JP2009019054A - Dry syrup preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a dry syrup preparation of L-carbocysteine in which the sourness inherent to L-carbocysteine can be improved by a simpler production method, which can be relatively easily dispensed, is conveniently carried with, can be easily taken as it is, can be taken by suspending or dissolving before using the same and can be administered to subjects over a wide range from infants to the aged. <P>SOLUTION: The syrup preparation having relieved sourness of L-carbocysteine has been finished in a more convenient production process by blending a sugar alcohol and a sweetener with high sweetness. The syrup preparation of L-carbocysteine thus obtained can be relatively easily dispensed, is conveniently carried with, can be easily taken as it is, can be taken by suspending or dissolving before using the same and can be administered to subjects over a wide range from infants to the aged. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a dry syrup that reduces the acidity of L-carbocysteine, is convenient for prescription and carrying, and can be taken as it is or suspended or dissolved in water.

L-carbocysteine normalizes the content ratio of various mucins contained in the airway mucosa and lowers the viscosity of mucus. In addition, by repairing mucosal epithelium such as ciliated cells, the mucociliary transport system is improved and the excretion of the reservoir is promoted. Based on these actions, this drug has been found to be effective for expectoration of various respiratory diseases, drainage of chronic sinusitis, and drainage of exudative otitis media.
L-carbocysteine preparations include tablets, fine granules, suspension syrups, and syrups.

In general, liquid preparations such as syrups are inconvenient for a patient to carry, as well as being troublesome in dispensing operations at pharmacies and hospitals as compared to solid preparations. On the other hand, solid preparations are difficult to take for children and elderly people with weak swallowing ability. It is desired to develop a preparation that improves such points and is more excellent in ingestion and convenient for prescription and carrying.
Also, since L-carbocysteine has a strong acidity, to reduce this acidity, a large amount of saccharide is added to L-carbocysteine, or granules containing L-carbocysteine are subjected to special processing such as coating. There was a need. For this reason, preparations containing a large amount of saccharide increase the production and packaging costs, and increase the dose at one time, which is inconvenient for taking, dispensing, and carrying. In addition, the preparation with coating has a medical economic problem that the manufacturing process becomes complicated and the manufacturing cost increases.

The present inventors reduce the acidity of L-carbocysteine in a simpler manufacturing process without special processing such as coating on granules containing L-carbocysteine, and are convenient for taking, dispensing and carrying, A dry syrup preparation was completed that could be taken as it is or suspended or dissolved in water.
That is, the present invention is one or two selected from the group consisting of sugar alcohol, high-intensity sweetener, binder, flavoring agent, lubricant, preservative and carboxymethyl starch sodium, croscarmellose sodium and crospovidone. By blending more than one type of disintegrant, a dry syrup preparation that achieves a reduction in the acidity of L-carbocysteine by a simple production process that does not require special processing such as coating is provided.
The dry syrup of L-carbocysteine thus obtained can be dispensed with relatively easily, is convenient to carry, is easy to take as it is, and can be suspended or dissolved in water during use. It is a preparation that can be taken from children to the elderly.

  The sugar alcohol used in the present invention is a polyhydric alcohol obtained by reducing a carbonyl group of a sugar molecule. Examples thereof include mannitol, sorbitol, maltitol, powdered reduced maltose water candy, erythritol, xylitol and the like. Two or more of these sugar alcohols may be used.

  The high-intensity sweetener used in the present invention is a sweetener having a sweetness level 10 times or more that of sucrose. Examples include aspartame, saccharin and salts thereof, glycyrrhizic acid and glycyrrhizic acid salts such as dipotassium glycyrrhizinate, acesulfame potassium, stevia and the like. Two or more kinds of these high-intensity sweeteners may be used.

  The production method in the present invention is not particularly limited, and any known method such as fluidized bed granulation method, stirring granulation method, high speed stirring granulation method, rolling fluidized bed granulation method, and dry granulation method may be used. Can be manufactured.

  In the present invention, pharmaceutical additives such as binders, excipients, disintegrants, flavoring agents, lubricants, and coloring agents are optionally added for the purpose of further enhancing the ingestion and commercial value. can do. These additives may be used alone or in combination of two or more.

  The binder that can be optionally blended is not particularly limited as long as it can be used as a pharmaceutical additive. For example, polyvinyl pyrrolidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), gum arabic powder, polyvinyl alcohol, methyl cellulose, gelatin, pullulan and the like can be mentioned. Two or more of these may be used. Preferred examples of the binder include polyvinyl pyrrolidone and hydroxypropyl cellulose.

  There are no particular limitations on the disintegrant that can be optionally blended as long as it can be used as a pharmaceutical additive. The disintegrant acts as a suspending agent that enhances the dispersibility of L-carbocysteine when the dry syrup according to the present invention is prepared as a suspension. For example, crystalline cellulose, hydroxypropyl starch, carmellose, carmellose calcium, carmellose sodium, potato starch, corn starch, low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium, carboxymethyl starch sodium, etc. . Two or more of these may be used. Preferred disintegrants include crospovidone, croscarmellose sodium, and sodium carboxymethyl starch.

The flavoring agent that can be optionally blended is not particularly limited as long as it can be used as a pharmaceutical additive. For example, orange extract, orange oil, orange essence, spearmint oil, mint oil, vanilla flavor, lemon oil, l-menthol, peach flavor, grapefruit flavor, strawberry essence and the like can be mentioned.

  The lubricant that can be optionally blended is not particularly limited as long as it can be used as a pharmaceutical additive. Examples thereof include hydrous silicon dioxide, corn starch, sucrose fatty acid ester, stearic acid and its salts, fumaric acid, sodium stearyl fumarate, talc, polyethylene glycol and the like.

  The colorant that can be optionally blended is not particularly limited as long as it can be used as a pharmaceutical additive. For example, iron sesquioxide, yellow iron sesquioxide, caramel, etc. can be mentioned.

  When the dry syrup according to the present invention is prepared as a suspension or solution, a solubilizer pharmaceutical additive can be optionally blended for the purpose of further enhancing the solubility of L-carbocysteine.

The solubilizer that can be optionally blended is not particularly limited as long as it can be used as a pharmaceutical additive. For example, anhydrous sodium citrate, sodium citrate, sodium hydroxide, sodium hydrogen carbonate, sodium hydrogen carbonate, sodium hydrogen phosphate, anhydrous disodium phosphate, trisodium phosphate and the like can be mentioned. Two or more of these may be used.
In some cases, preservatives that can be used as pharmaceutical additives such as sodium benzoate, sodium dehydroacetate, and potassium sorbate can be added. Furthermore, excipients such as partially pregelatinized starch can be blended.

  EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

  L-Carbocysteine 250 g was mixed with powdered reduced maltose water candy 402 g, croscarmellose sodium 37.5 g, carboxymethyl starch sodium 15 g, sodium benzoate 3 g, aspartame 11.25 g, yellow iron sesquioxide 0.5 g, 112.5 g of a solution obtained by dissolving 11.25 g of hydroxypropyl cellulose in 95% ethanol was added and kneaded with a speed kneader (NSK-250 type, manufactured by Okada Seiko Co., Ltd.), and then a pelleter (EXKS-1 type, Fuji Powder Co., Ltd.) And granulated by extrusion. The obtained granulated product was dried with a ventilation dryer (30C type, manufactured by Fuji Powder Co., Ltd.) and sized with a sieve having an opening of 500 μm to obtain granules. To this granule, 15 g of hydrous silicon dioxide and 0.75 g of grapefruit flavor were added and mixed to obtain a dry syrup preparation.

  250 g L-carbocysteine, 450 g powdered reduced maltose water candy, 200.75 g erythritol, 37.5 g croscarmellose sodium, 15 g sodium carboxymethyl starch, 3 g sodium benzoate, 2.5 g sodium saccharin, 5 g dipotassium glycyrrhizinate, yellow three After taking 0.5 g of iron dioxide and mixing, 112.5 g of a solution obtained by dissolving 11.25 g of hydroxypropylcellulose in 95% ethanol was added and kneaded by a speed kneader (NSK-250 type, manufactured by Okada Seiko Co., Ltd.) Extrusion granulation was performed with a pelleter (EXKS-1 type, manufactured by Fuji Powder Corporation). The obtained granulated product was dried with a ventilation dryer (30C type, manufactured by Fuji Powder Co., Ltd.) and sized with a sieve having an opening of 500 μm to obtain granules. To this granule, 20 g of hydrous silicon dioxide and 1 g of grapefruit flavor were added and mixed to obtain a dry syrup preparation.

  After 1750 g of powdered reduced maltose water candy, 112.5 g of croscarmellose sodium, 45 g of sodium carboxymethyl starch, and 9 g of sodium benzoate were mixed with 750 g of L-carbocysteine, 33.75 g of hydroxypropyl cellulose and yellow iron sesquioxide 1. 400 g of a solution obtained by dissolving 5 g in 95% ethanol was added, and the mixture was stirred and granulated with a high speed mixer (FSGS-5 type, manufactured by Fukae Kogyo Co., Ltd.). The obtained granulated product was dried with a ventilation dryer (30C type, manufactured by Fuji Powder Co., Ltd.) and sized with a sieve having an opening of 500 μm to obtain granules. To this granule, 45 g of partially pregelatinized starch, 22.5 g of orange essence and 33.75 g of aspartame were added and mixed to obtain a dry syrup preparation.

  2750 g of powdered reduced maltose water candy, 262.5 g of croscarmellose sodium, 105 g of sodium carboxymethyl starch and 21 g of sodium benzoate were mixed with 1750 g of L-carbocysteine, and then mixed with 78.75 g of hydroxypropylcellulose and yellow iron sesquioxide 3. 952 g of a solution obtained by dissolving 5 g in 70% ethanol was added, and the mixture was stirred and granulated with a high speed mixer (FS-20 type, manufactured by Fukae Kogyo Co., Ltd.). The obtained granulated product was dried with a flow coater (FLO-15 type, manufactured by Freund Sangyo Co., Ltd.) and sized with a sieve having an opening of 500 μm to obtain granules. To this granule, 105 g of partially pregelatinized starch, 5.25 g of orange oil and 78.75 g of aspartame were added and mixed to obtain a dry syrup.

  L-Carbocysteine 4000 g, powdered reduced maltose water candy 6504 g, croscarmellose sodium 600 g, carboxymethyl starch sodium 240 g, sodium benzoate 48 g are taken and fluidized in a flow coater (FLO-15, manufactured by Freund Sangyo Co., Ltd.) 6000 g of a 3% aqueous solution of hydroxypropylcellulose was sprayed and granulated. The obtained granulated product was dried in a flow coater (FLO-15 type, manufactured by Freund Sangyo Co., Ltd.) and then granulated with a sieve having an opening of 500 μm to obtain granules. To this granule, 240 g of partially pregelatinized starch, 12 g of orange oil and 180 g of aspartame were added and mixed to obtain a dry syrup.

  Add 1596 g of powdered reduced maltose water candy, 150 g of croscarmellose sodium, 60 g of sodium carboxymethyl starch, 12 g of sodium benzoate, 45 g of hydroxypropylcellulose, 60 g of partially pregelatinized starch, 3 g of orange oil and 45 g of aspartame to 1000 g of L-carbocysteine After mixing, compression molding was performed with a roller compactor (MINI type, manufactured by Freund Corporation) to obtain flat plate-like flakes. The flakes were pulverized with a roll granulator (CRN-TS54 type, manufactured by Nippon Granulator Co., Ltd.) and then sized with a sieve having an opening of 500 μm to obtain a dry syrup agent.

  L-carbocysteine 15600g was mixed with powdered reduced maltose water candy 19032g, croscarmellose sodium 2340g, sodium carboxymethyl starch 936g, sodium benzoate 187.2g, iron sesquioxide 31.2g, and then hydroxypropylcellulose 499.2g. 7435 g of a solution in 80% ethanol was added, and the mixture was stirred and granulated with a high speed mixer (FS-GS100 type, manufactured by Fukae Kogyo Co., Ltd.). The obtained granulated product was dried with a flow coater (MTT-200F type, manufactured by Freund Sangyo Co., Ltd.) and sized with a sieve having an opening of 500 μm to obtain granules. To this granule, 1653.6 g of anhydrous sodium citrate, 4680 g of powdered reduced maltose water candy, 936 g of partially pregelatinized starch, 3.12 g of strawberry essence, and 936 g of aspartame were added and mixed to obtain a dry syrup preparation.

  178 g of L-carbocysteine, 155.6 g of powdered reduced maltose water candy, 50 g of croscarmellose sodium, 118 g of anhydrous disodium hydrogen phosphate, 53 g of anhydrous sodium citrate, 45 g of sodium dehydroacetate, 14 g of potassium sorbate, 0. 4 g and 270 g of hydrous silicon dioxide were taken and fluidized in a flow coater (FBG-1 type, manufactured by Freund Sangyo Co., Ltd.). After spraying 322 g of L-carbocysteine and 74 g of sodium hydroxide in 304 g of water, polyvinyl A solution obtained by dissolving 52 g of alcohol (partially saponified product) and 3 g of caramel in 465 g of water was sprayed and granulated. The obtained granulated product was dried in a flow coater (FBG-1 type, manufactured by Freund Corporation) to obtain granules. To this granule, 94 g of corn starch, 0.5 g of strawberry essence, 30 g of aspartame, and 10 g of dipotassium glycyrrhizinate were added and mixed to obtain a dry syrup preparation.

  L-carbocysteine was mixed with 15600 g of powdered reduced maltose water candy 19032 g, croscarmellose sodium 2340 g, sodium carboxymethyl starch 936 g, sodium benzoate 187.2 g and iron sesquioxide 31.2 g, and then mixed with 499.2 g of hydroxypropyl cellulose. 7625 g of a solution in 70% ethanol was added and granulated by stirring with a high speed mixer (FS-GS100, manufactured by Fukae Kogyo Co., Ltd.). The obtained granulated product was dried with a flow coater (MTT-200F, manufactured by Freund Sangyo Co., Ltd.) and then sieved to obtain granules. To this granule, 1653.6 g of anhydrous sodium citrate, 4680 g of powdered reduced maltose water candy, 936 g of partially pregelatinized starch, 46.8 g of peach flavor, and 936 g of aspartame were added and mixed to obtain a dry syrup preparation.

(Test Example 1)
Taste and ingestion were examined for the control preparation in which L-carbocysteine, sugar alcohol and high-intensity sweetener were mixed at the following mixing ratio and the preparations of Examples 1-9. Each preparation sample was suspended in water so as to contain 10% L-carbocysteine to prepare a test solution. This solution was taken by healthy adults and subjected to a taste sensory test. The results are shown in Tables 1 and 2.
From the results of this test, it was found that a dry syrup with good taste and excellent ingestibility can be obtained by using L-carbocysteine in combination with a sugar alcohol and a high-intensity sweetener.

(Test Example 2)
For the dry syrups according to the present invention obtained in Examples 3, 4, 5, 6 and 9, 1.5 g each was packaged and packaged with a packaging material consisting of polyethylene terephthalate and aluminum, and 40 ° C / 75% RH. It was stored for 6 months and the residual rate of L-carbocysteine was determined. The results are shown in Table 3. All the examples were stable.

  The present invention provides a dry syrup preparation of L-carbocysteine with reduced acidity of L-carbocysteine, which is easy to take as it is, can be taken even when suspended or dissolved in water, and from children. It can be taken even by elderly people. Further, the L-carbocysteine dry syrup of the present invention is a preparation which can be dispensed relatively easily and is convenient to carry.

Claims (4)

  One or two selected from the group consisting of L-carbocysteine, sugar alcohol, high-intensity sweetener, binder, flavoring agent, lubricant, preservative and carboxymethyl starch sodium, croscarmellose sodium and crospovidone A dry syrup preparation comprising a disintegrant of more than one species.   Powdered reduced maltose syrup as sugar alcohol, aspartame as high sweetener, hydroxypropylcellulose as binder, hydrous silicon dioxide as lubricant, sodium benzoate as preservative, carboxymethyl starch as disintegrant The dry syrup preparation of Claim 1 containing sodium and / or croscarmellose sodium.   The dry syrup preparation according to claim 1 or 2, comprising a granule containing L-carbocysteine, a sugar alcohol and a high-intensity sweetener, or a mixture containing the granule.   3. The dry syrup preparation according to claim 1 or 2, comprising a mixture containing granules containing L-carbocysteine and sugar alcohol and a high-intensity sweetener.