WO2013080271A1

WO2013080271A1 - Analgesic

Info

Publication number: WO2013080271A1
Application number: PCT/JP2011/077348
Authority: WO
Inventors: 拓司福野; 重松　紀仁; 忠与宮坂; 隆雄戸田; 信吾土居; 祥一川添
Original assignee: 東洋紡株式会社; 扶桑薬品工業株式会社
Priority date: 2011-11-28
Filing date: 2011-11-28
Publication date: 2013-06-06

Abstract

The purpose of the present invention is to provide a novel drug or method that uses buprenorphine or a pharmaceutically acceptable salt thereof. A drug for alleviating pain associated with disc herniation, pain associated with osteoarthritis of the spine, or pain associated with spinal canal stenosis, the drug attaching to the oral mucosa and containing buprenorphine or a pharmaceutically acceptable salt thereof.

Description

Painkiller

The present invention relates to a medicament for alleviating pain associated with disc herniation, pain associated with degenerative spondylosis, or pain associated with spinal stenosis, and a pain relieving method using the same. More specifically, the present invention reduces pain associated with herniated disc, pain associated with degenerative spondylosis, or pain associated with spinal canal stenosis, comprising buprenorphine or a pharmaceutically acceptable hydrochloride thereof as an active ingredient. The present invention relates to an intraoral mucosa patch preparation and a pain relieving method using the same.

Buprenorphine (N-cyclopropylmethyl-7α- (S-1-hydroxy-1,2,2-trimethylpropyl) -6,14-endo-ethano-6,7,8,14-tetrahydronorolipabin) It is a derivative of thebaine and is a non-anesthetic analgesic with high fat solubility. It is known that buprenorphine has a powerful analgesic effect 20 to 30 times that of morphine and has few side effects such as mental disorders and respiratory depression. Therefore, it is used for pre-anesthetic medication, maintenance of anesthesia, postoperative pain and cancer pain.

Buprenorphine is mainly used as an injection and a suppository because its bioavailability by oral administration is as low as about 10%. Development of sublingual tablets containing buprenorphine, percutaneous absorption preparations, oral mucosal patch preparations, and the like has been promoted from the viewpoint of improving bioavailability, handling, and sustainability. For example, Patent Document 1 (which is incorporated herein by reference) discloses a buprenorphine-containing oral mucosa patch preparation in which the blood concentration of buprenorphine is maintained within a certain therapeutically effective range for a certain period of time by a single administration. Has been.

Buprenorphine is mainly used as an analgesic for cancer pain, pain associated with myocardial infarction and postoperative pain. In addition to these pains, in recent years, Patent Document 2 (which is incorporated herein by reference) reports that buprenorphine is also effective for analgesia of neuralgia after herpes zoster.

However, the mechanism of analgesia by buprenorphine has not been fully elucidated, and it has been unclear whether it is effective against any pain other than the above pain.

JP-A-8-291070 WO2008 / 120562

Under such circumstances, an object of the present invention is to provide a pharmaceutical use or method for more effectively using buprenorphine or a pharmaceutically acceptable salt thereof.

The inventors of the present invention have conducted research day and night to solve the above problems, and surprisingly, buprenorphine, which has been conventionally used as an analgesic for cancer pain and pain after myocardial infarction, is a pain associated with disc herniation. The present inventors have found that the present invention has a particularly excellent palliative effect on specific pains such as pain associated with degenerative spondylosis and pain associated with spinal stenosis. Based on such findings, the present inventors have conducted further studies, and as a result, by administering buprenorphine for a certain period of time, the specific pain is significantly higher than pain associated with other diseases. It was found to be relaxed. The present invention has been completed based on this finding.

Below, the typical invention of this invention is illustrated.
Item 1 An immediate release layer containing buprenorphine or a pharmaceutically acceptable salt thereof as an active ingredient, and a sustained release layer containing buprenorphine or a pharmaceutically acceptable salt thereof as an active ingredient,
A medicament for alleviating pain associated with disc herniation, pain associated with degenerative spondylosis, or pain associated with spinal stenosis, which is an oral mucosa patch form.
Item 2 The sustained-release layer further contains (a) polyvinyl pyrrolidone or a pharmaceutically acceptable salt thereof, (b) polyacrylic acid or a pharmaceutically acceptable salt thereof, and (c) sodium bicarbonate. Item 1. The medicine according to Item 1.
Item 3 The pharmaceutical according to Item 2, wherein the blending ratio of (a) and (b) is (a) :( b) = 95: 5 to 5:95 in terms of mass.
Item 4. The medicament according to Item 2 or 3, wherein the sustained-release layer contains 7 to 7.5 parts by weight of (c) with respect to 100 parts by weight of (b).
Item 5 The medicament according to any one of Items 1 to 4, wherein the immediate release layer contains polyvinylpyrrolidone or a pharmaceutically acceptable salt thereof.
Item 6 The medicament according to any one of Items 1 to 5, wherein the active ingredient contained in the immediate release layer and the sustained release layer is buprenorphine hydrochloride.
Item 7 An immediate release layer containing buprenorphine or a pharmaceutically acceptable salt thereof as an active ingredient,
And a sustained-release layer containing buprenorphine or a pharmaceutically acceptable salt thereof as an active ingredient,
And a medicament in the form of an oral mucosal patch is administered to a patient suffering from pain associated with disc herniation, pain associated with degenerative spondylosis, or pain associated with spinal stenosis.
Item 8. An immediate release layer containing buprenorphine or a pharmaceutically acceptable salt thereof as an active ingredient, and a sustained release layer containing buprenorphine or a pharmaceutically acceptable salt thereof as an active ingredient,
A medicament for use in the relief of pain associated with disc herniation, pain associated with degenerative spondylosis or pain associated with spinal stenosis.
Item 9. An immediate release layer containing buprenorphine or a pharmaceutically acceptable salt thereof as an active ingredient, and a sustained release layer containing buprenorphine or a pharmaceutically acceptable salt thereof as an active ingredient,
Buprenorphine or a pharmaceutically acceptable product thereof for producing a medicament for alleviating pain associated with disc herniation, pain associated with degenerative spondylosis, or pain associated with spinal stenosis Salt used.

According to the present invention, pain associated with disc herniation, degenerative spondylosis, or spinal stenosis can be more effectively alleviated.

FIG. 1 shows the alleviation of pain associated with degenerative spondylosis by the medicament of the present invention. FIG. 2 shows the alleviation of pain associated with spinal stenosis by the medicament of the present invention. FIG. 3 shows the effect of alleviating pain associated with disc herniation by the medicament of the present invention.

Hereinafter, the present invention will be described in detail.
I. Medicament The medicament of the present invention contains buprenorphine or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutically acceptable salt of buprenorphine can be appropriately selected from the viewpoint of stability and the like, for example, inorganic salts such as hydrochloride, sulfate, phosphate and the like, and maleate and succinate. Organic acid salt etc. can be mentioned. Preferably, the active ingredient contained in the medicament of the present invention is a pharmaceutically acceptable salt of buprenorphine, more preferably buprenorphine hydrochloride.

The medicament of the present invention is an oral mucosa patch form having a sustained release layer and an immediate release layer. Buprenorphine or a pharmaceutically acceptable salt thereof as an active ingredient is contained in both the sustained-release layer and the rapid-release layer. Oral mucosa patch form means that the medicine has a shape suitable for sticking to the oral mucosa such as gums and maxilla, and buprenorphine which is an active ingredient or its pharmaceutically acceptable by sticking the medicine to the oral mucosa Means that it has a shape suitable to be released and absorbed through the oral mucosa into the blood vessels.

The sustained-release layer and the rapid-release layer are preferably applied more quickly than the active ingredient contained in the sustained-release layer by applying the medicament of the present invention to the oral mucosa. Can be of any structure as long as it allows the release of the active ingredient as a whole and is sustained. Preferably, the immediate release layer has a structure that disintegrates relatively quickly than the sustained release layer.

Pharmaceutical techniques that employ a multilayer structure in order to continuously release active pharmaceutical ingredients are known in the art, and the pharmaceutical of the present invention can be designed by arbitrarily selecting them. For example, JP-A-8-291070 discloses a bilayer oral mucosal patch preparation for continuous release of buprenorphine or a pharmaceutically acceptable salt thereof. WO2008 / 111647 (which is incorporated herein by reference) also discloses a method for producing an oral mucosa patch preparation in which buprenorphine hydrochloride is uniformly dispersed in the preparation and the stability of buprenorphine hydrochloride is improved Is disclosed. Therefore, the medicament of the present invention can be produced according to these descriptions.

Preferably, the sustained-release layer of the medicament of the present invention comprises (a) polyvinylpyrrolidone or a pharmaceutically acceptable salt thereof (hereinafter referred to as “(a) component” as appropriate), (b) polyacrylic acid or The pharmaceutically acceptable salt thereof (hereinafter referred to as “component (b)” as appropriate) and / or (c) sodium hydrogen carbonate (hereinafter referred to as “component (c)” where appropriate). Although not limited by theory, a sustained release action can be obtained by the binding property of polyvinylpyrrolidone or a pharmaceutically acceptable salt thereof and the adhesiveness of polyacrylic acid or a pharmaceutically acceptable salt thereof. Conceivable. In addition, since the release of buprenorphine can be hindered by a decrease in the swelling ability of polyacrylic acid under acidic conditions, sodium bicarbonate is used to enable the continuous release of buprenorphine even in an acidic environment. Formulated as a pH adjuster.

Polyvinylpyrrolidone or a pharmaceutically acceptable salt thereof may be a polymer composed only of N-vinyl-2-pyrrolidone as a monomer, and does not interfere with the properties as a sustained-release layer or a rapid-release layer. As long as it is a copolymer containing other monomer components. Examples of other monomer components include polyvinyl alcohol, alginic acid, and pharmaceutically acceptable salts thereof. When such other monomer components are contained in polyvinyl pyrrolidone, the proportion is usually preferably 30 mol% or less.

The polyacrylic acid or a pharmaceutically acceptable salt thereof may be a homopolymer obtained by polymerizing only acrylic acid, but contains other monomer components as long as the properties required for the sustained-release layer are not disturbed. May be. When other monomer components are contained in polyacrylic acid, the proportion of the other components is preferably 30 mol% or less.

The pharmaceutically acceptable salt of polyvinylpyrrolidone or acrylic acid is not particularly limited as long as sustained release of buprenorphine or a pharmaceutically acceptable salt thereof from the sustained release layer is possible. For example, sodium salt And alkali metal salts such as potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and ammonium salts.

The blending ratio of (a) polyvinylpyrrolidone or a pharmaceutically acceptable salt thereof and (b) polyacrylic acid or a pharmaceutically acceptable salt thereof blended in the sustained-release layer is determined by the target active ingredient. It can be appropriately selected depending on the release profile. Preferably, the blending ratio of the component (a) and the component (b) in the sustained release layer is (a) :( b) = 95: 5 to 5:95 in terms of mass. If the blending ratio of polyvinyl pyrrolidone is too high, sufficient adhesion to the mucous membrane of the pharmaceutical of the present invention cannot be obtained. On the other hand, if the blending ratio of polyvinyl pyrrolidone is too low, the swelling property due to polyacrylic acid is too large. This is because a foreign object sensation can occur when applied inside.

The content of the component (a) and the component (b) in the sustained release layer is 80% or more when the total content of the component (a) and the component (b) is 100% of the mass of the entire sustained release layer. It is preferable. The sustained-release layer can contain additives described later in addition to the component (a), the component (b), and the component (c).

The amount of component (c) in the sustained-release layer is not particularly limited as long as the pH in the sustained-release layer can be neutralized (for example, maintained at pH 6 to 8) in a neutral oral environment. However, it is preferably 7.0 to 7.5 parts by weight with respect to 100 parts by weight of the component (b) in the sustained release layer. If it is 7.0 parts by weight or more, the swelling ability of polyacrylic acid can be sufficiently ensured even in a neutral environment, and buprenorphine or a pharmaceutically acceptable salt thereof can be more reliably released. Can do. On the other hand, if it exceeds 7.5 parts by weight, the swelling of the carboxyvinyl polymer becomes too great, and the release of buprenorphine or a pharmaceutically acceptable salt thereof can be excessively fast.

The immediate release layer preferably contains polyvinylpyrrolidone or a pharmaceutically acceptable salt thereof in addition to the active ingredient. The content of polyvinylpyrrolidone or a pharmaceutically acceptable salt thereof incorporated in the immediate release layer is not particularly limited, but the active ingredient is relatively fast with respect to the release rate of the active ingredient from the sustained release layer. From the viewpoint of releasing the amount, it is preferably 50% or less of the entire rapid release layer in terms of mass. In addition to the active ingredient and polyvinylpyrrolidone or a pharmaceutically acceptable salt thereof, additives as described later can be appropriately blended in the immediate release layer.

The pharmaceutical of the present invention contains buprenorphine or a pharmaceutically acceptable salt thereof in an amount effective for alleviating pain associated with disc herniation, degenerative spondylosis or spinal stenosis. The amount of the active ingredient in the medicine is usually 0.05 to 1.5 mg per product. From the viewpoint of effective pain relieving action and suppressing the occurrence of side effects, the content of the active ingredient per pharmaceutical agent of the present invention is preferably 0.1-1 mg, more preferably 0.3-0. .8 mg.

The blending ratio of the active ingredient in the sustained-release layer and the active ingredient in the immediate-release layer can be appropriately adjusted according to the required pain relieving action. For example, when the immediate effect of pain relief is required, a larger amount of the active ingredient can be blended in the immediate release layer than in the sustained release layer. On the other hand, when it is desired to maintain the blood concentration of the active ingredient at a certain effective value or more for a long period of time, many active ingredients can be added to the sustained-release layer. In general, the content of buprenorphine or a pharmaceutically acceptable salt thereof blended in the sustained release layer is 0.05 to 1.0 mg, preferably 0.07 to 0.7 mg. The content of the active ingredient blended in the immediate release layer is usually 0.01 to 0.7 mg, preferably 0.03 to 0.5 mg. The mixing ratio of the active ingredient blended in the sustained release layer and the active ingredient blended in the rapid release layer is, in terms of mass, sustained release layer: fast release layer = 10: 1 to 1: 3, preferably 5 : 1 to 1: 1.

In addition to the above components, the sustained-release layer and the rapid-release layer include excipients, binders, lubricants, coloring agents, flavoring agents, fragrances, surfactants, and sweeteners that are commonly used in the field of pharmaceutical preparations. , And additives such as preservatives can be blended.

Examples of excipients include starch, crystalline cellulose, lactose, anhydrous silicic acid, mannitol, talc, sorbitol, and anhydrous calcium phosphate. Examples of the binder include starch, dextrin, tragacanth, gelatin, hydroxypropylcellulose, sodium alginate and the like. Examples of the lubricant include magnesium stearate, talc, and stearic acid. Examples of the colorant include blue No. 1, yellow No. 4, caramel, copper chlorophyllin sodium and titanium dioxide. Examples of the flavoring agent include menthol, peppermint oil, limonene, cineol, citric acid, malic acid, fumaric acid, tartaric acid, and various fragrances. Examples of the surfactant include various anionic surfactants, nonionic surfactants, amphoteric surfactants, and cationic surfactants. Examples of the sweetening agent include xylitol, erythritol, sodium saccharin, stevioside, stevia extract, paramethoxycinnamic aldehyde, neohesperidyl dihydrochalcone, and perilartin. Examples of the preservative include p-hydroxybenzoate ester and sodium benzoate.

As long as the medicament of the present invention is suitable for application to the oral mucosa, its shape and size are not particularly limited. For example, it can be a track field tablet or a round tablet. Preferably, the medicament of the present invention is in the form of a tablet having a two-layer structure, and the thickness thereof is usually 0.5 to 3 mm, preferably 1 to 2.5 mm.

II. Production Method The medicament of the present invention can be produced by a technique known in the art. In general, the medicament of the present invention is prepared by mixing each component of the sustained-release layer and each component of the rapid-release layer separately to prepare a granule, which is formed into a two-layer structure using a punch, a die, or a press. Can be manufactured by tableting. The following describes one preferred method for producing the medicament of the present invention.

Preparation of granules for immediate release layer Buprenorphine (for example, buprenorphine hydrochloride) is pulverized, and its 90% cumulative diameter is made 200 μm or less. By using the fine powder having such a cumulative diameter, it is possible to release buprenorphine faster than the release rate from the sustained release layer. The 90% cumulative diameter of buprenorphine hydrochloride is preferably 160 μm or less, more preferably 100 μm or less, and still more preferably 90 μm or less. The 50% cumulative diameter of buprenorphine hydrochloride is preferably 100 μm or less, more preferably 60 μm or less. On the other hand, if the particle size is excessively reduced, there is a possibility of re-aggregation due to micronization. Therefore, the 50% cumulative size of buprenorphine hydrochloride is preferably 10 μm or more.

The 90% cumulative diameter and 50% cumulative diameter of buprenorphine hydrochloride can be measured by conventional methods. For example, buprenorphine hydrochloride is dispersed in McIlvine buffer (pH 9.0) containing about 0.1% of a surfactant such as Triton X-100, and the volume-based particle size distribution of buprenorphine hydrochloride is measured with a particle size distribution meter. . From the measurement results obtained, assuming that the total volume is 100%, the volume is accumulated in order from the smallest particles, and the particle size of the particles when the cumulative volume reaches 50% of the total is taken as the 50% cumulative diameter. Similarly, the particle diameter when the cumulative volume is 90% is defined as 90% cumulative diameter.

The particle diameter can be adjusted according to a conventional method, for example, using a general pulverizer such as a hammer mill, and repeatedly performing pulverization and particle size distribution measurement until an appropriate particle diameter is obtained.

¡Buprenorphine hydrochloride with adjusted particle size is mixed with other ingredients. The blending components may be appropriately selected. However, since the rapid release layer disintegrates relatively quickly and releases buprenorphine hydrochloride, it is preferable to blend relatively many components used as an excipient or a disintegrant. For example, D-mannitol and / or talc are preferably blended. In addition, additives as described above can also be blended.

Mixing of buprenorphine hydrochloride and other components is preferably carried out dry without using water. This is because buprenorphine hydrochloride may become unstable when water is used. Mixing can be performed using a general mixer. The mixture is preferably adjusted in particle size by sieving, etc. in order to suppress adhesion between particles.

Next, granules are prepared using the mixture and an aqueous solution of polyvinylpyrrolidone as a binder. Granules can be prepared under general conditions using a fluid bed granulator common in the pharmaceutical field.

After granulation, the granules are thoroughly dried. The drying conditions such as temperature and time are not particularly limited as long as each component does not deteriorate. The obtained granules are preferably adjusted in particle size by sieving or the like.

Preparation of granules for sustained release layer Buprenorphine (for example, buprenorphine hydrochloride) to be added to the sustained release layer is pulverized so that its 90% cumulative diameter is 250 μm or less. By carrying out like this, reduction of the amount of active ingredients at the time of a formulation, and nonuniformity can be controlled. The 90% cumulative diameter of buprenorphine hydrochloride compounded in the sustained release layer is preferably 160 μm or less, and more preferably 100 μm or less. The 50% cumulative diameter of buprenorphine hydrochloride is the same as that of buprenorphine hydrochloride blended in the immediate release layer.

¡Buprenorphine hydrochloride with adjusted particle size is mixed with other ingredients. Since the sustained release layer gradually disintegrates and releases buprenorphine hydrochloride continuously, as described above, (a) polyvinylpyrrolidone or a pharmaceutically acceptable salt thereof, (b) polyacrylic acid or a pharmaceutical thereof And (c) sodium hydrogen carbonate. In addition, the above-mentioned additives can be blended in the sustained release layer.

The mixing of each component can be performed with a general mixer. The mixture is preferably adjusted in particle size. The particle size adjustment is preferably performed by pulverization and sizing from the viewpoint of suppressing reduction of active ingredients and non-uniformity. Crushing and sizing is not mere sieving or the like but pulverizing the mixture with a power mill or the like and sizing while suppressing adhesion between particles.

Granules for sustained release layer are granulated from the above mixture. Granules may be prepared by a conventional method, for example, by compressing the mixture. The obtained granules are preferably sized, and pulverized sized.

Tableting Step Next, the granule for immediate release layer and the granule for sustained release layer produced as described above are tableted using a tableting device to obtain a tablet having a two-layer structure. The tableting device is not particularly limited as long as it can produce a bilayer tablet. The tableting conditions can be adjusted from the tablet sample in consideration of the mass of the sustained-release layer and the quick-release layer, the hardness of the tablet, the thickness of the tablet, and the like.

The medicament of the present invention produced as described above is not only suppressed in the amount of buprenorphine hydrochloride in the production process but also excellent in storage stability. For example, even when stored for 6 months in a harsh environment of a temperature of 40 ° C. and a relative humidity of 75%, the amount of buprenorphine related substances is suppressed.

III. Administration method The method for alleviating each pain using the medicament of the present invention can be carried out by administering the medicament of the present invention to a patient suffering from pain associated with disc herniation, degenerative spondylosis, or spinal stenosis. it can. Since the medicament of the present invention is an oral mucosa patch form, it is administered by applying it to the oral mucosa (for example, the gums, the inside of the cheek).

The medicament of the present invention can be used preferably by sticking so that the sustained-release layer side is in contact with the oral mucosa. Thus, by applying the pharmaceutical agent of the present invention to the oral mucosa, first, the immediate release layer disintegrates to release buprenorphine, and the sustained release layer gradually disintegrates to gradually release buprenorphine hydrochloride. Therefore, the medicament of the present invention can suppress a rapid increase in the blood concentration of buprenorphine compared to an injection or the like.

The use of the medicament of the present invention can relieve pain associated with disc herniation, degenerative spondylosis, or spinal stenosis continuously while suppressing the occurrence of side effects. Furthermore, the medicament of the present invention also contributes to providing more comfortable sleep for patients suffering from the various types of pain described above.

Here, intervertebral disc herniation is a disease that often causes neuralgia due to compression of the spinal cord and nerve roots due to degeneration of the annulus fibrosus of the disc. Degenerative spondylosis is a lesion caused by a degenerative change of the spinal column, often accompanied by nodal pain, back pain, or back pain. With spinal canal stenosis, the spinal canal is congenitally narrowed or acquired narrowly, compressing nerves and causing pain from the waist to the thigh and calf.

The dosage and administration schedule of the medicament of the present invention can be appropriately adjusted in consideration of the severity of pain in the patient and the age, weight, sex, etc. of the patient. For example, in the case of an average adult, a drug containing 0.1 to 1.0 mg of buprenorphine or a pharmaceutically acceptable salt thereof may be used once or twice a day to cause pain. Administration can be continued until some injury or symptom is improved. From the viewpoint of obtaining a more effective pain relieving effect, the medicament of the present invention is preferably administered for 8 weeks or longer, more preferably 12 weeks or longer, and further preferably 16 weeks or longer.

Hereinafter, the present invention will be described with reference to examples.
Production example: Manufacture of buprenorphine preparation with oral mucosa

(1) Preparation of granules for immediate release layer Buprenorphine hydrochloride (100 g) was charged into a hammer mill and pulverized under the conditions of a screen opening of 0.5 mm and a rotational speed of 12,000 rpm to recover about 60 g of fine powder. Next, the particle size distribution of the fine powder was measured. Specifically, about 100 mg of the fine powder was placed in a centrifuge tube, and 10 mL of a dispersion (McIlvaine buffer containing 0.1% Triton X-100, pH 9.0) was further added and shaken vigorously. Immediately thereafter, the particle size distribution was measured using a particle size analyzer (manufactured by Nikkiso, model: Microtrac FRA). As a result, the 50% cumulative diameter was 25 μm, and the 90% cumulative diameter was 61 μm.

D-mannitol (723 g) sieved with a sieve having an opening of 500 μm and the above buprenorphine hydrochloride (2.156 g) were charged into a rocking mixer (manufactured by Aichi Electric, model: RM-10), and mixed at 60 ± 1 rpm for 5 minutes. It sieved with the sieve of 500 micrometers of mesh openings. *

While stirring purified water (1140 g), polyvinylpyrrolidone (manufactured by ISP, product name: PVP K30, 60 g) and edible blue No. 1 (0.0657 g) were added to obtain a solution. The mixed powder and the solution were charged into a fluid bed granulator (Freund Sangyo, model: FLO-5B) and granulated. Subsequently, using the same granulator, drying was performed until the exhaust temperature reached 40 ° C. or higher under the conditions of intake air temperature: 70 ± 5 ° C. and air volume: 2.0 ± 0.5 m ³ / min. The obtained granule was sieved with a sieve having an opening of 500 μm.

To 100 parts by mass of the obtained granules, 1 part by mass of sodium stearate sieved with a sieve having an opening of 500 μm and 0.56 parts by mass of talc were added, and a rocking mixer (manufactured by Aichi Electric Co., Ltd., model: RM-10) was added. ) And mixed at 60 ± 1 rpm for 3 minutes to prepare granules for immediate release layer. *

(2) Preparation of granules for sustained release layer Polyvinylpyrrolidone (manufactured by BASF, product name: PVP K90, 4000 g) was charged into a sample mill (manufactured by Fuji Paudal, product name: KIIW-2), and the screen opening: 0. Grinding was repeated 6 times under the conditions of 5 mm and a rotational speed of 12,000 rpm, and about 3600 g of crystals were recovered.

In a rocking mixer (manufactured by Aichi Electric, model: RM-10), buprenorphine hydrochloride (4.312 g) crushed in (1) above, pulverized polyvinyl pyrrolidone (853.5 g), polyacrylic acid (BF Goodrich, product name) : Polyacrylic acid 974P, 165.6 g), and sodium hydrogen carbonate (12.2 g). The number of revolutions was mixed at 60 ± 1 rpm for 15 minutes, and the sieve opening was further sieved with a 500 μm sieve. *

Next, the mixture was compressed by a roller compactor (Freund Sangyo, model: TF-MINI). Further, it was crushed with an oscillator (manufactured by Kikusui Seisakusho, model: 35C-2M). Further, the particles were sized with a power mill (Dalton, model: P-02S), and then sieved with a sieve having an opening of 500 μm. *

Here, the ratio of polyvinylpyrrolidone to the total of polyvinylpyrrolidone and polyacrylic acid in the sustained-release layer is about 83.8% by mass, and the ratio of sodium hydrogen carbonate to polyacrylic acid in the sustained-release layer is about 7. It was 4% by mass.

(3) Tableting The above-mentioned granule for immediate release layer and granule for sustained release layer were loaded into a tableting machine (manufactured by Hata Steel Co., Ltd., model: HT-AP-38LII), and tableted to apply buprenorphine to the oral mucosa A bilayer tablet was produced. The supply amount of both granules was adjusted so that the sustained-release layer mass of 10 tablets was 517.8 ± 10.2 mg and the total mass of 10 tablets was 900 ± 17.9 mg. Further, the single roll, the preload roll, and the main pressure roll were adjusted so that the tablet hardness was 4 kp or more and the thickness was 1.70 ± 0.1 mm. The thus prepared oral mucosal patch contains 0.1 mg of buprenorphine hydrochloride in the immediate-release layer and 0.2 mg of buprenorphine hydrochloride in the sustained-release layer.

In the above protocol, the double-layered tablet for oral mucosal patch in which the blending amount of buprenorphine hydrochloride alone is doubled and the blending amount of buprenorphine hydrochloride in the immediate release layer and the sustained release layer is 0.2 mg and 0.4 mg, respectively. Manufactured. Hereinafter, these buprenorphine hydrochloride tablets are referred to as 0.3 mg tablets and 0.6 mg tablets, respectively.

Test Example: Continuous Administration Test Asian patients from the age of 20 to 74 years who suffered from the following pain with which consent was obtained for this study were targeted for administration.

Patient group:
66 patients suffering from pain associated with degenerative spondylosis 66 patients suffering from pain associated with spinal canal stenosis 67 patients suffering from pain associated with disc herniation 32 patients suffering from neuralgia after herpes zoster 146 patients with complex local pain 55 affected patients 29 patients with postoperative neuropathic pain 29 patients with post-lumbar pain syndrome 15

The pain treatment carried out 4 days before the start of the test was continued as it was, and in addition to that, a test of continuously administering the 0.3 mg tablet or 0.6 mg tablet prepared in the above production example was conducted. However, addition of a new pain treatment other than the administration of the medicament of the present invention and a change in conventional pain treatment conditions were prohibited.

First, 0.3 mg tablets were administered to each subject once a day, and appropriately changed to 0.6 mg tablets while confirming the analgesic effect and safety so that the analgesic effect lasted for 24 hours. In addition, when the analgesic effect sustained for 24 hours was not obtained by administration of the 0.6 mg tablet or due to the occurrence of an adverse event, the 0.6 mg tablet was changed to the 0.3 mg tablet as necessary.

During the administration period, each subject was asked to evaluate the pain VAS value. The evaluation results were tabulated for each type of pain, and the average value was obtained. The results are shown in FIGS.

FIG. 1 shows a patient suffering from pain associated with osteoarthritis, a patient suffering from neuralgia after herpes zoster, a patient suffering from pain associated with complex local pain, a patient suffering from pain associated with postoperative neuropathy, and the lumbar spine Evaluation results from patients with postoperative pain syndrome are shown. As shown in FIG. 1, the pain associated with osteoarthritis was dramatically alleviated by administering the medicament of the present invention. This alleviating effect became more prominent by continuously administering the medicament of the present invention, and after 8 weeks from the start of administration, an even better alleviating effect than the effect on neuralgia after herpes zoster was obtained.

FIG. 2 shows a patient suffering from pain associated with spinal stenosis, a patient suffering from neuralgia after herpes zoster, a patient suffering from pain associated with complex local pain, a patient suffering from pain associated with postoperative neuropathy, and the lumbar spine Evaluation results from patients with postoperative pain syndrome are shown. As shown in FIG. 2, the pain associated with spinal stenosis was dramatically alleviated by administering the medicament of the present invention. This alleviating effect became more prominent by continuously administering the medicament of the present invention, and after 8 weeks from the start of administration, an even better alleviating effect than the effect on neuralgia after herpes zoster was obtained.

FIG. 3 shows a patient suffering from pain associated with herniated disc, a patient suffering from neuralgia after herpes zoster, a patient suffering from pain associated with complex local pain, a patient suffering from pain associated with postoperative neuropathy, and a post-lumbar surgery Evaluation results from patients with pain syndrome are shown. As shown in FIG. 3, the medicament of the present invention exhibits an excellent palliative action on pain associated with disc herniation. This alleviating effect is significantly better than the alleviating effect on neuralgia after herpes zoster.

As is apparent from the above results, the medicament of the present invention exhibits a particularly excellent palliative effect on pain associated with disc herniation, pain associated with degenerative spondylosis, or pain associated with spinal stenosis. In addition to pain relief, many patients suffering from pain due to disc herniation, pain associated with spondylosis, or pain associated with spinal stenosis can be improved by administering the medicament of the present invention. Experienced sleep.

Claims

An immediate release layer containing buprenorphine or a pharmaceutically acceptable salt thereof as an active ingredient, and a sustained release layer containing buprenorphine or a pharmaceutically acceptable salt thereof as an active ingredient,
A medicament for alleviating pain associated with disc herniation, pain associated with degenerative spondylosis, or pain associated with spinal stenosis, which is an oral mucosa patch form.
The sustained release layer further comprises (a) polyvinylpyrrolidone or a pharmaceutically acceptable salt thereof, (b) polyacrylic acid or a pharmaceutically acceptable salt thereof, and (c) sodium hydrogen carbonate. 1. The medicine according to 1.
The pharmaceutical according to claim 2, wherein the blending ratio of (a) and (b) is (a) :( b) = 95: 5 to 5:95 in terms of mass.
The medicine according to claim 2 or 3, wherein the sustained-release layer contains 7 to 7.5 parts by weight of (c) with respect to 100 parts by weight of (b).
The medicament according to any one of claims 1 to 4, wherein the immediate-release layer contains polyvinylpyrrolidone or a pharmaceutically acceptable salt thereof.
The medicament according to any one of claims 1 to 5, wherein the active ingredient contained in the immediate release layer and the sustained release layer is buprenorphine hydrochloride.