Glycine-based pharmaceutical composition of prolonged action and method of its obtaining

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry and represents pharmaceutical composition of prolonged action which includes non-agglomerated particles, containing active substance glycine and auxiliary substances, characterised by the fact that non-agglomerated particles represent nanoparticles with size from 170 to 500 nm, containing biodegradable polymer, as auxiliary substance polyvinyl alcohol as SAS, poloxamer as stabilising agent and cryoprotectant.

EFFECT: invention ensures increase of bioavailability of active substance glycine resulting from application in composition of biodegradable polymer, due to which coefficient of transmission and glycine assimilability increase, and time of glycine activity in organism grows.

4 cl, 5 ex

 

The invention relates to pharmaceutical industry, and in particular to pharmaceutical compositions for the manufacture of the drug glycine prolonged action on the basis of biodegradable polymers and excipients.

Pharmacological action of glycine is reflected in the change of many functions, and the estimated range of specific pharmacological activity, and indications for its use are very diverse, although not always substantiated experimentally and do not always have clinical confirmation.

According to current data glycine is one of the most widely used drugs in neurological clinical practice. It seems that its therapeutic efficacy is due to:

- universal anti-stress effect is not accompanied by a sedative effect;

- ability to normalize the condition of the nervous system during hyperphosphatemia, fatigue and intoxication;

- normalization of emotional and neurological status;

- improving mental performance, memory;

the presence of a neuroprotective effect;

- detoxifying action of the drug in the chemical (including pharmaceuticals) intoxication.

It should be noted, and other important properties of glycine, allowing you to apply it in different diseases is the be:

- the absence of contraindications and side effects;

- no age restrictions for admission;

- wide range of selection of individual dosages;

- ability to create complex treatment regimens in combination with other medicines.

Glycine increases the effectiveness of both typical and atypical antipsychotic drugs. In the patent US 6162827 A1 "Treatment of negative and cognitive symptoms of schizophrenia with D-serine" patented method for the treatment of schizophrenia, namely the reduction of negative symptoms of schizophrenia, using glycine.

Glycine penetrates into most body fluids and tissues of the body, including in a limited quantity in the brain; metabolized to water and carbon dioxide, its accumulation in the tissues does not occur.

Renowned pharmaceutical composition of the prolonged action on the basis of the glycine containing 98,1-and 99.8 wt.% not agglomerated particles of drug substance - aminouksusnoy acid (glycine), coated with a polymer shell microcapsules), including 97,6-99 wt.% drug and 1-2,4 wt.% film-forming, 0.1 to 1.0 wt.% lubricating and 0.1 to 0.9 wt.% water. In the song entered the Ripper, representing a medicinal substance in an amount of 0.1-10 wt.% by weight of the mixture. The method of obtaining the composition includes a preview of extortion is their crystals, coated with a polymer shell microcapsules), by drawing on not agglomerated particles of drug substance of the shell of the binder and add lubricating and loosening of the components. During the production of microcapsules and/or during interim storage, the moisture content in the shell is brought to a concentration of not more than 0.5 wt.%, and before adding lubricating and loosening of the components of the microcapsules is humidified with water to 0.1-0.9 wt.%. The resulting composition can be monitored over time raspadaemosti without the use of additional auxiliary substances (EN 2171673 C1, publ. 10.08.2001). Medicinal product on the basis of such composition is applied sublingually. Time raspadaemosti tablets is not less than 10 minutes and no more than 30 minutes.

It is known that the presence of the blood-brain barrier (BBB) complicates the treatment of many diseases of the Central nervous system, as it does not skip a number of drugs, including glycine.

Poor permeability of glycine through the BBB encourages physicians to apply mnogohramie number of glycine (30-100 g on one admission), which, however, does not achieve therapeutic effect, possibly due to the relatively rapid destruction without toxic effects, and due to the overpowering tissue barriers such as the BBB. Long is inoe circulating in the bloodstream optimal quantities of glycine can make the most of low bandwidth GEB for glycine. The creation of delivery and at the same time the Deposit of glycine using nanoparticles increases the bioavailability and efficacy of glycine as a pharmacological agent.

The objective of the proposed invention is to provide a highly effective composition of glycine prolonged action, which ensures its high bioavailability.

Thus, the need to have a constant source of glycine, capable for a certain period of time to maintain necessary for cell-level glycine, is a dominant pharmacological criterion for selecting parameters of a new drug. As such a source or depot support the optimal level of glycine in the mode of current needs, it is proposed to use nanoparticles loaded with glycine. In nanoparticle form glycine can act as fields glycine front Desk in the local sublingual region, and in other glycine-recipe areas of the body, eliminating physiological and even pathophysiological deficiency in this important neurotransmitter.

In connection with the above to create a glycine depot best suited biodegradable polymers, which, when introduced into the body, capable of long-circulating in the body for a controlled time (hours-days).

Technical re is the query result of the invention is to increase the bioavailability of the active substance - glycine as a result of use of the composition of the biodegradable polymer, whereby the ratio of transmission and absorption of glycine and increase the activity of glycine in the body increases.

Technical result is achieved by a pharmaceutical composition of prolonged action, including whether the particles containing the medicinal substance glycine and excipients, in which whether the particles are nanoparticles ranging in size from 170 to 500 nm, containing a biodegradable polymer, as auxiliary substances polyvinyl alcohol (PVA) as a surfactant, poloxamer as a stabilizer and cryoprotector in the following ratio, wt.%:

Glycine1÷50
A biodegradable polymer25÷65
Polyvinyl alcohol : 15÷30
Poloxamer0,3÷2,5
Cryoprotector5÷20

At the same time as the biodegradable polymer composition includes bioassimilable substance selected from a number of polylactide, or polylactic the/glycolide, or polybutyl-cyanacrylat.

As cryoprotectant composition comprises D-Mannitol, or glucose, or starch in an amount of 5÷20 wt.%.

The technical result is also achieved by a method of obtaining the above-described pharmaceutical composition, comprising a mixture of medicinal substance glycine with auxiliary substances and drying to obtain not agglomerated particles, in which to obtain a mixture of glycine with auxiliary substances are mixed solution of biodegradable polymer in an organic solvent (acetone, chloroform and the like) with an aqueous solution poloxamer and glycine, heat the mixture to remove the organic solvent, filter it, add in the mixture of cryoprotector and stirred, and drying the obtained mixture is performed by freeze-drying to obtain powder.

The invention provides for obtaining a new nonformula drug prolonged action "N-glycine" based on biodegradable polymers. Prepare consists of nanoparticles of biodegradable polymer loaded with active substance - glycine, which has led to an increase in the bioavailability of the active substance, along with free transport of molecules expected in the blood stream glycine associated with nanoparticles. The process of assimilation will occur is s not only in the oral cavity, but at different levels of the gastrointestinal tract (GIT), are used for this purpose a special polymer, namely a biodegradable, i.e. enzymatic destructible. Thanks to the new structure becomes possible to reduce the frequency and dose of the drug. Also nonprepared prolonged action of N-Glycine in the future will expand the range of indications for use of the drug, in particular as antipsychotic, will improve the efficiency of the course of pharmacotherapy at the established indications.

Drug prolonged action "Nano-Glycine", briefly "H-Glycine", belonging to metabolisim as a pharmacological tool belongs to the drug metabolic activity level. The active ingredient of nonprepared prolonged action "N-Glycine is aminosilica glycine. The product, N-Glycine" in appearance is a powdery porous mass of white and yellow. Can be used for preparation of a powder, tablet, capsule, solution of glycine, as well as injectable form of prolonged action.

New nanoscale drug dosage form has a sedative (calming), mild anxiolytic (anti-anxiety) and weak antidepressant effects. According to the results of preclinical studies of the drug can classific is encoded as practically non-toxic. Installed: dosage form aerogene and has no irritant effect.

The specific activity of the N-Glycine" was significantly higher than the Comparators (EN 2171673 C1), and was evident after 24 and 48 hours, which was not observed in the latter.

The composition and method for producing nanosized powder dosage form of the drug "H-Glycine".

The proposed method is based on the method of emulsification, which obtained nanoparticles based on biodegradable polymer.

The proposed composition includes:

- glycine - active substance.

- biodegradable polymer (polylactide, or polylactide/glycolide, or polybutyl-cyanoacrylate, or other),

polyvinyl alcohol (surfactant),

- poloxamer stabilizer,

- cryoprotector (D-Mannitol or starch, or glucose, or other).

Polyvinyl alcohol is used as a surfactant stabilizer secondary emulsion upon receipt of polymeric nanoparticles loaded with glycine.

Poloxamer is used as the primary stabilizer (water in oil) emulsion upon receipt of polymeric nanoparticles. Poloxamer (other names - pluronic, proxamol) is a nonionic surfactant, represents the block copolymers of polyethylene glycol and polypropyleneglycol with a molecular mass of from 4 to 15 thousand. Poloxamer applied and the finding as a specialized means of a separate process step. The purpose of step is to obtain a relatively stable spatial distribution of molecules of glycine, which is achieved by dissolving it in a solution poloxamer acting as special reaction medium. This achieves a kind of spatial "fixation" of the molecules of glycine. The creation of such a reaction medium, representing a dispersed system or specific colloidal solution, and opens the possibility, as determined by us experimentally, it becomes necessary condition for the formation of the subsequent process stages nanoparticles loaded with glycine, which may translate into a finished dosage form.

The proposed composition may include various poloxamer, for example, Poloxamer-188 in the amount of 0.3÷1.5 wt.% or Pluronic F127 in the amount of 0.5÷2.5 wt.%.

Cryoprotector, for example, D-Mannitol, or starch, or glucose, is used to prevent clumping of the nanoparticles during freeze-drying, as well as to ensure resuspendable prepared to separate particles during the formation of colloidal micellar system when used.

The following are examples of formulations of the proposed composition.

Example 1

The composition G1-1,

in wt.%:

Glycine31,5
Polylactid/glycolide PLGA 50/5031,5
Polyvinyl alcohol : 25,0
Pluronic F1271,0
D-Mannitol11,0

The ratio of glycine: PLGA 50/50 is 1:1.

Example 2

The composition of the Gl-2,

in wt.%:

Glycine10,0
Poly(DL-lactide)-COOHof 57.5
(PLA-COOH)
Polyvinyl alcohol : 24,5
Poloxamer 1882,7
D-Mannitol5,3

The ratio of glycine: PLA-COOH is 1:6

Example 3

The composition G1-5,

in wt.%:

Glycine11,8
Poly(DL-lactide)47,8
(DL-PLA)
Polyvinyl alcohol : 29,2
Poloxamer 18815
D-Mannitolthe 9.7

The ratio of glycine-DL-PLA is 1:4.

Example 4

Composition Gl-4,

in wt.%:

Glycine5,8
Polylactid/glycolide (PLGA 50/50)57,8
Polyvinyl alcohol : 16,2
Poloxamer 1880,6
Starch19,6

The ratio of glycine: PLGA 50/50 is 1:10

Example 5

The composition G1-3,

in wt.%:

Glycine19,7
Polybutyl-cyanoacrylate, RSA39,4
Polyvinyl alcohol : 28,1
Poloxamer 1881,4
Glucose11,4

The ratio of glycine: RVCA is 1:2.

Table 1 shows the size distribution loaded licina nanoc STIC biodegradable polymers.

Table 1
Ciphers sampleUnimodal analysisThe distribution of particles sizes
The value of size, nmThe average value, nmThe standard deviation, nmThe coefficient of variation, %
G1-1590502214,2
G1-24433245718
G1-33522797527
Gl-42561689053
G1-54132877325
P≤0,05

Excess glycine which can cause discomfort however, the drug is practically non-toxic by the results of experimental preclinical studies.

It should be noted also the lack of the drug dosage form "N-Glycine" irritating to the wall of the vein, epithelial tissue (skin, subcutaneous tissue, muscle and apyrogenicity fluids. A new drug is well tolerated and safe. Increased bioavailability of glycine reduced the drug 5 times.

The proposed method of producing a pharmaceutical composition as follows.

For nanoparticles according to the developed technology, the active substance is added to the reaction mixture, which is a solution of selected biodegradable polymer

An example of obtaining N-glycine.

Under stirring on a magnetic stirrer was dissolved in chloroform PLGA 50/50 and after 5 minutes a solution "A".

Under stirring on a magnetic stirrer was dissolved in water, glycine, poloxamer and received the solution "B".

Under stirring the solution "A" portions solution was added to "B". Was performed by homogenization to obtain a primary emulsion. Added PVA and stirring was carried out by repeated homogenization.

Evaporated chloroform under vacuum in a rotary evaporator. After evaporation was obtained colloidal solution of CH is CIN-polymer. This solution could contain large particles, for the Department which was carried out by filtration through a glass filter. Then added D-Mannitol and dissolved it. Then carried out the lyophilization within 20÷22 h at 0.03÷0.1 mbar. Got white liofilizovannye powder.

Below are the results of the test animals in the open-field test, which confirmed the high efficiency of the proposed pharmaceutical composition.

Open field (OP) is a classical test methodology for studying the behavior of rodents in an unfamiliar stress situation - an open, brightly lit space.

A study on rats conducted at the facility - OP, which represents a square area of size 100×100 mm, enclosed by a wall height of 400 mm (material - matte polystyrene). The space is divided into 25 squares and has a uniform illuminance 90 Suite.

Open field for mice is circular arena with a diameter of 600 mm with a wall height of 600 mm, divided into 36 equal sectors.

Table 2 shows the results of tests to study the effects of the claimed preparation of N-Glycine on the behavior of rats. A comparative analysis of the influence of N-Glycine and the comparison drug - substance Glycine on the behavior of white rats in the open field test after 1 hour after the/b injection showed that N-Glycine Okaz the characteristic expressed reliable anxioselective action throughout the range of tested doses (4,25 mg/kg, 8.5 mg/kg, was 12.75 mg/kg). Indicators of severity of anxiolytic and sedative components was significantly higher under the action of N-Glycine, indicating its higher efficiency.

Thus, the duration of the latent period of retirement from the starting area (PL) were in groups H-Glycine 5-10 times higher than in groups of Glycine in appropriate dosages. The absolute value of the length LP in groups H-Glycine to a lesser extent depended on the dose of the drug (3,3 sec to 5.0 sec)than in the groups of the reference preparation substance Glycine (0.3 sec-1.0 sec).

A comparative analysis of the influence of N-Glycine and Comparators Glycine production m CPP and Glycine production "Biotics" on the behavior of mice C55Bl/6 and BALB/c males in the open field test after the on/in the introduction of drugs (table 3) showed that a single injection of N-Glycine had a reliable calming effect in the whole range of tested doses (30 mg/kg, 15 mg/kg, 5 mg/kg), whereas in the/with the introduction of Comparators Glycine (m CPP) and Glycine ("Biotics") was accompanied by a significant difference from the behavior of animals from the control groups only under the influence of drugs at the doses of 30 mg/kg and 15 mg/kg and almost had no significant effect at a dose of 5 mg/kg And expressed the ity of the H-Glycine in the lowest dose (5 mg/kg) was equivalent to the effect of higher doses of Comparators (30 mg/kg).

It is important to note that with the introduction of N-Glycine is the smallest of the tested doses (5 mg/kg) on efficiency appeared to be equally effective most of the tested doses with Comparators (30 mg/kg). N-Glycine is the smallest of the tested doses have an impact on the performance of the behavior, and the Comparators in this dose had no significant influence.

The result shows that N-Glycine was produced significant anxiolytic, mild sedative effect on the performance behavior of inbred mice C55Bl/6 and BALB/c mice when tested in the open-field test.

Specific calming effect more clearly demonstrated in tests on mice of BALB/c, with d-Glycine had a more marked impact on the performance behavior of mice than the Comparators Glycine m CPP and Glycine "Biotics". Equally effective dose was found to be 5-6 times lower than Comparators (5 mg/kg under the action of N-Glycine of about 30 mg/kg, under the action of Comparators).

In tables 3-6 shows the results of a comparative study of the delayed effects of the drug prolonged action of N-Glycine in rats with different routes of administration.

Indicators of the behavior of rats in the OP are prognostic features what IKI levels of anxiety (fear) and resistance to emotional stress. In the modern view, the behavior of the animal in the OP reflects mainly the implementation of the conflict between the two motivations - the inherited program (instinct) research new environment (response to novelty) and the instinct of self-preservation, is reflected in the desire to minimize the potential danger from a new, unfamiliar environment (Leonard, 1989). The study of the new environment is carried out by behavioral responses GDS and the WDA. Hours are seen as a way of distant examination of space as an indicator of research activity (Sarkisova and others, 1996), is sensitive to the level of anxiety or action of anxiolytics (Krupina and others, 1996). Tactics survey of the field directly in the center, the waste towards the centre, free crossing the space, seen as an indicator of lower levels of anxiety. In General, it is believed that the reduction in the overall mobility of animals in this test is the result of increasing the level of their emotional stress. The desire to minimize the potential danger posed by the new environment, in the extreme, can cause complete immobility (reaction "freezing" (freezing). The starting location of the animal directly on the floor of the arena creates the conditions for the registration of the response of an animal on the emotional factor "neogidanno the ü", thus placing the rat in the center of the arena in most cases triggers izberatelnuyu reaction with a short latent period (LP), and the higher the anxiety level, the shorter the duration of the PL. At a lower level of anxiety animals will start after the estimated reaction, which takes some time. The classical influence of tranquilizers is reflected in the increasing values of PL, frequency and duration of output in Central and adjacent sectors of the field.

In accordance with the above interpretation, under the influence of a single systemic injection of N-Glycine rats with different routes of administration - both orally and intraperitoneally, showed significant anxiolytic and sedative effects of the drug on behavior of rats in the test animals in the open field test after 1 hour, 24 hours and 48 hours after single administration of the drug, which was not observed in the experiment after the introduction of the substance Glycine or drug comparison Glycine production m CPP.

N-Glycine, 1 h after injection (table 2) had expressed reliable anxioselective action throughout the range of tested doses (4,25 mg/kg, 8.5 mg/kg, was 12.75 mg/kg), whereas substance Glycine had significant behavioral changes in rats only at high doses (8.5 mg/kg, was 12.75 mg/kg). When this display is eating severity of anxiolytic and sedative components, was significantly higher under the action of N-Glycine, indicating its higher efficiency in relation to drug comparison,

Disposable oral (W/W) introduction N-Glycine rats after 24 hours or 48 hours from the moment of introduction (table 6) provided reliable anxiolytic and calming effect in the whole range of tested doses (4,25 mg/kg, was 12.75 mg/kg of 25.5 mg/kg), while in b/W drug comparison Glycine m CPP or Glycine "Biotics" neither after 24 hours (table 4)or 48 hours (table 5) from the moment of oral administration was not accompanied by a significant change in behavior relative to the control groups. Significant differences on the performance behavior of animals from the control groups were not found for any of the tested doses. Therefore, N-Glycine showed delayed specific effect after 24 hours and after 48 hours, indicating a prolongation specific anxioselective of action of the drug. Data quality and type of activity of the Comparators do not possess.

In tests on mice found that N-Glycine was produced significant anxiolytic and mild sedative effect on the performance behavior of inbred mice 55l/6 and BALB/c mice when tested in the open field test after/in the introduction (table 3). Specific calming effect ven the drugs more clearly demonstrated in tests on mice of BALB/c, when this N-Glycine had a significantly more pronounced effect on the performance behavior of mice than the Comparators Glycine m CPP and Glycine "Biotics". Equally effective dose of the drug N-Glycine was 5-6 times lower than Comparators (5 mg/kg under the action of N-Glycine of about 30 mg/kg, under the action of Comparators), indicating significantly greater efficacy of N-Glycine in this test.

The results also confirm the higher efficiency of N-Glycine compared with the closest analogue, because glycine is present in the same form as in the Comparators used in the research.

1. The pharmaceutical composition of prolonged action, including whether the particles containing the active ingredient glycine and excipients, characterized in that whether the particles are nanoparticles ranging in size from 170 to 500 nm, containing a biodegradable polymer, as auxiliary substances polyvinyl alcohol as a surfactant, poloxamer as a stabilizer and cryoprotector in the following ratio, wt.%:

Glycine1÷50
Biodegradable of polim the p 25÷65
Polyvinyl alcohol : 15÷30
Poloxamer0,3÷2,5
Cryoprotector5÷20

2. The composition according to claim 1, characterized in that the biodegradable polymer nano-carrier includes bioassimilable substance selected from a number of polylactide, or polylactide/glycolide, or polybutyl-cyanoacrylate.

3. The composition according to claim 1, characterized in that as a cryoprotectant comprises D-Mannitol, or glucose, or starch in an amount of 5÷20 wt.%.

4. A method of obtaining a pharmaceutical composition according to any one of claims 1 to 3, comprising the mixture of the active substance glycine with auxiliary substances and drying to obtain not agglomerated particles, characterized in that to obtain a mixture of glycine with auxiliary substances are mixed solution of biodegradable polymer in an organic solvent with an aqueous solution poloxamer and glycine, heat the mixture to remove the organic solvent, filter it, add in the mixture of cryoprotector and stirred, and drying the obtained mixture is performed by freeze-drying to obtain powder.



 

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3 cl, 5 ex, 15 tbl

FIELD: medicine; medical engineering.

SUBSTANCE: method involves supplying target materials and core materials, carrying out target materials ablation with washed-out particle materials being produced and coating core materials with the washed-out particle materials. The method is applied under pressure of approximately equal to 10 torr or higher. Coating of thickness from one to several nm is applied at atmospheric pressure with pseudo-fluidized particle substance state, achieved by means of pneumatic pseudo-fluidization, being used.

EFFECT: improved pharmacokinetic drug properties.

22 cl, 22 dwg

The invention relates to medicine and relates to tablets with intersolubility coating and method of its preparation
The invention relates to medicine, namely to technology drugs with bacterial preparations, method for obtaining microencapsulated forms of microorganisms using a copolymer of acrylic and methacrylic acids in aqueous suspension

The invention relates to a pharmaceutical dosage form for oral administration containing a proton pump inhibitor and one or more means of nonsteroidal anti-inflammatory therapy in the form of a metered dose of the drug, in which the proton pump inhibitor is protected intersolubility coating, means non-steroidal anti-inflammatory therapy, to a method for producing a dosage form and method for the treatment of side effects in the gastrointestinal tract as a result of treatment by means of a non-steroidal anti-inflammatory therapy

FIELD: medicine.

SUBSTANCE: invention refers to a liposomal preparative form for dermatological and external pharmacological application. A liposomal nanocapsule represents a hollow sphere formed by a bilayer lipid membrane containing inner and outer hydrophilic layers comprising an aqueous extract of peloids with a hydrophobic area of the bilayer lipid membrane in between, comprising a lipid extract of peloids and polar charged molecules being arranged on the surfaces of the inner and outer hydrophilic layers. The liposomal nanocapsule comprises: an aqueous extract of peloids - 64%, an lipid extract of peloids - 25%, an aqueous complex of humic acids - 10%, a phospholipid-based stabiliser - 1%.

EFFECT: invention provides enhanced therapeutic and cosmetic effect of the liposomal nanocapsule.

1 dwg, 1 tbl, 2 ex

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