JP5535640B2 - Fentanyl-containing transdermal absorption preparation - Google Patents

Description

  The present invention relates to a transdermally absorbable preparation containing fentanyl or a salt thereof as an active ingredient.

  Conventionally, injections containing fentanyl or a salt thereof as an active ingredient have been used as analgesics for cancer pain. Recently, in addition to injections, fentanyl-containing transdermal absorption agents have been developed, and percutaneous absorption of drugs is performed. Studies have been made on improving the performance and increasing the sustainability of the analgesic effect (Patent Documents 1 to 3).

  Examples of commercially available fentanyl-containing transdermal absorption agents include Durotep Patch (registered trademark), and such conventional transdermal preparations containing fentanyl should be applied for 3 days. However, the analgesic effect fluctuates greatly, which imposes a burden on the patient and sometimes reduces patient compliance.

Japanese Patent Laid-Open No. 10-45570 Japanese Patent Laid-Open No. 11-302161 JP 61-37725 A

  An object of the present invention is to newly provide a fentanyl-containing transdermal absorption preparation with a reduced burden on the patient.

  In the preparations for treating pain of patients who are forced to undergo long-term treatment such as cancer, such as fentanyl-containing transdermal absorption preparations, while the inventors have intensively studied to solve the above problems, In order to solve this problem, we have obtained new findings that patient compliance is reduced when the fluctuation in analgesic effect is large, and the peak / trough value of fentanyl-containing transdermal preparations is adjusted more appropriately. As a result of finding that the fluctuation of the analgesic effect can be suppressed and the burden on the patient can be reduced, the present invention has been completed.

That is, the present invention relates to a once-daily fentanyl-containing transdermal absorption preparation containing fentanyl or a salt thereof.
In addition, the present invention repeats administration once a day, reaches a steady state, and then obtains a CV value (standard) obtained from an average value and a standard deviation value of blood fentanyl concentration measured every day for at least three consecutive days. It is related with the said transdermally absorbable preparation whose deviation value / average value x100 (%)) is 40% or less.
The present invention further relates to the ratio of the minimum value (minimum value / maximum value) to the maximum value of blood fentanyl concentration measured every day for at least three consecutive days after repeated administration once a day and reaching a steady state. ) Is 0.5 or more.
The present invention also relates to the above transdermally absorbable preparation, wherein when the transdermally absorbable preparation is continuously administered once a day, the average peak / trough value of blood fentanyl concentration in a steady state is 1.8 or less.

Moreover, this invention relates to the said transdermally absorbable preparation which is a patch containing a support body, an adhesive, and a peeling sheet.
Furthermore, the present invention relates to the above transdermally absorbable preparation, wherein the patch is a matrix type.
The present invention also relates to the above-mentioned transdermal preparation containing fentanyl or a salt thereof at 0.10 to 0.45 mg / cm ² .
Furthermore, the present invention provides the transdermally absorbable preparation described above, wherein fentanyl or a salt thereof is contained in the adhesive at 0.10 to 0.45 mg / cm ² and the mass of the adhesive is ² to 10 mg / cm ^2. About.

The present invention also relates to the above transdermally absorbable preparation, which is a patch having a fentanyl or salt content of 1 to 2 mg per sheet.
Furthermore, this invention relates to the said percutaneous absorption preparation in which an adhesive contains a styrene-isoprene-styrene block copolymer.
The present invention also relates to the above transdermally absorbable preparation, wherein the adhesive contains an acrylic polymer.
Furthermore, the present invention relates to the transdermally absorbable preparation, wherein the support contains stretched polyethylene terephthalate.

The once-daily fentanyl-containing percutaneous absorption preparation of the present invention has a small peak / trough value of blood fentanyl concentration and changes in analgesic effect, unlike the conventional 3-day percutaneous absorption preparation applied for 3 days. Can be kept to a minimum, reducing the burden on the patient. In addition, a percutaneous absorption preparation with higher patient compliance that can effectively suppress pain such as cancer pain can be provided.
In particular, in the case of transdermal absorbents for treating pain of diseases that necessitate long-term medical treatment such as cancer, it has been difficult to consider patient compliance due to the long-term demand for sustained drug efficacy. However, the once-daily fentanyl-containing percutaneous absorption preparation of the present invention can provide a drug with high patient compliance since the drug effect lasts for a long time and the fluctuation in analgesic effect is small.

The graph of FIG. 1 shows an example in which the transdermally absorbable preparation of the present invention is continuously applied from the blood concentration when applied once for 24 hours and once for 72 hours. FIG. 2 shows the mean blood concentration of fentanyl after the 6th day (144 hours) in the case where the transdermal absorption preparation of the present invention is administered continuously for 1 day and when applied daily for 3 days. It is a graph which shows transition of (C). FIG. 3 shows that the percutaneously absorbable preparation of the present invention was administered three times continuously for three days (9 days), and then the fentanyl-containing percutaneously absorbable preparation of the present invention was continuously administered three times a day. It is a graph which shows transition of the VAS value change rate when the VAS value after the 7th day progress in case of (3 days, total 12 days) is 1.

Hereinafter, preferred implementation of the fentanyl-containing transdermal preparation of the present invention will be described in detail.
The fentanyl-containing transdermal absorption preparation of the present invention contains fentanyl or a salt thereof and is used for once-daily administration.
The pharmacologically active substance in the present invention is fentanyl itself or a salt thereof, and the fentanyl salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and may be an inorganic salt or an organic salt. Well, citrate, hydrochloride, fumarate, and the like, which are typical fentanyl salts, can be mentioned. Of these, fentanyl citrate is particularly preferred. Moreover, although fentanyl or its salt can also be used independently, you may mix and use 2 or more types.

  Furthermore, the fentanyl-containing percutaneous absorption preparation of the present invention repeats administration once a day, so that the concentration of fentanyl in blood measured every day (every 24 hours) in at least three consecutive days after reaching a steady state. The CV value (standard deviation value / average value × 100 (%)) obtained from the average value of the concentration (for example, the average value of blood concentration at 168, 192, and 216 hours in FIG. 2) and the standard deviation value is 40% or less. can do. More preferably, by setting the CV value to 30% or less, more preferably 20% or less, higher patient compliance can be obtained. The present invention obtains a continuous analgesic effect by keeping the CV value obtained by the mean value and standard deviation value of the blood fentanyl concentration measured every day for at least 3 consecutive days within a predetermined range. It can be done. Here, the standard deviation value / average value is a coefficient of variation, expressed as a CV value, and the so-called average value of blood concentration obtained by measuring the concentration of blood fentanyl in a plurality or individual patients and its standard deviation. It is a variation index calculated using the value.

  The fentanyl-containing transdermal absorption preparation of the present invention contains fentanyl or a salt thereof, and is a transdermal absorption preparation for once-daily administration. By continuously administering once a day, blood in a steady state is obtained. The average peak / trough value of the intermediate fentanyl concentration can be 1.8 or less, and the fluctuation of the analgesic effect of the patient is minimized by keeping the average peak / trough value of the blood fentanyl concentration in the steady state within a predetermined range. The pain of patients such as cancer pain can be reduced. More preferably, it is 1.6 or less, and particularly preferably 1.3 or less, the above-mentioned effect can be obtained more effectively.

  The peak / trough value in the present invention refers to the peak (maximum blood concentration) in the application period of the transdermally absorbable preparation (one day for daily administration) after the steady state during the continuous administration period. And the trough (minimum blood concentration). The steady state is usually a state after the time at least 3 times the apparent half-life of the blood concentration has elapsed from the start of administration, or the peak value or trough value of the blood concentration is kept almost constant. State in which the fluctuation is within 20%.

  In addition, the fentanyl-containing transdermal absorption preparation of the present invention is the minimum of the maximum value of the blood fentanyl concentration measured every day for at least 3 consecutive days after reaching a steady state by repeating administration once a day. The value ratio (minimum value / maximum value) is preferably 0.5 or more. By setting the minimum value / maximum value in such a range, it is possible to minimize fluctuations in the analgesic effect of the patient and reduce patient pain such as cancer pain.

  The ratio of the minimum value to the maximum value of the blood fentanyl concentration in the present invention is the average blood fentanyl at least every day for at least 3 consecutive days after repeated administration once a day and reaching a steady state. The concentration is measured, and the ratio of the maximum day value (maximum value) to the minimum day value (minimum value) among the three days in which the blood fentanyl concentration is measured is meant.

Furthermore, in the present invention, the content per unit area of fentanyl or a salt thereof contained in the transdermally absorbable preparation is preferably 0.10 to 0.45 mg / cm ² .
The percutaneously absorbable preparation of the present invention is not particularly limited as long as it shows the blood concentration characteristic of the present invention, but it is preferably a patch comprising a support, an adhesive and a release sheet. Such a patch is not particularly limited, but may be a reservoir type or a matrix type, and in particular, a matrix type containing a drug in an adhesive is more preferable than a reservoir type containing a drug in an organic solvent. From the advantage that skin irritation, rash and the like caused by an organic solvent hardly occur, the matrix type is preferable. Note that the matrix type includes a case where an adhesive layer containing a liquid such as water is included.

  When the transdermal absorbent of the present invention is a matrix-type patch, the material constituting the support in the patch is preferably a polyester film from the viewpoint of preventing migration of the drug to the support, particularly polyethylene. Ferme containing terephthalate or polyethylene terephthalate and ethylene vinyl acetate copolymer is preferred. In the case of a film containing polyethylene terephthalate and an ethylene vinyl acetate copolymer, they can be laminated and used.

When stretchable films such as polyurethane are used, there is a tendency that migration of the drug to the support tends to be observed, and when polyester films such as polyethylene terephthalate are used, such transition of fentanyl to the support tends to decrease. It is in.
Furthermore, although there are stretched and non-stretched types of ferm, when a film made of polyethylene terephthalate is used, adsorption of fentanyl or its salt to the support is suppressed when a film containing stretched polyethylene terephthalate is used. As a result, fentanyl or a salt thereof contained in the pressure-sensitive adhesive can be efficiently used for a transdermally absorbable preparation, and the characteristics of blood concentration in the present invention are easily obtained, which is particularly preferable.

The thickness of the polyester film used alone is not particularly limited, but is preferably 2 to 50 μm, more preferably 5 to 40 μm, and particularly 20 to 30 μm. It is preferable from the viewpoints of handleability and the feeling of use at the time of sticking.
The polyester film may be used in multiple layers. The material to be laminated is not particularly limited, but a soft material such as a non-woven fabric made of polyester fiber, a woven fabric, urethane, an ethylene vinyl acetate copolymer film is preferable, and a non-woven fabric, woven fabric, ethylene vinyl acetate copolymer A combined membrane is preferred, and an ethylene vinyl acetate copolymer membrane is particularly preferred. Although there is no limitation in particular about the thickness in the case of using by a multilayer, it can use by the same thickness as the case where a polyester-type film is used by a single layer for the same reason as the thickness in the laminated state.

  Further, the support may be colored by kneading a pigment (color pigment). For example, a white support can be obtained by adding titanium oxide. This white color makes it easy to print letters on the surface of the support, and even when using drugs that require attention in handling, the handling precautions can be printed in an easy-to-understand manner. If it is transparent, it becomes less noticeable when applied to the skin, which may reduce the mental burden of the patient.

In the present invention, the moisture permeability of the support is preferably 15 to 30 g / m ² · 24 hr. By setting the moisture permeability within this range, it can be applied for one day without peeling during application, and the effects of the present invention tend to be easily obtained.
Moreover, it is preferable that the bending rigidity of a support body is 0.01-0.20 g * cm < ² > / cm. If the flexural rigidity of the support is small, the patch tends to become entangled or wrinkled, making it difficult to handle.On the other hand, if it is too large, the patch is hard and difficult to handle. It is difficult to apply it according to the unevenness of the application part of the human body, and it is easy to peel off even with a slight movement of the skin, so a sufficient drug effect can be obtained by changing the application area This is because there is a possibility of not.
Moreover, it is preferable to mix | blend a fentanyl or its salt with the quantity of 0.05-20 mass% based on the mass of the whole adhesive from the viewpoint of the permeation | transmission amount and the physical property of formulation itself.

When the transdermally absorbable preparation of the present invention is used as a patch, it has an adhesive to adhere to the skin on at least one surface of the support.
In this case, the thickness of the pressure-sensitive adhesive layer is preferably 20 to 200 μm. If the thickness is too small, the pressure-sensitive adhesive layer cannot be extended and coated on the support, which causes inconveniences during the manufacturing process, and the permeation rate tends to be poor. On the other hand, if the thickness is too large, the manufacturing process This is because the above inconvenience occurs and the drug is used more than necessary, which tends to cause waste.
Moreover, it is preferable that fentanyl or its salt is contained in an adhesive at 0.10-0.45 mg / cm < ² >, and the mass of an adhesive layer is 2-10 mg / cm < ² >.

The fat-soluble polymer blended in the pressure-sensitive adhesive of the present invention is not particularly limited, but preferred examples include polyisobutylene (PIB), styrene-isoprene-styrene block copolymer (SIS), isoprene rubber, styrene-butadiene-styrene. Examples thereof include a block copolymer (SBS), an acrylic polymer (2-ethylhexyl acrylate, vinyl acetate, methacrylate, methoxyethyl acrylate, acrylic acid at least two types of copolymers) and the like. A mixture of seeds or more can be used. Among these, it is preferable to use PIB, SIS, and an acrylic polymer.
The fat-soluble polymer is 0.1 to 98% by mass, preferably 0.1 based on the total mass of the adhesive of the patch of the present invention, taking into consideration the physical properties of the preparation itself and good adhesion to human skin. -70 mass%, More preferably, 0.1-50 mass% is mix | blended.

By adding sodium acetate to the pressure-sensitive adhesive of the present invention, the skin permeability of fentanyl or a salt thereof becomes very high. Sodium acetate is preferably blended in an amount of 0.01 to 15% by mass, further 0.01 to 10% by mass, particularly 0.01 to 5% by mass, based on the mass of the entire pressure-sensitive adhesive. This is because if the amount of sodium acetate is small, the effect of remarkably improving skin permeability cannot be obtained sufficiently, and if it is too large, the irritation to the skin tends to increase.
When the fentanyl salt is fentanyl citrate, the blending mass ratio of fentanyl citrate and sodium acetate may be a blending ratio that is effective in terms of physical properties and skin permeability, but is typically 2: 1. The maximum effect is obtained. If the blending ratio of sodium acetate is small, the drug skin permeability tends to decrease rapidly, and conversely if the blending ratio of sodium acetate is large, it becomes a non-uniform preparation and adhesion tends to be poor.

  In addition, since the tackiness of the fat-soluble polymer is low, a tackifier can be added to the pressure-sensitive adhesive of the preparation in order to impart the pressure-sensitive adhesive to the preparation. Preferable examples of the tackifier include polyterpene resin-based, petroleum resin-based, rosin-based, rosin ester-based, and oil-soluble phenol resin-based tackifiers. The tackifier is preferably blended in an amount of 0.1 to 70% by mass, further 5 to 50% by mass, and particularly 10 to 35% by mass based on the mass of the entire adhesive of the preparation of the present invention.

  Moreover, fats and oils can also be mix | blended with an adhesive as a plasticizer for the improvement of the workability of the patch of this invention, and adjustment of adhesiveness. As fats and oils, for example, liquid paraffin, squalane, olive oil, camellia oil, bar shock oil, peanut oil and the like are preferable, and liquid paraffin is particularly preferable. It is preferable that fats and oils are mix | blended in the quantity of 1.0-70 mass%, further 10-60 mass%, especially 20-50 mass% based on the mass of the whole adhesive of the formulation of this invention.

  Moreover, an absorption promoter can also be mix | blended with the adhesive of the formulation of this invention as needed. The absorption enhancer may be any compound as long as it has a skin absorption promoting effect. For example, a fatty acid having 6 to 20 carbon chains, aliphatic alcohol, fatty acid ester or ether, aromatic And organic organic acids, aromatic alcohols, aromatic organic acid esters and ethers. Furthermore, lactic acid esters, acetate esters, monoterpene compounds, sesquiterpene compounds, Azone or its derivatives, glycerin fatty acid esters, sorbitan fatty acid esters, polysorbate, polyethylene glycol fatty acid esters, poly Examples thereof include oxyethylene hydrogenated castor oil type and sucrose fatty acid esters. Specifically, caprylic acid, capric acid, caproic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, lauryl alcohol, myristyl alcohol, oleyl alcohol, cetyl alcohol, methyl laurate , Isopropyl myristate, myristyl myristate, octyldodecyl myristate, cetyl palmitate, salicylic acid, methyl salicylate, ethylene glycol salicylate, cinnamic acid, methyl cinnamate, cresol, cetyl lactate, ethyl acetate, propyl acetate, geraniol, thymol Eugenol, terpineol, l-menthol, borneol, d-limonene, isoeugenol, isoborneol, nerol, dl-camphor, glycerin monolaurate, glyce Monooleate, sorbitan monolaurate, sucrose monolaurate, polysorbate 20, polyethylene glycol monolaurate, polyethylene glycol monostearate, HCO-60 (hardened castor oil), 1- [2- (decylthio) ethyl] azacyclopentane 2-one (hereinafter abbreviated as “pyrothiodecane”) is preferable, and lauryl alcohol, myristyl alcohol, ethylene glycol salicylate, and pyrothiodecane are particularly preferable.

  Such an absorption promoter is preferably 0.01 to 20% by weight, more preferably 0.1 to 10% by weight, particularly 0.5 to 5% by weight, based on the total weight of the adhesive of the preparation of the present invention. It is preferable to mix | blend in quantity. This is because if the amount of the absorption enhancer is too large, irritation to the skin such as redness and edema is observed, and if it is too small, the effect of the absorption enhancer tends not to be obtained.

Furthermore, in the patch of the present invention, a hydrophilic polymer can be blended as necessary to absorb aqueous components such as sweat generated from the skin. Examples of the hydrophilic polymer include light anhydrous silicic acid, cellulose derivatives (carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMCNa), methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), and hydroxypropylcellulose (HPC). , Hydroxyethyl cellulose (HEC), starch derivative (pullulan), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), vinyl acetate (VA), carboxyvinyl polymer (CVP), ethyl vinyl acetate (EVA), Eudragit (trade name) , Gelatin, polyacrylic acid, sodium polyacrylate, polyisobutylene maleic anhydride copolymer, alginic acid, sodium alginate, carrageenan, gum arabic, traga DOO, karaya, polyvinyl methacrylate are preferable, and light silicic anhydride, cellulose derivatives (CMCNa, HPMC, HPC, MC), Eudragit are preferred.
The hydrophilic polymer is preferably blended in an amount of 0.1 to 20% by mass, particularly 0.5 to 10% by mass, based on the mass of the entire adhesive of the patch of the present invention.

The adhesive of the patch of the present invention can contain other components such as a crosslinking agent, preservative, and antioxidant.
Examples of the crosslinking agent include amino resins, phenol resins, epoxy resins, alkyd resins, unsaturated polyester, and other thermosetting resins, isocyanate compounds, blocked isocyanate compounds, organic crosslinking agents, metals, and metal compounds such as inorganic compounds. System crosslinking agents are preferred. As the preservative, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate and the like are preferable. As the antioxidant, tocopherol and its ester derivatives, ascorbic acid, stearic acid ester, nordihuman logaretic acid, dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA) and the like are preferable. The adhesive of the patch of the present invention is particularly preferably composed of a non-aqueous base material.

  The pressure-sensitive adhesive can be produced by any method. For example, in the case of producing by the solvent method, other components are added to the organic solvent solution of the polymer to be blended, and after stirring, it is extended to a support and dried to obtain this preparation. Further, when the polymer to be blended can be applied by the hot melt method, after the polymer component is dissolved at a high temperature, the other components are added, stirred, and extended to the support. Can be obtained.

Further, the area of the patch of the present invention is not particularly limited as long as it is an area where a sufficient drug effect can be obtained, but it is preferably 5 to 60 cm ² from the viewpoint of medicinal effect, handleability, skin irritation and the like. .
And in the patch comprised by the above of this invention, fentanyl or its salt is contained in an adhesive, The content per unit area is 0.10-0.45 mg / cm < ² >, and an adhesive The mass per unit area is preferably ² to 10 mg / cm ² . By setting it in such a range, there is a tendency that characteristics of blood concentration of fentanyl of the present invention are likely to occur.

The transdermally absorbable preparation of the present invention can also be a patch with a content of fentanyl or a salt thereof of 1 to 10 mg, and may be a low dose of 1 to 2 mg.
In addition, for example, in combination with one or more patches containing 1 to 10 mg of fentanyl or a salt thereof, so that each can be properly used in the degree of pain of cancer pain, The patch can be standardized so that the dose can be adjusted by administration once a day. By doing in this way, it can aim at the relief of the pain by various cancers, for example, when the pain is severe, the dose can be adjusted.

Examples of the release sheet include release paper (release paper) that has been subjected to release treatment, cellophane, polyethylene, polypropylene, polyvinyl chloride, polyester, polyvinylidene chloride, and silicon processed paper.
The transdermally absorbable preparation of the present invention is not particularly limited to a patch as long as it can exhibit the blood concentration characteristics of the fentanyl of the present invention, and may be a coating agent such as a gel or cream, The patch does not need to be composed only of a support and an adhesive, and may be provided with various structures such as a membrane for adjusting drug permeability and a microneedle for promoting permeability depending on circumstances.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples.

Example 1
(Prescription)
Ingredient name Content (%)
SIS 16.0
PIB 7.0
Alicyclic saturated hydrocarbon resin 40.0
Liquid paraffin 31.0
Sodium acetate 2.0
Fentanyl citrate 4.0
Total amount 100.0

(Manufacturing method)
Fentanyl citrate, sodium acetate and liquid paraffin were mixed in a mortar and mixed with the remaining ingredients dissolved in toluene. After coating the obtained mixture on a release paper (release sheet), the solvent was removed by drying, and the mixture was bonded to a stretched PET support (thickness: 20 μm) to obtain a transdermal absorption preparation (matrix type). The pressure-sensitive adhesive containing fentanyl citrate was 50 g / m ² (fentanyl citrate per unit area: 0.2 / cm ² ).

Example 2
(Prescription)
Ingredient name Content (%)
Acrylic adhesive (Duro-Tak387-2287) 80.0
Isopropyl myristate 10.0
Fentanyl 10.0
Total amount 100.0

(Manufacturing method)
Fentanyl and isopropyl myristate were placed in a mortar and mixed well, and then mixed with an acrylic adhesive solution. After coating the obtained mixture on a release paper (release sheet), the solvent was removed by drying, and the mixture was bonded to a stretched PET support (thickness: 20 μm) to obtain a transdermal absorption preparation (matrix type). The pressure-sensitive adhesive containing fentanyl was 30 g / m ² (fentanyl per unit area: 0.3 mg / cm ² ).

Example 3
(Prescription)
Ingredient name Content (%)
Acrylic adhesive (Duro-Tak387-2516) 90.0
Fentanyl 10.0
Total amount 100.0

(Manufacturing method)
Fentanyl and an acrylic adhesive solution are mixed, and the resulting mixture is coated on a release paper (release sheet), then the solvent is removed by drying, and bonded to a stretched PET support (thickness: 20 μm) to be transdermally absorbed. (Matrix type) was obtained. The pressure-sensitive adhesive containing fentanyl was 20 g / m ² (fentanyl per unit area: 0.2 mg / cm ² ).

Example 4
A transdermally absorbable preparation (matrix type) was obtained by the same production method except that the support of Example 1 was changed from a stretched PET support to a laminate support of stretched PET and EVA membrane (manufactured by 3M: ScotchPak9732).

Example 5
A percutaneously absorbable preparation (matrix type) was obtained by the same production method except that the support of Example 2 was changed from a stretched PET support to a laminate support of stretched PET and EVA membrane (manufactured by 3M: ScotchPak9732).

Example 6
A transdermal absorption preparation (matrix type) was obtained by the same production method except that the support of Example 3 was changed from a stretched PET support to a laminate support of stretched PET and EVA membrane (manufactured by 3M: ScotchPak9732).

Test example 1
About 10 cm ² of a patch containing 4% of fentanyl citrate described in Example 1, it was applied to 5 adults for 1 day (24 hours), and another 5 adults for 3 days (72 hours) Pasting was performed, and blood was collected over time. Next, the blood fentanyl concentration in the obtained blood was measured by gas chromatography / mass spectrometry. Based on the measurement results, a graph of an example when the 1-day sticking is performed 14 times continuously and the 3-day sticking is performed 5 times continuously is shown in FIG.

Table 1 shows the peak / trough value at each pasting time obtained from the above results.

Test example 2
About 10 cm ² of the patch containing 4% of fentanyl citrate described in Example 1, it was applied 9 times a day for 7 adults, and 3 days for another 7 adults. The test was performed three times in succession, and blood was collected over time. Subsequently, the blood fentanyl concentration in the obtained blood was measured by a gas chromatography / mass spectrometry method.
FIG. 2 shows the transition of fentanyl mean blood concentration (C) after 6 days (144 hours) after application in each of the above groups.

In addition, the mean value and the standard deviation value of blood fentanyl concentration in any three consecutive days after the day when the blood fentanyl concentration reached a steady state were obtained, and the CV value (standard deviation value / The average value × 100 (%) is shown in Table 2.

In addition, Table 3 shows the ratio of the maximum value / minimum value of the blood fentanyl concentration in each group during any three consecutive days after the day when the blood fentanyl concentration reached a steady state.

Test example 3
The support used in Examples 1 to 6 was punched out to about 70 mmφ to obtain a test piece, and a moisture permeability test was performed in accordance with JIS Z0208 Condition B (each n = 3).
As a result of the test, the moisture permeability of the support used in Examples 1 to 6 was 19 to 26 g / m ² · 24 hr.

Test example 4
The support used in Examples 1 to 6 was cut to a width of 3 cm to obtain a sample, which was set in a pure bending tester (KES-FB-M2 measuring machine, manufactured by Kato Tech Co., Ltd.), and the curvature was 0.5 to 1 Measured at 0.5 cm ⁻¹ .
As a result of the measurement, the bending rigidity of the support used in Examples 1 to 6 was 0.0363 to 0.0716 g · cm ² / cm.

Test Example 5
In order to compare the pain-suppressing effect when the preparation described in Example 1 was applied for 3 days and when applied for 1 day, the following test was performed.
To the same patient, the preparation described in Example 1 was applied 3 times in succession for 3 days (9 days), and then the preparation was applied 3 times in succession for 1 day (3 days) (total 12 days). ) The VAS value (pain index) of each day after the third 3rd day application (7th to 9th days) was measured.

Three days pasting was repeated twice, and the change rate of the VAS value was obtained every 24 hours after 24 hours from the start of the third time (VAS value is 1), and the transition is shown in FIG.
As a result, in the case of 3-day application, after 48 hours had elapsed after the third application, the VAS value increased and the pain increased, but after switching to 1-day application (after the 10th day) , VAS value decreased again, and once enhanced pain was suppressed.

Claims (12)

A once-daily fentanyl-containing transdermal absorption preparation containing fentanyl citrate and sodium acetate, which is a patch comprising a support, an adhesive and a release sheet, the patch being a matrix type, Fentanyl acid is contained in the adhesive at 0.10 to 0.45 mg / cm ² , the mass of the adhesive is ² to 10 mg / cm ² , and the adhesive is polyisobutylene and styrene-isoprene-styrene block copolymer The area of the patch is 5 to 60 cm ² , the moisture permeability of the support is 15 to 30 g / m ² · 24 hr, and the flexural rigidity of the support is 0.01 to 0.20 g · cm ² / characterized in that cm, and the mean peak / trough values blood fentanyl concentration at steady state in the case of continuous administration once daily of the percutaneous absorption preparation 1. Made by adjusting the content of fentanyl citrate in the formulation by varying the area of the adjusted and patch content of 1cm per ² fentanyl citrate in the pressure-sensitive adhesive to be equal to or less than, the percutaneous absorption Formulation.   CV value (standard deviation value / average value) obtained from the average value and standard deviation value of blood fentanyl concentration measured every day for at least 3 consecutive days after repeated administration once a day and reaching a steady state The percutaneous absorption preparation according to claim 1, wherein x100 (%) is 40% or less.   CV value (standard deviation value / average value) obtained from the average value and standard deviation value of blood fentanyl concentration measured every day for at least 3 consecutive days after repeated administration once a day and reaching a steady state The percutaneous absorption preparation according to claim 1, wherein x100 (%) is 20% or less.   The ratio of the minimum value (minimum value / maximum value) to the maximum value of the blood fentanyl concentration measured every day for at least 3 consecutive days after repeating once a day administration and reaching a steady state is 0.5. The transdermally absorbable preparation according to any one of claims 1 to 3, which is as described above.   When the said percutaneous absorption preparation continues administration once a day, the average peak / trough value of the blood fentanyl density | concentration in a steady state is 1.3 or less, It is any one of Claims 1-4. Transdermal absorption preparation.   The transdermally absorbable preparation according to any one of claims 1 to 5, which is a patch having a fentanyl citrate content of 1 to 2 mg per sheet.   The transdermally absorbable preparation according to any one of claims 1 to 6, wherein the adhesive contains an acrylic polymer.   The transdermally absorbable preparation according to any one of claims 1 to 7, wherein the support comprises stretched polyethylene terephthalate. The transdermally absorbable preparation according to claim 8 , wherein the moisture permeability of the support is 19 to 26 g / m ² · 24 hr. The transdermally absorbable preparation according to claim 9 , wherein the support has a flexural rigidity of 0.0363 to 0.0716 g · cm ² / cm. A once-daily fentanyl-containing transdermal absorption preparation containing fentanyl citrate and sodium acetate, which is a patch comprising a support, an adhesive and a release sheet, the patch being a matrix type, Fentanyl acid is contained in the adhesive at 0.10 to 0.45 mg / cm ² , the mass of the adhesive is ² to 10 mg / cm ² , and the adhesive is polyisobutylene and styrene-isoprene-styrene block copolymer The average peak / trough value of the blood fentanyl concentration in the steady state when the once-daily administration of the transdermal absorption preparation is continued is 1, wherein the area of the patch is 5 to 60 cm ^2. By adjusting the content of fentanyl citrate per 1 cm ² in the pressure-sensitive adhesive to 8 or less and changing the area of the patch A method for producing the percutaneous absorption preparation, wherein the content of fentanyl citrate in the preparation is adjusted, and when the once per day administration of the percutaneous absorption preparation is continued, the blood fentanyl concentration in a steady state The content of fentanyl citrate in the pressure-sensitive adhesive is in the range of 0.10 to 0.45 mg / cm ² and the mass of the pressure-sensitive adhesive is ² to 10 mg so that the average peak / trough value of / cm ² of the respectively determined within the range, as well as adjusting the amount of fentanyl citrate in the formulation by varying the area of the patch within the 5～60Cm ^2, said method. It is a manufacturing method of the transdermal absorption preparation as described in any one of Claims 1-10, Comprising: When the once-daily administration of the said transdermal absorption preparation is continued, the average peak of the blood fentanyl density | concentration in a steady state / trough value content of fentanyl citrate in the pressure-sensitive adhesive such that 1.3 or less within the range of 0.10~0.45mg / cm ^2, and the mass of the adhesive 2 to 10 mg / cm ² And adjusting the content of fentanyl citrate in the preparation by varying the area of the patch within the range of 5 to 60 cm ² .

Images