Pharmaceutical composition and method of its receipt, the method of treatment of disorders, developing as a result of neurodegenerative processes
(57) Abstract:The invention relates to medicine, in particular to two-phase pharmaceutical composition for the treatment of neurodegenerative diseases. The invention lies in the fact that the two-phase composition comprises an MAO inhibitor and absorption inhibitor as an active substance in combination with the usual pharmaceutically acceptable additives. These components can be used to treat neurodegenerative diseases. In these compositions as the active component, i.e., the MAO inhibitor and inhibitor absorption, can be used N-(1-phenylisopropyl)-N-methylpropylamine or N-(4-forfinal)- isoprop-1-yl-1-methylpropylamine, or their salts, optically active isomers or metabolites. The invention relates to methods of producing pharmaceutical compositions, and method of treatment of clinical disorders, developing as a result of neurodegenerative processes. The invention provides for obtaining a pharmaceutical composition for the treatment of neurodegenerative diseases, with optimal properties with slow release. 3 S. and 14 C.p. f-crystals, 8 tab., 5 Il. The present invention relates to pharmaceutical ingredients in concentrations adequate relevant period and the level of these ingredients in the blood and in the brain; and also to a method for obtaining this composition.It is known that the monoamine oxidase (MAO) is one of the main enzymes of metabolism (H. Blaschko Pharmacol. Rev. 4, 415, (1951)) biogenic amines present in the nerve cells of the person. Due to the activity specified oxidase biogenic amines play an important role in neurotransmission, decompose on ineffective metabolites. It is established that in some diseases the levels of biogenic amines in the human brain is reduced.Agents that inhibit the enzyme (enzymes) metabolism, can help restore normal levels of these amines. For this reason, MAO inhibitors used for treatment of humans. The result of the research showed that MAO-a inhibition may cause serious side effects associated with potentiation ("cheese reaction") tiramina (structural-biogenic amine), which enters the body from food, which leads to high blood pressure and can lead to a fatal outcome [Piackar and employees, Psychopharmacolgy 73, 3087 (1981)].MAO exists in two forms, MAO-a and MA is spending a mixed type in the result, you can avoid dangerous side effect. Such inhibition may be carried out using (-)-deprenyl [(-)N-(1-phenyl-isopropyl)-N-methyl-Propylamine-hydrochloride] , which selectively and irreversibly inhibits the enzyme MAO-B [Elsworth et al., Psychopharmacology 57, 33 (1978)]. Due to the irreversible inhibition of the recovery of enzyme activity may be due to the re-synthesis of new enzyme.The process is irreversible inhibition of the enzyme proceeds in two stages. The first stage is reversible, and only the formation of the complex "second enzyme - inhibitor becomes irreversible. Half of the period of regeneration of the enzyme is 7-8 days [Oreland et al., J. Neural. Transm. Suppl. 32, 55-59 (1990)].The substrate specificity of the enzymes and the selectivity of most of the known inhibitors described Dogterom and colleagues [Medicinal Research Reviews, vol. 9, N 1, 45-89 (1989)]. It is known [Science 219, 979-980 (1980) and Burns Proc. Natl. Acao. Sci 80, 4546-550 (1983)] that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) due to its neurotoxic activity induces Parkinson's disease in humans and similar to the symptoms observed in animals. MPTP causes selective destruction of dopaminergic neurons in the striatum. Gisti brain of the patient, suffering from Parkinson's disease. It is known that this action MPTP can be prevented by using MAO inhibitors such as deprenyl. Such a role (-)-deprenyl is due to the inhibition of the conversion of MPTP to MPP+[Nature, 311, 467 (1984)]. MPTP-induced destruction of neurons can also be slowed down by using inhibitors of the uptake of dopamine (Proc.Natl.Acad.Sci. USA, 82, 2175, 1985), such as mazindol, by inhibiting the active uptake of MPP+(ion, methyl-phenyl-pyridinyl) dopaminergic neurons.During the operation of the MAO formation of hydrogen peroxide and oxygen free radicals, leading to oxidative destruction of neurons, MAO, which can be considered neurotoxicit enzyme, may also form ammonia and some heterocyclic isoquinolines [Maret et al., Drug metabolism. Review, 22, 292-332 (1990); P. Riederer et al., Acta Neurol. Scand. 126, 41 (1989); Renedetti and Dostert, Biochem. Pharm. Vol. 38, 555 (1989)].It is known that DSP-4[N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine], which is a neurotoxic agent, induces selective depletion of noradrenaline (NA) from noradrenergic neurons of the Central and peripheral nervous system [Grzanna et al., J. Histochem. Cytochem., 1435-1442, (1989)].It is also known that the inhibitor is ON - depleting effect of DSP-4 [Johnsson et al. , Neuroscience, 7, 2895 (1982); Ross Br. J. Pharmacol. 58, 521 (1976)], a MDL 72974A [(E)2 2-4-fluoro-betacarotenebetacarotene], which is a highly selective inhibitor of MAO-B has no properties, blocking catecholaminergic re-absorption, and is not able to warn DSP-4-induced toxicity [Finnegan et al., Eru. J. of Pharmacol., 184, 119-126 (1990)].(-)-Deprenyl may not be considered as a simple selective irreversible inhibitor of MAO-Century, It inhibits the absorption of dopamine, noradrenaline and tiramina nerve endings and peripheral ganglia, but only in extremely high doses [Kholl Advances in Biochem. Psychopharmacology, vol. 5, 393 (1972)]. Thus in addition to its MAO-inhibitory effect of deprenyl has the ability to inhibit absorption.The objective of the present invention to provide a pharmaceutical composition intended for the treatment of neurodegenerative diseases with optimum properties.It is established that:
1) Long-term inhibition of MAO can be achieved only at relatively high concentrations (15-40 MP/mg tissue) inhibitor in the brain and blood. However, if the concentration of the inhibitor is too high (30 mg/day), the concentration of which can lead to loss of selectivity of the inhibitor (will also inhibited MAO-A).2) Deprenyl and p-ferderer [N-(4-forfinal)-isoprop-1-yl]-N-methylpropylamine] have activity as the parent (original) compound and its metabolites.The results are illustrated in Fig. 1 and 2.After pills of rats labeled deprenyl and p-fiordaprile (ring-3H and propargyl-14(C) (1, 5, 10 mg/kg, respectively) examine the distribution of compounds in 15 areas of the brain (paired parts of the brain are examined separately, i.e. only been studied 25 sites in the brain and in the plasma within 96 hours as a function of time. It is established that a constant connection is absorbed quickly (15 min) and penetrates into the Central nervous system. Unmodified molecule deprenyl shows a short stay at the head of the brain, whereas the metabolites detected in the tissues over a longer period of time.The simultaneous presence of equal amounts of the two labels was observed for unmodified molecules (these data refer to the molar concentrations calculated for the two labels). As in the conducted experiments there is a rapid change of attitude3H/14C in the tissues, it is possible coroaspeladas) and their presence in the brain.3) Potential metabolites of deprenyl and p-fiordaprile (methylamphetamine, amphetamine and p-hermetically, p-perempatan respectively) have a significant capacity to inhibition of absorption and have the ability to in vivo-warning MRTR-neurotoxicity, not detecting when a substantial degree of inhibition of MAO. The results of the experiments are presented in tables 1, 2 and 3. Describes tests carried out according to the method Heikilla [Nature, 311, 467-469 (1984)].4) Potential metabolites of deprenyl and p-fiordaprile (methylamphetamine, amphetamine and p-formetanate, p-perempatan respectively) have the ability to in vivo-the warning (in doses of 1-5 mg/kg, i.p.) DSP-4-induced neurotoxicity without inhibiting MAO.The results are presented in table 8.Testing is carried out according to the method Finnegan [Finnegan et al., Eur.J.Pharmacol. , 184, 119-126 (1990)].The metabolites used in high concentrations in vivo (10 mg/kg; i.p. ), reduce the toxic effects of DSP-4, leading to death of the animal.5) Thus, for the prevention of neurotoxicity or through appropriate high concentrations of unchanged compounds, presupernovae MAO-B), either through irreversible inhibition of absorption requires the presence of metabolites over a long period of time.The maximum effect is achieved when both of these conditions.Thus, the composed task is achieved with new two-phase pharmaceutical compositions that contain the active ingredient compound with MAO-inhibiting action, and connection with the action, inhibiting the absorption, in combination with a standard auxiliary materials.Compositions of the present invention as an active ingredient contain 5-95 wt.% reversible or irreversible MAO inhibitor; 5-95 wt.% the absorption inhibitor, preferably with activity for an extended period of time in relation 1-19 : 1-19, preferably in the ratio of 1:1, 1: 2 or 1:3.This composition may be introduced at a dose of 5 to 20, and preferably 10 mg/day depending on the condition of the patient, severity of the clinical picture of the disease and the individual susceptibility of the patient.Because the absorption inhibitor does not have a long activity, the inhibitor site is hibitor MAO preferable to use deprenil, p-ferderer, their salts and optically active isomers, respectively.As inhibitors of absorption can be used preferably deprenil, p-ferderer or the compound of General formula I:
< / BR>where R1is a straight or branched C1-C8is an alkyl group, a C7-C10-phenylalkyl group or a phenyl group, a C3-C8-cycloalkyl group;
R2is a straight or branched C1-C8is an alkyl group or a C1-C8is an alkyl group substituted by halogen atom, hydroxy-C1-C4-alkoxy group or by one or two phenyl groups; phenyl group or a C3-C8-cycloalkyl group, provided that R1and R2together contain at least 3 carbon atom,
or its acid additive salts or metabolites.As the compounds of formula I it is preferable to use N-propyl-1-phenyl-2-pentylamine or acid additive salt; N-propyl-1-phenyl-2-butylamine or acid additive salt; or N-propyl-1-phenyl-2-hexylamine or acid additive salt.Two-phase compositions of the present invention receive Izvestia, contains micro-capsules; capsules; coated capsules, suspensions, pills for injection; suspension for injection using a known additional substances.As such additional substances may be preferably used the following materials:
a) as fillers sucrose, lactose, mannitol, starch, starch-talc-sucrose, calcifolic, hidroportos solution polyvidone (polyvinylpyrrolidon), etc.,
b) an additive that slows the action,
- freeze (stearic acid, palmitate stearic acid, glycerin-detribalised-stearate and so on);
other additives commonly used in pharmaceutical practice; derivatives of Eudragit and so on,
derivatives of cellulose: HPMC, CMC, EC and their salts.c) granulating fluid: water, ethanol, ethanol - water, isopropanol, isopropanol - water,
(d) binder: PVP/VA, Eudragit-derivatives, cellulose derivatives and their salts.The pharmaceutical composition can be obtained in situ, so that the patient received treatment with appropriate dose of MAO inhibitor required to achieve continuous 98% inhibition of MAO, and the appropriate dose of an inhibitor of Il, p-fiordaprile and compounds of General formula I is given in the descriptions to the U.S. patent N 4564706, Europatent N 186880 and patent Portugal 85799.Examples
1) two-phase pills get known method.Composition:
Dispersed phase: (obtained by double granulation)
a) Deprenyl 5 mg
Metozel to 4M (the high. grade) - 50 mg
Lactose 20 mg
Sufficient isopropanol to obtain granules;
b) Deprenyl 10 mg
Corn starch 40 mg
Avicel PH-101 20 mg
PVP K-25 - 10 mg
Sufficient isopropanol to obtain granules (can also be used distilled water).Continuous phase:
Magnesium stearate 8 mg
Talc - 15 mg
Aerosil-200 2 mg
2) Obtaining tablets with prolonged action, containing 15 mg of deprenyl
Deprenil 15 mg
Stearic acid - 30 mg
Eudragit (Eudragit) RSPM - 45 mg
Kollidon (Collidon) VA-64 - 47 mg
The carbopol 940 - 35 mg
Sarotex (Sterotex) - 25 mg
Magnesium stearate 3 mg
Tablets diameter 8 mm - 220 mg
Technology for the manufacture of tablets.1. Granules are produced by dry granulation, well known in codesslots, Sarotex (chopped) (hydrogenated cottonseed oil), Eudragit (Eudragit) RSPM (copolymer of esters of acrylic and methacrylic acid), deprenyl.2. The manufacture of pellets from the powder mixture is performed on an eccentric tablet press machine with a low number of revolutions per minute.The results of the test for dissolution. Conducted three parallel measurements. One cell contains 15 tablets.a) 316,5 SG (centigram)/15 pieces
b) 316,0 SG/15 pieces
c) 319,0 SG/15 pieces
As a medium for dissolving the use of artificial gastric fluid without pepsin (Ph. Hg. 11).Breeding = 0
d = 1 cm
= 256 mm
Time (minutes) - Dissolved active substance (%)
10 - 4,5
15 - 9,0
30 - 21,0
60 - 31,2
90 - 47,7
120 - 39,3
150 - 41,1
180 - 48,6
240 - 51,9
300 - 63,0
360 - 69,0
420 (7 hours) - 75,6
3) Get mushy pellets "fast" and "slow" action with the following composition:
Granules quick action
- Neural granules (sugar spheres) 61,1 mg
- Deprenyl and 16.3 mg
- Lactose and 16.6 mg
- Polyvidone (K30) of 6.3 mg
Granules slow action
Neutral granules (sugar spheres) to 44.6 mg
is about to 16.9 mg
- Castor oil about 1.7 mg
The method of manufacture.The sucrose crystals are covered with a mixture of starch and sucrose and giprospirtvino solution polyvidone and sucrose (sugar spheres).A mixture of deprenyl hydrochloride and lactose applied to the microspheres using alcohol solution polyvidone.In the case of obtaining granules "slow" actions on the basis of microgranules use spirit varnish of ethyl cellulose (plasticized state reserve and karsts oil and talc.To obtain the desired granule "fast and slow" steps, the required number of pellets "fast" and "slow" action mixed in the capsule by a method known per se.4) Obtaining a two-phase composition for percutaneous administration (UG-191).Components
Carbowax 35000 - 1,0
Carbowax 4000 - 16,0
Carbowax 400 - 53,0
1,2-propylene glycol and 2.0
Xanthan gum - 15,0
The deprenyl - 7,0
Cremophor (Cremophor EL) - 6,0
Components carbowax melted, the mixture was poured into a vessel with an agitator type Erweka at 50oC and stirred at stage 6. Deprenyl is dissolved and suspended in a mixture of propylene glycol and Cremophor EL at 50oC, after which the floor is smeshivayut within 1 minute. And finally, after raising the speed to the level 9) add xanthan gum partialiy 5 g each.After addition of each portion of the mixture stirred for 1 minute. Then the speed mixing reduces to the level of 3.5 and continue stirring until then, until the mixture has cooled (approx. 1.5 hours). The active substance is at 6.84%, and the stability of the composition corresponds to the desired level.Liquid crystal condition: 100%, translucent solid crystals 8-10 μm (Cremophor EL: the glycerol-polyethylene glycol-ricinoleate. Xanthan gum: a polysaccharide).Pharmacological data.When planning experimental conditions take into account the following factors:
direct in vivo measurements of the absorption-inhibitory capacity of the metabolites are impossible because of their reversible nature,
the ability to inhibition of MAO-B can be indirectly measured for pigs based on the activity of MAO-B of platelets as an indicator (platelets obtained from other species that do not contain easily measured activity of MAO-B enzyme),
measurement of neurotoxicity DSP-4 depending on the time (using the contents of noradren the doses of deprenyl, allow us to illustrate the correlation between the absence of neurotoxicity DSP-4 and adequate, but not too high in the blood metabolites of deprenyl.In a series of experiments using analytical techniques measure a constant level of metabolites of deprenyl in the blood of domestic pigs, as well as determine the MAO-a activity of platelets, brain and liver (table. 1 to 3).Experiments conducted on female domestic pigs (small white) weighing 20-25 kg During the experiments the pigs are placed in separate cells and give the same food, they consume up to it.Animal pills enter 5; 7,5; 10; 15 mg (-)-deprenyl tablets and 10 mg intravenously. Blood samples (5 ml) taken through 0; 0.08; 0,25; 0.5; 0,75; 1; 1,5; 2; 3; 4; 6; 12; 24 and 48 hours, placed in centrifuge tubes containing 500 IU of heparin, for analytical measurements. These samples are centrifuged for 10 minutes at 1500 rpm to separate the plasma. Assessment of metabolites is carried out by gas chromatography (GC) using a gas chromatograph (Hp-5890 (elution for methylamphetamine is 21.4 min).The results are shown in Fig. 3.Inhibition of neurotoxicity DSP-4 esmeraldo male Wistar rats weighing 170-200 g Animals are placed in cages (6 birds / cage), which maintain a constant temperature (22oC) and 12 h light per day. Food and water give on request. Rats pre-injected (pills) 3 mg/kg of the composition of example 3 (1 mg/kg "fast" comp. (F) + 2 mg/kg of "slow" comp. (S)), then after 1, 2, 4 and 8 hours animals injected (intraperitoneally) DSP-4 (50 mg/kg).Pre-treatment (-)-deprenyl animals kept on a starvation diet within 24 hours. Then rats delete the hippocampus and by HPLC to determine the content of norepinephrine.The results of the measurements are presented in Fig. 4.As can be seen from Fig. 4, the dose of deprenyl 3 mg/kg (p.o.) able to suppress the neurotoxicity of 50 mg/kg DSP-4, introduced rats intraperitoneally. In the case of the control ("fast") compositions such inhibition in the first period of time reaches a high level (86,1%), but then it decreases exponentially and after 8 hours falls to the level of DSP-4-treated control (19,6%). The claimed composition reaches the level of inhibition of 58.8%, i.e. the level, which is almost identical (54,5%) level, which gives the control composition in two hours (51,5%), however, in a subsequent period, BP is I almost unchanged for 8 hours. When using doses of deprenyl, part 4 mg/kg, found that of the control ("fast") composition stimulates neurotoxicity DSP-4 depending on the time in contrast to the declared ("fast and slow") of the composition (see Fig. 5). This means that the dose "fast" component cannot be increased infinitely, without causing unwanted side effects.Conversely, when used in the claimed compositions increased the number of "slow" component of the observed increase in the level of inhibition of MAO-A, which indicates the decrease in the selectivity of deprenyl.The results of the experiment are presented in table 4.When testing drugs for percutaneous introduction of the control group pills administered 10 mg (-)-deprenyl in a gelatin capsule (see tab. 5).For determining the activity of MAO-B through 0, 3, 6, 24, 48, 72 and 96 hours take blood samples. Through 96 hours after sampling blood pigs were slaughtered to determine the activity of MAO-B and MAO-A in isecheno the brain of pigs.The second group used as a control, treated with the drug for percutaneous introduction of UG-111, containing 10 mg of (-)-deprenyl. Blood samples taken after 0, 3, 6, 24, and 4 is the Arata use the patch and nylon coating. The skin is wiped with cotton wool soaked in ethanol, which is also used for HPLC analysis. After 48 hours of pigs were slaughtered to determine the activity of MAO-A and MAO-B in their brain.The third group of pigs is also used as a control, treated with drug UG-167, containing 20 mg (-)-deprenyl. Blood samples taken after 0, 3, 6, 24, 48 and 72 hours. After 48 hours, the patches were removed and carry out a similar procedure to that carried out for the second group.The fourth group of pigs treated with the drug UG-191, containing 30 mg of (-)-deprenyl. Blood samples taken after 0, 3, 6, 24, 72, and 96 hours. After 48 hours, the patches were removed and repeat the procedure described above for the second group.Blood is taken from the cranial cavity 20 mm plastic syringe containing 1.5 ml of 7.6%-aqueous solution of Na-citrate. The volume of blood (for each sample) is 18.5 ml.The activity of MAO determined radiometrically in accordance with the methods Wurtman and Axelrod [Biochem, Pharmacol. 12, 1414-19 (1963)], slightly modified K. Magyar (b: Monoamine Oxidases and their Selective Inhibition. Ed.: K. Magyar, Pergamon Press, Akademial Kiado, Budapest, 11-21 (1980)).To obtain preparations of platelets using the method described Willberg Oreland (Med.Biol., 54; 137-44; ia shown in table 6.The results of determining the activity of MAO in the brain are presented in table 7.Various control preparations have the following compositions, the particle size and the percentage of liquid crystal phases:
PEG 4000 - 16.0 g
PEG 400 - 60,0
Propylene glycol - 8.0 g
Cremophor El - 2.0 grams
Deprenyl HCl - 5.0 g
PEG 400 ad 100.0 g
Average particle size: 72,7 μm, the liquid crystal phase: 20%.UG-167
PEG 4000 - 19,0 g
PEG 400 - 55,0 g
Propylene glycol - 8.0 g
Xanthan gum - 10.0 g
Deprenyl HCl - 5.0 g
Peg 400 ad 100.0 g
Average particle size: 91-109 μm, the liquid crystal phase: 70-80%. 1. Two-phase pharmaceutical composition for the treatment of neurodegenerative diseases, containing the active ingredient and pharmaceutically acceptable additives, characterized in that the active substance contains an inhibitor of monoamine oxidase (MAO) and absorption inhibitor.2. The composition according to p. 1, characterized in that said inhibitor is a reversible or irreversible inhibitor of MAO prolonged action.3. The composition according to p. 1, characterized in that it contains an inhibitor of prolonged absorption dei.% and the inhibitor of the uptake of 5 - 95 wt. %.5. The composition according to p. 1, characterized in that it contains MAO inhibitor and an inhibitor of absorption in relation to(1 - 19) : (1 - 19).6. The composition according to p. 1, characterized in that it specified absorption inhibitor is used in the form of dosage forms with delayed action.7. The composition according to p. 1, characterized in that it is an MAO inhibitor is a hydrochloride of N-[1-phenylisopropyl]-N-methylpropylamine or its optically active isomer.8. The composition according to p. 1, characterized in that it is an MAO inhibitor is N-[4-forfinal] -isoprop-1-yl-N-methylpropylamine or its optically active isomer.9. The composition according to p. 1, characterized in that it is an inhibitor of the absorption delayed action is the hydrochloride of N-[1-phenylisopropyl]-N-methylpropylamine, or its metabolite, or their optically active isomers or metabolites.10. The composition according to p. 1, characterized in that it is an inhibitor of the absorption delayed action is N-[4-forfinal]-isoprop-1-yl-N-methylpropylamine or its metabolite, or their optically active isomers or metabolites.11. The composition according to p. 1, characterized in that its absorption inhibitor is a link the ilen group, C7- C10-phenylalkyl group, or panelgroup, or C3- C8-cycloalkyl group;
R2is a straight or branched C1- C8is an alkyl group or a C1- C8is an alkyl group substituted by halogen atom, hydroxy-group, C1- C4-alkoxygroup, or one or two phenyl groups, a phenyl group or a C3- C8-cycloalkyl group, provided that R1and R2together contain at least 3 carbon atom,
or its acid additive salts or metabolites.12. The composition according to p. 11, characterized in that it as an active ingredient is used as a compound of General formula I, where R3represents ethyl, through boutelou, hexeline, phenyl or phenylmethylene group.13. The composition according to p. 12, characterized in that it is a compound of General formula I is N-propyl-1-phenyl-2-pentylamine or acid additive salt, N-propyl-1-phenyl-2-butylamine or acid additive salt, or N-propyl-1-phenyl-2-hexylamine or acid additive salt.14. A method of obtaining a pharmaceutical composition for the treatment of neurodegenerative zabolevaniya and absorption inhibitor is mixed with a pharmaceutical acceptable excipients.15. The method according to p. 14, characterized in that the above composition is made in the form of a two-phase granules, tablets or preparation for percutaneous administration.16. The method of treatment of clinical disorders, developing as a result of neurodegenerative processes, including the introduction of the active substance, wherein the patient is administered an effective dose of the compositions of p. 1 to reach the level of inhibition of MAO constituting at least 98%, and permanent reversible level of inhibition of absorption.17. The method of treatment of clinical disorders, developing as a result of neurodegenerative processes under item 16, wherein the patient is administered MAO - inhibitory dose sufficient to achieve a constant level of inhibition of MAO constituting at least 98%, and the absorption - inhibitory dose sufficient to achieve a permanent reversible level of inhibition of absorption.Priorities for items:
20.12.91 on PP.1 - 3, 6 - 17;
08.12.92 on PP.4 and 5.
FIELD: medicine, anesthesiology, resuscitation.
SUBSTANCE: one should perform puncturing of epidural space at Th12-L1 level. Through the lumen of puncture needle one should introduce catheter to move it cranially at the depth of 3 cm. After that one should inject 10 ml 05%-marcaine solution to perform repeated injections per 5.0 ml every 4 h during 1-8 d. The effect is achieved due to unloading minor cycle of circulation.
EFFECT: higher efficiency of therapy.
FIELD: medicine, pharmacy.
SUBSTANCE: invention proposes new tablets with size less 3 mm with sustained-releasing the opioid analgesic drug for 30 min in the amount above 75%. Invention provides opioid for oral intake with taking into account individual necessity of patient due to selection of required amount of mictotablets by dispenser.
EFFECT: valuable properties of tablet, expanded assortment of medicinal formulations of opioid analgesics.
19 cl, 4 tbl, 4 ex
FIELD: medicine, endocrinology.
SUBSTANCE: the present innovation deals with preventing diabetes mellitus and its aftereffects. It is suggested to apply sibutramin and its analogs to decrease non-susceptibility to insulin in diabetes-free patients, prevent decreased tolerance to glucose and decrease the quantity of introduced insulin in diabetes-suffering patients and normalize body weight, as well.
EFFECT: higher efficiency of application.
28 cl, 3 dwg, 1 tbl
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new derivatives of benzene of the formula (I): wherein A represents a group taking among the following groups: -C≡C-, -CH=CH-, -CH2-CH2; n = 1 or 2; X represents hydrogen, chlorine or fluorine atom or methyl or methoxy-group; Y represents hydrogen, chlorine or fluorine atom; R1 represents cyclohexyl group monosubstituted, disubstituted, trisubstituted or tetrasubstituted with methyl group, phenyl group monosubstituted or disubstituted with fluorine or chlorine atom or methoxy-group, cycloheptyl, tert.-butyl, dicyclopropylmethyl, 4-tetrahydropyranyl or 1- or 2-adamantyl, or adamantine-2-ol group; or R1 represents phenyl group and in this case X and Y both represents chlorine atom; R2 represents hydrogen atom or (C1-C4)-alkyl group; R3 represents (C5-C7)-cycloalkyl, and salts of these compounds formed by addition of pharmaceutically acceptable acids, and their solvates and hydrates also. Also, invention relates to methods for preparing compounds of the formula (I) and to pharmaceutical composition able to interact with receptors sigma-2 based on these compounds. Invention provides preparing new compounds and medicinal agents based on thereof for treatment of autoimmune states, disturbance on heart contraction frequency and control against proliferation of tumor cells.
EFFECT: improved preparing methods, valuable medicinal properties of compositions.
18 cl, 14 tbl, 78 ex
SUBSTANCE: method involves administering typical tricyclic antidepressants combined with selective reverse serotonin capture inhibitors. Anxious version of subpsychotic level depressive syndrome of endogenous genesis being treated, intravenous drop-by-drop infusion of 2.-4.0 ml of 1% amitriptiline solution per 200 ml of physiologic saline is applied in 12-14 procedures combined with selective reverse serotonin capture inhibitor given per os, Zoloft is per os administered as the inhibitor at a dose of 50-100 mg. Then, supporting Zoloft therapy is applied at a dose of 100 mg during 3 months. Atypic version of depressive syndrome of subpsychotic level and endogenous genesis is treated with intravenous drop-by-drop infusion of 1.25% Melipramine solution at a dose of 2.0-4.0 ml per 200 ml of power supply source in 12-14 infusions combined with a reverse serotonin capture inhibitor. Paxyl is taken at a peroral dose of 40-60 mg as the inhibitor. Then, supporting Paxyl therapy is applied at a dose of 40-60 mg during 3 months.
EFFECT: enhanced effectiveness of treatment; reduced risk of complications; accelerated depressive syndrome relief.
SUBSTANCE: the suggested transdermal therapeutic system (TTS) is indicated for percutaneous injection of tolterodin for several days. It is, also, described the method for its manufacturing. The suggested TTS is being a self-gluing lamellar matrix structure that contains methacrylate copolymer including ammonium groups, at least, one plastifier and up to 25 weight% tolterodin. TTS is of good tolerance by skin and is of good physical and chemical stability at prolonged storage and application, it, also, has got good adhesive properties and can provide the penetration of maximal quantity of active substance through skin.
EFFECT: higher efficiency of application.
8 cl, 2 dwg, 3 ex, 3 tbl
FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.
EFFECT: improved and valuable properties of compounds.
6 cl, 5 tbl, 19 ex
SUBSTANCE: method involves applying fractal introduction of 0.2 mg/kg MT calypsol and 0.4 mcg/kg MT fentanyl every 10 min during operation. Additional local spinal cord root irrigation with 2% lidocaine solution at maximum traumatic operation moment.
EFFECT: enhanced effectiveness of treatment; preserved spontaneous patient respiration.
FIELD: organic chemistry, medicine.
SUBSTANCE: invention reports about preparing new substituted derivatives of 2-dialkylaminoalkylbiphenyl of the general formula (I):
wherein n = 1 or 2; R1 means cyano-group (CN), nitro-group (NO2), SO2CH3, SO2CF3, NR6aR7a, acetyl or acetamidyl; R2 means hydrogen atom (H), fluorine atom (F), chlorine atom (Cl), bromine atom (Br), cyano-group (CN), nitro-group (NO2), CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; or R1 and R mean in common group -OCH2O, -OCH2CH2O, CH=CHO, CH=C(CH3)O or CH=CHNH; R3 means H, F, Cl, Br, CN, NO2, CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; R4 and R5 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6 and R7 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6a means hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R7a means unsubstituted (C1-C6)-alkyl as their bases and/or salts of physiologically acceptable acids, with exception of compound representing 4-chloro-2'-dimethylaminomethylbiphenyl-2-carbonitrile and to a method for their preparing. Derivatives of 2-dialkylaminoalkylbiphenyl can be used in medicine for treatment or prophylaxis of pains, inflammatory and allergic responses, depressions, narcomania, alcoholism, gastritis, diarrhea, enuresis, cardiovascular diseases, respiratory ways diseases, cough, psychiatry disorders and/or epilepsy.
EFFECT: valuable medicinal properties of compounds.
13 cl, 2 tbl, 43 ex
FIELD: obstetrics and gynecology.
SUBSTANCE: over a 2-5 day period, 2.0 ml of Ginipral is administered once a day intravenously in a drop-by-drop manner followed by intravenously drop-by-drop administered 30-40 min later 2.0 ml of Instenone and, in the evening, 1 dragee Instenone orally. Afterwards, Instenone and Ginipral are administered orally: the former in dose of 1 dragee thrice a day with meal and the latter in dose of 1 pellet four times a day after meal until symptoms of the risk of prevention of pregnancy disappear.
EFFECT: prolonged pregnancy and prevented premature birth, which favors reduced irritation, normalized tonus, contractive activity of uterus, and improved psychic and emotional state of women.