Medicinal composition decomposing in mouth cavity rapidly and method for its preparing

FIELD: pharmaceutical technology, pharmacy.

SUBSTANCE: method involves addition sugar-alcohol and/or saccharide showing melting point by 5°C lower or above as compared with the first mentioned sugar-alcohol and/or saccharide to sugar-alcohol and/or saccharide followed by combined treatment of prepared powder by pressing and heating. Invention allows preparing medicinal compositions decomposing in mouth cavity rapidly being without water and showing light using owing to the presence of sufficient strength in preparing, transport in usual using. Method involves mixing, pressing and heating components that represent two or more sugar-alcohol and/or saccharide and active component wherein difference between melting points of one among two or more indicated sugar-alcohol and/or saccharide that shows the higher content and any remaining indicated two or more sugar-alcohol and/or saccharide is 5°C or above. Invention provides preparing strength rapidly soluble tablets.

EFFECT: improved preparing method, improved pharmaceutical properties of composition.

30 cl, 12 tbl, 28 ex

 

The technical field to which the invention relates.

This invention relates to medicinal compositions, rapidly disintegrating upon contact with the oral cavity, but also showing sufficient strength during manufacturing, transportation and application in the usual way, and the method of their manufacture.

Prior art

In a situation where society is rapidly aging, and the conditions of life change, there is an urgent need for the development of medicines that are easy to use and admission for the elderly, children and patients with limited fluid intake. In medicine standard solid preparations include preparative forms, such as tablets, granules, powders and capsules. However, such solid medicines cause some difficulties when receiving, require large amounts of water, and in addition, they are unpleasant to the taste. These problems are particularly serious when such drugs are elderly, children, or patients, restricted fluid intake. In addition, psychotic patients or others like them can when taking tablets or similar dosage forms immediately put them in her mouth, but later, when left alone, spit them out, instead of swallow.

Therefore, reported numerous studies with the frames and/or methods of manufacture and in Japan and abroad with the aim of providing solid dosage drugs, rapidly disintegrating or dissolving, even when they are in the mouth without water.

For example, in the case of " Zydis® Fast Dissolving Dosage Forms, drugs, dissolving in the oral cavity, commercially available from R.P.Scherer Ltd., or drugs, disintegrating in the oral cavity described in international patent application WO 93/12769 "Intrabuccally Disintegrating Preparation and Production Thereof", each product is made by filling pre-formed cells blister packaging solution or suspension of drug ingredients, and then the solution or suspension is subjected to drying by lyophilization or vacuum drying. However, such production methods require either drying by lyophilization or vacuum drying, and as a result the cost of production increases. Moreover, the disadvantage of the resulting tablets is that they are fragile and so fragile that it cannot withstand normal transportation.

According to the inventions described in patent applications JP 11-116464 A Rapid Dissoluting Solid Preparations and Production Process Thereof", WO 93/15724 Fast Soluble Tablets", or JP 6-218028 "Process and Apparatus for Forming Molded Tablets, and Molded Tablets, powder, containing a medicinal ingredient and a water-wetted, tabletroute, followed by drying. Such methods could be used to produce tablets having a very good ability to disintegration in the oral cavity and much more so on the s, but there are difficulties in weight control tablets as tabletroute wet powder. In addition, it requires special equipment as the production using conventional tabletiruemyh machines is almost impossible.

On the other hand, in patent applications JP 8-29105 "Pruduction Process of Fast Dissolving Tablets, and Fast Dissolving Tablets Produced by the Pruduction Process or JP 11-12161 A Process for Pruducing Intraoral Rapid-Disintegrating Preparations" describes a method of manufacturing the target of the drug, which includes tableting dry powder compacts at low pressure, the wetting CDs and then drying the wetted compacts. This method of manufacture also includes many stages, which increases the manufacturing time, thereby reducing its effectiveness.

However, all of the above manufacturing methods have the disadvantage as loss of use of the active ingredient, unstable in an aqueous environment, as this active ingredient is in contact with water for a long time.

The object of the present invention is a pharmaceutical composition, which quickly disintegrates when hit in the oral cavity and exhibits sufficient strength in the manufacture, transportation and use in the usual way and is extremely easy to use. Another object of the present invention is SP the method for producing a medicinal composition, needed easy to avoid contact between the active ingredient and water.

Description of the invention

As a result of intensive studies, the authors of the present invention discovered that the medicinal composition, rapidly disintegrating upon contact with the oral cavity and exhibiting sufficient strength at the time of manufacture, distribution and use in the usual way, can be obtained by adding to the sugar alcohols and/or saccharide of sugar alcohols and/or saccharide having a lower melting point than the first-mentioned sugar alcohols and/or saccharide, and then the combined processing of the obtained powder by mixing, pressing and heating.

More precisely, the present invention relates to a pharmaceutical composition obtained by at least mixing, pressing and heating, and a medicinal composition contains two or more of polyalcohols, xylytol and/or saccharides and active ingredient; and the difference between the melting points of two or more polyalcohols, xylytol and/or saccharides, which has a higher content of, and any of the remaining two or more polyalcohols, xylytol and/or saccharides is 5°s or greater.

The present invention also relates to a pharmaceutical composition obtained by at least mixing, pressing and nahrawan is, moreover, the pharmaceutical composition contains two or more polyalcohols, xylytol and/or saccharides and the active ingredient is unstable in an aqueous environment; and the difference between the melting points of two or more polyalcohols, xylytol and/or saccharides, which has a higher content of, and any of the remaining two or more polyalcohols, xylytol and/or saccharides is 5°s or greater.

The present invention also relates to a pharmaceutical composition obtained by at least mixing, pressing and heating, and a medicinal composition contains two or more polyalcohols, xylytol and/or saccharides and the active ingredient, melting point or decomposition which is 140° or more; and the difference between the melting points of two or more polyalcohols, xylytol and/or saccharides, which has a higher content of, and any of the remaining two or more polyalcohols, xylytol and/or saccharides is 5°s or greater.

The present invention also relates to a pharmaceutical composition obtained by at least mixing, pressing and heating, and a medicinal composition contains two or more polyalcohols, xylytol and/or saccharides and the active ingredient; the difference between the melting points of two or more polyalcohols, xylytol and/or saccharides, which has a higher content of, and any of the remaining dahili more polyalcohols, xylytol and/or saccharides is 5° Or more; and a medicinal composition test wetting has time wetting 10 seconds or less.

The present invention also relates to a pharmaceutical composition obtained by at least mixing, pressing and heating, and a medicinal composition contains two or more polyalcohols, xylytol and/or saccharides and the active ingredient; the difference between the melting points of two or more polyalcohols, xylytol and/or saccharides, which has a higher content of, and any of the remaining two or more polyalcohols, xylytol and/or saccharides is 5°or more; and when released into the oral cavity pharmaceutical composition disintegrates within 30 seconds.

The present invention also relates to a pharmaceutical composition obtained by at least mixing, pressing and heating, and a medicinal composition contains two or more polyalcohols, xylytol and/or saccharides and the active ingredient; the difference between the melting points of two or more polyalcohols, xylytol and/or saccharides, which has a higher content of, and any of the remaining two or more polyalcohols, xylytol and/or saccharides is 5°or more; and a medicinal composition has the strength of 2 KF or higher.

The present invention also relates to a pharmaceutical composition obtained by at least mixing the cation, pressing and heating, and a medicinal composition contains two or more polyalcohols, xylytol and/or saccharides and the active ingredient; the difference between the melting points of two or more polyalcohols, xylytol and/or saccharides, which has a higher content of, and any of the remaining two or more polyalcohols, xylytol and/or saccharides is 5°or more; and the total weight content of two or more polyalcohols, xylytol and/or saccharides is 75,0 to 99.95% of the total weight of the medicinal composition.

The present invention also relates to a pharmaceutical composition obtained by at least mixing, pressing and heating, and a medicinal composition contains two or more polyalcohols, xylytol and/or saccharides and the active ingredient; the difference between the melting points of two or more polyalcohols, xylytol and/or saccharides, which has a higher content of, and any of the remaining two or more polyalcohols, xylytol and/or saccharides is 5°or more; and the weight content of two or more polyalcohols, xylytol and/or saccharides, which has the lowest melting point is from 0.3 to 50.0% of the total amount of remaining (remaining) two or more polyalcohols, xylytol and/or saccharides.

The present invention also relates to a pharmaceutical composition obtained by, at least, the shift of the air traffic management, pressing and heating, and a medicinal composition contains two or more polyalcohols, xylytol and/or saccharides and the active ingredient; the difference between the melting points of two or more polyalcohols, xylytol and/or saccharides, which has a higher content of, and any of the remaining two or more polyalcohols, xylytol and/or saccharides is 5°or more; two or more sugar alcohols and/or saccharide are erythritol and trehalose; and the content of trehalose is from 0.3 to 50.0% by weight content of Eretria.

The present invention also relates to a pharmaceutical composition obtained by at least mixing, pressing and heating, and a medicinal composition contains two or more polyalcohols, xylytol and/or saccharides and the active ingredient; the difference between the melting points of two or more polyalcohols, xylytol and/or saccharides, which has a higher content of, and any of the remaining two or more polyalcohols, xylytol and/or saccharides is 5°or more; two or more sugar alcohols and/or saccharide are erythritol and one of xylitol and sorbitol, and the contents of one of xylitol and sorbitol is from 0.3 to 50.0% by weight content of Eretria.

The present invention also relates to a pharmaceutical composition obtained by at least mixing, pressing and heating, the rich medicinal composition contains two or more polyalcohols, xylytol and/or saccharides and an active ingredient; the difference between the melting points of two or more polyalcohols, xylytol and/or saccharides, which has a higher content of, and any of the remaining two or more polyalcohols, xylytol and/or saccharides is 5°or more; two or more sugar alcohols and/or saccharide is mannitol and xylitol, sorbitol or trehalose, and the content of any one of xylitol, sorbitol and trehalose is from 0.3 to 50.0% by weight on the content of mannitol.

The present invention also relates to a method for producing a medicinal composition comprising the stage of obtaining a mixture of the active ingredient and two or more polyalcohols, xylytol and/or saccharides, pressing the mixture into a compact, and heating the compact, characterized in that the difference between the melting points of two or more polyalcohols, xylytol and/or saccharides, which has a higher content of, and any of the remaining two or more polyalcohols, xylytol and/or saccharides is 5°s or greater.

The best ways of carrying out the invention

Every pharmaceutical composition of the present invention is characterized in that it contains two or more sharpercv and/or saccharides, and the difference between the melting points of two or more polyalcohols, xylytol and/or saccharides, which has a higher content of, and any of the remaining two or more polyalcohols, xylytol and/or sharedbetween 5° With or more. Medicinal compositions of the present invention is produced using the procedure of sintering of sugar alcohols(s) and/or saccharide(s)point(s) whose melting point(s) below 5°or more than one of the two or more polyalcohols, xylytol and/or saccharides, which has the highest content. Used here, the term "sintering procedure" means the compact of the powder being heated near the melting point of a substance with a low melting point is contained in the CD, called adhesion between the powder particles and shrinkage and compaction of the CD, with the result being a rejection or seal of the CD. In the present invention the power of the connection between the particles can be increased by cooling the medicinal composition that contains sugar alcohols(s) and/or saccharide(s) with low melting point, after heating the drug compound near the melting point of lower temperature. In other words, the pharmaceutical composition may be cast or compacted, so that he might have strength sufficient to withstand actual use. In this regard, the expression "strength sufficient to withstand actual use" means sufficient strength to withstand the manufacture, distribution and use. In particular, when l is the drug composition is in the form of tablets, this refers to the degree of strength sufficient to withstand, without fracture, in the process of packing in blister packing or unpacking. In the case of tablets, a strength sufficient to withstand actual use varies depending on its size and shape. However, preferably, its strength can be 0.5 KF or above, when the diameter or maximum length of less than 8 mm; 1 KF or above, when the diameter or maximum length of 8 mm or more but less than 10 mm; 2 KF or above, when the diameter or maximum length of 10 mm or more, but less than 15 mm; 3 KF or above, when the diameter or maximum length of 15 mm or more, but less than 20 mm; or 4 KF and above, when the diameter or maximum length is 20 mm or more.

Suitable examples of sugar alcohols(s) and/or saccharide(s)contained in each of the medicinal composition of the present invention may include monosaccharides, disaccharides and polyalcohols, xylytol. Specific examples may include aritra, mannitol, lactic, lactose, glucose, sucrose, ▫ maltitol, xylitol, sorbitol, trehalose and fructose. Can be applied to any two of these saccharides and/or polyalcohols, xylytol, or can be used in combinations of three or more of them. However, it is preferable that the difference between the melting points of two or more polyalcohols, xylytol and/or sah is the reeds, which has a higher content of, and any remaining polyalcohols, xylytol and/or saccharides was 5°s or greater.

With regard to the content of the two or more polyalcohols, xylytol and/or saccharides, their appropriate limits are determined depending on the combination of the contained sugar alcohols(s) and/or saccharide(s) and production conditions. Below is a specific description of the contents of the sugar alcohols(s) and/or saccharide(s) for each of the medicinal composition of the present invention. It should be noted that the value of contents, below, are calculated without taking into account the active ingredient or ingredients, different from sugar alcohols(s) and/or saccharide(s), such as additives that can be entered if necessary. The content of sugar alcohols(s) and saccharide(s), which has the lowest melting point, preferably may be from 0.1 to 75% by weight of the total content of the other sugar alcohols(s) and saccharide(s), with the most preferred concentration in the range from 0.3 to 50.0% by weight.

In the case of the combination of erythrite and trehalose, trehalose content may preferably be from 0.1 to 75% by weight content of Eretria, with contents ranging from 0.3 to 50.0% is most preferable. In the case of the combination of erythrite with one of xylitol or sorbitol, the content of one of Xili the a and sorbitol may preferably be from 0.1 to 75% by weight content of Eretria, moreover, the contents in the range from 0.3 to 50.0% is most preferable. In the case of a combination of mannitol and one of xylitol, sorbitol or trehalose, the content of one of xylitol, sorbitol and trehalose may preferably be from 0.1 to 75% by weight on the content of mannitol, and content in the range from 0.3 to 50.0% is particularly preferable. In the case of the combination of lactose and one of xylitol, sorbitol and trehalose, the content of one of xylitol, sorbitol and trehalose may preferably be from 0.1 to 75% by weight from the lactose content, and content in the range from 0.3 to 50.0%, especially preferably.

Medicinal compositions of the present invention can have all the advantages of the present invention even when they contain one or more additives other than the above polyalcohols, xylytol and/or saccharides. Examples of additives are lubricants, disintegrant, diluents, binders, colorants, flavorings, sweeteners, effervescent agents, surfactants and glidant.

There are no special restrictions on the active ingredient for use in the present invention, if only it can be used orally. Suitable examples may include one or more active ingredients selected from vitamins, antipyretic-analgesic-prothiofos Alitalia drugs antihistamines, antitussive agents, agents for the treatment or recovery of the gastric mucosa, analgetika-inflammatory agents, antipsychotics, antiemetics, antidepressants, antagonists of H1receptors, chemotherapeutic drugs, antibiotics, depressors, anti-arrhythmia, anti-anxiety agents, ACE inhibitors. Every pharmaceutical composition of the present invention may contain the active ingredient, usually in proportions of from 0.05 to 75% by weight, preferably from 0.05 to 50.0% by weight and most preferably from 0.05 to 25% by weight.

Specific examples of such active ingredients may include thiamine hydrochloride, nicotinamide, aspirin, acetaminophen, indomethacin, diphenhydramine hydrochloride, procaterol hydrochloride, meklofenoxat hydrochloride, lorazepam, phenobarbital, timiperone, calcium para-aminosalitsilata, ampicillin, carmofur, captopril, nifedipine, procainamide hydrochloride, perindopril erbumine, alimemazine tartrate, lofepramine hydrochloride, isoniazid, baclofen, cetirizine hydrochloride, isoxsuprine hydrochloride, N-methylscopolamine the methyl sulfate, trihexyphenidyl hydrochloride, timiperone and oxypertine.

In addition, pharmaceutical compositions of the present invention can be manufactured without the use of water. Therefore, active the ingredients, unstable in water, especially suitable for pharmaceutical compositions according to the present invention. The term "active ingredient unstable in aqueous medium"as used here means that the storage conditions for three months at 25°C and a relative humidity of 75%, its content is reduced by 5% or more in comparison with the initial value. Examples are thiamine hydrochloride, nicotinamide, aspirin, acetaminophen, indomethacin, diphenhydramine hydrochloride, procaterol hydrochloride, meklofenoxat hydrochloride, lorazepam, phenobarbital, calcium para-aminosalitsilata, ampicillin, carmofur, captopril, nifedipine, procainamide hydrochloride and perindopril erbumine.

As every pharmaceutical composition of the present invention obtained by heating, for the present invention are suitable thermally stable active ingredients. The term "thermally stable active ingredient"as used here, means the active ingredient with a melting point or decomposition 140°C or higher. Examples are alimemazine tartrate, lofepramine hydrochloride, isoniazid, baclofen, cetirizine hydrochloride, isoxsuprine hydrochloride, N-methylscopolamine the methyl sulfate, trihexyphenidyl hydrochloride, timiperone and oxypertine and perindopril erbumine.

The medicinal composition of the present invention can be produced by obtaining a mixture of the active ingredient, two or more polyalcohols, xylytol and/or saccharides and one or more additives, which can be delivered if necessary, molding the resulting mixture and further heating the thus obtained compact.

Next, description will be given of the example presented in the present invention, a method of manufacturing a pharmaceutical composition.

The pharmaceutical composition according to the present invention can be implemented using commonly used equipment for the production of medicinal drugs.

The active ingredient and two sugar alcohols(a) and/or saccharide(a) are mixed together using a v-mixer, double-cone mixer, granulated dryer fluidized bed, granulator with a shift from moisture, Nauta mixer, etc.

The resulting mixture is then pressed into compacts with conventional teletrauma machine, such as teletrauma machine with a single punch or rotary teletrauma machine. The pressure in the pelletizing may be set depending on the strength of the compacts and their properties, disintegration or dissolution in the oral cavity. Thus, the pressure may range from 100 to 2000 kg or so, preferably from 200 to 1800 kgs or so, and most preferably from 300 to 1500 kgs or so.

Then using standard drying mA the ins, for example, a convection oven at a constant temperature drying oven at a constant temperature vacuum drying oven or microwave oven, the compact is heated to obtain the medicinal composition of the present invention. The temperature of the heating may be in the range of 60 to 180°C, preferably from 70 to 160°S, and most preferably from 80 to 140°C. the heating Time may be from 0.5 to 240 minutes, preferably from 1 to 120 minutes, and most preferably from 3 to 90 minutes.

At the stage of mixing, if necessary, may be added one or more additives. The method of manufacturing according to the present invention can be carried out with the additional inclusion of pelletising stage following the stage of mixing. Stage granulation can be performed using a granulating drying fluidized bed, granulator with a shift from moisture, drum-type granulator, granulator, fluidized bed, pellet mill-extruder, etc.

In this case, the granulation comprises wet granulation and dry granulation. The term "wet granulation", as used here, means that the wet granulation is performed using a solution or suspension prepared by adding and dissolving or suspension of one or more additives to the above sah is repertum and/or sugars as needed or water and holding wet granulation. Specific ways wet granulation include (1) granulation in the fluidized bed, which includes the formation of the fluidized bed above ingredients by means of an air stream and spraying the solution or suspension prepared by adding and dissolving or suspension of one or more additives to the above polyalcohols, xylytol and/or sugars, as needed, or water in a fluidized bed in the drying process, so that the particles stick together and glomerida into pellets under the action of liquid-binding; (2) granulation with stirring, which includes adding water or a solution prepared by dissolving and/or suspension and polyalcohols, xylytol/or saccharides, and optionally one or more additives to the above ingredient and carrying out granulation while mixing; (3) the process of high speed granulation while mixing, similar to granulation under stirring, except for the application of high shearing forces, which is to carry out granulation by adding water or a solution prepared by dissolving and/or suspendirovanie polyalcohols, xylytol and/or saccharides and, optionally, one or more additives, when mixing the above ingredients at high speed; (4) the granulation of AKST what derounian, which consists of adding water or similar liquid to the above ingredients, stirring and pressing the mixed thus the mass through a die or a sieve so that the mixed mass is extruded into pellets; and (5) granulation by rolling, which consists in spraying or coating of water or a solution prepared by dissolving and/or suspension of polyalcohols, xylytol and/or saccharides and optionally one or more additives to the above ingredients, rolling, forming spherical particles [see "lyakuhin no Kaihatsu (Developments of Medicines)", Volume 11 - "Seizai no Tan-i Sosa and Kikai (Unit Operations and Machines for Pharmaceutical Preparations), Hirokawa Publishing Company]. All of these methods are applicable in the present invention.

The concentration of the solution or suspension obtained by optionally adding one or more additives to the polyalcohols, xylytol and/or polysaccharides and their dissolution or suspension may preferably be in the range of 5 to 80 wt.%, more preferably from 10 to 70 wt.%, preferably in the range from 20 to 60 wt.%.

"The above ingredients in the above-described methods (1)to(5) can be any ingredients that are sugar alcohols and/or saccharide, an active ingredient and one or more additives that can be added as needed, or one of ingredien is s (provided the polyalcohols, xylytol and/or polysaccharides are required).

In addition, when the active ingredient is unstable in aqueous medium, the active ingredient can be mixed after drying, if necessary, the process of granulation, without the inclusion of active ingredient in the above ingredients.

The term "dry granulation"as it is used here, means that the above ingredients granularit using extrusion and molding ingredients as they are, with their subsequent grinding to a suitable size.

Medicinal compositions of the present invention are characterized by a shorter period of wetting, measured using test wetting, known from the publication [Y. Bi, N. Sunada, Y. Yonezawa, K. Danjo, A. Otsuka and K. lida, Chem. Pharm. Bull., 44(11), 2121-2127 (1996)]. Time wetting can usually be 60 seconds or less, preferably 30 seconds or less, and most preferably 10 seconds or less.

Medicinal compositions of the present invention are characterized by the fact that they rapidly disintegrate in the oral cavity. The term "disintegration time in the oral cavity," as it is used here, means the time required for the tablet is completely disintegrated or dissolved in the mouth when healthy adult person puts it in their mouth without water. Time is of Espada in the mouth can usually be 90 seconds or less preferably 60 seconds or less, most preferably 30 seconds or less, and the best option is 15 seconds or less. When receiving the normal way the tablet can fall in a shorter time due to licking pill man, whom she found in the mouth, either as a result of compression of tablets man, whom she found in the mouth between the tongue and palate. Thus, pharmaceutical compositions, disintegration time in the oral cavity of each of which is 15 seconds or less are particularly preferred because they can be considered as having sufficient properties of disintegration in the oral cavity from the point of view of ease of application, when accepted by the elderly, children and patients, limited in the receiving water or people like them.

It was reported that there is good correlation between disintegration time in the oral cavity and the time wetting as measured in the test for wetting [Y. Bi, H. Sunada, Y. Yonezawa, K. Danjo, A. Otsuka and K. lida, Chem. Pharm. Bull., 44(11), 2121-2127 (1996)].

In the present invention, more preferred are pharmaceutical compositions, each of which contains the active ingredient in the range from 0.05 to 25% by weight of the total amount of the medicinal composition has the time wetting of 10 seconds or less to test Simachev the tion, when hit in the mouth dissolves in 30 seconds or less and has the strength of 2 KF or higher.

EXAMPLES

Hereinafter the present invention will be described in more detail in the following examples. However, be aware that the examples in no way limit the present invention.

Ways to test

In order to more specifically demonstrate the advantages of the present invention, the tablets obtained in the following comparative Examples and Examples were subjected to the following tests.

(Test)

Using the device to determine the strength of tablets production Elbaker GmbH, for each tablet was measured force of destruction along its diameter.

(Test disintegration in the oral cavity)

Each tablet was placed without water in the oral cavity of a healthy adult, and measured the time required for complete disintegration or dissolution of the tablets in his mouth.

(Test for wetting - Y. Bi, H. Sunada, Y. Yonezawa, K. Danjo, A. Otsuka, and K. lida, Chem. Pharm. Bull., 44(11), 2121-2127, 1996).

Sheet commercial napkin was folded so that was 10 cm in length and 11 cm in width, and placed in a Petri dish made of plastic. Folded napkin was soaked in water (6 ml). The tablet was placed on a moistened cloth, and measured the time (wetting), which is has been created to meet the water of the upper surface of the tablets.

Such a test for wetting was performed in case of impossibility of carrying out the above test disintegration in the oral cavity due to the properties of the active ingredient.

Example 1

Eritra and trehalose were mixed at a ratio 299:1, and using dropwinsonde equipment (manufactured by Shimadzu Corporation), was produced by tableting the resulting mixture (weight 300 mg, a pressure of 500 kgf, the punch 10 mm in diameter). Thus obtained compact was heated at a temperature of 120°C for 15 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Example 2

Eritra and trehalose were mixed at a ratio of 29.5:0.5 and was produced by tableting using odnorangovogo equipment in the same way as in Example 1. The obtained compact was heated at a temperature of 95°C for 60 minutes and then allowed to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Example 3

Eritra and trehalose were mixed at a ratio of 29:1, and was produced by tableting using odnorangovogo equipment in the same way as in Example 1. The obtained compact was heated at a temperature of 95°C for 60 minutes and then allowed to cool at room temperature DL is receiving tablets, quickly disintegrating in the oral cavity.

Example 4

Eritra and trehalose were mixed at a ratio of 2:1, and was produced by tableting using odnorangovogo equipment in the same way as in Example 1. The obtained compact was heated at a temperature of 80°C for 90 minutes and then allowed to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Comparative Example 1

Based on the formula presented in Table 1, was produced by tableting using odnorangovogo equipment in the same way as in Example 1. The obtained compact was heated at 95°C for 60 minutes and then allowed to cool at room temperature to obtain comparative samples.

Table 1
Conditions of manufactureAritraTrehalosePressure compressionConditions of heating
Added amount (mg)Weight (%)Added amount (mg)Weight (%)(kgs)Temp

(°)
Time (min)
Example 1299 99,710,350012015
Example 229598,351,75009560
Example 329096,7103,35009560
Example 420066,710033,35008090
Comparative Example 130010000,05009560

For each tablet after heating were measured strength and disintegration time in the oral cavity. The results are presented in Table 2.

Table 2
Conditions of manufactureStrength (KF)Disintegration time in the oral cavity (sec)
Example 14,38
Example 22,05
Example 32,810
Example 42,012
Comparative Example 10,88

It was confirmed that the tablet having a disintegration time in the oral cavity up to 30 seconds and has actual strength 2 KF or above can be manufactured by adding trehalose, sugar alcohols with a low melting point, for erythrite and by heating the resulting mixture, followed by pressing (Examples 1-4). On the other hand, in comparative Example 1, in which trehalose, sugar alcohols with a low melting point was not added, it was found that, despite the short disintegration time in the oral cavity, the strength was only 0,8 KF, which makes it impossible to get a tablet for real world applications.

Example 5

Eritra and xylitol were mixed at a ratio of 29:1, and using dropwinsonde equipment (manufactured by Shimadzu Corporation), was produced by tableting the resulting mixture (weight 300 mg, a pressure of 500 kgf, the punch 10 mm in diameter). Thus obtained compact was heated at a temperature of 90°C for 60 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Example 6

Tablets quickly disintegrating in the oral cavity, were obtained in the same way as in Example 5, except that xylitol was replaced by sorbitol.

Example 7

It was produced by tableting using odnowa conewago equipment in the same way, as in Example 5, except that eritra and xylitol were replaced by mannitol and trehalose, and mannitol and trehalose were mixed in a weight ratio of 11:1. Thus obtained compact was heated at a temperature of 120°C for 60 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Example 8

It was produced by tableting using odnorangovogo equipment in the same way as in Example 7, except that trehalose was replaced with xylitol. Thus obtained compact was heated at a temperature of 90°C for 60 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Example 9

It was produced by tableting using odnorangovogo equipment in the same way as in example 8, except that xylitol was replaced by sorbitol. Thus obtained compact was heated at a temperature of 110°C for 60 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Example 10

It was produced by tableting using odnorangovogo equipment in the same way as in Example 9, except that mannitol and sorbitol were replaced, respectively, lactose and trehalose. Thus obtained compact was heated at a temperature of 160°C for 60 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Example 11

It was produced by tableting using odnorangovogo equipment in the same way as in Example 10, except that trehalose was replaced with xylitol. Thus obtained compact was heated at a temperature of 100°C for 15 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Example 12

It was produced by tableting using odnorangovogo equipment in the same way as in Example 11, except that xylitol was replaced by sorbitol. Thus obtained compact was heated at a temperature of 110°C for 5 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Table 3
Conditions of manufactureSugar alcohols/SaccharideSugar alcoholsPressure compressionConditions of heating
Weight (mg)Weight (mg)(kgs)Temp (°)Time (min)
Example 5Aritra290Xylitol105009060
Example 6Aritra290Sorbitol105009060
Example 7Mannitol275Trehalose2550012060
Example 8Mannitol275Xylitol255009060
Example 9Mannitol275Sorbitol2550011060
Example 10Lactose275Trehalose2550016060
Example 11Lactose275Xylitol2550010015
Example 12Lactose275Sorbitol25500110 5

For each tablet after heating were measured strength and disintegration time in the oral cavity. The results are presented in Table 4.

Table 4
Strength (KF)Disintegration time in the oral cavity (sec)
Before heatingAfter heating
Example 50,203,115
Example 60,712,59
Example 71,023,025
Example 8-2,818
Example 91,633,622
Example 10-3,147
Example 11-2,537
Example 121,432,622

It was confirmed that the addition of combinations of erythrite and trehalose, the combination of erythrite and xylitol, a combination of erythrite and sorbitol, the combination of mannitol and trehalose, the combination of mannitol and xylitol, a combination of mannitol and sorbitol, and a combination of lactose and sorbitol, each whom I can provide a short disintegration time in the oral cavity, not exceeding 30 seconds, and the actual strength 2 KF or higher.

Example 13

Eritra and trehalose were mixed at a ratio of 29:1, and using dropwinsonde equipment (manufactured by Shimadzu Corporation), was produced by tableting the resulting mixture (weight 300 mg, a pressure of 100 kgf, the punch 10 mm in diameter). Thus obtained compact was heated at a temperature of 95°C for 60 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the mouth,

Example 14

Eritra and trehalose were mixed at a ratio of 29:1, was produced by tableting the resulting mixture using odnorangovogo equipment (weight 300 mg, a pressure of 300 kgf, the punch 10 mm in diameter). Then, using the method of Example 13, there were obtained tablets quickly disintegrating in the oral cavity.

Example 15

Eritra and trehalose were mixed at a ratio of 29:1, was produced by tableting the resulting mixture using odnorangovogo equipment (weight 300 mg, a pressure of 500 kgf, the punch 10 mm in diameter). Then, using the method of Example 13, there were obtained tablets quickly disintegrating in the oral cavity.

Example 16

Eritra and trehalose were mixed at a ratio of 29:1, was produced by tableting the resulting mixture using dropwinsonde the CSOs equipment (weight 300 mg, a pressure of 800 kgf, the punch 10 mm in diameter). Then, using the method of Example 13, there were obtained tablets quickly disintegrating in the oral cavity.

Example 17

Eritra and trehalose were mixed at a ratio of 29:1, was produced by tableting the resulting mixture using odnorangovogo equipment (weight of 300 mg, the pressure of 1000 kgf, the punch 10 mm in diameter). Then, using the method of Example 13, there were obtained tablets quickly disintegrating in the oral cavity.

Table 5
ExampleAritraTrehalosePressure compressionConditions of heating
Added numberWeight (%)Added numberWeight (%)(kgs)Temp (°)Time (min)
Example 1329096,7103,31009560
Example 1429096,7103,33009560
Example 1529096,7103,300 9560
Example 1629096,7103,38009560
Example 1729096,7103,310009560

For each tablet after heating were measured strength and disintegration time in the oral cavity. The results are presented in Table 6.

Table 6
ExampleStrength (KF)Disintegration time in the oral cavity (sec)
Example 131.45
Example 142.37
Example 152.810
Example 162.811
Example 172.912

Because when pressing with a pressure of 100 kgf was received low strength of 1.4 KF, even after heating, and failed to obtain a sufficient strength for practical use, it is established that for the pressing need of the pressure of a certain level or higher. On the other hand, when the squeezing pressure of 300 kgf and higher temperature is raised strength, necessary for practical application, which is 2 KF or higher. However, the strength did not change when the pressure was increased from 500 kgs to 800 kgs. Even when the squeezing pressure of 1,000 kgf, strength increased only by 0.1 KF from that which was achieved at 500 kgf. Therefore, it is shown that for pressing is sufficient squeezing pressure of a certain level or higher, and, ultimately, to achieve the actual strength necessary heat.

Example 18

Timiperone (1 mg) and trehalose (6 mg) were mixed with erythritol (193 mg), and using dropwinsonde equipment (manufactured by Shimadzu Corporation), was produced by tableting the resulting mixture (weight of 200 mg, the squeezing pressure of 500 kgf, the punch 8 mm in diameter). Thus obtained compact was heated at a temperature of 120°C for 6 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Comparative Example 2

Based on the formula presented in Table 7, in the same way as in Example 18 were obtained comparative samples.

Table 7
ExampleTimiperoneAritraTrehalosePressure compression Conditions of heating
Added numberAdded amount (mg)Added amount (mg)(kgs)Temp

(°)
Time (min)
Example 18119365001206
Comparative Example 2019375001206

For each tablet after heating were measured strength, disintegration time in the oral cavity and the time of wetting. The results are presented in Table 8.

Table 8
ExampleStrength (KF)Disintegration time in the oral cavity (sec)Time wetting (s)
Example 183,5-4
Comparative Example 23,2134

Between Example 18 and Comparative Example 2 is not detected by the time difference wetting. Because you know that there is good correlation between disintegration time in the oral cavity and the time of wetting, it is understood that the tablets of Example 18 and out the same properties rapid disintegration in the oral cavity, as the tablets of Comparative Example 2.

Example 19

Perindopril erbumine (1 mg) and trehalose (6 mg) were mixed with erythritol (193 mg) and using dropwinsonde equipment (manufactured by Shimadzu Corporation), was produced by tableting the resulting mixture (weight of 200 mg, the squeezing pressure of 500 kgf, the punch 8 mm in diameter). Thus obtained compact was heated at a temperature of 120°C for 6 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Comparative Example 3

Based on the formula presented in Table 9, in the same way as in Example 19, were obtained from control samples.

Table 9
ExamplePerindoprilAritraTrehalosePressure compressionConditions of heating
Added amount (mg)Added amount (mg)Added amount (mg)(kgs)Temp

(°)
Time (min)
Example 19119365001206
Comparative Example 3 019375001206

For each tablet after heating were measured strength, disintegration time in the oral cavity and the time of wetting. The results are presented in Table 10.

Table 10
ExampleStrength (KF)Disintegration time in the oral cavity (sec)Time wetting (s)
Example 194,4-4
Comparative Example 33,2134

Between Example 19 and Comparative Example 3 is not detected by the time difference wetting. Because you know that there is good correlation between disintegration time in the oral cavity and the time of wetting, it is understood that the tablets of Example 19 have the same properties rapid disintegration in the oral cavity, and the tablets of Comparative Example 3.

Example 20

In granulating the fluidized bed dryer (FLOW COATER Mini, manufactured by Freund Industrial Co., Ltd.) eritra (190 g) was granulated with 26.7 wt.% aqueous solution (37.5 ml) of xylitol when spraying air pressure of 1.5 kg/cm2at a feed rate of 0.8 ml/min After drying, using dropwinsonde about what rudovanie (manufactured by Shimadzu Corporation), it was produced by tableting the resulting powder (weight 300 mg, a pressure of 500 kgf, the punch 10 mm in diameter). Thus obtained compact was heated at a temperature of 90°C for 15 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Example 21

Granulation and tableting using odnorangovogo equipment were produced in the same manner as in Example 20, except that aritra was replaced by mannitol. Thus obtained compact was heated at a temperature of 90°C for 15 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Example 22

Granulation and tableting using odnorangovogo equipment were produced in the same manner as in Example 20, except that aritra was replaced by lactose. Thus obtained compact was heated at a temperature of 90°C for 15 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Example 23

In granulating the fluidized bed dryer (FLOW COATER Mini, manufactured by Freund Industrial Co., Ltd.), eritra (190 g) was granulated with 26.7 wt.% aqueous solution (37.5 ml) trehalose when is the t spraying air 1.5 kg/cm 2at a feed rate of 0.8 ml/min After drying, using dropwinsonde equipment (manufactured by Shimadzu Corporation), was produced by tableting the resulting powder (weight 300 mg, a pressure of 500 kgf, the punch 10 mm in diameter). Thus obtained compact was heated at a temperature of 95°C for 15 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Example 24

Granulation and tableting using odnorangovogo equipment were produced in the same manner as in Example 23, except that aritra was replaced by mannitol. Thus obtained compact was heated at a temperature of 95°C for 15 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Example 25

Granulation and tableting using odnorangovogo equipment were produced in the same manner as in Example 23, except that aritra was replaced by lactose. Thus obtained compact was heated at a temperature of 95°C for 15 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Example 26

In granulating the fluidized bed dryer (FLOW CATER Mini", production Freund Industrial Co., Ltd.) eritra (190 g) was granulated with 26.7 wt.% aqueous solution (37.5 ml) sorbitol at davlenie spraying air 1.5 kg/cm2at a feed rate of 0.8 ml/min After drying, using dropwinsonde equipment (manufactured by Shimadzu Corporation), was produced by tableting the resulting powder (weight 300 mg, a pressure of 500 kgf, the punch 10 mm in diameter). Thus obtained compact was heated at a temperature of 100°C for 15 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Example 27

Granulation and tableting using odnorangovogo equipment were produced in the same manner as in Example 26, except that aritra was replaced by mannitol. Thus obtained compact was heated at a temperature of 100°C for 15 minutes, and then gave them to cool at room temperature, to obtain tablets quickly disintegrating in the oral cavity.

Example 28

Granulation and tableting using odnorangovogo equipment were produced in the same manner as in Example 26, except that aritra was replaced by lactose. Thus obtained compact was heated at a temperature of 100°C for 15 minutes, and then gave them to cool at room is temperature, to obtain tablets, quickly disintegrating in the oral cavity.

Table 11
Conditions of manufactureSugar alcohols/SaccharideSugar alcoholsPressure compressionConditions of heating
TypeWeight (mg)TypeWeight (mg)(kgs)Temp (°)Time (min)
Example 20Aritra285Xylitol155009015
Example 21Mannitol285Xylitol155009015
Example 22Lactose285Xylitol155009015
Example 23Aritra285Trehalose155009515
Example 24Mannitol285Trehalose155009515
Example 25Lactose285 Trehalose155009515
Example 26Aritra285Sorbitol1550010015
Example 27Mannitol285Sorbitol1550010015
Example 28Lactose285Sorbitol1550010015

For each tablet after heating were measured strength, disintegration time in the oral cavity and the time of wetting. The results are presented in Table 12.

Table 12
Conditions of manufactureStrength (KF)Disintegration time in the oral cavity (sec)
Example 20of 5.426
Example 213,617
Example 227,918
Example 236,321
Example 245,632
Example 258,224
Example 261,714
Example 272,620
Example 283,734

1. Medicinal composition, rapidly disintegrating in the oral cavity, is made, at least by mixing, pressing and heating where specified medicinal composition contains two or more polyalcohols, xylytol and/or saccharides and the active ingredient; the difference between the melting points of said two or more polyalcohols, xylytol and/or saccharides, which has a higher content of, and any of the remaining above-mentioned two or more polyalcohols, xylytol and/or saccharides is 5°C or higher.

2. The medicinal composition according to claim 1, in which the active ingredient is unstable in an aqueous environment.

3. The medicinal composition according to claim 2, wherein said active ingredient is unstable in water, chosen from the following groups:

thiamine hydrochloride, nicotinamide, aspirin, acetaminophen, indomethacin, diphenhydramine hydrochloride, procaterol hydrochloride, meklofenoxat hydrochloride, lorazepam, phenobarbital, calcium paraaminosalicylic, ampicillin, carmofur, captopril, nifedipine, procainamide hydrochloride and perindopril erbumine.

4. The medicinal composition according to claim 2, in which the specified active ingredient unstable in an aqueous environment, is perindopril erbumine.

5. The medicinal composition according to claim 1, in which the active ingredient has a melting point or a point of collapse 140°C or higher.

6. The medicinal composition according to claim 5, wherein said active ingredient, the melting point or decomposition which is 140° (C or above, chosen from the following groups:

alimemazine tartrate, lofepramine hydrochloride, isoniazid, baclofen, cetirizine hydrochloride, isoxsuprine hydrochloride, N-methylscopolamine the methyl sulfate, trihexyphenidyl hydrochloride, timiperone and oxypertine.

7. The medicinal composition according to claim 5, wherein said active ingredient, the melting point or decomposition of which 140° (C or higher is timiperone.

8. The medicinal composition according to claim 1, which has a time wetting with 10 or less when the test for wetting.

9. The medicinal composition according to claim 1, which when placed in the mouth dissolves within 30 seconds

10. The medicinal composition according to claim 1, which has a strength of 2 KF or higher.

11. The medicinal composition according to claim 1, in which the total weight content of said two or more polyalcohols, xylytol and/or saccharides is 75,0 to 99.95% by weight of the specified medicinal composition.

12. The medicinal composition according to claim 1, in which the weight content of the two or more polyalcohols, xylytol and/or saccharides, which has the lowest melting point, with the hat from 0.3 to 50.0% of the total amount of remaining (remaining) specified two or more polyalcohols, xylytol and/or saccharides.

13. The medicinal composition according to claim 1, in which the two or more sugar alcohols and/or saccharide are erythritol and trehalose and trehalose content is from 0.3 to 50.0% by weight content of Eretria.

14. The medicinal composition according to claim 1, in which the two or more sugar alcohols and/or saccharide are erythritol and one of xylitol and sorbitol, and the content of one of xylitol and sorbitol is from 0.3 to 50.0% by weight content of Eretria.

15. The medicinal composition according to claim 1, in which the two or more sugar alcohols and/or saccharide is mannitol and xylitol, sorbitol and trehalose and the content of one of xylitol, sorbitol and trehalose is from 0.3 to 50.0% by weight on the content of mannitol.

16. The medicinal composition according to claim 1, in which the two or more sugar alcohols and/or saccharide is lactose and sorbitol and the content of sorbitol is from 0.3 to 50.0% by weight from the lactose content.

17. The medicinal composition according to any one of p-16, in which the weight of the contents of the specified active ingredient is from 0.05 to 25% of the total weight of the specified drug composition and the pharmaceutical composition used for the wetting has time wetting with 10 or less when placed in the mouth dissolves within 30 seconds and has a strength of 2 KF or higher.

18. The medicinal composition according to any of the at from the preceding paragraphs, in which the specified heating is carried out at a temperature of 80-140°C.

19. The medicinal composition according to any one of the preceding paragraphs in which the specified heat produced within 3-90 minutes

20. The medicinal composition according to any one of the preceding paragraphs, in which the above polyalcohols, xylytol and/or saccharides are two or more polyalcohols, xylytol and/or saccharides selected from the following group: aritra, mannitol, lactic, lactose, glucose, sucrose, ▫ maltitol, xylitol, sorbitol, trehalose and fructose.

21. The medicinal composition according to any one of the preceding paragraphs, which is fabricated, at least, mixing, granulation, pressing and heating.

22. The medicinal composition according to any one of the preceding paragraphs, which is in tablet form.

23. The medicinal composition according to any one of the preceding paragraphs, which is in the form of tablets with a strength of 0.5 KF or above, when the diameter or maximum length less than 8 mm; strength 1 KF or above, when the diameter or maximum length of 8 mm or more but less than 10 mm; with strength 2 KF or above, when the diameter or maximum length of 10 mm or more but less than 15 mm; with strength 3 KF or above, when the diameter or maximum length of 15 mm or more, but less than 20 mm; with strength 4 KF or above, when the diameter or maximum length of 20 mm or more.

24. Methods for the manufacture of a medicinal composition according to claim 1, including the stage of obtaining a mixture of the active ingredient and two or more polyalcohols, xylytol and/or saccharides, pressing this mixture into a compact, and heating the specified CD, and the difference between the melting points of said two or more polyalcohols, xylytol and/or saccharides, which has a higher content of, and any of the remaining above-mentioned two or more polyalcohols, xylytol and/or saccharides is 5°C or higher.

25. The method according to paragraph 24, in which the specified compaction is to pelletizing.

26. The method according A.25 in which the specified tableting is carried out at a pressure from 300 to 1500 kgf.

27. The method according to any of p-26, which specified the heating is carried out at a temperature of 80-140°C.

28. The method according to any of PP-27, in which the specified heat produced within 3-90 minutes

29. The method according to any of PP-28, in which the specified heat produced in a convection oven at a constant temperature in a drying oven at a constant temperature vacuum drying oven or a microwave oven.

30. The method according to any of PP-29, in which this mixture of these two or more polyalcohols, xylytol and/or saccharides granularit before pressing.



 

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11 cl, 2 dwg, 11 ex

FIELD: medicine, pharmacology.

SUBSTANCE: invention relates to arypyprazole anhydrous crystals B showing characteristic peaks in powdered roentgen rays diffraction at 2θ = 11.0°, 16.6°, 19.3°, 20.3° and 22.1°, specific infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and 779 cm-1 in IR-spectrum, endothermic peak at 141.5° in thermogravimetric/differential thermic analysis and endothermic peak at 140.7° C in differential scanning calorimetry, arypyprazole A hydrate, to methods for their preparing, pharmaceutical compositions comprising arypyprazole crystals B and methods for their preparing. Invention provides reduced hygroscopicity of arypyprazole crystals B.

EFFECT: improved preparing method.

57 cl, 14 tbl, 24 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a biologically active microparticles composition comprising microparticles that involve: (a) polymer taken among group consisting of poly-(α-hydroxyacid), polyhydroxybutyric acid, polycaprolactam, poly-ortho-ester, polyanhydride and polycyanoacrylate, and (b) the first part of detergent that is bound with polymer, and also complex adsorbed on microparticles complex that comprises: (a) biologically active macromolecule, and (b) the second part of detergent wherein the first part of detergent and the second part of detergent comprise the same detergent or different detergents and wherein biologically active macromolecule is taken above group consisting of polypeptide, polynucleotide, polynucleoside, antigen, pharmaceutical agent, hormone, enzyme, transcription or translation mediating agent, metabolite, an immunomodulating agent and adjuvant. Also, invention relates to methods for preparing the composition and its applying. Invention provides improvement of adsorption of biologically active agents on microparticles surface in delivery systems, especially, for medicinal agents that are characterized with high sensitivity and complexity in their preparing based on the composition proposed.

EFFECT: improved method preparing, improved and enhanced properties of composition.

44 cl, 1 tbl, 1 dwg, 7 ex

FIELD: medicine, pharmaceutical technology, pharmacy.

SUBSTANCE: invention relates to granulated composition containing 11-[4-[2-(2-hydroxyethyl)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine (quetiapine) or its pharmaceutically acceptable salt, preferably quetiapine fumarate, as an active substance and a water-soluble binding agent. Invention relates to a method for preparing this composition and to a method for treatment of patients with nervous system diseases such as psychotic states including schizophrenia. Invention alleviates dosing of drugs by patients in required dose and solves problem concerning maintenance of regimen and schedule of treatment.

EFFECT: improved and valuable properties of composition.

16 cl, 2 ex

FIELD: medicine, antibiotics.

SUBSTANCE: invention relates to cephalosporin antibiotic - cefuroximaxetil that is used in treatment of bacterial infections. Invention proposes a new form of cefuroximaxetil not forming gel in contact with an aqueous solution. New form represents a solid solution of cefuroximaxetil in polymer and/or solid dispersion on adsorbent. New form of cefuroximaxetil can be used for preparing a granulate that can be used in oral pharmaceutical compositions as tablets or powder. Exclusion of gel-formation allows improving solubility of cefuroximaxetil that results to enhancing absorption of cefuroximaxetil in digestive tract.

EFFECT: improved pharmaceutical properties of combinations.

23 cl, 3 dwg, 8 tbl, 19 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention relates to porous quick-breaking active ingredient-containing granules based on chitosan or basic derivative thereof prepared by drop-by-drop technique, wherein aqueous solution or dispersion of chitosan or basic derivative thereof, one or several active substances, optional secondary active substances, and acid are dropwise added to cooling fluid at maximum temperature -5°C. As a result, solution or dispersion is solidified in the form of drops, which are then separated and dried. Such procedure is used to prepare therapeutical or diagnostic agents.

EFFECT: avoided use of gelatin or collagen as carrier.

16 cl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to lyophilized composition comprising epotilone in the effective amount and mannitol or cyclodextrin. The second variant of the lyophilized composition involves epotilone and hydroxypropyl-beta-cyclodextrin. The preferable content of epotilone in the lyophilized composition is from 0.1% to 1.5%, and cyclodextrin - from 90% to 99% as measured for the total mass of solid components. Epotilone-containing lyophilized compositions can be used fro preparing an anti-tumor medicinal agent useful for parenteral administration and the lyophilized composition can be reduced preferably before administration directly. Epotilone-containing lyophilized compositions show improved indices of epotilone solubility and can retain stability for 24-36 months at temperature from 2°C to 30°C being without change of the solubility index.

EFFECT: improved and valuable properties of composition.

10 cl, 4 tbl, 14 ex

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