Rapidly disintegrating molded in the forms of materials and method of production thereof

 

(57) Abstract:

The material includes a filler and eritra. The ratio of filler and eritria is 5-100 wt.%. The filler includes one or more organic fillers and/or one or more inorganic fillers. The organic filler is selected from starch, cellulose and sugar alcohol, an inorganic filler of synthetic hydrotalcite, precipitated calcium carbonate and anhydrous dibasic calcium phosphate. Rapidly disintegrating extruded materials have a high capacity for disintegration and dissolution in the oral cavity or water, and so taking them is not difficult. Both materials have high hardness and therefore have good storage stability in the production process and delivery. Tablets using the new extruded materials useful for the elderly, children, or patients who have trouble swallowing. 2 C. and 20 C.p. f-crystals, 20 PL.

The invention relates to a rapidly disintegrating pressovannom in the forms of material, which is in practice sufficient strength during the processing of the compositions in the field of pharmaceuticals and food products and is the procedure of obtaining such material.

Solid oral compositions known in the field of pharmaceuticals and food products include tablets, capsules, lozenges, razzhevyvanie tablets, granules and powders. However, many compositions are adapted for easy ingestion by patients. There is a need to develop compositions, easily handled and convenient for swallowing the elderly, children and patients who have trouble swallowing. The lack of tablets and capsules is that they must when taking drink water. In addition, when the pill is large or when receiving a large number of pills patients have difficulty swallowing or tablet can become stuck in the throat or esophagus. These problems are very serious, especially for the elderly, children and patients who have trouble swallowing. Blockage of the throat sometimes leads to suffocation in these patients, and drugs, gets stuck in the esophagus, can cause inflammation. Tablets are medicines, gradually dissolving or disintegrating in the mouth, while in the mouth or throat, and does not require pouring water. However, sushestvuete. Razzhevyvanie tablets do not need to drink water, they swallow after grinding, but they are not suitable for the elderly or children with weak chewing effort. Granules and powders for ingestion should be taken with water, their disadvantage is that they tend to remain in the mouth, causing asphyxia and pain, penetrating between the teeth.

In recent years, in severe cases, with difficulty swallowing apply the method of administration through a tube, in which medication is administered through oral or perinatally gastric tube catheter. The method mostly used in practice, is the introduction with a syringe in the gastric tube catheter suspension obtained by adding crushed tablets or granules, or powder medicines in its current form in 20-30 ml of water. However, these procedures are complex, and catheters sometimes have a tendency to clogging, since the internal diameter of the catheter is only 2-4 mm

In contrast to the above medications, there are several fast disintegrating or soluble drug prep the patients with difficulty swallowing.

For example, Japanese patent publication (kokoku) 50445/1987 describes a molded material having a mesh structure with an open matrix obtained by filling the forms for pressing, made of PVC sheet, an aqueous solution containing gelatin, mixed with medicinal material, cooling and freezing of the solution, and then freeze-drying the frozen solution. The publication indicated that the mesh structure with an open matrix has a density component of 10-200 mg/ml, rapidly disintegrates in the oral cavity for 1-5 seconds and eaten sputum, and so prevents the spit of her patients, who do not like to take medicines.

In addition to Japan intraoral soluble drug, known as Zydis (registered name), supplied by R. P. Scherer (England). The composition of the drug is unknown, but it is produced using the process of lyophilization. The advantage of a medicinal product, obtained by lyophilization, is that it quickly falls apart, however, is fragile and brittle to such an extent that its hardness cannot be measured. Moreover, the development of such a drug in promyshlennyy CLASS="ptx2">

International patent publication WO 93/12769 describes intraoral disintegrating composition obtained by suspension drug substance, lactose and mannitol aqueous solution of agar gel solution to gel-like state by the Gulf of solution in the mold of a sheet of polypropylene made from RTR (inflator module with cells), drying the gel under reduced pressure and then sealing Packed in RTR products aluminum foil (blister pack). The obtained molded material has a density component 400-1000 mg/ml and disintegrates in the oral cavity for 5-20 seconds. The publication indicated that the hardness of the molded material is approximately 2 kg, and its removal from the blister pack (RTR) does not lead to cracking, breaking or crushing. However, since the molded material has low strength in comparison with conventional tablets, this material may be Packed in different packaging than blister (RTR), such as a bottle. The production of such material on an industrial scale is difficult, because its manufacture requires a long time.

Describes several interiorally decaying component is (kokai) 271054/1993 describes intraoral disintegrating composition, obtained by tableting a mixture containing a pharmaceutically active ingredient, a carbohydrate and a small amount of water for wetting the surface of the particles of the carbohydrate.

International patent publication WO 93/15724 describes a quick-dissolving tablet that has two features:

(1) the main component of the pill is a drug additive having a high dissolution rate in water, and

(2) in the manufacturing process of tablets containing medicinal material by wet granulation, the stirred mixture of medicinal material and medicinal additives having a high dissolution rate in water, is subjected to pressing in molds and then dried.

Posted in Japanese patent application (kokai) 218028/1994 describes the following:

(1) method of molding to obtain tablets by wet method, comprising filling the forms wet mixed material and forming with the use of pressing forms, and

(2) method of molding to obtain tablets with a wet method in which before pressing the wet pellets in the pressed or pressovanne-monotonous surface wet tablets cause the powder to prevent them sticking of the tablets by downloading the wet powder into the holes for molding pellets and molding the powder into tablets, the form is used after blending prevent the sticking of the film to at least one surface of the above-mentioned wet powder inside the hole.

Because these methods include wet pelleting, while forming them use the humidifier, and the molding is carried out at low pressure. Therefore, they produce porous tablets with emptiness after drying, soft and easily disintegrating.

However, because these methods include loading and pressing the wet powder with low fluidity, their disadvantage is that the number of downloaded material varies and often is sticking. Moreover, they require special equipment for drying soft molded material retains shape, with production on an industrial scale low.

To solve this problem was developed interiorally disintegrating composition obtained by the method of dry tabletting, having a high performance.

Posted in Japanese patent application (kokai) 310558/1993 describes obtaining well-disintegrating solid composition of the medicinal product, ensuring reduce dreadinny or gelatin, etc., by mixing mannitol or lactose, having a low bonding and molding characteristics, and the powder or granular sorbitol having a bulk density of 60 g/100 ml

International patent publication WO 95/20380 describes intraoral rapidely extruded to form a product having a high ability to disintegration and solubility in the oral cavity, which is obtained by incorporating the saccharides having a low molding characteristics, and saccharides having high molding characteristics. In this publication indicate that extruded in the form of the product has a hardness of 3-6 kg for tablets with a diameter of 10 mm and the time of the dissolution in the oral cavity 15-25 seconds. However, pressure forming is 50-400 kg/kick (64-509 kg/cm2) and is quite low in comparison with the conventional pressure stamping, constituting approximately 1000 kg/cm2. This implies that the resulting molded product is fragile compared to conventional tablets and has a very low shock if dropped.

The tablet obtained by molding at low pressure forming, have a high potential for disintegration and dissolution rate, but low hardness. Tablet is integratsii and the rate of dissolution.

Conventional tablets possess high hardness, prevent them from breaking in the processes of production and delivery; however, because their purpose is the release of the pharmaceutically active ingredient by disintegration and dissolution of oral input pills in the digestive tract, they are not designed for quick disintegration and dissolution in the oral cavity. Hence, these pills have insufficient capacity to disintegration and solubility in the oral cavity. None of the known types of tablets do not have a high potential for disintegration and dissolution in the oral cavity and simultaneously high hardness.

There is therefore a need for tablets with high capacity for disintegration and dissolution when hit in the mouth or water and not destroyed in the process of production and delivery.

The aim of the present invention is the provision of a rapidly decaying compacted in the forms of material having a high capacity for disintegration and dissolution when hit in the mouth or water, as well as high strength to prevent its destruction in the process of production and delivery.

The other I quickly disintegrating molded in the form of material, having excellent characteristics as mentioned above, do not include the complex stages and does not need complicated equipment using the dry method is usually used to obtain tablets.

To solve the above problems were conducted thorough research, and quite unexpectedly, it was found that the tableting mixture of erythrite and ingredient selected from organic and inorganic fillers, results in a rapidly decaying compacted in the forms of material having a high capacity for disintegration and dissolution when hit in the mouth or water, as well as high strength to prevent its destruction in the production process, ensuring, thus, the composition of the invention.

Accordingly, the present invention provides a rapidly decaying extruded in the form of the material, characterized in that it comprises (a) a filler and (b) eritra.

Embodiments of the invention

In the context of this description the expression "rapidly disintegrating extruded in the form material" means extruded to form a material having practically sufficient strength for process the invention, include inorganic fillers and organic fillers selected from starch, cellulose and sugar alcohols.

Examples of starches include corn starch, potato starch, wheat starch, rice starch, partially pre-gelatinising starch, pre-gelatinising starch, hydroxypropionic starch and starch carboxymethyl sodium. Among these preferred starches are corn starch, partially pre-gelatinising starch and pre-gelatinising starch. The diameter of the grains starches used in this invention is not limited. However, the diameter of the grains of starch preferably should not exceed 500 μm considering the fact that the granules of a larger size usually cause rough feeling in the mouth.

Examples include cellulose, microcrystalline cellulose, powdered cellulose, nitrosamino hydroxypropylcellulose, carmellose, carmellose-Sa and cross-linked carmellose-Na. Among these cellulose are preferred microcrystalline cellulose, powdered cellulose, nizkozameshhennoj hydroxypropylcellulose, carmellose. The diameter of the grains of the cellulose used is below, that granules of larger size usually cause rough feeling in the mouth.

Examples of sugar alcohols include sugar alcohols in addition to Eretria; for example, D-mannitol, D-sorbitol, xylitol, ▫ maltitol, anhydrous maltose, water maltose, anhydrous lactic, water lactic and revitalizing syrup maltose. Among these alcohols, preferred are D-mannitol, xylitol and ▫ maltitol. The diameter of the grains of the sugar alcohols used in this invention is not limited. Preferably the diameter of the grains should be 500 μm or below taking into account the fact that the granules of a larger size usually cause rough feeling in the mouth.

Examples of inorganic fillers used in this invention include synthetic hydrotalcite, precipitated calcium carbonate, anhydrous doonally calcium phosphate, gidratirovannuyu silicon dioxide, light anhydrous silicic acid, calcium silicate, magnesium aluminosilicate, magnesium oxide and magnesium hydroxide. Among these fillers are preferred synthetic hydrotalcite, precipitated calcium carbonate and anhydrous doonally calcium phosphate. The diameter of the grains of the fillers used in this invention are not specifically limited. Prcno cause rough feeling in the mouth.

These fillers can be used individually or in combination.

Aritra the present invention is podslushivaet obtained by fermentation of glucose, and is chetyrekhtomnym sugar alcohol having the following formula:

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Eritra is a white crystalline powder having a melting point of 119oWith and easily soluble in water. The heat of dissolution of eritria is -42,9 cal/year / This podslushivaet, providing a feeling of coolness and freshness, does not exhibit water-absorbing properties and having a degree of sweetness equivalent to 70-80% of the sweetness of sugar. The diameter of the grains of eritria used in this invention are not specifically limited. However, due to the fact that the granules of a larger size cause rough feeling in the mouth, it is preferable to aritra having a diameter of grains of 500 μm or below.

The total amount of filler (a) and erythrite (b) is preferably 30-99 wt.%, more preferably 50-99 wt.% and most preferably 70-99 wt. % of the total mass quickly readimage extruded in the form of the material. Amount less than 30 wt.% leads to a lack of maintenance of these ingredients, which leads to Afleet 5-100 wt. %, more preferably 10-70 wt.% and most preferably 20-50 wt.%. In the absence of the filler (a) having problems pelletizing ("hat" phenomenon, in which the upper part of the tablet is broken horizontally like a hat), which can be prevented by adding a filler (a) to erythrite (b). On the other hand, if the ratio of filler (a) to erythrite (b) exceeds 100 wt.%, the content of eritria is insufficient, resulting in an increase in disintegration time and dissolution. In particular, when using cellulose, they are preferably added in an amount of 5-70 wt.%, more preferably 5-50 wt.% in relation to the number of Eretria.

Pharmaceutically active ingredients that can be used in this invention are not specifically limited; they may be added in accordance with the proposed use in the form of powder, crystals, oils, solvents or any other species. Instead of the active ingredients can be added to any other optional ingredients. Examples of such optional ingredients below.

Examples of vitamins include vitamin a, vitamin D, vitamin (such as d--tocopherol acetate), vitamin B1(such as t the e), vitamin C (as ascorbic acid and sodium ascorbate), vitamin B12(such as hydroxocobalamin acetate), nicotinamide, calcium Pantothenate, one.

Examples of antipyretics, analgesics, anti-inflammatory drugs include aspirin, acetaminophen, ethenzamide, ibuprofen, Ketoprofen, indomethacin and aminopyrine.

Examples of antihistamines include alimemazine tartrate, chlorpheniramine maleate, diphenhydramine hydrochloride, clemastine fumarate, carbinoxamine maleate, dimenhydrinate and meclizine hydrochloride.

Examples funds cough include codeine phosphate, Dihydrocodeine phosphate, dextromethorphan hydrobromide, noscapine and noscapine hydrochloride.

Examples of bactericidal substances include pyridinium chloride, dequalinium chloride, chlorhexidine chloride, iodine and modesty potassium.

Examples of antacids means include a silicate of magnesium, alumosilicate magnesium, synthetic hydrotalcite, synthetic aluminum silicate, magnesium oxide, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, anhydrous doonally calcium phosphate and extract scopolia (scopolia).

Examples of medicinal raw materials include aloe, fennel, bark Fel is Shen, the bark of mallotus, tubers chubarky and herb ephedra.

Examples of means for protection of the gastric mucosa include cetraxate hydrochloride, sodium azulene sulfonate, aldioxa, L-glutamine, sodium-copper chlorophyllin, methylmethane of sulfonyl chloride.

Examples painkillers antispasmodics include M-metilscopolamine the methyl sulfate, scopolamine hydrobromide, atropine methyl bromide, metilscopolamine chloride, the extract of belladonna, scopolia extract, these aminobenzoate, scoplamine butyl and timeperiod bromide (timepidium).

Examples of anti-constipation include aloe, rhubarb, Bisacodyl and sodium picosulfate.

Examples of psychotropic drugs include timiperone, oxypertine, diazepam, nitrazepam, flunitrazepam, lorazepam, haloperidol and bromperidol.

Examples of antagonists of N2receptors include cimetidine, famotidine, ranitidine hydrochloride, nizatidine and roksatidina acetate hydrochloride.

Examples of the antiulcer funds include cetraxate hydrochloride, teprenone, sulpiride, sukralfat, plaunotol and gefarnate.

Examples of antibiotics include tetracycline, oxytetracycline, metatsiklina, doxycycline, minocycline, chloramphenicol and eritromicina.

Examples of Central nervous system stimulants include caffeine anhydrous caffeine and caffeine and sodium benzoate.

Pharmaceutically active ingredients in this invention can be used individually or in combination. Examples of preferred effective ingredients include antipsychotics, antihistamines, antagonists of N2-receptor anti-ulcer remedies, vitamins, gastrointestinal remedies, cough remedies and expectorants, anti-constipation, remedies against seasickness (motion sickness) and Central nervous system stimulants. Further, these ingredients can be added not only to pharmaceutical preparations for humans, but also to the veterinary pharmaceutical tools, agricultural chemicals and medical drugs for the diagnosis. The present invention also can be used in many cases where it may be useful, for example, in relation to healthy foods, nutritional supplements, to eliminate the bad breath, staining plaques, funds added to the bath, and detergents.

The amount of pharmaceutically active ingredients, more preferably 1-30 wt.% from the content of solids.

The present invention may contain various additives commonly used to obtain tablets, if they do not violate the properties of the materials according to this invention.

Examples of such additives include lubricating agents, disintegrators, diluents, binding agents, dyes, odorants, podslushivala, corrigentov, effervescent agents and surfactants.

Examples of lubricating agents include magnesium stearate, calcium stearate, stearic acid, talc, fatty acid esters of sucrose, polyethylene glycol and hydrogenated oils.

Examples of disintegrating agents include alginic acid, calcium alginate, powdered tragant, crosspovidone, powdered agar and bentonite.

Examples of diluents include lactose, sucrose, glucose, fructose, light anhydrous silicic acid, calcium silicate, and calcium lactate.

Examples of binding agents include acacia, sodium alginate, polymers of carboxyvinyl, gelatin, dextrin, pectin, sodium polyacrylate, pullulan, methylcellulose, hydroxypropylcellulose, hypromellose, polyvinyl alcohol, polyvinyl pyrrolidone and macrogol.

Examples of fragrances include oranges, lemons, peppermint and menthol. Examples of podslushivala include saccharin sodium, aspartame, the disodium glycyrrhizinate, Peconic Kapiolani (stevia) and thaumatin.

Examples of agents that enhance the taste, include sodium chloride, magnesium chloride, disodium inosinate, sodium L-glutamate and honey.

Examples of effervescent agents include a combination of acid, such as citric acid, tartaric acid or malic acid, and bases such as sodium bicarbonate or sodium carbonate.

Examples of surfactants include polyoxyl 40 stearate, sorbitane esters of fatty acids, polyoxyethylene-hydrogenated castor oil, Polysorbate, glyceryl the monostearate and sodium monododecyl sulfate.

The above additives may be added individually or in combination at any stage of the process of obtaining a rapidly decaying compacted in the forms of the material. For example, these additives may be added optionally in a suitable amount at the time of mixing the pharmaceutically active ingredient, filler (a) and Erie"ptx2">

Rapidly disintegrating compressed in the forms of material in accordance with this invention to obtain, for example, by pressing forms essentially dry composition containing the filler (a) and eritra (b). More specifically, a rapidly decaying extruded in the form of the material in accordance with this invention are obtained by the direct or poslerevolyutsionnogo drying of the filler (a), Eretria (b) and, optionally, a pharmaceutically active ingredient and the above-mentioned additives essentially to dryness, followed by pelletizing. The details of the process are described below.

Method 1

The filler (a), aritra (b) and, optionally, a pharmaceutically active ingredient and the above additives are mixed and pressed into forms (direct pressing method).

Method 2

The filler (a), aritra (b) and, optionally, pharmaceutically active ingredients and the above additives are mixed, formed into flakes, pressed in molds to obtain tablets or tablets large size, then crush them into granules, and, if desired, be connected with the above additives, dried to essentially dry state, followed by pressing in the form (the way tabletas asepticheski active ingredients and the above additives are mixed. The mixture granularit by adding water or an aqueous solution or suspension of starch and/or sugar alcohol with subsequent granulation. Granules essentially dried. Then optionally add the above additives. The resulting mixture is essentially dried and pressed into forms (compaction method by wet granulation).

Method 4

Pharmaceutically active ingredients are divided into groups a and b, and from them receive the relevant granules using the method of pressing by wet granulation (Method 3). If necessary, then add the above additives. The resulting mixture is dried to being to dryness, followed by pressing in the way of pressing the heterogeneous granules).

Rapidly disintegrating compressed in the forms of material in accordance with this invention will be received, using equipment normally used in the manufacture of medicinal preparations. Specifically, the mixing produced by using a mixer with dual drum granulator fluidized bed, granulation machine with mixer, nauta mixer or cross-rotary mixer.

To obtain extruded in the form of product in the form of flakes way is using rotary tablet machine.

Wet granulation is carried out, using a granulator, fluidized bed; rotary granulating machine, fluidized bed, causing the coating granulation machine with agitator; a cylindrical extrudible granulator or extrudible granulator wet.

Pressing in the forms performed by means of apparatus normally used for forming tablets. For example, using a tablet machine with a single punch, rotary tablet machine or a multi-layer rotary tablet machine.

Forming pressure during tableting can be arbitrarily set based on the hardness of moldable material, as well as the ability of moldable material to disintegration and dissolution when hit in the mouth or water. A characteristic feature of this invention is the fact that the ability of moldable material to disintegration and dissolution when hit in the mouth or water does not deteriorate significantly, even if the material was subjected to high molding pressure. Thus, the molding pressure may be the same as when receiving conventional tablets, i.e., 400-2000 kg/cm2, predpochtite 800-1600 mg/cm3preferably 1000-1400 mg/cm3. Set the hardness is not less than 2 kg, preferably 2-15 kg, more preferably 3-10 kg, if the diameter or the major length of the quickly disintegrating molded in the form of the material is 10 mm

Thus obtained rapidly decaying extruded in the form of the material has an excellent ability to disintegration and dissolution when hit in the mouth or water, high hardness and excellent resistance when dropped.

The ability to disintegrate and dissolve rapidly disintegrating molded in the form of the product according to this invention varies depending on the size of the product. Preferably disintegration time, measured in accordance with Japanese Pharmacopoeia (see the description of the method of determination of disintegration without the use of auxiliary drive this in the Japanese Pharmacopoeia, 12th edition, section "Tablets"), is 60 seconds in the case, if the diameter or the major length of the quickly disintegrating molded in the form of the material is less than 8 mm; 90 seconds if the size is not less than 8 mm and less than 10 mm; 120 seconds in the case, if the size is not IU the beam, if the size is not less than 20 mm, the ability to disintegration and dissolution in the oral cavity, measured from the conditions of the time required for disintegration or dissolution, is 40 seconds in the case, if the diameter or the major length of the quickly disintegrating molded in the form of the material is less than 8 mm; within 60 seconds if the size is not less than 8 mm and less than 10 mm; within 90 seconds if the size is not less than 10 mm and less than 15 mm; within 120 seconds in the case if the size is not less than 15 mm and less than 20 mm; and within 180 seconds in the case, if the size is not less than 20 mm, all the parameters are defined from the moment of placing material in the oral cavity. Specifically, the preferred disintegration time is usually 5-120mm seconds, preferably 5-60 seconds, more preferably 5-30 seconds, if the diameter or the major length of the quickly disintegrating molded in the form of the material is less than 10 mm, and the time required for disintegration and dissolution in the oral cavity (i.e., the time required for complete dissolution of the tablet in the oral cavity of a healthy adult without water, but only with the help of saliva) is usually 5 to 90 seconds, preferably risovanny in the forms of material in accordance with this invention disintegrates or dissolves in the presence of saliva. The use of pressure in the oral cavity, in particular the pressure of the upper jaw, and tongue, or friction about language, in particular "litania" and so on , leads to a reduction in disintegration time or dissolution of the tablets. If the pill is taken by the patient with a dry mouth or a patient that produce less saliva, for the disintegration or dissolution of the tablet in the oral cavity can be used cold or warm water. Alternatively, the tablet in accordance with this invention can take exactly the same with the water, as conventional tablets.

Rapidly disintegrating extruded in the form of the material according to this invention does not disintegrate or dissolve instantly (for example, within 1 second), which gives the patient the opportunity to obtain intraoral sensory feeling or desire to spit out the pill.

The hardness (measured by the device for determining the hardness of the tablets quickly disintegrating molded in the forms of material in accordance with this invention is usually not less than 2 kg, preferably 2-15 kg, more preferably 3-10 kg, if the diameter or the major length of the quickly disintegrating molded in the form of the material is 10 mm shockproof if dropped (provided the Lee and defined as { (damaged tablet)/ (researched tablets)} 100 (%)), typically, approximately 0-50%, preferably 0-20%, more preferably 0%.

Thus, a rapidly decaying extruded in the form of the material in accordance with this invention has a high hardness, not allowing him to break during production and delivery. The tablet also satisfactorily bear the operation for its removal from the blister pack (RTR). Moreover, the tablet has a hardness that allows you to sack her vials (i.e., packaging containers, e.g. glass or plastic). Upon release tablets of aluminum sheet, blister (RTR) if the tablets have a diameter of 8 mm, it is preferable that they had a hardness of 1 kg or higher, and if the tablets have a diameter of 10 mm, it is preferable that they had a hardness of 2 kg or above, although the size and shape of the tablets can change the range of this characteristic. When packing vials tablets with 10 mm in diameter, preferably have a hardness of 3 kg or above in order to withstand the stresses to which they may be exposed during the delivery process.

Rapidly disintegrating compressed in the forms of material in accordance with this izobreteniem. Also, because eritra is a sugar alcohol, the reaction of Malaga (Mallard) (in which the amino acid and saccharide become light-brown, also known as the amino-carbonyl reaction) occurs. It is preferable in the sense that the presence pharmaceutical ingredient having an amino group, prevents the appearance of brown color, which leads to improved stability in time.

Rapidly disintegrating compressed in the forms of material in accordance with this invention is used as a medicinal product, which can easily take elderly patients or children or as a medicinal product safely accept normal older patients, for the treatment or prevention of various diseases in the same way as conventional medicines. The material also has excellent ability for long-term storage and stability.

Form a rapidly decaying compacted in the forms of material in accordance with this invention are not specifically limited. Examples of the form of tablets include triangular, square, round, animal, incorrect (type Caplets), all in the form of a ring (x recognition can be letters or other designations. Tablets can be coated using the method of coating is usually applied when getting drugs from the floor.

The present invention is hereinafter described in detail and with examples, which should not be construed as limiting the invention.

Test methods

For a more complete description of this invention the tablets obtained in Comparative Examples and Examples, have the following characteristics of the medicinal product.

(1) Test for hardness

For measuring the hardness in the direction of the diameter used the device for determining the hardness of tablets (manufactured by Freund Sangyo K. K.; a device for determining the hardness of tablets Schleuniger). The test was subjected to 5 tablets and calculated the average.

(2) Test on an intraoral disintegration and dissolution

Testing was attended three healthy adult males (ages 25, 30 and 30 years). We measured the time required for complete disintegration or dissolution of the tablets in their intra-oral saliva (without water). I calculated the average result obtained from three people.

(3) the Test for disintegration

In accordance with the test for disintegration of telego disk device for determination of disintegration, produced Toyama Sangyo K. K.). The test was subjected to 6 tablets and calculated the average.

(4) Test the resistance in the fall

The tablet was dropped from a height of 50 cm on a plate of stainless steel and has determined the extent of damage. In each case the test was subjected to 10 tablets, and determined the extent of their damage.

(5) Pressure punching

Measured pressure forming. Shows the pressure forming impact (kg/shot), and corresponding values, translated in pumping pressure per unit area (kg/cm2); the results are presented as average pressure.

(6) the Density tablets

Measured the mass and thickness of 10 tablets. To determine the density of the tablets used average measurement results. The density of tablets = (weight of the tablet)/(volume pills).

Comparative Example 1

For comparison, aritra (product Nikken Chemical Co., Ltd., passing through a sieve of 42 mesh (350 microns) and lactose were placed in a granulator with a mixer in the amounts shown in Table 1 (composition, see number 1). The ingredients were mixed for 3 minutes and then was added water (40 ml) for granulation. After granulating the obtained granules were dried, isogram was added magnesium stearate (0.5. %), and then stirred. The resulting mixture was molded into tablets with a flat surface and rounded edges and a diameter of 10 mm, using a tablet machine with a single punch. Tablets, each weighing 400 mg, was obtained using three different values of pressure forming. The results of tests conducted with the tablets thus obtained, are shown in Table 2 (columns marked with 1).

Comparative Example 2

For comparison, repeating the procedure of Comparative Example 1 on the basis of the composition given in Table 1 (composition indicated by figure 2), using anhydrous glucose instead of lactose. The results of tests conducted with the thus obtained tablets, are shown in Table 2 (column 2).

Comparative Example 3

For comparison, repeating the procedure of Comparative Example 1 on the basis of the composition given in Table 1 (composition indicated by figure 3), using sucrose instead of lactose. The results of tests conducted with the thus obtained tablets, are shown in Table 3 (column 3).

Comparative Example 4

For comparison, aritra (product Nikken Chemical Co., Ltd., passing through the sieve size 42 mesh (350 microns) and lactose on Uchenna figure 4). The ingredients were mixed for 3 minutes and then was added 5 wt./about. % aqueous solution of polyvinyl alcohol (200 ml) for granulation, while the air pressure when spraying was 2 kg/cm2and the rate of spraying 20 ml/min After drying the obtained granules were sifted through a sieve size of 16 mesh (1000 μm). To the sifted granules were added magnesium stearate (0.5%), and then stirred. The resulting mixture was molded into tablets with a flat surface and rounded edges and a diameter of 10 mm, using a tablet machine with a single punch. Tablets, each weighing 400 mg, was obtained using three different values of pressure forming. The results of tests conducted with the thus obtained tablets, are shown in Table 3 (column identified by the number 4).

Example 1

Eritra (product Nikken Chemical Co., Ltd., passing through the sieve size 42 mesh (350 μm) and corn starch were placed in a granulator fluidized bed in the quantities listed in Table 4 (composition, see number 1). The ingredients were mixed for 3 minutes and then added to water (800 ml) for granulation, while the air pressure when spraying was 2 kg/cm2and the rate R is Roseanne the granules was added magnesium stearate (0.5%), and then stirred. The resulting mixture was molded into tablets with a flat surface and rounded edges and a diameter of 10 mm, using a tablet machine with a single punch. Tablets, each weighing 400 mg, obtained using three different values of pressure forming. The results of tests conducted with the thus obtained tablets, are given in Table 5 (columns marked with 1).

Example 2

Repeating the procedure of Example 1 based on the compositions shown in Table 4 (composition indicated by figure 2), using microcrystalline cellulose instead of corn starch. The results of tests conducted with the thus obtained tablets, are given in Table 5 (column 2).

Example 3

Repeating the procedure of Example 1 based on the compositions shown in Table 4 (composition indicated by figure 3), using corn starch, microcrystalline cellulose and partially pre-gelatinising starch instead of corn starch. The results of tests conducted with the thus obtained tablets, are shown in table 6 (column 3).

Example 4

Repeating the procedure of Example 1 based on the composition shown in That the partially pre-gelatinising starch instead of corn starch. The results of tests conducted with the thus obtained tablets, are shown in table 6 (column 4).

Example 5

Eritra (product Nikken Chemical Co., Ltd., passing through the sieve size 42 mesh (350 μm) and corn starch were placed in a granulator fluidized bed in the quantities listed in Table 7 (composition, see number 5). The ingredients were mixed for 3 minutes and then was added 20 wt. /about. % aqueous solution of D-mannitol (175 ml) for granulation, while the air pressure when spraying was 2 kg/cm2and the rate of spraying of 18 ml/min

After drying the obtained granules were sifted through a sieve size of 16 mesh (1000 μm). To the sifted granules were added magnesium stearate (0.5. %), and then stirred. The resulting mixture was molded into tablets with a flat surface and rounded edges and a diameter of 10 mm, using a tablet machine with a single punch. Tablets, each weighing 400 mg, was obtained using three different values of pressure forming. The results of tests conducted with the thus obtained tablets listed in Table 8 (column identified by the number 5).

Example 6

Repeating the procedure of Example 5 on the basis of complacency cellulose instead of corn starch. The results of tests conducted with the thus obtained tablets listed in Table 8 (column 6).

Example 7

Eritra (product Nikken Chemical Co., Ltd., passing through the sieve size 42 mesh (350 μm) and corn starch were placed in a granulator fluidized bed in the quantities listed in Table 9 (composition, see number 7). The ingredients were mixed for 3 minutes and then was added to 70 wt./about. % aqueous solution of xylitol (32 ml) for granulation, while the air pressure when spraying was 2 kg/cm2and the rate of spray - 6 ml/min After drying the obtained granules were sifted through a sieve size of 16 mesh (1000 μm). To the sifted granules were added magnesium stearate (0.5. %), and then stirred. The resulting mixture was molded into tablets with a flat surface and rounded edges and a diameter of 10 mm, using a tablet machine with a single punch. Tablets, each weighing 400 mg, was obtained using three different values of pressure pressing. The results of tests conducted with the thus obtained tablets listed in Table 10 (column identified by the number 7).

Example 8

Repeating the procedure of Example 7 based on the composition, when is ellulose instead of corn starch and stirring for 3 minutes, and then using an 8 wt. /about. % aqueous solution of xylitol (200 ml). The results of tests conducted with the thus obtained tablets listed in Table 10 (column 8).

Example 9

Eritra (product Nikken Chemical Co., Ltd., passing through the sieve size 42 mesh (350 μm)) and synthetic hydrotalcite was placed in a granulator, fluidized bed in the quantities specified in Table 11 (composition, see number 9). The ingredients were mixed for 3 minutes and then added to water (800 ml) for granulation, while the air pressure when spraying was 2 kg/cm2and the rate of spraying 20 ml/min After drying the obtained granules were sifted through a sieve size of 16 mesh (1000 μm). To the sifted granules were added magnesium stearate (0.5. %), and then stirred. The resulting mixture was molded into tablets with a flat surface and rounded edges and a diameter of 10 mm, using a tablet machine with a single punch. Tablets, each weighing 400 mg, was obtained using three different values of pressure forming. The results of tests conducted with the thus obtained tablets, are shown in Table 12 (column indicated by figure 9).

Example 10

Repeated procedures is established calcium carbonate instead of synthetic hydrotalcite. The results of tests conducted with the thus obtained tablets, are shown in Table 12 (column 10).

Example 11

Eritra (product Nikken Chemical Co., Ltd., passing through the sieve size 42 mesh (350 μm) and ascorbic acid were placed in a granulator fluidized bed in the quantities specified in table 13 (composition indicated by figure 11). The ingredients were mixed for 3 minutes and then was added water (240 ml) for granulation, while the air pressure when spraying was 1.5 kg/cm2and the rate of spraying of 24 ml/min After drying the obtained granules were sifted through a sieve size of 16 mesh (1000 μm). To the sifted granules were added microcrystalline cellulose in amounts specified in Table 13 (composition indicated by the numeral 11) and magnesium stearate (0.5. %), and then stirred. The resulting mixture was molded into tablets with a flat surface and rounded edges and a diameter of 10 mm, using a tablet machine with a single punch. Tablets, each weighing 400 mg, was obtained using three different values of pressure forming. The results of tests conducted with the thus obtained tablets, are shown in Table 14 (column, indicated by the numeral 11).

Example 13

Eritra (product Nikken Chemical Co., Ltd., passing through the sieve size 42 mesh (350 μm)), cimetidine, microcrystalline cellulose and low substituted hydroxypropylcellulose respectively in the amounts shown in table 15, were placed in a granulator fluidized bed. The ingredients were mixed for 3 minutes and then was added to 8 wt./about. % aqueous solution of D-mannitol (100 ml) for granulation, while the air pressure when spraying was 1.5 kg/cm2and the rate of spraying 20 ml/min After drying the obtained granules were sifted through a sieve size of 16 mesh (1000 μm). To the sifted granules were added magnesium stearate (0.5%), and then stirred. The resulting mixture was molded into tablets with a flat surface and rounded edges, with a diameter of 10 mm, using a tablet machine with a single punch. Tablets, each weighing 400 mg, was obtained using three different values of pressure forming. The results of tests conducted with the thus obtained tablets, private,4 g) was placed in a granulator, fluidized bed. The ingredients were mixed for 3 minutes, and then added 3 wt./about. % solution of polyvinyl alcohol (2520 ml), containing an extract of scopolii (108 g) for granulation, while the air pressure when spraying was 1.75 kg/cm2and the rate of spray 120 ml/min After drying the obtained granules were screened for ordering through a sieve size of 16 mesh (1000 μm) to obtain pellets of A.

(2) Precipitated calcium carbonate (3000 g), magnesium hydroxide (1500 g), aritra (1050 g) and corn starch (240 g) were placed in a granulator, fluidized bed. The ingredients were mixed for 3 minutes, and then added 3 wt. /vol.% solution of polyvinyl alcohol (2000 ml) for granulation, while the air pressure when spraying was 2,75 kg/cm2and the rate of spray 120 ml/min After drying the obtained granules were sifted through a sieve size of 16 mesh (1000 μm) to obtain pellets Century

(3) Aritra (5490 g) and corn starch (306 g) was placed in a granulator, fluidized bed. Then was added 10 wt./vol.% solution extract scopolii (540 ml) and purified water (1700 ml) for granulation, while the air pressure when spraying was 1.5 kg/cm2and the speed of time is Holocene granules With.

(4) Light anhydrous silicic acid (6 g) and corn starch (102 g) was added to 1-menthol (12 g). The ingredients were well mixed and crushed in a mortar to obtain a tenfold diluted powder in 1-menthol.

(5) Granules (660 g) obtained in the procedure (1), granules (117 g) (procedure 2) and granules (1950) (procedure 3) were weighed respectively. The ingredients were added 60 g of tenfold diluted powder in 1-menthol obtained by the above procedure (4), and 45 g of magnesium stearate, followed by stirring. The resulting mixture was formed into tablets using a tabletting machine with a single punch, equipped with a standard concave punches having a diameter of 13 mm Tablets, each weighing 647,5 mg, was obtained using three different values of pressure forming. The results of tests conducted with the thus obtained tablets, are shown in Table 18.

Example 15

Eritra (product Nikken Chemical Co., Ltd., passing through the sieve size 42 mesh (350 μm)), corn starch, anhydrous caffeine, nitrate thiamine, pyridoxine hydrochloride, calcium Pantothenate, nicotinamide and aspartame in amounts shown in Table 19, were placed in a granulator with pseudois is the coffee (100 ml) for pelletizing when this air pressure when spraying was 1.5 kg/cm2and the rate of spray 15 ml/min After drying the obtained granules were sifted through a sieve size of 16 mesh (1000 μm). To the sifted granules were added tenfold diluted powder in 1-menthol (1 wt.%) (8.5 wt. parts of corn starch was added 1 wt. part 1-menthol and 0.5. part of light anhydrous silicic acid powder was obtained by mixing the ingredients and grinding them in a mortar) and magnesium stearate (0.5%), and then stirred. The resulting mixture was molded into tablets with a flat surface and rounded edges and a diameter of 8 mm using a tablet machine with a single punch. Tablets weighing 240 mg each, were obtained using two different values of pressure forming. The results of tests conducted with the thus obtained tablets, are shown in Table 20.

Industrial applicability

Rapidly disintegrating compressed in the forms of material in accordance with the present invention rapidly disintegrates and dissolves when it gets into the mouth or water, so it easy to swallow. It also has a high hardness, having excellent storage stability in the process pestware, it can be mainly used for the treatment and prevention of diseases in patients, particularly the elderly, children and patients who have trouble swallowing.

Moreover, in accordance with the process of this invention rapidly decaying extruded in the form of the material having the above excellent characteristics can be obtained very easily and does not require complex manufacturing steps or special equipment.

In addition, since the method according to this invention uses a method of dry tabletting, the material can be shaped into tablets, which are granules of different types or multilayer tablets. In addition, this method is applicable for the production of pharmaceutical preparations containing many ingredients in mutually varying quantities.

1. Fast-disintegrating extruded in the form of the material, characterized in that it comprises (a) a filler, which represents one or more organic fillers selected from starch, cellulose and sugar alcohol, and/or one or more ingredients selected from inorganic fillers, and (C) aritra, while otnowennii in the forms of material p. 1, in which the starch is one or more ingredients selected from corn starch, potato starch, partially pre-gelatinizing starch and pre-gelatinizing starch.

3. Rapidly disintegrating extruded in the form of the material under item 1, in which the starch is a corn starch.

4. Rapidly disintegrating extruded in the form of the material under item 1, in which the cellulose is one or more ingredients selected from microcrystalline cellulose, powdered cellulose, nitrosamines hydroxypropylcellulose and carmellose.

5. Rapidly disintegrating extruded in the form of the material under item 1, in which the sugar alcohol is one or more ingredients selected from D-mannitol, xylitol and maldita.

6. Rapidly disintegrating extruded in the form of the material under item 1, in which the inorganic filler is one or more ingredients selected from synthetic hydrotalcite, precipitated calcium carbonate and anhydrous dibasic calcium phosphate.

7. Rapidly disintegrating extruded in the form of the material under item 1, in which the cellulose representation is l for p. 1, in which the filler comprises microcrystalline cellulose and D-mannitol.

9. Rapidly disintegrating extruded in the form of the material under item 1, further comprising a cage.

10. Rapidly disintegrating extruded in the form of the material under item 9, in which the cage is a crosspovidone.

11. Rapidly disintegrating extruded in the form material according to any one of paragraphs. 1-10, which includes a pharmaceutically active ingredient.

12. Rapidly disintegrating compressed in the forms of material on p. 11, in which the pharmaceutically active ingredient is one or more components selected from vitamins, antipyretics, analgesics, anti-inflammatory drugs, antihistamines, tools, cough, bactericidal substances, antacid funds, medicinal raw materials, of means for protection of the gastric mucosa, pain spasmolytic, anti-constipation, antagonists of N2-receptor, antiulcer agents, antibiotics, antihypertensive drugs, anti-arrhythmic drugs, gastrointestinal funds face drugs, anti-motion sickness (motion sickness) and stimulat which the pharmaceutically active ingredient is one or more components, selected from hydrochloride of cetraxate, cimetidine, famotidine, hydroxychloride ranitidine, nizatidine hydrochloride and acetate roksatidina.

14. Rapidly disintegrating extruded in the form material according to any one of paragraphs. 1-13, in which the total amount of filler (a) and erythrite (b) is 30-99% of the total mass of rapidly disintegrating molded in the forms of material.

15. Rapidly disintegrating extruded in the form material according to any one of paragraphs. 1-14, which is a tablet.

16. Rapidly disintegrating extruded in the form material according to any one of paragraphs. 1-15, which in the measurement of disintegration in accordance with the method of its determination without the use of auxiliary disk disintegrates or dissolves within 60 s in that case, if the diameter or the major length of the quickly disintegrating molded in the form of the material is less than 8 mm; over 90 in that case, if the size is not less than 8 mm and less than 10 mm; 120 C if the size is not less than 10 mm and less than 15 mm; 180 in that case, if the size is not less than 15 mm and less than 20 mm; and within 240 in that case, if the size is not less than 20 mm

17. Rapidly disintegrating extruded to form the case, if the diameter or the major length of the quickly disintegrating molded in the form of the material is less than 8 mm; 60 seconds in the case, if the size is not less than 8 mm and less than 10 mm; over 90 in that case, if the size is not less than 10 mm and less than 15 mm; within 120 seconds in the case, if the size is not less than 15 mm and less than 20 mm; and within 180 s, if the size is not less than 20 mm

18. Rapidly disintegrating extruded in the form material according to any one of paragraphs. 1-17, which has a density of 800-1600 mg/cm3.

19. Rapidly disintegrating extruded in the form material according to any one of paragraphs. 1-18, which has a hardness of 0.5 kg or above in the case, if the diameter or the major length of the quickly disintegrating molded in the form of the material is less than 8 mm; hardness 1 kg or above in the case, if the diameter or the major length of the quickly disintegrating molded in the form of material is not less than 8 mm and less than 10 mm; hardness 2 kg or more, if the diameter or the major length of the quickly disintegrating molded in the form of material is not less than 10 mm and less than 15 mm; hardness of 3 kg or more, if the diameter or the major length of the quickly disintegrating molded in the form of material colaspidosoma extruded in the form of material is not less than 20 mm

20. A method of obtaining a quickly disintegrating molded in the form of material, characterized in that the essentially dry composition comprising (a) a filler and (C) aritra, are compressed in the forms used for the filler, which represents one or more organic fillers selected from starch, cellulose and sugar alcohol, and/or one or more ingredients selected from inorganic fillers, in respect of the specified filler (a) to erythrite (C) 5-100 wt. %.

21. The method according to p. 20, in which the pressing forms is a tableting.

22. The method according to p. 20 or 21, in which the pressure in the forms is 400-2000 kg/cm2.

 

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