Oral pharmaceutical preparations decreased in bitterness by masking

ES 2 273 409 T3

DESCRIPTION

Oral medicine that prevents unpleasant and similar taste.

Field of the invention

The present invention relates to a composition for oral administration or an oral medicament that can prevent an unpleasant taste.

Previous technique

Many techniques have been developed to mask a drug that has an unpleasant taste. For example, a process for coating a granulated agent with a water-soluble film is known (JP-A 4-282,312) and a process for obtaining a powder and the like by melting a waxy substance having a melting point in the range of 40 to 100 ° C in which a drug having an unpleasant taste is allowed to disperse and then solidify (JP-A 7-267,850). On the other hand, for liquids, to improve the sensation when taking the medicine, a method is known to use liquids in oral administration such as syrups, which are widely used as a suitable dosage form for children, the elderly, etc. Although syrup is a sweet-tasting dosage form, if a molten drug tastes unpleasant, it is difficult to administer as a simple sweet taste cannot prevent an unpleasant taste and further decreases the compliance of a patient. Furthermore, in JP-A 4-346,937, as a method for reducing a bitter taste, a method for reducing a bitter taste has been described which comprises the step of adding a gelling agent selected from agar, gelatin or κ-carrageenan and a seasoning agent for a substance having a bitter taste, so as to obtain a jelly-like state for seasoning. With the gelatinous state, this procedure reduces the contact of a bitter tasting substance with the tongue and by using a flavoring agent, a partially melted bitter tasting substance, masks the bitter taste.

JP-A-4,235,136 describes alginate salts as bitterness reducers.

JP-A-4,262,758 describes carrageenans as bitterness reducers in KCl preparations.

US-B-5,013,557 describes carrageenans, alginic acids and xanthan gums, as flavor maskers for sucralfate.

US-B-5,286,489 describes how copolymers with acid groups can interact with drugs with an amino or amido group, thereby masking their unpleasant taste.

Many techniques such as those described above have been examined in order to mask a drug that has an unpleasant taste, but has a complicated manufacturing process, an unsuitable effect, and a quality problem. Also, they have not yet been successful, so yet another technique is needed.

Description of the invention

According to a first aspect of the present invention, there is provided a pharmaceutical composition for oral administration comprising a basic drug and an anionic acid polysaccharide selected from carrageenan, chondroitin sulfate, dextran sulfate, alginic acid, gellan gum and xanthan gum, the base drug itself has an unpleasant taste and interacts with the polysaccharide to reduce the unpleasant taste by slowing the rate of binding of the base drug to taste receptors, where the base drug is ticlopidine hydrochloride, maprotiline hydrochloride, ifenprodil tartrate, berberine hydrochloride, digitoxin, sulpirin, azelastine hydrochloride, ethylephrine hydrochloride, diltiazem hydrochloride, propanolol hydrochloride, chloramphenicol, aminophylline, erythromycin, phenobarbital, calcium pantothenate, indeloxacin hydrochloride, aminoguanidine hydrochloride, donepezil hydrochloride, (RS) -1- (isopropoxycarbonyloxy) ethyl (+) - (6R, 7R) -7 {( z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide} -3-N, N-dimethylcarbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] octo-2en-2-carboxylate or cefcapene hydrochloride.

According to a second aspect of the present invention, there is provided a method for reducing the unpleasant taste of a basic medicine comprising the step of combining an anionic acid polymer selected from carrageenan, chondroitin sulfate, dextran sulfate, alginic acid, gellan gum and xanthan gum with a basic medicine, the isolated basic medicine having an unpleasant taste, interacting with the polysaccharide to reduce unpleasant taste by slowing the rate of binding of the base drug to taste receptors, where the core drug is ticlopidine hydrochloride, maprotiline hydrochloride, ifenprodil tartrate, berberine hydrochloride, digitoxin, sulpirin , azelastine hydrochloride, ethylephrine hydrochloride, diltiazem hydrochloride, propanolol hydrochloride, chloramphenicol, aminophylline, erythromycin, phenobarbital, Calcium pantothenate, indeloxacin hydrochloride, aminoguanidine hydrochloride, donepezil hydrochloride, (RS) -1- (isopropoxycarbonyloxy) ethyl hydrochloride (+) - (6R, 7R) -7 {(z) -2- (2- aminothiazol-4-yl) -2-hydroxyiminoacetamide} -3-N, N-dimethylcarbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] octo-2-en-2-carboxylate or cefcapene hydrochloride.

ES 2 273 409 T3

A basic substance referred to in the present invention means that its free form shows basicity and in the case of salt formation, it is not necessarily basic.

In the present invention, the basic medicine having a bitter taste is ticlopidine hydrochloride, maprotiline hydrochloride, ifenprodil tartrate, berberine hydrochloride, digitoxin, sulpirin, azelastine hydrochloride, ethylephrine hydrochloride, diltiazem hydrochloride, propanol hydrochloride, chloramphenicol, aminophylline, erythromycin, phenobarbital, calcium pantothenate, indeloxacin hydrochloride, aminoguanidine hydrochloride, donepezil hydrochloride, (RS) -1- (isopropoxycarbonyloxy) ethyl (+) - (6R, 7R) -7 {(z) -2- (2-aminothiazol-4-yl) 2-hydroxyiminoacetamide} -3-N hydrochloride salt, N-dimethylcarbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] octo-2-en-2-carboxylate or cefcapene hydrochloride. Among these compounds, especially excellent effect is exerted for donecepyl hydrochloride and (RS) -1- (isopropoxycarbonyloxy) ethyl (+) - (6R, 7R) -7 {(z) -2- (2) hydrochloride salt -aminothiazol-4-yl) -2-hydroxyiminoacetamide} -3-N, N-dimethylcarbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] octo-2-en-2-carboxylate. Donecepyl hydrochloride is chemically called 1-benzyl-4- (5,6-dimethoxyindanon-2-yl) methylpiperidine hydrochloride salt, which is a mild to medium grade Alzheimer's disease therapeutic drug and its aqueous solution has a strong bitterness and numbs the mouth. Furthermore, (RS) -1- (isopropoxycarbonyloxy) ethyl (+) (6R, 7R) -7 {(z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide} -3 hydrochloride salt -N, N-dimethylcarbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] octo-2-en-2-carboxylate is an effective antibiotic in oral administration, however, it has a strong bitter taste .

The pharmaceutical composition of the present invention comprises an acidic polysaccharide selected from carrageenan, chondroitin sulfate, dextran sulfate, alginic acid, gellan gum, xanthan gum, and a salt thereof. Regarding carrageenan, some types such as ι, κ, λ and the like are known, any type can be used and, especially, for liquids or jellies, κ-carrageenan and λ-carrageenan are preferred, dextran sulfate being also preferred.

For solids, κ-carrageenan, sodium chondroitin sulfate and sodium alginate are especially preferred.

Commercial carrageenan obtained from: System Bio Industries Co., Ltd., USA, etc. can be used.

As regards an oral medicament in the present invention it is understood as a dosage form that can be administered orally as solids, liquids or jellies. Typical examples of the solids include granules, fine granules, powders, tablets, pills, etc. and typical examples of the liquids include syrups, elixirs, emulsions, suspensions and the like and, especially, granules, fine granules, powders, syrups and jellies.

These dosage forms are described in the Japanese Pharmacopoeia, except for jellies.

A method for administering a drug orally related to the present invention should not be especially limited and according to a property of each drug, the oral drug can be administered orally one to several times a day before, after or between meals.

Since the amount of a drug in solids is different according to a property of each drug, it is generally not said, but the amount of the drug in one administration is usually in the range of 0.1 to 1000 mg.

The concentration of a drug in oral liquids that prevents an unpleasant taste is usually in the range of 0.1 to 500 mg / ml, preferably in the range of 0.5 to 100 mg / ml. When the drug is donepezil hydrochloride, the concentration is preferably in the range of 0.5 to 5 mg / ml.

In the present invention, the ratio of an anionic polymer to a basic substance is usually in the range of 0.1 to 20 parts by weight, preferably 0.5 to 10 parts by weight relative to 1 part by weight of a basic substance.

In the case that the oral medicine referred to in the present invention is the solid, the medicine and the anionic polymer are homogeneously mixed to obtain an unpleasant taste preventive effect. In addition, the drug and fillers and the like are mixed and, separately, an anionic polymer is dissolved in a solvent such as water, mixed with another fixing agent, if necessary, and then gradually added to the drug to granulate, obtaining also as a result, an unpleasant taste preventive effect. Depending on the type of medicine, some medicines have a greater preventive effect on the unpleasant taste as they are granulated.

A process for the manufacture of an oral medicine for preventing an unpleasant taste related to the present invention should not be especially limited, and the medicine can be manufactured by a process that is normally used. For example, for granules, fillers such as lactose, mannitol, starch and crystalline cellulose, etc., disintegrants and the like such as carboxymethylcellulose, etc., are further mixed in a drug and κ-carrageenan, adding a solution with a binding agent such as hydroxypropylcellulose, the granules can be manufactured using a granulator that is normally used. And furthermore, a process for the manufacture of a liquid oral medicine should not be especially limited. For example, a basic drug and an anionic polymer are dissolved in water to make oral fluids. In addition, a sweetening agent such as cane sugar, xylitol, mannitol, glucose, aspartame and saccharin and a taste modifying agent such as

ES 2 273 409 T3 vanilla essence and apple aroma. Since the oral medicament related to the present invention prevents an unpleasant taste, characteristic of the medicament, such as a bitter taste, numbness and contraction, it is easily administered and improves patient compliance. In particular, it is effective in children and the elderly. A mechanism by which the oral medicament related to the present invention prevents an unpleasant taste is set forth as follows. That is, it is considered that when a basic substance that has an unpleasant taste interacts with an acidic polysaccharide to dissolve in saliva, or by reducing free forms in a solution, the speed of binding of the basic substance to a receptor on the tongue decreases and, in addition, the appearance of numbness is also diminished.

Experimental example

Test 1

2 mg / ml of an aqueous solution of donepezil hydrochloride was prepared. Then 50 mg of κ-carrageenan, chondroitin sulfate or dextran sulfate were dissolved in 5 ml of the aqueous solution. Two candidates (who were represented as A and B in the table) kept the same amount of the solution in their mouths and then evaluated the degree of a bitter taste and numbness taking into account five degrees. The results are shown in Table 1.

As is evident from Table 1, the bitter taste of donepezil hydrochloride can be remarkably controlled by adding λ-carrageenan and the like.

Test 2

The effect of carrageenan as an unpleasant taste and numbness preventative was examined using ticlopidine hydrochloride (20 mg / ml), maprotiline hydrochloride (5 mg / ml) and ifenprodil tartrate (4 mg / ml). An examination procedure and an evaluation standard were based on test 1. Results are shown in table 2.

As is evident from Table 2, the bitter taste and numbness of each drug can be remarkably controlled by adding carrageenan. In particular, the taste of ticlopidine hydrochloride is very bitter and stimulating, but this demonstrates the excellent effect of the present invention as the bitter taste and numbness can be remarkably controlled by adding carrageenan.

Test 3

Sodium alginate, sodium chondroitin sulfate, κ-carrageenan, ι-carrageenan, mannitol, corn starch, copolyvidone and the like were mixed with the hydrochloride salt of (RS) -1- (isopropoxycarbonyloxy) ethyl (+) - (6R, 7R) -7 {(z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide } -3-N, N-dimethylcarbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] octo-2en-2-carboxylate (shown as compound A in table 3) in proportions shown in Table 2 and granules were prepared according to the procedure of Example 3. The test was carried out by three candidates keeping 0.5 g of each granulate to be examined in their mouths and the criterion was made through a seven-degree evaluation pattern that shows the following: +4: impossible to administer due to strong bitterness, +3: very bitter, +2: bitter, +1: a little bitter, 0: tasteless, -1: not bitter, -2: quite good.

The results are shown in Table 3.

It is evident from Table 3 that the granules combined with the anionic polymer related to the present invention remarkably control the bitter taste.

Test 4

According to the treatment shown in table 4, ticlopidine hydrochloride, κ-carrageenan, corn starch, mannitol and hydroxypropylcellulose (represented as HPL-C in table 4) were sufficiently mixed and then water was added and granulated to obtain granules. Two candidates kept 0.5 g of this granulate in their mouths and gave the criteria. The standard evaluation was based on Example 1. The result is shown in Table 4.

It is evident from Table 4 that the present invention applied can prevent a very unpleasant taste of ticlopidine even in the solid state.

From the tests shown above, the remarkable effect of the present invention applied is evident.

Examples

In the following, the present invention will be described in more detail according to the examples, but the scope of the present invention should not be limited to these examples.

ES 2 273 409 T3

Example 1

100 mg of donepezil hydrochloride, 300 mg of sodium saccharin and 14 g of povidone were dissolved in 50 g of purified water and, separately, 700 mg of κ-carrageenan were added to 50 g of purified water and heated to 80 ° C to dissolve it. After cooling, both solutions were mixed and 300 mg of methyl paraben and 20 mg of propyl paraben were dissolved in a small amount of propylene glycol to add to the previous mixture, thus making the syrups.

Example 2

40 g of xylitol was added to 50 g of purified water and heated to 80 ° C to dissolve. Separately, 200 mg of donepezil hydrochloride was dissolved in 50 ml of purified water and 0.56 g of κ-carrageenan, 1.0 g of λ-carrageenan, 0.15 g of locust bean gum, 0.22 g of gellan gum, 0.15 g of xanthan gum, 0.19 g of sodium citrate, 0.19 g of sodium lactate, 0.94 g of lactose and 40 g of powdered hydrogenated maltose starch syrup, plus , the purified water containing xylitol prepared above was added and stirred at 90 ° C. After cooling the mixture to 80 ° C, 0.6 g of citric acid was added, to which was added purified water, so that the total weight was 200 g. It was pipetted into containers in a 10 g portion and then cooled to make jellies.

Example 3

15 g of the hydrochloride salt of (RS) -1- (isopropoxycarbonyloxy) ethyl (+) - (6R, 7R) -7 {(z) -2- (2-aminothiazole) were mixed, for use in the mobile granulator -4-yl) -2-hydroxyiminoacetamide} -3-N, N-dimethylcarbamoyloxymethyl-8-oxo-5-thia1-azabicyclo [4.2.0] octo-2-en-2-carboxylate, 15 g of κ-carrageenan, 30 g of cornstarch and 40 g of mannitol, and about 20 ml of water was slowly added and the wet dough was made and then dried through a 32 mesh size sieve, thus manufacturing the granules.

Example 4

15 g of the drug substance used in Example 3, 15 g of sodium chondroitin sulfate and 70 g of mannitol were mixed, for use in a granulator, and about 20 ml of water were slowly added and the wet mass was made and then dried. through a 32 mesh size screen, thus making the granules.

Example 5

For use in a granulator, 15 g of the drug substance used in Example 3, 15 g of carrageenan (mixture of ι-carrageenan and κ-carrageenan), 15 g of copolyvidone and 55 g of mannitol were mixed and slowly added about 15 ml of water and the wet mass was made by then drying through a 32 mesh size screen, thereby making the granules.

Example 6

For use with the fluidized bed granulator, 58 g of the drug substance used in Example 3, 58 g of κ-carrageenan, 120 g of corn starch, 130 g of mannitol and 16 g of aerosil were mixed, spraying 8 g of sodium alginate dissolved in 392 ml of water and a small amount of pigment red-102. Subsequently, 2 g of strawberry essence were pulverized and dried, mixing with 8 g of aspartame, thus producing fine granules.

Example 7

For use with the fluidized bed granulator, 15 g of the drug substance used in Example 3, 14.5 g of κ-carrageenan, 30 g of cornstarch and 40 g of mannitol were mixed, spraying 0.5 g of λ-carrageenan dissolved in 25 ml of water, thus producing fine granules.

Example 8

For use in the mobile granulator, 10 g of pivoxil cefcapene hydrochloride, 10 g of κ-carrageenan, 30 g of cornstarch, 48 g of mannitol and 2 g of aspartame were mixed and 20 ml of water were slowly added, making the wet mass and then dried through a 32 mesh size screen, thus making the granules.

ES 2 273 409 T3

TABLE 1

Evaluation pattern

<td>Bitterness</td><td>Without sensation</td><td>Sensation weak</td><td>Slightly bitter</td><td>Bitter</td><td>Very bitter</td>

<td>Numbness</td><td>Without</td><td>Sensation</td><td>Slightly</td><td>Asleep</td><td>Very</td>

<td></td><td>sensation</td><td>weak</td><td>asleep</td><td></td><td>I numb</td>

<td></td><td></td><td></td><td></td><td></td><td>do</td>

<td></td><td> -</td><td> ±</td><td> +</td><td> ++</td><td> +++</td>

Results

<td rowspan="2">Sample/ candidate</td><td colspan="2">TO</td><td colspan="2">B</td>

<td>Bitterness</td><td>Numbness</td><td>Bitterness</td><td>Numbness</td>

<td>Donepezil hydrochloride</td><td> +++</td><td> +++</td><td> +++</td><td> +++</td>

<td>Donepezil hydrochloride + κ-carrageenan</td><td> +</td><td> ±</td><td> +</td><td> +</td>

<td>Donepezil hydrochloride + dondroitin sulfate</td><td> ++</td><td> ++</td><td> +++</td><td> ++</td>

<td>Donepezil hydrochloride + dextran sulfate</td><td> +</td><td> ±</td><td> +</td><td> +</td>

TABLE 2

<td rowspan="2">Sample / Candidate</td><td colspan="2">TO</td><td colspan="2">B</td>

<td>Bitterness</td><td>Numbness</td><td>Bitterness</td><td>Numbness</td>

<td>Ticlopidine sulfate</td><td> +++</td><td> +++</td><td> +++</td><td> +++</td>

<td>Ticlopidine sulfate + ^K-</td><td> ±</td><td> ++</td><td> ±</td><td> ++</td>

<td>carrageenan (1 mg / ml) + ^λ-</td><td></td><td></td><td></td><td></td>

<td>carrageenan (1 mg / ml)</td><td></td><td></td><td></td><td></td>

<td>Ticlopidine sulfate + * -</td><td> -</td><td> +</td><td> -</td><td> ±</td>

<td>carrageenan (2 mg / ml)</td><td></td><td></td><td></td><td></td>

<td>Maprotiline Hydrochloride</td><td> ++</td><td> +</td><td> +</td><td> +</td>

<td>Maprotiline Hydrochloride + ^K-</td><td> -</td><td> -</td><td> -</td><td> -</td>

<td>carrageenan (2 mg / ml)</td><td></td><td></td><td></td><td></td>

<td>Ifenprodil tartrate</td><td> +</td><td> -</td><td> ++</td><td> -</td>

<td>Ifenprodil tartrate +</td><td> ±</td><td> -</td><td> -</td><td> -</td>

<td>carrageenan (2 mg / ml)</td><td></td><td></td><td></td><td></td>

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TABLE 3

<td>Composition</td><td>Prescription (%)</td><td>Candidate A</td><td>Candidate B</td><td>Candidate C</td>

<td>Compound A</td><td> 15</td><td> +4</td><td> +3</td><td> +4</td>

<td>Mannitol</td><td> 85</td><td></td><td></td><td></td>

<td>Compound A</td><td> 15</td><td> +1</td><td>0 to +2</td><td> +1</td>

<td>Sodium alginate</td><td> 15</td><td></td><td>note 1</td><td></td>

<td>Mannitol</td><td> 70</td><td></td><td></td><td></td>

<td>Compound A</td><td> 15</td><td> 0</td><td> 0</td><td> 0</td>

<td>Chondroitin sulfate sodium</td><td> 15</td><td></td><td></td><td></td>

<td>Mannitol</td><td> 70</td><td></td><td></td><td></td>

<td>Compound A</td><td> 15</td><td> 0</td><td> 0</td><td> 0</td>

<td>"-Carrageenan</td><td> 15</td><td></td><td></td><td></td>

<td>Cornstarch</td><td> 30</td><td></td><td></td><td></td>

<td>Mannitol</td><td> 40</td><td></td><td></td><td></td>

<td>Compound A</td><td> 15</td><td> -1</td><td>0 to +1</td><td> 0</td>

<td> “ ^Y '-carrageenan</td><td> 15</td><td></td><td>Note 1</td><td></td>

<td>Copolyvidone</td><td> 15</td><td></td><td></td><td></td>

<td>Mannitol</td><td> 55</td><td></td><td></td><td></td>

<td>Compound A</td><td> 15</td><td> 0</td><td> -1</td><td> 0</td>

<td>"-Carrageenan</td><td> 14,5</td><td></td><td></td><td></td>

<td>^ -carrageenan</td><td> 0,5</td><td></td><td></td><td></td>

<td>(solvent was added)</td><td></td><td></td><td></td><td></td>

<td>Cornstarch</td><td> 30</td><td></td><td></td><td></td>

<td>Mannitol</td><td> 40</td><td></td><td></td><td></td>

<td>Compound A</td><td> 14,5</td><td> -2</td><td> -2</td><td> -2</td>

<td>"-Carrageenan</td><td> 14,5</td><td></td><td></td><td></td>

<td>Sodium alginate</td><td> 2</td><td></td><td></td><td></td>

<td>(solvent was added)</td><td></td><td></td><td></td><td></td>

<td>Cornstarch</td><td> 30</td><td></td><td></td><td></td>

<td>Mannitol</td><td> 32,5</td><td></td><td></td><td></td>

<td>Aerosil</td><td> 4</td><td></td><td></td><td></td>

<td>Strawberry essence</td><td> 0,5</td><td></td><td></td><td></td>

<td>Red n ° 102</td><td>traces</td><td></td><td></td><td></td>

<td>Aspartame</td><td> 2</td><td></td><td></td><td></td>

Note 1: When administered with water, the bitterness was felt after

ES 2 273 409 T3

TABLE 4

<td colspan="3"></td><td>Control</td><td>Prescription η 1</td><td>Prescription n 2</td><td>Prescription n 3</td>

<td>Prescription</td><td colspan="2">Ticlopidine</td><td> 100</td><td> 100</td><td> 100</td><td> 100</td>

<td>n</td><td colspan="2">"-Carrageenan</td><td> 0</td><td> 100</td><td> 200</td><td> 300</td>

<td></td><td colspan="2">Mannitol</td><td> 670</td><td> 570</td><td> 470</td><td> 370</td>

<td></td><td colspan="2">Cornstarch</td><td> 200</td><td> 200</td><td> 200</td><td> 200</td>

<td></td><td>HPC-</td><td>-L</td><td> 30</td><td> 30</td><td> 30</td><td> 30</td>

<td></td><td colspan="2">Total</td><td> 1000</td><td> 1000</td><td> 1000</td><td> 1000</td>

<td>Results</td><td>TO</td><td>Bitterness</td><td> +</td><td> ±</td><td> -</td><td> -</td>

<td></td><td></td><td>Numbness</td><td> +++</td><td> +++</td><td> +</td><td> ±</td>

<td></td><td>B</td><td>Bitterness</td><td> +</td><td> +</td><td> -</td><td></td>

<td></td><td></td><td>Numbness</td><td> +++</td><td> +++</td><td> ±</td><td> -</td>

mg / g of a granule