JP7219979B2 - Orally disintegrating tablet having a coating layer - Google Patents

Description

TECHNICAL FIELD The present invention relates to an orally disintegrating tablet having a coating layer.

In recent years, for patients with weak swallowing ability such as the elderly and children, patients with limited water intake, and patients who are busy and do not have water, tablets are disintegrated with only saliva in the oral cavity to make it easier to swallow. The importance of orally disintegrating tablets characterized by However, since orally disintegrating tablets are designed to disintegrate with a small amount of saliva, tablet hardness is low and they are easily broken in a packaging machine when each single dose is packaged (single package). Furthermore, orally disintegrating tablets containing light-labile drugs are susceptible to storage environment.

When a drug that is unstable to light is tableted, light is generally shielded by applying a coating layer containing a coloring agent (light-shielding agent) to the tablet containing the drug, or by mixing the drug and a coloring agent. There is known a method of achieving stabilization by

However, when a drug that is unstable to light is made into an orally disintegrating tablet, if a coating layer containing a coloring agent is applied to the uncoated tablet in order to achieve photostability, there is a concern that the coating layer will delay disintegration. . An orally disintegrating tablet having a coating layer must dissolve the coating layer quickly in the oral cavity, and the tablet body must also quickly disintegrate. In addition, when dissolving the coating layer, mouthfeel such as taste and touch as an orally disintegrating tablet must also be considered.

Patent Document 1 discloses that at least one of maltose, maltitol, sorbitol, xylitol, fructose, glucose, lactitol, isomaltose, lactose, erythritol, mannitol, trehalose and sucrose is added to less than 10 mL of water at 20°C in an amount of 1 g or more. It contains a water-soluble substance that is soluble and has a hydroxyl group in the molecule and a molecular weight per unit hydroxyl group of 200 or less, and a polyvinyl alcohol-based resin, and the weight of the polyvinyl alcohol-based resin and the water-soluble substance in the coating layer. A stable orally disintegrating coated tablet containing a drug other than nalfurafine or a pharmacologically acceptable salt thereof, which is coated with a coating layer having a ratio of 1:0.1 to 1:9, has excellent speed. It is described that it does not crack even under high humidity while having disintegrating properties. It is also described that the decomposition of drugs can be improved by blending a light-shielding agent in the coating layer. However, the mouse feel is completely unknown.

JP 2013-177438 A

The present inventors have experimentally produced an orally disintegrating tablet obtained by compressing a mixture of a photolabile drug, a coloring agent and other additives, but the effect of sufficiently suppressing the photodegradation of the drug was obtained. I couldn't. On the other hand, when an orally disintegrating tablet containing a drug that is unstable to light was coated with a coating layer containing a coloring agent and a polyvinyl alcohol-based resin, a prototype of an orally disintegrating tablet was produced. did it. However, the application of the coating layer causes a slight delay in disintegration, and when it is put in the mouth, it causes a sense of discomfort that it is not an orally disintegrating tablet, and the mouthfeel is poor. Found it.

The present invention satisfies the characteristics required for an orally disintegrating tablet such as rapid disintegration and hardness in the oral cavity, suppresses photodegradation of light-labile drugs, and provides excellent mouthfeel. An object of the present invention is to provide an orally disintegrating tablet having a coating layer.

As a result of extensive research, the present inventors have found that an orally disintegrating tablet containing a drug that is unstable to light is coated with a coating layer containing a high-intensity sweetener, a polyvinyl alcohol-based resin, and a colorant. As a result, the present inventors have found that it is possible to provide an orally disintegrating tablet having a coating layer that can suppress the degradation of a drug by light while achieving both rapid disintegration and hardness, and that has an excellent mouth feel, thereby completing the present invention.

ADVANTAGE OF THE INVENTION According to the present invention, an orally disintegrating tablet having a coating layer that is excellent in photostability and mouthfeel while satisfying the properties required for an orally disintegrating tablet, namely rapid disintegration and hardness in the oral cavity, is provided. can do. More specifically, an orally disintegrating tablet containing a drug that is unstable to light is coated with a coating layer containing a high-intensity sweetener with high water solubility, a polyvinyl alcohol-based resin, and a colorant having a light-shielding effect. By coating with, the decomposition of the drug by light can be suppressed. In addition, it is possible to provide an orally disintegrating tablet having a coating layer that has a short dissolution time of the coating layer, a sufficient tablet strength for handling as a pharmaceutical, and an excellent mouth feel.

The present invention will be described in detail below.
In this specification, unless otherwise specified, % is % by mass.
In this specification, a numerical range indicated using "to" means a range including the numerical values before and after "to" as the minimum and maximum values, respectively.

The "orally disintegrating tablet" according to the present invention is an uncoated tablet having no coating layer.
The "orally disintegrating tablet having a coating layer" according to the present invention is an orally disintegrating tablet obtained by coating the surface of an orally disintegrating tablet with a coating composition.

The "coating layer" according to the present invention contains a high-intensity sweetener, a polyvinyl alcohol-based resin and a colorant. Although the amount of the coating layer varies depending on the shape and size of the tablet, it may be 10 μg/mm ² or more per surface area of the orally disintegrating tablet, preferably 15 to 30 μg/mm ² .

As used herein, the term “high-intensity sweetener” means a sweetener having a sweetness 100 times or more as high as that of sucrose. “Sweetness” is a measure of the strength of sweetness, and is a relative ratio when the strength of sweetness of 1% by mass of sucrose (20° C.) is set to 1. Examples of high-intensity sweeteners according to the present invention include saccharin sodium, acesulfame potassium, aspartame, sucralose, stevia, dipotassium glycyrrhizinate, thaumatin and neotame, with saccharin sodium, acesulfame potassium and aspartame being preferred, and saccharin sodium being more preferred. preferable. The high-intensity sweeteners can be used singly or in combination of two or more.
The amount of the high-intensity sweetener is preferably 5% or less, more preferably 0.1 to 5%, even more preferably 1 to 3.5%, based on the weight of the coating layer. This is because a very small amount of a high-intensity sweetener can give a sweet taste.

The "polyvinyl alcohol-based resin" according to the present invention means polyvinyl alcohol (PVA) and derivatives or copolymers thereof. Polyvinyl alcohol is preferably used as the polyvinyl alcohol-based resin.
Polyvinyl alcohol is usually produced by the complete or partial saponification of polyvinyl acetate. Those with a degree of saponification of 97 mol% or more are called fully saponified products, and those with a degree of saponification of 78 to 96 mol% are called partially saponified products. Although the degree of saponification of polyvinyl alcohol is not particularly limited, it is preferable to use a partially saponified product.
A commercial item can be used for the "polyvinyl alcohol-based resin" according to the present invention. Commercially available polyvinyl alcohols include, for example, Gohsenol (registered trademark) (Mitsubishi Chemical Co., Ltd.), J-Poval (Japan Vinyl Acetate & Poval Co., Ltd.), Kuraray Poval (Kuraray Co., Ltd.), polyvinyl alcohol 4-88, 5 -88, 8-88, 18-88, 26-88, 28-99, 40-88 (Merck Co.) and the like. Derivatives of polyvinyl alcohol include, for example, polyvinyl alcohol copolymers, and commercially available products include, for example, POVACOAT (registered trademark) Type F, Type R, and Type L (Daido Kasei Kogyo Co., Ltd.). Examples of polyvinyl alcohol copolymers include polyvinyl alcohol/polyethylene glycol/graft copolymers, and commercially available products include Kollicoat IR (BASF Japan Ltd.).
The polyvinyl alcohol-based resin can be used alone or in combination of two or more.
The amount of the polyvinyl alcohol-based resin is preferably 30% or more, more preferably 30 to 69%, even more preferably 30 to 59%, relative to the mass of the coating layer. A good coating layer can be formed when the amount of the polyvinyl alcohol-based resin is 30% or more with respect to the mass of the coating layer.

The "coloring agent" according to the present invention may be any coloring agent having a light shielding effect, and examples thereof include titanium oxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide and talc. Titanium oxide, iron sesquioxide, and yellow iron sesquioxide are preferred, and titanium oxide is more preferred, in terms of light shielding effect. The colorants may be used singly or in combination of two or more.
Although the amount of the coloring agent varies depending on the amount of the photolabile drug and photosensitivity, it is preferably 30 to 70%, more preferably 40 to 70%, of the mass of the coating layer.

In addition to the components described above, the coating layer according to the present invention may optionally contain pharmaceutically acceptable additives within a range that does not impair the effects of the present invention. Examples of such additives include coating agents, glossing agents, flavoring agents, and the like. Coating agents include, for example, triethyl citrate, glycerin fatty acid ester, sucrose fatty acid ester, talc, triacetin, castor oil; propylene glycol, macrogol 400, macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000, Macrogol such as Macrogol 6000, Macrogol 20000 and Macrogol 35000; starches such as cornstarch, sodium starch glycolate and partially pregelatinized starch; microcrystalline cellulose, light silicic anhydride, carmellose calcium, low substituted hydroxy Propylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, gum arabic powder, gelatin, pullulan, carmellose sodium, ethylcellulose and aminoalkylmetal lylate copolymers. Brightening agents include, for example, talc, light anhydrous silicic acid, magnesium stearate, calcium stearate, carnauba wax and refined shellac. Flavoring agents include, for example, mints such as menthol and peppermint, lemon, orange, grapefruit, strawberry, chocolate and coffee.

The method for preparing the coating layer composition used in the present invention is not particularly limited. It can be prepared by dissolving or dispersing the agent.
The method for forming the coating layer on the orally disintegrating tablet is not particularly limited, but it can be formed using, for example, a pan-type coating apparatus, a fluidized bed coating apparatus, or a ventilated dry pan-type coating apparatus.
If the hardness of the orally disintegrating tablet having a coating layer is low, the tablet may be broken during transportation or storage.

In the present invention, the term "mouthfeel" means the taste, texture, texture, etc. when a tablet is taken in the mouth. Mouthfeel is said to be excellent in terms of the taste and texture that does not make you feel that it is not an orally disintegrating tablet until it begins to disintegrate (while the coating layer is dissolving).
If the coating layer is tasteless during dissolution, the dissolution time of the coating layer in the oral cavity is felt to be longer than it actually is, and the discomfort is large, and the mouthfeel is poor. The shorter the intraoral dissolution time of the coating layer, the less the discomfort and the better the mouthfeel. Therefore, the intraoral dissolution time of the coating layer according to the present invention is preferably within 15 seconds, more preferably within 10 seconds, and even more preferably within 8 seconds.

Generally, orally disintegrating tablets are designed to disintegrate in the oral cavity without water within 60 seconds. Therefore, the orally disintegrating tablet used in the present invention is usually within the range used as a tablet that can be disintegrated and swallowed only by saliva present in the oral cavity, preferably the disintegration time in the oral cavity is The composition and manufacturing method are not particularly limited as long as the time is within 45 seconds, preferably within 40 seconds, and even more preferably within 30 seconds. The orally disintegrating tablet used in the present invention can be produced, for example, by a method commonly used in the pharmaceutical field such as a direct compression method, an indirect compression method, and a casting method. The orally disintegrating tablet having a coating layer of the present invention is not limited to be taken without water, and may be taken with water.

The orally disintegrating tablet used in the present invention contains a photolabile drug and, if necessary, a pharmaceutically acceptable additive.
Examples of "photolabile drugs" include nisoldipine, azelnidipine, mecobalamin, cimetidine, mequitazine, olanzapine, donepezil, selegiline, irsogladine, bepotastine, ramosetron, naftopidil, polaprezinc, rizatriptan, midodrine, risperidone, ondan Setron, loratadine, montelukast, azulene sulfonic acid, etizolam, enalapril, captopril, glibenclamide, chlormadinone acetate, doxazosin, triazolam, domperidone, ketotifen, bromperidol, pravastatin, simvastatin, pitavastatin, rosuvastatin, atorvastatin, loperamide, lisinopril, rilmazafon , alfacalcidol, bromocriptine, pramipexole, losartan, valsartan, candesartan cilexetil, telmisartan, azilsartan, ramelteon and linagliptin, and pharmacologically acceptable salts and solvates thereof.
Examples of such additives include excipients, disintegrants, binders, plasticizers, corrigents, flavoring agents, coloring agents, lubricants, and the like.

The usefulness of the orally disintegrating tablet having a coating layer of the present invention will be described in the following test examples and examples, but the present invention is not limited by these.

(Reference example 1)
Azilsartan (hereinafter abbreviated as "compound A") 40 parts by mass (hereinafter abbreviated as "parts"), 14 parts of lactose hydrate and 6 parts of corn starch were mixed, and hydroxypropyl cellulose and A liquid obtained by dissolving 1 part of Macrogol 6000 in purified water was added to granulate, dried, and sieved to obtain compound A-containing granules. 70.8 parts of D-mannitol, 13 parts of crospovidone and 2.7 parts of light silicic anhydride are mixed, and a solution obtained by dissolving 0.2 parts of hydroxypropyl cellulose in purified water is added to granulate and dry. and sieved to obtain shaped granules. 62 parts of the compound A-containing granules, 86.7 parts of the excipient granules, 28.6 parts of crystalline cellulose and 2.7 parts of magnesium stearate were mixed and tableted to give gostone-shaped tablets each weighing 180 mg and having a diameter of 8 mm. (Uncoated orally disintegrating tablet) was obtained.

(Example 1)
1.6 parts of polyvinyl alcohol, 0.1 parts of sodium saccharin, 1.4 parts of titanium oxide and 0.075 parts of yellow ferric oxide were dissolved or dispersed in purified water to prepare a coating liquid having a solid content of 10%. Using a spray pan-type coating machine (HCT-60 type), at a set temperature of 75 to 80 ° C., the coating liquid was sprayed on the uncoated orally disintegrating tablets produced in Reference Example 1, and 180 mg tablets were obtained. An orally disintegrating tablet having a coating layer of 3 mg was obtained.

(Example 2)
1.6 parts of polyvinyl alcohol, 0.1 parts of acesulfame potassium, 1.4 parts of titanium oxide and 0.075 parts of yellow ferric oxide were each dissolved or dispersed in purified water to prepare a coating liquid having a solid content of 10%. . Under the same conditions as in Example 1, the coating liquid was sprayed onto the uncoated orally disintegrating tablet produced in Reference Example 1 to obtain an orally disintegrating tablet having a coating layer of 3 mg per 180 mg tablet.

(Example 3)
1.6 parts of polyvinyl alcohol, 0.1 parts of aspartame, 1.4 parts of titanium oxide and 0.075 parts of yellow ferric oxide were each dissolved or dispersed in purified water to prepare a coating liquid having a solid content of 7%. Under the same conditions as in Example 1, the coating liquid was sprayed onto the uncoated orally disintegrating tablet produced in Reference Example 1 to obtain an orally disintegrating tablet having a coating layer of 3 mg per 180 mg tablet.

(Comparative example 1)
A coating liquid was prepared by dissolving or dispersing 1.6 parts of polyvinyl alcohol, 1.4 parts of titanium oxide and 0.075 parts of yellow ferric oxide in purified water. Under the same conditions as in Example 1, the coating liquid was sprayed onto the uncoated orally disintegrating tablet produced in Reference Example 1 to obtain an orally disintegrating tablet having a coating layer of 3 mg per 180 mg tablet.

(Comparative example 2)
1.6 parts of polyvinyl alcohol, 0.1 part of maltitol, 1.4 parts of titanium oxide and 0.075 parts of yellow iron sesquioxide were each dissolved or dispersed in purified water to prepare a coating liquid. Under the same conditions as in Example 1, the coating liquid was sprayed onto the uncoated orally disintegrating tablet produced in Reference Example 1 to obtain an orally disintegrating tablet having a coating layer of 3 mg per 180 mg tablet.

(Test Example 1) Measurement of tablet hardness For the uncoated orally disintegrating tablet of Reference Example 1 and the orally disintegrating tablets having a coating layer of Examples 1 to 3 and Comparative Examples 1 and 2, tablets were measured using a digital hardness meter. was measured, and the average hardness of each 3 tablets was calculated. Table 1 shows the results.

(Test Example 2) Measurement of Dissolution Time of Coating Layer and Evaluation of Mouth Feel Regarding the uncoated orally disintegrating tablet of Reference Example 1 and the orally disintegrating tablets having the coating layer of Examples 1 to 3 and Comparative Examples 1 and 2 , the oral disintegration time was measured by 4 healthy adults. The dissolution time of the coating layer was calculated by subtracting the oral disintegration time of the uncoated orally disintegrating tablet from the oral disintegration time of the orally disintegrating tablet having the coating layer. In addition, regarding the mouthfeel in the dissolution process of the coating layer, it was evaluated as "good" when no discomfort was felt as an orally disintegrating tablet, and as "uncomfortable" when it was felt. Table 1 shows the results.

(Test Example 3) Photostability test The uncoated orally disintegrating tablets of Reference Example 1 and the orally disintegrating tablets having the coating layers of Examples 1 to 3 and Comparative Examples 1 and 2 were spread evenly on a petri dish and white. It was stored for one week under light irradiation of a fluorescent lamp of 1000LX. After storage, compound A and its analogues were measured by the HPLC method under the following conditions. Photostability was evaluated by calculating the area percentage (%) of the photodegradation product (relative retention time 0.49) to the total peak area derived from compound A and its analogues. Table 1 shows the results.
Column: octadecylsilylated silica gel for liquid chromatography Mobile phase: concentration gradient control by changing the mixture ratio of water/acetic acid (100) (1000:1) and acetonitrile Flow rate: about 0.7 mL/min
Measurement wavelength: 250 nm

In Examples 1-3 and Comparative Examples 1-2, tablet strength sufficient for handling as pharmaceuticals and rapid dissolution of the coating layer were exhibited. The oral disintegration time of the uncoated orally disintegrating tablet of Reference Example was 25 seconds.
In Examples 1 to 3, since sweetness was felt while the coating layer was dissolved, there was no discomfort as an orally disintegrating tablet, and the mouthfeel was good. On the other hand, Comparative Example 1 containing no sweetening agent in the coating layer and Comparative Example containing maltitol (having a sweetness of 0.8 to 0.9 times the sweetness of sucrose as 1) in the coating layer. In 2, it was tasteless while the coating layer was dissolving, and it was unpleasant as an orally disintegrating tablet.
Examples 1-3 and Comparative Examples 1-2, in which a coating layer containing a colorant was provided, showed the photostabilization effect of a photolabile drug.

(Reference example 2)
40 parts of compound A, 14 parts of lactose hydrate and 6 parts of corn starch are mixed, and a solution obtained by dissolving 1 part each of hydroxypropyl cellulose and macrogol 6000 in purified water is added to granulate, dried and regulated. Granules containing Compound A were obtained. 70.18 parts of D-mannitol, 14.3 parts of crospovidone and 3.3 parts of light anhydrous silicic acid were mixed, and a solution obtained by dissolving 0.22 parts of hydroxypropyl cellulose in purified water was added to granulate. , dried and sieved to obtain excipient granules. 62 parts of the compound A-containing granules, 88 parts of the excipient granules, 27.3 parts of crystalline cellulose and 2.7 parts of magnesium stearate were mixed and tableted to give a gostone-shaped tablet with a weight of 180 mg and a diameter of 8 mm (not A coated orally disintegrating tablet) was obtained.
The uncoated orally disintegrating tablet of Reference Example 2 was tested in the same manner as in Test Examples 1 to 3 above. It was 0.206%.

(Example 4)
1.3 parts of polyvinyl alcohol, 0.05 parts of sodium saccharin, 0.08 parts of macrogol 6000, 2.7 parts of titanium oxide and 0.1 parts of yellow ferric oxide were dissolved or dispersed in purified water to give a solid content of 10%. was prepared. Using a spray pan type coating machine (HCT-60 type), at a set temperature of 75 to 80 ° C., the coating liquid was sprayed on the uncoated orally disintegrating tablets produced in Reference Example 2, and 180 mg tablets were obtained. An orally disintegrating tablet having a coating layer of 4.23 mg was obtained.
When the orally disintegrating tablet having the coating layer of Example 4 was tested in the same manner as in Test Examples 1 to 3, the hardness was 39.2 N, the coating layer dissolution time was 8 seconds, the mouthfeel was good, and the photodegradation product was 0.000%.

(Reference example 3)
8 parts of ramelteon (hereinafter abbreviated as "compound B"), 30 parts of partially pregelatinized starch and 0.5 parts of light silicic anhydride are mixed, and 0.5 parts of hydroxypropyl cellulose is dissolved in water/ethanol. The resulting liquid was added to granulate, dried, and granulated to obtain core granules. A solution obtained by dissolving or dispersing 1 part of hypromellose and 0.1 part of talc in purified water was sprayed on the obtained core granules, dried, and then 3.5 parts of aminoalkyl methacrylate copolymer E, 3.5 parts of ethyl cellulose and talc were added. A liquid obtained by dissolving or dispersing 3.5 parts in water/ethanol, respectively, was sprayed and dried to obtain compound B-containing granules. 50 parts of lactose hydrate, 2.5 parts of light anhydrous silicic acid, 10.7 parts of crospovidone and 0.08 parts of yellow ferric oxide were mixed, and 0.8 parts of hydroxypropyl cellulose was dissolved in purified water. The liquid was added to granulate, dried, and sieved to obtain shaped granules. 50.6 parts of the compound B-containing granules, 64.08 parts of the excipient granules, 34.5 parts of crystalline cellulose, 10 parts of lactose hydrate, 0.22 parts of flavor, 0.16 parts of sucralose and 1 part of magnesium stearate were mixed and tableted to obtain gostone-shaped tablets (uncoated orally disintegrating tablets) having a weight of 160.56 mg and a diameter of 7.5 mm.
When the uncoated orally disintegrating tablet of Reference Example 3 was tested in the same manner as in Test Examples 1 and 2, the hardness was 53.6 N and the orally disintegrating time was 30 seconds or less.

(Example 5)
1.3 parts of polyvinyl alcohol, 0.05 parts of thaumatin, 0.1 parts of hypromellose, 1.7 parts of titanium oxide and 0.01 parts of yellow iron sesquioxide are dissolved or dispersed in purified water, respectively, and coated with a solid content of 10%. A solution was prepared. Using a spray pan-type coating machine (HCT-60 type), at a set temperature of 75 to 80 ° C., the coating liquid was sprayed on the uncoated orally disintegrating tablet produced in Reference Example 3, and 160.56 mg An orally disintegrating tablet having a coating layer of 3.16 mg per tablet was obtained.
When the orally disintegrating tablet having the coating layer of Example 5 was tested in the same manner as in Test Examples 1 to 3, the hardness was 57.1 N, the coating layer dissolution time was less than 10 seconds, and the mouthfeel was good. .

(Test Example 4) Photostability test The uncoated orally disintegrating tablet of Reference Example 3 and the orally disintegrating tablet having the coating layer of Example 5 were spread evenly on a petri dish and exposed to light irradiation with a white fluorescent lamp of 1000LX. Stored for 1 week. After storage, compound B and its analogues were measured by the HPLC method under the following conditions. Photostability was evaluated by calculating the area percentage (%) of the photodegradation product (relative retention time 0.43) to the total peak area derived from compound B and its analogues.
Column: Phenylhexylsilylated silica gel for liquid chromatography Mobile phase: Concentration gradient control by changing the mixing ratio of perchloric acid solution (1→1000) and methanol/acetonitrile mixture (17:3) Flow rate: about 1.2 mL/min
Measurement wavelength: 288 nm

The photodegradation product of the uncoated orally disintegrating tablet of Reference Example 3 was 0.088% (total illumination of 1,200,000 lx hr), whereas the orally disintegrating tablet having the coating layer of Example 5 was A decomposed product was 0.028% (total illuminance 1,200,000 lx·hr). Example 5, which provided a coating layer containing a colorant, demonstrated the photostabilizing effect of a photolabile drug.

Claims (5)

An orally disintegrating tablet containing azilsartan is coated with a coating layer containing at least one high-intensity sweetener selected from sodium saccharin, acesulfame potassium and aspartame, a polyvinyl alcohol resin and a coloring agent. An orally disintegrating tablet having a coating layer. 2. The orally disintegrating tablet having a coating layer according to claim 1, wherein the content of said high-intensity sweetener is 5% or less relative to the mass of the coating layer. 3. The orally disintegrating tablet having a coating layer according to claim 1 or 2 , wherein the polyvinyl alcohol-based resin is polyvinyl alcohol. The orally disintegrating tablet having a coating layer according to any one of claims 1 to 3 , wherein the coloring agent is at least one selected from titanium oxide, yellow ferric oxide, ferric oxide and black ferric oxide. The orally disintegrating tablet having a coating layer according to any one of claims 1 to 4, wherein the content of the coloring agent is 30 to 70% with respect to the mass of the coating layer.