The microcrystals, the way to obtain microcrystals, the pharmaceutical composition

 

(57) Abstract:

The invention relates to a new method of crystallization of organic substances and especially of saraivanov, it astrana, androstane, pregnane, 19-nor-pregnane, cholestan or their esters at positions 3 and/or 7. The subject of the invention is a method of crystallization of microcrystals of pharmaceutically active substances, which allows the machining operation to obtain a pre-defined homogeneous granulometric class, which is that the substance is dissolved in a ternary mixture formed a lipophilic solvent, a hydrophilic solvent and a surface-active agent at a temperature close to boiling, then leave the mixture to reach a temperature at which crystallization starts, and separating the resulting crystals. 3 C. and 22 C.p. f-crystals, 21 ill., 3 table.

The invention relates to the field of pharmacotechnology and more specifically to a method for producing active principles for pharmaceutical use with controlled grain size distribution.

It is known that the size of the crystals of pharmaceutical acting early plays an important role during the preparation of dry or liquid pharmaceutical forms, C that differences in the kinetics of dissolution occur due to modifications of the crystal structure or the surface properties of crystals or associated with modifications of the values of the contact surface /G. GILLAR Labo. Pharm - Prob Toch et N 309, 359 - 369/1981//.

To improve the kinetics of dissolution of the active principles with limited solubility, typically use smaller particles.

This problem is usually solved through the use of mechanical grinding /crushing/ or micronisation /reduction of the jet of air/.

A study on various progestational substances /HUTTENRAUCH and researcher. ISP, Pharma/5,10/, 642-646/1989//, showed that the influence of particle size on the dissolution rate is closely related to the solubility of substances.

Studies of large numbers of molecules for therapeutic applications has shown that particle size and physico-chemical properties of the active principles, which result from mechanical treatments, causes the accumulation of the active principle in pharmaceutical forms by modification of their percentage, and rate of dissolution /see FDA-paper - Guidelines Manuf Control Form ANDAS, 1985/.

However, these methods are unsuitable for grinding comminution all effectors, some of which have low melting and become pasty or elastic.

Other operating beginnings in force Soares crusher.

In the document /NAKAGAWA al. Chem. Pharm. Bull 30, 242/1982// indicates that the specific surface area and crystallinity have a very large influence on the chemical stability in the solid state powder product.

The dissolution rate also depends on the crystallinity of the product /Century A. HENDRIKEN. Int. Journ. of. Pharm., 60, 243-252/1990//.

When studying the effect of mechanical treatments, in particular, grinding on the physicochemical properties of many active principles, members of the galenical forms, it was found that existing start changed their physico-chemical characteristics after these treatments.

Thus, it was found that happened:

the loss of crystallinity /confirmed by the diffraction of x-rays/;

- change their specific surface area SW /which can be double or triple/;

- deterioration of the chemical stability, confirmed by differential thermal analysis temperature decomposition /for some active principles of the fall of the melting temperature was 10-15oC/;

- change their surface properties, which complicates the manufacture of powdered drugs. In article GILLARD, cited above, describes what morphometric who fluidity.

These changes in physico-chemical properties of various active principles described M. OTSUKA and N. KANENIWA in International Journal of Pharmacentics 62, 65-73/1990/ and the references cited in this article.

In addition, it indicates the effect of reducing the size of particles obtained by grinding, to the hardness of the tablets produced from these products /see SAGAWA J.-J. Powder. Technol. fap., 20, 737-743/1983//.

Experimental data TAWASHI STP Pharma. 6/5/299-301/1990/ illustrate the dependence that exists between the decrease of particle size and morphology of the product itself. This dependence is expressed mainly in the irregularity of the surface of the particles and the correlation that exists between the surface of the particles and the physical behaviour of powders during the preparation of pharmaceutical preparations. Rough /uneven /the appearance of the surface, affecting the ability to yield the product, represents one of the important factors that affect the quality of the powder mixture used to obtain a pharmaceutical preparation. The impact of the reduction mechanism plays a more important role in the solubility of the current beginning.

Other studies have also shown that Krista is socialist/ in the compression process /see C. FUHRER STP PHARMA 6/5/, 294-298/1990//.

The result of grinding is to replace the crystal equivalent agglomerates of smaller crystals, which do not improve either the solubility or dissolution rate of the current beginning.

Moreover, mechanical grinding, for example, knife grinder, can contaminate the product metal particles or oil.

The purpose of the invention is to devise a method of obtaining crystals of the active agent by nonmechanical with controlled particle size at constant practical percentage and without destroying the crystals of the original product.

This goal is achieved by the proposed method, which is that the product that we want to secretariaat, dissolved in a ternary mixture formed a lipophilic solvent, a hydrophilic solvent and a surface-active agent, at a temperature close to the boiling point of the solvent mixture, and the solution is cooled to a temperature at which crystallization starts, and then separating the formed crystals, which have the same crystal system as crystals, originally used to dissolve the solvent in the crystallization of inorganic salts, in particular the sodium perborate /A. CHIANESE and other Process Technol Proc. 89, so 6 /ind Krist.87/ 261-264/, according to which the use of surfactant in water for recrystallization of sodium perborate, or for example, J. BLASZCZAK al.Kryst Przem. Krajowe Symp. Mater Konf. 3-I /56 WYAM /89, 95-101, hydrated aluminum fluoride.

In the literature, there are also publications that study the crystallization to obtain began acting in a particular crystal system, such as SAS, G. A. J. M. T. et al., that use a deposition method to obtain the current beginning zakristallizuetsya in the monoclinic system /Europe. patent 389,035-SA /1991/ 114:214521/ or then for the Department of polymorphic forms such as terfenadine /2 crystalline forms/ see T. G. FAWCETT AND others, U.S. patent N 4742175 /. According to other methods of preparing the micro-crystals by deposition in the "anti-solvent", dissolving the active principle in water-soluble solvent and injective in CO2/see PLT Int. Appl. 90.30.782-CA/1990/ 113:178284 K/.

In the method of the invention the hydrophilic solvent is chosen so that it is mixed or dissolved in a lipophilic solvent to provide a homogeneous solution. Preferably it is formed by water mixture and in particular water, to the t to use ternary mixture, formed by solvent selected from the group of alcohols (methanol, ethanol, butanol, isopropanol) ketones (acetone, methyl ethyl ketone or methyl isobutyl ketone) ethyl acetate, isobutylacetate and water, the percentage of which in the binary mixture is 0-12%.

Surface-active agent is preferred nonionic surface-active agent selected in the group comprising complex polyoxyethylene esters sorbitan and fatty acids containing at least 8 C-atoms; simple polyoxyethylene esters of fatty alcohol containing at least 8 C-atoms, and complex polyoxyethylene esters of stearic acid.

The nonionic surfactant is chosen from those which have ampilly character, but with a predominance of hydrophilic character, with a hydrophilic-lipophilic balance greater than 12, for example, a complex polyoxyethylene esters sorbitan and fatty acids, such as Twins 20; 40; simple polyoxyethylene esters of fatty alcohol, for example BPIJ 56-58-78-96-98-99-G3816 and 3820, G3910 and 3920 or 254-257 or RENEX or CREMOPHOR or type PLURONIC F68.

Also suitable complex polyoxyethylene esters of stearic acid, such as MYRJ 49,51,52,53,59, as they also improve dissolve the temperature of recrystallization for overload protection.

Depending on the group used active principles, it is preferable to use ternary mixture formed by the above solvents containing from 1 to 12% water and 0.01-10% surfactant, and particularly preferably 0.05 to 5%.

This ternary mixture can be prepared in one stage or in several successive stages, first dissolving the active principle in one of the solvents to which, if necessary, add a surfactant, and then enter another solvent.

The volume and nature of ternary mixtures used for recrystallization, is chosen depending on the given particle size class of the studied pharmaceutical forms and depending on the desired output.

For a particular effective beginning you should make ternary diagram used mixtures and to determine the proportions of the solvents. The volume of the ternary mixture depends on the solubility of the current beginning at the boiling point under reflux in the mixture. The good solubility necessary to have a fairly high concentration in the mass, since solubility is a factor influencing the growth of crystals during ohla good their distribution in the liquid mass, and so to foster their inclusion in the system, to improve the liquid and solid phases during recrystallization and thus influence on the surface tension of an interface liquid/solid. The proximity effect in the crystallization process can disrupt the regular crystal growth and lead to groups that do not have a very clear form. Only the regular arrangement in space of the particles forming it distinguishes crystals from amorphous substances, where the arrangement of the particles messy.

The temperature of the heating ternary mixtures plays an important role. Triple mixture containing the active principle, which need to recrystallizing, bring up to temperature, the most close to boiling above mixture to provide a significant concentration recrystallizing substances and to minimize the recrystallization temperature of the substance.

The size of the crystals is also changed depending on the concentration and ratio of the lipophilic solvent/hydrophilic solvent. The amount of hydrophilic solvent passes through the optimal value when working, for example, with progestational substances. It is 2-5% in PR is 35-70 μm and preferably 5% to reduce this variation to 35-55 μm.

With 7.5% of the same above-mentioned solvent particle size class increases up to 70-100 μm. The increase in the content of the hydrophilic solvent leads to larger crystals. In addition, working in more or less diluted environment also leads to the crystals more or less large size, depending on the used surfactants. The rule that get smaller the crystals, if the active principle is found in significant concentrations in the environment for crystallization from monasteries, not always justified in the present method, recrystallization.

The cooling rate, the temperature at which recrystallization, the nature of the ternary mixture and the concentration of the active beginning of the change depending on the desired particle size class and the degree of cooling, and stirring speed environment is defined in advance for each experiment. The current selection to the beginning of the filtration is performed at temperatures that range from +45oC to -10oC.

The transfer of this method on an industrial scale for some substances leads to some differences in particle size class: so, for promestriene, the cat in the transfer method on an industrial level.

The active principle is preferably a compound with a steroid structure and in particular the derived Estrada, androstane, pregnane, 19-nor-pregnane or cholestan.

Derived estrana can be called estradiol, estrone, estriol or nor-testosterone, their simple and/or esters. A more concrete example of the derived estrana is simple propyl ester simple 17-methyl ether of estradiol /promestriene/ or 16-nor-testosterone-undecanoate.

Of the derivatives of androstane can be called testosterone, its ethers and esters in position 17; testosterones. substituted in position 4,6,7 there or 16, for example, 4-chloro-testosterone-6-methyl-testosterone, 7-methyl-testosterone; esters of fatty acids testosterone, cyclopentylacetic or cyclohexylpropionate of testosterone. Derivatives, substituted in position 17, androstene-2, for example, 17-acetoxy-alpha-ethinyl-alpha-androst-2-ene.

Of derivatives Pregnana can be called progesterone, its simple enol ethers, cyclic or linear amines, alpha-gidroksilirovanii derivatives, ethers, alpha-oksiprogesterona, esters Alfa-oksiprogesterona; progesterones, substituted in position 1; in new molecules, such as cortisone, prednisone, medrol, dexamethasone, betamethasone or triamcinolone.

Of the derivatives of 19-nor-progesterone can be called alpha-hydroxy-19-nor-progesterone, its ethers in position 17; its esters in position 17, also substituted 19-nor-progesterones such as 6-methyl-alpha-hydroxy-19-nor-progesterone, its ethers in position Alfa and its esters in position 17A, such as 6-methyl-3,20-dioxo-alpha-19-nor-4,6-diene and its esters.

Of the derivatives of cholestane can be called bile acids, cholesterol and its esters, ergosterol, stigmasterol, calciferol.

Microcrystalline compounds obtained according to the method of the invention are applicable basis in dry pharmaceutical compositions. It is a regular tablets or pills of variable selection, gelatin capsules with the medicine or granules; a liquid pharmaceutical composition suitable for drinking suspensions or injectable suspension for injection intramuscularly or intra-articular, vaginal compositions such suspensions in bioadhesive gels, candles or bulbs with medicinal substances.

The following examples illustrate the invention, but in no way a cut.

Example 1: the Microcrystals hydrocortisone

At the boiling point under reflux dissolve 10 g of hydrocortisone in 10 volumes of solvent formed:

for 95.8% of methyl ethyl ketone

- 4,0% water and

- 0.2% Tween-20.

Refluxed for 5-10 minutes under stirring and make sure that there are no longer suspended particles. With stirring, the mass is cooled to -10oC. and kept at this temperature for 1 hour and the formed crystals are sucked off. The crystals are washed with water and dried under reduced pressure at a temperature close to 50/60oC. the Thus obtained crystals for the largest particles have a size of 25 x 30 µm, and for the smallest particle size 5 x 10 µm. So pl.to: 221,5 - 220oC.

LD/methanol/: +1562o.

Example 2: Microcrystals dexamethasone-acetate

At the boiling point under reflux dissolve 10 g of dexamethasone-acetate in 4 volumes of solvent formed:

- 89,0% methyl ethyl ketone

to 10.5% water and

- 0.5% of the Miry 51.

Maintained at the boil under reflux for 30 minutes. Filtered off the insoluble matter and the filtrate is cooled the Ute water and dried them at 60oC is 80 x 50 μm for the largest and 8 x 10 ám for the smallest. So pl.to: 226-227 of theoC.

LD/methanol/: 842o.

Example 3: Microcrystals dexamethasone-acetate

At the boiling point under reflux dissolve 10 g of dexamethasone-acetate in 4 volumes of solvent formed:

- 87,6% acetone

to 12.0% oxen and

- 0.4% Tween-20.

Isolated as in the previous example and get the crystals, for which the largest are the size of 200 x 75 µm, and for the small 100 x 50 µm. So pl.to: 228oC.

LD/methanol/: +862o.

Example 4 : Microcrystals prednisolone

At the boiling point under reflux dissolve 10 g of prednisolone in 5 volumes of solvent formed:

- 94,8% methyl ethyl ketone

to 5.0% water and

- 0.2% Tween-20.

Allocate as described in the previous experiments /cooling to -10oC/.

Get the crystals with a maximum size of about 55 x 40 μm and the minimum size 35 x 24 microns. So pl.to: 240o1.

LD/methanol/: +1674.

Example 5 : Microcrystals nomegestrol-acetate

At the boiling point under reflux dissolve 10 g nomegestrol the ptx2">

Very slowly leave the temperature to drop, with stirring, by external cooling, up to -5oC. and kept at this temperature for 15 minutes. Separate the crystalline mass is sucked off and then washed with water and dried under reduced pressure. The thus obtained crystals have a size of 50 x 25 μm for the largest particles up to 10 x 10 ám for the smallest particles.

Example 6 : Microcrystals nomegestrol-acetate

Working as in example 1, but using 2 volumes of ternary solvent formed:

to 92.4% of methyl ethyl ketone

- 7,5% water

- 0.1% Tween-20.

Get the microcrystals, the size of which ranges from 100 x 100 µm for the most up to 65 x 35 ám for the smallest crystals.

Example 7 : Microcrystals nomegestrol-acetate

Working as in example 1, but using 2 volumes of ternary solvent formed:

- 94.9% ethyl ketone

to 5.0% water

- 0.1% Tween-20.

Get the microcrystals whose size is 55 x 40 µm for the most up to 35 x 25 µm smallest.

Example 8 : Microcrystals nomegestrol-acetate

Working as in example 1, but using 2 volume trainout microcrystals, the size is 150 x 65 μm for the largest up to 90 x 50 µm smallest.

Example 9 : Microcrystals nomegestrol-acetate

Working as in example 1, but using 1.5 volume ternary solvent formed:

- 94.9% ethyl ketone

to 5.0% water

- 0.1% Tween-20.

Get the microcrystals whose size is 120 x 40 μm for the largest up to 70 x 50 µm for the little ones.

Example 10 : Microcrystals promestriene

Working as in example 1, but dissolving part promestriene in 4 volumes of ternary solvent formed:

- 94,9% absolute ethanol

to 5.0% water

- 0.1% Tween-20.

Get the microcrystals whose size is 55 x 40 µm for the most up to 35 x 25 µm for the little ones.

Example 11 : Microcrystals promestriene

Work, as in the previous example, dissolving 30 kg promestriene in 3 volumes of ternary solvent formed:

- 94.9% methylethylketone or 85,320 l

to 5.0% water or 4,500 l

- 0.2% Tween-20 or 0,80 l

Cooled to -10oC. After 15 minutes of incubation at this temperature, the resulting crystals filtered off. Washed with water and dried Italy have a size, which is 125 x 100 μm for the largest up to 80 x 50 µm for the little ones.

Products that are used in this example, /raw, crushed and microcrystalline/ gone differential thermal analysis.

Separate tests of raw and pulverized product /C114 and C114B/ two pulverized products /C108B and C114B/ and raw and microcrystalline product /C109 and C109M/ given the following results:

- research products C108B, C114B and C114 under identical experimental conditions in the temperature range from 12 to 142oC, showed that these three products during differential kolorimetricheskogo analysis with scan temperature have similar characteristics.

The melting of these compounds gives similar between a temperature of about 64oC and the enthalpy of melting from 72 to 74 j/,

The micro-crystals with a melting point 64,57oC and enthalpy of melting and 73.2 j/g, therefore, comparable with other products.

Example 12 : Microcrystals nomegestrol-acetate

Carry out two experiments on the crystallization according to the method of the invention from 30 kg nomegestrol-acetate.

The product is dissolved in 4 volumes of ternary solvent the product has the following particle size range /laser granulometer COULTER LS 130/:

experience 1: the party 037 MC2;

experience 2: party L MS.

For these two experiments, the results are statistically comparable for one particle size class, all particles which have a size less than 100 microns.

When you cut various industrial parties state that most irregular /see curves parties 23, 27, 33, 35/ granulometric classes.

Example 13:

Carry out experiments on larger parties in 40, 60 and 90 kg according to the method described in example 12, and also get good results.

Experience with 90 kg control S4-part 3 gives the following particle size distribution:

in % /size/:

134,60 10%

77,82 25%

40,33 50%

19,43 75%

8,917 90%

Example 14 : Microcrystals progesterone

Work, as in the previous examples, dissolving the product at the boiling point under reflux in 6 volumes of solvent generated from:

- 93,4% ethanol,

- 6,0% water

- 0.6% Tween 40.

Separate cold formed crystals, which are washed with water and dried. The thus obtained crystals have a size of 150 x 80 µm for the biggest and 10 x 20 ám for the smallest.

Example 15 : Microcrystals 17--acetoxy-17L-ethinyl-5L-Andro is rinicom in 4 volumes of a mixture of solvent, formed from:

to 96.5 ethyl acetate

- 3,2% water

0.8% Tween - 20.

Allocate as described above in previous examples. The thus obtained crystals have an average grain size distribution of 40-60 microns.

So pl.to: 125-129oC.

Example 16 : Microcrystals androstanolone /4-dihydrotestosterone/

Work, as in the examples above, dissolving the product at the boiling point under reflux 7.5 volumes of solvent generated from:

- 91,8% methanol

to 8.0% water

- 0.2% Tween-20.

Separated in a cold formed crystals, which are washed with water and dried. The crystals have an average grain size distribution 120 microns.

So pl.to: 1822oC. LD/alcohol/: 302oC.

A study using differential thermal analysis carried out on the industrial parties nomegestrol-acetate before grinding after grinding and after microcrystallization:

samples A and B for nomegestrol before chopping;

samples C and D for nomegestrol after crushing;

samples E and F for nomegestrol after microcrystallization.

Microcrystallization is performed on the product before crushed the solid. Transition solid - liquid celebrated according to the samples at 178179,1oC.

Enthalpy is about 6.8 j/,

The deviation of temperature in the transition solid - liquid was lower for samples E and F, originating from microcrystalline product according to the claimed method.

Thermogravimetric analysis carried out on the sample /8/, the original product. On this type of product at temperatures of experience 25 to 700oC the weight loss is almost entirely about 400oC.

You can also explore granulometric classes, received by way of microcrystallization with showing analyzer, equipped with a console /un logiciel/ VIDS 1V.

On recrystallized industrially product, according to the method of example 12 /control 037 MC2/ carry out the study. The results are expressed in μm for the size /parameter length/ μm and2for surfaces.

This type of analysis allows to confirm the results obtained by laser grain size distribution.

In the field of small particles are small particles of 9-16 μm, characteristic of the particles observed by laser granulometry.

Analysis balleseros granulometry.

Chromatographic study /liquid chromatography high pressure/ allows you to demonstrate the harmful effects of crushing.

For nomegestrol-acetate this destruction can be estimated as about 0.2%.

Some examples of industrial parties emphasize this phenomenon:

- Party 028 031 and: the party before crushing;

- Party B and B: the same party after crushing.

Studies using liquid chromatography high pressure, carried out at two different wavelengths /245 and 290 nm/ made for better separation of impurities such as 3-keto-Delta-4 - from those of 3-keto-Delta-4,6-pregnadien.

To resolve this destruction was considered several ways:

one is grinding when cooling equipment, and the other uses the crystallization method according to the invention.

For comparison carried out in practice, these both at the same party acting beginning.

The party marked 037-MS - MS are 3 experience recrystallization on installations with 30 kg, to confirm the suitability of the method described for this class size.

Studies using the same conditions, that the conditions specified above.

These experiments show that:

- crushing, carried out with cooling, does not eliminate the product from the resolution;

- crystallization according to the method of the invention allows to obtain the active principle of the best quality and within the specified class granulometry, without resorting to the method of crushing.

This phenomenon of chemical destruction is also found on other steroid products, in a more or less considerable extent, depending on actual beginning.

The following examples illustrate compositions using microcrystalline products obtained according to the invention, in particular derivatives Pregnana.

The specified particle size class is the most characteristic product /more than 80%/.

Example 17 : Tablets with prolonged selection

A single composition with different doses:

microcrystalline nomegestrol-acetate /200-300 μm/1,25 - 10,00 mg

Aerosil 200 0.37 to 0.50 mg

preziral ATO 5 1.85 to 2.25 mg

metozel E. 4 55,00 - 70,00 mg

Avicel PH 101 10,00 - 20,00 mg

lactose up to a total weight for the 1st tablet 185,00 - 200,00 mg

Example 18 : Tablets with accelerated selection

The single is l 200 0,37 - 0.50 mg

preziral ATO 5 1.85 to 2.00 mg

Avicel PH 102 50,00 - 70,00 mg

Explotab or Polyplasdone XL 5,0 - 25,00 mg

lactose up to a total weight for the 1st tablet 185,00 - 225,00 mg.

Example 19 : Tablets nomegestrol-acetate

A single composition with different dose

microcrystallites nomegestrol-acetate /200-300 μm/ 1,25 - 10,00 mg

Aerosil 200 0.37 to 0.50 mg

preziral ATO 5 1.85 to 2.25 mg

Avicel PH 101 55,00 - 70,00 mg

lactose up to a total weight for the 1st tablet 185,00 - 220,00 mg.

Processing of the results by the distribution function for WEIBULL D. GIBASSIER and other STP PHARMA, 1/10, 967-973/1985// shows a significant difference between the three formulations.

The curves of dissolution, characterized by the parameter of this function, give 0,148 for composition with the quick selection 1,015 for composition with the normal selection and 1,914 for composition with prolonged wanted.

The method of the invention, therefore, allows to obtain the particle size class of the beginning of the current corresponding to the needs of implemented forms.

Note that these two pharmaceutical forms, implemented from the industrial parties have equivalent bioaccumulation.

Example 20 : Injectively form Oy 5 ml:

microcrystallites the medroxyprogesterone-acetate or microcrystalline nomegestrol-acetate /15-40 μm/ 500,00 mg

polyethylene glycol 4000 200,00 mg

preservatives 0.006 mg

chloride and sodium citrate 0.15 mg

water for injection to a total weight of 5.00 mg

Example 21 : Vaginal or gynecological capsule

a/. A single dosage to 1 capsule:

microcrystallites progesterone /200-300 μm/ 50 - 500,00 mg

pharmaceutical vaseline 0,200 g

sorbitol-sesquioleate 0,200 g

perhydrosqualene synthetic 1.85 g

dry shell: gelatin, glycerin, stabilizers for one soft capsules weight of 2.55 g

b/. microcrystallites nomegestrol-acetate 20,00 mg

Witepsol N and N to the total weight 1st bulb with medicinal substance 2,8,

Example 22 : Bioadhesive gel for skin or gynecological application

The formula for 100 g:

microcrystallites progesterone 2.0 - 3.0 g

the glycol 4,0 - 6,0 g

carboxypolymethylene polymers of 0.5 - 1.0 g

preservatives 0.3 mg

triethanolamine to a pH of 6.5

purified water to a total weight of 100 g

Example 23 : Gynecological bioadhesive foam

The formula for the 1st bottle with dispenser /sabutan 5,5%

the main excipient F 25/1 to the total weight of 50.0 g

Before using to mix the suspension. The dose is distributed over 100-250 mg

Example 24 : Medications injected subcutaneously

The formula for 100 g of material processed:

nomegestrol-acetate 5.0 g

polycholorinated to the total weight 100 g

The temperature of the mixture should not exceed 185oC in order not to aggravate the crystalline form of the current beginning.

Example 25 : Intrauterine device with a reservoir

Tank made from Silastic length 2.5 - 3.5 cm, thickness of 0.4 - 0.8 mm and a diameter of 2 mm.

100 g of suspension:

microcrystallites progesterone /80/250 μm 0,600 - 1.0 g

in the form of a suspension in:

suspendisse agent 0.5 g

synthetic perhydrosqualene to the total weight of 100.0 g

Example 26 : Plaster /bandage/

The contents of the tank is a drug per 100 g:

microcrystallites nomegestrol-acetate /80 - 250 µm/ 0.5 g

carboxypolymethylene polymer 0.2 g

colloidal silicon dioxide 0.2 g

silicone oil to the total weight 100 g

Derived astronav.

Example 27 : Tablets

Unit composition:

microcrystallites estradiol /10/50 μm/ 1,0/BR> Aerosil 200 1,0 - 2,0 mg

preziral ATO 5 1,5 - 3,0 mg

polyplasdone XL 2,5 - 5,0 mg

lactose to the total weight for the 1st tablet to 185.0 - 220,0 mg.

Example 28 : Bioadhesive gels estradiol or promestriene

The formula for 100 g of gel:

microcrystallites the estradiol or promestriene 1,0 - 2,0 g

propylene glycol 5,0 - 10,0 g

carboxypolymethylene polymer 0.5 - 1.0 g

preservatives 0.3 mg

triethanolamine to pH 6 to 6.5

purified water to a total weight of 100.0 g

Example 29 : Vaginal capsule

The formula for one capsule:

microcrystallites the estradiol 1.0 mg

Labrafil M 1944 CS 0.5 g

perhydrosqualene 1.3 grams

dry shell: gelatin, glycerin, stabilizers for one soft capsule 2.1,

Example 30 : Plaster /bandage/

The contents of the tank is a drug per 100 g:

microcrystallites estradiol /80/100 μm/ 0.5 - 1.0 g

Aerosil 0.5 g

synthetic perhydrosqualene to the total weight of 100.0 g

Derived androstenol.

Example 31 : tablets

A single composition for the 1st pill weight 380 mg:

microcrystallites 17-acetoxy-17L-ethinyl-5L-androst-2-EN 20.0 mg

Avicel pH 101 91,20 mg

Aerosil 0.45 mg

preziral ATO 5 7, is in the literature.

Example 32. Gynecological gel

The composition for 100 g:

microcrystallites androstanolone /DNT/ 2.50 g

propylene glycol 2.50 g

transcutol 5,00 g

preservatives 0.08 g

viscous agent /tea/ 0.25 g

carboxypolymethylene polymer 1.50 g

purified water to a total weight of 100 g

Example 33 : Oral capsule

Microcrystallites testosterone-heptylate 50,00 mg

oleic acid to the total weight for the 1st capsules 250,00 mg

Shell: gelatin, preservatives, glycerin

Derived from compounds, derivatives of 21-hydroxy-pregnane.

Example 34 : Oral tablet

A single composition for the 1st tablet:

microcrystallites prednisone /80/150 µm/ 2,50 mg

Avicel pH 102 50,00 mg

Aerosil 1,80 mg

Preziral ATO 5 2,00 mg

lactose to the total weight 1st tablet 128,70 mg.

Example 35 : Oral tablet

A single composition for the 1st pill

microcrystallites prednisone /80/150 mm/ 0,50 mg

Avicel PH 102 50,00 mg

Aerosil 1.70 mg

Preziral ATO 5 2,00 mg

lactose to the total weight 1st tablet 130,00 mg.

Example 36: For dermal applications

The composition for 100 g:

microcrystallites dexamethasone-acetate /100-325 μm/ 0.05 to 0.10 g
I water until the total weight of 100.00 g

Example 37: Injectively suspension

A single composition for the 1st ampoule capacity of 2 ml:

microcrystallites dexamethasone-acetate /<80 μm/ 10,00 mg

The dissolved substance suspension:

Polysorbate 80 0.015 g

sodium carboxymethyl cellulose 0,010 g

sodium chloride 0,010 g

water p.p.i to a total volume of 2.00 ml

Explanations to Fig. 1A/21 - 21B/21

Fig. 1A/21 describes the definition of the state of stelopererad:

- Start peak = 172,6oC; K1 = 2,401; S/K1/ = -2,1753;

- End peak = 198,5oC; K2 = 2,791; S/K2/ = -1,8858

Enthalpy = 9,665 E + 002 MJ

or -1,639 E + 001 cal/g

or -6,855 E + 001 j/g

Endothermic peak TR = 181, 385774333

Peak temperature peak = 179,6oC

Determining the status of stelopererad:

The range of temperatures to determine Tg

- start temperature = 174,2oC

- temperature end = 181,1oC

Three glass transition temperature: 176,7o- 178,8oand to $ 179.7oC

Slope = 7,91818986688

Fig. 1B/21 describes the determination of the state of stelopererad

- Start peak = 171,4oC K1 = 2,474 S/K1 =-3,1993;

- End peak = 201,1oC; K2 =2,920; S/K2/ = -2,7929

Enthalpy = -1,182 E + 003 MJ

or -1,598 E +cal/g

or -6,6798 + 001 j/g

Endothermic peak TR = 181, for to determine Tg:

- start temperature = which is 171,5oC

- start temperature = 181,9oC

Three glass transition temperature; 173,8 - 178,3 and 179,4oC

Slope =-5,74403141606

Fig.24/21 gives:

- initial temperature : TO RUB 285.2

- finite temperature : 379,3 TO

- scan rate : 2,00 C/min

gamma gain : 1,000 mV

the mass of the sample : 37,200 mg

- speed capture sample: 2,08

- preservation : 1,357 degrees (points)

Fig. 2B/21 makes determination of the state of stelopererad

The range of temperatures to determine Tg:

- start temperature = 61,79oC

- temperature end = 66,63oC

Three glass transition temperature: 64,0; -64,79 and compared with 65.38oC

The variation of Cp = 6,64 cal/g C

Integration with linear baseline:

- start peak = 62,06oC

- end peak = 74,23oC

- low start = 64,89oC

Enthalpy = -0,27672 E + 004 MJ

or 0,74389 E + 002 j/g

or 0,17796 H + 002 cal/g

or -0,66202 + 0,03 calendarmickie pic

Peak temperature peak = 66,56oC

Fig. 3A/21 /DEEG C114B/ gives:

- initial temperature : TO RUB 285.2

- finite temperature : 525,0 TO

- scan rate : 2,00 C/min

gamma gain : 1,000 mV

the mass of the sample : 25,400 mg

- skya of stelopererad

The range of temperatures to determine Tg:

- start temperature = 62,29oC

- temperature end = 66,57oC

Three glass transition temperature: 64,1 - 64,55 and 64,98oC

The variation of Cp = 4,58 cal/g

Integration with linear baseline:

- the beginning of the peak - 62,16oC

- end peak = 75,38oC

Low start = 64,62oC

Enthalpy: = -0,18837 E + 004 MJ

or -0,45064 E + 003 mcal

or -0,7461 E + 002 j/g

or 0,17742 E + 002 cal/g

Endothermic peak:

Peak temperature peak = 66,44oC

Fig. 4/21 gives:

- initial temperature: TO RUB 285.2

- finite temperature : 415,2 TO

- scan rate : 2,00 C/min

gamma gain: 1,000 mV

the mass of the sample : 42,200 mg

- speed capture sample : 2,08

- initial preservation : 1,875 degrees

- end-preservation: 1,875 degrees in the dossier

Integration with basic linear line:

- start peak = 61,16oC

- end peak = 73,61oC

Temperature start: 64,75oC

Enthalpy: = 0,30705 E + 004 MJ

or -0,73458 E + 003 mcal

or 0,72762 E + 002 j/g

or 0,17407 E + 002 cal/g

Endothermic peak:

Peak temperature peak: 66,69oC

Determining the status of steklovareniye = collected 66.36oC

Three glass transition temperature, 63,7; 64,22 and 65,24o< / BR>
Variation Cf = 5.17 cal/g C

Fig. 5A/21 /Ref DEEG C. 114/ gives:

- initial temperature: TO RUB 285.2

- finite temperature: 415,2 TO

- scan rate: 2,00 C/min

gamma gain: 1,000 mV

the mass of the sample: 61,600 mg

- speed capture sample: 2,08 C.

- preservation: 1,875 degrees

Fig. 5B/21 makes determination of the state of stelopererad:

The range of temperatures to determine Tg:

- start temperature = 57,84oC

- temperature end = 67,94oC

Three glass transition temperature: 63,6 - 64,31 and 65,52oC

The variation of Cp = 5,24 cal/g C

Integration with basic linear line:

- start peak = 57,08oC

- end peak = 77,00oC

Temperature start: 64,78oC

Enthalpy = -0,45478 E + 004 MJ

or -0,10879 E + 004 mcal

or -0,73828 E + 002 j/g

or -0,17662 E + 002 cal/g

Endothermic peak:

Peak temperature peak = 66,90oC

Fig.6/21 gives:

- initial temperature: TO RUB 285.2

- finite temperature: 415,2 TO

- scan rate: 2,00 C/min

gamma gain: 1,00 mV

the mass of the sample: 35,800 mg

- speed capture sample: 2,08 C.

- preservation: perature start = 61,65oC

- temperature end = 67,04oC

Three glass transition temperature: 64,4, 64,57 and 65,59oC.

The variation of Cp = of 7.48 cal/g C

Integration with linear baseline:

- start peak = 61,65oC

- end peak = 73,26oC

Temperature start: 64,65oC

Enthalpy: - 0,26606 E + 004 MJ

or 0,62695 E + 003 mcal

or 0,73203 E + 002 j/g

or 0,17512 E + 002 cal/g

Endothermic peak

Peak temperature peak = 66,90oC

Fig.7/21 gives:

/28.08.1990 - 9 hours. 10 minutes/

Analysis of particle size using couler (R) LS Ref A00890.S 18

The title of the dossier: AO 890 S 18 Group 1D: AO 890

Sample 1D : TX 066, party 037 MC 2

Room experience: A. P. C. Simms

Comments - dispersion: glycerol and ultrasounds in Coultronic (France)

Start time: 10 hours 42 minutes - August 25, 1990

Duration of experience: 90 C.

Darkening: 6%

Ambiguity PIDS : 30%

Optical model: Fraunhofer, including P1DS

Statistical volume /arithmetic/ AO 890. S18

Calculations of 0.10 μm - 834,40 μm

Volume: 100,0%

Average 22,49 μm; the limits of reliability of 95% : 19,4-25,56 μm

Medicine of 19.72 μm; standard deviation: 15,67 μm

the ratio of mean/median: 1,141

Edit: 245,5 μm2< / BR>
Mo is; 10,00 25,00 50,00 75,00 90,00

size, microns: 45,20 32,64 of 19.72 10,10 3,771

Fig. 8A/21:

Integration with linear baseline:

1. Starting peak = 173,9oWITH K 1 = 2,490

Endothermic peak TP = 181,881617

Peak temperature peak = 180,1oC

Sample AND

Fig. 8B/21

2. Peak temperature peak = 180,2oC

Determining the status of stelopererad:

The range of temperatures to determine Tg:

initial temperature = 169, 5mmoC

- final temperature = 181,5oC

Three glass transition temperature: 176,4, 178,1 and 179,5oC

Tilt: - 6,4818199304

Fig.9A/21

Sample C

The range of temperatures to determine Tg:

- initial temperature: 173.5 metricoC

- finite temperature: of 180.5oC

Three glass transition temperature: 177,2; 178,9 and 179,4oC

Tilt: - 11,8392024107

TP = 181,252441

Peak temperature peak = 179,00oC

Fig. 9B/21

Sample D

Determining the status of stelopererad

The range of temperatures to determine Tg:

- start temperature = 173.5 metricoC

- temperature end = 181,0oC

Three glass transition temperature: 178,0; 179,1 and to $ 179.7oC

Tilt: - 21,4280794192

Fig. 10/21

This loss of mass is carried out in three stages /TG mg/min/ # 54/55 m is losing weight

Blue curve: temperature experience

purple curve: TG /mg/min/

Fig. 11/21

Analysis of particle size using a CoulterrLS - 9 hours. 39 minutes - August 28, 1990 - AO 889. S01

The title of the dossier: AO 889. S01

Group 1D : AO 889

Sample 1D : TX 066, party 037 MC1

Number of experiments: 1

Operators: APC Simm

Comments: the variance Nonidet and ultrasounds

Coulter France - nomegestrol-acetate

start time: 11 hours 5 minutes - August 24, 1990

duration of experience: 91 with.

Darkening : 5%

ambiguity pids : 23%

Optical model: Fraunhofer including PIDS

PC: version 1.10 13 h 07 min Friday 2 March 1990

Statistical volume/arithmetic/ AO 889.S

Calculations of 0.1 μm - 834,40 μm

Volume: 100%

average: 32,93 μm

median: 31,12 μm

the ratio of mean/median: 1,058

fashion: 44,70 μm

The limits of reliability of 95% : 29,02 - 36,84 μm

Standard deviation: 16,96 μm

Edit: 398,4 μm2< / BR>
coefficient of variation : 60,61%

tilt: 3,640 e - 001 tilt to the right

Curtosis : 5,857 e - 001 Platykurtigue

% 10,00 25,00 50,00 75,00 90,00

size, microns 61,21 47,02 31,12 17,27 7,31

Fig. 12/21 shows a study in the microscope sample nomegestrol-acetate /TX 066/

Sample MC 2

the field surface: 30.54 ode 991

028001. LED: 30 may 1991 13 hours. 50 minutes

Scale Y: 0,008 AU/FS

time calibration: 21 msec. 4

importance: normal

resolution: 3 μm

time range: 2.4 to 25 minutes

interval: 1 sec.

baseline: outside

vacation /mitigation/ : 5 degrees

deviation: 0,002 AU/min

width: 0,001 minutes

double duration: 30 minutes

sample name: TX /1-00-1/

speed paper: 4 mm/min.

ultra-spherical ODS column : 4.6 mm 1D x 250 mm

filling material: C. 18

mobile phase: acetonitrile 360 MeOH 240 H 20 400

the flow rate: 1.3 ml/min

Pressure 2300 PSI

tilt: 0,001 AU/min

height: is 0.0002 AU

minimum surface: 0,00002 AU/min

negative PEAK: out

Fig. 16/21

Analysis of particle size using a CoulterRLS

the title of the dossier: 4-3 2 Group 1D:881#91

Sample 1D: TX 066 Ref. S4 party 3

room experience: 2

operator. R. J. B. C.

Comments - environment: water-dispersion, 1% NONIDET in DN U/S nomegestrol-acetate Ech. Theramex via France

Start time: 15 hours 37 minutes - June 24, 1991

duration of experience: 91

darkening: 8%

ambiguity SDIP 54%

Fraunhofer optical model, including PIDS
calculations of 0.10 μm - 900,00 μm

volume : 100%

average 34,76 μm, limits the accuracy with 95% 27,20 - 44,41 μm median 40,33 μm, standard deviation: 1,251,

the ratio of mean/median: 0,862

Edit: 1,564

fashion: 42,62 μm

coefficient of variation: 35,25%

tilt: - 1,270 lean to the left

Kurtosis : 3,027 Leptokurtigue

%> 10,00 25,00 50,00 75,00 90,00

size, microns 134,6 77,82 40,33 19,43 8,917

Fig. 17/21

Analysis of particle size using a CoulterRLS 16 hours 24 minutes

may 11, 1990 023 S 03

the title of the dossier: 023 S 03

group 1D: 023

sample 1D: TX 066 023

number of experiments: 3

the operator Martine Julin

comments: dispersion Coulter with anti-foam

start time: 13 hours 33 minutes may 9, 1990

duration of experience: 61

darkening: 9%

optical model: Fraunhofer

PC version: 1,10 13 h 07 min Friday 2 March 1990

statistical volume /arithmetic/ 023 S 03

calculations of 0.10 μm - 834,40 μm

volume: 100%

average: 59,70 μm

median: 53,75 μm

the ratio of mean/median: 1,111

fashion: 73,31 μm

the limit of accuracy with 95% : 49,10 - 70,30 μm

standard deviation: 54,07 μm

edit: 2923 μm2< / BR>
coefficient of variation: 90,57%

tilt: 3,390 c - 000 tilt to the right

Kirtosis : 3,530 - 001 Platykurti>number of experiments: 14

operator: Martin JULIN

comments: dispersion Coulter with anti-foam

start time: may 9, 1990 - 14 hours 34 minutes

duration of experience: 61

darkening: 12%

optical model: F

PC: version. 1,10 - 13 h 07 min Friday 2 March 1990

statistical volume /arithmetic/ 027 S 01

calculations of 0.10 μm - 834,40 μm

volume: 100.00% of

average: 69,86 μm

median: 70,30 μm

the ratio of mean/median: 0,994

fashion: 86,45 μm

the limits of reliability of 95% : 61,10 - 78,62 μm

standard deviation: of 44.67 μm

change: 1995 μm2< / BR>
coefficient of variation: 63,94%

tilt: 1,361 e - 000 tilt to the right

Kurtosis : 5,038 e + 000 Leptokurtigue

Fig. 20A/21 20/21

Statistical volume/arithmetic/ 035 B - S01

calculations of 0.10 μm - 834,40 μm

volume: 100%

Fig. 21A. 1/21

to = 00:7,+d = 03:36 F= 17,5 = 1,914

RSD = 0,04813

1 - status

2 - remove

3 - shift

4 is a graphical fashion

5 - factor exposure /rapport d' impression/

6 - insulation

7 - adaptation to fashion

System dissolving tablets Philips PU 8620 V1.0 date 04/10/91

Fig. 21A/2,21

to = 00:00 td = 254:48 F= 461,4 = 0,148 RSD = 0,30028

1 - the Statute of experience

2 - remove

baptazia fashion

System dissolving tablets Philips PU 8629 V 1,0 date 14/10/91

Fig. 21B.1-21

G XVIII 190 best adaptation according to Weibull G XVIII 182

to = 00:07 td = 00:47 F= 26,4 = 1,096 RSD = 0,03932

System dissolving tablets hilis PU 8620 V1 0 date 04/10/91

Fig. 21B.2/21

G 198 XVIII best adaptation Weibull TX 47 066 party 04

to = 00:07 td = 00:43 F= 24,0 = 1/015 RSD = 0,04808

Positive effect:

1) size range particle depends on the chosen solvent system.

Thus, in example 5, the majority of the crystals have a size in the range of 10-50 microns.

Example 6 the majority of the crystals have a size in the range from 65 to 100 microns.

In example 7 the majority of the crystals have a size in the range from 35 to 55 μm.

In example 8 uses the same volume of the solvent mixture, but with a high content of water; the size of the crystals is from 90 to 150 microns.

In example 9 used the same solvent mixture as in example 7, but with a smaller volume of solvent; the size of the crystals is from 75 to 120 μm.

In example 10 using the same solvent mixture as in example 7, but in greater volume; the result is larger crystals in toraysee mixture, the water content), you can get a mixture of crystals whose size is in the range from 35 to 300 μm, while the main characteristic of the resulting mixture is that more than 75% of the crystals have the desired granularity.

The microcrystals according to the invention are of particular interest because they are small, they are uniform and have a higher solubility parameters.

So, the product according to example 8 has a solubility equal to 8 μm/ml, whereas the non-crystallized product, but simply crushed product (crystals 200-250 microns) has a solubility of only 4-5 μm/ml

The results of pharmacokinetic studies presents charts (see Appendix, Fig. 1) drawn with curves on them. They compared the pharmacological curve crushed nomegestrol (Luteal) and the crystalline compound of example 8 (code name TX 47066).

Within 12 h significantly improved pharmacokinetics.

These results show the advantage of the claimed products.

When analyzing individual bioequivalence calculated for the total ASC (TX47066/LUTENYLR), their average value is 1,020,66.

For 2 subjects out of 12 (16.7%) of the bioequivalence above 1,20 (subjects N 2: 1,28 - N 6: 1,48).

This distribution is compatible with the standards of the FDA, depending on the number of subjects included in the study (2, 4, 11).

The homogeneity of the individual bioequivalence presents graphs 6-17, which change 12 forms HOM AC is on the subject.

Maximum peaks

The deviation between average values of the maximum peak is 11%; confidence interval relations peaks (F 1,11) too large so that you can make a conclusion about the exact bioequivalence in this parameter (ID= from 0.88 to 1.38). However, it remains within the range of 0.7-1,43", valid for the assessment of bioequivalence criterion of "maximum peak" (8,9,11). In addition, the period of maximum peak close to 2 songs (2-6 h for LUTENYLRand 1.5 - 6 h for TX47066).

Thus, thanks to the invention can, without changing the properties of steroids, but changing the size of their crystals, to obtain the product or with the quick selection of the active principle, if the crystals are small in size, and to reach more quickly a biological effect, or delayed release of active start, if kristas definition of biostatement and farbkomposition (pill) on the basis of the active principle in the form of microcrystals, in particular, on the basis of nomegestrol in the form of the acetate salt according to example VIII (code TX47066) and relatively with biouswoyaemosti commercial farbkomposition in the form of crushed product (luteal) with the same active early. The results showed higher biouswoyaemosti crystalline forms of nomegestrol in farbkomposition compared to the powder form of the composition. Thus, the results obtained on 12 volunteers, is expressed by the following indicators:

a higher maximum concentration of the drug: 12,35 + 1,483 ng/ml against 11,10 + 1,248;

higher maximum duration:

3,13 + 0,453 against 2,58 + 0,336 h;

the area under the curve (ASC) more:

117-242 ng/ml/h) against (109-235,7 ng/ml/h) and the effect of the drug over prolonged;

the days shorter:

34,91 h against 38,21 PM

In the same way are pharmaceutical compositions and with other active principles, in microcrystalline form. In the application the applicant sends graphics comparison nomegestrol in a commercial product lutenyl with drug TX47066.

1. The microcrystals of pharmaceutically active substances homogeneous reg that the active ingredient is derived estrana.

3. The microcrystals under item 1, characterized in that the active substance is derived androstane.

4. The microcrystals under item 1, characterized in that the active substance is derived Pregnana.

5. The microcrystals under item 1, characterized in that the active ingredient is a derivative of 19-norpregnane.

6. The microcrystals under item 1, characterized in that the active substance is derived cholestan.

7. The microcrystals under item 1, characterized in that the active substance is a 21-hydroxy, 4-pregnenolone derived.

8. The microcrystals on PP.1 and 2, characterized in that the derived estrana selected from the group consisting of estradiol, estrone, estriol 19-nortestosterone, simple monoamino in position 3 of these compounds, diesters in the provisions 3,17 these compounds and esters of these compounds.

9. The microcrystals on PP.1 and 3, characterized in that the androstane derivative selected from the group consisting of testosterone, simple esters of testosterone esters testosterone, testosterone derivatives, substituted in position 4, 6, 7, or 16 halogen or lower alkyl, and its derivative 17-ethinyl-acetoxy-5-androstene-2.

10. Microcristallina of progesterone, simple enol ethers progesterone, cyclic or linear enamines of progesterone, 17-hydroxyprogesterone, esters of 17-hydroxyprogesterone, progesterones, substituted alkyl, trifluoromethyl or halogen in position 1, position 6, in position 7 and/or in position 16 and esters and ethers of this last connection.

11. The microcrystals on PP.1 and 5, characterized in that a derivative of 19-nor-pregnane is Sterol selected from the group formed by 17-hydroxy-19-nor-progesterone, ethers in position 17 17-hydroxy-19-nor-progesterone esters in position 17 17-hydroxy-19-nor-progesterone, 6-methyl-17-hydroxy-19-nor-progesterone, ethers in position 17 6-methyl-17-hydroxy-19-nor-progesterone, esters in position 17 6-methyl-17-hydroxy-19-nor-progesterone, 6-methyl-3,20-dioxo-17-hydroxy-3,20-dioxo-19-nor-pregnadien-4,6 derived 3,20-dioxo-6-methyl-19-nor-pregnadien-4,6 containing in positions 17 and 21 methyl or ethyl.

12. The microcrystals on PP. 1 and 7, characterized in that the 21-hydroxy, 4-pregnenolone derivative is a corticosteroid selected from the group consisting of cortisone, prednisone, dexamethasone, desoximetasone is Azaniah 17 and 21 and their esters in position 21.

13. The way to obtain microcrystals pharmaceutically active substances PP. 1 - 12 method recrystallization from a solvent mixture, wherein the pharmaceutically active substance is dissolved in a ternary mixture formed by lipophilic solvent selected from the group consisting of low molecular weight saturated alcohols, alkylthio and alkylalcohol, hydrophilic solvent is at least partially soluble in the lipophilic solvent selected from the group consisting of water and lower saturated alcohols and surface-active agent selected from the group consisting of Tweens, Mirj, Pluronics, at a temperature of, probably the most close to the boiling temperature of the above mixture, then cool the solution to a temperature below 0oC, allow to start crystallization, then separated crystalline mass, which is dried, washed and dried under reduced pressure.

14. The method according to p. 13, wherein the hydrophilic solvent is mixed with a lipophilic solvent in amounts up to 12%.

15. The method according to p. 13, wherein the hydrophilic solvent is chosen so that it is mixed with a lipophilic solvent obrazovaniye an aqueous mixture, formed by one or more oxygen-containing solvents.

17. The method according to p. 13, wherein the non-ionic surface-active agent is soluble in the lipophilic solvent or a hydrophilic solvent and necessarily in a mixture of two solvents at once.

18. The method according to p. 13, wherein the ternary mixture of lipophilic solvent, a hydrophilic solvent and a surface-active agent prepared in one stage or in several stages.

19. The method according to p. 13, characterized in that the concentration of surface-active agent in the ternary mixture is in the range from 0.01 to 10%.

20. The method according to p. 13, characterized in that the content of surface-active agent in ternary solvent is enclosed preferably in the range of from 0.05 to 5%.

21. Pharmaceutical composition with controlled release of active substances containing the active ingredient and pharmaceutically acceptable carriers, characterized in that the active substance it contains a substance steroid patterns in microcrystalline form on PP.1 - 12 in an effective amount.

22. The composition according to p. 21, characterized in that the active ingredient is made in the CLASS="ptx2">

23. The composition according to p. 21, characterized in that the active substance is derived estrana selected from the group consisting of estradiol, ethers in position 17 - estradiol and diesters in positions 3 and 17 estradiol, under item 8.

24. The composition according to p. 21, characterized in that the active substance is androstane derivative selected from the group consisting of testosterone, 19-nor-testosterone, esters of fatty acids testosterone and esters fatty acids of 19-nor-testosterone, PP.8 and 9.

25. The composition according to p. 21, characterized in that the active substance is a 21-hydroxypregnenolone derivative selected from the group consisting of cortisone, prednisone, dexamethasone, betamethasone, desoximetasone, medrol, as well as their esters in position 17 and/or 21, p. 12.

 

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