KR20130049740A - Film coating composition and oral solid preparation - Google Patents

Abstract

PURPOSE: A film coating composition is provided to have excellent chewy texture and to improve eruption, thereby providing an oral solid agent with high gloss. CONSTITUTION: A film coating composition comprises 100.0 parts by weight of a base material which contains a single methyl cellulose or methyl cellulose with hydroxy propyl cellulose and/or polyvinylalcohol; 18-150 parts by weight of a plasticizer; and 40-500 parts by weight of talc. The oral solid agent comprises a drug-containing core part and the film coating composition sealing the core part. A manufacturing method of the oral solid agent comprises a step of spreading solution, in which the film coating composition is dissolved or dispersed, on a drug-containing core part; and a step of drying the spread composition. [Reference numerals] (AA) Elution rate(%); (BB) Predetermined (plain tablet); (CC) Example 4; (DD) Example 8; (EE) Example 1; (FF) Example 5; (GG) Example 9; (HH) Example 2; (II) Example 6; (JJ) Comparative example 1; (KK) Example 3; (LL) Example 7; (MM) Time(minutes)

Description

FILM COATING COMPOSITION AND ORAL SOLID PREPARATION

The present invention relates to film coating compositions and oral solid preparations using the same.

Film coating or dragees in the oral solid preparations, masking against the unpleasant taste of the drug, shading to maintain the stability of the drug, colored coating to improve the identification of oral solid preparations, during the transport of oral solid preparations It is widely used for the purpose of preventing abrasion damage or improving the aesthetics of a product.

In particular, it is known that high gloss is obtained by coating sugars on the aesthetic appearance of tablets. As an attempt to impart high glossiness to tablets, it is proposed to impart high glossiness to the tablet surface by using a composition in which polyethylene glycol and talc are blended in hydroxypropylmethylcellulose in a specific ratio (Patent Document 1). Moreover, as a masking method of bitterness, the film coating which does not collapse in an oral cavity is proposed by applying the gelling characteristic of methylcellulose and film-coating using methylcellulose (patent document 2). Moreover, the method of excellent the masking of bitter taste and improving the elution property of a drug by mix | blending a saccharide or sugar alcohol with methyl cellulose is proposed (patent document 3).

Japanese Patent Publication No. 2008-201713 Japanese Patent Laid-Open No. 60-13719 Japanese Patent Laid-Open No. 2001-151672

However, the coating of sugar takes a long time to process the sugar, and there are problems such as an increase in manufacturing cost, an increase in the difficulty of taking the preparation, and deterioration in stability due to degeneration of the protein, which is the main component of the gelatin used for coating. Moreover, although the tablet which has high glossiness is obtained with the film coating composition of patent document 1, the oral solid formulation coated with hydroxypropyl methylcellulose dissolves quickly in a mouth, and it feels sticky in a mouth, or is slippery Because there is a feeling of distance, there was a problem that it is difficult to take depending on patients such as elderly people and infants. This is attributable to the rapid dissolution of the film because the thermal gelation temperature of hydroxypropylmethylcellulose is high and does not cause thermal gelation in the oral cavity. On the other hand, when methyl cellulose is used as listed in Patent Literature 2, since methyl cellulose cannot be dissolved due to thermal gelation at 37 ° C., it is possible to take without feeling sticky or slippery. There is a concern that the dissolution of the drug is delayed as a cause. Therefore, although Patent Document 3 proposes that the elutability is improved by blending a saccharide or a sugar alcohol with methyl cellulose, the improvement of the elutability by this method is not sufficient, and the moisture permeability is improved by blending the sugar and the like. There was a problem that the stability at the time of preservation of tablets could not be secured.

Compared with the conventional film coating, the present invention provides a film coating composition having excellent texture in the oral cavity and improved dissolution property, and providing an oral solid formulation with high gloss by coating with the film coating composition. The purpose.

MEANS TO SOLVE THE PROBLEM As a result of earnestly examining in order to solve the said subject, the present inventors discovered that the said objective was achieved by mix | blending a plasticizer and talc in a specific ratio with methylcellulose, and completed this invention.

According to the present invention, methyl cellulose alone or in addition to methyl cellulose comprises at least 100 parts by weight of a base having hydroxypropyl cellulose and / or polyvinyl alcohol, 18 to 150 parts by weight of a plasticizer, and 40 to 500 parts by weight of talc A film coating composition is provided. Also provided is an oral solid formulation comprising at least a core portion containing a drug and at least the film coating composition covering the core portion. Further, a method for producing an oral solid preparation comprising at least a step of applying a solution obtained by dissolving or dispersing the film coating composition in a solvent to a core portion containing at least a drug and a subsequent drying step is provided.

When the oral solid preparation is coated using the film coating composition of the present invention, the sticky feeling and slipperiness in the oral cavity is improved compared to the conventional film coating, and the mouthfeel is excellent, and the swallowing can be smoothly swallowed. It is possible to provide an oral solid preparation with improved elution which can elute the active ingredient rapidly. In addition, according to the present invention, it is possible to provide an oral solid preparation to which high gloss is given without coating sugar.

1 shows the results of the dissolution test of Examples 1 to 8 and Comparative Example 1. FIG.

The film coating composition of the present invention contains at least a base, a plasticizer and talc having hydroxypropyl cellulose and / or polyvinyl alcohol in addition to methyl cellulose alone or in addition to methyl cellulose.

It is preferable that the viscosity of methyl cellulose (hereinafter also referred to as "MC") is so low that it can be sprayed as a high concentration solution in order to apply a coating. Specifically, the viscosity of 2 mass% aqueous solution in 20 degreeC becomes like this. Preferably it is 2-50 mPa * s, More preferably, it is 2-25 mPa * s, Especially preferably, it is 2-15 mPa * s. If it is less than 2 mPa * s, since MC degree of polymerization falls extremely, there exists a possibility that the intensity | strength as a film cannot be maintained. Moreover, when it exceeds 50 mPa * s, since the density | concentration of coating aqueous solution must be suppressed low, it may not be practical. In addition, the said viscosity can be measured by the viscosity measuring method as described in the 16th revised Japanese pharmacy.

Although the substitution degree of the methoxy group of MC is not specifically limited, Preferably it is 26.0-33.0 mass%, More preferably, it is 27.5-31.5 mass%. In addition, substitution degree of MC can be measured by the method based on the measuring method of substitution degree of methylcellulose, hydroxypropylmethylcellulose, and hydroxypropyl cellulose which were described in the 16th revised Japanese pharmacy.

In addition to the base of MC alone, a base in which hydroxypropyl cellulose (hereinafter also referred to as "HPC") and polyvinyl alcohol (hereinafter also referred to as "PVA") may be used.

It is preferable that the viscosity of HPC is lower in order to perform coating. Specifically, the viscosity of 2 mass% aqueous solution in 20 degreeC becomes like this. Preferably it is 2-50 mPa * s, More preferably, it is 3-10 mPa * s, Especially preferably, it is 6-10 mPa * s. If it is less than 2 mPa * s, since MC degree of polymerization falls extremely, there exists a possibility that the intensity | strength as a film cannot be maintained. Moreover, when it exceeds 50 mPa * s, since the density | concentration of coating aqueous solution must be suppressed low, it may not be practical. In addition, it can measure by the measuring method similar to MC.

The degree of substitution of the hydroxy propoxy group is not particularly limited, but is preferably 53.4 to 77.5 mass%, more preferably 60.0 to 70.0 mass%. In addition, substitution degree of HPC can be measured by the measuring method similar to MC.

Although the compounding quantity of HPC is not specifically limited, From a viewpoint of improving the elution property of MC, it is 49: 51-10: 90, More preferably, it is 45: 55-35: 65 by mass ratio of MC and HPC. When the amount of HPC is less, the improvement of dissolution property is inferior, and when the amount of the other HPC is high, the oral solid preparation may cause a slippery or sticky feeling in the oral cavity.

PVA is preferably polyvinyl alcohol (completely saponified) and polyvinyl alcohol (partly saponified) as defined in the pharmaceutical additive specification. Saponification degree of the fully saponified polyvinyl alcohol is 97 mol% or more, and partial saponification polyvinyl alcohol, Preferably saponification degree is 78-96 mol%.

The average degree of polymerization of PVA is preferably 200 to 3500, more preferably 400 to 1000. The average degree of polymerization of PVA can be measured by the measuring method of average degree of polymerization described in JIS K6726.

The blending amount of PVA is not particularly limited, but from the viewpoint of compatibility with MC, the mass ratio of MC and PVA is preferably 90:10 to 10:90, more preferably 50:50 to 15:85, particularly preferably 40 : 60 to 20:80. When the amount of PVA blended is less than the above-mentioned preferred range, the elution improvement may be inferior. When the amount of PVA blended is above the preferred range, when the oral solid preparation is taken, a feeling of slipping and stickiness occurs in the oral cavity. There is.

Examples of the plasticizer used in the present invention include polyethylene glycol, glycerin, propylene glycol, triacetin, triethyl citrate, and the like, and polyethylene glycol is particularly preferable in view of excellent compatibility with MC and imparting high gloss. .

Although the weight average molecular weight of polyethyleneglycol is not specifically limited, From a viewpoint of providing high gloss, Preferably it is 200-35000, More preferably, it is 1500-35000. The weight average molecular weight of polyethyleneglycol is obtained by polystyrene conversion using gel permeation chromatography (GPC).

Although content of the plasticizer in a film coating composition is 18-150 mass parts with respect to 100 mass parts of bases, Preferably it is 22-100 mass parts, More preferably, it is 40-80 mass parts. If the content of the plasticizer is less than 18 parts by mass, the glossiness of the tablet is inferior, and even if the plasticizer is blended more than necessary, the economic efficiency is poor. In addition, the base may be selected from a base of MC alone, a base including MC and HPC, a base including MC and PVA, and a base including MC, HPC and PVA.

The content of talc in the film coating composition is 40 to 500 parts by mass, preferably 80 to 380 parts by mass, and more preferably 150 to 250 parts by mass with respect to 100 parts by mass of the base. If the content of talc is small, the glossiness of the tablet is inferior, and economical is inferior even if the talc is blended more than necessary.

The film coating composition of the present invention contains the plasticizer and talc in the above-mentioned ratio, thereby promoting the collapse of the coating film at the edge portion with a small amount of coating, and dissolution of the drug from the coating film of MC which does not dissolve at 37 ° C. I think.

As needed, a coating composition can also add the drug normally accepted by pharmaceutical, surfactant which improves the dispersibility of a composition, a coloring agent, a pigment, a sweetener, a coating agent, an antifoamer, etc.

Oral solid preparations include at least a core portion containing a drug and a film coating composition covering the core portion.

The drug is not particularly limited as long as it is a drug that can be orally administered.

The core portion containing at least a drug may be blended with various additives commonly available in the art, such as excipients, binders, disintegrants, lubricants, anti-agglomerating agents, dissolution aids of pharmaceutical compounds, and the like. Examples of excipients include sugars such as white sugar, lactose, mannitol, and glucose, starch, crystalline cellulose, calcium phosphate, calcium sulfate, and the like. Polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone, glucose , White sugar, lactose, maltose, dextrin, sorbitol, mannitol, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, macrogols, gum arabic, gelatin, agar, starch and the like. Examples of the disintegrating agent include low-substituted hydroxypropyl cellulose, carmellose or salts thereof, croscarmellose sodium, carboxymethyl starch sodium, cross polyvinylpyrrolidone, crystalline cellulose and crystalline cellulose and carmellose sodium. Can be. Examples of the lubricant and anti-agglomerating agent include talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, waxes, hardened oils, polyethylene glycols, sodium benzoate and the like. Moreover, organic acids, such as a fumaric acid, a succinic acid, malic acid, adipic acid, etc. are mentioned as a dissolution adjuvant of a pharmaceutical compound. Content of these additives can be suitably determined according to the kind of chemical | medical agent, etc.

Examples of oral solid preparations coated with the film coating composition of the present invention include tablets, granules, fine granules, capsules, and the like, with tablets being particularly preferred.

Next, the manufacturing method of an oral solid preparation is demonstrated.

The device of the coating can use conventionally known means. In general, spray coating is performed, and in this case, a fan coating apparatus, a drum type coating apparatus, a fluidized bed coating apparatus, or a stirring flow coating apparatus may be used. The spray apparatuses accompanying these apparatuses include air spray, airless spray, 3 Any of the fluid spray can be used.

As a method for applying the film coating composition solution of the present invention, for example, using the coating apparatus described above, a film coating composition in which an additive is further added to MC, a plasticizer, and talc as needed, to the core portion containing the drug. The solution which melt | dissolved or disperse | distributed in organic solvents, such as water or ethanol, or these liquid mixture, is adjusted, and it apply | coats by spray etc. are mentioned.

Polyethylene glycol of MC, HPC, PVA, and plasticizer is water-soluble, and is also dissolved in a mixed solution of water and an organic solvent such as ethanol. Talc is an inorganic powder and is dispersed without dissolving in water or an organic solvent. In consideration of dispersion, the average particle diameter of talc is preferably in the range of 0.1 to 20 µm using a laser diffraction scattering method.

Thereafter, the oral solid preparation can be prepared by extracting in the same coating apparatus or from the same coating apparatus, drying by heating or the like.

Although drying in particular is not restrict | limited, In terms of providing a high gloss, it is preferable to carry out polishing simultaneously with drying, Preferably, let the oral solid preparations rub with each other at the time of drying (polishing). Drying is performed, for example in the above-mentioned coating apparatus, Preferably it is 20-100 degreeC, More preferably, it is the temperature of 30-80 degreeC. By rotating or stirring the inside of a coating apparatus, polishing can be performed simultaneously with drying. Further, drying is preferably performed for 10 minutes or more, more preferably 20 minutes to 60 minutes, particularly preferably 20 minutes to 40 minutes, with or without polishing. Even if polishing is carried out with drying or drying for 60 minutes or more, there is no change in glossiness and economical efficiency.

The coating amount of the film coating composition coated on the surface of the core portion (predetermined tablet) depends on the type, form, size, surface state of the solid-forming formulation, and the properties of the medicaments and additives contained in the solid formulation. For example, it is 1-10 mass% with respect to predetermined | prescribed, More preferably, it is 1-7 mass%, Especially preferably, it is 2-6 mass%. If the coating amount is too small, a complete film cannot be obtained, while if too large, the time required for coating may be required.

In the oral solid preparation of the present invention, undercoating is carried out using various coating bases commonly available in the art such as hydroxypropylmethylcellulose under the film layer containing the film coating composition, thereby forming a plurality of films. A multilayer film-coated oral solid preparation may be used.

The oral solid preparation thus prepared has a time until the release of the drug of 85% or more in the dissolution test (37 ° C., puddle method, 50 revolutions / minute, 900 ml of water in a solvent) described in the 16th revised Japanese Pharmacy. It is preferably within 10 minutes from the start of the test. In addition, the glossiness of the surface of the oral solid formulation was measured 60-degree mirror gloss using a precision gloss meter (GM-26D (20 ° / 60 °) type, Murakami Color Research Institute) (tablet holder 5mm (phi), measuring area: about 3x3 mm), Preferably it is 6.0 or more. In addition, the oral solid preparation can be taken without feeling slippery or sticky in the oral cavity when taken.

[Example]

EMBODIMENT OF THE INVENTION Hereinafter, although an Example is given and this invention is demonstrated concretely, this invention is not limited to these.

Example 1

2 parts by mass of riboflavin (manufactured by Tokyo Tanabe Pharmaceutical Co., Ltd.), 90 parts by mass of lactose (Floint Industrial Co., Ltd., dilactose S), 8 parts by mass of low substitution degree hydroxypropyl cellulose (11% by mass of hydroxypropyl group substitution), stearic acid 0.5 parts by mass of magnesium powder was mixed, and a rotary tableting machine (Vergo manufactured by Kikusui Seisakusho) was used to obtain a diameter of 8 mm, a tableting pressure of 1t, a tableting preload of 0.3t, a rotation speed of 20 rpm, and a weight of 200 mg per fixed weight. It was compressed into tablets to prepare a predetermined containing riboflavin in the drug.

Next, 13.5 g of MC (28 mass% of methoxy group substitution degree, the viscosity of 2 mass% aqueous solution in 20 degreeC is 4.0 mPa * s), 8.1 g of polyethyleneglycol (Nipbon Yushi Corporation, macrogol 6000) (to MC 0.60), talc (Crown Co.) 27.0g (2.0 for MC) and titanium oxide (Ishihara Sangyo Co., Ltd.) were dissolved and dispersed in 396.0g of purified water to prepare a coating solution.

Using the said coating solution, it coat | covered to 5 mass parts with solid content mass with respect to predetermined 100 mass parts on condition of the following. After completion of the coating, drying and polishing were performed for 30 minutes at an air supply temperature of 60 ° C. and a fan rotation speed of 24 rpm in the coating apparatus to obtain a target coated tablet.

The coating conditions used are as follows.

Device: Ventilated Fan Coater (Inner Diameter 33cm)

Input amount: 1 kg

Intake temperature: 80 ℃

Exhaust temperature: 47-50 ℃

Intake air volume: 1㎥ / min

Fan speed: 18 to 24 rpm

Spray rate: 6g / min

Spray air pressure: 150 k㎩

Example 2

In the preparation of the coating solution of Example 1, 24.75 g of MC, 5.45 g of polyethylene glycol (0.22 for MC), 19.80 g of talc (0.8 for MC), 9.90 g of titanium oxide, and 490.11 g of purified water were changed. A coating solution was prepared and coated tablets were obtained in the same manner as in Example 1.

Example 3

In the preparation of the coating solution of Example 1, 10.5 g of MC, 2.31 g of polyethylene glycol (0.22 for MC), 39.9 g of talc (3.8 for MC), 4.2 g of titanium oxide, and 293.09 g of purified water were changed. A coating solution was prepared and coated tablets were obtained in the same manner as in Example 1.

Example 4

In the preparation of the coating solution of Example 1, 18.0 g of MC, 22.5 g of polyethylene glycol (1.25 for MC), 14.4 g of talc (0.8 for MC), 7.2 g of titanium oxide, and 537.9 g of purified water were changed. A coating solution was prepared and coated tablets were obtained in the same manner as in Example 1.

Example 5

In the preparation of the coating solution of Example 1, 10.5 g of MC, 13.13 g of polyethylene glycol (1.25 for MC), 39.9 g of talc (3.8 for MC), 4.2 g of titanium oxide, and 282.28 g of purified water were changed. A coating solution was prepared and coated tablets were obtained in the same manner as in Example 1.

Example 6

In the preparation of the coating solution of Example 1, the coating solution was changed to 16 g of MC, 2.88 g of polyethylene glycol (0.18 for MC), 32 g of talc (2.0 for MC), 6.4 g of titanium oxide, and 342.72 g of purified water. To prepare a coated tablet in the same manner as in Example 1.

Example 7

In the preparation of the coating solution of Example 1, 25 g of MC, 15 g of polyethylene glycol (0.60 for MC), 12.5 g of talc (0.5 of MC), 10 g of titanium oxide and 437.5 g of purified water were changed to prepare a coating solution. In the same manner as in Example 1, a coated tablet was obtained.

Example 8

In the preparation of the coating solution of Example 1, the viscosity of the 6.4 g MC and HPC (Nippon Soda Co., Ltd., hydroxy propoxy group substitution degree 63 mass%, 2 mass% aqueous solution at 20 ° C. were 8.0 mPa · s ) Add 9.6 g (MC: HPC = 4: 6), 9.6 g polyethylene glycol (0.60 for MC / HPC), 32.0 g talc (2.0 for MC / HPC), 6.4 g titanium oxide, purified water The coating solution was prepared by changing to 336.0 g, and coated tablet was obtained in the same manner as in Example 1.

Example 9

In the preparation of the coating solution of Example 1, 4.8 g of MC was added, and 11.2 g (MC: PVA = 3: 7) of PVA (made by Nippon Chobiboshi, polymerization degree 500, saponification degree 88 mol%) was added, and polyethylene glycol was added. 9.6 g (0.60 for MC / PVA), talc 32.0 g (2.0 for MC / PVA), titanium oxide 6.4 g, purified water to 336.0 g to prepare a coating solution, coating in the same manner as in Example 1 A tablet was obtained.

Comparative Example 1

In the preparation of the coating solution of Example 1, without adding polyethylene glycol, talc and titanium oxide, MC 56.0g was changed to 744.0g of purified water to prepare a coating solution, and the coating tablets were obtained in the same manner as in Example 1.

Comparative Example 2

In the preparation of the coating solution of Example 1, without coating polyethylene glycol, MC 14g, talc 53.2g (3.8 for MC), titanium oxide 5.6g, purified water to 277.2g to prepare a coating solution, Example In the same manner as in 1, a coated tablet was obtained.

Comparative Example 3

In the preparation of the coating solution of Example 1, without adding talc, 22.5 g of MC, 28.13 g of polyethylene glycol (1.25 for MC), 9 g of titanium oxide, and 390.32 g of purified water were prepared to prepare a coating solution. In the same manner as in 1, a coated tablet was obtained.

Comparative Example 4

In the preparation of the coating solution of Example 1, the coating solution was changed to 16 g of MC, 2.4 g of polyethylene glycol (0.15 for MC), 32 g of talc (2.0 for MC), 6.4 g of titanium oxide, and 343.2 g of purified water. To prepare a coated tablet in the same manner as in Example 1.

Comparative Example 5

In the preparation of the coating solution of Example 1, 25 g of MC, 15 g of polyethylene glycol (0.60 for MC), 7.5 g of talc (0.3 for MC), 10 g of titanium oxide and 442.5 g of purified water were changed to prepare a coating solution. In the same manner as in Example 1, a coated tablet was obtained.

Comparative Example 6

In the preparation of the coating solution of Example 1, MC was substituted with hydroxypropylmethylcellulose (

Methoxy group substitution degree of 28%, hydroxy propoxy group substitution degree of 9%), 16.0 g of hydroxypropylmethylcellulose, 9.6 g of polyethylene glycol, 32.0 g of talc, 6.4 g of titanium oxide, and 336.0 g of purified water. A coating solution was prepared in the same manner as in Example 1 to obtain a coated tablet.

<Evaluation of Elution Characteristics of Coating Tablets>

The dissolution test of the coated tablets obtained in Examples 1 to 9 and Comparative Examples 1 to 6 was evaluated by the dissolution test (37 ° C., puddle method, 50 revolutions / minute, solvent 900 ml of water) of the 16th revised Japanese pharmacy base. It was done. The elution behavior of Examples 1 to 9 and Comparative Example 1 is shown in FIG.

Sampling of the dissolution test was performed 1 minute, 3 minutes, 5 minutes, 7 minutes, 10 minutes, 20 minutes, and 30 minutes after the start of the dissolution test. The elution time was obtained as the elution time. Indicated.

As is apparent from FIG. 1 and Table 1, the coated tablet of the present invention has improved elution as compared with the coated tablet of Comparative Example 1.

<Evaluation of glossiness of coated tablets>

The glossiness of the coated tablets obtained in Examples 1 to 9 and Comparative Examples 1 to 6 was 60 degree mirror gloss using a precision gloss meter (GM-26D (20 ° / 60 °) type, manufactured by Murakami Shikisai Institute of Technology). Table 1 shows the result of measuring the degree (tablet holder 5 mmφ, measuring area: about 3x3 mm).

As is apparent from Table 1, the coated tablets of the present invention exhibited high glossiness as compared to the coated tablets of Comparative Examples 1-5.

<Evaluation of presence of slippery feeling in oral cavity>

The coated tablets obtained in Examples 1 to 9 and Comparative Examples 1 to 6 were administered to 6 healthy adults, and the number of people who felt slippery in the oral cavity is summarized in Table 1.

As is apparent from Table 1, the coated tablet of the present invention did not exhibit a slippery feeling in the oral cavity, whereas the coated tablet of Comparative Example 6 showed a slippery feeling.

Claims (5)

A film coating composition comprising at least 100 parts by weight of a base having hydroxypropyl cellulose and / or polyvinyl alcohol in addition to methyl cellulose alone or methyl cellulose, 18 to 150 parts by weight of a plasticizer, and 40 to 500 parts by weight of talc. The film coating composition of claim 1, wherein the plasticizer is polyethylene glycol. An oral solid preparation comprising at least a core portion containing a drug and at least the film coating composition according to claim 1 or 2 covering the core portion. A method for producing an oral solid preparation comprising at least a step of applying a solution obtained by dissolving or dispersing the film coating composition according to claim 1 or 2 in a solvent to a core portion containing at least a drug, and a subsequent drying step. The method for producing an oral solid formulation according to claim 4, wherein the drying step is performed for 10 minutes or more, including polishing while drying the oral solid formulation after application.

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