Tablet preparing by direct pressing and comprising 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid as active component

FIELD: medicine, pharmacy, pharmaceutical technology.

SUBSTANCE: invention relates to pharmaceutical compositions as tablets, namely, to a tablet preparing by direct pressing and comprising 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or its pharmaceutically acceptable salts as an active component taken in the amount from 5 to 140 mg as measured for a pure acid, an excipient, a dry binding agent, a disintegrating agent and a lubricating substance, and to a method for its preparing. As an excipient the claimed composition comprises the combination of at least two recipients but with exception of lactose, and it comprises 20-80 weight% of excipient chosen from group comprising microcrystalline or powder-like cellulose and calcium hydrophosphate, and 0.001-50 weight% of one or more recipients chosen from group comprising mannitol and phosphates or hydrophosphates of alkaline or alkaline-earth metals. As a disintegrating agent the composition comprises maize starch taken in the amount 7-15%. The content of lubricating agent is 1%.

EFFECT: improved preparing method of tablet.

3 cl, 19 tbl, 7 ex

 

The technical field

The invention relates to pharmaceutical compositions in the form of tablets obtained by direct pressing, which contain 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (hereinafter referred to as "alendronova acid") or its pharmaceutically acceptable salt as an active ingredient, and an inert pharmaceutical fillers (excipients).

Prior art

For many years known action bisphosphonic acids on skeletal system. So, in the journal Acta. Endocrinol. 76, 613 (1976) have published data on the inhibition of bone resorption in rats with the introduction of the substances concerned, and in Brit. J. Pharmacology, 21, 127 (1963) - data delay development of chronic arthritis. In the patent literature describes the action of 1-hydroxy-1,1-ethylidenenorbornene acid and 3-amino-1,1-propylaminosulfonyl acid (respectively, patents US 3683080/1972 and DE 2405254/1974) on calcium metabolism. In the patent US 4621077 (1984) described the treatment of urolithiasis and inhibition of bone resorption 4-amino-1-hydroxy-1,1-butylidenephthalide acid.

In addition, many patents contains information about pharmaceutical compositions with the above-mentioned compounds. For example, in the patent DE 2405524 (1974) provides a pharmaceutical composition comprising 3-amino-1-hydroxy-1,1-propylenebis the first acid in combination with lactose, starch and magnesium stearate dosage forms in the form of tablets or in combination with lauryl - for capsules. In the patent EP 550395 (1991), although an example of the same lactose, starch and stearic acid, we are talking about the pharmaceutical composition of bisphosphonic acids, a variety of which are not included. In the patent EP 274158 (1986) claimed the right to family of bisphosphonates, including heterocyclic Deputy, in relation to medicinal forms as capsules (starch, valium) and in the form of tablets (lactose, starch, magnesium stearate). In the patent EP 600834 (1992), extending to the use of bisphosphonic acids, which were already protected cited above patent EP 550392 in relation to the treatment of fractures, named the following dosage forms for oral administration: the pill, the core of which is formed of the active ingredient and microcrystalline cellulose, and tablets containing lactose, starch, gelatin, talc, magnesium stearate and silicon dioxide.

Pharmaceutical dosage form containing, in particular, 4-amino-1-hydroxy-1,1-butylidenephthalide acid (alendronate acid) and its salts, described in the patent US 4621077 (1984) on the name of Rosine, which shows examples of formulations at 10 and 20 mg:

mg
Substancemg
Alendronate sodium2512,5
Lactose8480
Hydrolyzed starch55
Talc58,5
Magnesium stearate11

In the international application WO 95/29679 describes a method for medicines containing salt alendronova acid, using wet granulation. This method consists in mixing the active ingredient and diluent with the formation of the wet powder mass, which is formed into granules by the method of wet granulation (for example, planetary granulator). The obtained granules are dried, crushed to obtain a standard particle size and mixed with dezintegriraat substance and lubricant. After final mixing, the mixture predecesso preliminary compression is subjected to more pressing to obtain a predetermined shape of the tablets. As for the examples of the composition, most produced by this technology tablets consists of lactose, microcrystalline cellulose, magnesium stearate and sodium salt croscarmellose. In addition to lactose, patent examined the use of other thinners t the PA calcium phosphate, mannitol, powdered cellulose, swelling in cold water starch or microcrystalline cellulose. The preferred composition of the diluents mentioned mixture of lactose and microcrystalline cellulose. First, as is well known, may interact with alendronate sodium, especially in the presence of water, contributing to the acceleration of its destruction, while the second chemically inert with respect to alendronic acid, but at the same time has some hygroscopic properties, which again leads to an increase in humidity and interoperability of lactose with the active ingredient. Every pellet as dry and wet method represents an additional stage of any process, when compared with direct pressing. It allows compression of such mixtures, with the direct pressing of which would not have been able to get the desired quality pills. On the other hand, during a particularly wet granulation, when the product is exposed to moisture and heat, created unfavorable conditions for organic substances with higher sensitivity.

Although due to its satisfactory capacity to pressing lactose, no doubt, is an extremely common diluent, it has n whom negative properties. So, often there is a darkening in conditions of high relative humidity (above 80%). In addition, this process, intensifying under the action of heat, newepoetin in relation to specific types of lactose (this may be associated with the contents of the trace). In the case of application of the active ingredients, containing a primary amino group, may be reaction Maiar [L.C.Maillard: Compt. Rend. 154. 66 (1912)], accelerating under the action of alkaline substances, which contributes to the darkening of the drug with a simultaneous decrease in content of the active ingredient. Therefore, it is not recommended to use lactose for the preparation of medicines, including a primary amino group that is typical of most bisphosphonic acids with high curative effect.

One of the ways to solve compositions containing bisphosphonic acids and lactose, proposed in the application WO 94/12200 filed by the company Merck Company. It refers to the composition and method of production of drugs based on bisphosphonic acids using the technology of direct pressing. As can be seen from this document, the tablet contains, in addition to the active ingredient, a diluent in the form of anhydrous or hydrous lactose, dry binder, dezintegriruetsja substance and maziausiai substance. Described in a pending application, the process is neposredstvennogo pressing is characterized by the following distinctive features:

composition: active ingredient, anhydrous lactose, microcrystalline cellulose, magnesium stearate, sodium salt carmellose (carboxymethylcellulose);

method of making: first, the active ingredient is mixed with one-third microcrystalline cellulose and a half anhydrous lactose; then the pre-mixture is mixed with the remnants of both excipients and again mix; add with stirring sodium salt carmellose, then magnesium stearate, getting the final mixture, which after homogenization are compressed.

Due to the described method eliminates the need for a long and inefficient process using granulation.

As the results described in this proposal comparative testing stability of the finished product is carried out at a temperature of 40°C and a relative humidity of 75%, resulting in the use of more simple and cost-effective technology can receive the product with high resistance. In a sealed package of the drug obtained by direct pressing, after three months remains to 98.5% of the initial amount of alendronate against a 94.6% for granular product. The lack of stability associated with wet granulation, increased by the introduction of the wasp is Italia, that allows you to provide content of alendronate in granulated product after testing resistance at 99.7%.

However, these measures do not allow to solve fully the problem of lack of stability associated with the reaction of the Maiar. Included so far in the tablet of the substance is lactose, cellulose, carmellose (more detailed information, see, for example, Guide for pharmaceutical excipients, published in 1994, the American pharmaceutical Association), exhibit hygroscopic properties, resulting in a corresponding medication contained within the General packaging without adding driers, gradually begins to absorb atmospheric humidity, which is not observed for the two-year guarantee of its stability during storage in humid and warm place.

In the application WO 99/04773 method-related inhibition of bone resorption with the use of regimens one or two times a week or, in some cases, one dose in two weeks, the claimed pharmaceutical compositions containing 70 or 140 mg alendronova acid. Described in this proposal recipe completely corresponds to the one given in the above application WO 94/12200:

Substancemg
Alendronate sodium45,68
Lactose71,32
Microcrystalline cellulose80
Crosscarmellose2
Magnesium stearate1

As can be seen from the above review of the existing patent literature, it lacks any combination of excipients, which would provide a complete and reliable solution to the problem of obtaining the optimal composition of tablets with alendronova acid.

Theoretically, this problem can be solved by substitution of lactose by other diluents, some of which are discussed below.

a) Mannitol

Mannitol is one of the most common solvents used for preparation of tablets containing moisture-sensitive substances. Because it is not subject to reaction Maiar (does not contain a hydroxyl group glycosides), it is suitable for compositions with amines or amino acids, including aminobisphosphonates acid. Due to the extremely high stability, it can serve as an additive compositions for injection containing aminobisphosphonates.

Medicines with lactose in standard packaging insufficiently stable for a sufficient time in an environment with a relative humidity greater than 90%. Additionally, products containing amino acids, under ergeni reaction Maiar in such humidity. The instability of same products with mannitol, owing to the excessive moisture content is observed only at a relative humidity of over 98%.

Gained experience in the practical application of mannitol shows quite positive results, particularly with respect to technology wet granulation. However, its use in direct compression is not recommended because of its low performance pressuemosti.

b) calcium Phosphate

Phosphate of calcium is another extremely stable diluent suitable for compositions exposed neposredstvenna pressing. He possesses the desired properties of high stability and compressibility, but at the same time suffers from the disadvantage that is some alkalinity, which can adversely affect the stability of the product.

C) Microcrystalline cellulose

Microcrystalline cellulose (MCC) should be used for compositions exposed neposredstvenna pressing, solid binders, which have a significant effect on the compressibility of the tablet. The increase in the content of MCC reduces the requirements to the compressibility of the solvent. In some cases, MCC is able to fully replace the diluent. However, the hygroscopicity ICC could have a adverse is th effect on the stability of the finished product.

g) Modified starches

It is one of the possible options when choosing fillers for the present compositions. However, and here the hygroscopicity of such starches can adversely act on the stability of the finished product.

All the above cases are substances that, unlike disaccharides type laktos not show incompatibility with aminophosphate type alendronova acid. However, the degree of stability and characteristics of pressuemosti be different from case to case.

According to experts, the replacement of lactose another diluent is not particularly recommended. This approach can explain the observed usually in practice the worst characteristics of pressuemosti considered substances. Among the disadvantages of diluents, which are used in the compositions subjected to the direct pressing, often referred to as their lack of compressibility, which leads to the necessity of applying presses, high pressure in order to achieve the desired hardness of the tablets. However, this modification leads to poor regeneration of the contents of the tablet and, as a consequence, the need to use special expensive dezintegriruetsja substances of the type mentioned above sodium salt carmellose. In some cases the mixture, the floor is obtained by direct pressing, may exhibit poor fluidity characteristics that can impede proper regulation of the weight of the tablets and in some cases effective use of sophisticated presses at their full capacity. Often the characteristics of the fluidity of the mixture subjected to pre-compression, improve the introduction of stearates. Most suitable for these purposes is magnesium stearate.

Strengths lactose as diluent for the composition prepared by the method of direct pressing, and the unsuitability of other diluents can be best exemplified through their characteristics of pressuemosti and equilibrium moisture content (adsorption isotherm), is given as an example.

Comparative characteristics of pressuemosti for mannitol, cellulose and lactose are given, in particular, Guide for pharmaceutical excipients.

From the comparison of these substances can be seen that the least suitable for direct extrusion is granular mannitol, since an increase of the compression ratio up to a level of more than 12 kN does not give any appreciable increase in the hardness of the tablets, in contrast to lactose, which is the hardness of the tablets increases essentially in proportion to the compression. This result has significant implications for the quality control of tablets. Features : the policies pressuemosti cellulose virtually identical to those for lactose in the whole range of considered values of compression.

The second important parameter of the considered substances is their hygroscopicity.

If you take into account the hygroscopic properties of the considered substances, the best diluent can, apparently, be considered mannitol as increasing its moisture content is observed at a relative humidity of about 98%. Lactose is also quite suitable diluent even taking into account the absorption of atmospheric moisture, as a significant increase in moisture content becomes visible at a relative humidity of about 90%. Cellulose absorbs the appropriate amount of water already at 70%atmospheric humidity. Poor sustainability of products with diluents should be expected only in the case of the use of cellulose, whereas the use of mannitol and lactose yields, respectively, the best and very good value stability.

These facts indicate that lactose combines two qualities that are crucial for the preparation of tablets, high quality and stability. Therefore, we can assume that the replacement of lactose other solvent will lead to deterioration of the quality of the product.

So, for example, mannitol is used in cases when the corresponding process using granulation does not depend on any concrete is x parameters pressuemosti above the excipients. Microcrystalline cellulose, acidic phosphates or starches are involved in the process as a binder in smaller quantities and can be proposed as diluents.

When replacing lactose with other diluent should take into account the different scale of the deterioration in the quality of the product for different active ingredients. As a rule, is not required in advance to find out whether you meet the requirements to the quality of the product included in this specific Pharmacopoeia, and whether the tablet ever used. It may be further assumed that when such quality is achievable, you will need to find a special composition within a relatively time-consuming optimization process.

From a review of the current state of Affairs in this area shows that although lactose and chemically reacts with alendronate, it is an extremely convenient diluent, which combines, on the one hand, the necessary stability (except under conditions of very high humidity, when higher resistance gives mannitol) and, on the other hand, good compressibility (close to the compressibility microcrystalline cellulose). Based on the accepted chart compressibility and adsorption isotherms, we can conclude that the replacement of lactose another diluent will result in p is receiving tablets or with less resistance or with less hardness.

However, it was unexpectedly discovered that lactose can still be replaced by another solvent and to obtain a more stable substance with all the advantages of high quality dosage forms as tablets, thus solving the problem of the reaction of the Maiar, involving lactose.

Our solution allows to obtain a stable medication in tablet form that meets all the requirements that apply to drugs for oral administration. In addition, these requirements are met in a wide range of concentrations used excipients.

The invention

The subject of the invention is obtained by direct pressing of the tablet containing the active ingredient is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic (alendronate) acid or its pharmaceutically acceptable salt in an amount of from 5 to 140 mg per net acid - reducing agent, a dry binder, dezintegriruetsja substance and lubricant substance, and this tablet contains as diluent combination of at least two solvents, excluding lactose. It was unexpectedly discovered that the use of such diluents becomes possible to use the direct extrusion for the manufacture of tablet is based alendronate, demonstrating the required physical properties and sufficient strength for a long period.

According to a preferred variant implementation, the tablet contains at least two diluent, excluding lactose, which are based on the total weight of the tablet, from 20-80 wt.% diluent selected from the group comprising microcrystalline or powdered cellulose and calcium phosphate, and 0.001-50 wt.% one or more diluents selected from the group comprising mannitol, modified starches and phosphates or hydrogen phosphates of alkaline and alkaline-earth metals.

This composition meets the following requirements for her range of requirements:

a) provides the product with a resistance greater than the resistance of structures on the basis of lactose developed up to the present time, which is especially apparent when using higher concentrations of the active ingredient;

b) it is possible to make a small easy to swallow tablets, in which the applied active ingredients, with lesser activity;

C) remains the same extremely high level of performance of pressuemosti subjected to preliminary compression of the mixture and the quality of the finished tablets, as well as for structures on the basis of lactose, even in broad di is the range of concentrations of the diluent;

d) upon reception of tablets of such structure creates the effect of inhibition of bone resorption, is identical to that provided by existing structures;

accordingly, it can be prescribed for the treatment of diseases associated with bone resorption, particularly osteoporosis;

d) the degree of dilution, i.e. the selection of the active substance in the fluid, simulating gastric environment, which is crucial for the biological availability of the active substance, characterized by higher values than specified in the standards; it should also be borne in mind that this option does not deteriorate in wet environments over time.

In accordance with the preferred embodiment, the tablet according to the invention contains 20-75 wt.% diluent selected from the group comprising microcrystalline cellulose and calcium phosphate, 5-50 wt.% diluent selected from the group comprising mannitol and calcium phosphate, and optionally up to 20 wt.% other diluents. The preferred composition of the diluent is: 10-50 wt.% mannitol and 30-70 wt.% microcrystalline cellulose, depending on the weight of the tablets.

As shown in the examples below, by using a combination of diluents according to the invention, excluding lactose, it is possible to obtain an acceptable St is istwa tablets during cheap the pressing process, providing gentle handling sensitive substances and does not require the steps of granulating or pre-granulation of the components. As a consequence, a totally new vision of the whole complex of issues related to pharmacy using bisphosphonic acids.

The pharmaceutical composition obtained by direct pressing, includes, generally, a dry binder, dezintegriruetsja substance maziausiai substance and the diluent.

Possible disadvantages associated with the compressibility of the solvent can be removed by application of a dry binder. Carefully choosing the proportions of the diluent and dry binder, you can even intensify the disintegration of the tablets in the environment of gastric juice and, consequently, to increase the availability of the active ingredient to the patient's body.

In the case of the use of excessively strong dezintegriruetsja substances is a significant decrease in the stability of the tablets in a humid environment. The same effect can occur when selecting a dry binder, containing potent disintegrity component. The right combination of binding and dezintegriruetsja properties of the tablets is of great importance to optimize the pressing process. With respect to the situation, using the receiving alendronova acid and its salts are preferred dezintegriruetsja substances with less high activity, which only complement and support dezintegriruetsja action of dry binder.

As for lubricants, they can be used in the compositions according to the invention in accordance with standard technology.

If you take a combination of, for example, microcrystalline cellulose (MCC) and mannitol, it should be borne in mind that the ICC also assumes the functions of diluent (in addition to the function of the dry binder), so the introduction of a second diluent is mannitol can lead to a significant reduction in the stability of the composition.

In addition, it was found that the tablet with the desired properties can be prepared using the excipients do not already discussed above combination of cellulose and mannitol, and other substances. So, for example, using a combination of acid phosphate and mannitol also allows to obtain a product with an extremely high resistance. Similarly the combination of modified starch with mannitol produces a drug with the desired quality.

Although the combination of different diluents or use one excipient to perform multiple functions (e.g., MCC) allows to obtain a product with the best characteristics when selecting the composition of the tablets is quite possible to do a single diluent.

The following examples provide detailed to illustrate the process of selecting a composition with the right combination of components and confirm sufficient stability of dosage forms on the basis of alendronato according to the present invention.

EXAMPLES

Example 1

Test - lactose (composition described in WO 94/12200)

Composition one tablet (the values are given in mg):

Alendronate sodiumof 13.05
Anhydrous lactose103,95
Granulated microcrystalline cellulose80,00
Sodium salt of carboxymethylcellulose2,00
Magnesium stearate1,00

The manufacturing process. First alendronate mixed with one-third microcrystalline cellulose and a half anhydrous lactose. Then, the resulting preliminary mixture is mixed with the remnants of both excipients and again mix. Add while stirring the sodium salt carmellose, then magnesium stearate, getting the final mix. After homogenization of the mixture an additional premesis is by subjecting it to compression.

The results of the tests for stability

The data below relate to the content of active ingredient in the product in% to the original condition and appearance of the product (explored its color according to the hue from white to practically white, which was specified condition for this particular test). Test conditions: 40°C, relative humidity 75%.

The frequency of testing3 months6 months
% to the initial state98,5-
Appearancesatisfactory-

Example 2

Optimization of the composition is a chemically inert diluent

In contrast to the known manufacturing techniques based on the use of lactose (Example 1), in this example, lactose was replaced with mannitol, which has a higher resistance, and carboxymethyl - starch, showing less activity and performs simultaneously the function of the dry binder instead of the microcrystalline cellulose. Corn starch is included in an amount ten times smaller than the number mannitol, used as substances that promote dezintegratsii tablets, and not as a diluent.

The process is manufacturing. Prepare a mixture of alendronate, mannitol and corn starch. Then prior to this mixture was added magnesium stearate. After further mixing, the mixture is extruded.

Sodium alendronate trihydrateof 13.05
Corn starchof 11.15
Mannitol104,50
Magnesium stearate1,30

Due to the above-described replacement of the excipients managed to get a tablet, but smaller, with the same amount of active ingredient as in Example 1.

The application of the considered composition was allowed to get a tablet with the desired characteristics. Its physical properties are shown below in the table for Example 3.

Example 3

Optimization of the composition described in Example 2.

Dosage form tablets 10 mg alendronova acid (of 13.05 mg of alendronate monosodium of three-hydrate).

As shown by preliminary tests demonstrated in Example 2, the introduction of mannitol instead of lactose in the tablet 10 mg alendronova acid provides obtaining the specified parameters tablets, the disintegration time is less than 15 minutes and fragility (shortening) less than 1% when the content of corn starch from 7 to 15%.

However, to achieve optimal the x and stable characteristics subjected to preliminary compression of the mixture must be added to the composition in Example 2 dry binder. For this test as a binder was selected microcrystalline cellulose.

For further improvement was the preparation of such composition that could combine the strengths of both excipients, being at the same time deprived of their disadvantages. For this specific case mannitol was taken as a substance that would ensure the sustainability of the product, and microcrystalline cellulose as the agent that gives the pill the necessary hardness. For all of the above examples used the same process, which consisted in the following.

Mixed in a special vessel alendronate, mannitol, corn starch and microcrystalline cellulose when the rotation speed of the mixer is equal to 14 rpm, at normal temperature and relative humidity (respectively, 25°and 60%). To the pre-mixture was added magnesium stearate. After homogenization subjected to preliminary compression of the mixture was subjected to pressing in a rotary press with obtaining tablets flat cylindrical or oval mass of 130 mg.

Was a preliminary quality control of tablets using the following criteria.

Tablets must meet the following requirements set forth in Art. 97 the European Pharmacopoeia or, in appropriate cases, suitable the departmental technical specifications:

uniformity of weight:±5%
dezintegriruetsja:within 15 minutes
hardness:not less than 30 N
fragility:no more than 1%

Data on the composition in mg all of the following tables always refer to one pill.

The composition And

65% mannitol (M) and 15% microcrystalline cellulose (MCC)

Sodium alendronateof 13.05
Mannitol84,50
Granulated microcrystalline cellulose20,00
Corn starchof 11.15
Magnesium stearate1,30

Dezintegriruetsja tablets was completed within 1 minute (set point - no more than 15 minutes), and the values of hardness and fragility were kept within the relevant technical requirements. It was found that the composition meets the accepted criteria.

Composition

30% M and 50% ICC

62,50
Sodium alendronateof 13.05
Mannitol42,00
Granulated microcrystalline cellulose
Corn starchof 11.15
Magnesium stearate1,30

Friability of the tablets decreased even more, and the characteristics of its transport was excellent. Therefore, an additional test was selected for this composition.

The composition of

20% M and 60% ICC

Sodium alendronateof 13.05
Mannitol26,00
Granulated microcrystalline cellulose78,50
Corn starchof 11.15
Magnesium stearate1,30

Excellent characteristics of the tablets obtained for the previous part, have survived here.

Part D

10% and 70% ICC

Sodium alendronateof 13.05
Mannitol13,00
Granulated microcrystalline cellulose91,50
Corn starchof 11.15
Magnesium stearate1,30

The physical parameters of all the above formulations tablets met all specified requirements.

Comparison of physical properties alendronate tablets

Structure Example23A3B3C3D6The approximate content of the MCC in%01548607080The approximate content of M in%80653220100 Requirement      Hardness (H)not less than 25 N253550707092Friability (%)no more than 1%0,90,50,150,1500Disintegration (C)900905020151515

As can be concluded from the above data, the tablet with the use of mannitol as a diluent demonstrates physical properties that meet the technical requirements. The increase in the share of MCC leads to a noticeable improvement of these t the century Upon reaching 50%of the content of the ICC is the dramatic improvement of the investigated properties (reduction of fragility, the reduction time dezintegratsii and increase hardness).

Example 4

Composition, demonstrating optimal proportions used excipients - stability tests.

Based on the results of the tests are briefly described in the Example 3, the composition with characteristics that perfectly meet the requirements of compressibility and resilience, selected for control tests on sustainability, held on tablets with the following content components. The tablets were (in mg):

Sodium alendronateof 13.05
Mannitol42,00
Granulated microcrystalline cellulose62,50
Corn starchof 11.15
Magnesium stearate1,30

The manufacturing process. Prepare a mixture of alendronate, mannitol, corn starch and granulated microcrystalline cellulose. Then prior to this mixture was added magnesium stearate. After further homogenization of the mixture subjected to preliminary compression extruded using the equipment and conditions described in Example 3.

And the test for resistance

In the above-described technology was used to four pellets. Below are the results of their tests for stability under the most severe conditions (40°C, relative humidity 75%).

Individual test results

Given in tables values relate to the quantitative analysis of the active ingredient in the product in% to the original condition and appearance of the product (explored its color according to the hue from white to practically white, which was specified condition for this particular test).

a) Party And

The frequency of testing3 months6 months
% to the initial state (titration)99,4100,1
Appearancesatisfactorysatisfactory

Disintegration of tablets: completed within 1 minute (15 minutes).

Dissolution: 100% active ingredient were selected within 30 minutes (requirement - not less than 75% in 30 minutes).

The tablet has demonstrated properties significantly better than those that are prescribed by the European Pharmacopoeia.

b) the Party

The frequency of testingmonth 6 months
% to the initial state (titration)100,799,7
Appearancesatisfactorysatisfactory

b) the Party

The frequency of testing3 months6 months
% to the initial state (titration)100,3100,7
Appearancesatisfactorysatisfactory

b) Party D

The frequency of testing3 months6 months
% to the initial state (titration)100,299,8
Appearancesatisfactorysatisfactory

The resulting average values for the four tests for stability

b) the Party

The frequency of testing3 months6 months
% to the initial state (titration)100,15100,08
Standard deviation0,47/td> 0,39
Standard deviation1,140,92

The obtained results demonstrate the absence of reducing the amount of active ingredient in the tablets during the accelerated testing for resistance, carried out with 3-month and 6-month intervals. The difference between two mean values was less than the corresponding standard deviation.

The average value for all eight dimensions, constituting 100,11±0,43%, is evidence that the content of sodium salt alendronova acid in the tablet after 3 - and 6-month storage at 40 °C and a relative humidity of 75% is close to its original 100%specific value that occurred at the beginning of the test. None of the analyses undertaken resulting value content of active ingredient was not less than 99%.

The above results show that the stability of the investigated structure was higher than alendronate dosage forms used to date (see Example 1).

Example 5

As diluent used phosphate of calcium.

Both the composition of the calcium phosphate were prepared by two-stage mixing the first mixture of the active ingredient, calcium hydrogen phosphate is, corn starch and mannitol or microcrystalline cellulose homogenized, and then introduced into a mixture of magnesium stearate and re-homogenized by stirring, and then was subjected to pressing. The compositions are given in tables in mg per tablet. a) the composition of the acidic calcium phosphate and microcrystalline cellulose

Sodium alendronateof 13.05
Phosphate calcium42,00
Granulated microcrystalline cellulose62,50
Corn starchof 11.15
Magnesium stearate1,30

b) the composition of the acidic calcium phosphate and mannitol

Sodium alendronateof 13.05
Mannitol42,00
Phosphate calcium62,50
Corn starchof 11.15
Magnesium stearate1,30

The application of both compounds has made it possible to obtain tablets that meet the requirements of brittleness, hardness and disintegration.

Example 6

As diluent used microcrystalline cellulose.

Relative to breadboard the process, see Example 3.

Sodium alendronate trihydrateof 13.05
Corn starchof 11.15
Microcrystalline cellulose104,50
Magnesium stearate1,30

The application of this composition was allowed to get a tablet that meets the requirements of brittleness, hardness and disintegration.

Example 7

The composition contains 70 mg alendronova acid.

Regarding the processing composition see Example 3.

The composition shown in the table in mg per tablet.

Sodium alendronate trihydrate91,35
Corn starch10,00
Microcrystalline cellulose97,50
Mannitol48,65
Magnesium stearate2.50

Time dezintegratsii tablets containing 70 mg alendronova acid was less than 1 minute (requirement - no more than 15 minutes), and friability of the tablets was significantly lower than the required value of 1%.

1. The tablet obtained by direct pressing, containing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or its pharmaceutically acceptable salt as AK the active ingredient in an amount of from 5 to 140 mg per pure acid, thinner, dry binder, 7-15% corn starch and 1% lubricant, characterized in that it contains as a diluent combination of at least two solvents, excluding lactose, and this combination includes in the calculation on the total weight of the tablet 20-80 wt.% diluent selected from the group comprising microcrystalline or powdered cellulose and calcium phosphate, and 0.001-50 wt.% one or more diluents selected from the group comprising mannitol and phosphates or hydrogen phosphates of alkaline and alkaline-earth metals.

2. The tablet according to claim 1, characterized in that it contains in the calculation on the total weight of the tablet 10-50 wt.% mannitol and 30-70 wt.% microcrystalline cellulose.

3. A method of manufacturing a tablet, characterized in claim 1 or 2, including homogenization of the mixture containing the active ingredient, a combination of diluents, dezintegriruetsja substance and dry binder, adding a lubricant and pressing.



 

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8 cl, 16 ex

FIELD: medicine, medicinal biochemistry, pharmaceutical technology.

SUBSTANCE: invention proposes the composite that comprises complex of vitamins D3, B6, C, K and calcium salts, citric acid, lactose and sorbitol as the special supplement, and lubricating agent and correcting agent for taste and/or odor. The method for preparing the composite involves mixing the above said components and if necessary the following tableting process of the prepared mixture. The new composite shows stability of quality indices in the store process being among them index "the content of vitamin D3" that provides the fitness time above 2 years and absence of by-side adverse toxic effect that is typical for destruction products of active components.

EFFECT: improved preparing method, improved and valuable properties of composite.

7 cl, 1 tbl, 4 ex

FIELD: sterilization agents and facilities in medicine.

SUBSTANCE: sterilization method comprises first-step treatment of an object with 0.05-0.3% (based on active component) solution of biocide agents based on clatrate of quaternary ammonium compound with urea and second-step treatment with solution containing 2.5-3.5% hydrogen peroxide. Kit contains (i) concentrate of biocide agent based on clatrate of quaternary ammonium compound with urea and (ii) peroxide compound.

EFFECT: allowed quick achievement of sterility of objects and suppressed final stage of washing objects in sterile water or other liquid to remove the rest of biocides.

13 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: pills comprise natural interferon or recombinant -α, -β or -γ manifesting activity in low or high doses. Pills comprising interferon inductor in the amount of 100 mcg to 25 mg or interferon inductor in the amount of l/5-1/20 of therapeutical unit dose with one of recombinant human gene engineering interferons in the amount of 500-1000 IU taken in 2:1 - 3:1 proportion.

EFFECT: enhanced effectiveness in stimulating local oromucosal and systemic immune response; increased antiviral organism resistance.

6 cl, 3 tbl

FIELD: medicine, in particular dry azithromicine mixtures to produce azithromicine pellets by direct pressing.

SUBSTANCE: claimed formulation contains non-dehydrated azithromicine selected from group containing B, D, E, F, G, H, J, M, N, O, P, Q, R forms or mixtures thereof, and at least one pharmaceutically acceptable carrier. Pellet containing non-dehydrated azithromicine mixture and at least one pharmaceutically acceptable carrier, as well as azithromicine pellet obtained by providing of dry mixture containing non-granulated azithromicine A and at least one pharmaceutically acceptable carrier, followed by direct pressing said mixture also are disclosed.

EFFECT: direct pressable azithromicine-containing formulations; azithromicine pellets having acceptable hardness and frangibility.

14 cl, 6 ex, 1 dwg, 6 tbl

FIELD: veterinary.

SUBSTANCE: invention provides (i) compacted vaccine composition containing lyophilized antigenic component and an auxiliary component enhancing dissolution and (ii) stable compacted vaccine composition containing a second lyophilized component including neutralizing antibodies against above lyophilized antigenic component. Invention further provides syringe containing vaccine composition, kit, and method of immunizing veterinary animal.

EFFECT: increased stability of composition.

50 cl, 11 ex

FIELD: medicine.

SUBSTANCE: the suggested solid dosed form of disinfectant contains a quaternary ammonium compound as an active substance and/or its compounds as clathrates, preferably, clathrate carbamide didecyldimethylammonium bromide and/or chloride, and additional substance - an acid component chosen out of boric acid, water-soluble acidic salts of phosphoric acids, acidic salts of sulfuric acid. The innovation provides wide range of antimicrobial activity being of high stability, solubility, low toxicity, comfort in usage and transportation.

EFFECT: higher efficiency.

17 cl, 8 ex, 2 tbl

FIELD: medicine, pharmacy, pharmaceutical industry.

SUBSTANCE: invention proposes a pharmaceutical composition used as a nootropic agent. The nootropic agent represents the condensed extract from the plant Atragene sibirica (family Ranunculaceae) prepared by condensing the liquid alcoholic extract from plant the Atragene sibirica under vacuum at temperature 50°C up to the moisture content 25%, and filling agents comprising lactose, microcrystalline cellulose, polyplazdon XL-10, potato starch, aerosil, magnesium stearate chosen in the definite ratio of components. Agent possesses the effective nootropic effect.

EFFECT: valuable medicinal property of pharmaceutical composition.

2 cl, 7 tbl, 4 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a soluble, carbonated, anti-inflammatory, analgesic and antipyretic agent as a tablet. Agent comprises acetylsalicylic acid, caffeine, ascorbic acid, paracetamol, basic component, acidic component and accessory substances. Invention provides the possibility of rapid release of the preparation in blood, decreasing time for undesirable contact of the preparation with stomach mucosa and its high activity.

EFFECT: valuable medicinal and pharmaceutical properties of agent.

6 cl, 6 tbl, 11 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to the development of a new medicinal agent representing the complex enzyme preparation with the digestive effect. Agent comprises enzyme pectate lyase providing effective cleavage of vegetable food intercellular substances, in particular, pectin and protopectin that results to formation of the homogenous and easily digestible mass, and promotes to assimilation vegetable food that is not assimilated by human organism that results to the more complete digestion of food, its cleavage and assimilation of nutrient substances. The optimal content of enzyme pectate lyase and pancreatin in a tablet covered by the enterosoluble envelope promotes to the more rapid and complete digestion of food in intestine and shows significant advantages as compared with the known digestive preparations.

EFFECT: improved and valuable properties of agent.

5 cl, 11 tbl

FIELD: experimental medicine.

SUBSTANCE: on should introduce solution into fracture area at the following ratio of ingredients, g/l: 1-hydroxyethylidenediphosphonic acid 1.80 - 2.06, water-free calcium chloride 1.44 - 2.22, gadolinium (III) nitrate hexahydrate 0.30 - 0.40, dysprosium (III) chloride hexahydrate 0.038 - 0.076, moreover, solution's pH corresponds to 7.3 - 7.8. The present innovation enables to shorten the process of bony tissue regeneration in the site of its lesion or defect and, also, shorten the period for restoring normal physiological function of traumatized bone.

EFFECT: higher efficiency of regeneration.

22 ex, 1 tbl

The invention relates to new derivatives of anhydride methylenephosphonic acid of the formula I, where Y1, Y2, Y3and Y4group OR1, NR2R3, OCOR1, OCNR2R3, O(CO)OR1, O(SO2R1or OP(O)R2(OR3), where R1, R2and R3- H, C1-22alkyl, aryl, possibly substituted, or SiR3where R3- C1-C4alkyl, provided that at least one of the groups Y1, Y2, Y3and Y4other than the group OR1or NR2R3, Q1and Q2Is H, F, Cl, Br, I, methods of obtaining these new compounds as well as pharmaceutical preparations containing these new compounds

The invention relates to medicine, namely to pharmaceutical drugs ibandronate or its physiologically acceptable salts for oral administration, and is a drug for the treatment of hypercalcemia, osteoporosis, tumor osteolysis, Paget's disease
The invention relates to medicine

FIELD: experimental medicine.

SUBSTANCE: on should introduce solution into fracture area at the following ratio of ingredients, g/l: 1-hydroxyethylidenediphosphonic acid 1.80 - 2.06, water-free calcium chloride 1.44 - 2.22, gadolinium (III) nitrate hexahydrate 0.30 - 0.40, dysprosium (III) chloride hexahydrate 0.038 - 0.076, moreover, solution's pH corresponds to 7.3 - 7.8. The present innovation enables to shorten the process of bony tissue regeneration in the site of its lesion or defect and, also, shorten the period for restoring normal physiological function of traumatized bone.

EFFECT: higher efficiency of regeneration.

22 ex, 1 tbl

FIELD: medicine, pharmacy, pharmaceutical technology.

SUBSTANCE: invention relates to pharmaceutical compositions as tablets, namely, to a tablet preparing by direct pressing and comprising 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or its pharmaceutically acceptable salts as an active component taken in the amount from 5 to 140 mg as measured for a pure acid, an excipient, a dry binding agent, a disintegrating agent and a lubricating substance, and to a method for its preparing. As an excipient the claimed composition comprises the combination of at least two recipients but with exception of lactose, and it comprises 20-80 weight% of excipient chosen from group comprising microcrystalline or powder-like cellulose and calcium hydrophosphate, and 0.001-50 weight% of one or more recipients chosen from group comprising mannitol and phosphates or hydrophosphates of alkaline or alkaline-earth metals. As a disintegrating agent the composition comprises maize starch taken in the amount 7-15%. The content of lubricating agent is 1%.

EFFECT: improved preparing method of tablet.

3 cl, 19 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with applying biphosphonate for treating osteonecrosis and/or osteonecrosis dissecans. This medicinal preparation could be additionally applied for preventing the development of osteonecrosis and/or osteonecrosis dissecans and any complications associated with both diseases. Biphosphonate acts for the decrease or prevention of severe degree of deformation and/or destruction of a bone or a cartilage and provides the chance to form new bony tissue in a patient.

EFFECT: higher efficiency of therapy.

38 cl, 7 dwg, 1 tbl

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