JP2010138123A - Fentanyl-containing oral mucosal patch - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an oral mucosal patch which can be applied to the oral mucous membrane to allow fentanyl to be efficiently and quickly absorbed to exhibit the drug effect. <P>SOLUTION: The fentanyl-containing oral mucosal patch 10 is constituted of a drug layer 1 and support layers 2 arranged on both sides of the drug layer 1 and the drug layer contains fentanyl or a salt thereof as an active ingredient and an edible water-soluble polymer, and the supports layers 2 contain a coating agent and an edible water-soluble polymer. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to an oral mucosa patch preparation containing fentanyl or a salt thereof as an active ingredient.

  Fentanyl is an opioid analgesic that exerts a major pharmacological effect on the central nervous system in clinical conditions. The main medicinal effects are analgesia and sedation. In particular, in order to relieve acute postoperative pain and chronic cancer pain, injections containing fentanyl citrate and transdermal absorption agents containing fentanyl as an active ingredient ( It is clinically used as a patch, Patent Document 1). In addition, a mucosal patch that is applied to the oral mucosa and absorbs fentanyl is known (Patent Document 2).

However, although the injection can increase the blood concentration of fentanyl in a short period of time and obtain an immediate effect, the burden on the patient during administration is great. Moreover, although the transdermal absorbent of patent document 1 penetrates fentanyl into the skin and absorbs it, it is difficult to increase the blood concentration in a short time because fentanyl is hardly absorbed. Furthermore, since the mucosal patch of Patent Document 2 releases fentanyl continuously and gradually increases the blood concentration, it is difficult to raise fentanyl to an effective blood concentration in a short time.
In recent years, there has been a demand for a preparation capable of increasing the blood concentration of fentanyl in a short time by a simple means, but a fentanyl-containing preparation capable of obtaining immediate effects while reducing the burden on patients is still known. Absent.

Japanese Patent No. 2547726 JP 2002-275066 A

  Accordingly, an object of the present invention is to provide an intraoral mucosa patch preparation that can be affixed to the oral mucosa and efficiently and quickly absorb fentanyl and exert its medicinal effects.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have surprisingly found a film in which a support layer containing a specific component is laminated on both sides of a drug layer containing fentanyl or a salt thereof and the specific component. It was found that a preparation capable of rapidly increasing the blood concentration of fentanyl by rapidly dissolving or disintegrating due to moisture in the oral cavity was obtained.
That is, the present invention comprises fentanyl or a salt thereof, a drug layer containing an edible water-soluble polymer, and a support layer disposed on both sides of the drug layer and containing a coating agent and an edible water-soluble polymer. A fentanyl-containing intraoral mucosa patch preparation is provided.

The fentanyl-containing intraoral mucosal patch preparation of the present invention has mucosal absorbability, and is applied to the oral cavity and rapidly dissolved or disintegrated (rapidly dissolved) by moisture in the oral cavity, and the fentanyl released from the preparation is absorbed into the oral cavity. It can be absorbed quickly through the mucosa. As a result, while reducing the burden on the patient, the blood concentration of fentanyl can be rapidly increased to express immediate analgesia and sedation, which is particularly effective for breakthrough pain.
Moreover, since the fentanyl-containing intraoral mucosa patch preparation of the present invention can be taken only with moisture in the oral cavity, it has good handling properties and excellent portability.

First, terms used in this specification will be described.
As used herein, the term “oral mucosal patch preparation” refers to a preparation in which the preparation is dissolved or disintegrated in the oral cavity and fentanyl released from the preparation is absorbed through the oral mucosa.
The term “intraoral mucosal patch” means that the mucous membrane is covered with mucus in the oral cavity. Examples of “oral mucosa” include the mucous membrane of the floor (sublingual mucosa), the mucous membrane of the cheek (buccal mucosa), the mucous membrane of the gums (gingival mucosa), the mucous membrane of the palate (paratal mucosa), and the mucous membrane of the lips. Illustrated. Among these, the gingival mucosa and the sublingual mucosa are preferable in that the support layers disposed on both sides of the preparation can be attached to the mucosa. As a result, fentanyl released from the two support layers can be absorbed through the respective mucous membranes, and the blood concentration of fentanyl can be increased more rapidly.
The term “fast dissolution” refers to rapid dissolution or disintegration in the oral cavity even when the preparation is taken without water.
The term “unit preparation” means a minimum unit of a preparation to be taken. For example, in the case of preparations individually packaged, the preparation is a single preparation, and a cutting line defining the shape is provided. In the case of a sheet-form preparation in which a plurality of preparations are arranged in a matrix, it is one preparation separated along the cutting line.

  Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. In the description of the drawings, the same elements are denoted by the same reference numerals, and redundant description is omitted. For the convenience of illustration, the dimensional ratios in the drawings do not necessarily match those described.

FIG. 1 is a cross-sectional view showing an embodiment of the fentanyl-containing intraoral mucosa patch preparation (hereinafter also simply referred to as “oral mucosa patch preparation”) of the present invention.
The intraoral mucosa patch preparation 10 according to this embodiment is composed of a drug layer 1 and a support layer 2 disposed on both sides thereof, and has a three-layer structure.
The drug layer 1 contains fentanyl or a salt thereof as an active ingredient and an edible water-soluble polymer, and the support layer 2 contains a coating agent and an edible water-soluble polymer.

  As fentanyl or a salt thereof, those commonly used in the art can be used without particular limitation, but the form of the free base is preferable from the viewpoint of drug absorbability. The salt of fentanyl is not particularly limited as long as it is a pharmacologically acceptable salt. For example, an acid addition salt with a pharmacologically acceptable acid is preferable, and specifically, hydrochloric acid, sulfuric acid, phosphoric acid, Salts with inorganic salts such as hydrobromic acid; organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, acetic acid, lactic acid, p-toluenesulfonic acid, and methanesulfonic acid The salt of is illustrated.

The content of fentanyl or a salt thereof in the intraoral mucosa patch preparation of the present invention can be appropriately set, but is 0.1 to 10% by mass based on the total mass of the unit preparation, and further 0.2 to 8% by mass. %, Particularly preferably 0.3 to 7% by mass. Further, the content of fentanyl or a salt thereof in the drug layer is preferably 0.1 to 15% by mass, more preferably 0.2 to 10% by mass, and particularly preferably 0.3 to 9% by mass. By setting it as such content, an immediate effective analgesic effect can be expressed more reliably.
In addition, the intraoral mucosa patch preparation of the present invention can be administered to the oral cavity in 1 to several times per day, and the dose may be appropriately increased or decreased depending on the age, body weight and medical condition.

The edible water-soluble polymer is not particularly limited as long as it is an edible polymer compound having a property of forming a film when the aqueous solution is dried. Hydroxypropyl cellulose (HPC), Hydroxypropylmethylcellulose (HPMC, hypromellose), hydroxyethylcellulose (HEC), carboxymethylcellulose sodium (CMC-Na), carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose potassium (CMC-K), carboxymethylcellulose (CMC) , Polyvinylpyrrolidone (PVP) and at least one selected from the group consisting of sodium alginate are preferably used. Thereby, control of dissolution or disintegration by moisture such as saliva in the oral cavity becomes easy, and the film strength can be increased.
Among them, HPC, HPMC, and PVP are preferable, and it is particularly preferable that HPC and PVP are contained in the drug layer and HPMC is contained in the support layer.

  As the HPC, one produced by a known method may be used, or a commercially available product (for example, Saneigen FFI Co., Ltd., Nippon Soda Co., Ltd., etc.) may be used. The degree of substitution in HPC is not particularly limited, but those containing 50 to 80%, particularly 53.4 to 77.5% of hydroxypropoxyl groups are suitable. In addition, although the viscosity of HPC is not specifically limited, For example, the dynamic viscosity of 2 mass% aqueous solution in 20 degreeC is 2.0-10 mPa * s, Especially 2.0-5.9 mPa * s is preferable. In addition, in this specification, kinematic viscosity of 2 mass% aqueous solution is measured by the method as described in the 15th revision Japanese Pharmacopoeia.

On the other hand, as HPMC, you may use what was manufactured by the well-known method, and a commercial item (for example, Shin-Etsu Chemical Co., Ltd., Dow Chemical Japan Co., Ltd., Matsumoto Yushi Seiyaku Co., Ltd.) May be used.
The degree of substitution between methoxyl group and hydroxypropoxyl group in HPMC is not particularly limited, but preferably contains 10 to 50%, more preferably 16.5 to 40%, particularly 28 to 30% of methoxyl group, 2 to 35% hydroxypropoxyl group, and further 4 to 32%. What contains 7 to 12% especially is preferable. Among these, HPMC containing 25 to 33% of methoxyl group and 5 to 15% of hydroxypropoxyl group is particularly suitable. As a commercial item, HPMC1828, HPMC2208, HPMC2906, and HPMC2910 are suitable, for example, and HPMC2910 is especially suitable. The viscosity of HPMC is not particularly limited. For example, the kinematic viscosity (15th revised Japanese Pharmacopoeia) of a 2% by mass aqueous solution at 20 ° C. is 3.0 to 15 mPa · s, particularly 3.0 to 6 mPa. -S is preferable.

As PVP, you may use what was manufactured by the well-known method, and also use a commercial item (For example, Daiichi Kogyo Seiyaku Co., Ltd., BASF Japan Co., Ltd., Gokyo Sangyo Co., Ltd.). Also good.
The K value and average molecular weight (Mw) in PVP are not particularly limited, but from the viewpoint of improving the film strength, the K value is 10 to 120, more preferably 15 to 110, further 25 to 100, and particularly 80 to 100. The average molecular weight (Mw) is preferably 2500 to 3000000, more preferably 8000 to 2000000, and particularly preferably 30000 to 1500,000. The K value is a value calculated by applying a relative viscosity value (25 ° C.) with respect to water to the Fikentscher's equation, measured by a capillary viscometer, and Mw was measured by a light scattering method. Value.

  The content of the edible water-soluble polymer in the intraoral mucosa patch preparation of the present invention can be appropriately set, but is 60 to 98% by mass, more preferably 70 to 97% by mass, particularly 70 to 97% by mass based on the total mass of the unit preparation. 80-97 mass% is preferable. Further, the content of the edible water-soluble polymer in the drug layer is preferably 70 to 98% by mass, more preferably 80 to 98% by mass, and particularly preferably 85 to 98% by mass, and the edible water-soluble polymer in the support layer. The content is preferably 80 to 98% by mass, more preferably 85 to 95% by mass, and particularly preferably 87 to 92% by mass.

  The coating agent is not particularly limited as long as it is edible, and examples thereof include titanium oxide, ethyl cellulose, kaolin, carboxyvinyl polymer, carboxymethyl ethyl cellulose, crystalline cellulose, stearic acid, calcium stearate, and shellac. . Of these, titanium oxide, kaolin and shellac are preferred from the viewpoint of improving handling properties, and titanium oxide is particularly preferred.

  The content of the coating agent in the intraoral mucosa patch preparation of the present invention can be appropriately set, but is 0.1 to 1.0% by mass, and further 0.2 to 0.7% based on the total mass of the unit preparation. % By mass, particularly 0.3 to 0.5% by mass is preferred. Further, the content of the coating agent in the support layer is preferably 0.5 to 5% by mass, more preferably 1 to 3.5% by mass, and particularly preferably 1.5 to 3% by mass. The drug layer can also contain a coating agent, but from the viewpoint of the pressure-bonding performance of the drug layer, it is preferable not to contain a coating agent.

  In the present invention, the drug layer and / or the support layer may further contain a plasticizer. The plasticizer is not particularly limited as long as it is compatible with the edible water-soluble polymer and can provide flexibility. For example, glycerin, sesame oil, sorbitol, castor oil, propylene glycol, polyoxyethylene poly Oxypropylene glycol, polysorbate 80 (polyoxyethylene (20) sorbitan oleate), polyethylene glycol [for example, macrogol 400 (polymerization degree n of oxyethylene units is 7 to 9, the same applies hereinafter), macrogol 600 (n 11 to 13), Macrogol 1500 (n is an equal mixture of 5 to 6 and n is 28 to 36), Macrogol 4000 (n is 59 to 84), Macrogol 6000 (n is 165 to 210) ] And a combination of one or more selected from these is preferable. Among these, glycerin, propylene glycol, and polyethylene glycol are preferable, and polyethylene glycol having a degree of polymerization of oxyethylene units of 7 to 9 is particularly preferable.

  The content of the plasticizer is preferably 1 to 15% by mass, more preferably 2 to 10% by mass, and particularly preferably 3 to 7% by mass based on the total mass of the unit preparation. Further, the content of the plasticizer in the drug layer is preferably 1 to 15% by mass, more preferably 2 to 10% by mass, particularly preferably 3 to 7% by mass, and the content of the plasticizer in the support layer is 1 to 20 mass%, 3-15 mass%, Furthermore, 5-10 mass% is especially preferable.

  Moreover, the intraoral mucosa patch preparation of the present invention may contain one or more commonly used pharmacologically acceptable carriers, if necessary. Examples of the carrier include, but are not limited to, excipients, colorants, disintegrants, antioxidants, and corrigents. In the intraoral mucosa patch preparation of the present invention, it is not necessary to contain a pH adjuster in the drug layer and the support layer.

  Excipients include magnesium hydroxide alumina, silicon dioxide, anhydrous sodium sulfate, anhydrous calcium hydrogen phosphate, sodium chloride, hydrous amorphous silicon oxide, magnesium aluminate silicate, calcium silicate, magnesium silicate, and light anhydrous silica. Inorganic excipients such as acid, heavy anhydrous silicic acid, magnesium oxide, calcium sulfate; candy powder, starch, fructose, caramel, agar, xylitol, paraffin, cellulose, sorbitol, sucrose, fructose, maltose, lactose, sucrose Organic excipients such as glucose, pullulan, polyoxyethylene hydrogenated castor oil, maltitol, reduced maltose water candy, powdered reduced maltose water candy, sorbitol, erythritol, xylitol, mannitol, lactitol, trehalose, reduced palatinose, maltose Illustrated That. These can be used alone or in combination. Among these, powdered reduced maltose water candy and mannitol are preferable from the viewpoint of improving solubility or disintegration property in the oral cavity.

  The colorant is not particularly limited as long as it is commonly used in the art and is edible. For example, yellow iron sesquioxide, brown iron oxide, caramel, black iron oxide, titanium oxide, iron sesquioxide , Tar dye, aluminum lake dye, copper chlorophyllin sodium. These can be used alone or in combination. Of these, titanium oxide and aluminum lake dye are preferable from the viewpoint of solubility and dispersibility.

  Examples of the disintegrant include carmellose and salts thereof, starch, sucrose fatty acid ester, gelatin, dextrin, dehydroacetic acid and salts thereof, povidone, polyoxyethylene hydrogenated castor oil, and polyoxyethylene polyoxypropylene glycol.

  Examples of the antioxidant include ascorbic acid, sodium bisulfite, sodium sulfite, sodium edetate, erythorbic acid, tocopherol acetate, dibutylhydroxytoluene, natural vitamin E, tocopherol, and butylhydroxyanisole.

  Examples of the corrigent include acidulants such as ascorbic acid, malic acid and salts thereof; and sweeteners such as aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, and saccharin sodium.

  The content of these pharmaceutical additives can be appropriately set. For example, the content of the excipient is preferably 0.1 to 5% by mass based on the total mass of the unit preparation, and the colorant is 0.05-10 mass% is preferable on the basis of the total mass of the unit preparation. The content of the disintegrant is preferably 1 to 8% by mass based on the total mass of the unit preparation, and the poorly water-soluble polymer substance is preferably 1 to 10% by mass based on the total mass of the unit preparation. Further, the antioxidant is preferably 0.1 to 5% by mass based on the total mass of the unit preparation, and the taste-masking agent is preferably 1 to 10% by mass based on the total mass of the unit preparation.

  The intraoral mucosa patch preparation of the present invention has a three-layer structure in which a support layer, a drug layer, and a support layer are sequentially laminated, but when the same kind of layers are laminated adjacently, they are In order to perform the same function in close contact with each other, the present invention handles substantially one layer. In addition, the intraoral mucosa patch preparation of the present invention may be provided with a functional layer between the drug layer and the support layer as long as the object of the present invention is not impaired. As such a functional layer, for example, a moisture-proof layer mainly composed of ethyl cellulose and moisture-proof is exemplified.

The total thickness of the intraoral mucosa patch preparation of the present invention is preferably 10 to 300 μm, more preferably 30 to 200 μm, and particularly preferably 50 to 150 μm. In addition, the thickness of the support layer is preferably 1 to 100 μm, more preferably 3 to 50 μm, particularly preferably 5 to 30 μm, and the thickness of the drug layer is preferably 9 to 250 μm, more preferably 30 to 200 μm, and particularly preferably 50 to 150 μm. Thereby, it becomes possible to make it melt | dissolve or disintegrate rapidly in an oral cavity, and can further promote absorption of a fentanyl. The thickness of the functional layer can be appropriately set within a range that does not impair the object of the present invention.
In addition, the size of the intraoral mucosa patch preparation of the present invention is not particularly limited as long as it is easy to take, but it is preferably, for example, about 1 to ⁴ cm ² . Further, the shape is not particularly limited as long as it is easy to take, but for example, a shape such as a square, a circle, and an ellipse can be appropriately selected.

The oral mucosal patch preparation of the present invention is preferably dissolved or disintegrated in water within 5 minutes in order to rapidly dissolve or disintegrate in the oral cavity and rapidly increase the blood concentration of fentanyl. The dissolution time in water is preferably within 5 minutes, particularly preferably within 3 minutes. The drug elution rate is preferably 85% by mass or more / 15 minutes, more preferably 90% by mass or more / 15 minutes.
Here, in the present specification, the dissolution time in water and the drug elution rate are those measured by the following water solubility test.

5. Water solubility test A test piece cut to a size of 120 mm ² square is collected, put in a test solution (purified water 900 mL), and the 15th revised Japanese Pharmacopoeia [B] General Test Method. Formulation Test Method 6.10 Dissolution Test Method According to the paddle method (P587), the test is performed at 50 rpm using a sinker. Complete dissolution is visually confirmed, and the elapsed time is taken as dissolution time. The test is performed 5 times, and the average value is taken as the water dissolution time. In addition, the drug elution amount at the time when 15 minutes have elapsed is measured five times, and the average value of the drug elution rate calculated from the drug elution amount is defined as the drug elution rate.

  The intraoral mucosa patch preparation of the present invention is preferably dissolved or disintegrated in the oral cavity within 180 minutes, more preferably within 120 minutes, and particularly within 90 minutes. In the present specification, the dissolution time in the oral cavity is measured by the following oral dissolution test.

The test piece was cut to the size of the oral dissolution test square 120 mm ² was collected, which was attached to the buccal mucosa of healthy adults, the test piece to measure the time until complete dissolution only saliva in the oral cavity .

  The intraoral mucosa patch preparation of the present invention can be produced by appropriately selecting conventional or known methods. For example, it is manufactured by laminating a first support layer on a release film such as a polyethylene terephthalate film (PET), further laminating a drug layer, and then laminating a second support layer on the drug layer. Can do. Further, the intermediate product 1 in which the first support layer is laminated on the release film, and further the first drug layer is laminated, and the second support layer is laminated on the release film separately, and further the second drug It is also possible to produce the intermediate product 2 by laminating the layers, and then laminating the two drug layers so that the drug layers face each other. The compositions of the first and second support layers and the first and second drug layers may be the same or different.

  EXAMPLES Hereinafter, although an Example etc. demonstrate this invention further more concretely, this invention is not limited to the following Example.

[Example 1]
A solution obtained by adding 0.90 g of titanium oxide to 94.50 g of absolute ethanol was subjected to ultrasonic treatment in an ultrasonic bath to obtain a titanium oxide dispersion. Next, the obtained titanium oxide dispersion was filtered using a 200 mesh filter, 40.50 g of purified water, 3.60 g of Macrogol 400, and 40.50 g of HPMC were added and stirred to obtain a support layer preparation solution. .
Fentanyl-containing solution was obtained by adding 0.10 g of fentanyl and 1.50 g of Macrogol 400 to 60.00 g of absolute ethanol and stirring and mixing. Next, 20.00 g of HPC-SSL and 2.40 g of polyvinylpyrrolidone K90 were added to the fentanyl-containing solution and mixed by stirring to obtain a drug layer preparation solution.

Using each of the prepared solutions, a fentanyl-containing intraoral mucosa patch preparation was prepared by the following procedure.
1) Production process of intermediate product 1 Set the PET film after the silicone release treatment on the unwinding shaft of the coating machine, supply the support layer preparation liquid to the dam part, and the surface of the PET film (surface not subjected to the silicone release treatment) After applying the support layer preparation liquid, the film was dried with hot air at 70 ° C. to form a first support layer having a thickness of about 10 μm. Next, the PET film on which the first support layer is formed is set again on the unwinding shaft, and after the drug layer preparation liquid is applied on the first support layer, it is dried with hot air at 40 ° C. and has a thickness of about 40 μm. The intermediate product 1 in which the first drug layer was formed was obtained.
2) Production process of intermediate product 2 By the same procedure as that of intermediate product 1, intermediate product 2 having a second support layer having a thickness of about 10 μm and a second drug layer having a thickness of about 40 μm was obtained.
3) Crimping step The first drug layer of the intermediate product 1 and the second drug layer of the intermediate product 2 are bonded so that they face each other, and both are crimped at a crimping temperature of 70 ° C., and the support layer, drug layer and support An intermediate product 3 having a three-layer structure in which layers were sequentially laminated was obtained.
4) Peeling process One PET film of the intermediate product 3 was peeled. Subsequently, it cut | judged to the area 1.2cm < ² >, the other PET film was peeled, and the fentanyl containing intraoral mucosal patch preparation based on this invention was obtained.

[Examples 2 to 8]
Except having changed each compounding component and the compounding quantity into the thing of Table 1, the fentanyl containing intraoral mucosa patch preparation of Examples 2-8 was manufactured by the method similar to Example 1, respectively.

[Comparative Example 1]
A solution obtained by adding 0.90 g of titanium oxide to 94.50 g of absolute ethanol was subjected to ultrasonic treatment in an ultrasonic bath to obtain a titanium oxide dispersion. Next, the obtained titanium oxide dispersion is filtered using a 200-mesh filter, 40.50 g of purified water, 3.60 g of Macrogol 400 and 40.50 g of HPMC are added and mixed by stirring to obtain a support layer preparation liquid I. It was.
A solution obtained by adding 0.90 g of titanium oxide to 94.50 g of absolute ethanol was subjected to ultrasonic treatment in an ultrasonic bath to obtain a titanium oxide dispersion. Subsequently, the obtained titanium oxide dispersion was filtered using a 200-mesh filter, purified water 40.50 g, macrogol 400 3.60 g, and hydroxypropyl methylcellulose phthalate (hypromellose phthalate ester, HPMCP) 40.50 g. And stirring and mixing were performed to obtain Support Layer Preparation Liquid II.
Fentanyl-containing solution was obtained by adding 0.10 g of fentanyl and 0.50 g of Macrogol 400 to 60.00 g of absolute ethanol and stirring and mixing. Next, 21.00 g of HPC-SSL and 2.40 g of polyvinylpyrrolidone were added to the fentanyl-containing solution and mixed by stirring to obtain a drug layer preparation solution.

1) Manufacturing process of intermediate product 1 Set the PET film that has been subjected to silicone release treatment on the unwinding shaft of the coating machine, supply the support layer preparation liquid I to the dam part, and the surface of the PET film (surface that has not been subjected to silicone release treatment) The support layer preparation liquid I was applied to the substrate and dried with hot air at 70 ° C. to form a first support layer having a thickness of about 10 μm. Next, the PET film on which the first support layer is formed is set again on the unwinding shaft, and after the drug layer preparation liquid is applied on the first support layer, it is dried with hot air at 40 ° C. and has a thickness of about 40 μm. The intermediate product 1 in which the first drug layer was formed was obtained.
2) Manufacturing process of intermediate product 2 Set the PET film that has been subjected to silicone release treatment on the unwinding shaft of the coating machine, supply the support layer preparation liquid II to the dam part, and the surface of the PET film (surface that has not been subjected to silicone release treatment) The support layer preparation liquid II was applied to (2) and dried with hot air at 70 ° C. to form a second support layer having a thickness of about 10 μm. Next, the PET film on which the second support layer is formed is set again on the unwinding shaft, and after the drug layer preparation liquid is applied on the second support layer, it is dried with hot air at 40 ° C. and has a thickness of about 40 μm. The intermediate product 2 in which the first drug layer was formed was obtained.
3) Crimping step The first drug layer of the intermediate product 1 and the second drug layer of the intermediate product 2 are bonded together so as to face each other, and both are crimped at a crimping temperature of 70 ° C., and the support layer I, drug layer and An intermediate product 3 having a three-layer structure in which the support layer II was sequentially laminated was obtained.
4) Peeling process One PET film of the intermediate product 3 was peeled. Subsequently, it was cut into an area of 1.2 cm ² and the other PET film was peeled off to obtain a fentanyl-containing intraoral mucosa patch preparation.

  Table 1 shows the composition per unit preparation (one fentanyl-containing oral mucosa patch preparation) obtained in each Example and Comparative Example.

  The oral mucosal patch preparations obtained in each Example and Comparative Example were subjected to the following solubility test in water and oral dissolution test. The results are shown in Table 2.

5. Water solubility test A test piece cut to a size of 120 mm ² square is collected, put in a test solution (purified water 900 mL), and the 15th revised Japanese Pharmacopoeia [B] General Test Method. Formulation Test Method 6.10 Dissolution Test Method According to the paddle method (P587), a test was performed at 50 rpm using a sinker. Complete dissolution was confirmed visually, and the elapsed time was taken as dissolution time. The test was performed 5 times, and the average value was taken as the water dissolution time. Further, the drug elution amount at the time of 15 minutes was measured five times, and the average value of the drug elution rate calculated from the drug elution amount was taken as the drug elution rate.

  As is clear from Table 2, the oral mucosa patch preparations obtained in Examples 1 to 8 dissolved or disintegrated in water within 5 minutes, and the drug elution rate was 85% by mass or more / 15 minutes. It was a formulation. In contrast, the oral mucosal patch preparation obtained in Comparative Example 1 has a dissolution or disintegration in water of 30 minutes or more, and further has a drug elution rate of 44.1% by mass / 15 min. It was a difficult formulation.

It is a figure which shows one Embodiment of the fentanyl containing oral-mucosal patch preparation of this invention.

Explanation of symbols

1: Drug layer 2: Support layer 10: Fentanyl-containing intraoral mucosa patch preparation

Claims (7)

Fentanyl or a salt thereof, and a drug layer containing an edible water-soluble polymer,
A fentanyl-containing intraoral mucosa patch preparation comprising a coating layer and a support layer containing an edible water-soluble polymer disposed on both sides of the drug layer.   The oral mucosa patch preparation according to claim 1, wherein the drug layer and the support layer further contain a plasticizer.   The edible water-soluble polymer is at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose / sodium, carboxymethylcellulose / calcium, carboxymethylcellulose / potassium, carboxymethylcellulose, polyvinylpyrrolidone and sodium alginate. The intraoral mucosa patch preparation according to claim 1 or 2, which is a seed.   The intraoral mucosa patch preparation according to any one of claims 1 to 3, wherein the coating agent is titanium oxide.   The edible water-soluble polymer is hydroxypropylcellulose having a kinematic viscosity of 2.0 to 10 mPa · s at 20 ° C. or a kinematic viscosity of 2 to 15% at 20 ° C. The intraoral mucosa patch preparation according to any one of claims 1 to 4, which is hydroxypropylmethylcellulose of 0 mPa · s.   The intraoral mucosal patch preparation according to any one of claims 1 to 5, wherein the dissolution time in water is within 5 minutes and the drug elution rate is 85% by mass or more / 15 minutes.   The oral mucosa patch preparation according to any one of claims 1 to 6, wherein the oral mucosa is a gingival mucosa or a sublingual mucosa.

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