 10 to 80 mg, preferably about 34.3 mg per unit patch. have.

The transdermally absorbable preparation of the patch, cataplasma or patch according to the present invention may be prepared according to a conventional method used in the pharmaceutical field using the components described above.

The granisetron-containing transdermal absorption preparation according to the present invention not only exhibits a high granisetron transdermal absorption rate, but also has no skin irritation upon attachment.

By effectively suppressing nausea and vomiting, which may occur due to the side effects of anticancer drugs administered to cancer patients, through continuous drug delivery through the skin (transdermal), it is possible to reduce patient discomfort and increase compliance.

1 is a view showing the transdermal absorption rate (μg/cm2) of granisetron for a transdermal preparation prepared according to an embodiment of the present invention and a SANCUSO ^{® patch product (LG Chemical) of Comparative Example 1. FIG.}
2 is a photograph showing the sagging of the adhesive layer (left) and cold flow (right) when the granisetron-containing transdermal absorbent preparation prepared in Example 8 is attached to the skin and then removed using a general camera. sketch a photo
3 is a photograph taken using a general camera of the sagging of the adhesive layer (left) and cold flow (right) of ^{the SANCUSO ®} patch product (LG Chemical) of Comparative Example 1 when removed after being attached to the skin. schematize
FIG. 4 is a diagram of a photograph taken using a video microscope system of the keratin removed by the adhesive layer after attaching the granisetron-containing transdermal absorption preparation prepared in Example 8 to the skin.
FIG. 5 is a schematic photograph of the dead skin cells removed by the adhesive layer after attaching ^{the SANCUSO ® patch product (LG Chemical) of Comparative Example 1 to the skin using a video microscope system.}

The terms used in this specification have been selected as currently widely used general terms as possible while considering the functions in the present invention, which may vary depending on the intention or precedent of a person skilled in the art, the emergence of new technology, and the like. In addition, in a specific case, there is a term arbitrarily selected by the applicant, and in this case, the meaning will be described in detail in the description of the corresponding invention. Therefore, the term used in the present invention should be defined based on the meaning of the term and the overall content of the present invention, rather than the name of a simple term.

Unless defined otherwise, all terms used herein, including technical and scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Terms such as those defined in a commonly used dictionary should be interpreted as having a meaning consistent with the meaning in the context of the related art, and should not be interpreted in an ideal or excessively formal meaning unless explicitly defined in the present application. does not

Numerical ranges are inclusive of the values defined in that range. Every maximum numerical limitation given throughout this specification includes all lower numerical limitations as if the lower numerical limitation were expressly written. Every minimum numerical limitation given throughout this specification includes all higher numerical limitations as if the higher numerical limitation were expressly written. Any numerical limitation given throughout this specification shall include all numerical ranges within the broader numerical range, as if the narrower numerical limitation were expressly written.

Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are provided for easier understanding of the present invention, and the content of the present invention is not limited by the examples.

Granisetron was purchased from Yeonyeon Pharmaceutical, and an acrylate polymer without a functional group as an adhesive was purchased from Henkel (product name: Duro-Tak ^TM 87-9301), and propylene glycol monooleate, a transdermal absorption accelerator ; hereinafter 'PGML', trade name: Lauroglycol - Gattefosse), aminomethyl propandiol (hereinafter 'AMPD', trade name: AMPD - ANGUS), diethyleneglycol monoethyl ether (hereinafter 'DGME', trade name: Transqutol P - Gattefosse), propylene glycol dicaprylocaprate (hereinafter 'PGDC', trade name: Labrafac - Gattefosse), propylene glycol monocaprylate (Propyleneglycol monocaprylate; hereinafter 'PGMC', trade name: Capryol - Gattefosse) Prepare glycerol monooleate (hereinafter 'GMO', trade name: Peceol - Gattefosse) and caprylocaproyl macrogol-8 glyceride (hereinafter 'CCMG', trade name: Labrasol - Gattefosse) and other reagents and solvents were purchased from Sigma-Aldrich Korea.

Example

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the present invention is not limited by the examples.

Examples 1 to 10: Preparation of transdermally absorbed preparations

After dissolving granisetron and transdermal absorption accelerator in methylene chloride in a 70 mL vial, the adhesive was added in a predetermined ratio and uniformly mixed in a roll mixer for 2 hours to prepare a drug-containing adhesive layer composition. The compounding amount of the drug-containing adhesive layer composition of each Example is shown in Tables 1 to 3 below (unit of content of each component: wt%).

After leaving for 30 minutes to remove air bubbles, a silicone-treated release film is placed on the coating machine and the drug-containing adhesive layer composition is dried and coated to a thickness of 110 μm, and then dried for 6 minutes while raising the temperature from 40°C to 80°C. to prepare a drug-containing adhesive layer.

Thereafter, the supporting layer film was laminated and compressed using a pressing roller, and then cut using a patch cutter to obtain a final product (patch agent).

[Table 1]

[Table 2]

[Table 3]

Comparative Example 1

LG Chem's SANCUSO ^® patch product sold in Korea was set as a control group.

Experimental Example 1: Transdermal absorption rate

Experimental method

Put isotonic phosphate buffer (Phosphate buffered saline solution, PBS solution pH = 7.4) as a receptor in a Franz-type diffusion cell, and maintain 32°C similar to the skin temperature, and stir at 600rpm with a magnetic stirrer Dissolved gas in the solution was removed by stirring at a constant speed. Thereafter, a patch cut to fit the upper donor cell of the Franz-type diffusion mechanism was attached to a membrane for transdermal absorption (Strat-M, Merck KGaA, Darmstadt, Germany), and mounted on the Franz-type diffusion mechanism. After that, 200 μl of the receptor part solution was collected every predetermined time, and 200 μl of a new isotonic phosphate buffer (PBS solution pH=7.4) was supplemented. The collected samples were analyzed by high performance liquid chromatography (HPLC), and the analysis conditions were as follows.

Analysis conditions

Column: C18, 4.6mm × 250mm, 5㎛ (Themo hypersil gold)

Mobile phase: dilution 1.6 mL of phosphoric acid with 800 mL of water, and mix with 200 mL of acetonitrile. After that, add 1 mL hexylamine and adjust the pH using triethylamine (pH 7.5 ± 0.05).

Flow rate: 1.5 mL/min

Column temperature: 40 ℃

Injection volume: 10 μl

Detection: UV 305nm

result

Example 1 (mixing of PGML and AMPD), Example 4 (mixing of PGML and DGME), Example 5 (mixing of PGML and PGDC), Example 6 (mixing of PGML and PGMC) , In the case of the transdermal absorption preparations of Example 7 (a mixture of PGML and GMO) and Example 8 (a mixture of PGML and CCMG), it was confirmed that the transdermal absorption was superior to that of the control (Comparative Example 1) ^{, which is a SANCUSO ® patch product, especially PGML} When (propylene glycol monooleate) and CCMG (caprylocaproyl macrogol-8 glyceride) were mixed and used, the transdermal absorption was excellent (Example 8).

Experimental Example 2: Confirmation of the sagging of the adhesive layer and the skin residue (cold flow)

Experimental method

The granisetron-containing transdermal preparation prepared according to Example 8, which had the best transdermal absorption among the above Examples, and the ^{control (Comparative Example 1), which is a SANCUSO ®} patch product, were attached to human skin for 30 minutes and then removed when removed. The sagging and skin residues (cold flow) were taken by using a general camera, and the pictures are shown in FIGS. 2 and 3 .

result

In the case of the granisetron-containing transdermal absorbent preparation prepared according to Example 8, it ^{was confirmed that the degree of sagging of the adhesive layer was less than that of the SANCUSO ®} patch product (see the left side of FIGS. 2 and 3), and also the skin residue (cold flow). ) did not occur (see the right side of FIGS. 2 and 3).

Experimental Example 3: Check the degree of damage to the stratum corneum

Experimental method

The granisetron-containing transdermal preparation prepared according to Example 8, which had the best transdermal absorption among the above Examples, and the ^{control (Comparative Example 1), which is a SANCUSO ®} patch product, were attached to human skin for 30 minutes and then removed when removed. The degree of damage to the stratum corneum of the skin was confirmed by photographing the dead skin cells removed by using a video microscope system (product name: SV-55, Sometech), and this is shown in FIGS. 4 and 5 .

result

4 and 5 , it was confirmed that in the case of the transdermally absorbable preparation containing granisetron prepared according to Example 8, the degree of exfoliation by the adhesive layer was less than that ^{of the SANCUSO ® patch product.} Through this, it was confirmed that the granisetron-containing transdermally absorbed preparation prepared according to Example 8 was an excellent transdermally absorbed preparation that did not damage the keratin when applied to the human body.

The transdermally absorbable granisetron formulation according to the present invention can be usefully used as an antiemetic agent because it can deliver an effective amount of a drug required to the patient while significantly improving the patient's medication compliance compared to the oral formulation.

Claims (8)

In the transdermal absorption preparation comprising a drug-containing layer containing granisetron as an active ingredient,
The drug-containing layer further comprises a transdermal absorption accelerator and an adhesive,
The pressure-sensitive adhesive is a transdermal absorbent preparation comprising an acrylate-based polymer without a functional group. The method of claim 1,
The content of granisetron is 1 to 25% by weight of the total drug-containing layer. The method of claim 1,
The transdermal absorption enhancer is any one or more fatty acid esters selected from the group consisting of glycerol monooleate, propylene glycol monooleate and sorbitan monolaurate; Any one or more propanediols selected from the group consisting of 2-amino-2-methyl-1,3-propanediol, 3-amino-1,2-propanediol and 2-amino-1,3-propanediol ; any one or more glycerides selected from the group consisting of caprylocaproyl macrogol-8 glyceride and caprylocaproyl polyoxyl-8 glyceride; and one or more glycols selected from the group consisting of diethylene glycol monoethyl ether and propylene glycol dicaprylocaprate. The method of claim 1,
The content of the transdermal absorption enhancer is 0.1 to 25% by weight of the total drug-containing layer. The method of claim 1,
The content of the functional group-free acrylate-based polymer is 70 to 99.9% by weight of the total drug-containing layer. The method of claim 1,
The average thickness of the drug-containing layer is 20 ~ 140 ㎛ granisetron transdermally absorbable preparation. The method of claim 1,
A transdermally absorbable preparation for the prevention or treatment of vomiting or postoperative nausea and vomiting caused by chemotherapy treatment. The method of claim 1,
The transdermally absorbable preparation is in the form of a patch.

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