Pharmaceutical composition

FIELD: pharmacy.

SUBSTANCE: invention relates to a granulated pharmaceutical composition comprising granulated material and erythritol. Granulated material comprises a medicinal substance of unpleasant taste and wax. Also, invention relates to a pharmaceutical product for oral using that comprises the indicated granulated composition. The composition masks unpleasant taste of a medicinal agent and provides good feeling in oral using. The granulated composition can be swallowed easily by elderly humans, children and patients suffering with dysphagia. Except for, the product is useful for administration by using a tube.

EFFECT: improved and valuable properties of composition.

15 cl, 5 tbl, 6 ex

 

The scope of the invention

This invention relates to a granulated pharmaceutical composition that masks the unpleasant taste of the drug and provides a pleasant feeling in oral application, and finished pharmaceutical forms derived from it.

Background of the invention

Oral application of the drug having an unpleasant taste, predisposes to reduced compliance sick mode and regimens and in many cases lead to poor results expected therapeutic effect.

Known methods of masking the unpleasant taste finely granular medicines provide a method of coating by sputtering with the use of water-insoluble polymers and methods of using microencapsulation or supplements sweetening agents. An example of a method of coating by sputtering with the use of water-insoluble polymers used to prepare gradually released medicinal product is presented in Japanese patent laid application (kokai) No. 30709/1987, which contains the drug core is coated by ethylcellulose, and the rate of release of drug can be controlled by varying the thickness ethylcellulose coverage. However, suggested technologist who I aim to gradually release drugs and does not provide technology, apply for fast release of drugs, which can mask the unpleasant taste. Covered drug from water-insoluble polymer give sandy taste in the mouth of the patient for oral use and cause pain when injected between the teeth of the patient; such problems are created for ease of injection. How microencapsulation has the disadvantages that it makes the procedure for preparation of the complex due to the use of organic solvents and is accompanied by low yield and high production cost. The method of using the additive sweetening agents, gives a weak masking effect for medicines that have a strong unpleasant taste.

In Japanese patent laid application (kokai) No. 242568/1995 proposed granular medicines, obtained by fusing when heated hydrophobic substances with a melting point 45-90°and surfactants, dissolution or suspension of the medicinal product, which has an unpleasant taste, and the transmitting agent, granulating the mixture by spray granulation. In the specified publication surfactant and the transmitting agent is introduced to speed up the elution of drugs, and they are contained in the composition respectively the public in quantities of 5-35%. However, the surfactants preferably used in small quantities from the point of view of security. Thus, taking into account the formation of finished pharmaceutical preparative forms, it is desirable to spray granular products contain smaller amounts of additives, to allow the introduction of other additives in increased quantities. Thus, surfactants and transmitting agents preferably used in the smallest possible quantities. In Japanese patent laid application (kokai) No. 267850/1995 proposed pharmaceutical composition obtained by mixing one or more kinds of medicines that have an unpleasant taste, one or more types of water-soluble polymers and one or more types of wax; heating and granulating molten wax along with medication(you) and soluble(s) polymer(s). In this publication, water-soluble polymers are added for the same purpose as above, i.e. to increase the dissolution rate of the drug. Water-soluble polymers is administered in a pharmaceutical composition in an amount of 5-60%. For the reasons mentioned above, water-soluble polymers are preferably not used at all or used in the smallest possible quantities.

<> Solid granules, incidentally, powdered products, preferably have good adaptability to the introduction with the use of the tube, in addition to the above the ability of masking the unpleasant taste. Introduction with application tube" refers to the method of administration, which is suitable for application to a patient who has difficulty swallowing finished pharmaceutical preparative forms. According to the introduction by means of a tube of powdered drug is dispersed in water, and then the dispersion is transferred into a syringe for injection of the dispersion to a patient through a tube inserted in the nose or the digestive tract. In many cases, the dispersion is prepared immediately before use. It is therefore necessary to powder the drug was uniformly dispersed in a short period of time and so it does not clog the syringe or tube. Powder ready preparative forms covered dependent on the pH of the polymer such as methacrylic acid copolymer, elektrolitnoy liquid, such as purified water or glucose solution, clogging up the syringe or tube. Therefore, these powder products obtained with the use of sugar as a filler, such as lactose, also cause blockages in the syringe or tube and thus not applicable for the introduction of using the tube.

In mind vychislitel is the subject of this invention is the presentation of a granular pharmaceutical composition, having an excellent ability to mask the unpleasant taste of the medicine and to provide a pleasant sensation of oral application. Another object of this invention is the provision of pharmaceutical finished formulation containing it.

Description of the invention

This invention is a granulated product containing a drug having an unpleasant taste, and covers an extensive study of the properties of the product. Unexpectedly, the inventors have found that the introduction of the sugar alcohol in combination drug having an unpleasant taste, and waxy substances can give a granular pharmaceutical product that has an excellent ability to mask unpleasant taste and provides a pleasant feeling for oral use, leading to the implementation of the invention. The inventors also discovered that the pharmaceutical product suitable for administration using a tube.

Accordingly, in the first aspect of the present invention proposed a granular pharmaceutical composition containing a drug having an unpleasant taste, waxy substance and a sugar alcohol. In the second aspect of the present invention, a method for preparing a granular pharmaceutical composition. In the third aspect Dunn is th invention is proposed pharmaceutical product for oral administration, containing granulated pharmaceutical composition.

The best ways of carrying out the invention

In this invention, the term "unpleasant taste" refers to any bitter taste, wagamama effect, acrid taste, unpleasant irritation and unpleasant smell.

No particular limitations are imposed on drugs that have Neplatny taste, if the drug is above the taste and applicable as a pharmaceutical agent. Examples of medicines are the hydrochloride of cetraxate, echappe, nefiracetam, hydrochloride talampicillin, hydrochloride indenolol, hydralazine hydrochloride, chlorpromazine hydrochloride, hydrochloride tiaramide, berberine chloride, digitoxin, sulpirid, hydrochloride azelastina, hydrochloride etilefrine, diltiazem hydrochloride, propranolol hydrochloride, chloramphenicol, aminophylline, erythromycin, clarithromycin, phenobarbital, calcium Pantothenate, hydrochloride indeloxazine, hydrochloride aminoguanidine, hydrochloride of bifemelane, hydrochloride 1-(isopropoxycarbonyl)-ethyl ester 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-hydroxykynurenine]-3-N,N-dimethylcarbamoyl-3-cefem-carboxylic acid, (E)-3-(2-methoxy-3,6-dimethyl-1,4-benzoquinone-5-yl)-2-[5-(3-pyridyl)pentyl]-2-Papanova acid, aminophylline, theophylline, diphenhydramine, metoclopramide, fenil tazon, phenobarbital, ampicillin, cimetidine, famotidine, nizatidine, acetoaminophen, epirizole, pyrazinamide, caffeine, ethionamide, carvedilol, ranitidine hydrochloride, hydrochloride, acetate roksatidina, imipramine hydrochloride, ephedrine hydrochloride, diphenhydramine hydrochloride, hydrochloride tetracycline, doxycycline hydrochloride, hydrochloride nafazolina, hydrochloride of noscapine, papaverine hydrochloride, the hydrobromide of dextromethorphan, bromide of timepice, maleate of chlorpheniramine, tartrate alimemazine, hydrochloride pilsicainide, methyl sulfate N-methylscopolamine, maleate cinepazide, arginine hydrochloride, histidine hydrochloride, lysine hydrochloride, lysine acetate, the crude medicinal substances or extracts of Corydalis Tuber, Phellodendron Bark, Coptis a rhizome, Nux vomica, Ephedra Herb, Ipecac, Scopolia a rhizome, Belladonna or Sophora Root; connection pyridonecarboxylic acid represented by the formulas (1) through (4), and their salts:

(where each of R1a, R1band R1cmeans C1-C6 linear or branched alkyl group which may have a Deputy, C3-C6 cyclic alkyl group which may have a Deputy, aryl group which may have a Deputy, or a heteroaryl group which may have a Deputy;

each of R2a, R2b, R2cand R2dmeans a hydrogen atom or a C1-C6 linear or the branched alkyl group, which may have a Deputy, or an amino group;

each of R3a, R3b, R3cand R3dmeans a hydrogen atom or a halogen atom;

R4aor R4cmeans a hydrogen atom, halogen atom, C1-C6 linear or branched alkyl group which may have a Deputy; or C1-C6 linear or branched CNS group which may have a Deputy;

R5dmeans a hydrogen atom or a C1-C6 linear or branched alkyl group which may have a Deputy; and

each of the Ya, Yb, Ycand Ydmeans a nitrogen-containing group); and 4,5,6,7-tetrahydrothieno[3,2-C]pyridine or their salts represented by the formula (5):

[where R1means a phenyl group which may have 1 to 3 substituents selected from C1-C4-alkyl group, halogen atom, fluoro-substituted C1-C4 alkyl groups, C1-C4 CNS group, fluoro-substituted C1-C4 CNS group, ceanography and nitro;

R2means a hydrogen atom, carboxyl group, C1-C6 alkoxycarbonyl group or a C1-C7 aliphatic acyl group which may have a Deputy selected from a halogen atom, hydroxyl group, C1-C4 CNS group and cyanopropyl; and

R3means 4,5,6,7-tetrahydrothieno[3,2-C]pyridine-5-ilen group, to the which may have a Deputy, selected from hydroxyl groups, C1-C4 CNS group, C1-C4 CNS group which may be substituted by C1-C4-alkoxyl or C1-C6, alkanoyloxy, C7-C14 of aralkylated, C1-C18-alkanoyloxy, C3-C7-cycloalkylcarbonyl, C6-C10 of arylcarboxylic, C1-C4 of alkoxycarbonylmethyl and C7-C14 of uralelektromontazh].

The above derivatives pyridonecarboxylic acid represented by the formula(1), (2), (3) or (4), and their salts and the method of their derivation are described in the following reference: Japanese laid patenie application (kokai) No. 53-141286, 55-31042, 57-46986, 57-77683, 60-36482, 60-64979, 60-228479, 62-252772, 62-252790, 62-277362, 1-230558, 1-258666, 1-294680, 2-28178, 2-124873, 2-231475, 5-271229, 7-309864, 8-41050 and WO 91/02526, WO 94/14794, WO 94/15933, WO 95/5373, WO 96/37475, WO 96/39407, WO 97/29102, WO 97/19072, WO 97/40037, WO 98/02431, WO 98/13370, WO 98/18783, WO 98/24781, WO98/52939, WO 98/54169 or WO 98/58923. These publications disclose methods of making the compounds and salts. Compounds represented by formula (5), and their salts can be obtained by the method described in Japanese patent laid applications (kokai) No. 50-46688, 58-10583, 59-27895 and 6-41139.

Any of the above compounds represented by the formulas(1), (2), (3), (4) or (5)may have asymmetric carbon atom and can exist as optical isomers or diastereoisomers. Such isomers per se, arbitrary mixtures, racemic mixtures, etc. are covered by the scope of this invention. In Sopianae connection represented by formulas (1) through (5), may exist in the form of their salts, their hydrates or their solvate, which are also included in the scope of this invention.

In relation to the masking effect of the medicinal product, which has an unpleasant taste, preferably poorly soluble in wax; more preferably soluble in water and poorly soluble in the wax.

Among the above compounds represented by formulas (1) through (4), and their salts, examples of preferred compounds are the following:

In addition, among the compounds represented by formula (5), and their salts, examples of preferred compounds are the following:

2-hydroxy-5-(α-cyclopropanecarbonyl-2-Chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine,

2-hydroxy-5-(α-propionyl 2-terbisil-4,5,6,7-tetrahydrothieno[3,2-C]pyridine,

2-hydroxy-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine,

2-acetoxy-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine,

2 propionyloxy-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine,

2 butyryloxy-5-(α-cyclopropanecarbonyl-2-terbisil)4,5,6,7-tetrahydrothieno[3,2-C]pyridine,

2 pivaloyloxy-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine,

2 valeriote-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine,

2 hexanoate-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine,

2-tert-butoxycarbonylamino-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine,

2 pivaloyloxymethyl-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine,

5-(α-cyclopropanecarbonyl-2-Chlorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrofuro[3,2-C]pyridine,

5-(α-propionyl 2-terbisil)-2-oxo-2,4,5,6,7,7a-hexahydrofuro[3,2-C]pyridine,

5-(α-cyclopropanecarbonyl-2-terbisil)-2-oxo-2,4,5,6,7,7a-hexahydrofuro[3,2-C]pyridine,

2-acetoxy-5-(α-cyclopropanecarbonyl-2-Chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine,

2-hydroxy-5-(α-2-forcecoercion-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine,

5-(α-2-forcecoercion-2-terbisil)-2-oxo-2,4,5,6,7,7a-hexahydrofuro[3,2-C]pyridine,

2-acetoxy-5-(α-2-forcecoercion-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine,

5-(α-methoxycarbonyl-2-Chlorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrofuro[3,2-C]pyridine,

2-acetoxy-5-(α-methoxycarbonyl-2-Chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine,

5-(αtags shall carbonyl-2-terbisil)-2-oxo-2,4,5,6,7,7a-hexahydrofuro[3,2-C]pyridine,

2-acetoxy-5-(α-methoxycarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine,

5-(2-Chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine (generic name: ticlopidine; available as hydrochloride, ticlopidine),

5-(α-methoxycarbonyl-2-Chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine (generic name: clopidogrel; is available in the form of sulphate clopidogrel),

5-(α-methoxycarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno-[3,2-C]pyridine,

5-(α-cyclopropanecarbonyl-2-Chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine,

5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine,

5-(α-propionyl 2-Chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine and

5-(α-propionyl 2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine; and their salts.

In this invention, the drug having an unpleasant taste is preferably ofloxacin, levofloxacin, hydrate sitafloxacin, hydrochloride of cetraxate, nefiracetam, hydrochloride, ticlopidine or sulfate clopidogrel.

Examples of the wax (in particular, wax, having a melting point of 40-150°C), which is applicable in this invention are fats and oils, such as hydrogenated oils (for example hydrogenated castor oil, hydrogenated soybean oil, hydrogenated rapeseed oil, HYDR is generowanie cottonseed oil), and fats and oils of vegetable or animal origin (for example, Carnauba wax, white beeswax, beef fat); alcohols and polyhydric alcohols, such as higher alcohols (e.g. stearyl alcohol, cetanol) and glycols (for example, macrogol 4000, macrogol 6000); fatty acids and their derivatives, such as higher fatty acids (e.g. stearic acid, palmitic acid and glycerides of fatty acids and esters of fatty acids with sucrose (for example, a monoglyceride of a fatty acid, a triglyceride of a fatty acid; and a mixture of two or more of these substances. Of these hydrogenated oils, fatty acids and derivatives of fatty acids are preferred; hydrogenated oils, higher fatty acids and esters of fatty acids are more preferred; and, in particular, the preferred hydrogenated oils, monoglycerides of fatty acids, triglycerides of fatty acids and stearic acid. From the point of view of the effect of masking the unpleasant taste of drugs, the wax preferably has a melting temperature lower than a drug.

In this invention it may be preferable to the use of sugar alcohols having a low heat of dissolution; for example, aritra, xylitol, sorbitol, ▫ maltitol, or a mixture of two or more of these compounds. From the point of view of feeling when the pen is material the use of preferred sugar alcohol, having a heat of dissolution - 30 cal/g or less, particularly preferred eritra and xylitol.

In this invention from the viewpoint of solubility and the effect of masking the unpleasant taste of the weight ratio of drug having an unpleasant taste, the wax is preferably in the range between 1:1 and 1:5, more preferably between 1:2 and 1:3. The percentage of sugar alcohol in the mixture is preferably 10 wt.% or more, more specifically 10-99,9 wt.%, more preferably 20-80 wt.%, most preferably 30-70 wt.%.

Granular composition of this invention can be prepared as follows. The wax is melted by heating and the drug having an unpleasant taste, dispersed or dissolved in it. Then, the resulting dispersion or solution is subjected to primary granulation to form granules. The granules are mixed with sugar alcohol or granules are subjected to secondary granulation.

The primary granulation can be carried out by spray granulation or by granulation of the melt. Alternatively, the solution can be cooled to solidification and subsequent fragmentation. The preferred spray granulation. In particular, the preferred spray cooling and spray drying, since these methods can easily Yes is the substance of fine particles, do not cause unpleasant stranger mouth feel. The size of the granules is preferably in the range of 50-200 μm, in particular 80-120 microns.

If the spray granulation is carried out for the primary granulation, may be added a small amount of surfactant to reduce the adhesion of the granules to the inner walls of the processing apparatus during spray cooling. The amount of surfactant may preferably be in the range of 0.5-5 wt.%, in particular, preferably 1-4 wt.% or so.

Secondary granulation of the sugar alcohol and granules obtained primary granulation may be carried out by wet granulation in the fluidized bed with the use of a solution of a binder such as a solution hydroxypropylcellulose, hydroxypropylmethylcellulose or polyvinylpyrrolidone. Alternatively, the secondary granulation can be performed by pelleting in a hot melt, where it is used as a binding substance with a low melting point such as polyethylene glycol or glycerol monostearate.

Granular pharmaceutical composition of the present invention preferably get one of the methods above. In short, the primary granulation can be formed granules, in the which the drug is uniformly dispersed in the wax, than reach successful masking of unpleasant taste due to the very low solubility of the wax in the mouth. In the mouth the sugar alcohol is dissolved in the saliva for approximately ten seconds, leaving the wax-containing medication in the form of a dispersion. However, since particles of waxy substances are microspheres, they do not cause sand unpleasant taste in the mouth. Sugar alcohols, in particular eritra and xylitol, are sweet and give a feeling of freshness and coolness in the mouth, providing the effect of Maksimovna unpleasant taste of the drug. After swallowing the wax releases the drug in the digestive tract, allowing the absorption of the drug in the body.

Granulated pharmaceutical composition of the present invention can be obtained with or without other additives as needed in the form of finished pharmaceutical preparative forms for oral administration, such as powders, granules, dry syrups, tablets and capsules. In particular, the preferred powders, granules and dry syrups.

Examples of additives that are applicable for the above ready preparative forms can be a binder such as polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylcellulose, hypromellose, methylcellulose, polyethylene glycol or monostearate; and a sweetener, such as aspartame, sodium saccharinate, sodium saccharin, thaumatin or stevia; flavoring agents, such as d1-menthol and 1-menthol; - thinning agents, such as light anhydrous silicic acid, alumosilicate magnesium, talc, synthetic aluminum silicate and ethylcellulose; disintegrant, such as cross-carmellose-calcium, starch-calcium gluconate and nizkozameshhennoj hydroxypropylcellulose; and pH regulators such as sodium citrate and sodium bicarbonate. Additives include water-soluble polymers. In this invention, such additives containing water-soluble polymers are preferably used in small quantities, that is, they are 0.1-5% by weight, particularly preferably 1-4% by weight of the pharmaceutical composition.

Examples

This invention is hereinafter described in more detail by means of examples, which should not be construed as limiting the invention.

Example 1

Glycerol monostearate (200 parts by weight) was melted at 90°and it was evenly dispersible levofloxacin (100 parts by weight). The dispersion was sprayed with cooling using a spray dryer to obtain so small granules. To the granules (300 parts by weight) were added eritra (630 parts by weight), and the mixture was stirred using pellet fluidized bed. Then was injected in mesh aqueous solution of polyvinyl alcohol (10% weight/vol.) in number, equivalent to 10 parts by weight of polyvinyl alcohol prior to granulation in the fluidized bed. After injection of the pellets were dried in the granulator, fluidized bed. The obtained granules were sieved using sieve No. 30 (the size of the sieve mesh: 500 μm), receiving the powder.

Example 2

Glycerol monostearate (197 parts by weight) was melted at 90°and were added monooleate polyoxyethylene(20)sorbitol (Polysorbate 80) (3 parts by weight). The resulting mixture was evenly dispersible levofloxacin (100 parts by weight). The dispersion was sprayed with cooling using a spray dryer to obtain so small granules. To the granules (300 parts by weight) were added eritra (630 parts by weight), and the mixture was stirred using pellet fluidized bed. Then was injected into the mixture an aqueous solution of polyvinyl alcohol (10% weight/vol.) in an amount equivalent to 20 parts by weight of polyvinyl alcohol prior to granulation in the fluidized bed. After injection of the pellets were dried in the granulator, fluidized bed. The obtained granules were sieved using sieve No. 30 (the size of the sieve mesh: 500 μm), receiving the powder.

Similar to that described in examples 1 and 2 method received powdery finish formulation of ofloxacin, hydrate sitafloxacin, hydrochloride Cetra is SATA or nefiracetam.

Test example 1 (estimating the effect of masking the unpleasant taste: touch probe 1)

Powder (940 mg)obtained in example 1 and the powder (950 mg)obtained in example 2 were subjected to a sensory test. Each of the powders was actually placed in the mouth in a quantity equivalent to 100 mg of levofloxacin, and evaluated the taste and the feeling. It was found that two powder mask the unpleasant taste of the drug for more than 30 seconds. 10 seconds after swallowing mouth remained extraneous sensations.

Sample test 2 (evaluation of the effect of masking the unpleasant taste: test solubility 1)

Powder (940 mg)obtained in example 1 and the powder (950 mg)obtained in example 2 were tested to evaluate the effect of enabling IRQ-unmasking unpleasant taste, which was carried out with application of the device to test for solubility (test liquid: 500 ml of purified water; the temperature of the test fluid 37°; way blade mixer; rotation speed: 100 rpm./min). The use of one drug served as a control. The results are shown in table 1. The solubility of a drug in the initial stage significantly reduced compared to a case of using one drug.

Table

The test results on leaching
Time (seconds)10203060
Only medication588393103
Example 1261229
Example 25121940

Test example 3 (assessment of possibility of introduction with application tube 1)

The powders obtained in examples 1 and 2 were evaluated for their ability to use in the introduction through the tube. Each of the powders (950 mg) was dispersible in purified water (20 ml). The dispersion was placed in a disposable syringe, which was connected with enteral nutritional tube (trade name ARGAIL, production Japan Sharwood; new enteral feeding tube; the inner diameter of 1.0 mm). The dispersion was extrudible from a syringe, and the upper end of the syringe and the upper end of the tube was checked for clogging. The results are shown in table 2.

Table 2

The results of the evaluation adaptability to the introduction using tube
Results
Example 1No clogging was observed at the top of the end of the syringe or the upper end of the tube
Example 2No clogging was observed at the upper end of the syringe or the upper end of the tube

In examples 1 and 2 were not observed clogging, and thus, it was found that both smooth introduction.

Test example 4 (sample solubility 1)

Powder (940 mg)obtained in example 1 and the powder (950 mg)obtained in example 2 were subjected to the test for solubility, which was held in the apparatus for sample solubility (test fluid: 900 ml of the first liquid, is described in the Pharmacopoeia of Japan, disintegration test; the temperature of the test fluid: 37°; way blade mixer; rotation speed: 50 rpm./min). As is obvious from table 3, found that these powders exhibit excellent solubility.

Table 3

The results of the tests of solubility (average solubility (%))
Timeafter 5 minafter 10 minafter 20 minafter 30 minafter 45 minafter 60 min
Example 1100100100100100100
Example 298989898 9898

Example 3

The triglyceride fatty acids (216 parts by weight) was melted at 80°and added monooleate polyoxyethylene(20)sorbitol (Polysorbate 80) (11.2 parts by weight). The resulting mixture was evenly dispersible sulfate clopidogrel (and 97.8 parts by weight). The dispersion was cooled by spraying using a spray dryer with the formation of small granules. To the granules (325 parts by weight) were added eritra (169 parts by weight) and aspartame (5 parts by weight) with the formation of powder.

Example 4

The triglyceride fatty acids (216 parts by weight) was melted at 80°and added monooleate polyoxyethylene(20)sorbitol (Polysorbate 80) (11.2 parts by weight). The resulting mixture was evenly dispersible sulfate clopidogrel (and 97.8 parts by weight). The dispersion was sprayed with cooling using a spray dryer, with the formation of small granules. To the granules (325 parts by weight) were added eritra (169 parts by weight), followed by stirring using pellet fluidized bed. Then the mixture was injected aqueous solution of polyvinyl alcohol (10% weight/vol.) in an amount equivalent to 20 parts by weight of polyvinyl alcohol prior to granulation in the fluidized bed. After injection of the pellets were dried in the granulator, fluidized bed. The obtained granules (514 parts by weight) of the MCA is ivali with aspartame (5 parts by weight), receiving the powder.

Example 5

The triglyceride fatty acids (216 parts by weight) was dissolved in dichloromethane. The resulting mixture was evenly dispersible sulfate clopidogrel (and 97.8 parts by weight) and ethylcellulose (32.6 parts by weight). The dispersion was cooled by spraying using a spray dryer, to thereby obtain pellets. To the granules (346,4 parts by weight) were added eritra (147,6 parts by weight) and aspartame (5 parts by weight), while receiving the powder.

Example 6

The triglyceride fatty acids (216 parts by weight) was dissolved in dichloromethane. The resulting mixture was evenly dispersible sulfate clopidogrel (and 97.8 parts by weight) and ethylcellulose (32.6 parts by weight). The dispersion was sprayed with cooling using a spray dryer, to thereby obtain pellets. To the granules (346,4 parts by weight) were added eritra (147,6 parts by weight), followed by stirring using pellet fluidized bed. Then the mixture was injected aqueous solution of polyvinyl alcohol (10% weight/vol.) in an amount equivalent to 20 parts by weight of polyvinyl alcohol prior to granulation in the fluidized bed. After injection of the pellets were dried in the granulator, fluidized bed. The obtained granules (514 parts by weight) was mixed with aspartame (5 parts by weight), receiving the powder.

Comparative example 1

triglyceride fatty acids (135 parts by weight) was melted at 80° With, and were added monooleate polyoxyethylene(20)sorbitol (Polysorbate 80) (7 parts by weight). The resulting mixture was evenly dispersible sulfate clopidogrel (61 part by weight). The dispersion was sprayed with cooling using a spray dryer, to thereby obtain pellets. To the granules (346,4 parts by weight) was added lactose (147,6 parts by weight) and aspartame (5 parts by weight), while receiving the powder.

Test example 5 (estimating the effect of masking the unpleasant taste: touch probe 2)

Each of the powders obtained in examples 3 to 6 were subjected to a sensory test. Each of the powders was actually placed in the mouth in a quantity equivalent to 100 mg of sulfate clopidogrel, and evaluated the taste and the feeling. It was found that all of these powders was masking the unpleasant taste of the drug for more than 30 seconds. 10 seconds after pragativadi mouth remained a stranger sensation.

Test example 6 (estimating the effect of masking the unpleasant taste: test solubility 2)

The powder (500 mg)obtained in examples 3 through 6 were tested to evaluate the effect of enabling IRQ-unmasking unpleasant taste, which was carried out using the apparatus for testing solubility (test liquid: 300 ml of purified water; the temperature of the test fluid 37°; way blade mixer; the rotation speed is s: 100.min). As a result, it was confirmed that each powder is able to significantly reduce the solubility of the drug in the initial stage compared with the case in which the used one drug.

Test example 7(assessment of possibility of introduction with the use of tube - 2)

The powders obtained in comparative example 1 and example 5 were evaluated for their ability to introduction with application tube. Each of the powders (500 mg) was dispersible in purified water (20 ml). The dispersion was placed in a disposable syringe, which was connected with enteral nutritional tube (trade name ARGAIL, production Japan Sharwood; new enteral feeding tube; the inner diameter of 1.0 mm). The dispersion was extrudible from a syringe, and the upper end of the syringe and the upper end of the tube was checked for clogging. The results are shown in table 4.

Table 4

The results of the evaluation adaptability to the introduction using tube
Results
Comparative example 1Watched plugging the upper end of the tube directly after the filing of the powder, and the dispersion was hard pushed from the tube
Example 5There were no signs of clogging the upper end of the syringe or the upper end of the tube

The results of comparative example 1 show that the comparative product is too complex for effective implementation and therefore is not suitable for insertion through the tube. On the contrary, the product of example 5 does not cause undesirable clogging, which makes possible its smooth introduction.

Test example 8 (sample on the solubility of 2)

Powder (326,5 mg)obtained in example 3 was tested for leaching, which was carried out using a test apparatus for leaching (test fluid: 900 ml of the first liquid, as described in the Pharmacopoeia of Japan (containing about 1% lauryl), disintegration test; the temperature of the test fluid: 37°; way blade mixer; rotation speed: 50 rpm./min). As shown in table 5, it was found that the powder of example 3 exhibits excellent solubility.

Table 5

The test results on leaching
Timeafter 10 minafter 15 minafter 20 minafter 30 minafter 45 minafter 60 min
The average level of leaching (%)75,7of 83.488,594,099,7100,9

Industrial application of the Britania

This invention provides a ready preparative form, which is perfectly masks the unpleasant taste of the medicine and which gives a pleasant feeling when administered orally and therefore easily eaten even the elderly, children and patients suffering from dysphagia. Specified pharmaceutical finished formulation form is also applicable to the introduction of using the tube.

1. Granulated pharmaceutical composition comprising a granular material, comprising a medicinal substance having an unpleasant taste, and wax; and eritra.

2. Granulated pharmaceutical composition according to claim 1, where the drug having an unpleasant taste, slightly soluble in wax.

3. Granulated pharmaceutical composition according to claim 1, where the drug having an unpleasant taste, soluble in water and poorly soluble in the wax.

4. Granulated pharmaceutical composition according to any one of claims 1 to 3, where the wax has a melting point of 40-150°C.

5. Granulated pharmaceutical composition according to any one of claims 1 to 4, wherein the wax is a substance selected from the group consisting of hydrogenated oils, fats, and oils of vegetable or animal origin, higher alcohols, glycols, higher fatty acids, glycerides of fatty acids, esters of fatty acids with sugar is Oh, and combinations of two or more of these components.

6. Granulated pharmaceutical composition according to any one of claims 1 to 5, where the drug having an unpleasant taste selected from the group consisting of hydrochloride of cetraxate, acappela, nefiracetam, hydrochloride talampicillin, hydrochloride indenolol, hydralazine hydrochloride, chlorpromazine hydrochloride, hydrochloride tiaramide, berberine chloride, digitoxin, sulpiride, hydrochloride azelastina, hydrochloride etilefrine, diltiazem hydrochloride, hydrochloride propranolol, chloramphenicol, aminophylline, erythomycin, clarithromycin, phenobarbital, calcium Pantothenate, hydrochloride indeloxazine, hydrochloride aminoguanidine, hydrochloride bifemelane, hydrochloride 1-(isopropoxycarbonyl)ethyl ester 7β-[2-(2-aminothiazol-4-yl)-2(Z)-hydroxykynurenine]-3-N,N-dimethylcarbamoyl-3-teamcasanova acid, (E)-3-(2-methoxy-3,6-dimethyl-1,4-benzoquinone-5-yl)-2-[5-(3-pyridyl)pentyl]-2-propanolol acid, aminophylline, theophylline, diphenhydramine, metoclopramide, phenylbutazone, phenobarbital, ampicillin, cimetidine, famotidine, nizatidine, acetaminophen, epirizole, pyrazinamide, caffeine, ethionamide, carvedilola, ranitidine hydrochloride, hydrochloride acetate roksatidina, imipramine hydrochloride, ephedrine hydrochloride, hydrochl the reed diphenhydramine, hydrochloride tetracycline, hydrochloride doxycycline, hydrochloride nafazolina, hydrochloride of noscapine, papaverine hydrochloride, hydrobromide of dextromethorphan, bromide of timepice, maleate of chlorpheniramine, tartrate of alimemazine, hydrochloride pilsicainide, methyl sulfate N-methylscopolamine, maleate cinepazide, arginine hydrochloride, histidine hydrochloride, lysine hydrochloride, lysine acetate; crude drugs or their extracts, derivatives of pyridonecarboxylic acid represented by the formulas (1) through (4) and their salts:

where each of R1a, R1band R1cmeans C1-C6 linear or branched alkyl group which may have a Deputy, C3-C6 cyclic alkyl group which may have a Deputy, aryl group which may have a Deputy, or a heteroaryl group which may have a Deputy;

each of R2aR2b, R2cand R2dmeans a hydrogen atom or a C1-C6 linear or branched alkyl group which may have a Deputy; or amino group;

each of R3a, R3b, R3cand R3dmeans a hydrogen atom or a halogen atom;

R4aor R4cmeans a hydrogen atom, halogen atom, C1-C6 linear or branched alkylene the group, which may have a Deputy; or C1-C6 linear or branched CNS group which may have a Deputy;

R5dmeans a hydrogen atom or a C1-C6 linear or branched alkyl group which may have a Deputy, and each of the Ya, Yb, Ycand Ydmeans a nitrogen-containing group.

7. Granulated pharmaceutical composition according to any one of claims 1 to 5, where drug having an unpleasant taste is ofloxacin.

8. Granulated pharmaceutical composition according to any one of claims 1 to 5, where drug having an unpleasant taste is levofloxacin.

9. Granulated pharmaceutical composition according to any one of claims 1 to 5, where drug having an unpleasant taste is sulfate clopidogrel.

10. Granulated pharmaceutical composition according to any one of claims 1 to 9, where the drug having an unpleasant taste, and wax are mixed in a ratio of from 1:1 to 1:5 by weight and the composition has a content of eritria at least 10% by weight.

11. Granulated pharmaceutical composition according to any one of claims 1 to 10, which is obtained by melting the wax when heated by dispersing or dissolving therein a medicinal product, which has an unpleasant taste primary granulation mixture with the formation of granulirovanie the th product and mixing the granulated product with erythritol or secondary granulation granulated product and eritria.

12. Granulated pharmaceutical composition according to any one of claims 1 to 11, where the primary granulation is a spray granulation.

13. Granulated pharmaceutical composition according to claim 11 or 12, where the size of the particles obtained in the first granulation equal 50-200 microns.

14. Pharmaceutical product for oral administration, containing granulated pharmaceutical composition according to any one of claims 1 to 13.

15. Pharmaceutical product for oral administration for 14, which contains the dosage form of powder or granules.



 

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11 cl, 2 dwg, 11 ex

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57 cl, 14 tbl, 24 ex

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16 cl, 2 ex

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23 cl, 3 dwg, 8 tbl, 19 ex

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5 cl, 2 ex

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31 cl, 3 ex, 1 tbl

FIELD: medicine.

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EFFECT: higher efficiency.

1 tbl

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6 cl, 5 dwg, 13 ex, 3 tbl

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3 cl, 2 tbl

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4 cl

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23 cl, 3 dwg, 8 tbl, 19 ex

FIELD: medicine, cardiology, pharmacy.

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EFFECT: improved and valuable pharmaceutical properties of composition.

17 cl, 9 ex

FIELD: medicine, pharmacy.

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EFFECT: valuable medicinal properties of composition.

5 ex

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EFFECT: valuable medicinal and pharmaceutical properties of composition.

32 cl, 4 tbl, 1 ex

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