Pharmaceutical compositions consisting of multiple particles with sustained-release of serotonin reuptake selective inhibitor

FIELD: pharmacy.

SUBSTANCE: invention proposes pharmaceutical compositions consisting of multiple particles with sustained-release of serotonin reuptake selective inhibitor (SRSI) with membrane cover comprising ammonium-methacrylate copolymer, or compositions comprising SRSI particles mixture, or compositions comprising SRSI particles mixture in form of sustained-release of SRSI, Also, invention relates to method for treatment of depression involving administration of these compositions. In particular, SRSI represents fluoxetine, fluvoxamine, sertraline or their salt. Proposed compositions provide a less index of fluctuations that reflects lower values of maximal concentrations of substance in plasma blood after multiple administrations, safety and good tolerance also.

EFFECT: improved medicinal and pharmaceutical properties of compositions.

11 cl, 5 dwg, 26 tbl, 6 ex

 

The technical FIELD

The present invention relates to pharmaceutical compositions with controlled release and, in particular, to forms with controlled release of fluvoxamine and other selective (selective) inhibitors of reuptake of serotonin, intended for oral administration.

PRIOR art

Selective inhibitors of reuptake of serotonin (IIPS) (selective serotonin reuptake inhibitors, SSRf), typical representatives of which are uoxetine, fluvoxamine, paroxetine and sertraline) are used, along with other applications, such as antidepressants. In the following description, when referring to IIPS links will collectively refer to fluvoxamine, unless otherwise stated.

Maleate of fluvoxamine is a selective inhibitor of reuptake of serotonin (NT), belonging to the chemical class of 2-amino-ethyl-oxime-ethers of aralkylamines. Chemically it is known as the maleate 5-methoxy-4'-(trifluoromethyl)valerophenone-(E)-O-(2-amino-ethyl)oxime (1:1) and has the empirical formula C15H21O2N2F3·C4H4O4. Fluvoxamin and other Joksimovi esters disclosed in the description of U.S. patent No. 4085225 (US Philips Corp.). Described pharmaceutical compositions for tablets, suppositories and injections.

It was found that h is on fluvoxamin effectively reduces symptoms of depression and helps with obsessive compulsive disorders. It is convenient to introduce in the form of tablets (25 mg, 50 mg and 100 mg) in the form of the maleate of fluvoxamine, commercially available under the trademark Luvox (firm Solvay Pharmaceuticals Inc.). Traditional treatment fluvoxamine usually start with a single injection of 50 mg at night. The dosage can be gradually increased by steps of 50 mg every 4-7 days, subject to its portability, to achieve maximum therapeutic effect, but it should not exceed 300 mg per day. Preferably, the total daily dose, if it exceeds 100 mg, enter two separate portions. If these portions are not equal, the larger dose is usually given at night.

Fluvoxamin actively metabolized by the liver and is removed from the urine by the kidneys. Luvox® effect of extensive first penetration, which usually gives the size of the absolute bioavailability of about 53%. Usually after administration of a single oral dose Luvox® the peak level observed after 3-8 hours Indicated that the time of half-excretion fluvoxamine of plasma in healthy young volunteers in stationary phase after multiple oral doses of 100 mg per day equal to 15.6 hours

As indicated above, the dosage used is usually tablets fluvoxamine titrated to establish tolerated dose, with maximum therapeutic effect, divided into two portions doses greater than 100 mg Procedure article is panchaloha titration and side effects, accompanying the usual introduction once daily doses greater than 100 mg may reduce patients ' adherence to treatment and to postpone the achievement of therapeutic effect.

The closest analogue of the claimed invention is a composition as described in published international application WO 99/01121 A1, published 14.01.1999. However, this known structure is not able to provide specific parameters release, designed to provide optimal mode of treatment.

Therefore, the aim of the present invention is to propose a composition of controlled release selective inhibitor of reuptake of serotonin (NT). Another objective of the present invention is to propose a composition with controlled release of IIPS, suitable for administration no more than the average 12-hour intervals. Another worthless goal of the invention is to propose a composition with controlled release of IIPS, suitable for administration once or twice a day. Further, the present invention is to provide a method for treatment of depression and/or obsessive compulsive disorder.

The INVENTION

The present invention offers consisting of many particles of the pharmaceutical composition of controlled release selective inhibitor of reuptake of serotonin (IIPS) for oral the applications, which contains particles of a specified HIPS or its pharmaceutically acceptable salt, covered with controlling the rate of release of the polymer, providing a controlled release of the above HIPS for at least 12 hours after oral administration. The particles are preferably in the form of granules or beads.

Preferably next to these granules contain the core of the specified HIPS or its pharmaceutically acceptable salt, covered with the specified controlling the rate of release of the polymer with the formation of controlling the rate of release of the membrane surrounding the specified kernel.

According to one embodiments of the invention, controlling the rate of release of the membrane is composed of a predominant share pharmaceutically acceptable film-forming, water-insoluble polymer and (but not necessarily) smaller fraction of pharmaceutically acceptable film-forming, water soluble polymer, and the ratio of water insoluble polymer to water soluble polymer, if the specified water-soluble polymer is present, shall be such as to ensure that the rate of release of HIPS, allowing you to maintain a controlled release of HIPS for a period of not less than 12 hours after oral administration.

However, the membrane can be composed and the pharmaceutically acceptable film-forming, water-insoluble polymer. Alternatively, the membrane may be a mixture controlling the rate of release polymers, consisting of a predominant proportion of pharmaceutically acceptable film-forming, water-insoluble polymer and a smaller share pharmaceutically acceptable film-forming, water-soluble polymer.

Polymers that can be used to generate a speed control release membrane, described in more detail below.

According to a particularly preferred variant implementation, controlling the rate of release of the membrane contains ammonium methacrylate copolymer, as described below.

The core may contain an organic acid, and component HIPS and organic acid are present in a ratio of from 50:1 to 1:50.

Organic acid, if used, is preferably selected from adipic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid and tartaric acid. Component HIPS and organic acid, if the latter is present, preferably contained in a ratio of from 20:1 to 1:1 and more preferably in a ratio of from 10:1 to 2:1.

The active ingredient in the pharmaceutical composition of the present invention may, of necessity, represent the manage any selective inhibitor of the reuptake of serotonin. In particular, suitable active ingredients for use in the present invention include ingredients selected from citalopram, clomipramine, fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone and zimeldine, which are all in varying degrees, inhibit the re-uptake of serotonin.

The active ingredient may be present in free base form or in the form of pharmaceutically acceptable salts such as hydrochloric form or malata form.

Also suitable for application of the active ingredient may be present either in the form of a single sufficiently optically pure enantiomer or as a mixture of enantiomers - racemic or otherwise.

Preferred IIPS is fluvoxamin or its pharmaceutically acceptable salt.

According to one embodiments of the invention, the rate of release of IIPS of particles measured in vitro in 0.05 M phosphate buffer at pH 6.8 using a paddle apparatus USP type II for measuring dissolution according to USP (US Pharmacopoeia XXII)mainly corresponds to the following parameters go into solution:

(a) For 0.5 hour measurements in the specified device is released not more than 15% of IEPS;

(b) within 1 hour of measurement in the specified device is released no more than 25% of all IEPS;

(c) 2 hours of measurement in the specified is parate released from 20% to 75% of all IEPS;

(a) 4 hours of measurement in the specified device is released at least 75% of all IEPS;

(e) within 6 hours of measurement in the specified device is released is not less than 85% of all HIPS.

According to another variant implementation, the rate of release of IIPS of particles measured in vitro in 0.05 M phosphate buffer at pH 6.8 using a paddle apparatus USP type II for measuring dissolution according to US Pharmacopoeia XXII, mainly corresponds to the following parameters go into solution:

(a) within 4 hours of measurement in the specified device is released no more than 20% of all IEPS;

(b) 6 hours of measurement in the specified device is released no more than 45% of all IEPS;

(c) For 8 hours of measurement in the specified device is released from 45% to 80% of all IEPS;

(a) within 10 hours of measurement in the specified device is released at least 70% of all IEPS;

(e) within 12 hours of measurement in the specified device is released at least 80% of all HIPS.

The kernel contains (but not necessarily) a lubricating substance, such as, for example, sodium stearate, magnesium stearate, stearic acid or talc.

The core preferably contains IEPS or its pharmaceutically acceptable salt and connected with him organic acid (if present), enclosed in a polymeric material or binder, which is hereafter referred here by a polymeric material, if not indicated is ANO other. Component HIPS and polymeric material are preferably in the ratio from 1:1 to 100:1, more preferably from 5:1 to 30:1. The polymeric material can be rapidly soluble in water or, alternatively, may be freely permeable to thirty-two and water. However, the polymeric material can also be insoluble in water or, alternatively, may be permeable to thirty-two and water. Can also be used mixtures of any of the above-mentioned polymers, provided that the used polymer (polymers) effectively provide provide coverage of all IEPS in the kernel. The ratio of water-soluble/permeable and water-insoluble/poorly permeable polymers may be installed by a particular combination of selected polymers.

Preferably, the core contains:

(a) a powder mixture containing HIPS or its pharmaceutically acceptable salt, organic acid selected from adipic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid and tartaric acid; and

(b) a pharmaceutically acceptable polymer material, with specified polymer material is present in the amount, effectively providing coverage throughout the powder mixture in the kernel.

The core may contain alternating layers of the decree is Noah powder mixture and the polymer material.

The term "water soluble polymer" in the sense it is used here, includes a polymer permeable to water, such as Eudragit RL. Similarly, the term "water insoluble polymer" in the sense it is used here, includes polymers are permeable to water, such as Eudragit RS.

As the water-soluble polymer suitable polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, oxypropylation, oksipropilmetiltselljuloza or polyethylene glycol, or mixtures thereof.

As the water-insoluble polymer suitable ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), acetate-propionate, cellulose, acetate-butyrate cellulose, acetate-cellulose phthalate, cellulose triacetate, poly (methyl methacrylate), polimetilmetakrilat, polybutylmethacrylate, polyisobutylene, polyacrylnitrile, polyisobutylcyanoacrylate, polyarylethers, polyphenylmethyl, polymethylacrylate, polyisopropylene, polyisobutylene, paleoclimatologist, polyethylene, low density polyethylene, high density polyethylene, polyethylene oxide, polyethylenterephthalat, polivinilbutilovy ether, polyvinyl acetate, polyvinyl chloride or polyurethane, or their mixture.

A suitable polymer, which is easily permeable to fluvoxamine and water is, is polymer, commercially available under the trademark Eudragit® RL. A suitable polymer which is poorly permeable to fluvoxamine and water, is a polymer, commercially available under the trademark Eudragit® RS, or polymer, the permeability of which depends on pH, such as commercially available under the trademark Eudragit® L, Eudragit® S or Eudragit® E. the Polymers of the Eudragit family® is a polymeric lacquer substances based on acrylate and/or methacrylates.

Polymer materials are commercially available under the trademark Eudragit® RL and Eudragit® RS is an acrylic resin constituting the copolymers of esters of acrylic and methacrylic acid with a low content of Quaternary ammonium groups (as indicated in the brochure "Eudragit®" company Rohm Pharma GmbH (1985). Ammonium groups are present as salts and increase the permeability of the lacquer films. Eudragit® RL and RS is accordingly permeable (RL) and low permeability (RS), regardless of the pH of the material. Eudragit® L is an anionic polymer synthesized from methacrylic acid and methyl ester of methacrylic acid. It is insoluble in acids and pure water. He becomes soluble in neutral and slightly alkaline environment. The permeability of Eudragit® L depends on the pH. Above pH 5.0, the polymer becomes higher permeability. (Eudragit® L described in the brochure "Eudragit®" firm ohm Pharma GmbH (1986)).

Polymers Eudragit S and Eudragit L can be combined in any proportion in one covering film. Using a combination of polymers, it is possible to theoretically obtain a covering film that is soluble at pH values between pH values at which soluble Eudragit L and Eudragit S.

The polymeric material of the core may consist only of Eudragit RS, as described hereafter in the examples.

HIPS, organic acid (if present) and the polymeric material preferably are increasing on a Central inert core. This core may consist of grains of small drops of sugar/starch having an average diameter in the range of from 0.4 to 0.85 mm, usually from 0.71 to 0.85 mm for the composition without the organic acid and usually from 0.6 to 0.71 mm for composition with an organic acid. The actual size of the grain may vary depending on the desired for a particular part number input medicines/organic acid. The core can be created in a normal capacity to cover. Alternatively, HIPS, organic acid and polymeric material can be increased on a Central inert core, as defined above, in the automatic system to cover - for example, in the granulator CF. The core may also contain, in addition to the above components, additional components such as a dispersant Agay is t, easy slip agent and/or surfactant.

The polymer coating used to create controlling the rate of release of the membrane may also include one or more auxiliary agents selected from a filler, a plasticizer and suppressor pricing.

Typical fillers include talc, dust, silica, glyceryl-monostearate, magnesium stearate, calcium stearate, kaolin, colloidal silicon dioxide, gypsum, silica micron size, and magnesium trisilicate.

The preferred filler is talc.

The amount of filler ranges from about 2% to about 500% by weight, referred to the total dry weight of the polymer, preferably from 100% to 450%, more preferably from 410% to 440%.

The polymer coating may also include material that contribute to the treatment (processing) of polymers. Such materials are commonly known as "plasticizers" and include, for example, adipate, azelate, benzoate, citrates, isobutane, phthalates, Sabatini, stearates and glycols.

Typical plasticizers include acetylated monoglycerides; butylphenyl-butylglycol; dibutylated; diethylphthalate; dimethylphthalate; tiltall-ethylglycol; glycerol; ethylene glycol, propylene is likely; treatmentfrom; triacetin; tripropionin; diacetin; dibutyl phthalate; acetyl-monoglyceride; glycols; castor oil, triethylcitrate; polyhydric alcohols, esters of acetic acid, glycerol triacetate, acetyltributyl citrate dibenzylidene, DirectInput, butylacrylate, diisononylphthalate, dioctyladipate, epoxydecane Tallat, triisooctyl-trimellitate, diethylhexylphthalate, di-n-octylphthalate, di-ISO-octylphthalate, di-ISO-decylphthalate, di-n-undeciphered, di-n-tridecilateral, tri-2-ethylhexyl-trimellitate, di-2-ethylhexyladipate, di-2-ethylhexylamine, di-2-ethylhexyladipate, dibutylsebacate, glyceryl-monocaprylin and glyceryl-monocaprate.

The preferred plasticizer is dibutylsebacate.

The amount required for the use of the plasticizer is preferably from 10% to 50%, most preferably about 20%, relative to the weight of dry polymer.

An example of a foaming agent is simethicone (Simethicone). The amount required for the use of the foaming agent in the coating is preferably from 0% to 0.5% of the final composition.

The amount of polymer required for the formation of particles is determined based on the desired parameters of drug delivery, including the number dedicated to the delivery of the medication, the required speed of its release and particle size. The coating membrane polymer ranges from 10% to 100% increase in weight of the cores, preferably 25-70% weight gain due to polymer. Controlling the rate of release of membrane particles, including all solid components, such as the copolymer, filler, plasticizer and possible (not mandatory) additives and auxiliary substances for processing, increases the weight of the cores from approximately 11% to 450%, preferably weight gain from 30% to 160%. The polymer layer can be applied by any known method, including spray application. Spraying can be carried out using the apparatus for coating a moving layer (fluidized bed coaters (preferably Wurster coating)or in the system tray cover.

Covered kernel after applying the polymer layer (s) is subjected to drying or maturing. "Curing" means that the particles maintained at a controlled temperature for a time sufficient to ensure stable speeds release. Maturation can be performed, for example, in thermostat or in the device for drying a moving layer. Maturation can be performed at any temperature above room temperature.

The polymer coating can be applied isolating or enclosing layer.

Isolating or enclosing layer may be deposited on poly the black coating to prevent agglomeration of the particles.

The core is conveniently cover (packaging) controlling the rate of release of a polymer membrane containing at least one polymeric material, as described above. The core may be covered with any number of coating layers required to achieve the necessary speed of release.

Controlling the rate of release of the membrane may be a single polymer or a mixture of two or more polymers.

Water-insoluble polymer membrane is one of the above polymers for the core, it includes polymers permeable or impermeable to water, as described here above.

Similarly, the water-soluble polymer membrane is one of the above polymers for the core, it includes a polymer permeable to water, as described here above.

Ammonium methacrylate copolymers, including polymers, supplied by the company Rohm & Haas under the trademark Eudragit RS and Eudragit RL, which are mentioned above, are particularly suitable for use in controlling the rate of release of the membrane in the compositions of the present invention. These polymers are insoluble in pure water, dilute acids, buffer solutions or digestive fluids over the whole range of physiological pH values. Film swell in water and in digestive fluids regardless of pH values). the swollen state, they become permeable to water and dissolved active substances. The permeability of the films depends on the ratio ethylacrylate (EA), multimedialnych (MMA) and trimethylammoniumchloride chloride (THERE-C1) groups in the polymer. The polymers having a ratio EA:MMA:THERE is C1 = 1:2:0,2 (Eudragit RL), more permeable than polymers with a ratio of 1:2:0,1 (Eudragit RS). Films with Eudragit RL described as "insoluble film with high permeability, and film with Eudragit RS described as "insoluble film with low permeability".

The form of pharmaceutical compositions for oral administration with controlled release of HIPS of the present invention can be either in the form of multiple particle compositions, or in the form of tablets. The term "consisting of many particles", as used here, includes discrete particles, pellets, mini-tablets and their mixtures or combinations. Consisting of many particles form for oral dosages of the present invention may contain a mixture of two or more populations of particles, pellets or mini-tablets having different release characteristics in vitro and/or in vivo. For example, consisting of many particles form for oral dosage may contain a mixture component for permanent release and component for controlled release, placed in a suitable capsule, for example hard or soft gelatin capsule. If composed the C set of particles of the pharmaceutical composition is placed in the capsule, it can be administered by swallowing capsules or opening indicated capsules and plasma components into the food. Alternatively, consisting of many particles of the pharmaceutical composition may be placed in a bag (sachet).

Particles with one or more support materials-fillers can be compressed into tablet form, such as a multilayer tablet. Usually multi-layered tablet may consist of two layers, which may contain the same or different amounts of the same active ingredient having the same or different parameters of the release, or it may contain in each layer of different active ingredients. Such a multilayer tablet may be optional covered in controlling the release of the polymer so as to introduce additional properties of a controlled release.

As indicated above, the pharmaceutical formulations with controlled release of IEPS and forms for oral dosages of the present invention can contain auxiliary agents, such as, for example, diluents, lubricants, surfactants, dezintegriruetsja agents (leavening agents), plasticizers, caking agents, fogging agents, pigments, flavorings and other Specialists in this area is understandable, the exact choice of fillers and their relative amounts, to some extent, depend on the final form of oral dosages, which includes a pharmaceutical composition with controlled release of HIPS.

Suitable diluents include, for example, pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of these listed substances. Examples of diluents include microcrystalline cellulose, such as supplied under the trademark Avicel, including, for example, Avicel pH101, Avicel pH102, Avicel pH112, Avicel pH200, Avicel rn and Avicel pH302; lactose such as lactose monohydrate, anhydrous lactose and Pharmatose DCL21 (Pharmatose - trademark), including anhydrous, monohydrate and dried by spray drying forms; dibasic calcium phosphate such as Emcompress (Emcompress - trademark); mannitol; starch; sorbitol; sucrose and glucose.

Suitable lubricating agents, including agents acting on the fluidity intended for pressing powder are, for example, colloidal silicon dioxide, such as Aerosil (Aerosil-trademark); talc; stearic acid, magnesium stearate, calcium stearate and stearyl-fumarate sodium.

Suitable disintegrating agents include, for example, poorly sewn, polyvinylpyrrolidon is, corn starch, potato starch, maize starch and modified starches, sodium salt of cross-carmellose, cross-povidone, sodium starch glycolate, and combinations thereof and mixtures.

According to further aspect of the present invention features a pharmaceutical composition with controlled release of IEPS for oral administration, which is a mixture of particles, as defined above.

According to further aspect of the present invention features a pharmaceutical composition with controlled release of IEPS for oral administration, which is a mixture of particles, as defined above, in a mixture with form IEPS or its pharmaceutically acceptable salt intended for immediate release to ensure rapid achievement of effective therapeutic sense of the content of his blood.

Preferably the form IEPS intended for his immediate release, represents granules, as defined above, without a specified controlling the rate of release of the membrane.

According to one embodiments of the invention, the rate of release of HIPS of the pharmaceutical composition, measured in vitro in 0.05 M phosphate buffer at pH 6.8 using a paddle apparatus USP type II for measuring dissolution according to USP (US Pharmacopoei XXII), basically corresponds to the following parameters go into solution:

(a) within 1 hour of measurement in the specified device is released no more than 20% of all IEPS;

(b) 2 hours of measurement in the specified device is released no more than 60% of all IEPS;

(c) within 4 hours of measurement in the specified device is released not less than 20% of all IEPS;

(d) 6 hours of measurement in the specified device is released not less than 35% of all IEPS;

(e) For 8 hours of measurement in the specified device is released at least 50% of all IEPS;

(f) For 10 hours of measurement in the specified device is released at least 70% of all IEPS;

(g) within 12 hours of measurement in the specified device is released at least 75% of all HIPS.

According to another variant implementation, the rate of release of HIPS of the pharmaceutical composition, measured in vitro in 0.05 M phosphate buffer at pH 6.8 using a paddle apparatus USP type II for measuring dissolution according to US Pharmacopoeia XXII, mainly corresponds to the following parameters go into solution:

(a) within 1 hour of measurement in the specified device is released no more than 20% of all IEPS;

(b) 2 hours of measurement in the specified device is released no more than 45% of all IEPS;

(c) within 4 hours of measurement in the specified device is released from 20% to 70% of all IEPS;

(d) 6 hours of measurement in the specified device is released from 35% to 85% And the SS;

(e) For 8 hours of measurement in the specified device is released at least 50% of all IEPS;

(f) For 10 hours of measurement in the specified device is released at least 70% of all IEPS;

(g) within 12 hours of measurement in the specified device is released at least 75% of all HIPS.

According to another variant implementation, the rate of release of HIPS of the pharmaceutical composition, measured in vitro in 0.05 M phosphate buffer at pH 6.8 using a paddle apparatus USP type II for measuring dissolution according to US Pharmacopoeia XXII, mainly corresponds to the following parameters go into solution:

(a) 2 hours of measurement in the specified device is released no more than 50% of all IEPS;

(b) 6 hours of measurement in the specified device is released not less than 35% of all IEPS;

(c) For 22 hours of measurement in the specified device is released at least 80% of all HIPS.

Pharmaceutical composition for administration once a day may contain a mixture of controlled release, as defined above, intended for immediate release form specified HIPS of up to 75% by weight, preferably from about 10% to 50% by weight.

According to another aspect of the present invention features a method of treating depression, obsessive compulsive disorder or other painful conditions, Powergen is th effect IIPS, consisting in the introduction to the patient in one of these States, a therapeutically effective amount consisting of many particles of the pharmaceutical composition with controlled release of HIPS.

In order to avoid repetition, the invention will be further described in detail with reference to fluvoxamin as a typical example.

A BRIEF DESCRIPTION of GRAPHIC MATERIALS

Figure 1 is a graph showing the dependence of the percentage of released drug from time (h) for capsules controlled release according to example 2.

Figure 2 is a graph showing a time-dependent (h) concentration fluvoxamine in plasma (ng/ml) after a single injection, as described in example 3, for various pharmaceutical compositions prepared according to the present invention, in comparison with the curve of its concentration in the plasma for tablets supplied under the trademark Luvox.

Figure 3 is a graph showing dependence of the concentration of fluvoxamine in plasma (ng/ml) time (h) under conditions of rapid and controlled release, as described in example 4.

Figure 4 is a graph showing dependence of the concentration of fluvoxamine in plasma (ng/ml) time (h) under steady-state conditions for the product prepared in example 1, in comparison with the curve of its concentration in the plasma for tablets, comes with a C what's under the trademark Luvox, as described in example 5.

Figure 5 is a graph showing dependence of the concentration of fluvoxamine in plasma (ng/ml) time (h) under steady-state conditions for product D prepared in example 1, in comparison with the curve of its concentration in the plasma for tablets supplied under the trademark Luvox as described in example 6.

The invention will be further illustrated by the following examples.

DESCRIPTION of embodiments of the INVENTION

Example 1

Getting four consisting of many particles of pharmaceutical formulations with controlled release of fluvoxamine

Cooking filled medicine balls

Were two parties-filled medicine balls, respectively, 1 and 2, and the details of the formulations are shown in table 1. Part 2 was selected for the preparation of beads with controlled-release (KB). This party preferred party 1, since it gave a more rapid drug release and was therefore considered more appropriate for immediate release (HB) servings.

Table 1

Details of formulations for balls filled with fluvoxamine
The batch number12
CompositionWeight (kg)Weight (kg)
M is lead of fluvoxamine 12,45012,450
Talc3,5503,550
(% of active component)28,5%28,5%
Only16,00016,000
Grain small drops (of 0.71-0.85 mm)5,0005,000
EudragitRS(12,5%) (polymer solid component)1,6181,413

Filled medicine balls were prepared by mixing maleate of fluvoxamine and talc for 5 min prior to the formation of homogeneous powder in the mixer (homogenizer) E 5904. Homogeneous powder and sugar grains sprayed with Eudragit RS in turn was applied to small grain pills. The beads were dried in a thermostat at 55°C for 20 h to remove solvent. Then the beads were sieved to remove agglomerates.

Then determined the capacity and the solubility of the thus obtained are filled medicine balls. Determination of solubility were carried out in the apparatus USP Apparatus 2 with 900 ml phosphate buffer pH 6.8 and the speed of rotation of the blades 50 rpm All the measurements were repeated 6 times.

Table 2 shows the results of determining capacity. According to the measured capacitance when using grains small bean size of 0.71-0.85 mm was achieved filling medication 0,53%.

Table 2

The results of determination of the capacity-filled medicine balls with 100 mg of fluvoxamine
The batch numberReal capacity (mg/g)
1537,6
2530,1

The results of measurements of transition in solution are summarized in table 3. The results comply with the technical requirements of United States Pharmacopeia products for immediate-release, according to which for 45 minutes should be released at least 75% (e.g., party 1 for 45 min released 97,2%; in lot 2 for 45 min at 99.1%). Because part 2 has been the best parameters of dissolution, this party was selected to cover to get the balls controlled release.

Table 3

The results of determination of the transition in the solution-filled medicine balls with 100 mg of fluvoxamine
The batch number12
Time (min)The percentage release
15of 87.088,7
3093,996,1
4597,2of 99.1
60to 97.199,7
12099,2101,6

Preparation of balls controlled release

Balls controlled release was obtained, covering the polymer-filled medicine balls. The solution for a polymer coating and talc was applied alternately with controlled speed. The introduction of talc at this stage prevents the agglomeration of the beads during the coating process.

During this procedure, samples were taken balls at levels of polymer coatings 4%, 6%, 8%, 10%, 12% and 15%.

Details of the formulation obtained for the party specified in table 4. Details of the formulation of polymer coating for 100 mg contains fluvoxamin balls controlled release (KB) are summarized in table 5. The preparation stage balls controlled release were as follows: filled medicine balls covered in apparatus CF750 Coater with a solution for a polymer coating composition: Eudragit RS with isopropyl alcohol (IPA) and dibutylsebacate (DBS) as a plasticizer in the presence of talc to prevent agglomeration. The beads were dried in a thermostat at 55°C for 20 h to remove residual solvent. Then the beads were sieved to remove agglomerates.

Table 4

Details of the formulation for the balls KB 100 mg fle is examina
CompositionWeight (kg)
Balls with immediate release fluvoxamine15,000
Talc9,0669
(% polymer solid component)(504,5)
Eudragit RS + DBS in covering solution29,1625
(6.17% of the polymer solid component)(1,797)

Table 5

Details of the formulation for the polymer used in the preparation of beads KB 100 mg fluvoxamine
The solution to coverEudragit RS + plasticizer
CompositionWeight (kg)
Eudragit RS(12,5)18,000
Isopropyl alcohol18,000
DBS0,450
Only36,450

Measure capacitance and transition in solution was performed on the resulting beads KB (i.e. 4%, 6%, 8%, 10%, 12% and 15%). Testing transition in solution was carried out in the apparatus USP Apparatus 2 with 900 ml phosphate buffer pH 6.8 and the speed of rotation of the blades 50 rpm Testing was performed for 22 hours

Data containers for beads KB 100 mg fluvoxamine are summarized in table 6. From this table it is seen that with what achenium percent polymer coating reduces the capacity (balls with 4% coverage have the capacity 464,8 mg/g in comparison with 295,9 mg/g for the balls with 15% coverage). This result was expected, since the values of capacitance calculated as the ratio of actual capacity to the final weight of the ball (mg/g).

Table 6

The results of measurements containers for beads KB 100 mg fluvoxamine
Polymer coating (%)
Weight %%4,08,010,0to 12.015,0
Capacity (mg/g)464,8386353329,6295,9

The results of measurements of transition in solution are summarized in table 7.

Table 7

The measurement results of the transition in the solution for the balls KB 100 mg fluvoxamine
Coverage (%)4,06,08,010,0to 12.015,0
Time (h)Release (%)
0,54,32,22,70,81,01,1
1,0the 15.62,83,21,71,81,9
2,062,3 8,45,32,01,71,5
4,093,348,76,62,11,81,7
6,096,583,226,26,53,42,5
8,098,492,959,823,24,12,4
10,097,696,3to 78.341,811,32,7
22,0100,1100,896,598,883,356,2

Cooking capsules KB 100 mg of the maleate of fluvoxamine

White/opaque white gelatin capsules of size 2 were subjected to tandem filling with kapsuljatora Bosch (E5572). For all four products were selected portion 600, the operating Parameters kapsuljatora were installed so as to provide the necessary percentage in each of the two types of balls controlled release. In tables 8A and 8B shows the details of formulations for capsules KB 100 mg of the maleate of fluvoxamine. Products marked as a, b, C and D.

Table 8A

Details of the formulation for the purs KB 100 mg of the maleate of fluvoxamine
No. of productAndin
Composition%mg/capsuleThe batch size (kg)%mg/capsuleThe batch size (kg)
Fluvox. beads KB 4% coverage100215,150,60060129,00,360
Fluvox. the KB balls with 6% coverage---4096,20,240
Fluvox. beads KB with 8% coating------
Only100215,150,600100225,20,600

0,372
Table 8B

Details of the formulation for capsules KB 100 mg of the maleate of fluvoxamine
No. of productD
Composition%mg/capsuleThe batch size (kg)%mg/capsuleThe batch size (kg)
Fluvox. beads KB 4% coverage62133,404086,060,240
Fluvox. the KB balls with 6% coverage------
Fluvox. beads KB with 8% coating38its 98.450,22860155,440,360
Only100231,850,600100241,50,600

To obtain the desired speed of the transition in the solution for three of the products, using dual fill were "mixed" two different layers of polymeric coatings.

For the obtained capsules KB were measured capacity and speed of transition in solution. Testing transition in solution was carried out in the apparatus USP Apparatus 2 with 900 ml phosphate buffer pH 6.8 and the speed of rotation of the blades 50 rpm Testing was performed for 22 hours

Table 9 summarises the results of the measurement containers for capsules with 100 mg of active substance. It is seen that the preparation of the capsules was successful, as all parties capsules had a capacity of more than 97 mg/g

Table 9

The results of measurements containers for capsules KB 100 mg fluvoxamine
Product Real capacity (mg/g)
And97,6
In99,0
98,4
D99,6

Table 10 shows the results of measurements of the speed of transition of a substance in solution for capsules with 100 mg drugs. The results confirm that a double filling is a convenient way of "mixing" of balls with different levels of polymer coating. Used combinations were successful in the sense that their behavior is consistent with theoretical predictions.

Table 10

The measurement results of the transition in the solution for capsules KB 100 mg fluvoxamine
Product:AndInD
Time (h)Release (%)
0,55,12,852,753,15
1,015,88,8the 7.855,35
2,063,441,3535,725,7
4,0to 91.679,5569,9551,55
6,097,3br93.18,55 71,0
8,0the 98.995,891,582,75
10,0100,599,6596,190,85
22,098,6the 98.9100,85102,85

Example 2

Receive capsules with additional control release

Preparation of balls filled with medicine

Filled medicine balls received, as described in example 1, except that the beads were dried in a thermostat at 55°C for 18 hours Sifting led on sieves with openings of 0.98 mm and 1.5 mm, the details of the formulations are shown in table 11.

Table 11

The details of the recipe for filled fluvoxamine balls
The batch number34
CompositionWeight (kg)Weight (kg)
Maleate of fluvoxamine12,45012,450
Talc (% of active component)3,550 28,5%3,550 28,5%
Only16,00016,000
Grain small bean5,0005,000
(of 0.71-0.85 mm)(of 0.71-0.85 mm)
Eudragit RS 12.5% of the solid polymeric substances)1,3161,316

For received-filled medicine balls were rated capacity and the degree of transition of a substance in solution.

Testing transition in solution was carried out in the apparatus USP Apparatus 2 with 900 ml phosphate buffer pH 6.8 and the speed of rotation of the blades 50 rpm All measurements with UV detection were repeated six times.

In table 12 detailed results of measurements of capacity. The results of measurements of capacity show that the use of grains small drops was achieved degree of fullness medicine 54%. Included measurements of capacitance and transition into the solution for the previous parties HB and KB from example 1 (respectively part 1 and part 2), because the balls of these parties were used to prepare capsules.

Table 12

The measurement results of the capacity for balls filled with maleate of fluvoxamine
no partyReal capacity (mg/kg)
3537,1
4530,1

In table 13 and figure 1 summarizes the results of the measurements go into solution. The results comply with the technical requirements of the U.S. Pharmacopeia for products with non-the slow release (HB), according to which for 45 minutes should be released at least 75% of the product (for example, in batch 3 for 45 min released 95.4 percent; in lot 4 for 45 min at 99.1%).

Table 13

The results of measurements of the transition of the drug in the solution for the balls. filled with maleate of fluvoxamine
no party:34
Time (minutes)Release (%)
1584,688,7
18not definednot defined
3093,896,1
4595,4of 99.1
48not definednot defined
6096,599,7
120of 97.8101,6

Preparation of balls controlled release

Balls controlled release was obtained by coating the polymer-filled medicine balls. The solution for a polymer coating and talc was applied simultaneously with a controlled speed. The introduction of talc at this stage prevents the agglomeration of the beads during the coating process.

Batch of HB covered with a solution for coating the baking soda is containing Eudragit RS and dibutylsebacate (solution for coating contained 7,4% solids: polymer + plasticizer).

During this process, samples were taken balls at levels of polymer coatings 4%, 6%, 8%, 12% and 15%. Table 14 shows the details of the formulations obtained for the party. Table 15 summarizes the details of the formulation of polymer coating for beads KB 100 mg fluvoxamine. Balls controlled release received in accordance with the procedure described above in example 1, but without phase sifting.

Table 14

The details of the recipe for filled maleate of fluvoxamine beads KB
no party:56
Input balls filled with medicine43
CompositionWeight (kg)Weight (kg)
Balls HB with fluvoxamine15,00015,000
Talc9,06697,909
(% polymer solids)(504,0)(386)
The solution for coating Eudragit RS + DBS29,126527,693
(PD15349)(PD15482)
(6,17% polymer solids)(1,797)(2,049)

Table 15

De the Ali formulation of the polymer, used in cooking filled the maleate of fluvoxamine beads KB
The solution to coverEudragit RS + plasticizer
CompositionWeight (kg)
Eudragit RS(12,5)18,000
IPS18,000
DBS0,450
Only36,450

Measure capacitance and transition in solution was performed on the resulting beads with controlled-release (i.e. 4%, 6%, 8%, 10%, 12% and 15%). Testing transition in solution was carried out in the apparatus USP Apparatus 2 with 900 ml phosphate buffer pH 6.8 and the speed of rotation of the blades 50 rpm Testing was performed for 22 hours

The results of the measurement containers for beads KB 100 mg fluvoxamine summarized in tables 16 and 17.

Table 16

The results of measurements containers for beads KB maleate of fluvoxamine
no party56789
The coating polymer4,0%6,0%8,0%12,0%15,0%
Capacity (mg/kg)441,9406,9375,9326,5to 290.5

Table 17

The results of measurements containers for beads KB maleate of fluvoxamine obtained in example 1
The coating polymer4,0%6,0%8,0%10%12,0%15,0%
Capacity (mg/kg)464,8415,8386353329,6295,9

When comparing the measured values with the values of the capacity for a party of example 1 is detected difference, especially at the level of 4% (for example, in example 1:4%=464,8 mg/g).

The results of measurements of transition in solution are summarized in tables 18 and 19. As expected, with increasing coating polymer increases the delay period and occurs at a much slower transition of a substance in solution.

Table 18

The results of measurements of the transition of a substance in solution for beads KB maleate of fluvoxamine (floor Eudraait RS + DBS)
no party56789
Coverage (%)4,06,08,0to 12.015,0
Time (h) The amount of released drug (%)
0,53,52,41,61,82,0
1,014,12,91,61,41,5
2,067,96,11,82,12,2
4,092,565,410,22,01,5
6,096,888,954,23,31,7
8,0102,499,7an 80.26,81,0
10,0104,3to 103.891,423,21,9
22,0of 98.297,299,396,079,0

4,3
Table 19

The results of measurements of the transition of a substance in solution for beads KB maleate of fluvoxamine example 1
Coverage (%)4,06,08,010,0to 12.015,0
Time (h)The amount of released drug (%)
0,52,22,70,81,01,1
1,0the 15.62,83,21,71,81,9
2,062,38,45,32,01,71,5
4,093,248,76,62,11,81,7
6,096,583,226,26,53,42,5
8,098,492,959,823,24,12,4
10,097,696,3to 78.341,811,32,7
22,0100,1100,896,598,883,356,2

It was expected that the party with the degree of polymer coating 8% will give similar results measurements go into solution because it was assumed that the party 5 party in example 1. The differences can be explained by the small difference in the process. The product from example 5 gave a more acceptable mode of transition in solution.

Cooking capsules KB 100 mg of the maleate of Fluvoxamine

White/atovo white gelatin capsules of size 2 were subjected to tandem filling with kapsuljatora Bosch (E5572). For a product was chosen lot size 0,4789 kg, and for product D - 0,4919 kg. Settings kapsuljatora were installed so as to provide the necessary percentage in each of the two types of balls controlled release. Table 20 shows the details of formulations for capsules KB 100 mg of the maleate of fluvoxamine.

Table 20

Details of the formulation for capsules KB 100 mg of the maleate of fluvoxamine
no party1011
Composition%m g/capsuleThe batch size (kg)%mg/capsuleThe batch size (kg)
Fluvox. beads KB 4% coverage60br135.80,27164090,50,1810
Fluvox. beads KB with 8% coating40103,60,207360155,40,3109
Only100239,40,4789100245,90,4919

To investigate the impact of power and stationary mode in example 4 and examples 5 and 6, respectively, it was necessary to have capsules KB 100 mg pharmaceutical is tion with the schedule release graphics like this for capsules product C and product D, which were used for the biological test example 3. For this purpose it was decided to use beads coated with 8% in example 1 and the balls coated with 4% of the party 5 in this example.

To keep some consistency, it was decided to adhere to product D ratio in combination 40% balls with 4% coverage and 60% of the balls with 8% coating, and for a product With the ratio in combination was changed to rounded values 60% balls with 4% coverage and 40% of the balls with 8% coating.

Measure capacitance and transition in solution was performed on the obtained capsules KV. Testing transition in solution was carried out in the apparatus USP Apparatus 2 with 900 ml phosphate buffer pH 6.8 and the speed of rotation of the blades 50 rpm Testing was performed for 22 hours

Table 21 summarizes the results of measuring containers for capsules with 100 mg of fluvoxamine.

Table 21

The results of measurements containers for capsules KB 100 mg fluvoxamine
no partyReal capacity (mg/g)
1097,3
1196,2

The results of measurements of the transition of a substance in a solution very close to the results for capsules product From the product D, obtained in example 1.

New batches of capsules were given a somewhat greater speed of transition in solution, as can be seen from table 22 and figure 1.

Figure 1 is a curveandthe batch No. 10, and curvebthe batch No. 11.

Table 22

The results of measurements of the transition of a substance in solution for capsules KB 100 mg fluvoxamine
no party1011
Time (h)The amount of released drug (%)
0,5was 2.764,78
1,09,0410,26
2,045.99 per35,45
4,074,2358,88
6,085,6275,42
8,092,7686,48
10,096,5792,24
22,0100,36100,80

Example 3

Biological studies

The first goal of biological research was to compare the bioavailability of a 100 mg capsules with compositions A-D (products A-D), which are referred to in examples 1 and 2, with tablets 100 mg Luvox® (Solvay Pharmaceuticals Inc.). The second objective was to obtain characteristics change the plasma concentration of the composition KB in comparison with tablets 100 mg Luvox® .

In biological studies used an open label, single dose, five-introduction, five periods, randomized planning and cross-breeding season ("washing") at least 10 days between days of administration.

Compartmentally evaluation of pharmacokinetics based on the content of fluvoxamine in plasma, measured in blood samples. Blood samples were collected before administration of the drug and at the following time points after the introduction of the reference and the tested drugs: 0 (before the introduction of), 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 20, 24, 30, 36, 48, 72 and 96 hours.

Were registered ten (10) persons who participated in the trials until they complete. All 10 people participated in studies of the pharmacokinetics and tolerability.

Diagnosis and main criteria for inclusion in the test:

Were selected healthy men aged 18 to 40 years who had a phenotype of increased metabolism of dextromethorphan.

The tested products, dosage and route of administration

Capsules KB 100 mg fluvoxamine - product a (very quick transition in the solution).

Capsules KB 100 mg fluvoxamine - product (jump to the solution).

Capsules KB 100 mg fluvoxamine - product (transition in solution with an average speed).

Capsules KB 100 mg fluvoxamine - product D (a slow transition in p is the target).

Participating in the trial received a single oral dose of one capsule and 240 ml of tap water, and then for 10 h was not eating.

Reference product, dose and route of administration

Tablets Luvox® 100 mg (product E).

Participating in the trial received a single oral dose of one tablet and 240 ml of tap water, and then for 10 h was not eating.

Pharmacokinetics

Using decompartmentalise methods were calculated following pharmacokinetic parameters: area under the curve of concentration of drug in plasma from time from time of dose to the point of the last sampling (AUC(0-t)); area under the curve of concentration of drug in plasma from time extrapolated to infinity (AUC(O-∞)); the maximum measured concentration of drug in plasma (Cmax) and the time at which this concentration was measured (tmax); the concentration at the point 24 h (C24h); the relative bioavailability of the test substance (s) in comparison with the product compare (Frel(%)); the time at which the concentration of drug in the plasma is reduced by 50% (t1/2and the constant final speed removal (elimination) of the first order (Kel).

Statistical methods

Was performed descriptive statistics about abode desired pharmacokinetic parameters. To assess differences in the behavior of the preparations was applied program analysis of variance (ANOVA).

The results of Pharmacokinetic studies

The results of the statistical analysis and confidence intervals for the pharmacokinetic parameters are summarized in table 23. Curves average plasma concentration against time is presented in figure 2, where the curveandcorresponds to the product curveb- product D and curvewith- drug comparison Luvox®.

Table 23

Summary statistics and confidence intervals for the untransformed pharmacokinetic parameters
The product And the Average ± standads.The product In the middle ± standtkeThe product With the Average ± standtkeProduct D Average ± standtkeLuvox® Average ± standtke
AUC(0-∞) (ng/MLC)919,960±747,1321014,213±885,705872,731±688,717725,457±450,5491047,194±959,337
Frel(%)95,201±31,844101,486±24,93691,152±25,71483,053±34,432-
Cmax(ng/ml)40,514±16,491 40,611±17,97331,361±15,03522,711±9,14644,576±23,132
tmax(h)5,600±0,8436,900±2,0256,900±1,66312,400±at 5,296*4,200±1,614
C24h(ng/ml)13,79±9,4515,95±14,0315,57±11,92to 13.09±7,4913,73±13,03

CONCLUSION

All tested pharmaceutical compositions of the present invention have amaxreduced compared with the reference product (tablets Luvox®), and this value is significantly lower than the products C and D. For all compositions of the present invention tmaxprolonged compared with the maximum time for tablets Luvox®. For product D tmaxsignificantly increased. The relative bioavailability for all compositions is at least 80% in comparison with Luvox tablets®.

Example 4

Determination of the influence of food on the relative bioavailability of the pharmaceutical composition with controlled release of fluvoxamine

The study was conducted to assess the effect of food on the relative bioavailability of the product prepared in example 2.

Methodology

Research used open marking, odncrt the second dosage, double introduction, two-period, randomized crossover planning a 10-day breeding season, between periods of administration. Compartmentally evaluation of pharmacokinetics based on the content of fluvoxamine in the plasma. Blood samples were collected before the introduction of drugs and in the following times after administration of the reference and the tested drugs: 0 (before administration), through 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 20, 24, 30, 36, 48, 72 and 96 h after injection.

The number of people (planned and surveyed)

The study involved 16 people, 13 men and 3 women with a mean age of 27.3 years. Subject No. 9 interrupted the examination for personal reasons after blood withdrawal for 72 h in the 2nd period. All 16 people participated in the pharmacokinetic analysis.

Diagnosis and main criteria for participation in research

Healthy men and women aged 18 to 45 years with the phenotype of increased metabolism of dextromethorphan.

Test product, dose and route of administration

The subject received a single oral dose of the product and take it with 180 ml of water, followed by either fasting for 10 hours at night, rich or fatty foods.

Pharmacokinetics

Using decompartmentalise methods were calculated following pharmacokinetic parameters: area of the od curve, the concentration of drug in plasma from time from time of dose to the point of the last sampling (AUC(0-t)); the area under the curve of concentration of drug in plasma from time extrapolated to infinity (AUC(0-∞)); the maximum measured concentration of drug in plasma (Cmax) and the time at which this concentration was measured (tmax); the relative bioavailability (F) of the composition under conditions of starvation and nutrition; the time at which the concentration of drug in the plasma is reduced by 50% (t1/2and the constant final speed of elimination of the first order (Kel).

Statistical methods

Were calculated decompartmentalise pharmacokinetic parameters and conducted descriptive statistical processing. To assess differences in the modes was applied program analysis of variance (ANOVA).

The results of the study of pharmacokinetics

The results of pharmacokinetic data are summarized in table 24 and figure 3. Figure 3 curveandcomplies with the conditions of starvation and curveb- food conditions.

Table 24

Average pharmacokinetic parameters of plasma after administration of a single dose of the product under conditions of starvation or food (in parentheses are standard deviation)
The number of observed individuals (N=16)Product

starvation
Product

power
Cmax(ng/ml)26,63 (8,15)31,45 (12,79)
tmax(h)7,13 (2,66)8,00 (2,07)
AUC(0-∞) (ng/ml·h)667,43 (328,07)760,03 (319,43)

Middle Cmaxand AUC(0-∞) fluvoxamine in the presence of food increased respectively by 18% and 14%. It is concluded that this increase has no clinical significance. In the presence of food has no signs of dumping dose of the pharmaceutical composition of controlled release.

CONCLUSION

Found that both modes in this group of people safe and well tolerated. For the composition of controlled release did not reveal any clinically significant interactions with food.

Example 5

Determination of pharmacokinetics of fluvoxamine after the introduction of healthy volunteers male multiple doses of capsules KB 100 mg fluvoxamine and tablets 100 mg Luvox®

The study was conducted to determine the pharmacokinetics of fluvoxamine after the introduction of healthy volunteers male multiple doses prepared in example 2 product and 100 mg Luvox®.

Methodology

The research used multiple dose, open label, two injection mode, two-period, randomized crossover planning Dnevnik the cleaning time between the introduction of the last dose of fluvoxamine in period 1 and the first dose of fluvoxamine in period 2.

The number of people (planned and surveyed)

The study involved twelve (12) people, whose average age was 26,3 years, and 10 of them completed the full survey. Two men broke participate in research for reasons not related to the investigational drugs. The remaining 10 people participated in the determination of the pharmacokinetics.

Diagnosis and main criteria for participation in research

Healthy male volunteers aged 18 to 45 years inclusive with the phenotype of increased metabolism of dextromethorphan.

Test product, dose and route of administration

The product

Each of the monitored received one oral dose per day, take it with 180 ml of tap water for 10 consecutive days in each period of drug administration.

Pharmacokinetics

Blood samples were collected at the following time points after the introduction of the reference and the tested drugs on the 10th and 27th day: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 20, 24, 30, 36 and 48 hours

In addition, each morning on days 1 to 10 and 18 to 27 before the introduction of the drug was selected predosavia blood samples.

Using decompartmentalise methods identified the following pharmacokinetic parameters fluvoxamine after each course: area under the curve of concentration of drug in plasma from the time in 24-hour interval on the Le repeated administration (AUC(0-τ )); the maximum concentration of drug (Cmaxand her achievements (tmax); the time of the establishment of steady state minimum plasma concentration (Cmin); the average concentration in the plasma during the interval of doses (Cav); the relative bioavailability (F) of the product in comparison with Luvox tablets®determined by the ratio of AUC(0-τ); the magnitude of the fluctuations from the peaks to the failures, defined as the ratio (Cmax-Cmin)/Cav).

Statistical methods

To assess differences in pharmacokinetic parameters between the two modes of treatment fluvoxamine was proposed descriptive statistics. In each period the introduction of drugs compared to the minimum concentration of fluvoxamine in plasma to determine, is there a stationary state after 10 consecutive injections.

The results of the study of pharmacokinetics

The results of pharmacokinetic data are summarized in table 25 and figure 4. Figure 4 curveandcorresponds to the product, and curveb- reference medication Luvox®.

Table 25

Average pharmacokinetic parameters of plasma after repeated administration once a day for 10 days 100 mg of the maleate of fluvoxamine in the form of either a product or tablets uvox® (in parentheses are standard deviation)
N=10, maleProductTablets Luvox®
Withmax(ng/ml)91,85 (63,67)107,00 (73,52)
tmax(h)8,90 (1,97)6,80 (2,15)
Cmin(ng/ml)44,51 (34,78)43,76 (41,15)
AUC(0-τ) (ng/ml·h)1543,18 (1136,99)1738,55 (1392,42)
Index Fluctuations0,85(0,22)1,13(0,38)

The relative bioavailability of the product, calculated on the basis of AUC(0-τ), was 94,0% compared with Luvox tablets®. The product also had a smaller index fluctuations, reflecting lower values Withmaxin comparison with Luvox tablets®.

CONCLUSION

Both drugs were safe and well-tolerated in this group of healthy men. The product after repeated administration behaved like tablets Luvox® and gave the smaller fluctuations of concentrations of fluvoxamine in plasma.

Example 6

Determination of pharmacokinetics of fluvoxamine after repeated administration in healthy volunteers-men capsules KB 100 mg fluvoxamine and tablets 100 mg Luvox®

The study was conducted to determine the pharmacokinetics of fluvoxamine on the Le repeated administration in healthy volunteers-men prepared according to example 2 product D and 100 mg Luvox® .

Methodology

The research used multiple dose, open label, two injection mode, two-period, balanced, randomized, cross plan with a 7-day period of purification between the introduction of the last dose of fluvoxamine in period 1 and the first dose of fluvoxamine in period 2.

The number of people (planned and surveyed)

In study involved fourteen (14) people, whose average age was 31,1 year. All 14 people have completed the survey and participated in the determination of the pharmacokinetics.

Diagnosis and main criteria for participation in research

Healthy male volunteers aged 18 to 45 years with the phenotype of increased metabolism of dextromethorphan.

Test product, dose and mode of administration:

Product D

Each of the monitored received one oral dose per day, take it with 180 ml of tap water for 10 consecutive days in each period of drug administration.

Test product, dose and route of administration

Pills 100 mg Luvox® (maleate of fluvoxamine).

Each of the monitored received one oral dose per day, take it with 180 ml of tap water for 10 consecutive days in each period of drug administration.

Pharmacokinetics

Was applied the same procedure as in the case p is of emer 4.

Statistical methods

Was adopted the same format, as in the case of example 4.

The results of the study of Pharmacokinetics

The results of pharmacokinetic data are summarized in table 26 and figure 5. Figure 5 curveandcorresponds to the product of D and the curveb- reference medication Luvox®.

Table 26

Average pharmacokinetic parameters of plasma after repeated administration once a day for 10 days 100 mg of the maleate of fluvoxamine in the form of product D or tablets Luvox® (in parentheses are standard deviation)
N=14 menProduct DTablets Luvox®
Withmax(ng/ml)114,87129,59
(58,09)(62,86)
tmax(h)7,79to 6.43
(1,19)(2,24)
Cmin(ng/ml)57,4154,56
(34,39)(32,69)
AUC(0-τ) (ng/ml·h)1929,092109,30
(1048,27)(1085,63)
Index fluctuations0,770,91
&x0200A; (0,27)(0,19)

The relative bioavailability of D calculated from AUC(0-τ), was 91,0% compared with Luvox tablets®. Product D also had a smaller index fluctuations, reflecting lower values Withmaxin comparison with Luvox tablets®.

CONCLUSION

Both drugs were safe and well-tolerated in this group of healthy men. The composition KB (controlled release) after repeated administration behaved like tablets Luvox® and gave the smaller fluctuations of concentrations of fluvoxamine in plasma.

1. Consisting of many particles of the pharmaceutical composition of controlled release selective inhibitor of reuptake of serotonin (IIPS) for oral administration, providing controlled release of the above HIPS over a period of time not less than approximately 12 h after oral administration, characterized in that the composition contains particles comprising a core containing the specified HIPS or its pharmaceutically acceptable salt, covered with controlling the rate of release coated membrane containing ammonium methacrylate copolymer.

2. The composition according to claim 1, characterized in that the particles are granules.

3. The composition according to claim 1, characterized in that h is on the core further comprises an organic acid, moreover, component HIPS and organic acid are in a ratio of from 50:1 to 1:50.

4. The pharmaceutical composition according to claim 1, characterized in that HIPS is fluvoxamine or its pharmaceutically acceptable salt.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that the membrane coating is present in such quantity that it makes the particle mass increases from about 4% to about 15% by weight of the kernel.

6. The pharmaceutical composition according to claim 5, characterized in that the weight increase is 4, 6, 8, 10, 12 or 15% by weight of the kernel.

7. The pharmaceutical composition according to claim 1, characterized in that IIPS selected from fluoxetine, fluvoxamine, paroxetine, sertraline, or their pharmaceutically acceptable salts.

8. Pharmaceutical composition with controlled release of IEPS for oral administration containing a mixture of particles as defined in any one of claims 1 to 7.

9. Pharmaceutical composition with controlled release of IEPS for oral administration containing a mixture of particles as defined in any one of claims 1 to 7, in mixture form for immediate release of HIPS or its pharmaceutically acceptable salt to ensure rapid advances in blood a therapeutically effective level.

10. The pharmaceutical composition according to claim 9, characterized in that the form for immediate is svobodne IIPS is a granules as defined in claim 2, without a specified controlling the rate of release of the membrane surface.

11. A method of treating depression, obsessive compulsive disorder or other painful conditions, exposed to IIPS, wherein the patient is suffering from one of these States, is administered a therapeutically effective amount consisting of many particles of the pharmaceutical composition with controlled release of HIPS according to any one of claims 1 to 7, or pharmaceutical composition with controlled release of HIPS on any of PP and 10.



 

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2 dwg, 16 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 4-phenylpyridine N-oxides of the general formula (I) and their pharmaceutically acceptable acid-additive salts wherein R means hydrogen atom, lower alkyl or halogen atom; R1 means hydrogen atom; R2 and R2' mean independently of one another hydrogen, halogen atom, trifluoromethyl group, (lower)-alkoxy-group; or R2 and R2' can mean in common the group -CH=CH-CH=CH- optionally substituted with one or two substitutes taken among lower alkyl or (lower)-alkoxy-group; R3 and R3' mean independently of one another hydrogen atom, lower alkyl; R4 and R4' mean independently of one another -(CH2)mOR6 or lower alkyl; or R4 and R4' form in common with N-atom to which they are bound substituted R5-cyclic tertiary amine representing pyrrolidine-1-yl, piperidine-1-yl, piperazine-1-yl, morpholine-4-yl or 1,1-dioxomorpholine-4-yl; R5 means hydrogen atom, hydroxyl, -COOR3, -N(R3)CO-lower alkyl or -C(O)R3; R6 means hydrogen atom, lower alkyl; X means -C(O)N(R6)-, -N(R6)C(O)-; n = 0, 1, 2, 3 or 4; m = 1, 2 or 3. Also, invention describes a medicinal agent comprising these compounds. Compounds can be used as drugs in treatment or prophylaxis of diseases associated with antagonists of NK-1 receptor.

EFFECT: valuable medicinal properties of agent.

6 cl, 32 ex

FIELD: veterinary science.

SUBSTANCE: the present innovation deals with applying biologically active substance of adaptogenic action as eracond at the dosage of 45-55 mg/kg body weight in the form of 10%-aqueous solution daily during three 3-d-long courses at 3-d-long interval. The innovation provides decreased negative impact of stress-factors upon animal body, upon immune state, especially.

EFFECT: higher efficiency of prophylaxis.

1 ex, 2 tbl

FIELD: medicine, psychiatry, pharmacy.

SUBSTANCE: invention relates to the orally decomposition composition comprising mirtazapine. A single dosed medicinal formulation decomposing rapidly after its oral administration is bioequivalent to usual tablet but shows advantages with respect to adverse effects, effectiveness, anxiolytic effects, dream-improving effects, and acceleration of onset effect of an antidepressant agent. Invention can be used in treatment of depression.

EFFECT: valuable medicinal and pharmaceutical properties of composition.

5 cl, 1 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: medicine.

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.

The invention relates to pharmaceutical

The invention relates to a new compound of the formula I

in which R represents an aromatic acyl fragment, which optionally has one or more substituents, which may be the same or different and which are selected from hydroxy, methoxy and amino

FIELD: medicine, psychiatry, pharmacy.

SUBSTANCE: invention relates to the orally decomposition composition comprising mirtazapine. A single dosed medicinal formulation decomposing rapidly after its oral administration is bioequivalent to usual tablet but shows advantages with respect to adverse effects, effectiveness, anxiolytic effects, dream-improving effects, and acceleration of onset effect of an antidepressant agent. Invention can be used in treatment of depression.

EFFECT: valuable medicinal and pharmaceutical properties of composition.

5 cl, 1 tbl, 2 ex

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

FIELD: veterinary science.

SUBSTANCE: the suggested methods and compositions provide transfer of biologically active compound, antigen predominantly, in animal body. Efficient quantity of biologically active compound should be put into microcapsules made of biocompatible material the size of which do not exceed 10 mcm, then one should introduce efficient quantity of these microcapsules, perorally, preferably, for animals under immunization. As material for microcapsules one usually applies a biologically active polymer or copolymer being of capacity to pass through gastro-intestinal tract or being localized at mucosal surface not being affected by biodegradation. This provides the transfer of biologically active compound onto Peyer's patches or other mucosa-associated lymphatic tissues, that provides inducing systemic immunity and activization of mucosal immunity system.

EFFECT: higher efficiency.

22 cl, 12 ex, 19 tbl

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

The invention relates to the field of pharmaceutical industry, namely pharmaceutical compositions for the manufacture of tablets and prolonged action, in particular tablets for sublingual application, and to methods of producing such compositions
The invention relates to the field of cosmetology and relates to a technology for cosmetic skin care

The invention relates to medicine, namely to the technology of production of microcapsules, and can be used in the pharmaceutical industry

The invention relates to medicine, namely to pharmaceutical compositions for the manufacture of tablets and prolonged action, in particular tablets for sublingual application, and to methods of producing such compositions

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a pharmaceutical preparation based on angiotensin-converting enzyme inhibitor, its using in prophylaxis of insult, diabetes and/or congestive cardiac insufficiency and corresponding methods for its using in patient with maintenance heart function and subjected for risk of cardiovascular attack due to previous history of ischemic disease, insult or peripheral arterial disease. In particular, inhibitor of angiotensin-converting enzyme can be chosen from ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. Invention promotes to reducing the total lethality of patients group in case of cardiovascular diseases, cardiac attacks and insults, the necessity for carrying out procedures for revascularization (such as surgery operation for coronary shunt, angioplasty with using balloon and so on) and diabetic complication are diminished.

EFFECT: improved and valuable medicinal properties of preparations.

19 cl, 1 ex

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