JP2011051986A - Pasting preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pasting preparation containing rasagiline as a drug component, resistant to discoloration of an adhesive layer even by storing for a long time and keeping a sufficient drug content and percutaneous permeability. <P>SOLUTION: The pasting preparation is provided with a substrate and an adhesive layer placed on the substrate, wherein the adhesive layer contains a pharmaceutically acceptable acid addition salt of rasagiline, an amine compound and an adhesive base, and the adhesive base is a (meth)acrylate polymer which does not contain vinyl acetate as a monomer unit. The pasting preparation is used to administer 27-220 μg/kg body-weight of rasagiline once or twice per week for human. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a patch preparation.

  Rasagiline ((1R) -2,3-dihydro-N- (2-propynyl) -1H-inden-1-amine) is a compound having a monoamine oxidase inhibitory action and is used for the prevention and treatment of Parkinson's disease. Its structural formula is represented by the following formula (I). In the United States, the effects of single-agent administration in patients with early Parkinson's disease have been confirmed, and a 0.5 mg or 1 mg tablet once a day approved by the US Food and Drug Administration (FDA) in 2006 is recommended Has been.

  Rasagiline mesylate, rasagiline mesylate, is a white to off-white powder that is readily soluble in water or ethanol, but hardly soluble in isopropanol.

  For example, Patent Document 1 discloses an inert support layer that does not chemically react with a substrate component, a substrate layer containing rasagiline or a pharmaceutically acceptable salt thereof, and a protective layer that must be peeled off before use. The substrate layer is a drug reservoir containing an organic polymer material, and an inorganic or organic material as a regulator, the reservoir contains rasagiline, and the substrate further contains one or more types of rasagiline transdermally. A rasagiline transdermal drug patch for the prevention or treatment of nervous system diseases, characterized in that it contains a substance that promotes absorption is described.

Special table 2009-529011

  Since rasagiline mesylate is a highly hydrophilic drug, it is difficult to obtain the skin permeation rate necessary for transdermal delivery of the drug when it is made into a patch preparation. In the adhesive preparation containing rasagiline mesylate, the present inventors formulated sodium hydroxide in the pressure-sensitive adhesive layer in order to obtain a necessary skin permeation rate. As a result, the skin permeation rate of rasagiline was increased, but the adhesive layer was discolored during storage of the patch preparation, and the content of rasagiline was significantly reduced.

  Therefore, the present invention aims to provide a patch preparation containing rasagiline as a drug and capable of maintaining sufficient drug stability and skin permeation rate without causing discoloration of the adhesive layer even after long-term storage. To do.

  The present invention provides a patch preparation containing rasagiline which is used so that 27 to 220 μg / kg body weight of rasagiline is administered to a human once or twice a week. Such a patch preparation is useful in that it can be easily administered to patients with Parkinson's disease, who often have dysphagia, and in terms of improving compliance.

  The present invention also provides a patch preparation comprising a support and an adhesive layer disposed on the support, the adhesive layer comprising a pharmaceutically acceptable acid addition salt of rasagiline, an amine compound, and an adhesive. The adhesive base is a (meth) acrylic polymer not containing vinyl acetate as a monomer unit, and 27 to 220 μg / kg body weight of rasagiline per time for one week for humans. A patch preparation is provided that can be used once. Here, 27-220 μg / kg body weight of rasagiline is an amount converted to free rasagiline, not salt. As will be described later, even if such a patch preparation is stored for a long period of time, the adhesive layer does not change color, and sufficient drug stability and skin permeation rate can be maintained.

  The amine compound is more preferably triethanolamine. As will be described later, triethanolamine is highly effective in suppressing the reduction of rasagiline contained in the patch preparation.

  In the above-mentioned patch preparation, the ratio between the number of moles of pharmaceutically acceptable acid addition salt of rasagiline and the number of moles of the amine compound is more preferably in the range of 1: 0.1 to 1: 2. . With such a ratio, the stability of the drug and the skin permeation rate can be increased.

  The adhesive base is more preferably a (meth) acrylic acid alkyl ester copolymer that does not contain a vinyl acetate monomer as a copolymerization monomer. Such an adhesive base is highly effective in suppressing discoloration of the adhesive layer.

  The adhesive base preferably further has a hydroxyl group or a carboxyl group. Thereby, the skin permeation rate of the drug can be adjusted.

  Said adhesive layer contains 50 mass% or more and less than 100 mass% adhesive base, and this adhesive base contains the copolymerization monomer unit which has a carboxyl group of more than 0 mass% and 10 mass% or less. Further preferred. Thereby, the skin permeation rate of the drug of the patch preparation can be set to a rate at which a therapeutically effective blood drug concentration can be maintained once or twice a week.

  INDUSTRIAL APPLICABILITY According to the present invention, there is provided a patch preparation containing rasagiline as a drug and capable of maintaining sufficient drug stability and skin permeation rate without discoloring the adhesive layer even after long-term storage.

It is a perspective view which shows one Embodiment of the adhesive preparation of this invention. It is a graph which shows the result of the in vitro skin permeation test of the patch preparation of Examples 1-4. 3 is a graph showing the results of an in vitro skin permeation test of the patch preparation of Example 2. 4 is a graph showing the results of an in vitro skin permeation test of the patch preparation of Example 3. 6 is a graph showing the results of a drug administration simulation in Test 6. 10 is a graph showing the results of a drug administration simulation in Test 7.

  Hereinafter, preferred embodiments will be described with reference to the drawings. In the description of the drawings, the same elements are denoted by the same reference numerals, and redundant description is omitted. In addition, the drawings are exaggerated for easy understanding, and the dimensional ratios do not necessarily match those described.

  FIG. 1 shows an embodiment of the present invention. The patch preparation 1 includes a support 2 and a pressure-sensitive adhesive layer 3 arranged on the support 2. The pressure-sensitive adhesive layer 3 does not contain a vinyl acetate monomer, but contains a pharmaceutically acceptable acid addition salt of rasagiline, an amine compound, and a pressure-sensitive adhesive base. The patch preparation 1 may further include a release sheet 4 as shown in FIG. In this case, when the patch preparation 1 is stuck on the skin, the release sheet 4 is peeled off and stuck.

  As a material for the support 2, a material that can support the pressure-sensitive adhesive layer and is excellent in flexibility is preferable. Specifically, polyesters such as polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate; polyolefins such as polyethylene and polypropylene; polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, nylon, polyurethane, cellulose derivatives, polyacrylonitrile, etc. Fabrics such as films, woven fabrics and nonwoven fabrics, porous membranes, foams, paper materials, or laminates thereof, which are mainly formed from components selected from synthetic resins and cotton, can be suitably used. . However, as described later, from the viewpoint of preventing discoloration of rasagiline, it is more preferable that the material of the support does not contain a vinyl acetate monomer unit.

  The drug contained in the pressure-sensitive adhesive layer 3 is a pharmaceutically acceptable acid addition salt of rasagiline. The pharmaceutically acceptable acid addition salt of rasagiline is rasagiline and methanesulfonic acid (mesyl acid), ethylsulfonic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, formic acid An addition salt with one or more acids selected from acetic acid, propionic acid, lactic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, citric acid, malonic acid, and the like, preferably rasagiline mesylate. It is preferable to mix | blend a medicine in 1-25 mass% with respect to an adhesive layer.

  The amine compound contained in the pressure-sensitive adhesive layer 3 is specifically a low-molecular alkylamine compound such as a monoalkylamine, dialkylamine, trialkylamine, monoalkanolamine, dialkanolamine, trialkanolamine, Those in which each alkyl group and alkanol group have 1 to 6 carbon atoms are preferred, and triethanolamine is most preferred.

  Since the compounding amount of the amine compound is suitable for increasing the stability of the drug and the skin permeation rate, it is equivalent to the total acid functional group contained in the adhesive layer 3 containing the drug or 0.5 to 2 thereof. It is preferable that it is double. Alternatively, the ratio between the number of moles of the drug and the number of moles of the amine compound is preferably in the range of 1: 0.1 to 1: 2. When the number of moles of the amine compound is equal to that of the drug, a high skin permeation rate of the drug is obtained and immediate release is achieved, and when the number of moles of the amine compound is smaller or larger, sustained release is achieved.

  In the present specification, “vinyl acetate monomer unit” and “vinyl acetate monomer unit” are used synonymously. The adhesive base contained in the adhesive layer 3 does not contain a vinyl acetate monomer unit. Specifically, a (meth) acrylic acid alkyl ester or a copolymer containing no vinyl acetate monomer as a copolymerizable monomer and having a main monomer unit of (meth) acrylic acid alkyl ester can be suitably used. In the present specification, (meth) acrylic acid means acrylic acid and methacrylic acid corresponding thereto, and (meth) acrylate means acrylate and methacrylate corresponding thereto.

  In the above (meth) acrylic acid alkyl ester, the alkyl group may be linear or branched, and preferably has 4 to 13 carbon atoms. Specifically, esters of (meth) acrylic acid such as butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and tridecyl can be preferably used, but 2-ethylhexyl acrylate is particularly preferable. The main monomer unit is preferably 40 to 100% by mass of the adhesive base.

  As the monomer copolymerized with the main monomer, a monomer that is not a vinyl acetate monomer unit can be used. As will be described later, when the pressure-sensitive adhesive layer of the rasagiline-containing patch preparation contains a vinyl acetate monomer unit, discoloration of the pressure-sensitive adhesive layer is observed. The inventors have found that the pressure-sensitive adhesive layer containing rasagiline can prevent discoloration of the pressure-sensitive adhesive layer by including a copolymer monomer that is not a vinyl acetate monomer unit. Suitable copolymerizable monomers include (meth) acrylic acid hydroxyalkyl ester, vinyl pyrrolidone, (meth) acrylic acid amide, (meth) acrylic acid, itaconic acid, maleic acid and the like. In the above (meth) acrylic acid hydroxyalkyl ester, the alkyl group may be linear or branched, and preferably has 4 to 13 carbon atoms. Specifically, 2-hydroxyethyl (meth) acrylate, 3-hydroxypropyl (meth) acrylate, 4-hydroxybutyl (meth) acrylate, and the like can be suitably used. These copolymerization monomers are preferably 0 to 40% by mass of the adhesive base, and affect the adhesiveness of the adhesive layer and the drug release properties.

  The adhesive preparation has a relatively high content of monomer units having a hydroxyl group such as a non-functional adhesive base having no polar functional group such as a hydroxyl group or a carboxyl group, or a hydroxyalkyl ester of (meth) acrylic acid. When it contains, it exhibits immediate drug release characteristics. On the other hand, when the patch preparation contains an adhesive base containing a relatively large amount of monomer units having a carboxyl group such as (meth) acrylic acid, it exhibits sustained release drug release characteristics.

  A monomer unit having a hydroxyl group and a monomer unit having a carboxyl group can coexist. For example, when the molar ratio of the former and the latter is in the range of 100: 0 to 10:90, it can be administered to a human once a week. The blood drug concentration of rasagiline in a therapeutically effective amount can be maintained. The blood drug concentration of a therapeutically effective amount of rasagiline is about 0.1 to 0.5 (ng / mL).

  A (meth) acrylic acid alkyl ester copolymer containing 2 to 10% by mass of a monomer unit having a carboxyl group is contained in the pressure-sensitive adhesive layer in an amount of 50% by mass or more, more preferably 70% by mass or more. Thus, a patch preparation having excellent drug release durability is provided.

  Specifically, non-functional adhesive bases such as DuroTak 87-9301 and DuroTak 87-900A, and the like, and adhesive bases having a hydroxyl group such as DuroTak 87-202A and DuroTak 87-2510, adhesives having a hydroxyl group and a carboxyl group. As the base, DuroTak 87-2074 and the like, and as the adhesive base having a carboxyl group, DuroTak 87-200A, DuroTak 87-235A and the like can be suitably used. These adhesive bases are provided by Henkel and none contain vinyl acetate monomer units.

  The pressure-sensitive adhesive base that does not contain a vinyl acetate monomer unit is preferably blended in the range of 50% by mass to less than 100% by mass, more preferably 60 to 98% by mass of the pressure-sensitive adhesive layer. In this case, the remaining component is also composed of a component having no vinyl acetate monomer unit.

  The number of carboxyl groups present in the adhesive base can be measured, for example, by neutralization titration. The number of hydroxyl groups present in the adhesive base can be measured, for example, by reacting acetic anhydride to esterify the hydroxyl groups and then titrating the consumed acetic acid.

  As long as the adhesive base does not contain vinyl acetate as a monomer unit, an adhesive base containing a monomer unit having a carboxyl group, an adhesive base containing a monomer unit having a hydroxyl group, and a non-functional adhesive base Any single component selected from the group consisting of may be used, or a mixture of two or more may be used. When the adhesive base is used as a mixture, the adhesive base containing a monomer unit having a carboxyl group is preferably 0 to 90% by mass of the whole adhesive base, and the adhesive base containing a monomer unit having a hydroxyl group is used. It is preferable that it is 10-100 mass% of the whole adhesive base, and it is preferable that a non-functional adhesive base is 0-90 mass% of the whole adhesive base.

  The pressure-sensitive adhesive layer can contain, for example, a tackifier, a softener, a stabilizer, an absorption accelerator, and the like as necessary.

  Tackifiers include alicyclic saturated hydrocarbon resins; rosin, rosin glycerin ester, hydrogenated rosin, hydrogenated rosin glycerin ester or rosin pentaerythritol ester, rosin derivatives; terpene resin, petroleum resin or maleic acid Resins and the like can be suitably used.

  Softeners include paraffin oils such as liquid paraffin; animal oils such as squalane and squalene; vegetable oils such as almond oil, olive oil, camellia oil, castor oil, tall oil and peanut oil; silicone oils; liquids such as polybutene and polyisoprene Rubber or the like can be suitably used. Moreover, these softeners may be used alone or in combination of two or more.

  As the stabilizer, tocopherol and its ester derivative, ascorbic acid and its ester derivative, dibutylhydroxytoluene, butylhydroxyanisole and the like can be suitably used.

  Absorption promoters include fatty alcohols such as isostearyl alcohol, fatty acids such as capric acid, propylene glycol monolaurate, isopropyl myristate (IPM), fatty acid derivatives such as lauric acid diethanolamide, propylene glycol (PG), polyethylene Glycols such as glycol can be suitably used. It is preferable to mix | blend an absorption promoter in 0-25 mass% of an adhesive layer.

  The release sheet 4 covers the pressure-sensitive adhesive layer, and is peeled off when the patch preparation is applied to a patient. As the release sheet 4, a polyester such as polyethylene terephthalate, polybutylene terephthalate, or polyethylene naphthalate; a polyolefin such as polyethylene or polypropylene; a resin film such as polyacrylonitrile; In order to facilitate, it is preferable that the surface is subjected to a release treatment with silicone, Teflon (registered trademark) or the like.

  The rasagiline-containing patch preparation can be produced, for example, by the following method. First, rasagiline pharmaceutically acceptable acid addition salt, amine compound and adhesive base, and optionally added adhesive layer components such as tackifier, softener, stabilizer, absorption enhancer, etc. Is dissolved in a solvent such as toluene, hexane, heptane, ethyl acetate. Next, this solution is apply | coated on a peeling sheet, a solvent is dried and removed, and an adhesive layer is formed. Subsequently, the support is bonded to the pressure-sensitive adhesive layer and cut into a predetermined shape.

  Since the rasagiline-containing patch preparation has a function of inhibiting the degradation of dopamine by monoamine oxidase (type B), it can be used alone or in combination with levodopa, for example, to suppress the progression of signs or symptoms of early or advanced Parkinson's disease or Useful for treatment. Levodopa is a precursor of dopamine and is a kind of therapeutic agent for Parkinson's disease.

  Since patients with Parkinson's disease often have dysphagia, provision of a patch preparation is useful. In addition, since rasagiline is often administered for a long period of time, the drug release duration of the patch preparation is, for example, a long period of about 1 week in order to reduce the burden on the patient and It is preferable in terms of improvement.

  Also, rasagiline-containing patch preparation is used to enhance the therapeutic effect of antitumor drugs while protecting normal cells from damage, prevention and treatment of Alzheimer's disease, depression, restless leg syndrome, multiple sclerosis, withdrawal symptoms, Application to such is expected.

Rasagiline-containing patch preparation, in terms of ease of use, area 5～200Cm ^2, more preferably, 10 to 40 cm ^2, particularly preferably from 20 cm ^2. The skin permeation rate of rasagiline is 1.0 to 3.0 (mg / 7 days), more preferably 1.7 to 2.3 (mg / 7 days) in terms of free body, and per unit area 0.1 to 3.0 (μg / cm ² / hour), more preferably 0.20 to 1.5 (μg / cm ² / hour), still more preferably 0.25 to 1.0 (μg / cm). ² / hour). A skin permeation rate within this range has a therapeutic effect on Parkinson's disease. This skin permeation rate is preferably maintained for at least 12-168 hours after administration. By maintaining the skin permeation rate over the above time range, the frequency of administration of the patch preparation can be once or twice a week.

  The blood drug concentration of rasagiline is 0.1 to 0.5 (ng / mL), more preferably 0.2 to 0.4 (ng / mL) in terms of free form over 12 to 168 hours after administration of the patch preparation. ) Is preferably maintained. The patch preparation is preferably administered once or twice a week, more preferably once.

Incidentally, in human transdermal delivery of rasagiline, the metabolic rate (CL _tot ) is 94.12 to 125.67 (L / hr), (the blood half-life T _1/2 is 1.34 hr, and the distribution volume V _d is 182. ˜243 L), assuming that the steady-state blood concentration (C _ss ) is 0.23 (ng / mL), the drug release rate (Flux) required in the one-compartment model is expressed by the following equation (1): Calculated,
(Flux) = (C _ss ) × (CL _tot ) = 21.7-28.9 (μg / hr) (1)
Rasagiline will be transdermally delivered at a rate of 21.7 to 28.9 (μg / hour) in terms of free body. Here, if the area of the patch preparation is 20 cm ² , for example, the above formula (1 ) Divided by this area,
(Flux) = 1.08-1.45 (μg / cm ² / hour)
It becomes.

  In the present specification, maintaining sufficient drug stability suppresses the degradation of rasagiline contained in the patch preparation, and even when stored for a long period of time, for example, one month, sufficient rasagiline skin permeation rate is achieved. It means that the content of rasagiline necessary to achieve remains.

  The rasagiline-containing patch preparation is preferably used so that rasagiline having a weight of 27 to 220 μg / kg body weight (free body equivalent) is administered to a human once or twice a week. The dose of rasagiline can be set by adjusting the area of the patch preparation to be applied or adjusting the content of rasagiline in the patch preparation. A dose of rasagiline less than 27 μg / kg body weight may not maintain a therapeutically effective amount of blood drug. Further, even if the dose of rasagiline exceeding 220 μg / kg body weight is set, improvement of the therapeutic effect may not be expected, and side effects may occur.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples of the present invention. However, the present invention is not limited to these examples, and various modifications can be made without departing from the technical idea of the present invention. Can be changed.

(Test 1)
(Evaluation of discoloration of sample)
As an adhesive base, DuroTak 87-2516, DuroTak 87-4287 and DuroTak 87-2202A (Henkel) shown in Table 1 were used.

  Drugs, sodium hydroxide, and propylene glycol were mixed with these adhesive base solutions in the composition shown in Table 2, and sealed in sample tubes, which were designated as samples 1 to 24, respectively. The color of each sample was observed immediately after preparation and after standing overnight at room temperature. In Table 2, the unit is mass%. The amount of the adhesive base indicates the amount as a solid content excluding the solvent. Moreover, sodium hydroxide was mixed so that it might become equimolar with the drug in each sample. The molecular weight of each drug is as follows: rasagiline mesylate = 267.34, formoterol fumarate = 840.91, pramipexole hydrochloride = 302.26, naratriptan hydrochloride = 371.93, citalopram hydrobromide = 405.35, tolterodine tartrate = 475.57, palonosetron hydrochloride = 332.87, ropinirole hydrochloride = 296.84.

The discoloration of the observed sample was evaluated according to the following criteria.

Evaluation 1: No discoloration.
Evaluation 2: The color at the time of preparation from transparent to pale yellow changed to pale yellow after standing overnight.
Evaluation 3: The color at the time of preparation from transparent to pale yellow changed to yellow after standing overnight.
Evaluation 4: The color at the time of preparation from transparent to pale yellow changed to orange after standing overnight.
Evaluation 5: The color at the time of preparation from transparent to pale yellow changed to dark orange after standing overnight.

The results are shown in Table 3.

  In the sample containing naratriptan, citalopram, tolterodine, and palonosetron, there was almost no discoloration and no coloration (samples 10 to 21), whereas in samples containing rasagiline, pramipexole, formoterol, ropinirole, Some of the color changed from yellow to dark orange (Samples 1 to 9).

  On the other hand, some of the samples containing the polyacrylate adhesive bases DuroTak 87-2516 and DuroTak 87-4287 containing vinyl acetate monomer units changed color from yellow to dark orange (Samples 1-2, 4 and 4). -5, 7-8), and the sample containing the polyacrylate adhesive base DuroTak 87-202A not containing vinyl acetate monomer units showed slight discoloration (Samples 3 and 6). However, in the case of formoterol fumarate, discoloration was also observed in the sample containing a polyacrylate adhesive base that did not contain vinyl acetate monomer units (Sample 9). Moreover, even if it was the adhesive base containing a vinyl acetate monomer unit, there existed a case where it was hard to discolor with the drug to contain (samples 10-11, 13-14, 16-17, 19-20). Although rasagiline mesylate and pramipexole hydrochloride are easily discolored drugs, the discoloration of the sample was remarkably prevented by mixing with an adhesive base containing no vinyl acetate monomer unit (samples 3 and 6). The discoloration of ropinirole hydrochloride was observed even when mixed with an adhesive base not containing vinyl acetate monomer units (Sample 24).

(Test 2)
(Quantification of drugs contained in patch preparations)
A patch preparation (Sample 25 to Sample 42) having the composition shown in Table 4 was prepared, and the drug contained in each patch preparation was quantified. DuroTak 87-202A is a polyacrylate adhesive base that does not contain vinyl acetate monomer units and has hydroxyl groups. DuroTak 87-4287 is a polyacrylate adhesive base containing vinyl acetate monomer units and having hydroxyl groups. In Table 4, the amount of the adhesive base indicates the amount as a solid content excluding the solvent.

(Preparation of patch preparation)
A patch preparation containing the adhesive base DuroTak 87-202A or DuroTak 87-4287 was prepared by the following procedure.

To the drug and sodium hydroxide, 5 g of methanol as a solvent was added and dissolved, and an adhesive base was added thereto to obtain a uniform solution. This solution was applied to a silicone-treated surface of a 75 μm thick polyethylene terephthalate film as a release sheet at a constant thickness (100 μm after drying). Next, the solvent was removed by drying to form an adhesive layer. Subsequently, a 43.2 μm-thick polyethylene / polyester laminated film as a support was bonded so that the polyester surface was in contact with the pressure-sensitive adhesive layer to obtain a patch preparation. The patch preparation was cut into 64 cm ² and packaged with an aluminum laminated bag.

  A patch preparation containing SIS (styrene-isoprene-styrene block copolymer) as an adhesive base was prepared by the following procedure.

A uniform solution was prepared by adding 100 g of toluene as a solvent to SIS and liquid paraffin. Next, 5 g of methanol as a solvent was added and dissolved in the drug and sodium hydroxide. The above SIS and liquid paraffin solutions were added to obtain a uniform solution. This solution was applied to a silicone-treated surface of a 75 μm thick polyethylene terephthalate film as a release sheet at a constant thickness (100 μm after drying). Next, the solvent was removed by drying to form an adhesive layer. Subsequently, a 43.2 μm-thick polyethylene / polyester laminated film as a support was bonded so that the polyester surface was in contact with the pressure-sensitive adhesive layer to obtain a patch preparation. The patch preparation was cut into 64 cm ² and packaged with an aluminum laminated bag.

  The drug contained in each patch preparation prepared by the above procedure was quantified immediately after preparation by the following quantitative method.

(Quantification of rasagiline)
5 cm ² of each patch preparation was collected, 20 mL of methanol was added to extract the drug, and rasagiline (free body) was quantified with a UV detector using high performance liquid chromatography (ODS column).

(Quantification of palonosetron)
5 cm ² of each patch preparation was collected, 20 mL of methanol was added to extract the drug, and palonosetron (free body) was quantified with a UV detector using high performance liquid chromatography (ODS column).

(Quantification of tolterodine)
5 cm ² of each patch preparation was collected, 20 mL of methanol was added to extract the drug, and tolterodine (free body) was quantified with a UV detector using high performance liquid chromatography (ODS column).

  Table 5 shows the results of quantifying the drug contained in each patch preparation (Sample 25 to Sample 42). The quantitative results are shown with the theoretical amount of drug calculated from the mass of the adhesive layer and the amount of drug blended being 100%. The unit is mass%.

  In the patch preparation not containing sodium hydroxide, the drug corresponding to the theoretical amount added was quantified. In the patch preparation containing rasagiline mesylate mixed with sodium hydroxide, there was a marked decrease in drug amount in samples 25, 27 and 29 to which sodium hydroxide was added. On the other hand, in the patch preparation containing palonosetron hydrochloride and tolterodine tartrate, the amount of drug decreased little even when sodium hydroxide was added.

(Test 3)
(Evaluation of discoloration of patch preparation)
A patch preparation (sample 43 to sample 49) having the composition shown in Table 6 was prepared, and the discoloration was evaluated. DuroTak 87-900A, DuroTak 87-9301, DuroTak 87-200A, DuroTak 87-2510, DuroTak 87-202A, DuroTak 87-235A, and DuroTak 87-2074 are all polyacrylate adhesive bases that do not contain vinyl acetate monomer units. It is. In Table 6, the amount of the adhesive base indicates the amount as a solid content excluding the solvent.

(Preparation of patch preparation)
To the drug and sodium hydroxide, 5 g of methanol as a solvent was added and dissolved, and an adhesive base was added thereto to obtain a uniform solution. This solution was applied to a silicone-treated surface of a 75 μm thick polyethylene terephthalate film as a release sheet at a constant thickness (100 μm after drying). Next, the solvent was removed by drying to form an adhesive layer. Subsequently, a 43.2 μm-thick polyethylene / polyester laminated film as a support was bonded so that the polyester surface was in contact with the pressure-sensitive adhesive layer to obtain a patch preparation. The patch preparation was cut into 64 cm ² and packaged with an aluminum laminated bag.

  Immediately after the preparation of each patch preparation, the color of the pressure-sensitive adhesive layer was observed and evaluated for brown or orange discoloration. As a result, no discoloration was observed in any patch preparation of Samples 43 to 49.

(Test 4)
(Evaluation of storage stability of patch preparations)
Triethanolamine was added instead of sodium hydroxide, and patch preparations of Examples 1 to 4 and Comparative Examples 1 and 2 were prepared with the compositions shown in Table 7. In Table 7, the amount of the adhesive base indicates the amount as a solid content excluding the solvent. PG means propylene glycol, and IPM means isopropyl myristate. Example 4 was formulated with 50% moles of triethanolamine as the number of moles of drug. The other sample was formulated with the same number of moles of triethanolamine as the drug.

  A quantitative determination of the drug content of the patch preparation and an in vitro skin permeation test were performed to evaluate the storage stability of the patch preparation.

(Preparation of patch preparation)
The patch preparations of Examples 1 to 4 were prepared by the following procedure. To a drug, triethanolamine, propylene glycol (PG) and isopropyl myristate (IPM), 5 g of methanol as a solvent was added and dissolved, and an adhesive base was added thereto to obtain a uniform solution. This solution was applied to a silicone-treated surface of a 75 μm thick polyethylene terephthalate film as a release sheet at a constant thickness (100 μm after drying). Next, the solvent was removed by drying to form an adhesive layer. Subsequently, a 43.2 μm-thick polyethylene / polyester laminated film as a support was bonded so that the polyester surface was in contact with the pressure-sensitive adhesive layer to obtain a patch preparation. The patch preparation was cut into 64 cm ² and packaged with an aluminum laminated bag.

The patch preparation of Comparative Example 1 was prepared by the following procedure. A uniform solution was prepared by adding 100 g of toluene as a solvent to SIS (styrene-isoprene-styrene block copolymer). Next, 5 g of methanol as a solvent was added and dissolved in the drug, triethanolamine, propylene glycol (PG), oleyl alcohol, and liquid paraffin. The above SIS solution was added to make a uniform solution. This solution was applied to a silicone-treated surface of a 75 μm thick polyethylene terephthalate film as a release sheet at a constant thickness (100 μm after drying). Next, the solvent was removed by drying to form an adhesive layer. Subsequently, a 43.2 μm-thick polyethylene / polyester laminated film as a support was bonded so that the polyester surface was in contact with the pressure-sensitive adhesive layer to obtain a patch preparation. The patch preparation was cut into 64 cm ² and packaged with an aluminum laminated bag.

The patch preparation of Comparative Example 2 was prepared by the following procedure. A homogeneous solution was prepared by adding 100 g of toluene as a solvent to PIB (polyisobutylene). Next, 5 g of methanol as a solvent was added and dissolved in the drug, triethanolamine, propylene glycol (PG), oleyl alcohol, and liquid paraffin. The above PIB solution was added to this to make a uniform solution. This solution was applied to a silicone-treated surface of a 75 μm thick polyethylene terephthalate film as a release sheet at a constant thickness (100 μm after drying). Next, the solvent was removed by drying to form an adhesive layer. Subsequently, a 43.2 μm-thick polyethylene / polyester laminated film as a support was bonded so that the polyester surface was in contact with the pressure-sensitive adhesive layer to obtain a patch preparation. The patch preparation was cut into 64 cm ² and packaged with an aluminum laminated bag.

(Determination of drug)
The drug contained in each patch preparation immediately after preparation was quantified by the same operation as the method in Test 2 above. Table 8 shows the results of quantification with the theoretical amount of drug calculated from the mass of the adhesive layer and the amount of drug added as 100%. The unit is mass%.

  The patch preparations of Example 3 and Example 4 are included in each patch preparation immediately after preparation, after storage for 1 month at 25 ° C., and after storage for 1 month at 40 ° C. by the same procedure as in Test 2 above. Quantified drugs. Table 9 shows the results of quantification with the theoretical amount of drug calculated from the mass of the adhesive layer and the blended drug amount being 100%. The unit is mass%.

  Compared to the results of drug content of the patch preparations of Sample 25 and Sample 27 in Test 2 above containing sodium hydroxide (Table 5), the patches of Example 3 and Example 4 containing triethanolamine It was found that in the formulation, the decrease in drug content was significantly suppressed.

(Test 5)
(In vitro skin permeation test)
The cryopreserved human skin was thawed and attached to a flow-through cell in which warm water at 32 ° C. was circulated around the outer periphery with the dermis side as the receptor layer side. Next, a patch preparation (area: 1 cm ² ) is affixed to the stratum corneum side of the skin, and 168 hours every 12 hours at a rate of 1.0 mL / hour using a phosphate buffer (pH 7.4) as a receptor layer. The receptor solution was sampled until the flow rate was measured and the drug concentration was measured using high performance liquid chromatography. The skin permeation rate of the drug per hour was calculated from the obtained measured value, and the skin permeation rate of the drug per unit area of the skin in a steady state was obtained.

  The result of the in vitro skin permeation test of the patch preparations of Examples 1 to 4 is shown in FIG. The patch preparation of Comparative Example 1 had a high skin permeation rate of the drug, but was insufficient in persistence (not shown). Moreover, the patch preparation of Comparative Example 2 was inferior to other patch preparations in terms of the skin permeation rate of the drug, and was insufficient in sustainability (not shown). Further, in the patch preparation of Comparative Example 2, the pressure-sensitive adhesive layer did not have appropriate tackiness for adhering to the skin.

  The patch preparation of Example 2 was subjected to an in vitro skin permeation test immediately after preparation, after storage for 1 month at 25 ° C. and after storage for 1 month at 40 ° C. The results are shown in FIG. Even after storage for 1 month, the skin permeation rate of the drug was the same as that immediately after preparation.

  The patch preparation of Example 3 was subjected to an in vitro skin permeation test immediately after preparation, after storage for 1 month at 25 ° C. and after storage for 1 month at 40 ° C. The results are shown in FIG. Even after storage for 1 month, the skin permeation rate of the drug was the same as that immediately after preparation.

(Test 6)
(Drug administration simulation)
Based on the result of the in vitro skin permeation test of the patch preparation of Example 4, a drug administration simulation was performed. Specifically, information on the skin permeation rate, lag time, skin thickness used in the test, etc. obtained in the above in vitro skin permeation test, and pharmacokinetic parameters (dose, distribution volume) for intravenous administration , Disappearance rate constant) information, rasagiline blood concentration transition when transdermal administration of the patch preparation of Example 4 to human (70 kg body weight), Fick's second law membrane permeation model and 2-compartment pharmacokinetics Predicted by model.

Transition of blood drug concentration when the patch preparation of Example 4 having an area of 20 cm ^{2 and} containing 12 mg of rasagiline mesylate was transdermally administered to a human (body weight 70 kg) once a week for 4 weeks. The simulation results are shown in FIG. Here, when a patch preparation containing 12 mg of rasagiline mesylate was transdermally administered to a human weighing 70 kg, the dose of rasagiline (in free form) was rasagiline mesylate having a molecular weight of 267.34 and free form of rasagiline. Since the molecular weight is 171.10, it is calculated as 109.7 μg / kg body weight by the following formula (2).
12 mg × 171.10 ÷ 267.34 ÷ 70 kg = 109.7 μg / kg body weight (2)
FIG. 5 also shows the results of changes in blood drug concentration when 1 mg of rasagiline mesylate was orally administered once a day for 7 days.

  In oral administration, the fluctuations in the blood drug concentration are very large, but when a patch preparation is administered, the difference between the upper and lower blood drug concentrations is small and the therapeutically effective amount of the blood drug is low. (0.1 to 0.5 ng / mL in terms of free form) was shown to be maintainable.

(Test 7)
(Drug administration simulation)
Based on the results of the in vitro skin permeation test of the patch preparations of Examples 3 and 4, drug administration simulations were performed in the same manner as in Test 6.

When the patch preparation of Example 4 having an area of 20 cm ^{2 and} containing 12 mg of rasagiline mesylate is transdermally administered to a human (body weight 70 kg) once a week for 4 weeks, it contains 6 mg of rasagiline mesylate. When the patch preparation of Example 4 having an area of 10 cm ² was transdermally administered to a human (body weight 70 kg) twice a week (once every 3.5 days) for 4 weeks, and rasagiline mesylate When the transdermal administration of the patch preparation of Example 3 having an area of 10 cm ² containing 5 mg twice a week (once every 3.5 days) and continuously for 4 weeks to a human (70 kg body weight), The simulation result of the transition of the blood drug concentration is shown in FIG. In any case, it was shown that a therapeutically effective amount of blood drug concentration (0.1 to 0.5 ng / mL in terms of free body) can be maintained.

  According to the present invention, it is possible to maintain a therapeutically effective blood drug concentration by administration once or twice a week, containing rasagiline as a drug, and the adhesive layer does not discolor even when stored for a long period of time. A patch preparation capable of maintaining the drug content and the skin permeation rate is provided.

  DESCRIPTION OF SYMBOLS 1 ... Patch preparation, 2 ... Support body, 3 ... Adhesive layer, 4 ... Release sheet.

Claims (7)

  A patch preparation containing rasagiline, which is used so that 27 to 220 μg / kg body weight of rasagiline is administered to a human once or twice a week. A patch preparation comprising a support and an adhesive layer arranged on the support,
The pressure-sensitive adhesive layer contains a pharmaceutically acceptable acid addition salt of rasagiline, an amine compound, and a pressure-sensitive adhesive base, and the pressure-sensitive adhesive base does not contain vinyl acetate as a monomer unit (meth) acrylic polymer And
27-220 μg / kg body weight of rasagiline is used to be administered to humans once or twice a week,
Patch preparation.   The patch preparation according to claim 2, wherein the amine compound is triethanolamine.   The patch according to claim 2 or 3, wherein a ratio between the number of moles of the pharmaceutically acceptable acid addition salt of rasagiline and the number of moles of the amine compound is in the range of 1: 0.1 to 1: 2. Formulation.   The adhesive preparation according to any one of claims 2 to 4, wherein the adhesive base is a (meth) acrylic acid alkyl ester copolymer that does not contain a vinyl acetate monomer as a copolymerization monomer.   The adhesive preparation according to any one of claims 2 to 5, wherein the adhesive base has a hydroxyl group or a carboxyl group. The pressure-sensitive adhesive layer contains the pressure-sensitive adhesive base in an amount of 50% by mass or more and less than 100% by mass,
The adhesive preparation according to claim 6, wherein the adhesive base comprises a copolymerized monomer unit having a carboxyl group of more than 0% by mass and 10% by mass or less.

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