Solid dosage form for oral administration of pharmaceutically active substances that have adverse organoleptic properties

 

(57) Abstract:

Usage: in medical practice. The essence of the invention: solid pharmaceutical form, preventing adverse organoleptic properties of active substances, contains a core with an active substance coated with a polymer membrane, soluble at pH 5 and above. Dosage form contains one or more pharmaceutically acceptable organic acids. The acid may be: fumaric, citric, ascorbic and wine. The shell of the nucleus can be made of the following polymers: a copolymer of methacrylic acid and methyl methacrylate or ethyl methacrylate, talatalatat cellulose phthalate of oksipropilmetiltselljulozy, polyvinylacetate, shellac, activatestatusnotifications, carboxymethylcellulose, trimellitates cellulose and a copolymer of maleic acid and a derivative of phthalic acid. 6 C.p. f-crystals, 3 tables.

The invention relates to dosage forms containing the composition, which mask the taste of orally injected drugs.

Oral introduction of solid dosage forms, e.g. tablets, often causing problem swallowing in patients, especially in children and the elderly. For Wallpaper is bletcham, which quickly dissolved in the mouth or in full spoon of water, and a bag (sachet) with monodose, the contents of which are dissolved or suspended in a glass of water.

However, unfortunately, many drugs have an unpleasant, bitter or irritating taste and, therefore, it is necessary to mask the taste. For taste masking particles medication may be covered with a membrane, which prevents the release of medicines into the water (if it is in water before swallowing) and in the oral cavity during swallowing, but releases the drug after ingestion.

The most suitable membranes for this purpose are impervious to water and saliva, but which dissolve under the action of the environment of the gastrointestinal tract. Among the most acceptable membranes can lead those that are composed of polymers that are insoluble in water or in an acid environment, but soluble at pH 5, i.e. in the environment of the gastrointestinal tract. However, the pH of the saliva is also higher than this value, so that a partial dissolution of the membrane with the subsequent occurrence of an unpleasant taste may begin in the mouth.

For example, the famous oral preparation consisting of a core containing the drug with NC in water [1]

Now it was discovered that this difficulty can be eliminated or minimized by the addition of acidic substances to the oral input pharmaceutical forms, so the acid compounds are dissolved with the establishment of a microenvironment around the coated particles, which prevents the dissolution of the polymers made from the membrane. Consequently remains masking taste in the mouth when you cover the drug.

According to the invention offers a solid dosage form for oral administration consisting of a core containing the active substance and coated with a polymer membrane, which is soluble only at a pH of 5 or above. At this dosage form contains a pharmaceutically acceptable organic acid to reduce or prevent dissolution of the membrane in the oral cavity. The acid number 1-20% by weight of the total form.

The core may be, for example, by the medicine, for example, in crystalline form, or it may be granules containing the drug.

The form can be prepared by coating a core with a polymer that forms a polymer membrane, and adding acidic compounds.

As the organic acid lekarstvi wine.

The polymer shell of the nucleus can be made from a group of polymers comprising a copolymer of methacrylic acid and methyl methacrylate or ethyl methacrylate, talatalatat cellulose phthalate of hydroxypropylmethylcellulose, polyvinylacetate, shellac, accentuated the hypromellose, carboxymethylcellulose, trimellitates cellulose or a copolymer of maleic acid and a derivative of phthalic acid.

As the active substance form can contain, for example, an antibiotic or ibuprofen. The kernel size can be in the range of 100-1200 mm. Preferably the size of the kernel is 200-700 μm. Dosage form may be in the form of tablets or pouch (sachet).

The invention provides masking of the taste of the medicine contained in pharmaceutical formulations by coating a polymer membrane, which is soluble only at a pH of 5 or above. When this acidic compound reduces or prevents the dissolution of the membrane in the oral cavity.

According to the invention, the drug will be released only when the covered core (e.g., particles) pass through the stomach and reach the intestines where the pH is 6 or higher (this happens quickly, osobennaya is that can be obtained masking the taste of the action by using a membrane that is insoluble at high pH (above 5) and soluble at low pH (1.2 to 1.5), such as, for example, Eudragit E; it is insoluble in the oral cavity (and therefore has a beneficial effect on the masking of taste and soluble in the intestinal tract. However, if the movement of the dosage form is particularly fast, which may be particles of small size and an empty stomach, there is a risk of incomplete dissolution of the membrane and also incomplete absorption of the medication.

The invention also differs from that described in the patent EP-A-O 101 418, where the substance, for example, carbohydrates and polysaccharides, are added to compositions containing cover the drug, for example, semi-permeable and independent of pH membranes. These substances prevent or provide slowly allocation of drugs through the membrane, whereas in the present invention the acidic substances prevent the dissolution of the membrane covering the drug, not the dissolution of drugs.

The invention is particularly suitable for medication with particularly unpleasant taste or that can irritate the mouth; as illustrative, but not ogranichivaya, cimetidine, carboxymethylcysteine, thiopropyl, dextromethorphan hydrobromide, codeine and its salts, 5-aminosalicylic acid, macrolides, and antibiotics such as penicillin and its derivatives, erythromycin and its complex or simple esters (for example, roxithromycin), cephalosporin and tetracyclines. Before coating, it is advisable to pelletize the medication, although granulation is not significant.

However, the granulation is useful for optimizing the particle size distribution of the particles and can be essential when using known dry (seal) or wet technology.

Preferably the core (for example, containing the drug in crystalline or granular form) has a size in the range from 50, 100 or 200 µm to 1500, 1200, or 700 μm. The preferred interval size is 100-1200 μm, preferably 200-700 μm.

For masking the unpleasant taste of the medicine it is covered by a membrane consisting of polymers mentioned above, having pH-dependent solubility, and more specifically, polymers, insoluble in the acid environment and soluble at pH 5 or higher.

Cover the drug in these polymers can be carried out by a known method is 3 415 758 and 3 341 416 and in the European patent 0038585.

the floor in the trays to cover, as shown in the examples of the Italian patent 929112 and canadian patent 879042.

the floor in the liquefied layer, as shown in the examples in U.S. patent 3 186 827 and 3 253 944 D. E. Wurster.

Coated granules drugs are very thin and irregular and, therefore, have a large surface area. Due to the fact that the membrane has only a few micrometers thickness even at high mass percentage of the membrane, so within a short time, during which all or some portion of the particles remains fully or partially in the mouth, dissolution or swelling, even partial, of the membrane may occur with subsequent release of unpleasant taste.

Now it was discovered that this difficulty can be eliminated or minimized in accordance with the invention, if the recipe is to add an acidic substance in such quantity to maintain the microenvironment at pH below 5 during the stage of passage through the oropharyngeal cavity. Obviously, more acidic microenvironment better, although an excess of the acid itself can give a bad taste.

It was found that the optimum amount of acid varies in head is to be placed. As illustrative, but not limiting examples of acidic compounds can lead fumaric, citric and tartaric acids.

Compositions of the invention may be in a pharmaceutical form that is easy to give to children, the elderly and patients with difficulty swallowing. Examples are formulations of pills and a sack with monodose. Examples of tablets are tablets that can be chewed or which dissolve in the mouth or quickly desagregirutee (e.g., one minute) in small quantities (tablespoon) water pouches with monodose can be given directly or suspended in a small amount of water (e.g. 20-50 ml).

Example 1.

(A) Preparation of the granulate

Put 2000 of roxithromycin in a laboratory mixer, mixed with an aqueous solution consisting of 257 g of polyethylene glycol 6000 and 600 g of purified water.

Granularit on the 600 µm sieve and dry the granules at a temperature of approximately 45oC. Use fractions between 500 and 210 μm.

(B) Coating the granules in the liquefied layer.

Placed 350 g of Eudragit L 100-55, 121 g IH sodium hydroxide, 122,1 g of talc, 36 g of triethylcitrate, of 57.8 g Ozernoy perfumes and 1910 g of purified water in a vessel made of stainless Bunny insert Worcester, and sprayed a pre-prepared suspension via atomizer.

Dried granules at a temperature of about 50oC sifted through a sieve 600 micron.

The selection of the coated granules is determined in artificial juices in accordance with the method described in USP XXII (blade stirrer, 200 rpm./min, see table. 1

(C) Preparation of tablets

Put 346,8 g microcrystalline cellulose, 66 g Kollidon CL, 18 g of sodium saccharin, 90 g of fumaric acid, 6 g of lauryl sodium, 12 g of Aerosil, 30 g strawberry perfumes, 12 g of magnesium stearate and 451,2 g of granulate (B) in a cubic mixer.

Stirred for 20-25 min and pressed.

Tablet weight 172 mg contains 60 mg of roxithromycin.

The formulation of these tablets was studied, it was shown that they disintegrate in less than 30 s in a tablespoon of water or directly in the mouth. To maintain masking the taste is added fumaric acid, which supports the microenvironment at pH lower than that at which dissolves the membrane.

The resulting protection is satisfactory, indeed, as can be seen from the data presented in paragraph (C), the allocation under relatively acidic pH is low, therefore, unpleasant taste l is giant will be released in the intestinal tract, when will be achieved this pH, as shown by tests on bioavailability.

Example 2.

(A) Preparation of the granulate

Put 1400 g of ibuprofen in a laboratory mixer and mixed with a solution composed of 210 g of 95% ethanol and 37 g of ethyl cellulose.

Granularit on a sieve of 500 μm and dried granulate with approximately 45oC. Use the fraction between 500 and 210 μm.

(B) Coating the granules of coacervation

Prepare a solution of 1870 g of purified water, 100 g phthalate cellulose acetate and 25.7 sodium bicarbonate.

Prepare a solution containing 600 g of sodium sulfate in 2800 g of purified water. Placed in a container of pre-cooked solution phthalate cellulose acetate, a solution of 1500 grams of sodium sulfate and 600 granulate (A). Stirred for about 5 minutes and add the remaining solution of sodium sulfate.

Filtered the obtained microcapsules and washed with water until, until you remove the sodium sulfate. Dried microcapsules at approximately the 50oC for 3-4 h and sieved through a sieve 600 micron.

Determine the allocation of the coated granules in artificial juices in accordance with the method described in USP XXII (blade stirrer, 150 rpm./min, see table. 2.

Stirred for 20-25 min and pressed.

One tablet weighing 40 6,5 mg contains 200 mg of ibuprofen.

Formulation of tablets examined by the method of example 1, to obtain rapid disintegration in the mouth or in a tablespoon of water and add fumaric acid to maintain the microenvironment at acidic pH.

Example 3.

(A) Preparation of the granulate

Put 2000 erythromycin in laboratory mixer and stirred for about 20 min with 1380 g of an aqueous solution of 15% hydroxypropylmethylcellulose. Granularit through a sieve 720 μm and dried in an oven at approximately 40oC for 15-20 h

Use fraction between 500 and 210 μm.

(B) Coating the granules in the liquefied layer

Put 550 g of granulate (A) (500-210 ám) UNI Glatt container with liquefied layer with insert Wurster, and is sprayed through an atomizer 7140 g of a solution having the following composition: 428,7 g phthalate of hydroxypropylmethylcellulose, 21,3 g plasticizers 1340 g of ethyl alcohol, 5350 g of methylene chloride.

Dried is renal determine in artificial juices in accordance with the methodology described in USP XXII (blade stirrer, 100 rpm./min, see table. 3

(C) Preparation of bags with montazemi.

In a cubic mixer placed 2490 g of sorbitol, 165 g xanthan resin, 18 g of PVP K 30, 1.5 g of saccharin sodium, 37,5 g of citric acid, 112,5 g grapputo odorants, 22,5 g of talc, 0.4 g of sodium docusinate and 873 g of the granules (B).

Stirred for 20-25 min and divided into bags made of paper (aluminium) non-toxic polyethylene and sealed.

One 2400 g package monodose contains 250 mg of erythromycin.

Similarly to the procedure in examples 1 and 2 in the composition of the package add citric acid to preserve acidic pH and, therefore, mask the taste in the oropharyngeal cavity.

Similar results to maintain taste masking produced by adding acids in the finished recipe when replacing erythromycin a cephalosporin or penicillin and their derivatives.

1. Solid dosage form for oral administration of pharmaceutically active substances that have adverse organoleptic properties, consisting of a core containing the active substance coated with a polymer shell, characterized in that it further comprises a pharmaceutically prier 5 and above.

2. Form p. 1, characterized in that as organic acids it contains one or more acids selected from the group: fumaric, citric, ascorbic and wine.

3. Form PP.1 and 2, characterized in that the polymer shell is made of polymers selected from the group comprising a copolymer of methacrylic acid and methyl methacrylate or ethyl methacrylate, talatalatat cellulose, flatheadlibertybell, polyvinylacetate, shellac, accentuated the hypromellose, carboxymethylcellulose, trimellitates cellulose or a copolymer of maleic acid and a derivative of phthalic acid.

4. Form PP.1 to 3, characterized in that the active substance it contains an antibiotic or ibuprofen.

5. Form PP.1 to 4, characterized in that the kernel size is in the range of 100 to 1200 μm.

6. Form under item 5, characterized in that the kernel size is in the range of 200 to 700 μm.

7. Form PP.1 to 6, characterized in that it is made in the form of tablets or pouch (sachet).

 

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