WO2015152190A1

WO2015152190A1 - Granular solid formulation containing cephalosporin ester, and method for producing same

Info

Publication number: WO2015152190A1
Application number: PCT/JP2015/060034
Authority: WO
Inventors: 美咲吉村; 佳子久保; 哲規山川; 将司金子; 裕將冨田
Original assignee: 富山化学工業株式会社
Priority date: 2014-03-31
Filing date: 2015-03-31
Publication date: 2015-10-08
Also published as: JP6196730B2; JPWO2015152190A1

Abstract

A granular solid formulation containing drug granules that contain (1) a core substance and (2) a drug-containing layer covering the core substance, wherein a granular solid formulation in which the drug-containing layer contains a cephalosporin ester and a heat-meltable substance, the content ratio of heat-meltable substance is 10-20% relative to the mass of the drug granules, and the content ratio of cephalosporin ester is 20-40% relative to the mass of the granular solid formulation has a high drug content, exceptional stability and elutability, and reduced bitterness, and is useful as a formulation that improves compliance in children and/or the elderly.

Description

Granular solid preparation containing cephalosporin ester and method for producing the same

The present invention relates to a granular solid preparation containing a cephalosporin ester and a method for producing the same.

The granular solid preparations such as powders, fine granules, granules and dry syrups can be freely changed in dosage. Therefore, these formulations are important in improving medication compliance for children and / or the elderly. In granular solid preparations that can be easily taken by children and / or the elderly, it is required to suppress unpleasant tastes such as astringency and bitterness of medicinal ingredients (Non-patent Document 1).
In recent years, it has been reported that resistant bacteria of Streptococcus pneumoniae and Haemophilus influenzae are increasing in the pediatric field and otolaryngology field (Non-Patent Documents 2, 3, and 4).
Based on such current situation, it is predicted that high-dose administration of oral cephalosporin esters such as cefteram pivoxil, cefcapene pivoxil, and cefditoren pivoxil will be essential (Non-patent Documents 4 and 5). .

Cephalosporin esters are β-lactam antibiotics, and for example, cefteram pivoxil, cefcapene pivoxil and cefditoren pivoxil are known. However, these drugs can have an unpleasant bitter taste. In order to obtain a granular solid preparation that is easy to take a drug having a bitter taste, it is necessary to devise methods such as imparting sweetness and masking the bitter taste.
So far, composite granular solid preparations in which the bitter taste of cefteram pivoxil is reduced are known (Patent Document 1).

Japanese Patent No. 3837062

The drug content of granular solid preparations such as cephalosporin ester fine granules that are easy for children to take is only 10%. Therefore, when a high dose is administered, the upper limit (1 g) of the recommended single dose in the pharmacist association guidelines may be exceeded.
On the other hand, as a method for reducing the bitter taste of a drug, a method is known in which a sweetener layer is coated on the surface of a drug-containing coating layer that coats a core substance using an aqueous solution of a sweetener. However, when a granular solid preparation containing a cephalosporin ester having a high drug content is produced by this method, the drug may leak and cause bitterness.
Development of a granular solid preparation containing a cephalosporin ester having a high drug content, excellent stability and dissolution, and reduced bitterness is strongly desired.

An object of the present invention is to provide a granular solid preparation containing a cephalosporin ester having a high drug content, excellent stability and dissolution, and reduced bitterness.
Another object of the present invention is to provide a method for producing a granular solid preparation containing a cephalosporin ester having a high drug content, excellent stability and dissolution, and reduced bitterness.

Under such circumstances, the present inventors have conducted intensive research,
(1) a core substance, and (2) a drug-containing layer that coats the core substance,
A granular solid preparation containing drug granules containing
The drug-containing layer includes a cephalosporin ester and a hot melt material,
The content of hot melt material is 10-20% with respect to the mass of drug granules,
The content of cephalosporin ester is 20-40% of the mass of the granular solid preparation. Despite the high drug content of the granular solid preparation, it is excellent in stability and dissolution and reduces bitterness. As a result, the present invention was completed.

The present invention provides the following.
[1] A granular solid preparation comprising a drug granule comprising (1) a core substance and (2) a drug-containing layer covering the core substance, wherein the drug-containing layer comprises a cephalosporin ester and a hot-melt substance A granular solid preparation in which the content of the hot-melt material is 10 to 20% with respect to the mass of the drug granules, and the content of the cephalosporin ester is 20 to 40% with respect to the mass of the granular solid preparation .
[2] The granular solid preparation according to [1], wherein the content of the hot melt substance is 11 to 18% with respect to the mass of the drug granules.
[3] The hot-melt material is one or more selected from hydrogenated oil, higher alcohol, higher fatty acid, wax, vegetable or animal fat, ethylene oxide polymer, and sugar or glycerin fatty acid ester. [1 ] Or the granular solid preparation according to [2].
[4] The granular solid preparation according to [1] or [2], wherein the hot-melt material is a sucrose fatty acid ester.
[5] The granular solid preparation according to any one of [1] to [4], wherein the cephalosporin ester is cefteram pivoxil, cefcapene pivoxil, or cefditoren pivoxil.
[6] The granular solid preparation according to any one of [1] to [4], wherein the cephalosporin ester is cefteram pivoxil.

[7] The granular material according to any one of [1] to [6], further comprising one or more disintegrants selected from crospovidone, carmellose calcium and croscarmellose sodium in the drug-containing layer. Solid formulation.
[8] The granular solid preparation according to [7], wherein the disintegrant is one or two selected from crospovidone and carmellose calcium.
[9] The granular solid preparation according to [7], wherein the disintegrant is crospovidone.
[10] The granular solid preparation according to any one of [1] to [9], further comprising thaumatin.
[11] The composition according to [10], further comprising one or more sweeteners selected from sucrose, aspartame, neotame, saccharin, sodium saccharin, stevia, sucralose, trehalose, erythritol, sorbitol, xylitol and acesulfame potassium. Granular solid formulation.
[12] The granular solid preparation according to [11], wherein the sweetener is one or more selected from sucrose, aspartame and acesulfame potassium.
[13] The granular solid preparation according to any one of [1] to [12], wherein the granular solid preparation is a powder, fine granules, granules, or dry syrup.

[14] A method for producing a granular solid preparation comprising drug granules comprising (1) a core substance, and (2) a drug-containing layer covering the core substance, wherein the drug-containing layer comprises a cephalosporin ester and a hot melt The content of the hot melt substance is 10-20% with respect to the mass of the drug granules, the content of the cephalosporin ester is 20-40% with respect to the mass of the granular solid preparation, A production method comprising coating a core substance with a powder containing a cephalosporin ester and a hot-melt substance, and forming a drug-containing layer on the surface of the core substance.
[15] The production method according to [14], wherein the content of the hot-melt material is 11 to 18% with respect to the mass of the drug granule.
[16] The hot melt material is one or more selected from hydrogenated oil, higher alcohol, higher fatty acid, wax, vegetable or animal fat, ethylene oxide polymer and sugar or glycerin fatty acid ester. [14 ] Or the production method according to [15].
[17] The production method according to [14] or [15], wherein the hot-melt material is a sucrose fatty acid ester.

[18] The production method according to any one of [14] to [17], wherein the cephalosporin ester is cefteram pivoxil, cefcapene pivoxil, or cefditoren pivoxil.
[19] The production method according to any one of [14] to [17], wherein the cephalosporin ester is cefteram pivoxil.
[20] The production according to any one of [14] to [19], wherein the drug-containing layer further contains one or more disintegrants selected from crospovidone, carmellose calcium and croscarmellose sodium. Method.
[21] The production method according to [20], wherein the disintegrant is one or two selected from crospovidone and carmellose calcium.
[22] The production method according to [20], wherein the disintegrant is crospovidone.
[23] The production method according to any one of [14] to [22], further comprising forming a layer containing thaumatin that covers the drug-containing layer.
[24] The method according to [23], wherein the layer containing thaumatin contains a sweetener.
[25] The production according to [24], wherein the sweetener is one or more selected from sucrose, aspartame, neotame, saccharin, sodium saccharin, stevia, sucralose, trehalose, erythritol, sorbitol, xylitol, and acesulfame potassium. Method.
[26] The production method according to [24], wherein the sweetener is one or more selected from sucrose, aspartame, and acesulfame potassium.
[27] The production method according to any one of [14] to [26], wherein the granular solid preparation is a powder, fine granules, granules, or dry syrup.

The granular solid preparation of the present invention is a preparation containing a cephalosporin ester having a high drug content, excellent stability and dissolution, and reduced bitterness, and has improved compliance with children and / or the elderly. Useful as a formulation.
The production method of the present invention is useful as a production method of a preparation containing a cephalosporin ester having a high drug content, excellent stability and dissolution, and reduced bitterness.

The present invention is described in detail below.
In the present specification, a numerical range indicated using “to” indicates a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively.
Unless otherwise indicated,% used in this specification means the mass%.

The “granular solid preparation” of the present invention means “a preparation containing drug granules”.
“Drug granule” means “a granule comprising a core substance and a drug-containing layer covering the core substance”.
“Drug-containing layer” means “a layer containing a cephalosporin ester and a hot-melt material covering a core material”.
“Coating A” means “present on at least a part of the surface of A”.

<Core material>
Examples of the core substance used in the present invention include purified sucrose, D-mannitol, lactose, erythritol, xylitol and sorbitol. Purified sucrose and D-mannitol are preferred, and purified sucrose is more preferred.
The content of the core substance is preferably 30 to 60%, more preferably 35 to 55%, still more preferably 37 to 53% with respect to the mass of the granular solid preparation.

<Cephalosporin ester>
Examples of the cephalosporin ester used in the present invention include cefteram pivoxil, cefcapene pivoxil and cefditoren pivoxil, and cefteram pivoxil is preferable.
Cephalosporin esters are metabolized in the body to form cephalosporin and exhibit antibacterial activity. For example, cefteram pivoxil is metabolized in the body to cefteram and exhibits antibacterial activity.
Cefteram pivoxil can be produced, for example, by the method described in JP-B-60-52755.
Cephalosporin esters include hydrates, solvates and crystals of various shapes as well as amorphous forms.
The content of the cephalosporin ester is preferably 20 to 40%, more preferably 22 to 38%, still more preferably 23 to 35% with respect to the mass of the granular solid preparation.

<Hot melt material>
The hot-melt material used in the present invention melts by heating and acts as a coating agent for the granulated powder surface when a layer containing a drug is formed on the granulated powder surface.
Examples of the hot melt material used in the present invention include hardened oils such as hardened castor oil, hardened soybean oil and hardened rapeseed oil; higher alcohols such as stearyl alcohol and cetanol; higher fatty acids such as stearic acid and palmitic acid; carnauba wax Waxes such as cocoa butter and beef tallow; ethylene oxide polymers such as Macrogol 4000 and Macrogol 6000; and sugars such as sucrose fatty acid esters or fatty acid esters of glycerin, etc. May be used in combination. Preferable hot melt materials include sucrose fatty acid esters.
The content of the hot melt substance is preferably 10 to 20%, more preferably 11 to 18%, based on the mass of the drug granule.

<Drug-containing layer>
The drug-containing layer covers the core material and includes a cephalosporin ester and a hot melt material.
The drug-containing layer is present on at least a part of the surface of the core substance.
The drug-containing layer preferably covers 1/4 or more of the surface of the core substance, more preferably 1/2 or more, and covers the entire surface of the core substance. Further preferred.
The drug-containing layer preferably contains a disintegrant.
Examples of the disintegrant include one or more selected from crospovidone, carmellose calcium, and croscarmellose sodium.
The disintegrant is preferably one or two selected from crospovidone and croscarmellose sodium, and more preferably crospovidone.
The content of the disintegrant is preferably 1 to 7%, more preferably 2 to 4% with respect to the mass of the granular solid preparation.

<Particulate solid preparation>
The granular solid preparation includes a drug granule including (1) a core substance, and (2) a drug-containing layer covering the core substance.
Examples of granular solid preparations include powders, fine granules, granules, and dry syrup. The granular solid preparation may contain a solid substance not containing a drug in addition to the drug granule.
Examples of solids that do not contain a drug include solids intended for sweetness.

<Thomatin>
The granular solid preparation of the present invention preferably contains a “layer containing thaumatin covering the drug-containing layer”.
The thaumatin used in the present invention can be extracted and purified from the fruit of Thaumatococcus daniellii of the family of Marantaceae by a known method, but is commercially available thaumatin (for example, Sun Sweet T; Saneigen EF -Eye) can also be used. Also called thaumatin.
The content of thaumatin is preferably 0.001 to 0.2%, more preferably 0.005 to 0.1% with respect to the mass of the granular solid preparation.
The layer containing thaumatin is present on at least a part of the surface of the drug-containing layer.
The layer containing thaumatin preferably covers 1/4 or more of the surface of the drug-containing layer, more preferably 1/2 or more, and covers the entire surface of the drug-containing layer. More preferably.

<Sweetener>
The layer containing thaumatin preferably further contains a sweetener.
Examples of the sweetener used in the present invention include sucrose, aspartame, neotame, saccharin, sodium saccharin, stevia, sucralose, trehalose, erythritol, sorbitol, xylitol and acesulfame potassium, and sucrose, aspartame and acesulfame potassium. Is preferred.
Sweetening agents may be used in combination.
The content of the sweetening agent is preferably 1 to 10%, more preferably 2 to 7%, based on the mass of the granular solid preparation.

<Additives>
In the present invention, commonly used additives can be used as long as the effects of the present invention are not impaired. Such additives include lubricants, colorants, flavoring agents, surfactants, disintegrants and suspending agents.
Examples of the lubricant include magnesium stearate, talc, hydrous silicon dioxide, and light anhydrous silicic acid.
Examples of the colorant include iron sesquioxide, yellow sesquioxide, edible red No. 102, edible yellow No. 4, and edible yellow No. 5 and the like.
Examples of flavoring agents include essential oils such as orange oil, lemon oil, peppermint oil and pine oil; essences such as orange essence and peppermint essence; flavors such as cherry flavor, vanilla flavor and fruit flavor; apple micron, banana micron, Powder flavors such as peach micron, strawberry micron and orange micron; vanillin and ethyl vanillin.
Examples of the surfactant include sodium lauryl sulfate and dioctyl sodium sulfosuccinate.
Examples of the suspending agent include carmellose sodium, sodium alginate, methyl cellulose, polysorbate 80, tragacanth powder, carrageenan and xanthan gum.
These additives may be used either alone or in combination of two or more. The blending amount of the additive is not particularly limited, and may be appropriately blended so that the effect is sufficiently exhibited according to each purpose.

The granular solid preparation of the present invention can be used as a preparation of powders, granules, fine granules, dry syrups and the like by a conventional method using pharmaceutically acceptable excipients such as excipients, carriers and diluents as appropriate. However, for example, it is preferably used as a fine granule and powder for oral use and a suspension dispersed in water or syrup. The administration method, dose and number of administrations can be appropriately selected according to the age, weight and symptoms of the patient, but usually the amount that can exert the drug effect is divided into 1 to several times a day. Usually, for children, cefteram pivoxil may be orally administered in a daily dose of 9 to 18 mg (titer) / kg divided into three doses. For adults, 150-600 mg (titer) daily as cefteram pivoxil should be divided into 3 doses and administered orally after meals.

<Manufacturing method>
The method for producing a granular solid preparation of the present invention is a method for producing a granular solid preparation comprising drug granules comprising (1) a core substance, and (2) a drug-containing layer covering the core substance, wherein the drug-containing layer comprises: , Cephalosporin ester and hot melt substance, the content of hot melt substance is 10-20% with respect to the mass of drug granules, and the content of cephalosporin ester is with respect to the mass of the granular solid preparation The manufacturing method is characterized in that the core material is coated with a powder containing a cephalosporin ester and a hot-melt material to form a drug-containing layer on the surface of the core material.
The method for producing the granular solid preparation of the present invention is not particularly limited, but the core material heated to the vicinity of the melting point of the hot melt material is stirred, fluidized or fluidly stirred, the hot melt material, the cephalosporin ester and the necessary It is preferable to perform granulation near the melting point of the hot-melt material by adding a powder obtained by adding other additives according to the conditions. In this production method, the substance generated by melting the hot melt substance becomes a binder, and the cephalosporin ester and other additives are bound onto the core substance. More specifically, according to conventional methods such as fluidized granulation, rolling agitation granulation, and tumbling fluidized agitation granulation, “a layer containing a cephalosporin ester and a hot melt material covering a core material” A method for producing a granular solid preparation containing a drug granule containing sucrose is preferred, a tumbling stirring granulation method and a tumbling fluid stirring granulation method are more preferred, and a rolling fluid stirring granulation method is more preferred.

In the method for producing a granular solid preparation of the present invention, a method of forming a “layer containing thaumatin covering a drug-containing layer” is preferable.
In the method for producing a granular solid preparation of the present invention, a method in which a core material is coated with a powder containing a drug and a hot-melt material, and then a layer containing thaumatin is formed without adding water.
In this production method, it is preferable to use a rolling fluid stirring granulation method.

In the present invention, other layers may be formed according to a conventional method in addition to the drug-containing layer and the layer containing thaumatin as long as the effects of the present invention are not impaired.
For example, another layer may be formed between the core substance and the drug-containing layer, or another layer may be formed between the drug-containing layer and the layer containing thaumatin, and the surface of the layer containing thaumatin Other layers may be formed.
The other layer is a layer containing an additive generally used for a drug, and may be two or more layers.

Next, the present invention will be described with reference to examples, comparative examples, and test examples, but the present invention is not limited thereto.

Unless otherwise specified, the following components were used.
Cefteram pivoxil (Toyama Chemical Co., Ltd.)
Cefditoren pivoxil (Jeil Pharmaceutical Co. Ltd.)
Purified white sugar: Sukurene SR80 / 100
Refined white sugar pulverized product: Granulated sugar (Shisui Port Sugar Co., Ltd.)
Sucrose fatty acid ester: Ryoto sugar ester S-370F (Mitsubishi Chemical Foods)
Crystalline cellulose / carmellose sodium: Theolas RC-A591NF (Asahi Kasei Chemicals Corporation)
Carmellose calcium: ECG-505 (Nichirin Chemical Industry Co., Ltd.)
Carmellose sodium: CMC Daicel 1190J (Daicel Finechem Co., Ltd.)
Crospovidone: Polyplusdon XL-10 (IS Japan Co., Ltd.)
Croscarmellose sodium: Primerose (DMV Japan)
Aspartame (Ajinomoto Co., Inc.)
Acesulfame potassium: Sanet Pharma Grade D (MC Food Specialties Co., Ltd.)
Sucralose (San-Ei Gen FF I)
Saumatine: Sansuit T (Saneigen FFI Co., Ltd.)
Hydrous silicon dioxide: Carplex 80 (DSL Japan Co., Ltd.)
Colorant: Ferric sesquioxide (Hagi Kasei Co., Ltd.)
Flavoring agent: Strawberry Micron 1591 (Takasago International Corporation)

Unless otherwise specified, the following devices were used.
Rolling fluid granulation coating equipment: Multiplex MP-10 (Paurec Co., Ltd.)
Granulator: Power mill, Model P-5S, 24 mesh screen (Showa Giken Co., Ltd.)

As the core material, the colored sukurene used in the examples is charged with 78.0 kg of refined sucrose in a film coating apparatus (Doria Coater DRC1200; Pou Lec). A colored liquid consisting of 0.499 kg of purified water was sprayed and dried.

Example 1a
356 g of colored skrene was charged into a tumbling fluidized granulation coating apparatus set at a jacket temperature of 82 ° C., and a mixture of 309 g of cefteram pivoxil, 139 g of sucrose fatty acid ester and 29.0 g of carmellose calcium was stirred while rotating at 300 rpm. Added over a minute. After stirring for 3 minutes, the mixture was passed through a 20 mesh sieve to obtain a granular solid preparation.

Example 2a
371 g of colored skrene was charged into a tumbling fluidized granulation coating apparatus set at a jacket temperature of 82 ° C., and a mixture of 310 g of cefteram pivoxil, 124 g of sucrose fatty acid ester and 29.2 g of carmellose calcium was stirred while rotating at 350 rpm. Added over a minute. After stirring for 6 minutes, it was passed through a 20 mesh sieve to obtain a granular solid preparation.

Example 3a
362 g of colored skrene was charged into a tumbling fluidized granulation coating apparatus set at a jacket temperature of 82 ° C., and a mixture of 309 g of cefteram pivoxil, 133 g of sucrose fatty acid ester and 29.1 g of carmellose calcium was stirred while rotating at 300 rpm. Added over a minute. After stirring for 6 minutes, it was passed through a 20 mesh sieve to obtain a granular solid preparation.

Example 4a
299 g of colored skrene was charged into a tumbling fluidized granulation coating apparatus set at a jacket temperature of 85 ° C., and a mixture of 266 g of cefteram pivoxil, 127 g of sucrose fatty acid ester and 25.0 g of carmellose calcium was stirred with a rotation speed of 250 rpm. Added over a minute. Further, a mixture of 3.1 g of sucrose fatty acid ester, 40.1 g of purified sucrose pulverized product and 15.0 g of crystalline cellulose / carmellose sodium was added over 1 minute and stirred, and then passed through a 20 mesh sieve to obtain a granular solid preparation. It was.

Example 5a
In the same manner as in Example 4a, a granular granulated powder was produced using 299 g of colored skrane, 266 g of cefteram pivoxil, 127 g of sucrose fatty acid ester and 25.1 g of crospovidone. Further, 3.0 g of sucrose fatty acid ester, 40.0 g of purified white sugar pulverized product and 15.0 g of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.

Example 6a
In the same manner as in Example 4a, a granular granulated powder was produced using 299 g of colored skrane, 266 g of cefteram pivoxil, 127 g of sucrose fatty acid ester and 25.2 g of croscarmellose sodium. Further, 3.1 g of sucrose fatty acid ester, 40.1 g of purified sucrose pulverized product and 15.0 g of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.

Example 7a
30.9 kg of colored skelenium was charged into a tumbling fluidized granulation coating device (multiplex MP-200; Powrec Co., Ltd.) set at a jacket temperature of 80 ° C., while stirring at 110 rpm, 16.0 kg of cefteram pivoxil, sucrose A mixture of 6.86 kg fatty acid ester and 1.50 kg crospovidone was added over 20 minutes. After stirring for 17 minutes, 0.18 kg of sucrose fatty acid ester was added over 1 minute. After stirring for 1 minute, a mixture of 1.80 kg of purified sucrose ground product, 0.60 kg of carmellose sodium, 1.20 kg of aspartame, 0.60 kg of acesulfame potassium and 0.006 kg of thaumatin was added over 1 minute. After stirring for 6 minutes, the mixture was passed through a 20 mesh sieve to obtain a granular granulated powder. To the obtained granular granulated powder, a 20-mesh sieved product was added, and the mixture was stirred for 5 minutes at a stirring speed of 15 rpm using a 650 L box stirrer. Further, 0.30 kg of hydrous silicon dioxide and 0.06 kg of flavoring agent were added, and the mixture was stirred for 15 minutes at a stirring speed of 15 rpm using a 650 L box stirrer to obtain a granular solid preparation.

Example 8a
30.8 kg of refined white sugar was charged into a rolling fluidized granulation coating device (multiplex MP-200; POWREC Co., Ltd.) set at a jacket temperature of 80 ° C. Cefteram pivoxil 16.0 kg, sucrose fatty acid ester with stirring at 110 rpm A mixture of 7.02 kg, crospovidone 1.50 kg and colorant 0.0048 kg was added over 20 minutes. After stirring for 4 minutes, 0.18 kg of sucrose fatty acid ester was added over 1 minute. After stirring for 1 minute, a mixture of 1.80 kg of purified white sugar ground product, 0.60 kg of carmellose sodium, 1.20 kg of aspartame, 0.60 kg of acesulfame potassium, 0.006 kg of thaumatin and 0.0006 kg of colorant was added over 1 minute. After stirring for 6 minutes, the mixture was passed through a 20 mesh sieve to obtain a granular granulated powder. To the obtained granular granulated powder, a 20-mesh sieved product was added, and the mixture was stirred for 5 minutes at a stirring speed of 15 rpm using a 650 L box stirrer. Further, 0.30 kg of hydrous silicon dioxide and 0.06 kg of flavoring agent were added, and the mixture was stirred for 15 minutes at a stirring speed of 15 rpm using a 650 L box stirrer to obtain a granular solid preparation.

Example 9a
Charge 31.1kg of refined sucrose to a rolling fluidized granulation coating device (multiplex MP-200; Pauleck Co., Ltd.) set at a jacket temperature of 79 ° C, and 16.0 kg of cefteram pivoxil, sucrose fatty acid ester with stirring at 110 rpm A mixture of 7.02 kg, crospovidone 1.50 kg and colorant 0.009 kg was added over 26 minutes. After stirring for 5 minutes, a mixture of 1.80 kg of purified sucrose ground product, 0.60 kg of carmellose sodium, 1.05 kg of aspartame, 0.60 kg of acesulfame potassium and 0.003 kg of iron sesquioxide was added over 1 minute. After stirring for 6 minutes, the mixture was passed through a 20 mesh sieve to obtain a granular granulated powder. To the obtained granular granulated powder, a 20-mesh sieved product was added, and the mixture was stirred for 5 minutes at a stirring speed of 15 rpm using a 650 L box stirrer. Further, 0.15 kg of hydrous silicon dioxide, 0.15 kg of aspartame, 0.006 kg of thaumatin and 0.06 kg of flavoring agent were added and stirred for 15 minutes at a stirring speed of 15 rpm using a 650 L box stirrer to obtain a granular solid preparation.

Example 10a
388 g of purified white sugar was charged into a tumbling fluidized granulation coating device set at a jacket temperature of 80 ° C, and a mixture of 174 g of cefteram pivoxil, 130 g of sucrose fatty acid ester and 24.8 g of sucrose fatty acid was applied for 8 minutes while stirring at a rotation speed of 250 rpm. Added. Further, a mixture of 3.1 g of sucrose fatty acid ester, 40.3 g of purified white sugar pulverized product and 14.7 g of carmellose sodium was added over 1 minute, stirred, and then passed through a 20 mesh sieve to obtain a granular solid preparation.

Example 11a
Add 10.7g of purified sucrose to a mortar set at a temperature of 90-105 ° C, add a mixture of cefditoren pivoxil 5.3g, sucrose fatty acid ester 3.4g and crospovidone 0.7g while stirring with a pestle, 20 mesh A granular solid preparation was obtained by passing through a sieve.

Comparative Example 1a
A mixture of 8.3 g of cefteram pivoxil, 5.3 g of sucrose fatty acid ester and 0.8 g of carmellose calcium was added to a mortar heated to 80 ° C. with 10.1 g of purified white sugar and stirred with a pestle. Further, a mixture of 0.1 g of sucrose fatty acid ester and 0.5 g of crystalline cellulose / carmellose sodium was added and stirred, and then passed through a 20 mesh sieve to obtain a granular solid preparation.

Comparative Example 2a
A mixture of 2.7 g of cefteram pivoxil, 0.7 g of sucrose fatty acid ester and 0.3 g of carmellose calcium was added while stirring 3.6 g of purified white sugar in a mortar heated to 80 ° C. The resulting mixture was a mixture of granulated powder consisting of cefteram pivoxil, sucrose fatty acid ester and carmellose calcium, and purified white sugar with almost no coating layer.

Comparative Example 3a
389g of refined sucrose was charged into a tumbling fluidized granulation coating device set at a jacket temperature of 80 ° C, and a mixture of 288g cefteram pivoxil, 71g sucrose fatty acid ester and 27.1g carmellose calcium was stirred for 12 minutes while stirring at 250rpm. Added over time. After stirring for 11 minutes, the mixture was passed through a 20 mesh sieve to obtain a granular solid preparation.

Comparative Example 4a
298 g of refined sucrose was charged into a tumbling fluidized granulation coating apparatus set at a jacket temperature of 80 ° C., and 8 g of a mixture of 287 g of cefteram pivoxil, 164 g of sucrose fatty acid ester and 27.1 g of carmellose calcium was stirred with a rotation speed of 350 rpm. Added over a minute. After stirring for 4 minutes, the mixture was passed through a 20 mesh sieve to obtain a granular solid preparation.

In Examples 1a to 11a and Comparative Examples 1a, 3a and 4a, drug granules were obtained. On the other hand, in Comparative Example 2a, no drug granules were obtained.

Tables 1 to 3 show a list of prescriptions for Examples and Comparative Examples.

Table 4 shows the content (%) of the hot-melt substance with respect to the mass of the drug granules and the content (%) of the cephalosporin ester with respect to the mass of the granular solid preparation.

Example 1b
Add 40.2 parts of colored sukurene to a mortar set to 90-98 ° C and add a mixture of 33 parts of cefteram pivoxil, 16 parts of sucrose fatty acid ester and 3.2 parts of crospovidone while stirring with a pestle. Manufactured. Further, a mixture of 0.4 part of sucrose fatty acid ester, 5.2 parts of purified white sugar pulverized product and 2.0 parts of crystalline cellulose / carmellose sodium was added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.

Example 2b
In the same manner as in Example 1b, a granular granulated powder was produced using 40.2 parts of colored skraine, 33 parts of cefteram pivoxil, 16 parts of sucrose fatty acid ester and 3.2 parts of carmellose calcium. Furthermore, 0.4 part of sucrose fatty acid ester, 5.2 parts of purified white sugar pulverized product and 2.0 parts of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.

Example 3b
In the same manner as in Example 1b, a granular granulated powder was produced using 40.2 parts of colored skrane, 33 parts of cefteram pivoxil, 16 parts of sucrose fatty acid ester and 3.2 parts of croscarmellose sodium. Furthermore, 0.4 part of sucrose fatty acid ester, 5.2 parts of purified white sugar pulverized product and 2.0 parts of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.

Example 4b
38.6 parts of colored skrene is charged into a tumbling fluidized granulation coating apparatus set at a jacket temperature of 85 ° C, and granulated using 34.3 parts of cefteram pivoxil, 16.4 parts of sucrose fatty acid ester and 3.2 parts of carmellose calcium while stirring at 250 rpm. Granules were produced. Further, 0.4 parts of sucrose fatty acid ester, 5.2 parts of purified white sugar pulverized product and 1.9 parts of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.

Example 5b
In the same manner as in Example 4b, a granular granulated powder was produced using 38.6 parts of colored skraine, 34.3 parts of cefteram pivoxil, 16.4 parts of sucrose fatty acid ester and 3.2 parts of crospovidone. Further, 0.4 parts of sucrose fatty acid ester, 5.2 parts of purified white sugar pulverized product and 1.9 parts of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.

Example 6b
In the same manner as in Example 4b, a granular granulated powder was produced using 38.6 parts of colored skraine, 34.3 parts of cefteram pivoxil, 16.4 parts of sucrose fatty acid ester and 3.2 parts of croscarmellose sodium. Further, 0.4 parts of sucrose fatty acid ester, 5.2 parts of purified white sugar pulverized product and 1.9 parts of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.

Example 7b
48.8 parts of colored skrene is charged into a tumbling fluidized granulation coating apparatus set at a jacket temperature of 80 ° C., and stirred with 350 rpm, granulated using 26 parts of cefteram pivoxil, 11.2 parts of sucrose fatty acid ester and 2.4 parts of carmellose calcium A granulated powder was produced. Further, 0.3 part of sucrose fatty acid ester, 3.9 parts of purified white sugar pulverized product and 2.9 parts of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular composition. 2 parts of aspartame, 1 part of acesulfame potassium, 1 part of sucralose (sucralose; Saneigen FFI), 0.01 part of thaumatin, 0.5 part of hydrous silicon dioxide and 0.1 part of flavoring agent are added to the obtained granular composition. To obtain a granular solid preparation.

Example 8b
In the same manner as in Example 7b, a granular granulated powder was produced using 48.8 parts of colored skraine, 26 parts of cefteram pivoxil, 11.2 parts of sucrose fatty acid ester and 2.4 parts of crospovidone. Further, 0.3 part of sucrose fatty acid ester, 3.9 parts of purified white sugar pulverized product and 2.9 parts of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular composition. To the obtained granular composition, aspartame 2 parts, acesulfame potassium 1 part, sucralose 1 part, thaumatin 0.01 part, hydrous silicon dioxide 0.5 part and flavoring agent 0.1 part were added and mixed to obtain a granular solid preparation .

Example 9b
Charge 51.8 parts of refined sucrose to a tumbling fluidized granulation coating device (multiplex MP-200; Pauleck Co., Ltd.) set at a jacket temperature of 79 ° C. While stirring at 110 rpm, 26.6 parts of cefteram pivoxil and sucrose fatty acid ester 11.7 Particulate, 2.5 parts of crospovidone and 0.015 part of colorant were used to produce a granular granulated powder. Further, 3.0 parts of purified sucrose pulverized product, 1 part of carmellose sodium, 1.75 parts of aspartame, 1 part of acesulfame potassium and 0.005 part of coloring agent were added and stirred, and passed through a 20 mesh sieve. Further, 0.25 part of aspartame, 0.01 part of thaumatin, 0.25 part of hydrous silicon dioxide and 0.1 part of flavoring agent were mixed to obtain a granular solid preparation.

Example 10b
A mixture of 20.0 parts of cefteram pivoxil, 16.8 parts of sucrose fatty acid ester, and 3.2 parts of crospovidone is charged into a rolling fluidized granulation coating apparatus set at a jacket temperature of 80 ° C. with stirring at a rotational speed of 250 rpm. Was added over 8 minutes. Further, a mixture of 0.4 part of sucrose fatty acid ester, 5.2 parts of purified sucrose pulverized product and 1.9 parts of carmellose sodium was added over 1 minute and stirred, and then passed through a 20 mesh sieve to obtain a granular solid preparation.

Example 11b
40.5 parts of refined sucrose is charged into a tumbling fluidized granulation coating apparatus set at a jacket temperature of 80 ° C., and a mixture of 37.1 parts cefteram pivoxil, 11.7 parts sucrose fatty acid ester and 3.2 parts crospovidone while stirring at a rotation speed of 300 rpm. Was added over 10 minutes. Further, a mixture of 0.4 part of sucrose fatty acid ester, 5.2 parts of purified sucrose pulverized product and 1.9 parts of carmellose sodium was added over 1 minute and stirred, and then passed through a 20 mesh sieve to obtain a granular solid preparation.

Comparative Example 1b
In the same manner as in Example 1b, a granulated product was prepared using 40.2 parts of colored skrane, 33 parts of cefteram pivoxil, 16 parts of sucrose fatty acid ester and 3.2 parts of low-substituted hydroxypropylcellulose (L-HPC LH-11; Shin-Etsu Chemical Co., Ltd.). Granules were produced. Furthermore, 0.4 parts of sucrose fatty acid ester, 5.2 parts of purified white sugar pulverized product and 2.0 parts of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.

Comparative Example 2b
In the same manner as in Example 1b, a granular granulated powder was produced using 40.2 parts of colored sukurene, 33 parts of cefteram pivoxil, 16 parts of sucrose fatty acid ester and 3.2 parts of sodium carboxymethyl starch (Primogell; DMV Japan). Furthermore, 0.4 parts of sucrose fatty acid ester, 5.2 parts of purified white sugar pulverized product and 2.0 parts of crystalline cellulose / carmellose sodium were added and stirred, and passed through a 20 mesh sieve to obtain a granular solid preparation.

Tables 5 and 6 show a list of prescriptions for Examples and Comparative Examples.

Examples 1b-11b are formulations containing a disintegrant selected from crospovidone, carmellose calcium and croscarmellose sodium.
Comparative Examples 1b and 2b are preparations containing a disintegrant selected from low-substituted hydroxypropylcellulose and sodium carboxymethyl starch.
Examples 7b to 9b are preparations containing a disintegrant selected from crospovidone and carmellose calcium and further added with various sweeteners.

Example 1c
777 g of refined white sugar was charged into a tumbling fluidized granulation coating device set at a jacket temperature of 80 ° C, and a mixture of 399 g of cefteram pivoxil, 176 g of sucrose fatty acid ester, 37.5 g of crospovidone and 0.22 g of colorant was stirred at 300 rpm. This was added to produce a granular granulated powder. Further, a mixture of purified sucrose pulverized product 45.0 g, carmellose sodium 15.0 g and colorant 0.08 g was added and stirred, and passed through a 20 mesh sieve to obtain a granular composition. 96.6 g of the obtained granular composition was mixed with 0.25 g of hydrous silicon dioxide, 0.1 g of a flavoring agent and 0.1 g of thaumatin to obtain a granular solid preparation.

Example 2c
In the same manner as in Example 1c, granular granulated powder was produced using purified white sugar 777 g, cefteram pivoxil 399 g, sucrose fatty acid ester 176 g, crospovidone 37.5 g and colorant 0.22 g. Further, 45.0 g of purified sucrose pulverized product, 15.0 g of carmellose sodium and 0.08 g of colorant were added and stirred, and passed through a 20 mesh sieve to obtain a granular composition. 96.6 g of the obtained granular composition was mixed with 0.25 g of hydrous silicon dioxide, 0.1 g of flavoring agent, and 0.01 g of thaumatin to obtain a mixed powder. 48.5 g of the obtained mixed powder, 0.5 g of acesulfame potassium, 0.5 g of aspartame and 0.0285 g of thaumatin were mixed to obtain a granular solid preparation.

Comparative Example 1c
In the same manner as in Example 1c, granular granulated powder was produced using purified white sugar 777 g, cefteram pivoxil 399 g, sucrose fatty acid ester 176 g, crospovidone 37.5 g and colorant 0.22 g. Further, 45.0 g of purified sucrose pulverized product, 15.0 g of carmellose sodium and 0.08 g of colorant were added and stirred, and passed through a 20 mesh sieve to obtain a granular composition. 96.6 g of the obtained granular composition was mixed with 0.25 g of hydrous silicon dioxide and 0.1 g of a flavoring agent to obtain a granular solid preparation.

Comparative Example 2c
In the same manner as in Example 1c, granular granulated powder was produced using purified white sugar 777 g, cefteram pivoxil 399 g, sucrose fatty acid ester 176 g, crospovidone 37.5 g and colorant 0.22 g. Further, 45.0 g of purified sucrose pulverized product, 15.0 g of carmellose sodium and 0.08 g of colorant were added and stirred, and passed through a 20 mesh sieve to obtain a granular composition. 87.0 g of the obtained granular composition was mixed with 0.23 g of hydrous silicon dioxide, 0.09 g of flavoring agent, 1.35 g of acesulfame potassium and 1.35 g of aspartame to obtain a granular solid preparation.

Table 7 shows a list of prescriptions for Examples and Comparative Examples.

In Example 2c and Comparative Example 2c, the amount of the sweetening agent was set so that the sum of the products of the mass percentage and the sweetness degree of each sweetening agent was equal.
The sweetness degree is an index of the sweetness of the sweetener and is a value obtained by comparing the sweetness of the sweetener based on the sweetness of sucrose.

Test Example 1a (1) Initial solubility The preparations obtained in Examples 1a to 10a and Comparative Example 3a were used as test preparations.
A test preparation containing 50 mg of cefteram pivoxil was accurately weighed, placed in a 10 mL Spitz tube, added with 10 mL of distilled water, and stirred with a vortex mixer for 20 seconds. 1 mL of the resulting suspension was collected and filtered through a filter (Millex-LH, hydrophilic polytetrafluoroethylene (PTFE), pore diameter 0.45 μm, diameter 25 mm; Merck Millipore). The concentration of cefteram pivoxil in the obtained filtrate was measured under the following conditions.

Measurement condition detector: UV absorption photometer Measurement wavelength: 254nm
Column: COSMOSIL 4.6 × 150mm 5C18 (Nacalai Tesque)
Precolumn: Develosil ODS-UG-5 4.0 × 10mm (Nomura Chemical)
Column temperature: 25 ° C
Mobile phase: water / acetonitrile / pH 5.0 acetic acid / sodium acetate buffer (Japanese Pharmacopoeia) (525: 375: 100)
Flow rate: 1.4mL / min

Test Example 1a (2) Initial solubility The preparation obtained in Example 11a was used as a test preparation.
A test preparation containing 50 mg of cefditoren pivoxil was accurately weighed, placed in a 10 mL Spitz tube, added with 10 mL of distilled water, and stirred with a vortex mixer for 20 seconds. 1 mL of the resulting suspension was collected and filtered through a filter (Millex-LH, hydrophilic polytetrafluoroethylene (PTFE), pore diameter 0.45 μm, diameter 25 mm; Merck Millipore). The cefditoren pivoxil concentration in the obtained filtrate was measured under the following conditions.

Measurement condition detector: UV absorption photometer Measurement wavelength: 231nm

The results are shown in Table 8.

The preparations of Examples 1a to 11a had sufficiently low initial solubility, which is an index for feeling bitterness when taken, and showed excellent takeability. On the other hand, it was estimated that the granular solid preparation of Comparative Example 3a, in which the content of the hot-melt substance in the drug granules is 10% or less, has a high initial solubility and is easy to feel a bitter taste when taken.

Test Example 1b Initial solubility The preparations obtained in Examples 1b to 11b were used as test preparations.
The test was performed in the same manner as in Test Example 1a (1).
The results are shown in Table 9.

The preparations obtained in Examples 1b to 11b had sufficiently low initial solubility as an index for feeling bitterness at the time of taking, and showed excellent takeability.

Test Example 2a Dissolution Test The preparations obtained in Examples 4a to 10a, Comparative Example 1a and Comparative Example 4a were used as test preparations.
(1) Formulations obtained in Examples 4a to 6a and Comparative Example 1a 0.75 g of a test formulation containing 200 mg of cefteram was accurately weighed, and 900 mL of dissolution test 1st solution was used as the test solution. The dissolution test was carried out at 37 ° C. and 50 rpm according to the dissolution test method 2 (paddle method). After 15 minutes, take the test solution, filter with a membrane filter (full flow filter, polyvinylidene difluoride (PVDF), pore size 35μm; Lab ECX), and elution with UV-Vis absorbance method <Japan General Test Method 2.24> The rate (unit:%) was measured.

(2) Formulations obtained in Examples 7a to 10a and Comparative Example 4a 0.5 g of the test formulation containing 100 mg of cefteram was accurately weighed, and 900 mL of dissolution test 1st solution was used as the test solution. The dissolution test was conducted at 37 ° C. and 50 rpm in accordance with the dissolution test method 2 (paddle method). After 15 minutes, take the test solution, filter with a membrane filter (full flow filter, polyvinylidene difluoride (PVDF), pore size 35 μm; Lab ECX), and elution rate according to UV-Vis absorbance method <Japan General Test Method 2.24> (Unit:%) was measured.
Table 10 shows the results of (1) and (2).

The preparations of Examples 4a to 10a had an elution rate of 15% or more after 15 minutes and exhibited extremely rapid dissolution. On the other hand, the preparations of Comparative Examples 1a and 4a, in which the content of the hot melt substance in the drug granules is 20% or more, did not show rapid dissolution.

Test Example 2b Dissolution Test The preparations obtained in Examples 1b to 11b and Comparative Example 2b were used as test preparations.
The test was performed in the same manner as in Test Example 2a.
The results are shown in Table 11.

The preparations of Examples 1b to 11b all showed an elution rate of 85% or more after 15 minutes. These preparations greatly exceeded 85%, which is an excellent dissolution standard, and showed extremely good dissolution properties with respect to the preparation of Comparative Example 2b.

Test Example 3 Stability Test The preparations obtained in Examples 1b to 3b and Comparative Examples 1b and 2b were used as test preparations.
10 g of the test preparation was placed in a glass bottle and stored at 40 ° C. Three months after the start of the test, the residual rate of cefteram pivoxil of each test preparation was measured.
Further, the initial solubility and dissolution rate of each preparation were measured in the same manner as in Test Example 1a (1) and Test Example 2a.

0.75 g (containing 200 mg as cefteram) of the test preparation at the start of the test and 3 months after the start of the test was accurately weighed, and an acetonitrile aqueous solution was added to make exactly 200 mL. The particles were dispersed by sonication, and then filtered using a membrane filter (Millex-LH, hydrophilic polytetrafluoroethylene (PTFE), pore size 0.45 μm, diameter 25 mm; Merck Millipore), and the resulting filtrate The content of cefteram pivoxil was measured by high performance liquid chromatography under the same measurement conditions as in Test Example 1a.
As the acetonitrile aqueous solution, water was added to 1000 mL of acetonitrile to make 2000 mL as a whole.
From the measured content rate, the residual rate (%) was determined by the following equation.
Residual rate (%) = (content rate of cefteram pivoxil 3% after the start of the test (%) / content rate of cefteram pivoxil at the start of the test (%)) × 100
The results are shown in Table 12.

The preparations of Examples 1b to 3b had a residual rate of 95% or more, sufficiently low initial solubility, and an elution rate of 96% or more, which was excellent in storage stability. On the other hand, the preparations of Comparative Examples 1b and 2b had a residual rate of less than 95% and did not show sufficient stability.

Test Example 4a Stability test The preparations obtained in Examples 4a to 6a, 8a and 9a were used as test preparations.
100 g of the preparations of Examples 4a to 6a and 7.5 g of desiccant (made of zeolite) were placed in a plastic bottle (body: HDPE; cap: PP) and stored at 40 ° C. and 75% RH.
100 g of the preparations of Examples 8a and 9a and 15 g of desiccant (made of zeolite) were placed in a plastic bottle and stored at 40 ° C. and 75% RH.
The initial solubility of each test preparation 3 months after the start of the test and the residual rate 3 months after the start of the test were measured. Further, the initial solubility and dissolution rate of each preparation were measured in the same manner as in Test Example 1a (1) and Test Example 2a.

The results are shown in Table 13.

The preparations of Examples 4a to 6a, 8a, and 9a had a residual rate of 97% or more, sufficiently low initial solubility, and an elution rate of 84% or more, and were excellent in storage stability.

Test Example 4b Stability Test The preparations obtained in Examples 4b to 9b were used as test preparations.
In the same manner as in Test Example 4a, the residual rate, initial solubility and dissolution rate of cefteram pivoxil of each preparation were measured.
The results are shown in Table 14.

The preparations of Examples 4b to 9b had a residual ratio of 95% or more and were excellent in storage stability. Further, the initial solubility was sufficiently low, the elution rate was 85% or more, and the storage stability was excellent.

Test Example 5a Stability test The preparations obtained in Examples 8a and 9a were used as test preparations.
100 g of the test preparation and 15 g of a desiccant (made of zeolite) were placed in a plastic bottle (body: HDPE; cap: PP) and stored at 40 ° C. and 75% RH for 6 months. Six months after the start of the test, the residual rate, dissolution rate, and initial solubility of cefteram pivoxil of each preparation were measured.
The results are shown in Table 15.

The preparations of Examples 8a and 9a had a residual rate of 97% or more, sufficiently low initial solubility, and an elution rate of 95% or more, which was excellent in storage stability.

Test Example 5b Stability test The preparations obtained in Examples 8b and 9b were used as test preparations.
In the same manner as in Test Example 5a, the residual rate, initial solubility and dissolution rate of cefteram pivoxil of each preparation were measured.
The results are shown in Table 16.

The preparations of Examples 8b and 9b had a residual rate of 97% or more, sufficiently low initial solubility, and an elution rate of 95% or more, which was excellent in storage stability.

Test Example 6c Taste sensory test for bitterness (1)
A taste sensory test was conducted on five panelists. As the test preparation, the preparation of Example 1c and the preparation of Comparative Example 1c were used.
The panelist contained 0.5 g of the first test preparation in the mouth for 30 seconds, and evaluated the bitterness at the time of taking and after taking it using the following scores. 15 minutes after taking the first preparation, and after the taste in the mouth disappeared, the second preparation was taken and evaluated in the same manner.

<Evaluation criteria>
5 Feel no bitterness 4 Slightly perceive bitterness 3 Feel a little bitterness 2 Feel bitterness 1 Feel intense bitterness

The results of the average score of 5 panelists are shown in Table 17 and FIG.

Both the preparations of Example 1c and Comparative Example 1c had the same score when taken. In the preparation of Comparative Example 1c, the score after taking was lowered and the bitterness remaining in the mouth was strong, whereas in the preparation of Example 1c, the score after taking was not lowered and the bitterness was reduced significantly. .

Test Example 7c Taste sensory test for bitterness (2)
A taste sensory test was conducted on 15 panelists in the same manner as in Test Example 6c. As the test preparation, the preparation of Example 2c and the preparation of Comparative Example 2c were used.

In Comparative Example 2c containing assulfame potassium and aspartame as sweeteners, a significant decrease in the score after taking was observed from the time of taking, and the bitter taste remaining in the mouth after taking the preparation could not be reduced. On the other hand, in Example 2c blended with thaumatin, although the sweetness level of the whole granular solid preparation was the same as in Comparative Example 2c, the score after taking from the time of taking did not decrease, and the mouth after taking the preparation Residual bitterness was significantly reduced.

The granular solid preparation of the present invention is a preparation containing a cephalosporin ester having a high drug content, excellent stability and dissolution, and reduced bitterness, and has improved compliance with children and / or the elderly. Useful as a formulation.

The scores at the time of and after taking the preparations of Example 1c and Comparative Example 1c in the taste sensory test (1) (Test Example 6c) are shown.

Claims

(1) a core substance, and (2) a drug-containing layer that coats the core substance,
A granular solid preparation containing drug granules containing
The drug-containing layer includes a cephalosporin ester and a hot melt material,
The content of hot melt material is 10-20% with respect to the mass of drug granules,
A granular solid preparation having a cephalosporin ester content of 20 to 40% based on the mass of the granular solid preparation.
The granular solid preparation according to claim 1, wherein the content of the hot-melt material is 11 to 18% with respect to the mass of the drug granule.
The hot-melt material is one or more selected from hydrogenated oil, higher alcohol, higher fatty acid, wax, vegetable or animal fat, ethylene oxide polymer, and fatty acid ester of sugar or glycerin. The granular solid preparation described in 1.
The granular solid preparation according to claim 1 or 2, wherein the hot-melt material is a sucrose fatty acid ester.
The granular solid preparation according to any one of claims 1 to 4, wherein the cephalosporin ester is cefteram pivoxil, cefcapene pivoxil or cefditoren pivoxil.
The granular solid preparation according to any one of claims 1 to 4, wherein the cephalosporin ester is cefteram pivoxil.
The granular solid preparation according to any one of claims 1 to 6, wherein the drug-containing layer further comprises one or more disintegrants selected from crospovidone, carmellose calcium and croscarmellose sodium.
The granular solid preparation according to claim 7, wherein the disintegrant is one or two selected from crospovidone and carmellose calcium.
The granular solid preparation according to claim 7, wherein the disintegrant is crospovidone.
The granular solid preparation according to any one of claims 1 to 9, further comprising thaumatin.
The granular solid preparation according to claim 10, further comprising one or more sweeteners selected from sucrose, aspartame, neotame, saccharin, sodium saccharin, stevia, sucralose, trehalose, erythritol, sorbitol, xylitol and acesulfame potassium. .
The granular solid preparation according to claim 11, wherein the sweetener is one or more selected from sucrose, aspartame and acesulfame potassium.
The granular solid preparation according to any one of claims 1 to 12, wherein the granular solid preparation is a powder, fine granules, granules, or dry syrup.
(1) a core substance, and (2) a drug-containing layer that coats the core substance,
A method for producing a granular solid preparation containing a drug granule comprising
The drug-containing layer includes a cephalosporin ester and a hot melt material,
The content of hot melt material is 10-20% with respect to the mass of drug granules,
The content of cephalosporin ester is 20-40% with respect to the mass of the granular solid preparation,
A production method comprising coating a core substance with a powder containing a cephalosporin ester and a hot-melt substance, and forming a drug-containing layer on the surface of the core substance.
The production method according to claim 14, wherein the content of the hot-melt substance is 11 to 18% with respect to the mass of the drug granule.
The hot-melt material is one or more selected from hydrogenated oil, higher alcohol, higher fatty acid, wax, vegetable or animal fat, ethylene oxide polymer, and fatty acid ester of sugar or glycerin. The manufacturing method as described in.
The production method according to claim 14 or 15, wherein the hot-melt material is a sucrose fatty acid ester.
The production method according to any one of claims 14 to 17, wherein the cephalosporin ester is cefteram pivoxil, cefcapene pivoxil, or cefditoren pivoxil.
The production method according to any one of claims 14 to 17, wherein the cephalosporin ester is cefteram pivoxil.
The production method according to any one of claims 14 to 19, wherein the drug-containing layer further comprises one or more disintegrants selected from crospovidone, carmellose calcium and croscarmellose sodium.
The production method according to claim 20, wherein the disintegrant is one or two selected from crospovidone and carmellose calcium.
The production method according to claim 20, wherein the disintegrant is crospovidone.
The production method according to any one of claims 14 to 22, further comprising forming a layer containing thaumatin to coat the drug-containing layer.
The production method according to claim 23, wherein the layer containing thaumatin contains a sweetener.
The production method according to claim 24, wherein the sweetener is one or more selected from sucrose, aspartame, neotame, saccharin, sodium saccharin, stevia, sucralose, trehalose, erythritol, sorbitol, xylitol, and acesulfame potassium.
The production method according to claim 24, wherein the sweetener is one or more selected from sucrose, aspartame, and acesulfame potassium.
The production method according to any one of claims 14 to 26, wherein the granular solid preparation is a powder, a fine granule, a granule or a dry syrup.