Lyophilized preparation of fat emulsions and method thereof

 

(57) Abstract:

Usage: in medicine; concerns lyophilized fat emulsion and method of its production. The inventive lyophilized preparation of fat emulsions contains the drug and lyophilizers additive from the class of disaccharides maltose; the average particle size of lyophilized for storage and fat emulsion after dilution of the drug is 10-100 nm. A method of obtaining a lyophilized preparation containing a drug is injected into the fat emulsion prior to its lyophilization maltose as liabilitiesa supplements. 2 S. p. f-crystals.

The invention relates to a lyophilized fat emulsion containing a drug and an additive from the class of disaccharides.

The invention also concerns a method of producing a lyophilized preparation containing a drug, by introducing the additive from the class of disaccharides.

It is known that the fat emulsion comprising emulsion particles, the average size of 10-100 nm, improve the distribution of drugs in the patient's blood and the mi properties (patent application Japan NE - 2-203).

Usually when getting fat emulsions made to use pre-prepared canned form, which is easy to prepare the emulsion immediately before use.

If you consider the fact that the particle size of the fat emulsions changes over time, it is preferred that these fat emulsions were obtained in the form of liofilizovannyh drugs.

Another advantage liofilizovannyh drugs is that the drugs contained in fat emulsions, obviously, will also be stable at low temperatures and in dry condition.

Has long conducted research on the development of methods of freeze-drying emulsions. For example, in the disclosure of Japanese patent application S 62-501631 describes liposomes, different from the fatty emulsions of the invention, and the disclosures of patent applications in Japan S 60-224617 and SHO 60-239417 describes liofilizovannye preparations of emulsions of the type oil-in-water, etc. Technology lyophilization fat emulsions with a particle size of 0.2 μm was investigated from different points of view, as a result it was found that the re-dissolution of the emulsion after cleaning, the particle size is considerably increased. In addition, Doblo significant effect.

Fat emulsions are a collection of low-molecular compounds in water, and lyophilization with the preservation of this complex structure presents certain difficulties.

The authors of the invention have been investigated liofilizovannye drugs fat emulsion comprising emulsion particles with an average size of 10-100 nm, however, as a result of these studies, applicants are faced with many problems associated with obtaining these liofilizovannyh drugs, for example, the dried sediments were homogeneous, pasty or sticky, and were prone to cracking, delamination, shrinkage, etc., Other serious disadvantages of these drugs was the fact that after re-dissolving emulsion there was an increase in particle size emulsion, many of which exceed 100 nm.

To obtain liofilizovannyh drugs fat emulsions usually during lyophilization attempted to use supplements. Such additives were usually monosaccharides, such as glucose, disaccharides such as trehalose, other sugars, such as sorbitol, starch, etc., an amino acid such as glycine, dextran, ethylene glycol, or derivatives thereof (see, for example, an application for patelco recovered water with the formation of emulsions of the type oil-in-water" for parenteral administration. As the carrier in this known technical solution use a variety of carbohydrates, including maltose. However, maltose here mentioned only in the enumeration of the number of possible carbohydrates and not disclosed discovered by the inventors specific property maltose to facilitate the recovery of lyophilized in the fat emulsion with a particle size of 10-100 nm.

The author of the invention with particular care was repeated studies on preparation of liofilizirovannogo preparation of fat emulsions, consisting of particles with an average size of 10-100 nm. In the course of these studies it was unexpectedly found that the introduction of maltose during retrieval fat emulsion allows all of the above problems, and accordingly, we developed the present invention.

Therefore, the essence of the invention consists in the introduction of maltose in the process of getting liofilizovannyh drugs fat emulsion comprising emulsion particles with an average size of 10-100 nm.

Usually used as additives for lyophilization use sugars and other additives specified in the previous studies, such as amino acids, however, in accordance with the present invention the effect is on, even using the instead of maltose another saccharide, or any other supplements for lyophilization. It was found that the use of glucose, trehalose, etc., gives a somewhat satisfactory results in the case when the emulsion is subjected to repeated dissolution directly after lyophilization, but such results cannot be obtained if liofilizovannye product is subjected to rapid heating. And only maltose reveals a noticeable resistance to such rapid heating. This fact was first established by the authors of the present invention.

Liofilizovannye preparations according to the invention find a slight increase in the particle size of the emulsion after re-dissolution.

Liofilizovannye preparations according to the invention is obtained from the dried filtrate in the state that are absolutely identical to their condition immediately after lyophilizate, and their recovery by adding water or etc., does not cause any change in the size of the emulsion particles. Liofilizovannye preparations of the present invention, even when a rapid heating retain their excellent stability.

According to the invention maltose can be added at any stage before lyophilization in prone dissolved in water to add during emulsification. Maltose can be added during emulsification. And finally, it can be added to the fat emulsion directly before lyophilization.

In accordance with the invention, the number of added maltose has no specific limitations. Preferably, if this amount is 1-30% (wt./vol.), and more preferably 3-15% (wt./vol.).

According to the invention maltose with a high degree of reliability can be used in medicinal drug for therapeutic treatment, for example, by intravenous, without any toxic effect.

The temperature and the degree of pressure reduction during lyophilization can be those which are usually used in the standard way. These options are preferable to regulate the properties of the medicinal product contained in the emulsion, or its lipid component. Liofilizovannye fat emulsion according to the invention can easily be subjected to re-dissolve by adding the appropriate solution. Usually, such a solution includes water for injection and physiological solution, as well as other extracts used in such cases. The amount of solution should preferably when: no added surfactants or solvents, no heating.

This effect is another advantage of the invention.

Liofilizovannye preparations according to the invention are very stable and can remain in this stable state, even when stored at room temperature conditions, and their appearance remains almost unchanged even when stored at room temperature for more than one year, and the solubility and particle size does not change after adding water or etc.

As mentioned above, the emulsion particles with an average size of from 10 to 100 nm, which is the fatty emulsion according to the invention, can be saved as a result of their introduction in reticuloendothelial system (RES). These very small emulsion particles are stored in a higher concentration of blood than fat emulsion particles with a diameter of approximately 0.2 μm, and is able without any difficulty to leave the blood vessels through areas with increased vascular permeability. It is known that blood vessels contain different parts, called porous systems (porous systems: small porous systems have a pore diameter of up to 9 nm, and large porous systems have a pore diameter of 25-70 nm, and permeable the x vessels), as well as other intracellular space (and, vascular permeability is increased in a variety of lesions, for example, inflammations, tumors, atheroma, etc.,), in which very small emulsion particles can leak from the blood vessels through the above porous system and to penetrate inside the affected tissues. And at the same time, the drug contained in these particles, also visceral lesions. Thus, the drug is easily and selectively enters the lesions, in which the concentration of drug increases, resulting in its effect. On the other hand, the permeability of the particle size of 10-100 nm or less for normal cells is insufficient due to the presence of the above-mentioned porous systems, which prevent the penetration of these fine particles from the blood vessels in normal cells. Based on the foregoing, it is obvious that the fat emulsion with an average particle size of approximately 10 to 70 nm, and in particular, with an acceptable pore size of porous systems and at the proper distribution of the particles, fat emulsion with an average particle size of priblizitelen (see patent application Japan NE 2-203).

Suitable lipids for use in fat emulsions according to the invention are simple lipids, derived from animal vegetable or mineral lipids, lipid compounds and their mixtures. In particular, these lipids can be lipids, referred to in the examples, as well as, for example, lipids disclosed in the description of Japanese patent application NO 2-203.

Using liofilizovannyh preparations according to the invention can be easily introduced even those drugs that are unstable in vivo. In the emulsion according to the invention, the drug is in the oil droplets of lipids, i.e., in a state protected from the environment, and thus it is not subjected to enzymatic or nonenzymatic decomposition.

Medicines that can be applied liofilizovannye preparations according to the invention have no particular restrictions. Such means can be, for example, anti-inflammatory agents, analgesics, anti-allergic medicines, antibiotics, chemotherapeutic antineoplastic agents, antiviral agents, anti-atherosclerosis, gipolipidemicheskih, hypnotics, tranquilizers, local anasthesiologie means, fat-soluble vitamins, diagnostic reagents, etc., Examples of these tools can serve as mitomycin C and its derivatives, such as ancitabine, fluorouracil, farnesylated of mitomycin C, nonelectrolytic With, cholesteryloxycarbonyl With, farnesylacetone of mitomycin C, etc., derivatives of citarabinom, such as carmofur, futraful palmitate, 5-fluorouracil myristate, adriamycin, daunomycin, aclarubicin hydrochloride, aclarubicin, vinblastine, vincristin, esters of fatty acids tsitarabina, etc., antineoplastic agents, such as mitotane, estramustin, etc. antiviral agents, such as dicloflame, etc., steroids such as dexamethasone palmitate, hydrocortisone palmitate, prednisolone palmitate, dexamethasone stearate, methylprednisolone, paramethasone, fluoqinolona acetonide, betamethasone propionate, esters of fatty acids hydrocortisone, aldosterone, spironolactone, etc., and non-steroidal drugs, such as ibuprofen, flutamida acid, Ketoprofen, phenacetin, phenazone, aminopyrine, phenylbutazone indolacetic derived biganimalmovies acid, indomethacin, ethoxycarbonylmethylene Lysiloma acid and its derivatives. Can also be used analgesic agents such as tranilast, ketotifen, azelastine, etc. Suitable for use with antibiotics and chemotherapeutically means are tetracycline, erythromycin, midecamycin, amphotericin b and related compounds, minocycline, miconazole, etc., Examples of prostaglandins are PGE1, PGA1, alkalemia esters of PGA1, alkalemia esters of PGE1, PGE1derivatives PG12-derivatives, PGD derivatives, etc. as antihistamines can be used diphenylhydramine, orphenadrine, chlorphenoxamine, chlorpheniramine, promethazine, meclizine, cyproheptadine at, roksatidina acetate, etc. as local analiziruemykh funds can be used lidocaine, benzocaine, dantrolene, cocaine, tetracaine, piperocaine, mepivacain, etc., or their derivatives. Suitable hepaticelevations agents are, for example, malotilate, glycyrrhetic acid, ETHYLACETYLENE, methylglucamine, etc. as appropriate antiulcer agents are, for example, farnesol, geraniol, gefarnate, teprenone, plaunotol, sofalcone, etc., as agents of the Central nervous system can be used, for example, fenon, methaphetamine, imipramine, chlorimipramine, amitriptyline, mianserin, trimethadione, phensuximide, tetrabenazine, benchenane, camphor, dimenformon, strychnine, chlorpromazine, promethazine, prochlorperazine, mequitazine, triflupromazine, levomepromazine, difenidol, etc., or their derivatives.

Examples bronchodilators can be bestriding and other theophyllinate derivatives, methylephedrine, etc. Can also be used cholinergic blocking means, for example, benztropine, physostigmine, atropine, scopolamine, etc., cholinergic blockers, such as oxyphencyclimine, pirenzepine, atomically etc. blockers calcium, such as diltiazem, nifedipine, verapamil, etc. blocking means, for example, dibenzepin, phenoxybenzamine, etc. remedies against cough, such as noscapine, dextromethorphan, pentoxyverine, benproperine, etc., a therapeutic agent for the treatment of benign prostatic hyperplasia, such as gastrin, oxendolone, etc., a therapeutic agent for the treatment of glaucoma, such as pilocarpine, etc., means that activates the smooth muscles such as sparteine, papaverine, etc., a therapeutic agent for the treatment of hyperlipemia, such as clofibrate, simfibrate, probalitily, dilazep hydrochloride, ubidecarenone, flavoxate, cyclopropyl And vaccines such as influenza vaccine; divination, diphenylpyraline, genovali, mutation, tofisopam, lemon, etc. as fat-soluble vitamins can be used vitamin a and its derivatives, vitamin E and its derivatives, vitamin K and its derivatives, vitamin D and its derivatives, etc.

As an additional possibility is the use of gasolinevin and essential oils from raw material medicines, such as oil, apricot seed, fenceline oil, thyme oil, turpentine oil, eucalyptus oil, palm oil, poppy seed oil, Camellia oil, etc.

Examples of diagnostic reagents are compounds labeled with radioactive isotopes, radioactive drugs, iodirovannoye esters poppy oil fatty acid or a contrast medium containing radioactive iodine, etc.

For the purposes of the present invention can be used for virtually any medicinal product, although judging from the properties of the fat emulsion according to the invention is provided by the size of the particles, it is preferable to apply Clennam on vascular or immune system.

According to the invention the concentration of the drug in the emulsion can be adjusted accordingly, based on the biological activity of the drug. In addition, can be done in a proper correction of the concentration of the components of the emulsion in the emulsion preparations according to the invention, as well as medications.

To obtain liofilizovannyh preparations according to the invention may be used various known methods for producing fatty emulsions commonly used for such purposes. For example, these drugs can be obtained by the method in which all components, including medicine, fully emulsified in a homogenizer (Manton-Gauline, microfluidizer, an ultrasonic homogenizer or similar device; or a method in which all components solubilizing using surfactants (e.g., bile acid), a water-soluble solvent (e.g., ethanol, polyethylene, polyethylene glycol, etc.,), after which the surface-active substance, a water-soluble solvent, etc. is removed by dialysis gelfiltration, etc. can be added emulsifying additives in the form of a LM is a description, add drug.

The shape and the particle size of the fat emulsion according to the invention can be easily confirmed with an electron microscope, particle size analyzer with a light-diffusing device, membrane filter, etc.,

The fat emulsion according to the invention may contain the necessary auxiliary substances and additives that are commonly used in injections. For example, such additives can be antioxidants, antiseptics, stabilizers, isotonic agents, buffers, etc. Required and the optimal amount of these additives may vary depending on the purpose of use.

For lyophilization fat emulsions according to the invention, containing maltose, can be used already known technology. For example, the fat emulsion is placed in a 20 mm glass vessels (the height of the solution in the vessel is approximately 15 mm). According to the program emulsion lyophilized at temperatures from -40 to 30oC for a time period of about 15 hours (rigidity vacuum of about 0.2 Torr). The vessel was filled with nitrogen gas, and after the completion of the procedures for obtaining liofilizovannyh drugs vessels were sealed.

For more nagrania and the test results obtained drugs.

Example 1. 3 g of dexamethasone palmitate, 50 g of purified soybean oil and 20 g of purified egg yolk lecithin were mixed by heating the mixture at about 60oC, and then to the mixture was added as lyophilization additive aqueous solution of maltose, which contained 10% maltose, and the resulting mixture was stirred at gammexane to obtain the original emulsion solution. This emulsion solution was subjected to emulsification under pressure by using a homogenizer (Manton Ganline, resulting in the obtained emulsion containing emulsion particle size of 10-100 nm. This was followed by lyophilization in a standard way.

The condition of the dried sediment was very satisfactory, without any noticeable defects or shrinkage.

After adding to this draught of water for injection to restore emulsion dissolving the precipitate was achieved very quickly and completely, and without any noticeable changes in the size of emulsion particles after dissolution, indicating full recovery of the emulsion.

Example 2. 30 g of nifedipine, 0.6 g of purified soybean oil and 0.5 g of purified egg yolk lecithin were mixed and dissolved in 100 ml of rastvoritelya under reduced pressure. Then to the mixture was added 8 ml of 5% aqueous solution of maltose, followed by stirring in a homogenizer, resulting in a received original emulsion solution. To obtain a constant volume of 10 ml was added an additional amount of 5% aqueous solution of maltose, after which the mixture was subjected to emulsification using an ultrasonic homogenizer (Branson Model 185) for 60 min, cooling at this ice, and resulted emulsion containing emulsion particle size of 10-100 nm. Then the procedure of freeze drying was carried out in a standard way. The condition of the dried sediment was assessed as very good without any defects or shrinkage. In addition, after adding to it a draught of water for injection in order to restore the emulsion was achieved very quickly complete dissolution and at the same time without any noticeable changes in the size of emulsion particles after dissolution, indicating full recovery of the emulsion.

Example 3. 30 g of amphotericin b, 5 g of purified soybean oil and 5 g of purified egg yolk lecithin were mixed for homogenization using a mortar, and then added 10 g of maltose and continued stirring. To the resulting solution d the th received the original emulsion solution. Then up to a constant volume of 100 ml was added an additional amount of water for injection, after which the mixture was subjected to emulsification using multiplicator, cooling with this ice, and resulted emulsion containing emulsion particle size of 10-100 nm. Then the procedure of freeze drying was performed in a standard way. The condition of the dried sediment was assessed as very good, without any unwanted cracks, defects or shrinkage. In addition, after adding to it a draught of water for injection to recovery very quickly achieved complete dissolution and at the same time without any noticeable change of the particle size of the emulsion after dilution, indicating full recovery of the emulsion.

Example 4. 2 g of miconazole, 20 g of purified soybean oil and 30 g of purified egg yolk lecithin were mixed under heating at 60oC, after which the mixture to a final volume of 100 ml was added 20% aqueous solution of maltose, after which the mixture was subjected to emulsification using a homogenizer and received in the original emulsion solution. This solution was emulsiable using microfluidizer under pressure, resulting in CEG ulali standard way. The condition of the dried sediment was assessed as good, without any defects or shrinkage. In addition, after adding to it a draught of water for injection to recovery very quickly achieved rapid dissolution and was not observed any changes in the size of the emulsion particles after dissolution, indicating full recovery of the emulsion.

Example 5. 1 mg of cyclosporine A, 0.5 g cholesterol oleate and 0.5 g of purified egg yolk lecithin were mixed and dissolved in 10 ml of a mixture of chloroform and methanol (1/1, by volume), after which the solvent was completely removed using a rotary evaporator under reduced pressure. Then to the mixture was added 8 ml of 5% aqueous solution of maltose and stirred using a homogenizer, resulting in a received original emulsion solution. After this was added an additional amount of 5% aqueous solution of maltose to a constant volume of 100 ml and the resulting mixture was subjected to emulsification using an ultrasonic homogenizer (Branson Model 185) for 60 min, resulting in the obtained emulsion containing particles of a size of 10-100 nm. Then the procedure of freeze drying was carried out in a standard way. Solderable to this draught of water for injection to recovery very quickly achieved complete dissolution and was not observed any changes in the size of the emulsion particles after dissolution, that suggests that the emulsion can be fully restored.

Example 6. 3 mg of amphotericin b, 0.5 g of purified soybean oil, 0.4 g of purified egg yolk lecithin and 0.1 g of dimyristoylphosphatidylcholine were mixed and dissolved in 100 ml of a mixture of chloroform and methanol (1/1, by volume), after which the solvent was completely removed using a rotary evaporator under reduced pressure. Then to the mixture was added 8 ml of 0.1% saline solution followed by stirring using a homogenizer, resulting in a received original emulsion solution. The resulting mixture was subjected to emulsification using an ultrasonic homogenizer (Branson Model 185) for 60 min, resulting in the obtained emulsion comprising emulsion particles with a size of 10 to 100 nm. To this emulsion was added 1 g of maltose to dissolve, and then add water to a final volume of 10 ml lyophilization Procedure was carried out in a standard way. The condition of the dried residue was evaluated as very good, without any cracks, grooves or shrinkage. In addition, after adding to it a draught of water for injection to recovery very quickly achieved complete dissolution and not nabludatyelnii emulsion.

Example 7. 3 mg nonelectrolytic, 0.5 g of purified soybean oil, 0.4 g of hydrogenated egg yolk lecithin and 0.1 g of cholesterol were mixed and dissolved in 100 ml of a mixture of chloroform and methanol (1/1, by volume), after which the solvent was completely removed under reduced pressure using a rotary evaporator. Then to the mixture was added 5 ml of a 20% aqueous solution of maltose, followed by stirring using a homogenizer, resulting in a received original emulsion solution. To this solution was added an additional amount of 20% aqueous solution of maltose to a final volume of 10 ml, after which the mixture was subjected to emulsification using an ultrasonic homogenizer (Branson Model 185) for 60 min, and was obtained by emulsion containing particles of a size of 10-100 nm. The lyophilization was carried out in a standard way. The condition of the dried residue was evaluated as very good without any defects or shrinkage. In addition, after adding to it a draught of water for injections in order to restore it very quickly achieved complete dissolution and was not observed any changes in the size of the emulsion particles after dissolution, video of egg yolk lecithin were mixed and stirred, after which was added 500 ml of an aqueous solution of maltose containing 10% maltose as lyophilization additives and the mixture was stirred using homemaker, resulting in a received original emulsion solution. This solution was subjected to emulsification under pressure by using a homogenizer (Manton Gauline, and received in the emulsion, consisting of particles with a size of 10-100 nm. The lyophilization of the emulsion was carried out in a standard way. The condition of the dried residue was evaluated as very good, without any defects or shrinkage. In addition, after adding to it a draught of water for injection in order to restore the dissolution was achieved very quickly and was not observed any changes in the size of the emulsion particles after dissolution, indicating full recovery of the emulsion.

Test results

Fat emulsion with an average particle size of 35 nm, which were obtained using water for injection and contained 5% of purified soybean oil and 5% purified egg yolk lecithin were completely dissolved by adding various additives listed below, after which they were liofilizovane standard way. Below depict the military their heating or storage at 40oC for 1 month; the results of the evaluation of solubility obtained by adding water for injection; and the results of measurement of particle sizes.

Maltose (10%)

Immediately after receiving the

Appearance: very good. There are no cracks, gouges, shrinkage or insoluble lumps.

Solubility: when mixing by shaking manually observed full recovery of the emulsion in a few seconds.

The average portion size: 35 nm (unchanged).

After accelerated heat

Appearance: very good. There are no cracks, gouges, shrinkage, adhesion or insoluble lumps.

Solubility: completely restored by shaking manually for a few seconds.

Average particle size: 35 nm (no change).

Sucrose (10%)

Immediately after receiving the

Appearance: quite good, shrinkage, adhesion or so on, are missing.

Solubility: completely restored when shaken by hand for 20 or 30 seconds

Average particle size: 40 nm (no significant changes)

After accelerated heat

Appearance: a small shrinkage.

Trehalose (10%)

Immediately after receiving the

Appearance: quite good, shrinkage, adhesion or so on, are missing.

Solubility: completely restored when shaken by hand for 20 or 30 seconds

Average particle size: 38 nm (almost unchanged).

After accelerated heat

Appearance: a small shrinkage.

Solubility: not very good. Dissolves within a few minutes with shaking hand.

Average particle size: 160-180 nm.

Lactose (10%)

Immediately after receiving the

Appearance: quite good, shrinkage, adhesion or so on, are missing.

Solubility: dissolves completely, even when shaken by hand for 20 or 30 minutes the Solution is very muddy.

Average particle size: not less than 200 nm.

Glucose (5%)

Immediately after receiving the

Appearance: quite good, shrinkage, adhesion or so on, are missing.

Solubility: completely soluble, is restored within 20 or 30 min with shaking hand.

Average particle size: 42 nm (without major changes) after accelerated heat.

Appearance: significant at the. The solution turbid.

Average particle size: not less than 200 nm.

Mannitol (5%)

Immediately after receiving the

Appearance: it has been observed shrinkage and cracking. Solubility: soluble not completely even when shaken by hand for 20 or 30 minutes the Solution is very muddy.

Average particle size: not less than 200 nm.

Fructose (5%)

Immediately after receiving the

Appearance: it has been observed shrinkage and cracking.

Solubility: soluble not completely even when shaken by hand for 20 or 30 minutes the Solution is very muddy.

Average particle size: not less than 200 nm.

Sorbitol (5%)

Immediately after receiving the

Appearance: there was considerable shrinkage, cracking and adhesion.

Solubility: soluble not completely even when shaken by hand for 20 or 30 minutes, the solution is very muddy.

Average particle size: not measured (increasing the size too much).

L-arginine (2%)

Immediately after receiving the

Appearance: quite good, shrinkage, adhesion or etc., were observed.

Solubility: dissolved not completely even with shaking for 20 or 30 minutes the Solution is teaching

Appearance: it has been observed shrinkage and cracking.

Solubility: soluble not completely even when shaken by hand for 20 or 30 minutes the Solution is very muddy.

Average particle size: not less than 200 nm.

Glycine (2%)

Immediately after receiving the

Appearance: there was considerable shrinkage, cracking and adhesion.

Solubility: soluble not completely even when shaken by hand for 20 or 30 minutes the Solution was very muddy.

Average particle size: not less than 200 nm.

DL valine (2%)

Immediately after receiving the

Appearance: quite good, shrinkage, adhesion or etc., were observed.

Solubility: dissolved not completely even when shaken by hand for 20 or 30 minutes the Solution was very muddy.

Average particle size: not less than 200 nm.

DL-alanine (2%)

Immediately after receipt:

Appearance: quite good, shrinkage, adhesion, or etc., were observed.

Solubility: dissolved not completely even when shaken by hand for 20 or 30 minutes the Solution was very muddy

Average particle size: not less than 200 nm.

DL asparagine (2%)

Immediately after poet: was not completely dissolved even when shaken by hand for 20 or 30 minutes The solution was very muddy.

Average particle size: not less than 200 nm.

Low molecular weight dextran (0,5%)

Immediately after receiving the

Appearance: fairly good adhesion, shrinkage, or etc., were observed.

Solubility: dissolved not completely even when shaken by hand for 20 or 30 minutes the Solution was very muddy.

Average particle size: not measured (increasing the size too much).

High molecular weight dextran (0,5%)

Immediately after receiving the

Appearance: fairly good adhesion, shrinkage, or etc., were observed.

Solubility: dissolved not completely even when shaken by hand for 20 or 30 minutes the Solution was very muddy.

Average particle size: not measured (increasing the size too much).

Polyethylene glycol 6000 (1%)

Appearance: there was considerable shrinkage, cracking and adhesion.

Solubility: dissolved not completely even when shaken by hand for 20 or 30 minutes the Solution was very muddy.

Average particle size: not measured (increasing the size too much).

Starch (1%)

Appearance: good enough is Ivanyi manually for 20 or 30 minutes. The solution was very muddy.

Average particle size: not measured (increasing the size too much).

Hydroxypropylcellulose (1%)

Appearance: there was considerable shrinkage, cracking and adhesion.

Solubility: dissolved not completely even when shaken by hand for 20 or 30 minutes the Solution was very muddy.

Average particle size: not measured (increasing the size too much).

Polyvinylpyrrolidone (1%)

Appearance: there was considerable shrinkage, cracking and adhesion.

Solubility: dissolved not completely even when shaken by hand for 20 or 30 minutes the Solution was very muddy.

The average particle size (measured too large increase in size).

Albumin (1%)

Appearance: quite good, shrinkage adhesion or etc., were observed.

Solubility: not a complete dissolution even when shaken by hand for 20 or 30 minutes the Solution was very muddy.

Average particle size: not measured (too much increase in size).

The hypromellose (1%)

Appearance: significant shrinkage, cracking and edgeserver was very muddy.

Average particle size: not measured (too much increase in size).

Methyl cellulose (1%)

Appearance: there was considerable shrinkage, cracking and adhesion.

Solubility: not a complete dissolution even when shaken by hand for 20 or 30 minutes the Solution was very muddy.

Average particle size: not measured (too much increase in size).

Sodium carboxymethylcellulose (1%)

Appearance: quite good, shrinkage, adhesion or etc., were observed.

Solubility: not a complete dissolution even when shaken by hand for 20 or 30 minutes the Solution was very muddy.

Average particle size: not measured (too much increase in size).

Polyvinyl alcohol (1%)

Appearance: significant shrinkage, cracking and adhesion.

Solubility: dissolved not completely even when shaken by hand for 20 or 30 minutes the Solution was very muddy.

Average particle size: not measured (too much increase in size).

Glycerin (0.24 M)

Appearance: significant shrinkage, pasty appearance.

Solubility: dissolved not completely even was measured (too much increase in size).

Sodium chloride 0.15 M

Appearance: significant shrinkage, pasty appearance.

Solubility: dissolved not completely even when shaken by hand for 20 or 30 minutes. The solution was very muddy.

Average particle size: not measured (too much increase in size).

1. Dried product fat emulsion containing a drug and an additive from the class of disaccharides, characterized in that the preparation contains maltose as liabilitiesa additives, and the average particle size of lyophilized for storage and fat emulsion after dilution of the drug is 10 to 100 nm.

2. A method of obtaining a lyophilized preparation containing a drug, by introducing the additive from the class of disaccharides, characterized in that the fat emulsion prior to its lyophilization enter maltose as liabilitiesa additives, and the average particle size of lyophilized for storage and fat emulsion after dilution of the drug is 10 to 100 nm.

 

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SUBSTANCE: abnormally corpulent persons are treated by reduced-caloricity diet with limited content of carbohydrate-containing components and fats. In particular, caloricity of meal is reduced to 1200 kcal, including carbohydrate-containing components with glycemic index below 40. When initial weight is reduced by 5% and the weight is stabilized for 3 months, caloricity is increased to a specified value, calculated in terms of formula for daily caloricity recommended by World Health Organization taking into account sex, age, weight, and physical activity, glycemic index of carbohydrate-containing components ranging from 40 to 69 until the weight is lowered to desired level.

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3 tbl

Phospholipid gel // 2261088

FIELD: cosmetics, pharmacy.

SUBSTANCE: invention relates to a phospholipid gel stabilized against dilution by addition of tetra-, penta- or hexa-atomic alcohol and/or sugar, and to a method for it preparing. Gel is useful for making cosmetic or pharmaceutical compositions. Invention provides preparing a phospholipid gel showing the higher stability in applying on skin as compared with known phospholipid gels, and also in the presence of a medicinal agent, buffer or salt added to this gel.

EFFECT: improved and valuable properties of gel.

25 cl, 4 tbl, 4 dwg, 5 ex

FIELD: pharmacology.

SUBSTANCE: according to the present invention pharmacological composition is in form of quick soluble granules, containing particles of at least two different carrier materials with surface being at least partially coated with at least one layer, comprising 50-120 wt.pts, preferably, 60-100 wt.pts of at least one active ingredient based on 100 wt.pts of carrier material. Active ingredient is preferably insoluble or low soluble substance such as amino acids or antioxidants. The first carrier material comprises about 50-80 wt.% of total carrier material and has bulk density of 58-100 g/ml, preferably of 63-90 g/100 ml. The second carrier material has bulk density of 30-55 g/100 ml, preferably of 33-50 g/100 ml. Granulated composition has high solubility, high content of active ingredient and little amount of excipients. Further composition is quickly suspended in little amount of water, doesn't form agglomerates for a long time, ant has acceptable taste.

EFFECT: pharmacological composition in form of quick soluble granules with improved quality.

22 cl, 4 tbl, 5 ex

FIELD: medicine, pharmacy.

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

EFFECT: improved and valuable properties of composition.

10 cl, 4 tbl, 14 ex

FIELD: pharmaceutical technology, pharmacy.

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

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

30 cl, 12 tbl, 28 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention relates to parantheral composition based on oil-covered amphothericin B in form of structured emulsion containing a) oil phase (up to 30 mass/vol %), selected from vegetable oil group such as soy oil, sesame oil, safflower oil; b) amphothericin B (0.05-1 mass/vol %), dispersed in oil phase; c) water of aqueous phase; d) modified agent such as glycerol, mannitol, dextrose, dissolved in aqueous phase; and e) emulsifier, such as natural phosphatides (up to 3 mass/vol %) dispersed in aqueous phase. Composition of present invention allows achievement LD50 not less than 400 mg/kg in one dose administration and not less than 40 mg/kg in repeated administration in mice. Method for production of said composition also is disclosed.

EFFECT: parantheral composition of improved effectiveness.

14 cl, 11 ex, 15 dwg, 20 tbl

FIELD: medicine, oncology, pharmacology.

SUBSTANCE: invention relates to methods for preparing biologically active substances. Method for preparing a photosensitizer involves treatment of spirulina preliminary dried by lyophilization method in methanol for preparing a precipitate containing chlorin e6 followed by its washing out, suspending and repeated centrifugation. Prepared precipitate is dissolved in aqueous solution of N-methyl-D-glucamine, pH value is brought about to 7.75-8.20, then 510-520 ml of apyrogenic water is added to obtain the optical density of solution 200-210 U at 654 nm and pH = 9.0 followed by filtration of solution through filter with pores size 0.22 mmc and polyvinylpyrrolidone of molecular mass from 9600 to 11500 Da is added. Prepared photosensitizer for photodynamic therapy comprises chlorin e6 in the amount 98%, not less, N-methyl-D-glucamine in the mole ratio = 1:2 and polyvinylpyrrolidone of molecular mass from 9600 to 11500 Da wherein chlorin e6 has the following structural formula: . Invention provides the development of a new medicinal formulation possessing the more effective therapeutic properties for treatment of different oncological diseases by methods of photodynamic therapy based on the higher content of chlorin e6. Invention can be used for preparing a water-soluble form of highly purified chlorin e6 that can be used as a photosensitizer in photodynamic therapy of cancer and other neoplasm of different genesis.

EFFECT: improved preparing method, valuable medicinal properties of agent.

5 cl, 8 dwg, 3 ex

FIELD: pharmaceutical and food industries.

SUBSTANCE: invention relates to preparing water-soluble or water-dispersible carbohydrate-based powders and tablets. Carbohydrate matrix is composed of at least 90% carbohydrate, e.g. starch or sugar. Closed-porosity powder or tablet is treated with gas so that gas contained in pores enhances dissolution or dispersing when in contact with water. Gas can be selected from nitrogen, carbon dioxide, air, oxygen, helium, hydrogen, argon, neon, methane, ethane, krypton, chlorine, chlorofluorocarbon, and mixture thereof. Gas is forced preferably under pressure at temperature above Tg of carbohydrate. Powder or tablet can further contain protein, hydrocolloid, or fat and forms no foam on dissolution or dispersing.

EFFECT: improved consumer's property of powders and tablets.

35 cl, 1 dwg, 2 tbl, 5 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a hydrophilic pharmaceutical composition with hypoglycemic effect comprising nateglinide crystals of B-type as an active component. The composition has edge angle to water surface 111 degrees or less. This edge angle is created by addition at least one hydrophilic substance to the composition chosen from groups comprising of hydrophilic polymers, surfactants, sugars and sugar-alcohols. Invention provides easy method for preparing the composition, its high solubility and rather rapid release of nateglinide.

EFFECT: improved and valuable properties of pharmaceutical composition.

13 cl, 8 dwg, 4 tbl, 6 ex

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