JP2017190309A - Rivastigmine percutaneously absorbable preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a percutaneously absorbable preparation comprising a relatively large amount of rivastigmine and having an adhesive force to ensure safe administration over the whole administration period.SOLUTION: According to the present invention, a percutaneously absorbable preparation comprises a support layer and a pressure-sensitive adhesive layer. The adhesive layer contains, as essential components, 10 to 50% of rivastigmine or a pharmaceutically acceptable salt thereof, a self-crosslinking type adhesive agent, and an acrylic polymer having a glass transition temperature of room temperature or higher. The rivastigmine content is preferably 20 to 45%.SELECTED DRAWING: Figure 1

Description

The present invention relates to a percutaneous absorption treatment system comprising rivastigmine as a pharmaceutically active ingredient and comprising a support layer and an adhesive layer.

Rivastigmine is an acetylcholinesterase inhibitor and is used for the treatment of Alzheimer-type dementia (Patent Document 1). Rivastigmine is also useful in treating patients with symptoms of dementia and traumatic brain injury associated with Parkinson's disease. Rivastigmine is an effective drug, but when administered orally, it causes significant side effects on the digestive tract. Therefore, a transdermal administration method has been developed and is currently used in the form of a patch (Patent Document 2).

Since rivastigmine is easily oxidatively decomposed, a percutaneous absorption preparation supported in an acrylate polymer together with an antioxidant is disclosed (Patent Document 3). Rivastigmine transdermal absorption preparation (Patent Document 4, Patent Document 8, Patent Document 10) using acrylic polymer is published, but when rivastigmine which is liquid is mixed with acrylic adhesive, the adhesive is plasticized. There are practical difficulties. Furthermore, rivastigmine transdermal preparation using a silicone adhesive (Patent Document 5), rivastigmine transdermal preparation using an acrylic polymer and a polyhydric alcohol (Patent Document 6), acrylic, silicone, rubber, etc. A rivastigmine transdermal absorption preparation (Patent Document 7) and the like using the above adhesive has already been published. A percutaneous absorption preparation comprising a rivastigmine storage tank and a silicone adhesive layer is also disclosed (Patent Document 9). This percutaneously absorbable preparation has a problem in that it has a complicated structure and is expensive to manufacture, and when the silicone adhesive layer is broken, the drug in the reservoir flows out and loses its function as a percutaneously absorbable preparation.

Japanese Unexamined Patent Publication No. 63-238054 JP 09-118617 A (GB2203040) Japanese translation of PCT publication No. 2002-500188 (EP1047409) Japanese translation of PCT publication No. 2002-542277 Special table 2009-517468 JP 2012-236773 A JP 2012-051875 A Special table 2011-521975 gazette JP 2013-177419 A WO2013 / 031992

The percutaneously absorbable preparations published so far have practical problems and need to further improve the adhesive properties. The problem to be solved by the present invention is to have a relatively large amount of active ingredient, have an adhesive force to ensure safe administration over the entire administration period, and do not have an inappropriately large spread, It is an object of the present invention to provide a transdermally absorbable preparation that exhibits improved adhesion characteristics without changing the release characteristics of the composition, and has improved compliance, adhesion, and safety.

The transdermally absorbable preparation according to the present invention made to solve the above problems is composed of a support layer and an adhesive layer, and the adhesive layer is rivastigmine or a pharmaceutically acceptable salt thereof, a self-crosslinking adhesive. And an acrylic polymer having a glass transition temperature of room temperature or higher as an essential component.

In transdermal administration of rivastigmine, it is known that the concentration of rivastigmine in the percutaneous absorption preparation correlates with transdermal permeability. Therefore, it is desirable to make the rivastigmine concentration in the transdermal absorption preparation as high as possible. On the other hand, when the concentration of rivastigmine in the pressure-sensitive adhesive layer increases, there is a problem of reducing the pressure-sensitive adhesive properties, and there has been a demand for a solution to this contradiction.

In this study, it was shown that when the concentration of rivastigmine in the percutaneous absorption preparation was 10%, the percutaneous permeability was insufficient, and 20% or more was preferable. On the other hand, when the concentration is 50% or more, the pressure-sensitive adhesive system becomes extremely soft and there is a problem in practicality as a transdermally absorbable preparation. Therefore, it was clarified that the concentration of rivastigmine in the percutaneous absorption preparation was a preferable preparation satisfying both the drug percutaneous absorption and the physical properties of the adhesive when the concentration in the adhesive layer was 20% or more and 45% or less. By adding an appropriate amount of an acrylic polymer having a glass transition temperature of room temperature or higher even at 50%, it is possible to impart practical properties to the adhesive.

When the drug (active ingredient) is liquid at room temperature, increasing the drug content in the adhesive layer significantly reduces the adhesive properties of the adhesive. Transdermal preparations containing a large amount of rivastigmine, which is liquid at room temperature, in the adhesive layer, the adhesive layer becomes extremely soft, and the adhesive may adhere to the skin and stick to the skin when it is peeled off. .
However, when the pressure-sensitive adhesive is a self-crosslinking type, there is a feature that there is little decrease in cohesive force even when a large amount of drug is held. A pressure-sensitive adhesive that is not self-crosslinking is softened as a whole when a large amount of liquid drug is held, and produces adhesive residue when used as a transdermally absorbable preparation.

The self-crosslinking adhesive is characterized in that a crosslinking agent is incorporated in the adhesive, and is a pressure-sensitive adhesive that crosslinks by volatilizing a solvent by heating. In the present invention, an acrylate pressure-sensitive adhesive that crosslinks when the organic solvent is dried at 60 ° C. and generates a gel content is used.
Here, polyacrylate is acrylic acid, acrylic acid ester (especially ester with alcohol having 4 to 12 carbon atoms of alcohol), methacrylic acid ester (especially alcohol having 4 to 12 carbon atoms of alcohol). And a copolymer composed of vinylpyrrolidone, hydroxyalkyl acrylate and the like, and has a property of being soluble in an organic solvent such as ethyl acetate.

In the present invention, the cohesive strength of the pressure-sensitive adhesive is maintained by using a self-crosslinking pressure-sensitive adhesive, and a large amount of a solidifying agent is added to improve the pressure-sensitive adhesive properties. By adding a self-crosslinking adhesive and an acrylic polymer with a glass transition temperature of room temperature or higher as a solidifying agent, it is possible to obtain a transdermally absorbable preparation that promotes solidification of the adhesive layer and has no adhesive residue on the skin. It was.

As the solidifying agent, a polymer or cellulose having a glass transition temperature higher than room temperature is suitable. In the present invention, an acrylic polymer having a glass transition temperature of room temperature or higher, for example, butyl methacrylate-methyl methacrylate copolymer or polymethyl methacrylate resin (PMMA) is used.

In a preferred embodiment, the pressure-sensitive adhesive layer further contains auxiliaries such as extenders, antioxidants, colorants, skin penetration enhancers and / or preservatives. Such auxiliaries are known to the expert and can be selected from standard reference books.

The pressure-sensitive adhesive layer preferably contains an antioxidant such as α-tocopherol, ascorbyl palmitate or butylated hydroxytoluene (BHT).
The pressure-sensitive adhesive layer further comprises 2- (2-ethoxyethoxy) ethanol, glycerin, glycerin-ester, fatty acid, fatty acid salt, diethyl-toluolamide, propylene glycol, propylene glycol-ester, butanediol, isopropyl-ester, urea It is preferable to include a skin penetration enhancer such as

The adhesive strength of the transdermally absorbable preparation is preferably greater than 5N / 10cm2, more preferably greater than 10N / 10cm2. The adhesive strength of the transdermally absorbable preparation is preferably less than 100 N / 10 cm 2, more preferably less than 50 N / 10 cm 2. If the adhesive strength is less than 5 N / 10 cm 2, the preparation will peel off after dermal administration to humans. On the other hand, if it is larger than 100 N / 10 cm 2, there is a problem that the skin irritation increases when the preparation is peeled off or the adhesive does not remain on the skin. The size of the percutaneous absorption preparation is preferably 2 to 50 cm 2, and more preferably 5 to 20 cm 2.

The percutaneous absorption preparation of the present invention can be produced by any method known to those skilled in the art, but one preferred method includes the following steps.
a) producing an adhesive solution of the active ingredient,
b) coating the support layer with an adhesive solution of the active ingredient,
c) drying the coated active ingredient adhesive solution;
d) The composition of the adhesive layer to be punched and bagged, for example, the nature and amount of excipients and / or active agents, and the dimensions of the transdermally absorbable preparation can be freely selected by those skilled in the art.

The support layer is not in direct contact with the skin, and any suitable material or combination of materials, preferably impermeable to the active ingredient, can be used. Specifically, a flexible polymer film can be suitably used.
For example, polyethylene, polypropylene, polyethylene terephthalate, polyacrylonitrile, nylon, polyurethane, and the like. Moreover, the film which laminated the nonwoven fabric and the film can also be used as a support body. The nonwoven fabric is preferably a polyethylene terephthalate nonwoven fabric.
The drug (rivastigmine) of the present invention is a liquid, and when the drug is impregnated at a high concentration, the transdermally absorbable preparation is often softened and the adhesion to the support layer is often weakened. In such a case, it is advantageous to use a film support laminated with a polyethylene terephthalate nonwoven fabric because the pressure-sensitive adhesive is bitten by the nonwoven fabric and exhibits strong adhesion. The thickness of the support layer is preferably 10 μm to 200 μm.

The transdermally absorbable preparation of the present invention can be prepared taking into account the following aspects:
・ Time to release of active agent (lag time or delay time)
Active agent release rate (fast or slow)
Active agent release time (long or short)
• Reduced first-pass metabolism • Improved patient compliance • Reduced dosing interval Such aspects can be observed, for example, by standard in vitro dissolution tests in water or body fluids if desired, eg, artificial gastric fluid.

The exact amount of active ingredient to be administered and the amount of adhesive layer component will depend on a number of factors such as the condition to be treated, the desired duration of treatment and the rate of release of the active ingredient.
For example, the amount of active agent required and its rate of release are known in vitro or in vivo techniques that determine how long a particular active agent concentration remains in the plasma at a level that is acceptable for a therapeutic effect. Can be determined based on

The transdermally absorbable preparation of the present invention simplifies treatment, for example, allowing administration once a day, for example, for patients who have to administer the active agent more than once at a particular time. Such a composition may improve the tolerability of rivastigmine and allow for a higher starting dose and fewer dose titration steps.
The increased tolerability of rivastigmine can be confirmed by standard animal and clinical studies.

Since the percutaneous absorption preparation of the present invention contains a free or pharmaceutically acceptable salt cholinesterase inhibitor as an active agent, it can be used not only for prevention, treatment or delay of progression of dementia, but also for Parkinson's disease. It is also effective as a method for preventing, treating or delaying progression of dementia. The transdermally absorbable preparation of the present invention can also be used for the prevention, treatment or progression delay of Alzheimer's disease.

The present invention improves the efficacy and tolerability of rivastigmine and provides an average maximum plasma concentration of about 1-30 ng / mL for an average of about 2-16 hours after administration in a size of 3-50 cm2. Yes.

The transdermally absorbable preparation of the present invention has a simple structure because the drug-containing layer and the adhesive layer are integrated and held on the surface of the support layer, and does not have a reservoir, and the adhesive properties are improved from the conventional example. Yes.

Illustration of the amount of rivastigmine penetrating through human skin-time curve

Examples of the present invention will be described in detail, but the present invention is not limited to the examples.

(Measurement of self-crosslinking property of adhesive)
The pressure-sensitive adhesive is preferably a self-crosslinking polyacrylate containing a crosslinking agent. Since the detailed composition of the commercially available pressure-sensitive adhesive is not always clear, four types of commercially available acrylic pressure-sensitive adhesives were tested for their self-crosslinking properties. Here, Duro-Tak87-235A, Duro-Tak87-2677 and Duro-Tak387-2287 are manufactured by Henkel, USA, and MASCOS10C is manufactured by Kosmedy Pharmaceutical.

About 1 g of four kinds of commercially available acrylic pressure-sensitive adhesive solutions were cast on a PET release film, dried at 80 ° C. for 60 minutes, and the pressure-sensitive adhesive solid content after drying was accurately weighed (pressure-sensitive adhesive weight). The dried adhesive was immersed in 100 mL of ethyl acetate and allowed to stand at room temperature for 24 hours. The insoluble matter in ethyl acetate was separated, washed with ethyl acetate and dried at 80 ° C. for 60 minutes (gel weight). The ratio of gel weight to pressure-sensitive adhesive weight was calculated as a gel fraction (expressed as%). The results are shown in Table 1.
As a result, it was found that Duro-Tak87-2677 and MASCOS10C have self-crosslinking property, but Duro-Tak87-235A and Duro-Tak387-2287 have no self-crosslinking property.

(Evaluation of adhesive properties)
A rivastigmine transdermal absorption preparation containing rivastigmine, an adhesive, and a solidifying agent was prepared and applied to volunteers to evaluate adhesiveness.
The rivastigmine transdermally absorbable preparation needs to contain a large amount of rivastigmine free base in order to increase the effect. Therefore, the preparation becomes soft and the adhesive residue after application to the skin is a problem, so this evaluation was performed.

A predetermined amount of rivastigmine, adhesive, and solidifying agent was used as an ethyl acetate solution. Four types of adhesives described in Table 1 were used. As a solidifying agent, butyl methacrylate-methyl methacrylate copolymer (PlastoidB, Basf Co., Ltd.) or polymethyl methacrylate resin (PMMA) was used for the stabilization of drugs with α-tocopherol and BHT in all evaluation samples. Added to. Each evaluation sample solution was cast on a polyester film and dried to prepare a transdermal absorption preparation. Each percutaneously absorbable preparation is cut into 2 × 2 cm, attached to a volunteer, peeled off after 1 hour, and a list of preparation constituents evaluated for adhesiveness and the presence or absence of adhesive residue is shown in Table 2. The unit of the component is% by weight. In addition, the component after the decimal point is rounded off to the nearest 5% by weight.

The results of volunteer evaluation are as follows.
A: The formulation adheres well to the skin and does not come off. When removing the preparation, it can be removed smoothly and there is no adhesive residue on the skin. Adhesive properties of the drug product are appropriate
B: The preparation adheres strongly to the skin and does not come off. When the preparation is peeled off, the pressure-sensitive adhesive cohesively breaks down, resulting in adhesive residue on the skin. It is unsuitable as a preparation.
C: Since the preparation is hard and weakly sticky, it may fall off the skin when applied to the skin. It is unsuitable as a preparation.
From these results, it can be concluded that a suitable transdermally absorbable preparation can be obtained by selecting a self-crosslinking adhesive and using an appropriate amount of a solidifying agent.

3. Permeation characteristics Using full-thickness human skin, transdermal penetration of rivastigmine was examined by the following in vitro permeation test.
Human skin with a prototype rivastigmine patch (composition of Example 1, area = 1.3 cm2) is set in an improved Franz-type cell and sampled over time with a transdermal absorption test automatic sampling device (TransView C12, manufactured by Kosmedy Pharmaceutical) It was. 5.75 ml of PEG400: H2O (1: 3 w / w) mixture was used as the receptor medium. The test temperature was adjusted to 32 ° C. corresponding to the temperature of in vivo human skin with a water bath. A commercial product (Exelon Patch), which is a commercially available transdermal absorption preparation of rivastigmine, was used as the subject. Rivastigmine concentration in the receptor medium was measured by HPLC. The results of the transmission test are shown graphically in FIG. The amount of rivastigmine penetrating through the human skin in the free base showed permeability equivalent to or higher than that of a commercially available product when the content of rivastigmine was set to 30.0%.
In FIG. 1, the triangle mark (▲) is the result of the transdermally absorbable preparation of Example 1. The square marks (■) are the results of measuring commercially available products (Exelon Patch) under the same conditions.

Patches with different rivastigmine concentrations were prepared and permeation tests similar to the above were performed to summarize the 24-hour drug permeation amount (Table 3).
As a result of the transmission test, the following was found. The drug penetration rate in the in vitro test is approximately proportional to the drug concentration in the adhesive layer if the drug is liquid. Table 3 shows the results of measuring the amount of drug permeation while changing the rivastigmine concentration.

(Table 3) Prototype rivastigmine patch composition and drug penetration

In Comparative Example 9, the concentration of rivastigmine was too high, and the adhesive properties were broken, and the drug permeation amount test was not performed.
The concentration of rivastigmine and percutaneous permeability correlate, and when the concentration is 20% or less, the amount of drug permeation is small and inferior in practical use. On the other hand, when the concentration is 50% or more, the pressure-sensitive adhesive system becomes extremely soft, and the practicality as a transdermal absorption preparation becomes a problem. From the results in this table, it can be concluded that the amount (% by weight) of rivastigmine in the pressure-sensitive adhesive layer is preferably 10 to 50%, more preferably 20 to 45%.

Claims (5)

Consists of a support layer and an adhesive layer,
The adhesive layer is a transdermally absorbable preparation containing, as essential components, 10 to 50% rivastigmine or a pharmaceutically acceptable salt thereof, a self-crosslinking adhesive, and an acrylic polymer having a glass transition temperature of room temperature or higher. The transdermal absorption preparation according to claim 1, wherein the amount of rivastigmine in the adhesive layer is 20 to 45%. 3. The transdermal system according to claim 1 or 2, wherein the adhesive layer contains 29 to 64% of a self-crosslinking adhesive and 15 to 25% of an acrylic polymer having a glass transition temperature of room temperature or higher. Absorption formulation. The transdermally absorbable preparation according to any one of claims 1 to 3, wherein the acrylic polymer having a glass transition temperature of room temperature or higher is a butyl methacrylate-methyl methacrylate copolymer. The transdermally absorbable preparation according to any one of claims 1 to 4, wherein a film laminated with a polyethylene terephthalate nonwoven fabric is used as the support.

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