Stable crystalline dopc modifications

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel crystalline modification (R)-DOPC, which can be applied in pharmaceutical industry. Claimed is novel crystalline form of DOPC and method of its obtaining, as well as its application as component in obtaining medications. Claimed method consists in the fact that crystallisation of (R)-DOPC is carried out in aprotic solvent.

EFFECT: claimed crystalline form of DOPC is characterised by improved stability.

14 cl, 5 ex, 2 tbl, 11 dwg

 

The present invention relates to crystalline modifications DOTH, to methods for their preparation and their use for obtaining pharmaceutical compositions.

DOTH above and below refers to naturally occurring

1,2-dioleoyl-sn-glycero-3-phosphocholine, also referred to as

1,2-dioleoyl-sn-glycero-3-phosphatidylcholine,

1,2-dioleoyl-sn-glycero-3-phosphorylcholine,

(R)-2,3-bis(oleolux)propyl-2-(trimethylammonio)ethyl phosphate,

1,2-dioleoyl-L-α-lecithin or,

(R)-DOPH

they are not naturally occurring enantiomer

2,3-dioleoyl-sn-glycerol-1-phosphocholine,

racemic (R,S)-DOTH, and other mixtures of the above-mentioned enantiomers.

C44H84NO8P, MW786.11

CAS number: 4235-95-4 (R form) and 84366-67-6 (S shape)

Liposomes are synthetic multilayer vesicles (spherical in closed membranes) containing amphiphilic substance, as a rule, natural lipids, which are both hydrophilic substance can be encapsulated in the aqueous interior of the cavity and also lipophilic substances can be introduced into the internal cavity of the lipid membrane.

They are used in particular in cosmetics and in medicine, in particular in dermatology. In particular this includes vitamins, coenzymes, substances to protect the skin and sunscreen. Liposomes as respect for the ILO applied topically.

However, liposomes are gaining more and more importance in pharmaceutical technology as injecting liposomes enables you to achieve a certain distribution on the body than if the active compounds were applied in the freely dissolved form.

Thus, US 2006/0067998 A1 discloses a method in which colloidal way encapsulated composition, which contains curcumin or a derivative of curcumin as an active substance, is introduced for the treatment or prevention of cancerous diseases. Suitable compositions contain and based on lipid colloid and polymer colloid system, such as, for example, liposomes, nanoparticles, microparticles or copolymer micelles formed from block copolymers.

If enabled DNA, RNA or proteins, will be received lipoplex.

Nanoparticles are particles of approximately the same size as liposomes, but have no aqueous phase, but instead it is the oil phase or solid filler in their internal cavity. They are particularly suitable for the encapsulation of lipophilic substances.

Micro-emulsions are colloidal way dispergirovannykh, single-phase system containing water such as lipid and such surface-active substance components the options. They have a particle size 1-500 nm and behave similarly to liquids.

The effect of improving the solubility in the applications described above, is very important, in particular in respect of such peptide active compounds with generally low solubility, nucleotides, vaccines and other Biopharmaceuticals.

In addition, degradation of the active compounds in the body can be slowed, and thus be achieved with a slow-release.

(R)-DOTH belongs to a class of naturally occurring, zwitter-ion phosphocholine. Liposomes containing zwitter-ionic lipids, have a neutral surface, one or combined with other phosphocholine or other analyses such as lipid compounds.

However, the ability of liposomes based on DOFH and lipoplexes to penetrate into the cells and thus to transport the active compounds that are included in them, into the internal cavity cells (transfection) is especially important. Such liposomes often contain charged lipids, in particular to cationic lipids. However, applications in which lipoplex consist DOTH, have also been published, for example Sood and others in the Journal of the National Cancer Institute(2008), 100, 359-372.

All these properties also make DOTH very interesting for cancer therapy. Thanks to these features, the por is alagaesia the possibility of introducing RNA, DNA or conventional cytotoxic funds included in DOFH liposomes.

Medical, in particular parenteral applications create an extremely high quality requirements and the absence of impurities to the active compounds and excipients. Hence the authorities are very strict instructions regarding preparation, the ability of the drug to reproductions and descriptions of by-products of these compounds. In the case of substances introduced parenterally, microbiological impurities due to pathogenic microorganisms and endotoxins additionally it is necessary to strictly avoid and control.

DOTH is unstable at room temperature and thus is difficult in fact to prepare in acceptable purity to be suitable when used for the preparation of medicinal compositions.

As all the lipids, which are oleic acid radicals, such as, for example, natural phospholipids RALO and DOPE, DOFH is very sensitive to oxidation. However, the oxidation products of unsaturated derivatives of fatty acids generally have high toxicity.

This requires appropriate medicines and methods of treatment. DOTH is, for example, in the form of a lyophilisate or waxy solids and therefore can be floor is Chen in the appropriate quality only with great difficulty in industrial relations.

Conventional methods used to overcome the instability, such as, for example, the addition of antioxidants in the form of tocopherol or reduced L-glutathione, a very limited basic convenience and ease of use DOTH as interaction later with active compounds that will be introduced, cannot be excluded. The complete exclusion of oxygen during preparation, storage and use virtually not possible or can be achieved only with very great effort.

Thus, the manufacturer generally recommends that lyophilized DOTH were stored under protective gas at -20°C and guarantees a shelf life of only about 12 months. Although a longer shelf life is guaranteed for waxy DOTH, with added protection from oxidation, and storage shall similarly take place at -20°C.

And dried and waxy DOPH has a very high amorphous content.

In addition to its oxidative sensitivity, this amorphous DOTH is also extremely hygroscopic and volatile within an extremely short period of time at normal atmospheric humidity levels, to give an oily film. In addition, waxy DOFH can be broken only with difficulty and, as dried DOTH, may be the swesen only with difficulty. This makes the handling of this compound is much harder.

The literature reveals only different synthetic route for the preparation of amorphous DOPH:

Ichihara, etc., Chemistry and Physics of Lipids(2005), 137 (1-2), 94-99, description of the synthesis DOTH from SN-glycero-3-phosphocholine (GPC).

Roodsari, and others, Journal of Organic Chemistry(1999), 64(21), 7727-7737, describes the total synthesis DOTH from trityl glycerol.

Appeared in many other publications on the synthesis and application of DOPH, but they do not describe crystalline materials.

Lewis and others, Biochemistry(1988), 27(3), 880-7, and Biochemistry(1989), 28(2), 541-8, report dried DOTH.

Baer and Kindler in Biochemistry(1962), 1(3), 518-21, refer to the waxy DOTH.

Lekim, Biedermann and Ghyczy, DE 2647395, describes in General the purification of esters GPC by crystallization, but definitely crystallization DOTH not described.

Racemic DOFH can be obtained from racemic starting materials analogously to the method described for enantiomers.

In addition, none of the many publications does not cause the melting point to DOTH.

Thus, the present invention is to provide DOTH in high purity, if possible in crystalline form. An additional objective of the invention is to provide this connection, long shelf life and good processing properties, so that it could the be used to prepare pharmaceutical compositions. In addition, there is a strong need in the way of reproduction for the preparation of stable forms DOTH that can be performed on an industrial scale.

Surprisingly, it was found through experiments that, and racemic and enantiomerically pure, crystalline DOTH, which has a high chemical purity and excellent stability can be obtained in a simple way. The crystalline products obtained in this way are stable for a virtually unlimited time at room temperature under protective gas.

Crystal DOTH also produced as easily processed granular material, which has superior absorption.

Thus, they are suitable as an element or a starting material for the preparation of dosage forms.

The invention accordingly relates to the enantiomers stable crystalline modification DOTH and mixtures of enantiomers having the same crystalline form.

Stable crystal modifications can be in crystalline and partially crystalline form. They have never achieved purity >98% together with never before reached stability >99%, based on the initial value after storage for 12 months exclusion is m of air at 40°C and 75% relative atmospheric humidity and after 18 months at 25°C and 60% relative atmospheric humidity (without added protection against oxidation, in this case, see Table 1). Crystalline modification DOTH have the content is less than 1 equivalent of water or solvent crystallization on the equivalent DOTH.

Enantiomers clean DOTH is, for example, modification of the crystal type I layers and demonstrates the average acuity measurements x-ray powder diffraction (in this case, see Fig.1 and Table 2). Selected 2-theta values for different crystalline modifications are at 3.6, 5.3, 18.3, 19.3 and 21.7 (type I), measured with Cu Kα radiation. Slight differences of the individual layers from these values may occur if you have selected different instruments or recording methods, such as reflection or transmission, or capillary or window, or if a different recording conditions prevail relative atmospheric humidity or temperature.

Some of crystalline modifications have a very high content of crystalline substance, which is evident in the enthalpy of melting greater than 48 j/g melting Point of the crystalline modifications mainly is above 60°C (Fig.9).

In addition, the crystalline modification according to the invention produced as easily processed granular material (Fig.4). The crystalline nature and Transparent, and be clear under the microscope polarization (Fig.6).

Mixture of enantiomers Krista is symbolic DOTH, such as, for example, crystalline racemate, can also have the same spectra of the DRA.

The invention also relates to a method for preparing crystalline modifications DOTH, which is characterized by the fact that DOTH is crystallized from aprotic environment. Aprotic environment, which can be used for this purpose are aprotic solvents or mixtures thereof. Aprotic medium may also contain a small proportion of the proton solvents, such as, for example, water. In exceptional cases, 25 wt.% of protonic solvents may also be present in suitable conditions. Crystallization DOFH can be prizvedeno directly from the reaction solution without previous purification. Crystal DOFH can similarly be obtained by recrystalization amorphous, partially crystalline or crystalline material.

Suitable aprotic solvents are, in particular, ethers, such as, for example, tetrahydrofuran, methyltetrahydrofuran and dioxane, esters, such as, for example, ethylformate, methyl acetate, ethyl acetate, propyl, isopropyl acetate, butyl acetate, isobutyl acetate, dimethyl carbonate, diethylcarbamyl and 1,3-dioxolan-2-it, ketones, such as, for example, acetone, 2-butanone, methylisobutyl ketone, methylisobutylketone, and NITRILES, such as who, for example, acetonitrile. Additives proton solvents, as a rule, consist of alcohols, such as, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, ethylene glycol, methoxyethanol, ethoxyethanol, water or mixtures thereof.

Crystallization DOTH modifications mainly is definitely slow cooling of the prepared solution to a temperature below 30°C. the Crystals formed spontaneously or or the introduction of seed crystallization with the corresponding crystalline modification DOTH.

Various crystalline modifications DOFH can be converted into each other. Transformation can be achieved by thermal treatment of the isolated crystalline modifications at elevated temperatures or prolonged shaking their suspensions under conditions of crystallization.

The use of amorphous or partially crystalline DOTH as source material for recrystallization in the described method provides an extremely crystal DOTH, which has never previously achieved purity together with never before reached stability.

The invention also relates to the use of crystalline DOTH for the preparation of medicinal compounds as crystalline DOPH has prevoshodno the stability in solid form under these conditions and constant and very good quality for a virtually unlimited period.

The invention therefore also relates to pharmaceutical compositions resulting from the use of forms DOTH claims. They can be, for example, in the form of liposomes, lipoplexes, microemulsions and nanoparticles and contain, for example, an active compound from the group of peptides, nucleotides, vaccines and drugs.

This allows the specialist skilled in the art to apply the invention in its entirety. Even without additional comments it is assumed that the specialist skilled in the art will be able to apply the above-mentioned description, in the broadest scale. Existing description therefore allows the specialist skilled in the art to use and apply the invention in its entirety.

In case of any lack of clarity, it goes without saying that should be used in publication and available literature cited. Accordingly, these documents should be regarded as part of the content of the description of the invention the present description.

For better understanding and in order to illustrate the invention, the following examples, which are under the legal protection of the present invention. These examples also serve to illustrious the possible varieties. Due to the General justification of the principle of description of the invention, but the examples are not suitable for reducing the area of legal protection of the present application to him alone.

Temperature data in the examples and the description and in the claims, is always given in °C. Unless otherwise indicated, the data content is given in wt.%.

In addition, needless to say for professionals, skilled in the art that, in these examples and in the remainder of the description, the quantity of the component that is present in the compositions always totals 100 wt.% or 100 mol. percent of the composition as a whole, and may not exceed it, even if higher values could arise from the indicated percentage ranges. Unless otherwise indicated, data % are wt.%, unless that show in volumetric values.

Examples to illustrate the invention

Example 1

Crystallization of (R)-DOPH

200 g of amorphous (R)-DOTH dissolved in 1700 ml of acetonitrile at 25°C. the Solution is cooled to -10°C at 0.1°C/min, Crystallization begins at 10°C. When the crystallization completed, the product produce by filtration and dried in vacuum. The yield of crystalline (R)-DOPH is 180 g (90%).

Crystalline modification of (R,S)- and (S)-DOPH can be obtained in the same way.

<> Example 1A

Recrystallization DOTH of ethyl acetate

20.0 g DOTH dissolved in 100 ml of ethyl acetate at 35°C. the Solution is cooled rapidly to 20°C and then to -10°C at a speed of 0.01°C/min, during which crystallization starts. The crystals are filtered and dried at room temperature in vacuum. The output is 19.6 g of crystalline DOFH (98.1% of theoretical). When heated at 5°C/min, the product shows a melting point of 71°C and the enthalpy of melting 49.4 j/,

Example 2

Stability.

In order to determine the stability of the crystalline DOTH, substances are stored together with the comparative samples at 25°C and 60% relative humidity and at 40°C and 75% relative humidity, with the exception of air. The residual content DOTH is measured at periodic intervals and is compared to the original value.

The purity and content DOTH determined by HPLC.

For crystalline modification I of type were found the following values:

Table 1
The storage time in monthsStability of type I crystals of (R)-DOPH
25°C/60% relative humidity 40°C/75% relative humidity
wt.%Region-%wt.%Region-%
0100.0100.0100.0100.0

The storage time in monthsStability of type I crystals of (R)-DOPH
25°C/60% relative humidity40°C/75% relative humidity
wt.%Region-%wt.%Region-%
3100.9100.0100.099.9
699.3100.098.499.8
9100.8100.099.899.8
12 100.499.799.599.7
18100.699.8--

Example 3

Powder reginorum

In order to characterize the modification of the crystal DOTH accounted powder reginorum (GOK range of refraction) of these structures. For comparison, different powder x-ray (portable spectrum of refraction) and dried wax DOTH also logged.

For crystalline modifications DOTH type I obtained relative spectra of high absorption with a medium-sharp bands for lipids. The spectra indicate a high crystalline content. No amorphous components that are visible under a polarizing microscope.

Illustrative range can be seen in Fig.1 (type I). For comparison, spectra of commercially available amorphous samples also recorded under similar conditions and is shown in Fig.2 (lyophilized) and Fig.3 (wax).

Table 2 lists the selected 2-theta values for the crystalline modification I of type DOPH:

Table 2
Type Selected 2-theta values
Type I(R)-DOPH3.6, 5.3, 7.1, 8.8, 11.0, 12.3, 15.3, 17.6, 18.3, 19.3, 20.4, 21.1, 21.7, 22.8 and 26.4

Example 4

Modification

Crystalline modification DOTH type I produced as a granular bulk materials (Fig.4), while commercial samples DOTH obtained either as a freeze-dried or wax pieces (Fig.5).

Under the polarizing microscope clearly visible crystalline modification DOTH type I, as a crystalline material (Fig.6), while freeze-dried (Fig.7) and wax comparative materials (Fig.8) are amorphous.

Example 5

The melting properties

Measurements of differential scanning calorimetry (DSC) also show clear differences for crystalline modification DOTH type I (Fig.9) and dried (Fig.10) and wax comparative material (Fig.11).

1. Crystals of (R)-1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPH) with value 2-theta 3.6, 5.3, 7.1, 8.8, 11.0, 12.3, 15.3, 17.6, 18.3, 19.3, 20.4, 21.1, 21.7, 22.8 and 26.4, measured with Cu Kα radiation.

2. Crystals of (R)-DOPH under item 1, with a range according to Fig. 1 (Type I)

3. Crystals of (R) according to one of paragraphs.1 and 2, having a melting point of 71°C and the enthalpy of melting of 49.4 j/,

4. A method of obtaining a crystalline modification of (R)-DOP is, characterized in that the crystallization of amorphous (R)-DOTH conduct of one or more aprotic solvents.

5. A method of obtaining a crystalline modification of (R)-DOPH under item 4, characterized in that the aprotic solvent used ether, preferably tetrahydrofuran, methyltetrahydrofuran or dioxane.

6. A method of obtaining a crystalline modification of (R)-DOPH under item 4, characterized in that the aprotic solvent used ketone, preferably acetone, 2-butanone, methyl isobutyl ketone or methylisobutylketone.

7. A method of obtaining a crystalline modification of (R)-DOPH under item 4, characterized in that the aprotic solvent used nitrile, preferably acetonitrile.

8. A method of obtaining a crystalline modification of (R)-DOPH under item 4, characterized in that the polar solvent used ester selected from the group that includes ethyl formate, methyl acetate, ethyl acetate, propyl, isopropylacetate, butyl acetate, isobutyl acetate, dimethylcarbonate, diethylcarbamyl and 1,3-dioxolan-2-it, or their mixture.

9. Method according to one of paragraphs.4-8, characterized in that the aprotic medium used in a mixture with an alcohol selected from the group that includes methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, ethylene glycol, m is toxicarol and ethoxyethanol, or their mixture.

10. The method according to p. 4, characterized in that the crystallization is carried out directly from the reaction solution without prior purification.

11. The use of a crystalline modification of (R)-DOPH, alone or optionally in mixtures with other lipids, as a component of drugs.

12. Pharmaceutical composition for the transport of active compounds comprising the crystalline modification of (R)-DOPH and pharmaceutically active compounds, optionally together with auxiliary means or solvents.

13. Pharmaceutical composition comprising the crystalline modification of (R)-DOPH under item 12, characterized in that the pharmaceutically active compound is used as an active compound selected from the group of peptides, nucleotides, vaccines and cytotoxic funds.

14. Pharmaceutical composition comprising the crystalline modification of (R)-DOPH under item 12, characterized in that it consists of liposomes, lipoplexes, nanoparticles or microemulsions.



 

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9 cl, 11 ex, 1 tbl, 6 dwg

FIELD: physics.

SUBSTANCE: invention relates to the technology of growing crystals from salt solutions, particularly for growing KDP (KH2 PO4) group crystals which are widely used for making non-linear optical elements. The device has a crystallisation cup 1, a cover 2 of the crystallisation cup, a platform 4 with an inoculating crystal 5 and a mechanism for sealing the inoculating crystal. The cover 2 has an eccentric opening 10 which is tightly closed by a guide bushing 11, where the said opening is for letting in the mechanism for sealing the inoculating crystal 5, which is made in form of a cap 6 which is pressed to the surface of the platform 4 and hinged to an L-shaped bar 7, which can move coaxially with the guide bushing 11. Inside the bar 7 there is a channel 9 for connecting the cavity of the cap 6 to a pressure source. To connect the cavity of the cap 6 to the channel 9, there is a flexible bar 12 inside the L-shaped bar 7. The cap 6 is pressed to the platform 4 by a load or spring at the free end of the bar 7. The source of pressure applied inside the cap is atmospheric air.

EFFECT: crystals are widely used for making non-linear optical elements.

5 cl, 2 dwg

FIELD: chemistry.

SUBSTANCE: based on chemical equation 3CCl4+4NH3 = C3N4+12HCl, quantities of carbon nitride C3N4 and carbon tetrachloride CCl4 are preliminary calculated. Then prescribed amount of liquid NH3, in sealed vessel, and carbon tetrachloride CCl4 are introduced into reaction chamber. The chamber is secured, within it the vessel with NH3 is opened, the chamber is heated to temperature 195-200° and let stand for 1.5-2 hours, till the reaction is finished and crystalline carbon nitride C3N4 is obtained.

EFFECT: method is economically effective, and time of synthesis is shortened.

2 ex

FIELD: processes related to crystal growing from solutions, possibly high-speed growing of profiled crystals.

SUBSTANCE: rotary axial pump includes rotor and housing made of chemically stable material and having inlet windows, inlet and outlet separators and at least one nozzle for guiding solution. Housing is in the form of one non-detachable member with separators having radial plates. Rotor is made in such a way that it includes no more than two parts of chemically stable material while number and size of blades of rotor spiral correspond to dimensions of sections of inlet separator of housing. Rotor axle may be in addition reinforced with metallic rod having no contact with solution. Such pump has minimal quantity of slits and threaded joints that decreases probability of mass crystallization.

EFFECT: stable growing of crystals from solution due to eliminating sources of parasitic crystals occurring.

8 cl, 1 dwg

FIELD: chemical industry; other industries; devices for the protein crystals growing.

SUBSTANCE: the invention is pertaining to the field of the protein crystals growing and may be used for analysis of the processes of a crystallization and production of the monocrystals of proteins, in particular, in conditions of the microgravitation on the orbital space station. The device for crystallization contains: the crystallization chamber with the located in it settling chamber and the chamber of the crystallization cells, the mechanism of the crystallization process starting-up. The crystallization chamber is formed by the device structure component and the resilient membrane, under which there are the settling chamber, which is made in the form of the cylindrical cavity, in which the settler solution is arranged, and the chamber of the crystallization cells, which is made in the form of annular cavity located concentrically to the settling chamber and containing the seats distributed along the circumference for location of the crystallization cells. The membrane is linked with the gear of start-up of the crystallization process, which ensures the deformed state of the membrane, at which the settling chamber is hermetically blocked by the membrane, and also it is used for the removal of the membrane deformed state to provide communication of the cavities of the settling chamber and the chamber of the crystallization cells. Each crystallization cell contains the crystallization substrate, on which the protein solution is placed, the membrane with the micropores for transit of the vapors of the settlerand this membrane is pressed to the solution of the protein by the rigid perforated diaphragm. Such device is compact and ensures production of the biocrystalline films in conditions of the microgravitation with the minimal risk of the probability of the shift of protein solution during the device delivery to the orbital station and its return back to the earth.

EFFECT: the invention ensures production of the biocrystalline films in conditions of the microgravitation with the minimal risk of the probability of the protein solution shift during the device delivery to the orbital station and its return back to the earth.

5 dwg

FIELD: pharmacology, in particular pharmaceutical composition for obesity prophylaxis and treatment.

SUBSTANCE: invention relates to claimed composition containing crystalline sibutramine methanesulfonate hemihydrate, as well as methods for production and uses of crystalline sibutramine methanesulfonate hemihydrate.

EFFECT: product with improved solubility.

12 cl, 5 dwg, 5 tbl, 3 ex

FIELD: process engineering.

SUBSTANCE: evaporation of solvent from oversaturated solution surface in crystallisation vessel. Solvent vapors are condensed at vessel top part and directed to vessel bottom. Note here that solvent condensate is fed by the main pump to external container filled with crystalline material. This allows a continuous controlled dissolution of material while solution formed in contained is fed therefrom to vessel crystallisation zone filled with oversaturated solution. Portion of solution is directed by extra pump from container top section via bypass line into container bottom. At crystal growing, critical mass of crystalline matter inside container is controlled. Container is continuously filled with crystalline matter at crystal growing.

EFFECT: high-quality crystals grown at simple equipment.

5 cl, 1 dwg

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