Pharmaceutical composition containing docosahexaenoic acid ester for parenteral administration
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to pharmaceutics and represents a pharmaceutical composition for parenteral administration containing sub-micron particles of dosocahexaenoic acid ester dispersed in a water phase with the use of mixture of at least two surfactants specified in a) at least one fatty acid polyoxyethylene ester and b) at least one phospholipide derivative, as well as a method for preparing the above pharmaceutical composition.
EFFECT: invention provides higher pharmacological activity.
14 cl, 3 dwg, 3 tbl, 2 ex
The invention relates to pharmaceutical compositions for parenteral administration comprising an ester of docosahexaenoic acid.
Omega-3 fatty acids are polyunsaturated fatty acids, in particular, found in algae, oily fish (salmon, mackerel, sardines, tuna), rapeseed, walnut, soy, etc. As a General rule, the classification of fatty acids CH3-(CH2)n-COOH based on the carbon chain length (short for n=2-4, the average for n=6-8 and long for n≥10), the number of double bonds (unsaturated, mono - or polyunsaturated) and position of double bonds from the carbon atom in the carboxyl group. System using the notation ω specifies the length of the carbon chain, the number of double bonds and the position of the nearest double bond to the ω-carbon atom, starting from the specified ω-carbon atom, which is by definition the last carbon atom in the chain, the most remote from the carboxyl group.
The main fatty acids to ω-3 group are:
- linolenic acid 18:3(9, 12, 15)or agribusiness;
- eicosapentaenoic acid 20:5 (5, 8, 11, 14, 17) or EPA;
- docosahexaenoic acid 22:6 (4, 7, 10, 13, 16, 19) or DHA omega-3 fatty acids provide numerous beneficial effects for human health.
In the publication WO 01/46115 A1 summarizes the beneficial effects of the diet, the OS is consistent fish oil, rich in EPA and DHA, to reduce strokes and heart attacks. Parenteral form EPA and DNA mentioned in this publication in the form of suspension of globular particles obtained using methods well known to experts in the art, for example, by breeding non-ionic surface-active agent (surfactant) in water, heat it and add ester of DHA and EPA. In this application also describes emulsions intended for intravenous administration containing soybean oil and triglycerides, by quoting the publication on page 8, line 2 (Billman et al. 1997 Lipids 32 1161-1168).
However, using this method, it is difficult to obtain a stable parenteral preparations, ready to use, or to restore using freeze-dried form, where the average particle size is less than 100 nm, to include a large amount of the active ingredient and does not contain excessively high proportion of surfactant, which may be toxic with long-term use.
From DHA esters of nicotinic ether or pyridine-3-ylmethyl-CIS-4,7,10,13,16,19-docosahexaenoic acid is an ester, which represents a significant therapeutic interest.
The structural formula of nicotinic ester DNA or pyridine-3-ylmethyl-CIS-4,7,10,13,16,19-docosahexaenoic acid is shown below:
Molecular weight is 419,60 g, which corresponds to C28H37NO2.
This compound is highly lipophilic (Log P of about 7), where the solubility at equilibrium in water is <1 μg/ml Therefore, it is especially difficult to include in the preparation for parenteral administration.
The following DHA ester of particular interest is pantalony ester of DHA, otherwise known as antininjamovement, in particular, pantalony monoether EGK, 2,4-dihydroxy-3,3-dimethylbutylamino)papillomata-4,7,10,13,16,19-hexanoate having the following formula:
or any of its pharmaceutically acceptable salts, enantiomers, diastereoisomers or mixtures thereof, including racemic mixtures.
More specifically, this ester can be pantalony monoether DHA, having the following formula:
otherwise known as "D-pantalony ether DGK".
These esters are very effective, for example, in the treatment of atrial fibrillation, as described in WO 2007/147899. They act as a prodrug, releasing DHA in the body after hydrolysis.
In the present invention, the term "enantiomers" refers to optical isomeric compounds that have identical molecular formulas but differ in their question is rastenii configuration and which are not overlapping each other mirroring. The term "diastereoisomer" refers to isomers that are not mirror images of each other.
In accordance with the present invention a "racemic mixture" is a mixture of equal proportions levogyrate and programada enantiomers of chiral molecules.
In the present invention, the term "pharmaceutically acceptable" or "acceptable in respect of the pharmaceutical industry" refers to the fact that is suitable for use in preparation of pharmaceutical compositions, generally safe, non-toxic and is not biological or otherwise against unwanted and acceptable both for veterinary and medical pharmaceutical applications.
The term "pharmaceutically acceptable salt" refers to salts that are pharmaceutically acceptable, as defined in this application, and which possess the desired pharmacological activity of the parent compounds. Such salts include:
(1) salt accession acid formed with mineral acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, benzolsulfonat acid, benzoic acid, camphorsulfonic acid, citric acid, econsultation, fumaric acid, glucoheptonate acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonate acid, Mukanova acid, 2-naphthalenesulfonate acid, propionic acid, salicylic acid, succinic acid, Dibenzoyl-L-tartaric acid, tartaric acid, para-toluensulfonate acid, trimethylhexane acid, triperoxonane acid and the like; or
(2) salts formed when a proton acid, present in the parent compound either is replaced by a metal ion, for example, alkali metal ion, alkali earth metal ion or an aluminum ion; or combined with organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
Preferred pharmaceutically acceptable salts are salts formed from hydrochloric acid, triperoxonane acid, Dibenzoyl-L-tartaric acid and phosphoric acid.
It should be understood that any references to the pharmacy the automatic acceptable salts include forms accession solvent (solvate) or crystal forms (polymorphs), as defined in this application, the same salt accession acid.
The inventors have unexpectedly discovered that it is possible to obtain a composition comprising the ester of DHA, for parenteral administration, using a combination of two types of surfactants, polyoxyethylene ether fatty acids and derived phospholipid.
The present invention thus relates to a pharmaceutical composition for parenteral administration comprising submicron particles of ester of docosahexaenoic acid, dispersed in the aqueous phase using a mixture of at least two surfactants selected from at least one polyoxyethylene fatty acid ester and (b) at least one derived phospholipid.
In accordance with one form of the invention, the composition contains only two types of surfactants a) and b) as a surfactant.
Ester of docosahexaenoic acid may be of any type. He may, in particular, to represent ethyl ester or ether with vitamin b, as described in the publication WO 2007/147899.
In some forms of the invention it is a nicotinic ester of DHA, i.e. pyridine-3-ylmethyl-CIS-4,7,10,13,16,19-docosahexaenoic acid, or pantalony ester of DHA, in particular pantalony the DHA ester of 2,4-dihydroxy-3,3-dimethylbutyramide docosa-4,7,10,13,16,19-hexanoate, and, more specifically, D-pantalony ester of DHA, which are particularly difficult to include in the preparation for parenteral administration.
In one form of the invention, the concentration of ester of docosahexaenoic acid greater than or equal to 10 mg/ml, for example greater than or equal to 30 mg/ml
The first surfactant (a) belongs to a group polyoxyethylenated esters of fatty acids. Polyoxyethylene esters of fatty acids can be obtained through the interaction between fatty acid and ethylene oxide or polyethylene glycol.
In particular, Polyoxyethylene esters of fatty acids in accordance with the invention have the following formula (1) or (2):
(1) RCOO.(O. CH2CH2)nH
(2) R1COO.(O. CH2CH2)nCOOR2,
where R, R1and R2independently of one another represent alkyl or alkenylphenol the original fatty acids and n defines the length of the polymer chain from oxyethylene structural links. For example, n is from 10 to 60, for example, from 12 to 20, for example, 15.
The fatty acid may be saturated or unsaturated. It is gidroksilirovanii. The most common saturated fatty acids are the following:
|Trivial name||Name range is ur IUPAC||Chemical structure||Reduction||Melting point (°C)|
|Myristic||tetradecanoate acid||CH3 2)12COOH||C14:0||58,8|
Accordingly, R, R1or R2represents, for example, alkyl or alkenylphenol chain, such as alkyl, normal or did the run, for example normal, With3-C23for example, in C11-C23for example, C15-C21for example, the fatty acid is a long chain saturated fatty acid, that is, having more than 16 carbon atoms.
In one form of the fatty acid has from 12 to 24 carbon atoms, for example, from 14 to 22 carbon atoms, for example, from 16 to 20 carbon atoms, for example, it has 18 carbon atoms, for example, it is a stearic acid.
The ester may be a mono - or fluids fatty acids, or their mixture. In one form of the invention it is a mixture of mono - or diapir fatty acids. For example, polyoxyethylene the fatty acid ester is a macrogol-15 hydroxystearate (trade name: SOLUTOL HS15, manufacturer: BASF, Ludwigshafen, Germany). He is a non-ionic solubilizers agent essentially consisting of monoamino and diesters of 12-hydroxystearate acid and microhollow obtained by amoxilonline 12-hydroxystearate acid. The number of moles of ethylene oxide, interacting with one mole of 12-hydroxystearate acid, is 15. It is in the form of a yellowish waxy mass, very soluble in water.
In particular, polyoxyethylene esters of fatty acids suitable for use in the volume of us who Otsego of the invention, are non-ionic surfactants.
The second surfactant (b) belongs to the group of derivatives of phospholipids: it may, therefore, consist of lecithins of natural origin, such as, for example, lecithin soy, or eggs, phospholipids of natural origin, such as, for example, phospholipids, soy or eggs, or synthetic phospholipid, or mixtures thereof. For example, it may consist of neutral phospholipids, such as phosphatidylcholine, such as, for example, 1,2-dimyristoylphosphatidylcholine or 1-Palmitoyl-2-yearposition, and phosphatidylethanolamine, such as phosphatidylcholine; negatively charged phospholipids, such as phosphatidylglycerol, such as, for example, 1,2-dimyristoylphosphatidylcholine, phosphatidylserine, phosphatidylinositol and phosphatidic acid, such as phosphatidylglycerol; or mixtures thereof. For example, it may consist of a neutral phospholipid, such as phosphatidylcholine, or it may consist of a mixture of neutral phospholipid and negatively charged phospholipids such as 1-Palmitoyl-2-oleoylethanolamide and 1,2-dimyristoylphosphatidylcholine.
In a mixture of neutral phospholipid and the negatively charged phospholipid mass percentage of negatively charged phospholipids relative to the total weight of the composition of the mixture is what the Eney 10%, from 1% to 5%, for example, equal to 3%.
It may also consist of a mixture of lecithin natural origin with negatively charged phospholipid, in particular lecithin are chicken eggs 1,2-dimyristoylphosphatidylcholine.
The mass ratio of surfactant: surfactant (b) may be from 1:3 to 3:1, for example, it is equal to 1:1.
Derivatives of phospholipids have the General structure shown in Fig.1.
In one form of the invention derived phospholipid contains no soy lecithin or soy phospholipids.
In one form of implementation of the submicron particles are submicron particles, such as mixed micelles or vesicles, or hybrids micellar or vesicular structures.
Mixed micelle in accordance with the invention is a micelle, for example, a unit consisting of a mixture of two different types of surfactants (a) and (b), where the hydrophilic polar head of the molecule surfactants is located towards the aqueous phase and the hydrophobic chain is directed outward, in interaction with a complex ester of DHA.
The vesicles in accordance with the invention is a structure in which the surfactants are organized according to bisloinoi configuration identical to that which is found in cell membranes. These surfactants surround vacuole or water strips the ü.
Hybrid micellar and vesicular structures in accordance with the invention represents an intermediate structure between the mixed micelle and vesicles, not necessarily when the existence of a specified vacuoles.
Thus, for example, the composition in accordance with the invention is a dispersion of mixed micelles or vesicles, or hybrids micellar and vesicular structures. For example, these particles exhibit a surface flat fracture under an electron microscope after cristaliana.
In accordance with one form of implementation of the present invention, the composition in accordance with the invention is not in the form of an emulsion.
In one form of the present invention, sub-micron particles have an average size of <100 nm, for example from 25 to 70 nm, for example, with a polydispersity <0.5 (size and polydispersity determined using spectroscopy in the photon correlation instrument company of Malvern Zetasizer series).
In addition to the above sub-micron particles, the composition in accordance with the invention may also optionally contain:
- antioxidant agents, protecting ester of DHA, in particular the nicotinic ester or pantalony ester of DHA, and, in particular, D-pantalony ester of DHA from oxidation by the oxygen dissolved in the composition. Non-limiting examples of such is hentov include ascorbic acid and its derivatives, compounds which release sulfur dioxide, such as sodium metabisulfite, propylgallate, equivalent, butylhydroxyanisole, D,L-α-tocopherol, derivatives of ethylenediaminetetraacetic acid, and combinations thereof. Their content ranges from 0.01% to 1% (wt./vol.), more specifically from 0.01% to 0.50% (wt./vol.). Antioxidant agents are supplemented by the use of inert gases such as nitrogen or argon, at the time of receipt and packaging compositions for injection;
agents that regulate pH. These agents are known to experts in the art and include mineral or organic acids and bases and buffer systems. Their use allows you to set the pH of the composition in accordance with the invention to the value from pH=4 to pH=9, compatible with parenteral administration. This agent may, therefore, consist of ascorbic acid;
agents for regulating the osmolarity of the composition in accordance with the invention, in order to guarantee its isotonicity with blood. These agents are, for example, neutral molecules, such as carbohydrates, for example, is not necessarily restored monosaccharides (e.g. glucose or mannitol in a concentration of ≤5% (wt./about.)] or disaccharides (e.g. sucrose at a concentration of ≤10% (wt./about.)].
water for injection as the dispersion is first environment, for example, 5% glucose or 0.9% sodium chloride solution.
Compositions in accordance with the invention are in the form of aqueous dispersions, ready for introduction, or in the form of lyophilized dispersions that restore immediately before use with water for injection before administration.
In a non-limiting example, the concentration of 30 ng/ml or 3% (wt./about.) - nicotinic ester of DHA concentration SOLUTOL HS15 and derived phospholipid ranges from 2.5 to 5% (wt./about.) and from 0 to 10% (wt./vol.)., respectively. It is preferable to use a composition with 5% (wt./about.) SOLUTOL HS15 and 5% (wt./about.) derived phospholipid.
Drugs listed in the following table 1, illustrate the present invention. They can be cooked using the first method described in this application below.
|Nicotinic ester of DHA||3.00 g||3.00 g||3.00 g||3.00 g|
|1-Palmitoyl-2-yearposition||4,85 g||4,85 g|
|1,2-Dimyristoylphosphatidylcholine||0.15 g||0.15 g||0.15 g|
|Lecithin egg||4,85 g|
|SOLUTOLHS15||5,00 g||5,00 g||5,00 g||5,00 g|
|Ascorbic acid||0.20 g|
|5% glucose solution||to 100 ml||to 100 ml||to 100 ml||up to 100ml|
|The average particle size||28,6 nm||52,0 nm||of 65.1 nm||50,6 nm|
The present invention also relates to a method for obtaining a composition in accordance with the present invention, comprising the following stages:
- dispersion of ester of DHA, in particular the nicotinic ester of DHA or antenolol ester of DHA, in particular antenolol of monoether DHA, having the formula a or formula B, the derivative(derivative) of phospholipid and polyoxyethylene ether fatty acids, such as SOLUTOL HS15, in aqueous solution for parenteral administration, for example in 5% glucose solution, with stirring, for example, magnetic or paddle mixer, for example, at about 700 rpm, to obtain a homogeneous, but turbid dispersion,
- homogenization of the resulting dispersion, for example, using a rotor/stator of the turbine (for example, type Labortechnik KZT25 (IKA) or equivalent), for example, at about 13500 rpm, and then the high-pressure homogenizer (for example, type EMULSIFLEX C5 (AVESTIN) or equivalent), for example, at a pressure of from 1300 to 1600 bar,
- sterilization of the resulting colloid compositions, for example, by passing through a 0.2 μm filter for sterilization, such as filter type, MILLIPORE DURAPORE® or equivalent.
This way, chrome is in to include an additional stage consisting in filling a sterile filtrate in an aseptic atmosphere in a clean, pre-sterilized primary packaging materials.
This primary packaging represents, for example, or a sealed ampoule or vial, sealed with an elastomeric stopper and jaws lid or pre-filled syringe ready for injection.
An alternative way both surfactant (a) and (b) can be pre-jointly homogenized in an aqueous solution for parenteral administration, such as 5% glucose solution before the addition of ester of DHA, in particular the nicotinic ester of DHA or antenolol ester of DHA, in particular antenolol of monoether DHA, having the formula a or formula B, and the final homogenization.
Even when one alternative method of surfactant (a) and ester of DHA homogenized before adding the surfactant (b) with subsequent homogenization of the whole mixture. Then add solvent, for example a mixture of alcohol/water, for example ethanol/water, for example, 15,8:1 vol./about. respectively, and homogenization continue. Then the solvent is removed by vacuum drying. Then the resulting complex is diluted in 5% glucose solution. The resulting dispersion is optionally homogenized, for example, using a homogenizer high pressure is I.
The resulting preparation is sterilized by passing through 0.22 μm filter, as described above.
Any antioxidant agents, pH-regulating agents and/or isotonic agents are dissolved in the aqueous phase either before or after homogenization.
In one form of the pharmaceutical composition in accordance with the invention is intended for intravenous, intraarterial, intracardiac, subcutaneous, intradermal, intramuscular, intratrahealnogo, intrathecal, intraperitoneal, intraocular, intraventricular, intrapericardial, an intradural or intraarticular injection.
As a General rule, the compositions according to the invention is injected, as such or after dilution in a physiologically acceptable solution, such as 5% glucose or 0.9% sodium chloride solution.
These compositions can also enter via intraarterial, intracardiac, subcutaneous, intradermal, intramuscular or intratrahealnogo path.
The present invention also relates to pharmaceutical compositions in accordance with the invention for use as a medicine.
This drug is intended for the prevention and/or treatment of cardiovascular diseases, for example, selected from nadgauda what he and/or ventricular arrhythmia, tachycardia and/or fibrillation, for example atrial fibrillation; for the prevention and/or treatment of diseases caused by disturbances of the electric conductivity of myocardial cells; for the prevention and/or treatment of multiple risk factors for cardiovascular disease, for example, selected from hypertriglyceridemia, hypercholesterolemia, hyperlipidemia, dyslipidemia such as mixed dyslipidemia, arterial and venous thrombosis induced blood clotting and/or hyperactivity factor platelet aggregation II (thrombin) and/or arterial hypertension; primary or secondary for the prevention and/or treatment of cardiovascular diseases, resulting supraventricular and/or ventricular arrhythmia, tachycardia, atrial fibrillation and/or violations of the electric conductivity induced by myocardial infarction, primarily sudden death; and/or for posleinfarctne treatment.
The invention will be better understood in the light of the following graphic materials and tests for atrial fibrillation:
In Fig.1 presents the General structure derived phospholipids.
In Fig.2 presents the results of measurements of refractory periods of atrial have shot pigs after administration of the compositions in accordance with the invention (bolus of 10 mg/kg nicotine e the Ira DGK + cefuroxim 10 mg/mg of nicotinic ester of DHA within 40 minutes) when the stimulation frequency is 120 bpm (beats per minute) and 150 bpm.
In Fig.3 presents the results of measurements of refractory periods of atrial have shot pigs after introduction of the comparative compositions (comparative examples) (bolus of 10 mg/kg nicotinic ester of DHA + cefuroxim 10 mg/mg of nicotinic ester of DHA within 40 minutes) when the stimulation frequency is 150 bpm.
For example, the activity of the compositions in accordance with the invention, are shown in table 1, in the treatment of atrial fibrillation perfectly demonstrated pharmacological test below.
Male pigs of Landrace (22-25 kg) anaesthetize with isoflurane (1.5 to 3%). Then animals inkubiruut and ventilate to maintain arterial blood gas volumes in physiological limits. A left thoracotomy is performed in the fourth intercostal space. Artery and marmarou isolate the vein, the catheter is introduced into the vein for administration of the test drugs and the artery for blood pressure measurement and collection of blood samples. Spend tamponade pericardial. The electrocardiogram (ECG) fibrillation record continuously, three electrodes are placed on Picardy and sew. In this regard, the ECG provides information only at the stage of fibrillation. Two bipolar electrode is also placed on the left ear of the heart: they are used for electrical stimulation of the ear of the heart at a given frequency.
the donkey sufficient recovery period, you can start defining a refractory period of the Atria in controlled conditions. A continuous series of stimuli (S1) starting at very low voltage (0.1 V), is not sufficient to stimulate the heart. The voltage is gradually increased (intervals of 0.1 In) to determine the threshold of stimulation for monitoring the applied frequency. This threshold is determined at each frequency of stimulation. There are 4 frequency stimulation, 90, 120, 150 and 180 bpm. If a pig has a basic heart rate 90 bpm, the first frequency stimulation is not applied. Similarly, if the base frequency is low (<90 bpm), end test frequency stimulation (180 bpm) is not always stimulates the heart. As soon as the threshold is determined, the voltage stimulation S1 (series of 10 stimuli) is equal to twice the threshold, and the voltage extrastimuli S2 is 4-fold threshold. Every 10 S1 extrastimuli S2 starts during the refractory period (i.e. 80 MS after the end of S1, where the expected refractory period is at least 100 MS), and every 10 stimuli S1 extrastimuli separated from the end of S1 (5 MS increments) up until it will not cause the blow. The longest interval, not inducing the response to S2, is the refractory period of the Atria. Refractory period assessed 3 times in the sequence (expression medium), with 4 different stimulation frequencies, that is, 12 measurements. The test drug is administered in the form of a bolus and infos and within 40 min (time, necessary to assess all of the refractory periods). Thresholds are not re-calculate, refractory periods measured immediately (within 5 min after bolus). If the drug is active, refractory periods is expected to increase compared with the control phase.
It should be noted that only compositions in accordance with the invention, a positive answer to this pharmacological test, as illustrated in Fig.2 and 3.
Comparative examples are drugs that are very similar to drugs in accordance with the invention, as shown in table 2 below, but they exhibit low or negative pharmacological activity.
|Comparative example 1||Comparative example 2||Comparative example 3|
|Nicotinic ester of DHA||3.00 g||3.00 g||3.00 g|
|SOLUTOL HS15||5,00 g|
|Polysorbate 80||2.50 g|
|Medium chain triglycerides||2.50 g|
|5% glucose solution||to 100 ml||to 100 ml||to 100 ml|
Thus, it is noted that the absence of one of the surfactants (a) or (b), respectively, comparative example 3 and comparative example 1) in compositions for parenteral administration containing nicotinic ester of DHA, or the use of other surfactant than (a) or (b) (comparative example 2) does not allow to obtain the desired activity.
The preparation for injection, including pantalony the DHA ester having the formula
EPCS=phosphatidylcholine chicken eggs
1 - getting Way set is soobrazhenija in the presence of a solvent
Solutol HS 15 and pantalony the DHA ester having the formula, mixed at a temperature of 50°C until homogenization. Then add the phospholipids and the mixture is placed in a condition of magnetic stirring at 50°C for a time from 1 hour to 1 hour 30 minutes in an inert atmosphere, for example under nitrogen atmosphere. Ethanol and water, for example a mixture of ethanol/water [15,8:1 vol./vol.], add to the mixture, and stirring is continued in an inert atmosphere up until the lipids are not fully dispersed. The mixture is then treated for 30 min with ultrasound to obtain a complete dispersion of phospholipids. The resulting dispersion is placed in a vacuum for at least 24 h to remove solvent and water.
The complex is dissolved in 5% glucose solution. If the variance is opaque, it is homogenized by the homogenizer high pressure, while the variance will not be transparent and clear. The variance is sterilized by filter PVDF 0.22 μm.
2 - Method of obtaining by mixing antenolol ester of DHA with dispersion of phospholipids and Solutol HS 15
Phospholipids, Solutol HS 15 and 5% glucose solution was weighed, and the mixture is stirred with a magnetic stirrer and heated to 60°C. to obtain a dispersion. Then this dispersion is subjected to cycles of high-pressure homogenizer to obtain pure and/or transparent dispersion.
Then pantalony ester of DHA, with whom ormolu, add to the dispersion, and the mixture is homogenized for 1 to 2 min at 13500 rpm Dispersion is subjected to cycles of high-pressure homogenizer to obtain pure and/or transparent dispersion, for example not more than 5 cycles. The dispersion is filtered through a PVDF filter 0.22 μm.
3 - the Method of obtaining by mixing antenolol ester of DHA, phospholipids, and Solutol HS 15
All ingredients are weighed in the flask, add a magnetic stirrer and the flask is sealed in an inert atmosphere, for example under nitrogen atmosphere. The mixture is stirred for 30 minutes to obtain a homogeneous dispersion. The dispersion is homogenized at 13500 rpm for 1 to 2 minutes and treated with a high-pressure homogenizer to obtain a transparent and/or pure dispersion or constant transmittance, for example after 6 cycles. Drugs filtered on 0.22 μm filters and define the visual aspect, appearance under the microscope, pH, transmissivity and particle size during and after storage for 2 weeks at 4°C, 25°C and 40°C.
The drug was developed with the following compositions shown below in table 3:
|Connection||The drug is 30 mg of P-DHA/ml RALO||The drug is 30 mg of P-DHA/ml EPCS|
|Weight||Concentration (mg/ml)||Weight||Concentration (mg/ml)|
|Pantalony the DHA ester having the formula In||3,00||30,1||3,00||30,1|
|5% glucose solution||87,00||870,1||87,00||870,1|
The above examples were used to assess whether you can combine pantalony ester of DHA, for example pantalony ether having the formula In directly with excipients to form a complex, which can then be diluted with 5% glucose solution to obtain a dispersion suitable for injection.
The composition obtained in accordance with each of the 3 ways to obtain and analyze it.
The visual aspect and appearance of the drug observed under a microscope, pH, transmissivity and the particle size measured during and after storage for 2 to 4 weeks at 4, 25 and 40°C.
The conclusion from these observations is that the composition containing 30 mg antenolol of DHA ester having the formula V, in ml Solutol HS 15 and RALO, or EPCS operation with DPMG and 5% glucose solution can be obtained in accordance with the three described methods. the pH remained stable for two weeks, the particle size remained smaller than 100 nm. Peak decay is not observed in the HPLC chromatograms.
1. Pharmaceutical composition for parenteral administration comprising submicron particles of ester of docosahexaenoic acid, dispersed in the aqueous phase using a mixture of at least two surfactants selected from at least one polyoxyethylene fatty acid ester and (b) at least one PR is izvorovo phospholipid.
2. The pharmaceutical composition under item 1, characterized in that an ester of docosahexaenoic acid is a nicotinic ester.
3. The pharmaceutical composition under item 1, characterized in that an ester of docosahexaenoic acid is pantalony the DHA ester having the following formula:
or any of its pharmaceutically acceptable salts, enantiomers, diastereoisomers or mixtures thereof, including racemic mixtures.
4. The pharmaceutical composition according to p. 3, characterized in that an ester of docosahexaenoic acid is pantalony the DHA ester having the following formula:
5. The pharmaceutical composition under item 1, characterized by the fact that polyoxyethylene the fatty acid ester is a macrogol-15 hydroxystearate.
6. The pharmaceutical composition under item 1, characterized in that the derived phospholipid is selected from lecithins of natural origin, such as soy lecithin or lecithin are chicken eggs, phospholipids of natural origin, such as, for example, phospholipids, soy or eggs, or synthetic phospholipid, or a mixture thereof.
7. The pharmaceutical composition according to p. 6, characterized in that the derived postlip the Yes is a mixture of neutral phospholipid and the negatively charged phospholipid.
8. The pharmaceutical composition under item 1, characterized in that the concentration of ester of docosahexaenoic acid greater than or equal to 10 mg/ml, preferably higher than or equal to 30 mg/ml
9. The pharmaceutical composition under item 1, characterized by the fact that it represents the variance of the mixed micelles or vesicles, or hybrids of micellar and vesicular structures.
10. The pharmaceutical composition under item 1, characterized by the fact that the submicron particles have an average size of <100 nm, more particularly from 25 to 70 nm, with a polydispersity <0.5 in.
11. A method of obtaining a pharmaceutical composition according to any one of paragraphs.1-10, characterized in that it comprises the following stages:
- dispersion of ester of DHA, in particular the nicotinic ester of DHA, as defined in paragraph 2, or antenolol ether DGK specified in paragraph 3 or 4, derived (derived) phospholipid and polyoxyethylenated of fatty acid ester, in particular SOLUTOL HS15, in aqueous solution for parenteral administration, in particular, in 5% glucose solution, with stirring, in particular, at about 700 rpm to obtain a homogeneous, but turbid dispersion,
- homogenization of the resulting dispersion, for example, using a rotor/stator of the turbine, in particular approximately at 13500 rpm, and then homogenizer high pressure, in particular, when the pressure on the 1300 to 1600 bar,
- sterilization of the obtained colloidal drug, for example, by passing through a 0.2 μm filter for sterilization.
12. The pharmaceutical composition according to any one of paragraphs.1-10, characterized in that it is intended for intravenous, intraarterial, intracardiac, subcutaneous, intradermal, intramuscular, intratrahealnogo, intrathecal, intraperitoneal, intraocular, intraventricular, intrapericardial, an intradural or intraarticular injection.
13. The pharmaceutical composition according to any one of paragraphs.1-10 for use as a medicine.
14. The pharmaceutical composition according to p. 13, characterized in that the medicinal product is intended for prevention and/or treatment of cardiovascular diseases, for example, selected from supraventricular and/or ventricular arrhythmia, tachycardia and/or fibrillation, for example atrial fibrillation; for the prevention and/or treatment of diseases caused by disturbances of the electric conductivity of myocardial cells; for the prevention and/or treatment of multiple risk factors for cardiovascular disease, for example, selected from hypertriglyceridemia, hypercholesterolemia, hyperlipidemia, dyslipidemia such as mixed dyslipidemia, arterial and venous thrombosis, induced St is stevanie blood and/or hyperactivity factor platelet aggregation II (thrombin), and/or hypertension; for primary or secondary prevention and/or treatment of cardiovascular diseases due to supraventricular and/or ventricular arrhythmia, tachycardia, atrial fibrillation and/or violations of the electric conductivity induced by myocardial infarction, primarily sudden death; and/or for post-mi treatment.
SUBSTANCE: what is presented is a fused protein that is a Notch1 antagonist, which consists of a human Fc region fused with the EGF-like repeat 1-13 of Notch1 or the EGF-like repeat 1-24 of Notch1. Fc-portion is localised on a carboxy-terminal portion of the EGF-repeat. There are described a pharmaceutical composition for the protein-based Notch signal transmission inhibition and using it for preparing the pharmaceutical composition for treating an individual suffering from: tumour; ovarian cancer; metabolic disorder; vascular proliferative retinopathy. What is presented is using the fused protein for producing the pharmaceutical composition for inhibition: angiogenesis in the individual; physiological lymphangiogenesis or pathological lymphangiogenesis in the individual; tumour deposits in the individual.
EFFECT: using the invention provides the proteins expressed in a supernatant at a level by several times more than the fused protein containing the EGF-like repeats 1-36 of Notch1; they penetrate into the tumour better, maintain a ligand-binding ability with the fused protein containing the repeats 1-24, binds to DLL4 and JAG1, whereas the fused protein containing the repeats 1-13 only binds to DLL4, but not to JAG1 that can find application in therapy of various diseases related to the Notch1 activity.
18 cl, 124 dwg, 10 ex
SUBSTANCE: invention relates to novel compounds of general formula (1), which possess an affinity to the µ-opiod receptor and the ORL1-receptor. The invention also relates to the application of the said compounds for obtaining medications, which can be used in treatment of fear, stress and associated with stress syndromes, depressions, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, learning and memory disorders (as nootropic), withdrawal syndromes, alcohol and/or drug abuse and/or abuse of medications and/or alcohol, narcotic and medication addiction, etc. In general formula (1) (1) Y1, Y1 ', Y2, Y2 ', Y3, Y3 ', Y4 and Y4 ' in each case stand for -H; Q stands for -R0, -C(=O)-R0, -C(=O)OR0, -C(=O)NHR0, -C(=O)N(R0)2 or-C(=NH)-R0; R0 in each case stands for -C1-8-aliphate, -C3-12-cycloaliphate, -aryl, -heteroaryl, -C1-8-aliphate-C3-12-cycloaliphate, -C1-8-aliphate-aryl, -C1-8-aliphate-heteroaryl, -C3-8-cycloaliphate-C1-8-aliphate, -C3-8-cycloaliphate-aryl or -C3-8-cycloaliphate-heteroaryl; R1 and R2 independently on each other stand for -C-1-8-aliphate; R3 stands for -C1-8-aliphate, -aryl, -heteroaryl or -C1-8-aliphate-C3-12-cycloaliphate; n stands for 0; X stands for -NRA-;RA stands for -C1-8-aliphate; RB stands for -C1-8-aliphate; on condition that R1, R2, RA and RB simultaneously do not stand for the non-substituted-C1-8-aliphate.
EFFECT: increased efficiency of the application of the compounds.
9 cl, 11 tbl, 164 ex
SUBSTANCE: invention relates to bi- and polycyclic substituted isoquinoline and isoquinolinones of formula (I), or to its stereoisomeric and/or tautomeric forms and/or to its pharmaceutically acceptable salts, where R1 represents OH; R3, R4, R5 and R8 represents H; R7 represents halogen or (C1-C6) alkyl; R6 represents one (C1-C4)alkylene, bound to a cycloalkyl ring, in which (C1-C4)alkylene forms the second bond with the other carbon atom of the cycloalkyl ring with the formation of a bicyclic ring system, where in the bicyclic ring system one carbon atom is substituted with a group, independently selected from O, S or SO2; and if m and s equal 2 or m equals 3 and s equals 1, R6 represents a group CH2-CH-(CH2)2, which via one group CH2 is bound to the cycloalkyl ring, and two other CH2 groups are bound to different carbon atoms of the cycloalkyl ring, and if m equals 3 and s equals 3, R6 represents two methylene groups, bound to different carbon atoms of the cycloalkyl ring, where the methylene groups or group CH2-CH-(CH2)2 are bound to the carbon atoms of the cycloalkyl ring and form an adamantane system of formula (XX) , where L can be bound to any secondary or tertiary carbon atom, or R6 together with R11 and an N atom form (C5) heterocycloalkyl, bound with the cycloalkyl residue in the form of a spirocyclic ring system, where the bicyclic ring system, or the adamantane system, or a ring system, containing (C5) heterocycloalkyl, represent non-substituted or optionally substituted with substituent R9; R9 represents (C1-C6)alkyl, (C2-C6)alkenyl, (C6)aryl or cyclopropyl R11 and R12 independently on each other represent H or (C1-C6)alkylene-(C6)aryl; n equals 0 or 1; m equals 2 or 3; s equals 1, 2 or 3; L represents O; its stereoisomeric and/or tautomeric forms and/or its pharmaceutically acceptable salts. The invention also relates to the application of a formula (I) compound.
EFFECT: novel bi- and polycyclic isoquinoline and isoquinolinone derivatives, useful as inhibitors of Rho-kinase, are obtained.
22 cl, 22 ex
SUBSTANCE: peptide is characterised with sequence Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ ID NO: 16). The invention also relates to peptide/lipid complex based on the above peptide, in which phospholipid represents one or more of sphingomyelin, DPPC and DPPG, a pharmaceutical composition that contains it, and treatment methods of dyslipidemia, cardiovascular disease, endothelial malfunction, macrovascular illnesses and microvascular illnesses using it.
EFFECT: invention allows obtaining ApoA-I mimetic that is more stable in comparison to ApoA-I and that is easy to obtain.
14 cl, 21 dwg, 14 tbl, 24 ex
SUBSTANCE: on the first experimental day, cardiopathy is simulated by a single subcutaneous administration of equally portioned mixture of native egg albumin and Freund's complete adjuvant in rats. The mixture is administered at 0.2 ml of the mixture into 5 injection points: abdominally, into inguinal and axillary regions on the left and right. The cardiopathy is prevented by daily gastric administration of succinic acid 1.5 mmole/kg for 60 days through a probe.
EFFECT: higher clinical effectiveness.
2 dwg, 1 tbl, 1 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to the pharmaceutical industry and medicine. What is presented is using treo-3-phenylglutamic acid hydrochloride of the following structural formula: as an agent possessing the cardioprotective, antiplatelet, anticoagulant and membrane-protective properties under stress stimulation.
EFFECT: compound possesses the high cardioprotective, antiplatelet, anticoagulant and membrane-protective activity.
SUBSTANCE: invention relates to novel compound of salvianolic acid L with general formula (I) , to its pharmaceutically acceptable salts and hydrolysable ethers, with compound of salvianolic acid L having one pair of protons of trans-form double bond and one proton of single-substituted double bond; and compound of salvianolic acid L is intended for treating cardiovascular disease, capture of free radicals and/or prevention of excessive oxidation.
EFFECT: invention also relates to method of its preparation, medication, which contains salvianolic acid L, and its application for preparation of drug for treatment of cardio-cerebral-vascular diseases.
13 cl, 13 dwg, 17 tbl, 10 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to compound of formula (I) , where ring A is cycloalkane ring with number of members from 3 to 7, benzene ring or monocyclic 5-member or 6-member aromatic heterocyclic ring, containing 1 heteromember of ring, selected from the group, containing N and S, and benzene and heterocyclic rings can optionally have one or two similar or different substituents, selected from the group, containing halogen, HO-, R1-O-, H2N-C(O)- and NC-; Y is selected from the group, containing S, C(R12)=C(R13) and C(R15)=N; Z is selected from the group, containing C(R16); R1, R30, R33, R35, R54 and R55 independently on each other group R1, R30, R33, R35, R54 and R55 are selected from the group, containing (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C7)-cycloalkyl and (C3-C7)-cycloalkyl-(C1-C4)-alkyl-, and all of them can optionally have one or more similar or different substituents R70; R3 and R5 represent hydrogen; R4 and R6 are selected independently on each other, from the group, containing hydrogen and , (C1-C4)-alkyl; R12, R13, R15 and R16 are selected independently on each other, from the group, containing hydrogen, halogen and O2N-; R20 is selected from the group, containing hydrogen and (C1-C4)-alkyl; one of the groups R21 and R22 is group of formula II: R24-R23-, and the other of groups R21 and R22 is selected from the group, containing hydrogen, halogen, R30, HO-, R30-O-, R30-S(O)m-, H2N-, R30-NH-, R30-N(R30)-, R30-C(O)- and NC-; R23 is chain, containing from 1 to 5 chain members of which 0 or 1 chain member is heteromember of chain, selected from the group, containing N(R25), O, S, with other chain members being similar or different groups C(R26)(R26), where two adjacent groups can be bound to each other by double bond; R24 is selected from the group, containing hydrogen, R31, R31-O-, R31-NH-, R31-N(R31)-, R31-C(O)-NH-, HO-C(O)- and monocyclic, bicyclic or tricyclic ring with number of members from 5 to 10, which is saturated or non-saturated and contains 0, 1, 2 or 3 similar or different ring heteromembers, selected from the group, containing N, N(R32), O, S, and ring can optionally have on ring carbon atoms one or 2-3 similar or different substituents, selected from the group, containing halogen, R33, R33-O-, R33-S(O)m-, R33-C(O)-NH-, R33-S(O)2-NH-, R33-C(O)-, HO-C(O)-, H2N-C(O)-, R33-NH-C(O)-, R33-N(R33)-S(O)2-, NC-, oxo, phenyl and Het; on condition that total number of C, N, O and S atoms, present in two groups R23 and R24, constitutes not less than 5; R25 is selected from the group, containing hydrogen and (C1-C4)-alkyl; R26, independently on each other group R26, is selected from the group, containing hydrogen, fluorine, (C1-C4)-alkyl and HO-, or two groups R26, together with included into them chain members, form monocyclic ring with number of members 4, which is saturated and contains 1 ring heteromember, selected from the group, containing O; R31 is selected from the group, containing (C1-C6)-alkyl, which can optionally have one substituent R70; R32 is selected independently on each other, from the group, containing hydrogen, R35 and phenyl; R50 is selected from the group, containing R51-O- and R52-N(R53)-; R51 is selected from the group, containing hydrogen and R54; R52 is selected from the group, containing hydrogen; R53 is selected from the group, containing hydrogen; R70 is selected from the group, containing HO-, R71-O-, H2N-, R71-NH-, R71-N(R71)-, R71-C(O)-NH-, HO-C(O)-, H2N-C(O)- and phenyl; R71, independently on each other group R71, is selected from the group, containing (C1-C4)-alkyl; Het, independently on each other group Het, is monocyclic heterocyclic ring with number of members 5, which contains 1 or 2 similar or different ring heteromembers, selected from the group, containing N and S, and ring is saturated or non-saturated and optionally substituted with one or more similar or different substituents, selected from the group, containing (C1-C4)-alkyl; m, independently on each other number m, is integer number, selected from the group, containing 0, 1 and 2; phenyl, independently on each other phenyl group, can optionally have one or more similar or different substituents, selected from the group, containing halogen and (C1-C4)-alkyl.
EFFECT: invention also relates to method of obtaining compound of formula (I) and its application for manufacturing pharmaceutical for inhibiting receptor Edg-2.
17 cl, 14 tbl, 362 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutics, namely to a formulation for oral transmucosal administration which contains a lipid-lowering active substance specified in statins, fibrates or ezetimibe; an aqueous-alcohol solution consisting of water and 30° to 70° ethanol, wherein the above active substance is found in a stable and completely dissolved state with the pH value of the formulation falling within the range of 5.0 to 8.0. The invention also refers to a method for preparing the above formulation and using it for treating hyperlipidemia.
EFFECT: invention provides better efficacy for lower doses of the active substances (statins, fibrates and ezetimibe); their immediate bioavailability for hepatocytes and considerably reduced production of harmful metabolites that stands for eliminating the main side effects of these agents.
11 cl, 6 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to immunology and biotechnology. There are presented: an isolated antibody or its variant specifically recognising PCSK9, and a based pharmaceutical composition for lowering LDL-cholesterol. There are described: using for lowering blood cholesterol and/or LDL; reducing an incidence rate and/or correcting abnormal cholesterol and/or LDL; using for preparing a drug for lowering blood cholesterol and/or LDL; reducing the incidence rate and/or correcting abnormal cholesterol and/or LDL. There are disclosed versions of cell lines producing PCSK9 antibody or its antigen-binding portion and deposited in the American typical culture collection (ATCC) under Nos. PTA-8986, ATCC PTA-8984, ATCC PTA-8983, respectively. What is described is a coding nucleic acid and a host cell for producing the based antibody.
EFFECT: invention provides PCSK9 agonist antibodies that can find application in medicine for lowering cholesterol.
18 cl, 24 dwg, 9 tbl, 9 ex
SUBSTANCE: stabiliser includes modified chitosan which is obtained by modifying chitosan particles located in an emulsion of an organic solvent - water, with pH 6.0-6.5, by first reacting a mixture consisting of a carboxylic acid in an organic solvent and a condensing agent, and then with an organic base, wherein the carboxylic acid used is either palmitic acid or stearic acid or dodecanoic acid, the condensing agent used is a mixture of hydroxysuccinimide and an aliphatic carbodiimide or formaldehyde and an aliphatic isocyanide, and the organic base used is triethylamine.
EFFECT: effective liposome composition stabiliser which can be obtained using a simple method.
8 cl, 3 tbl, 5 ex, 7 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a carrier applicable for the local drug delivery. A drug is enclosed in a carrier, and the carrier comprises a coating able to release an enclosed drug as a result of a local stimulus. The coating additionally surrounds the contrast agent MR 19F which changes its detectability after being released from the carrier. The invention refers to a method for the drug delivery to an MRT-controlled individual, wherein the method involves administering the above carrier into the individual enabling the carrier releasing the drug, and forming MR 19F images with the use of a contrast produced by the contrast agent MR 19F.
EFFECT: invention enables monitoring the beginning of the drug release from the carrier.
18 cl, 11 dwg, 2 tbl, 2 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutics and concerns irinotecan liposomes or its hydrochloride containing irinotecan or its hydrochloride, neutral phospholipid and cholesterol, wherein the weight ratio of cholesterol to neutral phospholipid makes 1:3-5, and a method for preparing them.
EFFECT: liposomes have higher stability.
15 cl, 3 dwg, 10 tbl, 10 ex
SUBSTANCE: disclosed is a vesicle-containing composition which is characterised by that it contains: (A) a silicone-based surfactant which is silicon modified with polyoxyalkylene, (B) one or more anionic surfactants selected from polyoxyethylenealkyl(12-15)ether-phosphate, acylmethyltaurate and acylglutamate in amount of 0.001-0.2 wt %, (C) polar oil having IOB of 0.05-0.80 and/or silicone oil, and (D) water, which contains a water-soluble medicinal agent, in amount of 0.5-5 wt % of the weight of the composition, where the silicone-based surfactant (A) forms vesicles; the anionic surfactant(s) (B) is attached to the surface of the vesicles; and the polar oil and/or silicone oil (C) is present inside the bilayer membrane of the vesicles.
EFFECT: disclosed composition has excellent stability even in the presence of high concentrations of a water-soluble medicinal agent.
6 cl, 8 tbl, 10 ex
SUBSTANCE: liposomal pharmaceutical composition includes a medicinal substance, lipids in form of phosphatidylcholine and cholesterol, and additionally contains minor positively charged component in form of cetylpyridinium chloride or stearyl ethanolamine.
EFFECT: high bioavailability of the medicinal substance through active transport to body organs and tissue.
10 cl, 3 dwg, 5 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to medicine and deals with pharmaceutical composition for local application in form of gel, which contains enzyme deoxyribonuclease (DNA-ase) and/or ribonuclease (RNA-ase) and liposomes, which can be applied in medicine for treatment and prevention of viral infection.
EFFECT: invention ensures obtaining stable pharmaceutical compositions.
1 cl, 7 ex, 1 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a method for preparing a magnet-sensitive lipid composition. The declared method involves preparing a therapeutic agent containing cisplatin, a source of phospholipids and a magnetism carrier representing pirocarbon-coated ferric nanoparticles to be exposed to UV radiation. The above phospholipid source is the pharmacopeial drug 'Phosphogliv' with the composite prepared in the micellar form.
EFFECT: providing the uniformity and thermodynamic stability of the composite prepared over a short optimum period of time with using no organic solvents.
1 dwg, 2 ex
SUBSTANCE: liposomes are used as a matrix for activated ferment - horseradish peroxidase. To 5 mg of horseradish peroxidase oxygenated with a periodate method there added is 1 ml of liposome suspension in 0.01 M solution of carbonate-bicarbonate buffer at pH 9.5, and subjected to ultrasonic treatment during 1 min. Then it is incubated for 1 hour; immobilised with immunoglobulins in concentration of 5 mg during 2 hours at the temperature of 22±4°C; stabilised with 5 mg of sodium borane with further gel-chromatographic cleaning.
EFFECT: invention allows obtaining liposomal-immunoperoxidase conjugate for indication of infectious agents in an immunoenzymometric analysis and increasing service life of a preparation up to 6 years.
1 tbl, 3 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutical industry and represents a thermally-sensitive liposome for treating cancer in a subject, containing at least one phosphatidylcholine, at least one phosphatidylglycerol, monostearoyl phosphatidylcholine, pegylated phospholipid and an active substance specified in a group consisting of taxotere, docetaxel and carboplatin wherein the liposome has a gel to liquid transition point from approximately 39°C to approximately 45°C.
EFFECT: invention provides storage-stability for a long period of time of one month or more at low temperatures.
9 cl, 8 ex, 8 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions refers to medicine, and concerns a liposomal drug preparation containing a polyvalent ionic preparation as an active substance with one or more dissociating groups at dissociation constant 4.5-9.5, wherein a liposome has a size of about 30-80 mm and a phospholipid bilayer has a phospholipid with a phase transition temperature above the body temperature so that the phase transition temperature of the liposome is above the body; a method of treating a tumour in a patient involving administering the above liposomal drug preparation.
EFFECT: group of inventions provides the higher therapeutic efficacy index of the liposomal preparation, especially more effective control of liposomal drug preparation recovery after targeted on the involved area, reduced loss of the drug preparation during the blood circulation of the liposomal drug preparation and more effective drug release into the target tissues.
17 cl, 21 ex, 3 dwg, 9 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to the pharmaceutical and cosmetic industry, in particular to nanoemulsions of a water-in-oil type for transdermal application with biologically active compounds.A nanoemulsion of the water-in-oil type contains 35-80% of a hydrophobic phase, 1-15% of a hydrophilic phase, and a surface-active substance.
EFFECT: nanoemulsion of the water-in-oil type for transdermal application with biologically active compounds possesses good storage stability.
8 cl, 1 dwg, 1 tbl