KR20060085173A - Oral formulation for twice-daily administration - Google Patents

Abstract

The present invention provides an oral dosage formulation which can exert the maximum therapeutic effect against pigmentation caused by blotch, freckles, sunburn or skin disease in a formulation containing L-cysteine and ascorbic acid. It relates to a cysteine or a salt thereof and ascorbic acid or a salt thereof, and relates to a twice-daily oral dosage form characterized in that the single dose of L-cysteine is 90 to 150 mg.

Description

ORAL FORMULATION FOR TWICE-DAILY ADMINISTRATION}

The present invention relates to a twice-daily oral dosage form containing L-cysteine or a salt thereof and ascorbic acid or a salt thereof and having an excellent therapeutic effect against pigmentation caused by blotch, freckles, sunburn or skin disease. will be.

L-cysteine (2-Amino-3-mercaptopropionic acid) contains sulfur (S) in the molecule and contains sulfur that acts as a mercapto (SH) group donor in vivo It is one of the amino acids. This L-cysteine is believed to exhibit biochemical action by maintaining or reactivating the activity of the enzyme by the SH group contained in the molecule. In addition, L-cysteine has been applied to the treatment of leukopenia caused by various skin diseases and radiation therapy by normalizing skin metabolism, anti-allergic action, detoxification and the like.

Conventionally, the L-cysteine preparation is a medical drug. For eczema, urticaria, weakness, poisoning, vulgaris, and polymorphic erythema, a dosage of 80 mg of L-cysteine per dose is used 2-3 times a day. It is used. In addition, for leukopenia caused by radiation disorder, a formulation having a dose of 160 mg of L-cysteine per dose is used in three times a day.

On the other hand, in the general-purpose pharmaceutical field, a formulation containing L-cysteine and ascorbic acid is used for pigmentation such as blotch, freckles, sunburn or skin disease, general boredom, hangover, acne, eczema, urticaria, skin disease, weakness, etc. It is used. It is also used for the purpose of spreading vitamin C in old age when bleeding gums, bleeding prevention of nasal bleeding, physical fatigue, pregnancy and lactation, physical illness during illness or after illness. As for the method of taking the former preparation, for example, pigmentation such as blotch, freckles, sunburn, systemic boredom, hangover, acne, eczema, urticaria, skin disease, weakness, the dose of L-cysteine per dose is 80 mg, A formulation in which the dosage of ascorbic acid is 100 mg and the calcium pantothenate 8 mg is used three times a day. In addition, for the purpose of vitamin C dissemination of the old age at the time of scab, freckles, sunburn, pigmentation such as skin disease, gum bleeding, bleeding prevention of nose bleeding, physical fatigue, lowering physical strength during pregnancy, lactation, sickness or after illness, In the formulation of L-cysteine and ascorbic acid, the dosage of L-cysteine is 10-80 mg per dose, and the dosage of 100-500 mg of ascorbic acid is used in one or three times a day. .

By the way, with the formulation of L-cysteine and ascorbic acid, turnover of skin takes time to treat pigmentation caused by blotch, freckles, sunburn or skin disease, etc. Since it requires a period of months, it is necessary to continue taking it in the meantime.

However, in order to take L-cysteine as much as possible, it is necessary to divide L-cysteine 80 mg three times a day by dividing 240 mg three times a day. It is necessary to continue to take the preparation over this long period of three months, and it is easy to forget to take it as a patient in normal social life using a formulation with a large number of daily doses, and L-cysteine These branches did not exhibit the maximum therapeutic effect against pigmentation due to blotch, freckles, sunburn or skin disease. On the other hand, in formulations with fewer than three doses per day, the daily dose of L-cysteine decreases compared to formulations taking 80 mg of L-cysteine three times daily. There was something I could not get enough.

The present invention has been made in view of the above-mentioned phenomenon, and the problem is to maximize the therapeutic effect against pigmentation due to blotch, freckles, sunburn or skin disease in preparations containing L-cysteine and ascorbic acid. It is to provide an oral dosage form that can be exerted.

The present inventors intensively studied the formulations which can maximize the therapeutic effect against pigmentation caused by blotch, freckles, sunburn or skin disease in the formulation of L-cysteine and ascorbic acid.

As a result, it was found that separation of oral L-cysteine three times a day, orally administered twice a day, or better than the oral administration. In addition, when the formulation containing L-cysteine and ascorbic acid is applied to the treatment of pigmentation caused by blotch, freckles, sunburn or skin disease, L-cysteine 120mg per day is administered orally twice a day. -The present invention was completed by finding that the therapeutic effect is more excellent than the oral administration of cysteine 80 mg three times a day.

That is, the present invention contains L-cysteine or a salt thereof and ascorbic acid or a salt thereof, wherein the daily dosage of L-cysteine or a salt thereof is 90-150 mg, and the dosage form is twice a day. To provide.

Best Mode for Carrying Out the Invention

The twice-daily oral dosage form of the present invention (hereinafter, simply referred to as "the present invention formulation") is a combination of L-cysteine or a salt thereof and ascorbic acid or a salt thereof.

As L-cysteine or a salt thereof (hereinafter referred to as "L-cysteines") used in the preparation of the present invention, any of acid addition salts of L-cysteine such as L-cysteine hydrochloride, etc. can be used in addition to L-cysteine itself. Can be. In this invention, it is preferable to mix | blend this L-cysteine in twice daily dosage form oral preparation in the range of 90-150 mg with respect to a dose for adults, and it is 100 for a dose. It is more preferable to mix | blend in the range of -130 mg, and it is especially preferable to mix | blend with a twice-daily oral dosage form so that it may become 120 mg with respect to 1 dose.

Ascorbic acid or a salt thereof (hereinafter referred to as "ascorbic acid") as another component of the formulation of the present invention, in addition to ascorbic acid itself, ascorbic acid such as calcium ascorbate and sodium ascorbate Any of the acid salts can be used. They may also be used in combination. In the formulation of the present invention, it is preferable that the mass ratio of ascorbic acid to the ascorbic acid is in the range of 2: 1 to 1:20, more preferably in the range of 1: 1 to 1: 5. It is preferable and it is especially preferable that it is 4: 5.

The preparation of the present invention can be taken twice a day for the treatment and prevention of pigmentation caused by blotch, freckles, sunburn or skin disease, etc., but the treatment of systemic boredom, hangover, acne, eczema, urticaria, skin disease, weakness You may take it twice a day for the purpose of vitamin C dissemination in old age at the time of improvement, prevention of bleeding of gum bleeding or nasal bleeding, physical fatigue, pregnancy, lactation, physical illness, or illness.

You may mix | blend another pharmacologically active ingredient with the formulation of this invention other than the said L-cysteine and ascorbic acid which are essential components. As other pharmacologically active ingredients, pantothenic acid or salts or derivatives thereof such as pantothenic acid, calcium pantothenate, sodium pantothenate and panthenol, succinic acid d-α-tocopherol, succinic acid dl-α-tocopherol, succinic acid dl-α-tocopherol calcium and acetic acid d-α Vitamin E or derivatives thereof, such as tocopherol, dl-α-tocopherol acetate, d-α-tocopherol, dl-α-tocopherol, thiamine hydrochloride, thiamine nitrate, bistiamine nitrate, thiamine disulfide, thiamine diacetyl sulfate, hydrochloric acid Vitamin B ₁ or a derivative thereof, such as prsultiamine, dicetiamine hydrochloride, octothiamine, sicothiamine, bisbutyamine, bisbenthiamine, and benfotiamine, vitamin B ₂ or derivatives thereof such as riboflavin, riboflavin butyrate, and riboflavin sodium phosphate, Vitamin B ₆ or derivatives thereof, such as pyridoxine hydrochloride and pyridoxal phosphate, cyanocobaramin, hydroxobarbaraline hydrochloride, and hydroxyacetate Vitamin B ₁₂ or derivatives thereof such as socobaramin and mecobaramin, nicotinic acid or derivatives thereof such as nicotinic acid and nicotinic acid amide, yulmu, orotinic acid, biotin, gamma-olizanol, glucronolactone, glucuronamide, ubidecarenone and the like These can be mentioned and these 1 type, or 2 or more types can be used. Among these, preferable examples thereof include pantothenic acid or salts or derivatives thereof such as pantothenic acid, calcium pantothenate, sodium pantothenate, and panthenol.

The preparations of the present invention include tablets, granules, fine granules, powders, hard capsules, caplets, soft capsules, pills, dry syrups, chewables, troches, effervescent tablets, dropping agents, orally disintegrating tablets, oral fluids, syrups, and the like. Although it is preferable to use a solid oral dosage formulation, it may be used as a liquid oral dosage formulation such as an oral solution or a syrup. In addition, the formulations of the present invention may prepare L-cysteine or its salts and ascorbic acid or its salts in different formulations, and contain one dose together in the same package, It is preferable to set it as the formulation which mix | blended binoic acid or its salt simultaneously. In that case, it is preferable to make one dosage of L-cysteine or its salt, ascorbic acid or its salt, or one of its integral parts as a unit preparation.

The formulation of the present invention may be prepared by a conventional method by combining L-cysteine and ascorbic acid, and further blending other pharmacologically active substances as necessary. In that case, the usual formulation additive according to each formulation can be used. Examples of the additives include crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, povidone, polyvinyl acetal diethylamino acetate, white sugar, lactose, erythritol, reduced maltose syrup, calcium carbonate, Calcium lactate, carnaubaarrow, stearic acid, magnesium stearate, talc, sucrose fatty acid ester, titanium oxide, corn starch, partially alpha starch, pullulan, gum arabic, gelatin, macrogol, polyoxyethylene polyoxypropylene glycol, calcium silicate And dimethyl polysiloxane, fumaric acid, silicic anhydride, synthetic aluminum silicate, sodium lauryl sulfate, polysorbate 80 and the like. These formulation additives may be used in the formulations of the present invention as excipients, binders, glidants, disintegrants, lubricants, coating agents, plasticizers, solvents, dissolution aids, emulsifiers, suspending agents, stabilizers, preservatives, preservatives, colorants, sweeteners, flavoring agents, copulations. It can be added as an agent.

As a preferable aspect of the preparation of this invention, the tablet obtained by obtaining a predetermined | prescribed from L-cysteine or its salt, ascorbic acid or its salt, and a preparation additive, and then apply | coating one or more times with the coating liquid to the said predetermined | prescribed is mentioned. have. The coating is preferably sugar coating or film coating.

Moreover, as another preferable aspect of the formulation of this invention, the powder obtained by mixing L-cysteine or its salt, ascorbic acid or its salt, and agent additive is mentioned.

Moreover, as another preferable aspect of the formulation of this invention, the granule obtained by granulating L-cysteine or its salt, ascorbic acid or its salt, and formulation additive is mentioned.

Example

Although an Example is given to the following and this invention is demonstrated in more detail, this invention is not limited to this.

Example 1

Dragee preparations:

960 g of L-cysteine, 1200 g of ascorbic acid, 96 g of pantothenate, 96 g of crystalline cellulose, 128 g of partially alphaated starch, 80 g of hydroxypropyl cellulose, 16 g of hard silicic anhydride, 16 g of magnesium stearate and 16 g of talc were mixed well. Then, this mixture was compressed by a conventional method so that the weight per tablet became 200 mg to obtain a predetermined amount. Next, the tablets were put in a coating pan and coated with ethyl alcohol containing 5% by mass of hydroxypropyl methyl cellulose: purified water = 1: 1, until the weight gain per tablet became 10 mg. It was done. Again, a coating solution containing 2% by weight of talc, 2% by weight of titanium oxide, 3% by weight of calcium carbonate, 1% by weight of gum arabic, and 60% by weight of refined white sugar results in a weight gain of 100 mg per tablet. The sugar coating was performed until.

Thereafter, an aqueous solution containing 60% by mass of refined white sugar was coated until the weight increase per tablet was 100 mg, and L-cysteine 120 mg, ascorbic acid 150 mg, and calcium pantothenate 12 in two doses. As a dragee containing mg, a twice-dose type dragee preparation of the present invention was obtained.

Comparative Example 1

Comparative Dragee Formulations:

600 g of L-cysteine, 750 g of ascorbic acid, 60 g of calcium pantothenate, 1240 g of crystalline cellulose, 230 g of partially alphaated starch, 75 g of hydroxypropyl cellulose, 15 g of hard silicic anhydride, 15 g of magnesium stearate and 15 g of talc were mixed well. Then, this mixture was compressed by a conventional method such that the weight per tablet was 200 mg to obtain a predetermined amount. Next, the tablets were put in a coating pan and coated with ethyl alcohol containing 5% by mass of hydroxypropyl methyl cellulose: purified water = 1: 1, until the weight gain per tablet became 10 mg. It was done. Again, a coating solution containing 2% by weight of talc, 2% by weight of titanium oxide, 3% by weight of calcium carbonate, 1% by weight of gum arabic and 60% by weight of refined white sugar would give a 100 mg weight increase per tablet. The sugar coating was performed until.

Thereafter, coating was carried out with an aqueous solution containing 60% by mass of purified white sugar until the weight increase per tablet became 100 mg, and 80 mg of L-cysteine, 100 mg of ascorbic acid and calcium pantothenate in two tablets of one dose. As a dragee containing 8 mg, a comparative dragee formulation of 3 doses per day was obtained.

Test Example 1

Effects on pigmentation:

The dragee preparations obtained in Example 1 and Comparative Example 1 were each taken over 12 weeks for each 11 adults who were pigmented due to blotch, freckles, sunburn or dermatosis. The number of doses of the formulation of Example 1 was two tablets once a day, morning and evening twice, and the formulation of Comparative Example 1 was given two tablets three times a day, morning, lunch and evening. . After 12 weeks from the start of the dose, the improvement of pigmentation due to blotch, freckles, sunburn or skin disease was investigated by dividing it into remarkable improvement, moderate improvement, hardness improvement, and invariant. The results are shown in Table 1. Compared with Comparative Example 1, it was recognized that Example 1 had a high degree of improvement in pigmentation due to blotch, freckles, sunburn or skin disease, with a marked improvement and a moderate improvement. In addition, the expression of side effects was not recognized in either case.

A marked improvement Medium improvement or better Improvement of hardness Example 1 18.2% 63.6% 81.8% Comparative Example 1 9.1% 45.5% 81.8%

Example 2

Powder preparations (1):

200 g of L-cysteine, 250 g of ascorbic acid, 20 g of calcium pantothenate, 180 g of corn starch, 340 g of lactose and 10 g of magnesium stearate were uniformly mixed. The mixed powder obtained was distributed so as to be 600 mg per packet, and the dosage powder of the present invention was used twice daily as a distribution powder containing 120 mg of L-cysteine, 150 mg of ascorbic acid and 12 mg of calcium pantothenate in one dose. The formulation was obtained.

Example 3

Powder preparations (2):

150 g L-cysteine, 250 g ascorbic acid, 20 g calcium pantothenate, 180 g corn starch, 390 g lactose and 10 g magnesium stearate were uniformly mixed. The obtained mixed powder was distributed so as to be 600 mg per packet, and the dosage form of the present invention was twice as a distribution powder containing 90 mg of L-cysteine, 150 mg of ascorbic acid, and 12 mg of calcium pantothenate in one package of one dose. A powder formulation was obtained.

Example 4

Powder preparations (3):

250 g L-cysteine, 250 g ascorbic acid, 20 g calcium pantothenate, 180 g corn starch, 290 g lactose and 10 g magnesium stearate were uniformly mixed. The obtained mixed powder was distributed so as to be 600 mg per packet, and the dosage form of the present invention was twice as a distribution powder containing 150 mg of L-cysteine, 150 mg of ascorbic acid, and 12 mg of calcium pantothenate in a single dose. A powder formulation was obtained.

Example 5

Granule formulations:

Granulated with 240g L-cysteine, 300g ascorbic acid, 24g calcium pantothenate, 6g pyridoxine hydrochloride, 160g carboxymethylcellulose calcium, mannitol 937g, corn starch 247g, tartaric acid 60g, aspartame 12g, 12g acesulfame potassium and 2g fragrance To prepare granules. The granules thus obtained were distributed so as to be 1000 mg per packet, and the granules containing 120 mg of L-cysteine, 150 mg of ascorbic acid, 12 mg of pantothenate and 3 mg of pyridoxine hydrochloride in a single dose of 1 day of the present invention. Two dose granule formulations were obtained.

Example 6

Film coated tablet formulation (1):

720 g of L-cysteine, 900 g of ascorbic acid, 72 g of calcium pantothenate, 150 g of d-α-tocopherol acetate, 36 g of riboflavin, 840 g of crystalline cellulose, 66 g of lactose, 60 g of hard silicic anhydride, 18 g of magnesium stearate and 18 g of talc were mixed and mixed thoroughly. . Then, this mixture was compressed to a weight of 240 mg per tablet by a conventional method to obtain a predetermined amount. Next, the tablets were placed in a coating pan and coated with ethyl alcohol containing 5% by mass of hydroxypropyl methyl cellulose: purified water = 1: 1, until the weight gain per tablet became 10 mg. The present invention provides a film-coated tablet containing 120 mg of L-cysteine, 150 mg of ascorbic acid, 12 mg of calcium pantothenate, 25 mg of d-α-tocopherol acetate, and 6 mg of riboflavin in two tablets per day. A single dose film coated tablet formulation was obtained.

Example 7

Film coated tablet formulation (2):

720 g L-cysteine, 900 g ascorbic acid, 72 g calcium pantothenate, 60 g d-α-tocopherol acetate, 150 g pyridoxine hydrochloride, 840 g crystalline cellulose, 72 g lactose, 30 g hard silicic anhydride, 18 g magnesium stearate and 18 g talc were mixed thoroughly. . Then, this mixture was compressed to a weight of 240 mg per tablet by a conventional method to obtain a predetermined amount. Next, the tablets were placed in a coating pan and coated with ethyl alcohol containing 5% by mass of hydroxypropyl methyl cellulose: purified water = 1: 1, until the weight gain per tablet became 10 mg. 1 day of the present invention as a film-coated tablet containing 120 mg of L-cysteine, 150 mg of ascorbic acid, 12 mg of calcium pantothenate, 10 mg of d-α-tocopherol acetate, and 25 mg of pyridoxine hydrochloride in one dose of 2 tablets. A double dose film coated tablet formulation was obtained.

Since the preparation of the present invention has fewer doses than conventional three-day oral dosage preparations, L-cysteine or a salt thereof can be effectively ingested without forgetting to take it. Accordingly, the present invention contains L-cysteine, and is an excellent one capable of maximizing the therapeutic effect against pigmentation caused by blotch, freckles, sunburn or skin disease.

Claims (10)

A twice-daily oral dosage form containing L-cysteine or a salt thereof and ascorbic acid or a salt thereof, wherein the single dose of L-cysteine or a salt thereof is 90 to 150 mg. 2. The twice-daily oral dosage form of claim 1, wherein the single dose of L-cysteine or salt thereof is 120 mg. The dosage form of L-cysteine or its salt and ascorbic acid or its salt is 2: 1-1: 20 by mass ratio, The twice-daily oral dosage form of Claim 1 or 2 characterized by the above-mentioned. . The dosage form of L-cysteine or its salt and ascorbic acid or its salt is 4: 5 by mass ratio, The twice-daily oral dosage form of any one of Claims 1-3 characterized by the above-mentioned. The method of any one of claims 1 to 3, wherein ascorbic acid or salt thereof is one or two or more times selected from ascorbic acid, calcium ascorbic acid and sodium ascorbate. Dosage Oral Formulations. 6. The pantothenic acid or salt thereof or derivative thereof, vitamin E or derivative thereof, vitamin B ₁ or derivative thereof, vitamin B ₂ or derivative thereof, vitamin B ₆ or derivative thereof, vitamin B ₁₂ or derivatives thereof, nicotinic acid or a derivative thereof, Coix, Oro tinsan, biotin, gamma oryzanol, gluconic chronograph lactone, Gluck 1 il, characterized in that the blended acid amide and UB deca fluorenone alone or in combination of two or more selected from Two dose oral formulations. The tablets, granules, fine granules, powders, light capsules, caplets, soft capsules, pills, internal liquids, syrups, dry syrups, chewable tablets, troches, foamed tablets, according to any one of claims 1 to 6 Oral dosage form twice a day, characterized in that the dropping agent, orally disintegrating tablets. The method of claim 1, wherein the formulation is a tablet, the tablet obtains a predetermined from L-cysteine or a salt thereof, ascorbic acid or a salt thereof, and a formulation additive, and then the coating is performed one or more times with the coating liquid. Oral dosage form twice a day, characterized in that obtained. The twice-daily oral dosage form of claim 1, wherein the formulation is a powder and the powder is obtained by mixing L-cysteine or a salt thereof, ascorbic acid or a salt thereof and a formulation additive. 2. A twice-daily oral dosage form according to claim 1, wherein the dosage form is a granule and the granule is obtained by assembling L-cysteine or a salt thereof, ascorbic acid or a salt thereof and a formulation additive.