Methods of obtaining aripiprazole suspension and lyophilysed composition

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to method of obtaining aripiprazole suspension. Method includes the following stages: (a) combining aripiprazole mass and carrier with formation of primary suspension; (b) first refining of primary suspension with obtaining secondary suspension using apparatus for refining with large shearing force, dispersant, in which shearing force is applied for material processing, or high-pressure homogeniser; and (c) second refining of secondary suspension with obtaining final sterile suspension by high-pressure homogeniser. Claimed composition also relates to methods of obtaining lyophilysed composition from aripiprazole suspension.

EFFECT: claimed invention provides possibility of obtaining aripiprazole suspension with the average size of particles from 1 to 10 mcm, without necessity to use special crystallisation technologies for obtaining initial aripiprazole mass and without application of vacuum mixing at the stage of combining aripiprazole mass and carrier.

33 cl, 13 tbl, 15 ex

 

The technical FIELD

[0001]

The present invention relates to a method for producing a suspension of aripiprazole, and method for producing a lyophilized composition.

The LEVEL of TECHNOLOGY

[0002]

Aripiprazole is a medicinal substance, commonly known as an atypical antipsychotic agent. For the introduction of aripiprazole in the body suggests the use of the aqueous suspension of aripiprazole as an injectable dosage form. In particular, it is known that the suspension obtained by suspendirovanie aripiprazole with an average particle size of from about 1 to about 10 microns in the aquatic environment, has excellent characteristics in respect of slow release and bioavailability (Patent document 3).

[0003]

Grinding in aseptic conditions mass of aripiprazole using well-known methods are difficult to implement at the level of commercial production. For example, the method of grinding in a ball mill, for which use ceramic balls are widely used for wet grinding, has the following problems: the abrasion of the balls may cause pollution; in addition, the ball mill with the possibility of continuous sterilization today are remote from a commercial point of view.

[0004]

In addition, the method of grinding in a ball mill which can potentially cause problems "slippage" in which some large particles can pass balls. As shown in Patent Document 4, it is preferable to use a lot of aripiprazole with a given small particle size, preferably having an average size of about 100 μm or less, more preferably, about 95% of the crystals had a particle size less than 100 microns, with a slight deviation in particle size. However, obtaining such a mass of aripiprazole with an average particle size of about 100 microns or less requires the use of a specific technology crystallization, such as a method of colliding jets impinging jet crystallization)described in Patent Document 4.

[0005]

On the other hand, reduction of particle size can be achieved by using a high-pressure homogenizer; however, when 10% suspension of aripiprazole with an average particle size greater than 100 μm is ground by a homogenizer high pressure, there is a blockage in the line, which prevents the grinding. It is therefore desirable to use aripiprazole with an average particle size of about 100 microns or less.

[0006]

However, such suspension of aripiprazole with an average particle size of about 100 microns or less in solution media is accompanied by the formation of foam. Therefore, to obtain a homogeneous suspension is necessary to apply mixing under vacuum (with whom. Patent Document 3, Example 1 and paragraph 0089).

[0007]

With stirring under vacuum from the outside can be made to the air, which requires constant monitoring to prevent ingress of contamination from the external environment. Improvements in this aspect would be desirable.

[0008]

In Patent Document 1, a method for obtaining small particles containing a poorly water-soluble drug substance, which comprises the following stages:

(a) mixing with a large shear additives poorly water-soluble drug substance and one or more surfactants in the aquatic environment without adding organic solvent in the first temperature range at or above the melting temperature of poorly soluble drug substances with the formation of the heated suspension containing the specified medicinal substance, but such medicinal substance is in molten form;

(b) homogenizing the heated suspension in a first pressure range and within the first range of temperatures with the formation of the heated homogenate containing the specified medicinal substance, but such medicinal substance is in molten form;

(C) cooling the heated homogenate to a second range of the temperature below the melting temperature of poorly soluble drug substances with the formation of short-sustainable, the cooled homogenate containing the drug substance.

(g) applying a stabilizing particle energy process to refrigerated homogenate within a second temperature range below the melting temperature of a drug and within a second pressure range with the formation of the cooled dispersion of stabilized small particles containing the drug; and

(d) drying the cooled dispersion to obtain dried small particles containing a poorly water-soluble drug substance.

[0009]

However, according to the method presented in the Patent Document 1, the essential feature is to obtain emulsion is heated to a temperature higher than the melting temperature of medicinal substance, and this is an obstacle for conservation crystalline form.

[0010]

In Patent Document 2 describes effective ways solubilization or dispersion of poorly soluble compounds by adding a combination of a predetermined amount of oily component (oil), emulsifier and cyclodextrin. The paper proposed to use the mixer-homogenizer for rough emulsification, and the high-pressure homogenizer or an ultrasonic homogenizer to apply for fine emulsification.

However, Pat is Tomo Document 2 composition, containing solubilizing or dispersed poorly soluble compound is in the form of an oil emulsion, and not water suspension.

[0011]

Patent Document 3 describes a method of obtaining a sterile lyophilized composition, which comprises the following stages:

(a) obtaining sterile mass of aripiprazole with the desired distribution of particle sizes;

(b) obtaining a sterile medium for sterile mass of aripiprazole;

(C) combining sterile aripiprazole with sterile media to produce a sterile primary suspension, containing a sterile mixture of solids;

(g) the reduction in the average particle size of a sterile mixture of solid substances in a sterile primary suspension, for example by aseptic wet grinding until the particle size in the range from about 1 to about 100 μm, in particular approximately 1-10 μm with the formation of sterile final suspension; and

(e) liofilizirovannye sterile final suspension with the formation of the lyophilized composition.

The document says that wet grinding in a ball mill, preferably as a method of aseptic wet grinding stage (g).

[0012]

In non-Patent Document 1 noted that microfluidizer have two advantages compared with other methods of reducing Wed is the last particle size: the final products are not contaminated, and performance can be easily improved.

Patent Document 1: Japanese unexamined Patent Publication No. 2003-531162

Patent Document 2: Japanese unexamined Patent Publication No. 2005-22989

Patent Document 3: Japanese unexamined Patent Publication No. 2007-509148

Patent Document 4: Japanese unexamined Patent Publication No. 2007-509153

Patent Document 5: Japanese Patent No. 3760264

Patent Document 6: Japanese Patent No. 3750023

Non-patent Document 1: Kathleen J.Illing, et al., "Use of Microfluidizer Processing for the Preparation of Pharmaceutical Suspensions", Pharm. Tech., OCTOBER 1996, p.78-88.

Non-patent Document 2: "Study on Crystal Transformation of Aripiprazole" Satoshi Aoki, et al., The Fourth Japan-Korea Symposium on Separation Technology (October 6th-8th, 1996), str-940

Description of the INVENTION

The PROBLEM addressed by the INVENTION

[0013]

It is known that the suspension obtained by suspendirovanie aripiprazole with an average particle size of from about 1 to about 10 μm in aqueous media, have an excellent slow release characteristics. Wet grinding of aripiprazole in a ball mill, preferably having an average particle size of about 100 μm or less, more preferably about 95% of the crystals with an average particle size of 100 μm or less, known as the method of obtaining such suspension of aripiprazole with an average particle size of from 1 to 10 μm, the description is the R in Patent Documents 3 and 4.

[0014]

However, obtaining the mass of aripiprazole with an average particle size of about 100 microns or less requires special methods to get the mass of drug substances, such as crystallization method of colliding jets. Under suspension of the mass of aripiprazole with an average particle size of about 100 μm or less in the media should be stirring under vacuum.

[0015]

For this reason, it is desirable that the method of obtaining the envisaged application of the powdered material containing particles of aripiprazole size of 100 μm or more in an amount of 10% or more; preferably apply powder weight with an average particle size greater than 100 μm, in particular from about 110 μm to 1000 μm, more preferably from 200 μm to 400 μm, obtained by periodic crystallization, thereby eliminating the need for mixing under vacuum.

[0016]

Furthermore, the method of wet grinding in a ball mill has drawbacks: the abrasion of the balls can cause pollution, and, in addition, the ball mill with the possibility of continuous sterilization today are remote from a commercial point of view. For this reason, there is a need to develop ways to reduce the chance of contamination and ensure the use of the production on the equipment with the possibility of continuous sterilization.

The WAYS to SOLVE PROBLEMS

[0017]

The authors of the present invention have found that even when using mass aripiprazole containing 10% or more of particles of aripiprazole with a size of 100 μm or more and having an average particle size of from 20 to 1000 microns, the preferred weight aripirazole with an average particle size greater than 100 μm, in particular from 110 μm to 1000 μm, most preferably from 200 μm to 400 μm, the above problem can be solved by carrying out the first stage of grinding device for grinding with a large shearing force, such as mixer-homogenizer with a large shearing force; disperser, which uses the force shift for material processing, colloid mill, ultrasonic dispersing or emulsifying agent disperser, high-pressure jet type, such as a high-pressure homogenizer; and then carrying out the second stage grinding with the use of emulsifying apparatus for dispersing a high-pressure jet type, such as a high-pressure homogenizer.

The present invention is made on the basis of these factual findings and additional research and provides the following way:

Item 1: a method of obtaining a suspension of aripiprazole, which includes stages:

(a) combining weight of aripiprazole and wear the El with the formation of the primary suspension;

(b) first grinding the primary suspension with the formation of the secondary suspension; and

(C) a second grinding secondary suspension with the formation of the final suspension.

Paragraph 2: the Method according to claim 1, whereby in the first stage grinding (b) secondary suspension is obtained by grinding the primary suspension using the apparatus for grinding with a large shearing force, dispersant, which uses the power shift for material processing, colloid mill, ultrasonic dispersing or emulsifying agent of dispergator high-pressure jet type; and the second stage grinding (in) of the final suspension is obtained by grinding the secondary suspension using an emulsifier disperser, high-pressure jet type

Item 3: the Method according to claim 1 or 2, according to which stage of the first grinding (b) secondary suspension is obtained by grinding the primary suspension using the apparatus for grinding with a large shearing force or dispersant, which uses the power shift to the processing of the material; and the second stage grinding (in) of the final suspension is obtained by grinding the secondary suspension using high-pressure homogenizer.

Item 4: the Method according to claim 3, whereby at the stage (C) high-pressure homogenizer is used at a pressure grinding 300-1000 bar

Item 5: the Method according to claim 3 or 4, according to which stage (C) high-pressure homogenizer is used at a pressure grinding 300-600 bar.

Item 6: the Method according to any of PP-5, according to which stage (C) high-pressure homogenizer is used in the inlet temperature from 1 to 70°C.

Item 7: the Method according to claim 1 or 2, according to which stage of the first grinding (b) secondary suspension is obtained by grinding the primary suspension using a homogenizer high pressure; and the second stage grinding (in) of the final suspension is obtained by grinding the secondary suspension using high-pressure homogenizer.

Item 8: Method according to claim 1, 2 or 7, according to which stage of the first grinding (b) secondary suspension is obtained by grinding the primary suspension using high-pressure homogenizer at a pressure of grinding 50-200 bar; and the second stage grinding (in) of the final suspension is obtained by grinding the secondary suspension using high-pressure homogenizer at a pressure of grinding 200-1000 bar; the difference between the pressure of the grinding stage (b) and pressure grinding stage (b) is from 100 to 900 bar.

Item 9: the Method of claim 8, according to which stage (b) pressure grinding homogenizer high pressure is in the range of 50-200 bar; and is Tadei (in) grinding perform repeatedly and pressure grinding gradually increased from 200 to 1000 bar.

Item 10: the Method according to claim 9, according to which stage (b) final pressure grinding, developed by the high-pressure homogenizer is 300-600 bar.

Item 11: the Method according to any of claims 7-10, according to which stage (b) and (C) a high-pressure homogenizer is used in the inlet temperature from 1°to 50 ° C.

Item 12: the Method according to any one of claims 1 to 11, according to which the medium contains at least one suspendisse agent selected from the group comprising: carboxymethyl cellulose, salts of carboxymethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellose and polyvinylpyrrolidone.

Item 13: the Method according to any one of claims 1 to 12, whereby the weight of aripiprazole contains 10% or more of particles of aripiprazole size of 100 μm or more, and has an average particle size of from 20 to 1000 microns.

Item 14: the Method according to any one of claims 1 to 13, whereby the weight of aripiprazole has a mean particle size greater than 100 microns.

Item 15: the Method according to any one of claims 1 to 14, whereby the weight of aripiprazole has a mean particle size of from 110 to 1000 microns.

Item 16: the Method according to any one of claims 1 to 15, whereby the weight of aripiprazole has a mean particle size of from 200 to 400 microns.

Item 17: the Method according to any one of claims 1 to 16, according to which the aripiprazole suspension of aripiprazole has a mean particle size of from 1 to 10 microns.

p> Item 18: the Method according to any one of claims 1 to 17, according to which the aripiprazole suspension of aripiprazole has a mean particle size of from 1 to 5 microns.

Item 19: the Method according to any one of claims 1 to 18, according to which the aripiprazole suspension of aripiprazole has a mean particle size of from 2 to 4 microns.

Item 20: the Method according to any one of claims 1 to 19, according to which the aripiprazole suspension of aripiprazole has a mean particle size of from 2 to 3 microns.

Item 21: the Method according to any one of claims 1 to 6, which includes stages:

(I) the consolidation of sterile mass of aripiprazole with an average particle size of from 200 to 400 μm and sterile media (preferably sterile media containing sodium carboxymethyl cellulose) with the formation of sterile primary suspension;

(II) the first grinding sterile primary suspension using the apparatus for grinding with a large shearing force or dispersant, which uses the power shift for processing material to form a sterile secondary suspension; and

(III) a second grinding sterile secondary suspension using a homogenizer high pressure with the formation of sterile final suspension; and aripiprazole in sterile final suspension (i.e. the desired sterile suspension of aripiprazole) has an average particle size of from 1 to 10 μm (preferably from 1 to 5 μm, in particular from 2 to 4 μm).

Paragraph 22: the Method according to any one of claims 1 to 21, according to which the mass of the aripiprazole is in the form selected from the group comprising monohydrate and Anhydrous Crystals Century

Item 23: the Method according to any one of claims 1 to 22, further comprising a stage filtration end of the suspension through a filter with a nominal pore size of 10 to 225 microns.

Item 24: the Method of obtaining a lyophilized composition of the Aripiprazole Hydrate A, comprising the following steps: cooling the suspension obtained by the method according to any one of claims 1 to 23 and containing the Aripiprazole Hydrate And, to a temperature of from -20 to -55°C to the freezing of the suspension; and subsequent drying at a temperature below about 0°C.

Paragraph 25: the Method of obtaining a lyophilized composition containing aripiprazole in anhydrous form, including the following three stages:

(1) cooling the suspension of aripiprazole obtained by the method according to any one of claims 1 to 23, using the mass of aripiprazole in the form of a monohydrate or anhydrous crystals to a temperature of from -20 to -55°C to the freezing of the suspension;

(2) primary drying at a temperature below about 0°C.; and

(3) secondary drying at a temperature above about 0°C.

The results of the INVENTIONS

[0018]

The present invention provides excellent results, described below.

[0019]

(a) the production method of the suspension aripipra the La in accordance with the present invention, includes two-stage crushing weight of aripiprazole, is particularly effective when using the mass of aripiprazole with a content of at least 10% of the particles of aripiprazole size of 100 μm or more, having an average particle size of from 20 to 1000 microns, the preferred weight of aripiprazole having a mean particle size of more than 100 μm, in particular from 110 μm to 1000 μm, most preferably from 200 to 400 μm. However, regardless of the average particle size, using the method according to the present invention can easily obtain a suspension of aripiprazole having a mean particle size of 1 to 10 μm, preferably from 1 to 5 μm, more preferably from 2 to 4 μm, and most preferably from 2 to 3 microns.

[0020]

(b) When performing the two-stage grinding in accordance with the present invention, i.e. the first stage of grinding device for grinding with a large shearing force (e.g., mixer-homogenizer with a large shearing force), dispersant, which uses the power shift for material processing, colloid mill, ultrasonic disperser, or disperser, high-pressure jet type (e.g., homogenizer, high pressure); and the second stage grinding with the use of a disperser, high-pressure jet type (e.g., homogenizer, high pressure) may be the allowed to receive the suspension of aripiprazole with an average particle size of from 1 to 10 microns, even when using a powdered material with a large particle size, in particular the mass of aripiprazole with an average particle size greater than 100 μm, the obtained periodic crystallization, etc. So unlike Patent Document 4 special technology of crystallization, such as the way of colliding jets, are not required to obtain the mass of aripiprazole.

[0021]

(C) the Method according to the invention involves the use as a sterile mass aripiprazole weight, containing at least 10% of the particles of aripiprazole size of 100 μm or more and having an average particle size of from 20 to 1000 μm, preferably a lot of aripiprazole having a mean particle size of more than 100 μm, in particular from 110 μm to 1000 μm, and most preferably from 200 to 400 μm, for this reason, stage combining weight of aripiprazole and media, the first stage grinding stage and the second grinding can be performed without the use of mixing under vacuum, which is recommended in the Patent Document 3. This eliminates the possibility of mixing with outside air in the process of obtaining sterile composition and thus provides significant advantages of this method of obtaining sterile product.

[0022]

(g) moreover, no abrasion phenomena observed, for example, to specify the second mill, excludes caused them problems of pollution.

[0023]

(d) "slippage" of large particles, which is a problem when wet grinding in a ball mill, it happens much less frequently, and for this reason, there is formed a homogeneous suspension without larger (coarse) particles of aripiprazole. The resulting suspension of aripiprazole after grinding can be filtered through a filter with a smaller pore size to remove any substances that is useful from the point of view of control over extraneous substances.

[0024]

(e) Aseptic production on an industrial scale, CIP cleaning in place (CIP) and sterilization in place (SIP) is difficult in relation to equipment such as ball mills; however, the production equipment used in the specified grinding method (first stage and second grinding) according to the invention, allows for CIP and SIP. Therefore, the equipment can be easily sterilized by the method of continuous sterilization.

[0025]

(g) When in this way to obtain as a suspending agent for the carrier used carboxymethyl cellulose or its salt, it becomes possible to avoid excessive grinding, in which the average particle size is reduced below 1 micron.

The BEST WAY of carrying out the INVENTION

[0026]

Below we describe in more detail the description of the method of receiving according to the present invention.

[0027]

In the present invention, the term "average particle size" refers to the average volume diameter as measured by the methods of laser scattering (LLS). Measured the size distribution of particles methods LLS, and the average particle size was calculated based on the size distribution of particles.

[0028]

Weight Aripiprazole

The structural formula of Aripiprazole

[0029]

[Formula 1]

[0030]

Aripiprazole is an atypical antipsychotic agent, is used to treat schizophrenia. It is poorly soluble in water (<1 μg/ml at room temperature).

[0031]

The mass of the substance aripiprazole or powder mass may have any average particle size and size distribution of particles. Generally, it is preferable to use a lot of aripiprazole containing particles of aripiprazole size of 100 μm or more in the amount of at least 10%, having an average particle size of from 20 to 1000 μm; the preferred weight of aripiprazole having a mean particle size of more than 100 μm, in particular from 110 to 1000 μm, and most preferably from 200 μm to 400 μm.

[0032]

In addition, the crystalline form of the mass of aripiprazole is not limited to a specific type and any suitable form. For example, crystalline forms of aripiprazole include monohydrate described in C the patent Document 2 (in the present description, the term "monohydrate" refers to the monohydrate, described in non-Patent Document 2), Hydrate and Anhydrous Crystals, described in Patent Document 5, the Anhydrous Crystals, Anhydrous Crystals D, Anhydrous Crystals E, Anhydrous Crystals F and Anhydrous Crystals G, described in Patent Document 6. Of them, preferred are the monohydrate and Anhydrous Crystals Century

In the present invention using the monohydrate crystals (non-Patent Document 2) as the mass of aripiprazole, received a suspension of Hydrate A (Patent document 5) method according to the invention. Also using the Hydrate And the mass of aripiprazole may be obtained suspension Hydrate And method according to the invention. Anhydrous Crystals (Patent Document 5), Anhydrous Crystals, Anhydrous Crystals of D, Anhydrous Crystals E, Anhydrous Crystals of F and Anhydrous Crystals G (Patent Document 6) can also be used as a mass of aripiprazole. Using such crystals receive a suspension of aripiprazole, which is a mixture of Hydrate and anhydrous aripiprazole. In addition, the Anhydrous Crystals, Anhydrous Crystals, Anhydrous Crystals of D, Anhydrous Crystals E, Anhydrous Crystals of F and Anhydrous Crystals of G can be recrystallized from ethanol and water, or the like, obtaining thus monohydrate, and the resulting monohydrate can the be used as the weight of Aripiprazole.

[0033]

Media

The media used in the invention typically includes:

(1) one or more suspendida agents

(2) water for injection,

(3) possibly, one or more fillers or isotonic agents,

(4) possibly, one or more buffers, and

(5) possibly, one or more pH regulators.

[0034]

Suspendisse agent is present in amounts ranging from about 0.2 to about 10 wt. -%, preferably from about 0.3 to about 5 wt. -%, more preferably from about 0.4 to about 0.9% of the mass. calculated on the total mass of the sterile composition for injection (suspension of aripiprazole according to the invention). Examples suspendida agents suitable for use include, but are not limited to, one, two or more of the following substances: carboxymethyl cellulose or its salt (e.g. sodium salt of carboxymethyl cellulose), hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellose and polyvinylpyrrolidone; however, preferred is a carboxymethyl cellulose or its salt, in particular sodium salt. Other suspendresume agents suitable for use in the carrier of aripiprazole include various polymers, low molecular weight oligomers, natural and surfactants, including nonionic and ionic surface the active substances, such as cetylpyridinium chloride, gelatin, casein, lecithin (phosphatides), dextran, glycerol, gum Arabic, cholesterol, tragakant, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetosteatil alcohol, cetomacrogol emulsifiable wax, esters of sorbitol, polyoxyethylenated esters (e.g. esters of macrogol, such as cetomacrogol 1000), polyoxyethylene derivatives of castor oil, polyoxyethylene ether of sorbitol and fatty acids (for example, a commercially available Twin (registered trademark), for example, tween 20 (registered trademark) and tween 80 (registered trade mark)(manufacturer ICI Specialty Chemicals)); polyethylene glycols (e.g., Carbowaxs 3350 (registered trademark) and 1450 (registered trademark), Carbopol 934 (registered trademark) (manufacturer Union Carbide)), dodecyltrimethylammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecyl sulphate, calcium carboxymethyl cellulose, hydroxypropylcellulose (for example, LDCs, HPC-SL and LDCs-L), methylcellulose, hydroxyethylcellulose, hypromellose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminosilicate, triethanolamine, polyvinyl alcohol (PVA)polymer 4-(1,1,3,3-TETRAMETHYLBUTYL)-Fe the Ola with ethylene oxide and formaldehyde (also known as tyloxapol, superion and Triton), poloxamers (e.g., Pluronics F68 (registered trademark) and F108 (registered trademark), which are block copolymers of ethylene oxide and propylene oxide); poloxamine (e.g., Tetronic 908 (registered trademark), also known as Poloxamine 908 (registered trademark), which is tetrafunctional bpoc copolymer obtained by the sequential addition of propylene oxide and ethylene oxide to Ethylenediamine (manufacturer BASF Wyandotte Corporation, Parsippany, N.J.)); a charged phospholipid such as dimyristoylphosphatidylcholine, dioctylsulfosuccinate(DOSS); Tetronic 1508 (registered trade mark) (T-1508) (manufacturer BASF Wyandotte Corporation), dialkyl ethers sodium salt sulfonterol acid (e.g., Aerosol OT (registered trademark), which is dioctyltin ether sodium salt sulfonterol acid (American Cyanamid)); Duponol P (registered trademark), which is a lauryl sulfate (manufacturer DuPont); Tritons X-200 (registered trademark), which is alkylaryl polyester sulfonic acids (manufacturer Rohm and Haas); Crodestas F-110 (registered trademark), which is a mixture of stearate and distearate sucrose (manufacturer Croda Inc.); p-isononylphenol-(glycidol), also known as Olin-10G(registered trademark) or Surfactant 10-G (registered trademark) (manufactured by Olin Chemicals, Stamford, Conn.); Crodestas SL-40 (manufacturer Croda Inc.); and SA9OHCO, which is a18H37CH2(SOPS(CH3))-CH2(SNON)4(CH2OH)2(manufacturer Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl-β-D-glucopyranoside; n-decyl-β-D-multipurpose; n-dodecyl-β-D-glucopyranoside; n-dodecyl-β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl-β-D-thioglucoside; n-hexyl-β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-nonyl-β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-β-D - glucopyranoside; octyl-β-D-thioglucopyranoside; and others.

[0035]

Most of these suspendida agents known as pharmaceutical excipients and are described in detail in "Handbook of Pharmaceutical Excipients", published jointly by the American Pharmaceutical Association and the Pharmaceutical Society of great Britain (published by The Pharmaceutical Press, 1986), the contents of which are incorporated into this description by reference. These suspendresume agents available for purchase and/or can be obtained by using technologies known from the prior art.

[0036]

In the present invention as suspendida agents to obtain media is preferable to use carboxymethyl cellulose or its salt, hydroxypropylcellulose, hydroxypropylmethylcellulose the RAM, the hypromellose or polyvinylpyrrolidone. The use of carboxymethylcellulose (which hereinafter may be referred abbreviated as CMC) or a salt thereof (preferably sodium salt (which hereinafter may be referred to in abbreviated form as N)) is particularly effective against the risk of excessive grinding, in which the average particle size falls below 1 μm, even at the stage of the second grinding when grinding is carried out repeatedly or for a long period of time.

[0037]

The viscosity of solutions of carboxymethyl cellulose or its sodium salt may be set appropriately within a wide framework. Generally, it is preferable that the viscosity of 4% aqueous solution at 25°C was approximately 20 to 400 SP, especially from about 50 to 200 SP.

[0038]

If necessary, the carrier in the present invention may contain a filler (also called cryogenic/lyophilic protective agent) or an isotonic agent. The specified agent can be present in an amount presented in the range of from about 1 to about 10 wt. -%, preferably from about 1.5 to about 8 wt. -%, more preferably from about 2 to about 5% of the mass. calculated on the total mass of the sterile composition for injection (suspension of aripiprazole according to the invention). Examples of fillers Il is isotonic agents, suitable for use include, but are not limited to, one, two or more of the following ingredients: mannitol, sucrose, maltose, xylitol, glucose, starches, sorbitol, and others; the use of mannitol is preferable for the compositions with an average particle size of about 1 μm or above.

[0039]

If necessary, the carrier of the present invention may contain a buffer. The buffer is required in sufficient quantity to maintain the pH value of the water suspension of aripiprazole in the range from about 6 to about 8, preferably about 7. To achieve the pH value of the buffer depending on the type used in an amount of from about 0.02 to about 2 wt. -%, preferably from about 0.03 to about 0.1% of the mass. calculated on the total mass of the sterile composition for injection (suspension of aripiprazole according to the invention). Examples of buffers suitable for use include, but are not limited to, one, two or more of the following substances: sodium phosphate, potassium phosphate or TRIS buffer (TRIS), but the preferred sodium phosphate.

[0040]

The media according to the present invention can optionally contain a pH Adjuster in an amount sufficient to maintain the pH value of the water suspension of aripiprazole in the range from about 6 to about 7.5, preferably about 7; and if the pH of the aqueous suspension of lyophilized aripi is rasola need to raise or lower to achieve a neutral pH of about 7, can be added acid or base. Thus, when the pH value you want to lower, you can apply an acid pH Adjuster, such as hydrochloric acid or acetic acid. When the pH needs to be increased, it is possible to apply the basic pH Adjuster such as sodium hydroxide, potassium hydroxide, magnesium oxide or magnesium hydroxide; the preferred sodium hydroxide.

[0041]

The method of receiving according to the invention

The method of receiving according to the invention are described below.

As described above, the present invention provides a method of obtaining a suspension of aripiprazole, which includes stages:

(a) combining weight of aripiprazole and media education primary suspension;

(b) first grinding the primary suspension with the formation of the secondary suspension; and

(C) a second grinding secondary suspension with the formation of the final suspension.

In accordance with one preferred embodiment of the invention assumes the use of the following method: a method of obtaining a sterile suspension of aripiprazole in which the average particle size of the aripiprazole is from 1 to 10 μm, preferably from 1 to 5 μm, more preferably from 2 to 4 μm, most preferably from 2 to 3 microns, which includes stages:

(A) combining sterile mass of aripiprazole and sterile nose is the body with the formation of sterile primary suspension;

(B) first grinding sterile primary suspension using the apparatus for grinding with a large shearing force, dispersant, which uses the power shift for material processing, colloid mill, ultrasonic disperser, or emulsifier disperser, high-pressure jet type with the formation of sterile secondary suspension; and

(B) a second grinding sterile secondary suspension using an emulsifier disperser, high-pressure jet type with the formation of sterile final suspension.

[0043]

To perform the method of producing sterile suspensions of aripiprazole in accordance with the invention, it is necessary to maintain complete sterility when combining sterile and sterile aripiprazole media under aseptic conditions with the formation of a sterile suspension.

However, if it is possible to perform sterilization after receiving the required suspension of aripiprazole, using sterile aripiprazole and sterile media above described method, comprising a stage (A), (B) and (C)becomes optional.

[0044]

(A) stage Association Sterile Mass of Aripiprazole and Sterile Media with the Formation of Sterile Primary Suspension

This stage (A) consists of successive stages (a-1), (a-2) and (a-3)

(A-1) stage Receiving Sterile the Oh Mass Aripiprazole

At this stage, usually prepared sterile mass aripiprazole containing 10% or more of particles of aripiprazole size of 100 μm or more, having an average particle size of from 20 to 1000 μm, preferably sterile mass aripiprazole having a mean particle size of more than 100 μm, in particular from 110 μm to 1000 μm, most preferred from 200 to 400 microns.

The choice of sterilization method weight of aripiprazole is not limited and can be conducted from among the following techniques: aseptic crystallization, sterilization by autoclaving, gas sterilization, and radiation sterilization. Among them, preferable aseptic crystallization.

[0045]

Aseptic crystallization is a process in which a solution prepared by dissolving aripiprazole in a solvent, is sterilized by the method of filtration and so on, and then crystallization is carried out. The number of procedures such as continuous crystallization or periodic crystallization, is not limited.

[0046]

Sterilization by autoclaving, gas sterilization or radiation sterilization can be applied in accordance with the traditional methods, allowing sterilization of aripiprazole.

[0047]

It is known that sterile aripiprazole may be in such a crystalline form of the monohydrate, Hydrate And form the Anhydrous Crystals, Anhydrous Crystals, Anhydrous Crystals D, Anhydrous Crystals E, Anhydrous Crystals F, Anhydrous crystals of G, and so on, each of which is suitable for the composition according to the present invention. Among them monohydrate and Anhydrous Crystals are the most preferred forms.

[0048]

(2) the stage of Obtaining Sterile Media for Sterile Mass Aripiprazole

Media for sterile mass aripiprazole obtained by uniform dissolution of the above-mentioned suspending agent may be a filler or an isotonic agent, buffer and pH Adjuster in water for injection; and sterilizing the resulting solution media.

[0049]

The choice of sterilization method of solution of the carrier is not limited, but preferred is to filter through the filter. The pore size of the filter should preferably be about 0.2 μm.

[0050]

(A-3) stage Association sterile aripiprazole and sterile media with the formation of sterile primary suspension

Sterile weight of aripiprazole and sterile media are mixed under aseptic conditions with the formation of sterile primary suspension. The mixing process in aseptic conditions is not limited, while apply known technology aseptic mixing, such as the method of mixing in aseptic conditions with p the power of a mechanical mixing device with a stirrer. The process conditions under stirring is not limited. For example, the preferred mixing conditions are those in which the mixing of the powder particles with the environment occurs without foaming.

[0051]

The concentration of the sterile mass of aripiprazole, dispersible in sterile medium can be appropriately selected within a wide range, but typically is from about 10 to 400 mg/ml, preferably from 50 to 250 mg/ml, most preferably about 100 mg/ml

[0052]

The procedure of mixing in stage (a-3) can be performed at normal pressure (atmospheric pressure or at elevated pressures. Unlike Patent Document 3, in this method there is no need for a vacuum or reduced pressure. At high pressure, typically, the mixing process is preferably carried out at a gauge (gauge) pressure of from about 0 to 0.3 MPa. Predpochtitelnye temperature conditions at the stage of (a-3) temperature is from about 5 to 80°C., in particular from about 10 to 40°C. In contrast to the Patent Document 1 in this way there is no need to increase the temperature to or above the melting temperature of the mass of aripiprazole.

[0054]

(B) first stage grinding sterile primary suspension using the apparatus for grinding with b is a high shear (for example, mixer-homogenizer with a large shearing force), dispersant, which uses the power shift for material processing, colloid mill, ultrasonic disperser, or emulsifier disperser, high-pressure jet type (for example, high-pressure homogenizer) with a sterile secondary suspension

The particle size of the aripiprazole to reduce neobhodimogo level on the first stage of grinding. In an apparatus for grinding, applied at the first stage of grinding, you can use such devices that are capable of obtaining particles of a given size; for example, the apparatus for grinding with a large shearing force, dispersant, which uses the power shift for material processing, colloid mill, ultrasonic disperser (apparatus for grinding) or emulsifier disperser, high-pressure jet type (for example, a high-pressure homogenizer). Apparatus for grinding with a large shearing force or apparatus for dispersion, which uses the power shift for material processing, are preferred for use. Along with apparatus for grinding with a large shearing force, for example a mixer homogenizer with a large shearing force, there are various commercially available devices, for example, "Clearmix" (trade the arch, manufacturer M-Technique Co., Ltd.). Their use is not limited, as they provide grinding with a large shearing force, are tight and eliminates the formation of foam.

[0055]

The conditions under which the grinding using a mixer-homogenizer with a large shearing force, must be such as to provide particles of a given size. Given the size of the particles should be such as to prevent clogging of the production line homogenizer, at a subsequent stage of the second grinding. Typical conditions may be those in which the average particle size is reduced to approximately 5-100 μm, preferably up to 5-50 microns.

On the stage of the first grinding grinding is preferably performed using the above equipment with the speed of rotation of the rotary blade (rotor) from about 5 to 50 m/s, preferably from 10 to 40 m/s, most preferably from 15 to 35 m/s Especially effective work in apparatus for grinding with a large shearing force, such as mixer-homogenizer with a large shearing force (which is distributed under the trademark Clearmix), at this speed of rotation. For example, the secondary suspension with an average particle size of 10-20 microns, obtained from the primary suspension (4 l laboratory scale) at the first grinding using Clearmix CLM-1.5S when the speed of rotation is 28.3 m/s; and received from the primary suspensions (40 l, scale enlarged) at the first grinding using Clearmix CLM-9S or Clearmix CLM-15S at a speed of 28.3 m/S.

[0056]

Temperature conditions at the stage (B) should be from about 5 to 80°C., in particular from about 10 to 40°C.

[0057]

Instead mixer-homogenizer with a large shearing force can be applied to the apparatus for dispersion, which uses the power shift for material processing, namely apparatus for dispersion, which exerts a shear force to the particles of aripiprazole during the process. There are various commercially available devices for dispersion, including apparatus for dispersion, which uses the power shift for material processing (brand: T-50 Basic manufacturer IKA Japan, Inc.).

Conditions of grinding with the use of these devices for dispersion should be such as to provide particles of a given size. Given the size of the particles should be such as to prevent clogging of the production line homogenizer, at a subsequent stage of the second grinding. Typical conditions may be those in which the average particle size is reduced to approximately 5-100 μm, preferably up to 5-50 microns.

The colloid mill, ultrasonic mixing device (apparatus for grinding) or emulsifier dispersion is ATOR high-pressure jet type can also be applied on the merits in the above conditions.

[0058]

Grinding on the stage (B) can be performed at normal pressure (atmospheric pressure or at elevated pressures. Unlike Patent Document 3, in this method there is no need to resort to the conditions of vacuum or reduced pressure. At high pressure, typically, the mixing process is preferably carried out at a gauge (gauge) pressure of from about 0 to 0.3 MPa.

[0059]

(C) second stage grinding sterile secondary suspension using an emulsifier-disperser, high-pressure jet type (for example, high-pressure homogenizer) with a sterile final suspension.

The particle size of the aripiprazole is reduced to the required level at the second stage of grinding. Examples of apparatus for grinding used in the second stage grinding include emulsifier-disperser, high-pressure jet type, which is used for handling process fluids at high pressure. The preferred emulsifier is a disperser, high-pressure jet type is a high-pressure homogenizer, in which the pumped process fluid is expelled as a jet stream of high pressure by adjusting a specially designed valve in the area of release. Typical models of this type are EulsiFlex (manufacturer Avestin) and the high-pressure homogenizer production APV, NIRO SOAVI or Sanwa Machine Co., Inc. Can also be applied to other apparatus for dispersion, in which process fluid delivered under high pressure through nozzles of various shapes, arranged so that the jet of liquid faced each other. Typical models of this type are Microfluidizer (manufacturer Microfluidics), Starburst (manufacturer Sugino Machine Ltd.) and Nanomizer (manufacturer Yoshida Kikai Co., Ltd.).

Pressure grinding high-pressure homogenizer is preferably from about 300 to 1000 bar, preferably from about 300 to 600 bar. The temperature at the entrance of the homogenizer high pressure may vary within wide limits, but is usually about 1 to 70°C, preferably from about 5 to 40°C.

[0061]

At the second stage grinding under the above described conditions, the average particle size of the aripiprazole in the final suspension should be from about 1 to 10 μm, preferably from 1 to 5 μm, more preferably from 2 to 4 μm, most preferably from 2 to 3 μm. Suspension of aripiprazole with an average particle size of 2-3 μm is of interest because it has excellent absorption profile and not deposited during the production process.

The second grinding stage (C) can be performed by repeated transmission suspe the Ziya through the high-pressure homogenizer. In this case, can be applied the method of discrete transmission and method of recycling, providing similar results (see Examples 1-5 and Example 6, described below). Both systems can also be used in combination (see Example 7 below).

The method of discrete bandwidth essentially lies in the fact that the suspension is skipped portions through, for example, a high-pressure homogenizer until then, until you have processed all the noise portion to receive the treated suspension. After repeated processing of the suspension by the method of discrete bandwidth re-obtained suspension is again skipped portions through the high-pressure homogenizer until then, until you have processed all the noise portion with getting re-processed the resulting suspension; then the procedure is repeated.

Method of recycling essentially consists in that the container or receptacle with the suspension attached to the input, for example, to the high-pressure homogenizer, and the output of the homogenizer, with the formation thus recirculation line; and the slurry contained in the tank or vessel, continuously processed through a homogenizer, without extraction, therefore, the treated slurry is circulating in the recirculation line through the tank or vessel where it is) is carried out with the not yet processed by the suspension, and already this mixture is continuously passed through the homogenizer; thus, there is a recycling process suspension.

[0063]

Grinding on stage (In) does not require a vacuum or reduced pressure in the opposed Patent Document 3.

When using homogenizer high pressure on both (first and second) stage grinding stage (B) and (C) the production method, comprising the stages outlined above invention (A)-(C), preferably as described in the following stages (BB) and (CC), respectively.

[0067]

Stage (BB)

Stage (BB) according to the invention represents the first stage of grinding, in which a sterile primary suspension obtained in stage (A), is crushed by using a high-pressure homogenizer at a pressure of grinding from 50 to 200 bar, preferably 70-150 bar, obtaining a secondary suspension. It was found that this stage when it is executed avoids the above problems of clogging of the system.

[0068]

In other words, the use of high-pressure homogenizer at a pressure of grinding in the range from 50 to 200 bar, preferably from 70 to 150 bar, prevents clogging of the flow line homogenizer high pressure.

The temperature at the entrance of the homogenizer high pressure may vary within wide PR the Affairs, but, as a rule, is about 1 to 50°C., preferably from about 5 to 40°C.

[0069]

Sterile secondary suspension obtained as follows.

[0070]

Stage (IV)

Stage (IV) according to the invention represents a second stage of grinding, in which a sterile secondary suspension obtained in stage (BB), is crushed by using a high-pressure homogenizer at a pressure of grinding from 200 to 1000 bar to obtain a sterile final suspension. This stage provides a suspension of aripiprazole with the required particle size of from 1 to 10 μm, preferably from 1 to 5 μm, more preferably from 2 to 4 μm, most preferably about 2.5 microns.

[0071]

At stage (IV) require a higher pressure grinding homogenizer high pressure compared to the pressure of grinding on stage (WB). Typically, pressure grinding on stage (IV) is preferably set higher than the pressure at the stage (BB), approximately between 100 and 900 bar, especially about 200-500 bar.

[0072]

The preferred pressure grinding homogenizer high pressure stage (IV) is from 200 to 1000 bar, in particular from about 300 to 600 bar.

When multiple conducting grinding on stage (IV) pressure reduction can be gradually increased in the range from 200 to 1000 bar. In the this case, the final pressure is preferably from about 300 to 1000 bar, more preferably from about 300 to 600 bar.

[0073]

The temperature at the entrance of the homogenizer high pressure may vary within wide limits, but generally is from about 1 to 50°C, preferably from 5 to 40°C.

[0074]

The second grinding stage (IV) can be carried out by repeatedly passing the suspension through a homogenizer high pressure. The above method of discrete transmission and method of recycling that can be applied, provide similar results. Both methods can also be used in combination.

[0075]

Grinding on stage (IV) does not require a vacuum or reduced pressure in the opposed Patent Document 3.

The invention provides the ability to perform cleaning and sterilization of surfaces exposed to fluids used in apparatuses such as an apparatus for grinding with a large shearing force, dispersant, which uses the power shift for material processing, colloid mill, ultrasonic dispersing and emulsifying agent-disperser, high-pressure jet type, which is carried out using methods of cleaning in place (CIP) and sterilization in place (SIP). Continuous sterilization is also possible. CIP can be carried out using water, hot water, school is full of water, acidic water or an organic solvent, if necessary with the addition of one or more traditionally used detergents such as alkaline detergent, neutral detergent and acid detergent. SIP can be implemented using pure steam, hot water under high pressure, etc.

Thus, a sterile suspension of aripiprazole having a mean particle size of aripiprazole from 1 to 10 μm, obtained by grinding in aseptic conditions; at the stage (b) sterile primary suspension of aripiprazole obtained in stage (a) with the help of the apparatus for grinding with a large shearing force (such as a mixer-homogenizer with a large shearing force), dispersant, which uses the power shift for material processing, colloid mill, ultrasonic disperser, or an emulsifier-disperser, high-pressure jet type (such as a homogenizer, high pressure), the surface of the apparatus exposed to liquids, sterile obtaining sterile secondary suspension; and the resulting sterile secondary suspension is ground in aseptic conditions in stage (b) with emulsifier-disperser, high-pressure jet type (such as a homogenizer, high pressure), the surface of the apparatus exposed to liquids, sterilizat.

[0076]

Aqueous suspension of aripiprazole

Aripiprazole in aqueous suspension of aripiprazole obtained in accordance with the method according to the invention should have an average particle size of from 1 to 10 μm, preferably from 1 to 5 μm, more preferably from 2 to 4 μm, most preferably from 2 to 3 microns.

[0077]

In accordance with the method according to the invention it does not matter how big is the average size of the particles of the mass of aripiprazole; and the average particle size of the aripiprazole in the final suspension is controlled within the above range. Thus, the method has significant advantages: minor restrictions on obtaining sterile powder mass; in the case of applying powdered material with a large particle size of the capture of air bubbles in the process of getting the suspension happens less often, and also facilitated the process of defoaming; there is no need to apply negative pressure and therefore the likelihood of contamination from the outside air is significantly reduced.

In accordance with the method according to the invention can be obtained homogeneous end suspension, free from large particles of aripiprazole, and therefore the final suspension (i.e. the desired suspension of aripiprazole) may optionally be filtered for removal the foreign substances. Used the filter must have a pore size from 10 to 225 μm, preferably from 20 to 70 μm. Therefore, the method according to the invention may optionally include the final phase of filtering the suspension obtained in stage (b)through a filter with pore size from 10 to 225 microns.

[0078]

The final suspension (i.e. the desired suspension of aripiprazole) preferably contains aripiprazole at a concentration of about 10 to 400 mg/ml, more preferably from about 50 to 250 mg/ml, most preferably 100 mg/ml

[0079]

Sterile suspension of aripiprazole obtained by the method according to the invention, it is possible to introduce, for example, subcutaneously or intramuscularly as an injectable composition.

A method of Obtaining a Lyophilized Composition

Sterile suspension of aripiprazole obtained above described method, may be lyophilized to obtain a Lyophilized composition.

More specifically, the final suspension of aripiprazole may be lyophilized to obtain a Lyophilized composition necessary polymorphic forms (anhydrate, Hydrate, or a mixture thereof). To obtain a Lyophilized composition of the Aripiprazole Hydrate And as the mass of aripiprazole monohydrate use or Hydrate a And the suspension of hydrate As obtained by the method according to the invention, is subjected to the subsequent life is Itachi.

The lyophilization cycle includes cooling the suspension in the range from -20°C to -55°C With a suitable cooling rate until the freezing of the suspension, the stage of drying at a temperature below about 0°C. (preferably about 0°C to -15°C) under conditions sufficient vacuum (for example, about 1 to 100 PA) and within the required time (for example, before the formation of a lyophilized composition; usually within about 10 to 100 hours).

If you want to get a lyophilized composition containing aripiprazole in anhydrous form, as the mass of aripiprazole use aripiprazole in the form of a monohydrate or anhydrous crystals, and the suspension obtained by the method according to the invention, is subjected to subsequent lyophilization. The lyophilization cycle includes three stages (freezing, primary drying, and secondary drying). In particular, the lyophilization cycle consists of cooling the suspension in the range from -20 to -55°C With a suitable cooling rate until the freezing of the suspension; primary drying at a temperature below about 0°C. (preferably from about 0°C to -20°C) under conditions sufficient vacuum (for example, about 1 to 100 PA) and within the required time (usually about 10 to 100 hours); and secondary drying at a temperature above about 0°C. (preferably from 0°C to 60°C) under conditions sufficient vacuum for example, from about 0.1 to 20 PA) and within the required time (for example, before the formation of a lyophilized composition; usually about 10 to 100 hours).

Freeze-dried composition, thus obtained, can easily be recovered in the form of the desired suspension of aripiprazole with water for injection immediately before the introduction. Therefore, the lyophilized composition is applied as a composition prepared immediately before use. Despite the fact that the recovery method is extremely simple (just need to add water for injection to a specific part and manually shake the mixture), the suspension of aripiprazole obtained homogeneous.

EXAMPLES

[0080]

The examples below are given for a more detailed description of the present invention

[0081]

In each example, the average particle size is an average volume diameter as measured by means of diffraction particle size analyzer by laser scattering (LLS) (laser diffraction particle size analyzer SALD-3000J, manufacturer Shimadzu Corp.). The terms "10% diameter", "50% of the diameter and the 90% diameter in case of the size distribution of particles mean particle diameter at the point where the integral distribution curve (%) intersects with 10% of the value of the integral indicator; the particle diameter at the point where the interest is General distribution curve intersects with the 50% value, the particle diameter at the point where the integral distribution curve intersects with the 90% value, respectively. The measurements were carried out under the following conditions: environment - water; the refractive index of from 2.00 to 0.20i; cuvette flow cell.

In each example, both stage - getting media and combining weight of aripiprazole and media reception of the primary suspension - was carried out at room temperature (20 to 30°C), unless otherwise noted. The first stage of grinding for grinding primary suspension was carried out at a temperature of from 20 to 45°C, unless otherwise noted.

Used in each example, the high-pressure homogenizer is a commercially available high-pressure homogenizer (trade mark "PANDA 2K Type, manufacturer NIRO SOAVI).

[0082]

Example 1

(a) Sodium salt of carboxymethylcellulose (18.30 g), 91.52 g mannitol and 1.63 g of the one-deputizing monohydrate sodium phosphate was dissolved in purified water. The total mass was 2059.2, the Solution was brought to pH 7.0 with aqueous sodium hydroxide solution with a concentration of 1 mol/l and filtered through a filter with pore size 0.2 μm.

[0083]

In the resulting filtrate (1872) was dispersively a lot of aripiprazole monohydrate (208 g, the average particle size of the powder mass = 258 μm; 10% diameter = 99 μm; 50% diameter = 280 μm; 90% diameter = 609 µm)obtained spasonalivskoi crystallization, accessing primary suspension.

[0084]

Procedure dispersion to obtain primary suspensions was performed using a Three-One Motor (manufacturer HEIDON) under stirring by a stirrer with a diameter of 100 mm with a speed of from about 200 to 400 rpm (a Similar condition was used in the subsequent examples, unless otherwise specified).

[0085]

(b) Primary suspension was ground using a mixer-homogenizer with a large shearing force (brand: Clearmix (CLM-1.5S), manufacturer M Technique Co., Ltd.) at a speed of 18000 rpm for 7.5 minutes per liter. In the received secondary suspension.

[0086]

(C) the resulting secondary suspension was cooled or heated until a temperature at the inlet to about 10°, about 20°C., about 40°and about 60°C. the Suspension was crushed by a ten-fold passage through a high-pressure homogenizer at 600 bar by way of discrete bandwidth.

[0087]

The average particle size of suspensions, crushed once and tenfold chopped, measured using the analyzer size distribution of particles (SALD-3000J, manufacturer Shimadzu Corp.). The results shown below.

[0088]

Table 1
A number of Refinements The average Particle Size (µm)
10°C20°C40°C60°C
15.15.04.54.9
101.81.92.33.9

[0089]

From Table 1 follows:

(i) If the mass of aripiprazole monohydrate obtained by the method of periodic crystallizatio, even a single passing the suspension through a homogenizer high pressure at 600 bar and inlet temperature from 10 to 60°C in the second stage grinding (stage (C)) allows to obtain a suspension of aripiprazole with an average particle size of from 1 to 10 microns.

(ii) a Tenfold passing the suspension through a homogenizer high pressure at 600 bar and inlet temperature from 10 to 60°C in the second stage grinding (stage (C)) allows to obtain a suspension of aripiprazole with an average particle size of from 2 to 4 microns.

(iii) a Tenfold passing the suspension through a homogenizer high pressure at 600 bar and inlet temperature from 10 to 40°C in the second stage grinding (stage (C)) allows to obtain a suspension and is of pipradol with an average particle size of from 2 to 3 microns.

[0090]

This shows that the suspension with a set size of particles (1-10 μm, preferably 1-5 μm, more preferably from 2 to 4 μm) were obtained even when using a powdered material with a large particle size, which is one of the results of the present invention.

Similar results have been obtained with the use of sterile mass of aripiprazole and sterile media. Similar conditions were used in subsequent examples.

[0091]

Example 2

Sodium carboxymethyl cellulose (45.76 g), 228.80 g mannitol and 4.07 g of monohydrate one-deputizing phosphate sodium phosphate was dissolved in purified water. The total mass was 5148, the Solution was brought to pH 7.0 with aqueous sodium hydroxide solution with a concentration of 1 mol/l and filtered through a filter with pore size 0.2 μm.

[0092]

The resulting filtrate (1872) was dispersively a lot of aripiprazole monohydrate (208 g; average particle size poroshkovanii weight = 239 μm; 10% diameter = 99 μm; 50% diameter = 276 μm; 90% diameter = 632 μm)obtained by the method of periodic crystallization, to obtain the initial suspension.

[0093]

Primary suspension were crushed with Clearmix (CLM-1.5S) at a speed of 18000 rpm for 7.5 minutes per liter. In the received secondary suspension.

[0094]

The secondary suspension of ohlazhdeniya temperature at the inlet of about 20°C, and crushed by a ten-fold passage through the homogenizer high pressure at 300 bar, 600 bar and 1000 bar according to the method of discrete bandwidth. The average particle size of suspensions, once and tenfold chopped, measured using the analyzer size distribution of particles (SALD-3000J, manufacturer Shimadzu Corp.). The results shown below.

[0095]

Table 2
A number of RefinementsThe average Particle Size (µm)
300 bar600 bar1000 bar
15.74.54.3
102.61.92.5

[0096]

Table 2 indicates the following:

(i) If the mass of aripiprazole monohydrate obtained by the method of periodic crystallizatio, even a single passing the suspension through a high-pressure homogenizer at a pressure of from 300 to 1000 bar allows you to obtain a suspension of aripiprazole with an average particle size of from 1 to 10 microns.

(ii) a Tenfold passing the suspension through a high-pressure homogenizer at a pressure of from 300 to 1000 bar allows p in order to obtain a suspension of aripiprazole with an average particle size of from 2 to 3 microns.

(iii) obtaining a suspension of aripiprazole with an average particle size of from 2 to 3 μm is also possible at a pressure of 1000 bar. However, the necessary suspension of aripiprazole can be successfully obtained at a pressure of from 300 to 600 bar.

[0097]

Example 3

Sodium carboxymethyl cellulose (45.76 g), 228.80 g mannitol and 4.07 g of the one-deputizing monohydrate sodium phosphate was dissolved in purified water. The total mass was 5148, the Solution was brought to pH 7.0 with aqueous sodium hydroxide solution with a concentration of 1 mol/l and filtered through a filter with pore size 0.2 μm. Were used two types of sodium salt of carboxymethyl cellulose with a viscosity of 93 CPs (4% aqueous solution, 25°C) and 187 CPs (4% aqueous solution, 25°C).

[0098]

The resulting filtrate (1872) was dispersively a lot of aripiprazole monohydrate (208 g; average particle size of the powder mass, used to experience with the sodium salt of carboxymethyl cellulose with a viscosity of 93 SP = 258 μm; 10% diameter = 99 μm; 50% diameter = 280 μm; 90% diameter = 609 μm; the average particle size of the powder mass, used to experience with the sodium salt of carboxymethyl cellulose with a viscosity of 187 SP = 239 μm; 10% diameter = 99 μm; 50% diameter = 276 μm; 90% diameter = 632 μm)obtained by the method periodic crystallization, to obtain the initial suspension.

[0099]

Each of the primary suspensions were crushed with Cleamix (CLM-1.5S) at a speed of 18000 rpm for 7.5 minutes per liter. The result was secondary suspension.

[0100]

The secondary suspension was cooled to a temperature at the entrance about 20°C, and crushed by a ten-fold passage through a high-pressure homogenizer at 600 bar by way of discrete bandwidth. The average particle size of suspensions, once and tenfold crushed, was measured using the analyzer size distribution of particles (SALD-3000J, manufacturer Shimadzu Corp.). The results shown below.

[0101]

Table 3
A number of RefinementsThe average Particle Size (µm)
The viscosity of the Sodium Salt
Carboxymethylcellulose
93 SDR187 SDR
15.04.5
101.91.9

[0102]

The data of Table 3 indicate that the difference in viscosity N does not affect the grinding.

[0103]

Example 4

Sodium carboxymethyl cellulose (33.28 g), 166.40 g mannitol and 296 g of the one-deputizing monohydrate sodium phosphate was dissolved in purified water. The total mass was 3744, the Solution was brought to pH 7.0 with aqueous sodium hydroxide solution with a concentration of 1 mol/l and filtered through a filter with pore size 0.2 μm.

The resulting filtrate (1872) was dispersively a lot of aripiprazole monohydrate (208 g; average particle size of the powder mass = 386 μm; 10% diameter = 118 μm; 50% diameter = 356 mm; 90% diameter = 1640 μm)obtained by the method of periodic crystallization, to obtain the initial suspension. The procedure of dispersion for the preparation of initial suspension was performed using a Three-One Motor (manufacturer HEIDON) under stirring by a stirrer with a diameter of 50 mm at a speed of from about 700 to 800 rpm

[0104]

Primary suspension were crushed with Clearmix (CLM-1.5S) at a speed of 18000 rpm for 7.5 minutes per liter. The result was secondary suspension.

[0105]

Without controlling the temperature, the secondary suspension crushed by a ten-fold passage through a high-pressure homogenizer at 600 bar by way of discrete bandwidth. The average particle size of suspensions, once and tenfold chopped, measured with the analyzer size distribution of particles (SALD-3000J, manufacturer Shimadzu Corp.). The results shown below.

[0106]

Table 4
A number of RefinementsThe average Particle Size (µm)
15.0
103.0

[0107]

From Table 4 it is seen that even without controlling the temperature at the entrance, you can obtain a suspension of aripiprazole with an average particle size of from about 3 to 5 μm. By controlling the inlet temperature can be obtained suspension of aripiprazole with an average particle size less than 3 microns (see Examples 1 and 2).

[0108]

Example 5

Sodium carboxymethyl cellulose (45.76 g), 228.80 g mannitol and 4.07 g of the one-deputizing monohydrate sodium phosphate was dissolved in purified water. The total mass was 5148, For cooking used the sodium salt of carboxymethyl cellulose with a viscosity of 93 CPs (4% aqueous solution, 25°C) and 187 CPs (4% aqueous solution, 25°C). The solution was brought to pH 7.0 with aqueous sodium hydroxide solution with a concentration of 1 mol/l and filtered through a filter with pore size 0.2 μm.

[0109]

The resulting filtrate (1872) was dispersively a lot of aripiprazole monohydrate (208 g; average particle size of the powder mass = 239 μm; 10% diameter = 99 μm; 50% diameter = 276 μm; 90% diameter = 632 μm)obtained by the method of periodic crystallization, to obtain the initial suspension.

[0110]

Primary suspension ISM is lcale using Clearmix (CLM-1.5S) at a speed of 18000 rpm for 7.5 minutes per liter. The result was secondary suspension.

[0111]

The secondary suspension was cooled to a temperature at the entrance about 20°C, and crushed by a ten-fold passage through the homogenizer high pressure 300 bar by way of discrete bandwidth.

[0112]

The average particle size of suspensions, once and tenfold crushed, was measured using the analyzer size distribution of particles (SALD-3000J, manufacturer Shimadzu Corp.). The results shown below.

[0113]

Table 5
A number of RefinementsThe average Particle Size (µm)
The viscosity of the Sodium Salt of Carboxymethylcellulose
93 SP187 SP
15.35.7
102.52.6

[0114]

From Table 5 it follows that in the second stage of grinding, even when the pressure of the grinding homogenizer high pressure 300 bar, the difference in viscosity N no effect on grinding, as in Example 3.

[0115]

Primer

Sodium carboxymethyl cellulose (183 g), 915 g of mannitol and 16.3 g of the one-deputizing monohydrate sodium phosphate was dissolved in purified water. The total mass was 20592, the Solution was brought to pH 7.0 with aqueous sodium hydroxide solution with a concentration of 1 mol/l and filtered through a filter with pore size 0.2 μm.

[0116]

The resulting filtrate (18720 g) was dispersively a lot of aripiprazole monohydrate (2080 g; average particle size of the powder mass = 246 ám; 10% diameter = 103 μm; 50% diameter = 260 μm; 90% diameter = 548 μm)obtained by the method of periodic crystallization, to obtain the initial suspension.

[0117]

Primary suspension were crushed with Clearmix (CLM-9S) at a speed of 5700 Rev/min at 2.1 minutes per liter. The result was secondary suspension.

[0118]

The secondary suspension (500 ml) was subjected to a re-circulation, passing through the homogenizer high pressure, and cooled at the outlet of the homogenizer high pressure until a temperature input from about 15 to about 25°C. the Suspension was crushed during 32.5 minutes at a pressure of grinding 500 bar up to the time of discharge of the high-pressure homogenizer at a speed of 155 ml/min

[0119]

The average particle size of suspensions, crushed for 3.25 minutes and 32.5 minutes, measured with the analyzer size distribution is astiz (SALD-3000J, manufacturer Shimadzu Corp.). The results shown below.

[0120]

Table 6
The duration of Grinding time (minutes)The average Particle Size (µm)
3.253.5
32.51.7

[0121]

From Table 6 it follows that the necessary grinding, achieved using the method of discrete bandwidth, as shown in Examples 1-5, it is also possible for the recirculation. In addition, it is shown that even with multiple grinding by way of recycling for a long time, the average particle size is not reduced below 1 micron.

[0122]

Example 7

Sodium carboxymethyl cellulose (45.76 g), 228.80 g mannitol and 4.07 g of the one-deputizing monohydrate sodium phosphate was dissolved in purified water. The total mass was 5148, the Solution was brought to pH 7.0 with aqueous sodium hydroxide solution with a concentration of 1 mol/l and filtered through a filter with pore size 0.2 μm.

[0123]

The resulting filtrate (1872) was dispersively a lot of aripiprazole monohydrate (208 g; average particle size of the powder mass = 256 μm; 10% diameter = 109 μm; 50% diameter = 272 μm; 90% CI is m = 566 µm), received by way of periodic crystallization, to obtain the initial suspension.

[0124]

Primary suspension were crushed with Clearmix (CLM-1.5S) at a speed of 18000 rpm for 7.5 minutes per liter. The result was secondary suspension.

[0125]

The secondary suspension (500 ml) was cooled to a temperature at the entrance about 20°C, and crushed by a fourfold transmission through a high-pressure homogenizer at 500 bar. Then the suspension was subjected to repeated circulation, passing through the homogenizer high pressure, cooled at the outlet of the homogenizer high pressure until a temperature at the entrance about 20°C. the Suspension was additionally crushed by way of recirculation within 42 minutes at a pressure of grinding 500 bar up to the time of discharge of the high-pressure homogenizer at a speed of 155 ml/min

[0126]

The average particle size of suspensions, one and four crushed by the method of discrete transmission and four crushed by the method of discrete bandwidth and additionally crushed within 42 minutes by way of recycling, measured with the analyzer size distribution of particles (SALD-3000J, manufacturer Shimadzu Corp.). The results shown below.

[0127]

Table 7
A number of Refinements or Duration of GrindingThe average Particle Size (µm)
14.0
42.6
42 Minutes after 4-fold grinding1)1.6
1)the suspension was subjected to 4-fold chopping by way of discrete bandwidth and additionally crushed within 42 minutes by way of recycling.

[0128]

Table 7 shows that the method of discrete bandwidth can be used in combination with the method of recycling. In addition, even with multiple repetitions of the recirculating grinding for a long time, the average particle size is not reduced below 1 micron.

[0129]

Example 8

Sodium carboxymethyl cellulose (450 g), 2250 g of mannitol, 40 g of the one-deputizing monohydrate sodium phosphate and 160 g of an aqueous solution of sodium hydroxide with a concentration of 1 mol/l was dissolved in purified water. The total mass was 50625, the Solution was filtered through a filter with pore size 0.2 μm. The filtrate (748.8 g) was dispersively a lot of aripiprazole monohydrate (83.2 g; average particle size of powders is th weight = 256 μm; 10% diameter = 109 μm; 50% diameter = 272 μm; 90% diameter = 566 µm)obtained by the method of periodic crystallization, to obtain the initial suspension.

[0130]

Primary suspension were crushed with apparatus for dispersion, which uses the power shift for material processing (trade mark T-50 Basic manufacturer IKA Japan, Inc.) using the shaft, known under the General name of the generator (brand S50N (- G45G, manufacturer IKA Japan, Inc.), at a speed of 6400 rpm for 7.5 minutes per liter. The result was secondary suspension.

[0131]

The secondary suspension was cooled to a temperature at the entrance about 20°C and generally crushed five times, one at a time, passing through the high-pressure homogenizer at 300 bar and four times by the method of discrete transmittance at a pressure of 500 bar. The average particle size of suspensions, once and five times crushed, was measured using the analyzer size distribution of particles (SALD-3000J, manufacturer Shimadzu Corp.). The results shown below.

[0132]

Table 8
A number of RefinementsThe average Particle Size (µm)
16.4
52.7

[0133]

From Table 8 it follows that any apparatus for grinding can be used to first crushing, provided that it provides some degree of shear strength for grinding powder mass. This is suitable not only the above-mentioned mixer-homogenizer with a large shearing force (e.g., Clearmix), but and apparatus for dispersion (for example, T-50 Basic manufacturer IKA Japan, Inc.).

[0134]

Example 9

Sodium carboxymethyl cellulose (450 g), 2250 g of mannitol, 40 g of the one-deputizing monohydrate sodium phosphate and 160 g of an aqueous solution of sodium hydroxide with a concentration of 1 mol/l was dissolved in purified water. The total mass was 50625, the Solution was filtered through a filter with pore size 0.2 μm. The filtrate (748.8 g) was dispersively a lot of aripiprazole monohydrate (83.2 g; average particle size of the powder mass = 256 μm; 10% diameter = 109 μm; 50% diameter = 272 μm; 90% diameter = 566 µm)obtained by the method of periodic crystallization, to obtain the initial suspension.

[0135]

The initial suspension was cooled to a temperature at the entrance about 20°C and generally crushed six times by the method of discrete bandwidth, once passing through the high-pressure homogenizer at 100 bar (first stage grinding), and once flowing at 300 b is R, and four flowing at 500 bar (second stage grinding). The average particle size of suspensions, once crushed, crushed twice and six crushed, was measured using the analyzer size distribution of particles (SALD-3000J, manufacturer Shimadzu Corp.). The results shown below.

[0136]

Table 9
A number of RefinementsThe average Particle Size (µm)
118.6
24.7
62.4

[0137]

From Table 9 it follows that the high-pressure homogenizer can be used even at the stage of the first grinding, without causing clogging of the lines under reduced pressure grinding.

[0138]

Example 10

Sodium carboxymethyl cellulose (16.64 g), 83.20 g mannitol, 1.48 g of the monohydrate of onesemester sodium phosphate was dissolved in purified water. Total weight amounted 3704, the Solution was brought to pH 7.0 with aqueous sodium hydroxide solution with a concentration of 1 mol/l and filtered through a filter with pore size 0.2 μm.

[0139]

The resulting filtrate (1852) D. what was spirirual a lot of aripiprazole monohydrate (208 g; the average particle size of the powder mass = 238 μm; 10% diameter = 72 μm; 50% diameter = 274 μm; 90% diameter = 811 μm)obtained by the method of periodic crystallization, to obtain the initial suspension.

[0140]

Primary suspension were crushed with Clearmix (CLM-1.58) at a speed of 18000 rpm for 7.5 minutes per liter. In the received secondary suspension.

[0141]

Without controlling the temperature, the secondary suspension crushed by a ten-fold passage through a high-pressure homogenizer at 600 bar by way of discrete bandwidth. The average particle size of suspensions, once and tenfold chopped, measured with the analyzer size distribution of particles (SALD-3000J, manufacturer Shimadzu Corp.). The results shown below.

[0142]

Table 10
A number of RefinementsThe average Particle Size (µm)
14.5
103.4

[0143]

From Table 10 it follows that even without controlling the temperature at the entrance, you can obtain a suspension of aripiprazole with an average particle size of from about 3 to 5 μm. Controlling the temperature at the entrance, you can policiessince aripiprazole with an average particle size less than 3 microns (see Example 11 below).

[0144]

Example 11

Sodium carboxymethyl cellulose (16.64 g), 83.20 g mannitol, 1.48 g of the one-deputizing monohydrate sodium phosphate was dissolved in purified water. Total weight amounted 3704, the Solution was brought to pH 7.0 with aqueous sodium hydroxide solution with a concentration of 1 mol/l and filtered through a filter with pore size 0.2 μm.

[0145]

The resulting filtrate (1852) was dispersively a lot of aripiprazole monohydrate (208 g; average particle size of the powder mass = 238 μm; 10% diameter = 72 μm; 50% diameter = 274 μm; 90% diameter = 811 μm)obtained by the method of periodic crystallization, to obtain the initial suspension.

[0146]

Primary suspension were crushed with Clearmix (CLM-1.58) at a speed of 18000 rpm for 7.5 minutes per liter. The result was secondary suspension.

[0147]

The secondary suspension was cooled to a temperature at the entrance about 20°C, and crushed by a ten-fold passage through a high-pressure homogenizer at 600 bar by way of discrete bandwidth.

[0148]

The average particle size of suspensions, once and tenfold chopped, measured with the analyzer size distribution of particles (SALD-3000J, manufacturer Shimadzu Corp.). The results shown below.

[0149]

Table 11
A number of RefinementsThe average Particle Size (µm)
14.6
101.9

[0150]

From Table 11 it follows that even at low concentrations N as a suspending agent first transmission provides a suspension with an average particle size of from 1 to 5 μm, and a ten-fold transmission provides a suspension with an average particle size of 2 microns.

[0151]

Example 12

Sodium carboxymethyl cellulose (16.64 g), 83.20 g mannitol, 1.48 g of the one-deputizing monohydrate sodium phosphate was dissolved in purified water. Total weight amounted 3704, the Solution was brought to pH 7.0 with aqueous sodium hydroxide solution with a concentration of 1 mol/l and filtered through a filter with pore size 0.2 μm.

[0152]

The resulting filtrate (1852) was dispersively a lot of aripiprazole monohydrate (208 g; average particle size of the powder mass = 258 μm; 10% diameter = 99 μm; 50% diameter = 280 μm; 90% diameter = 609 μm)obtained by the method of periodic crystallization, to obtain the initial suspension.

[0153]

Primary suspension were crushed with Clearmix (CLM-1.5S) at a speed of 18000 rpm for 7.5 minutes per liter. The result was tricou suspension.

[0154]

The secondary suspension was cooled or heated until a temperature at the inlet to about 10°, about 20°C., approximately 40°and approximately 60°C, and crushed by a ten-fold passage through a high-pressure homogenizer at 600 bar by way of discrete bandwidth. The average particle size of suspensions, once and tenfold chopped, measured with the analyzer size distribution of particles (SALD-3000J, manufacturer Shimadzu Corp.).

The results shown below.

[0155]

Table 12
A number of RefinementsThe average Particle Size (µm)
10°C20°C40°C60°C
14.64.44.54.7
101.82.12.34.2

[0156]

From Table 12 it should:

(i) Even at low concentrations N can be obtained suspension with an average particle size of from 1 d is 5 μm, as in Example 1.

(ii) Even at low concentrations N can be obtained suspension with an average particle size of from 2 to 3 μm, as in Example 1, by raising its temperature at the inlet to about 40°C or below.

[0157]

Example 13

Sodium carboxymethyl cellulose (8.32 g), 41.60 g mannitol, 0.74 g of the one-deputizing monohydrate sodium phosphate was dissolved with purified water. Total weight amounted to 1852, the Solution was brought to pH 7.0 with aqueous sodium hydroxide solution with a concentration of 1 mol/l and filtered through a filter with pore size 0.2 μm.

[0158]

The resulting filtrate (740.8 g) was dispersively a lot of aripiprazole monohydrate (83.2 g; average particle size of the powder mass = 256 μm; 10% diameter = 99 μm; 50% diameter = 280 μm; 90% diameter = 609 μm)obtained by the method of periodic crystallization, to obtain the initial suspension. The procedure of dispersion for the preparation of initial suspension was performed using a Three-One Motor (manufacturer HEIDON) under stirring by a stirrer with a diameter of 50 mm at a speed of from about 300 to 500 rpm

[0159]

Primary suspension were crushed with Clearmix (CLM-1.5S) at a speed of 18000 rpm for 7.5 minutes per liter. The result was secondary suspension.

[0160]

The secondary suspension (450 ml) was subjected to a re-circulation, passing through the homogenizer high on the effect, and cooled at the outlet of the homogenizer high pressure until a temperature at the entrance about 20°C.

[0161]

The suspension was ground by way of recirculation within 72.5 minutes at a pressure of grinding 500 bar up to the time of discharge of the high-pressure homogenizer at a speed of 155 ml/min, the Average particle size of suspensions, crushed for 14.5 minutes and crushed within 72.5 minutes, measured with the analyzer size distribution of particles (SALD-3000J, manufacturer Shimadzu Corp.). The results shown below.

[0162]

Table 13
The duration of Grinding time (Minutes)The average Particle Size (µm)
14.52.2
72.51.5

[0163]

From Table 13 it follows that even at low concentrations N the necessary degree of grinding is possible with the use of recycling; in addition, even when multiple holding the recirculating grinding for a long time, the average particle size is not reduced below 1 micron.

Example 14

Each suspension of aripiprazole obtained by the method described in Examples 1-13 (2.5 ml)was placed and in the glass vial, negerlein closed with a rubber stopper. The vials was transferred to lyophilizator and liofilizirovanny under the following conditions:

(a) Freezing: the vials were cooled to -40°C. at a speed of 1°C/min and then left at -40°C for 6 hours;

(b) Drying: the pressure in the chamber was lowered to about 13 PA, the temperature on the shelf lyophilizate was raised to -5°C at the rate of 0.3°C/min; then continued drying for 55.5 hours at a pressure of approximately 13 PA and the temperature on the shelf lyophilizate about -5°C;

(C) the vials were closed under atmospheric pressure or partial vacuum with nitrogen or air, then removed from lyophilizate; and

(g) vials tightly closed aluminum caps. In each of the obtained freeze-dried suspensions contained aripiprazole in the form of a Hydrate A.

Example 15

Each suspension of aripiprazole obtained by the method described in Examples 1-13, were placed in a glass vial, negerlein closed with a rubber stopper. The vials was transferred to lyophilizator and liofilizirovanny under the following conditions:

(a) Freezing: the vials were cooled to -40°C. at a speed of 1°C/min and then left at -40°C for 6 hours;

(b) Primary drying: the pressure in the chamber was lowered to about 13 PA, the temperature on the shelf lyophilizate was raised to -5°C at the rate of 0.3°C/min; the village is E. this continued primary drying during 55.5 hours at a pressure of approximately 13 PA and the temperature on the shelf lyophilizate about -5°C;

(C) secondary drying: temperature on the shelf lyophilizate was raised to 25°C and continued drying for 24 hours at a pressure of approximately 13 PA; then the temperature on the shelf lyophilizate raised to 50°C and continued drying for 24 hours at a pressure of approximately 13 PA;

(g) the vials were closed under atmospheric pressure or partial vacuum with nitrogen or air, then removed from lyophilizate; and

(d) the vials tightly closed aluminum caps.

In each of the obtained freeze-dried suspensions contained aripiprazole in anhydrous form.

1. A method of obtaining a suspension of aripiprazole, which includes the following stages:
(a) combining weight of aripiprazole and media education primary suspension;
(b) first grinding the primary suspension with obtaining the secondary suspension using the apparatus for grinding with a large shearing force or dispersant in which to process material is applied shearing force; and
(C) a second grinding the secondary suspension to obtain the final suspension by grinding the secondary suspension using high-pressure homogenizer.

2. The method according to claim 1, characterized in that in stage (b) use a high-pressure homogenizer at a pressure of grinding from 300 to 1000 bar.

3. The method according to claim 1, characterized in that Thu is on stage (in) use the high-pressure homogenizer at a pressure of grinding from 300 to 600 bar.

4. The method according to claim 1, characterized in that in stage (b) using a homogenizer high pressure when the inlet temperature from 1°C to 70°C.

5. The method according to claim 1, characterized in that the medium contains at least one suspendisse agent selected from the group comprising carboxymethyl cellulose, salts of carboxymethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellose and polyvinylpyrrolidone.

6. The method according to claim 1, characterized in that the mass of aripiprazole contains particles of aripiprazole with a size of 100 μm or more in an amount of 10% or more and has an average particle size of from 20 to 1000 microns.

7. The method according to claim 1, characterized in that the mass of aripiprazole has a mean particle size greater than 100 microns.

8. The method according to claim 1, characterized in that the mass of aripiprazole has a mean particle size of from 110 to 1000 microns.

9. The method according to claim 1, characterized in that the mass of aripiprazole has a mean particle size of from 200 to 400 microns.

10. The method according to claim 1, wherein the aripiprazole suspension of aripiprazole has a mean particle size of from 1 to 10 microns.

11. The method according to claim 1, wherein the aripiprazole suspension of aripiprazole has a mean particle size of from 1 to 5 microns.

12. The method according to claim 1, wherein the aripiprazole suspension of aripiprazole has a mean particle size of from 2 to 4 microns.

13. The method according to the .1, wherein the aripiprazole suspension of aripiprazole has a mean particle size of from 2 to 3 microns.

14. The method according to claim 1, characterized in that:
(I) at the stage of the Association receive the sterile primary suspension by combining the sterile mass of aripiprazole with an average particle size of from 200 to 400 μm and sterile media;
however aripiprazole in sterile final suspension has an average particle size of from 1 to 10 microns.

15. The method according to claim 1, characterized in that aripiprazole in bulk aripiprazole is in the form selected from the group consisting of monohydrate and anhydride in the form of Crystals Century

16. The method according to claim 1, further comprising a stage filtration end of the suspension through a filter with pore size from 10 to 225 microns.

17. A method of obtaining a suspension of aripiprazole, which includes the following stages:
(a) combining weight of aripiprazole and media education primary suspension;
(b) first grinding the primary suspension with obtaining the secondary suspension using high-pressure homogenizer at a pressure of grinding from 50 to 200 bar; and
(C) a second grinding the secondary suspension to obtain the final suspension by grinding the secondary suspension using high-pressure homogenizer at a pressure of grinding from 200 to 1000 bar,
the difference between the pressure of izmelchenie is at the stage (b) and pressure grinding stage (b) is from 100 to 900 bar.

18. The method according to 17, characterized in that in stage (b) pressure grinding, developed by the homogenizer high pressure is in the range from 50 to 200 bar; and at the stage (C) grinding perform repeatedly and pressure grinding gradually increased in the range from 200 to 1000 bar.

19. The method according to p, characterized in that in stage (b) final pressure grinding, developed by the homogenizer high pressure is from 300 to 600 bar.

20. The method according to 17, characterized in that in stage (b) and (C) a high-pressure homogenizer is used in the inlet temperature from 1°C to 50°C.

21. The method according to 17, characterized in that the medium contains at least one suspendisse agent selected from the group comprising carboxymethyl cellulose, salts of carboxymethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose the hypromellose and polyvinylpyrrolidone.

22. The method according to 17, characterized in that the mass of aripiprazole contains particles of aripiprazole with a size of 100 μm or more in an amount of 10% or more and has an average particle size of from 20 to 1000 microns.

23. The method according to 17, characterized in that the mass of aripiprazole has a mean particle size greater than 100 microns.

24. The method according to 17, characterized in that the mass of aripiprazole has a mean particle size of from 110 to 1000 microns.

25. The method according to 17, is great for the decomposing those what mass of aripiprazole has a mean particle size of from 200 to 400 microns.

26. The method according to 17, wherein the aripiprazole suspension of aripiprazole has a mean particle size of from 1 to 10 microns.

27. The method according to 17, wherein the aripiprazole suspension of aripiprazole has a mean particle size of from 1 to 5 microns.

28. The method according to 17, wherein the aripiprazole suspension of aripiprazole has a mean particle size of from 2 to 4 microns.

29. The method according to 17, wherein the aripiprazole suspension of aripiprazole has a mean particle size of from 2 to 3 microns.

30. The method according to 17, wherein the aripiprazole in the mass of aripiprazole is in the form selected from the group consisting of monohydrate and anhydride in the form of Crystals Century

31. The method according to 17, further comprising a stage filtration end of the suspension through a filter with pore size from 10 to 225 microns.

32. A method of obtaining a lyophilized composition of the hydrate a of aripiprazole, which includes stages: cooling the suspension obtained by the method according to claim 1 or 17, and containing the aripiprazole in the form of a hydrate And, to a temperature from -20°C to -55°C to the freezing of the suspension; and subsequent drying at a temperature below about 0°C.

33. A method of obtaining a lyophilized composition containing aripiprazole in anhydrous form, which includes stages:
(1) cooling suspensionrebate, obtained by the method according to claim 1 or 17, using the weight of aripiprazole in the form of a monohydrate or anhydrous crystals to a temperature from -20°C to -55°C to the freezing of the suspension;
(2) the conduct of primary drying at a temperature below about 0°C.; and
(3) carrying out secondary drying at a temperature above about 0°C.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and salts thereof wherein R1 represents -A11-A12-; R2 represents tetrahydrofurylmethyl, tetrahydropyranylmethyl or tetrahydropyranyl; A11 represents a single bond, methylene or 3,2-ethylene; A12 represents C1-6 alkyl, C3-6 cycloalkyl or C3-6 cycloalkyl containing methyl; R3 represents methoxy, cyano, cyclobutyloxymethyl, methoxymethyl or ethoxymethyl; and R4 represents methoxy or chlorine. Also, the invention also refers to a pharmaceutical composition possessing corticotrophin-releasing factor (CRF) receptor antagonist activity, containing a compound of formula (I), to a therapeutic/preventive agent, and a method of treating the diseases specified in the patent claim.

EFFECT: there are presented the compounds of formula (I) as corticotropin-releasing factor (CRF) receptor antagonists.

20 cl, 2 dwg, 2 tbl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1), in which Ar is a group of formula (Ar-1) or (Ar-2), in which R1 is a halogen, R2 is hydrogen, R3 is hydrogen, R4 is hydrogen, alkyl or alkenyl, X is a nitrogen atom or CH, R5 and R6 are each hydrogen and h equals 1; 1 equals 1 or 2; m equals 1 or 2; n equals 0, 1 or 2; o equals an integer from 0 to 3, under the condition that n and o are equal to 0 at the same time. Values of group A are as given in claim 1 of the invention. Described also is a pharmaceutical composition having agonistic activity with respect to 7 serotonin (5-HT4-receptors), which contains a compound of formula (1) and an agent which stimulates enterokinesis or improves functioning of the alimentary canal, which contains a compound of formula (1) as an active ingredient.

EFFECT: novel compounds are obtained and described, which have strong affinity towards 4 serotonin receptors, which are useful as an agent which stimulates enterokinesis or an agent which improves functioning of the alimentary canal.

28 cl, 233 ex, 29 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are offered: a pharmaceutical combination comprising an a7 nicotinic receptor agonist, which represents (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofurane-2-carboxamide or a pharmaceutically acceptable salt or a solvate thereof, and at least one antipsychotic agent, wherein the mentioned combination provides a synergistic therapy of a mental disorder, the use thereof for preparing a therapeutic agent for treating or preventing the mental disorder, an appropriate method of treating, and a set comprising a package and the specified synergistic combination. What is shown is a synergistic effect of (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofurane-2-carboxamide in a combination with clozapine on the state of fear, or in a combination with quetiapine by a value of a start pulse (startle response and PPI).

EFFECT: what is presented is a combination of alpha 7 nicotinic agonist receptors and antipsychotic agents.

23 cl, 14 dwg, 1 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula

, wherein X represents a halogen atom or C1-6-alkyl; and has the value of 0, 1, 2 or 3; R1 represents H; R2 represents or ; R3 represents C1-6-alkyl, C3-10-cycloalkyl, phenyl, 6-member heterocycloalkyl representing tetrahydropyranyl, or 5-10-member heteroaryl specified in pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzo[1,3]dioxolyl and 2,3-dihydrobenzo[1,4]dioxynyl; which be substituted and contains one to five substitutes specified in the patent claim. The invention also refers to pharmaceutical compositions possessing high affinity to dopamine D3 receptor and serotonin 5-HT2A receptor containing said compounds, and the use thereof in preparing drugs.

EFFECT: preparing the compounds of formula (I) possessing high affinity to dopamine D3 receptor and serotonine 5-HT2A receptor.

15 cl, 4 dwg, 5 tbl, 78 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to novel compounds specified in [1-(3,4-difluorobenzyl)-piperidin-4-yl]-(5-trifluoromethylpyridin-2-yl)amine, 6-{methyl-[1-(3-trifluoromethylbenzyl)-piperidin-4-yl]amino}nicotinonitrile, 6-[1-(3-trifluoromethylbenzyl)-piperidin-4-ylamino]nicotinonitrile, 6-[1-(3-fluoro-5-trifluoromethylbenzyl)-piperidin-4-ylamino]nicotinonitrile, 6-[1-(3,5-difluorobenzyl)-piperidin-4-ylamino]nicotinonitrile, 6-[1-(3,4,5-trifluorobenzyl)-piperidin-4-ylamino]nicotinonitrile, 2-{methyl-[1-(3-trifluoromethylbenzyl)piperidin-4-yl]amino}isonicotinonitrile, 6-[1-(3-fluoro-5-trifluoromethylbenzyl)piperidin-4-ylamino]pyridin-2-carbonitrile, (1-benzyl-piperidin-4-yl)-(5-trifluoromethylpyridin-2-yl)amine, 6-[1-(3,5-difluorobenzyl)piperidin-4-ylamino]-pyridin-2-carbonitrile; 6-[1-(3,4,5-trifluorobenzyl)piperidin-4-ylamino]-pyridin-2-carbonitrile and 6-(1-benzyl-piperidin-4-ylamino)-pyridin-2-carbonitrile, to their pharmaceutically acceptable salts and stereoisomer forms used as antipsychotic agents, as well as to a based pharmaceutical composition.

EFFECT: preparing the compounds used as antipsychotic agents.

3 cl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new 1,2,4-triazine-3,5-dione derivatives of general formula (I) wherein A is a saturated hydrocarbon chain with chain length 4 to 6 atoms; R1 and R2 are optionally hydrogen or C1-C3-alkyl; R3 is branched C4-C6-alkyl or C3-C6-cycloalkyl; R4 - C1-C6-alkyl, C3-C6-cycloalkyl or fluorinated C1-C3-alkyl, their physiologically acceptable salts and N-oxides, and a pharmaceutical composition containing them.

EFFECT: new compounds show dopamine D3 receptor activity and may be used in treating the central nervous system diseases.

24 cl, 8 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely psychiatry, and may be used for treating subacute reactive depressive psychosis. That is ensured by prescribing a drug-induced therapy consisting of Paroxetin in a double daily dose of 25-50 mg per os for 30 days. Diazepam 20-22 mg is intramuscularly introduced twice a day for 30 days. Mexidol in a daily dose 400-450 mg is introduced intravenously drop-by-drop for the first 20 days, and than 450-500 mg per os in tablets for the following 10 days. 0.01% Timogen 1.2-1.3 ml is introduced intramuscularly once a day for 10 days. The drug-induced therapy is combined with a hyperbaric oxygenation therapy with overpressure 0.8-1.0 atmospheres at compression rate and decompression 0.1 atmospheres a minute. An isopression period makes 40 minutes 2 times a day for the first 10 days, and then once a day for the following 10 days.

EFFECT: invention enables achieving a manifested clinical effect ensured by the use of the given therapeutic scheme.

1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 2-substituted-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-ones and 2-substituted-2,3,5,6-tetrahydrooxazolo[3,2-a]pyrimidin-7-ones of formula (I): where p, n, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are described in the description. These compounds are modulators of metabotropic glutamate receptors (mGluR), particularly the mGluR2 receptor. Compounds in the present invention are therefore suitable for use as pharmaceutical agents, especially in treating and(or) preventing various disorders of the central nervous system (CNS), including, among others, acute and chronic neurodegenerative disorders, psychosis, convulsions, anxiety, depression, migraine, pain, sleep disorder and emesis.

EFFECT: improved method.

14 cl, 148 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present group of inventions refers to medicine, namely neurology and therapy, and concerns reducing mammalian anxiety level. That is ensured by delta-opioid receptor antagonists not penetrating through brain-blood barrier such as M-154129; ICI 154,129;N,N-Di(2-propenyl)-L-Tyr-N-[2- [[(S)-2-[[(S)-l-carboxy-3-methylbutyl]amino]-2-oxo-l- benzylethyl]thio]ethyl]-Gly-NH2.

EFFECT: provided anxiolytic effect ensured by reciprocity of the peripheral and central endogenic opioid system that causes activation of the delta opioid system in the central nervous system by suppression of peripheral delta-opioid receptors in stomach.

3 cl, 3 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of cycloalkylamines, possessing inhibiting activity with respect to, at least, one monoamine transporter, selected from group, consisting of serotonin transporter, dopamine transporter and norepinephrine transporter. In formula (IV): n equals 1; s equals 1; Y and Z each independently represents halogen; X represents OR5; where R5 stands for H or non-substituted C1-C10alkyl; A represents H, non-substituted C1-C10alkyl or halogen; R1 and R2 each independently represents H; R3 and R4 each independently represents H or on-substituted C1-C10alkyl.

EFFECT: invention relates to pharmaceutical composition, containing said compounds and to method of treatment or prevention of neurological disorder or eating disorder, mediated by activity of monoamine transporter, selected from group, consisting of serotonin transporter, dopamine transporter and norepinephrine transporter, such as depression, neurodegenerative disease, abuse with psychoactive substances, fibromyalgia, pain, sleep disorder, syndrome of attention-deficit disorder, syndrome of attention-deficit disorder with hyperactivity, restless legs syndrome, schizophrenia, anxiety, obsessive-compulsive disorder, panic disorder, post-traumatic stress, premenstrual dysphoria.

35 cl, 6 dwg, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical composition and represents method of lyophilisation of particles, which contain frozen liquid and have contained in them pharmaceutical composition, including provision of heat-conducting container, which has bottom and side walls; filling container with a layer of particles, with the layer including multiple strata of particles and having aspect ratio mot less than 1; providing source of heat above upper stratum of particles, with source of heat having surface facing upper stratum of the layer, where said surface is characterised by emissivity factor equal, at least, 0.4; impact on container-filling particles with pressure lower than atmospheric pressure; heating at least container bottom and said surface to conduct heat to particles in order to ensure sublimation of frozen liquid at pressure lower than atmospheric pressure; ceasing conduction of heat to particles after sublimation of frozen liquid.

EFFECT: invention ensures uniform drying of multiple layer of particles with obtaining homogenous product.

11 cl, 4 ex, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of biotechnology and immunology. Claimed is medication for treatment and prevention of TNF-dependent disorder, which contains molecule of TNF-binding nanobody, lyoprotector, surface-active substance and buffer, method of such medication obtaining, method of lyophilised preparation reduction and method of analysis of medication-manufacturing process, as well as method and set for treatment or prevention of TNF-dependent disorder.

EFFECT: invention ensures obtaining stable pharmaceutical preparations of TNF-binding nanobodies and can be applied in therapy of TNF-dependent diseases.

30 cl, 12 ex, 3 tbl, 32 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics. Lyophilised pharmaceutical composition contains IX factor, more than 90% of whose calcium-binding ability are preserved in storage within 6 months at 25°C and tregalose, taken in amount 0.5%-3% by volume. Method of preparing stable dry composition includes stages of mixing IX factor-containing solution with tregalose 0.5%-3% by volume with obtaining cryoprotective solution. Method of pharmaceutical composition lyophilisation includes stages of freezing pharmaceutical composition containing IX factor and tregalose by 0.5%-3% in volume at temperature -40°C or less, burning pharmaceutical composition at temperature approximately from -20°C to -35°C, reduction of pharmaceutical composition temperature to -40°C or less, drying pharmaceutical composition at the first stage of drying at temperature from 5°C to 20°C at lower pressure, drying pharmaceutical composition at the second stage of drying at temperature from 45°C to 55°C at lower pressure. Method of preparing IX factor-containing lyophilised composition ensures preservation of more than 90% of IX factor calcium-binding ability.

EFFECT: application of composition on the basis of tregalose in amount 0,5%-3% in volume ensures its stability for 6 months of storage at conditions of 25°C.

17 cl, 5 ex, 6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: method of obtaining drug-containing composition of polymeric micelles includes: dissolution of poorly dissolved in water drug and amphiphilic block copolymer in organic solvent; and addition to obtained mixture in organic solvent of water solution with formation of polymeric micelles. Method does not require carrying out separate operation of organic solvent removal before formation of micelles. Method is simple, reduces technological time and amenable to scaling.

EFFECT: in accordance with invention method polymeric micelles preserve their stability.

14 cl, 9 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chitosan carboxyalkylamide hydrogel and may be used for cosmetic and dermatological treatment of skin burns. Chitosan carboxyalkylamide hydrogel of pH close to that of skin and making 6.5 to 7.2 contains 40 to 90 mole % of the groups of N-carboxyalkylaminde D-glucosamine of formula (I) wherein n represents an integer 1 to 8, 60 to 10 mole % of the protic groups of D-glucosamine, and 5 to 15 mole % of the groups of N-acetyl-D-glucosamine. A method for preparing said hydrogel involves preparing an acid solution of chitosan of a degree of acetylation of 85 to 95%, providing a reaction of produced additive chitosan salt in an aqueous solution of diorganic acid and correcting pH of the prepared solution.

EFFECT: preparing the anhydrous product of chitosan carboxyalkylamide prepared by hydrogel dehydration.

12 cl, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to an non-aqueous pharmaceutical composition containing dehydrated active polypeptide containing 10-100 amino acids, and at least one semipolar proton organic solvent, with polypeptide dehydrated at pre-set pH differing by at least 1 pH unit from pi polypeptide in the aqueous solution and to a method for preparing the composition.

EFFECT: group of inventions provides improved stability of the non-aqueous composition of therapeutic peptide.

39 cl, 7 ex, 11 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: method for preparing a composition for injections containing sodium cevtriaxone and sodium tazobactam involves the following stages: (a) suspension of raw materials, i.e. sodium cevtriaxone, sodium tazobactam, sterilised water for injections, mixed solution of ethyl acetate and isopropyl alcohol, and anhydrous ethanol in mass relation making 3-5:1:2:5:9, with volume relation of ethyl acetate to isopropyl alcohol making 1:2-4; (b) dissolution of sodium cevtriaxone and sodium tazobactam in sterilised water for injections with added activated hydrocarbon and filtration; (c) addition of the mixed solution of ethyl acetate and isopropyl alcohol to the filtrate and agitation of the mixture; addition of a seed crystal of sodium cevtriaxone to the solution for crystallisation initiation; and finally washing of the crystals in anhydrous ethanol and crystal drying; and (d) lyophilisation to form the composition for injections containing sodium cevtriaxone and sodium tazobactam.

EFFECT: composition is characterised by high uniformity, high degree of purity and safety of use.

6 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to pharmaceutical composition, which contains parathyroid hormone (PTH), methionine, at least one SAS poloxamer and physiologically acceptable buffer preparation, which can be applied in animals and people, as well as to method of obtaining said composition and application.

EFFECT: group of inventions ensures composition solution stability and prolonged storage term.

19 cl, 11 ex, 22 tbl, 3 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is presented is a lyophilised preparation containing at least one nicotine - virus-like particle conjugate, and a stabiliser composition containing at least one nonreducing disaccharide and at least one non-ionic surfactant wherein the pre-lyophilisation pH value of the stabiliser composition makes 5.8 to 6.6, preferentially 6.0 to 6.4.

EFFECT: invention provides producing the effective lyophilised vaccinal preparation able to keep stability for a long period of time.

14 cl, 3 dwg, 4 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention refers to method, and concerns a method for making a lyophilised antiviral agent consisting of dissolving a peptide in water, mixing the prepared solution with a number of structure-forming substances, sterilising and lyophilising including freezing out and drying. As a peptide, the peptide His-Gly-Val-Ser-Gly-Trp-Gly-Gln-His-Gly-Thr-His-Gly is used.

EFFECT: invention provides optimising the process enabling preparing the broad-spectrum lyophilised antiviral agent corresponding to the certified pharmacopeial description of the manufacturer.

3 cl, 1 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a thermoreversible, thermoplastic pharmaceutical composition comprising: (a) a biologically active botulinum toxin and (b) a thermoplastic poloxamer wherein poloxamer stabilises botulinum toxin so that botulinum toxin keeps biological activity with botulinum toxin release from the pharmaceutical compositions in vivo, wherein the pharmaceutical composition can be prepared with no substances contained in blood, such as albumin and therefore without any infectious substances of blood components, such as prion.

EFFECT: invention provides high stability and high percentage of the toxin activity recovery.

18 cl, 6 ex

Up!