System of delivery of medicinal substance

FIELD: medicine; pharmacology.

SUBSTANCE: system of delivery of medicinal substance includes one department consisting from (i) of a kernel from thermoplastic polymer, filled with medicinal substance, (ii) an intermediate layer from the thermoplastic polymer filled with medicinal substance, and (iii) covers from the thermoplastic polymer, covering an intermediate layer and not containing medicinal substance, where the specified intermediate layer is filled (a) with crystals of the first pharmacologically active substance, and (b) the second pharmacologically active substance in the dissolved form and where the kernel is filled specified to the second pharmacologically active substance in the dissolved form. The delivery system is intended for vaginal introduction of the medicinal substance.

EFFECT: possibility of adjustment of rate of liberation of two or more active ingredients irrespective of others, at maintenance of long physical stability of system at room temperature.

51 cl, 21 dwg, 10 tbl, 4 ex

 

The technical field to which the invention relates.

The present invention relates to the field of women's contraceptive and hormone replacement therapy.

The present invention relates to a system (device) of drug delivery for the simultaneous selection of two or more active ingredients and, in particular, to a system of drug delivery using a vaginal ring that releases the active ingredients essentially at a constant level over a long period of time. Because the invention relates to a product for delivery of medicinal substance, which is intended for endovaginal applications, this application focuses on typical medical conditions for women, such as contraception, hormonogenesis. In particular, the product according to the invention has the shape of a ring and hereinafter will be referred to as a vaginal ring.

The level of technology

Vaginal rings are known. Prior art in this regard includes the following patents.

U.S. patents 3,995,633 and 3,995,634 that describe the separate, predominantly spherical or cylindrical tanks containing different active substances, which are collected in specially designed holders.

U.S. patent 4,237,885, which describes the tube or SPIRA the ü from a polymeric material, which is divided into parts by means of a set of "delimiters" located in the tube, after which each of the individual parts of the tube was filled with different active components in the silicone fluid and the two ends of this tube are successively connected to each other. In this allocation system, however, transportation (distribution) of the active material from one tank to another takes place through the wall of the tube, especially during long-term storage, thus setting a fixed ratio of allocation between existing active components will change over time.

In European patent publication EP 0,050,867 described two-layered vaginal ring, which includes pharmacologically acceptable supporting ring, covered with two layers of predominantly silicone elastomers, while the inner layer is a silicone elastomer filled with the active component.

In U.S. patent No. 4,292,965 describes the delivery system using the vaginal ring of three layers, made of silicone elastomers.

In U.S. patent No. 4,596,576 describes vaginal ring, consisting of two departments, where each Department contains a variety of active ingredients. For receiving the ring with a suitable constant level of separation of the various active the components of the final part of the departments are connected via glass tubes.

In patent publication WO 97/02015 describes a device from two divisions, the first division consists of a core (inner part), middle layer impregnated with medication, the outer layer is not impregnated with the drug, and the second part consisting of saturated medicine kernel (inner part), and not impregnated with medication outer layer.

In EP 876815 disclosed vaginal ring (Nuvaring®), which is designed for simultaneous selection progestogenic steroid and estrogen steroid with a fixed level of selection is equal to the physiological, over a long period of time. The system of drug delivery contains one Department, including a core of a thermoplastic polymer containing a mixture of progestogenic and estrogenic compounds, and a shell of thermoplastic polymer, this progestogenic composition is initially dissolved in the polymeric core material with a relatively low degree of saturation.

From the above patents, it is clear that, for example, the material layers and departments are those aspects of the invention-rings, which are important in the known structures.

All options were developed with the purpose of obtaining a profile of a permanent release, which is violated in the presence of two or more active components. The latter is of particular importance is in the field of contraception, because for this purpose often use a combination of progestin and estrogen. Also in hormone replacement therapy necessary o-rings that deliver a combination of drugs.

Among the above patents EP 876815 clearly sets the standard, which includes design, consisting of a single Department, which avoids the necessity of applying selectionsave polymer (organosilicone elastomer)used in EVA combinations, and releases two or more active compounds essentially at a constant level over a long period of time.

Like any technological product, the latter can be further improved at any time. Device for drug delivery, disclosed in EP 876815, is physically stable state only when stored at temperatures below room temperature. Storage and transportation of this device require a temperature lower than room temperature, which is a costly condition, and needs to exercise great care. Moreover, if the storage takes place at a temperature not lower than room temperature, steroid eventually crystallizes on the surface of the device shell, which can lead to uncontrolled release of high concentrations of emitted substances.

Improved delivery system lekarstvennoj the substance solves this problem, because it is physically stable at room temperature and, thus, does not require special conditions of storage and transport.

Moreover, in the improved system of drug delivery may regulate the speed of release of more than one pharmacologically active substance independently of the other while maintaining the physical stability of the system.

Disclosure of inventions

The object of the invention is a vaginal ring sandwich, physically stable at room temperature, from which at least two pharmacologically active substances can be released independently from each other.

The ring includes at least one Department, holding (i) a core of a thermoplastic polymer, comprising the medicinal substance, (ii) an intermediate layer of thermoplastic polymer, comprising the medicinal substance, (iii) a sheath of thermoplastic polymer covering the intermediate layer and not containing medicinal substances. The intermediate layer is filled with the crystals of the first active substance (a) and (b) a second active substance in dissolved form. The core is filled with the second active substance is not necessarily in the same concentration as in the intermediate layer.

Brief description of figures

The figure 1 shows the in vitro skorostyu.ishodny of etonogestrel (ENG) for all series size 4,0 mm

The figure 2 shows the in vitro rate of release of etonogestrel for all series 3.5 mm

The figure 3 shows the in vitro rate of release of ethinyl estradiol (EE) for all series size 4,0 mm

The figure 4 shows the in vitro rate of release of levonorgestrel for all series 3.5 mm

Figure 5 shows a schematic description of the object of the invention is a vaginal ring.

The figure 6 shows the in vitro rate of release of etonogestrel and ethinyl estradiol from one of ring A1.

The figure 7 shows the in vitro rate of release of etonogestrel and ethinyl estradiol from one ring A2.

The figure 8 shows the in vitro rate of release of etonogestrel and ethinyl estradiol from one ring A3.

The figure 9 shows the in vitro rate of release of etonogestrel and ethinyl estradiol from one ring A4.

The figure 10 shows the in vitro rate of release of etonogestrel and ethylestradiol from one ring B1.

The figure 11 shows the in vitro rate of release of etonogestrel and ethinyl estradiol from one ring B2.

The figure 12 shows the in vitro rate of release of etonogestrel and ethinyl estradiol from one ring B3.

The figure 13 shows the in vitro rate of release of etonogestrel and ethinyl estradiol from one ring B4.

The figure 14 shows the in vitro rate of release this is ogestrel in fabric options E, F, G, H and I.

The figure 15 shows the rate of release of etonogestrel in fiber options J, K, L, W, and X.

The figure 16 shows the speed of release of etonogestrel in fiber options M, N, O, P and Q.

The figure 17 shows the rate of release of etonogestrel in fiber options R, S, T, U and V

The figure 18 shows the rate of release of levonorgestrel in fiber options E, F, G, H and I.

The figure 19 shows the rate of release of levonorgestrel in fiber options J, K, L, W, and X.

The figure 20 shows the rate of release of levonorgestrel in fiber options M, N, O, P and Q.

The figure 21 shows the rate of release of levonorgestrel in fiber options R, S, T, U and V

A detailed description of the invention

The law of diffusion Fika regulates the selection of compositions, such as contraceptive steroids out of the ring. In accordance with this law, the mass that passes through the boundary (wall), is the inverse function of the thickness of this boundary (wall). In a two-layer structure steroid located closer to the outer layer (shell), diffuses in the first place, that as a result leads to the splitting of the outer layer of the kernel and, therefore, the diffusion distance will increase. The splitting of the outer layer of the kernel and, as a result, the increase in diffusion distance will result in a decrease in the rate wisweb the Denia. Speaking about the speed of release of one drug substance, the task of splitting and increasing the diffusion distance can be solved by accumulation (concentration) of drug substance in the intermediate layer between the placebo-shell and placebo-core. Because this drug is concentrated in a relatively thin layer, the lengthening of the diffusion distance in the process of release is minimal, which results in a more constant rate of release over time.

The rate of release from the cylindrical design of the tank/membrane is equal to:

L = length of cylinder

Dp= the diffusion coefficient of the compound in the shell of polymer,

Top/s= the distribution coefficient of steroid between the sheath and core polymer

ΔC = difference in concentration between the core (intermediate layer) and acceptrules cloth,

r0= total (all) radius, i.e. the radius, including the shell of the cylinder,

r1= the radius of the kernel.

The equation shows that the zero allocation is achieved when the right-hand side of the equation is constant, i.e. is not a function of time. Lengthening the diffusion distances due to fission is not significant in the three-layer structure, containing about the but medicinal substance, and therefore, the element (r0/r1) can be considered as almost constant (a constant). In the case when the steroid is in the intermediate layer in a dissolved state, the concentration gradient (Δ (C) will continuously decrease over time and, consequently, the rate of release of dM/dt will decrease (the deviation from the zero indicator of the kinetics of selection).

The object of the invention is a system for drug delivery, comprising at least two active medicinal substance.

The object of the invention is a system of drug delivery, in fact, is a typical ring intended for vaginal insertion, which includes at least one unit consisting of (i) the kernel of thermoplastic polymer, (ii) an intermediate layer of thermoplastic polymer, (iii) a sheath of thermoplastic polymer covering the intermediate layer, where the above-mentioned intermediate layer includes (a) crystals of the first pharmacologically active substance, (b) a second pharmacologically active substance in a dissolved state and where the above-mentioned core also includes the second of the above substance, not necessarily in the same the concentration in the intermediate layer.

The essence of this new three-layer ring according to the invention C is enabled in ensuring the possibility of regulating the speed of release of more than one pharmacologically active substance independently of the other while maintaining the physical stability of the ring at room temperature.

This task is achieved by (1) incorporating crystalline tanks (the first) of a substance in the intermediate layer rings, (2) filling in as the intermediate layer and the core ring of the second compound in a dissolved state, thereby increasing the reservoir containing the substance, and (3) determine the thinning shell rings.

In a preferred variant of the invention, the substances are steroids. For simplicity hereinafter, the inventors talk about steroids, although non-steroidal compounds are also included in this invention.

Molecules steroids incorporated into the crystal lattice, are in dynamic equilibrium with steroids dissolved in the polymer of the intermediate layer. When there is diffusion, the concentration of steroid in the polymer is equal to or close to the equilibrium concentration. Then the ring is placed in acceptyour tissue, steroid begins to diffuse out of the ring and the concentration of steroid dissolved in the polymer of the intermediate layer, will decrease slightly. As a result, the crystals of the steroid will begin to dissolve. Thus, the decrease of the concentration gradient due to diffusion spreading of the ring is balanced by the steroid in crystal reservoir. Figure 1 and 2 illustrate this stabilizing effect Chris who allow in the intermediate layer. First, the slope of the release curve is very flat, i.e. it indicates that the release is at zero for almost 10 days. After 10 days of release curve suddenly became steeper, i.e. the rate of release has become more dependent on time (less than zero order). Obviously, this point coincides with the time when the size and number of crystals in the polymer matrix is reduced to a certain point in the future when difundieran loss steroid ring can no longer be adequately balanced by dissolving crystals. When the majority of the crystals dissolved, the concentration gradient is no longer stabilized and since then there has been more steep curve. Stabilization of the concentration gradient through these mechanisms, when the dissolution of crystals steroid is faster compared to a loss of steroid when difundieran. Thus, the decrease in concentration is balanced to a certain extent and the overall effect will be zero, provided that the crystals in the polymer will dissolve relatively quickly.

In other words, the object is a three-layer structure is a three-ring including at least one unit consisting of (i) an intermediate layer, filled two steroids, with one (steroid) partially is away in the crystalline phase and partially dissolved in the polymer, and the other (steroid) is completely dissolved in the polymer, (ii) the core, filled with steroid (fully dissolved, but not necessarily in the same concentration as in the intermediate layer), and (iii) placebo-shell.

In the specified three-layer ring of the steroid accumulates In not only in the intermediate layer, but also in the nucleus. In one of the embodiments of the invention, the concentration of steroid In the same as in the core and the intermediate layer.

When filling and core and the intermediate layer steroid In the tank steroid In substantially increases, which leads to a fairly constant speed of release of this steroid for a long period of time (see figures 3 and 4). As a result of this construction, the rate of release of steroid and the rate of release of steroid In can be adjusted independently from each other. Moreover, filling of the steroid nucleus In also prevents back diffusion of the steroid In the intermediate layer back into the kernel. Reverse diffusion of steroid can lead to a sustainable reduction of concentration in the intermediate layer and, thus, lower profile release during storage (even before the spread of steroid In the core and the intermediate layer). Also steroid And can diffuse back into the kernel. It is, however, less critical is effective, since the concentration of steroid in the intermediate layer is stabilized by the presence of it in crystalline form. In a preferred embodiment of the invention the steroid And is in the dissolved form, but can, however, also fill in the kernel.

Thus, the concept of this three-layered vaginal ring is the concentration (higher concentration) of the steroid in a relatively thin intermediate layer, where part of it will be presented in the form of crystals dispersed in a thin intermediate layer. The expected rate of release of steroid And get control of the shell thickness. Therefore, steroid And included in the crystalline form, and steroid In in dissolved form that allows you to adjust the concentration of the steroid In accordance with a given shell thickness. With a relatively small volume of the intermediate layer, this approach can lead to a relatively small amount of content, which can lead to relatively rapid consumption of the substance. Possible too rapid consumption of a substance in a three-layered ring is prevented by filling the cores and also the second steroid ().

In another embodiment of the invention, the system of drug delivery is three-layered vaginal ring including at least one Department, which is (i) an intermediate layer, filled with steroid And partially in the crystalline phase and partially dissolved in the polymer and (ii) core, filled with steroid, which is completely dissolved in the polymer and (iii) placebo-shell. Although this ring design contains only one steroid in the intermediate layer (in contrast to the two steroids in the ring described above), but after some time is converted to a ring design, described above, where three or two steroid are in the intermediate layer. As long-time steroid In may diffuse into the intermediate layer and at a certain point in time, the ring will contain (i) an intermediate layer, impregnated two steroids, one (steroid), semi-crystalline phase and partially dissolved in the polymer, and the other (steroid), is completely dissolved in the polymer, (ii) the core is filled with steroid (completely dissolved) and (iii) placebo-shell.

Vaginal ring according to the invention can be produced in a known manner extrusion extrusion extrusion), such as co-extrusion and/or combined extrusion/blunderstone. Co-extrusion were subjected to the core, filled with a medicinal substance, an intermediate layer, filled with a medicinal substance, and an outer layer containing Lakers the public matter. Thus obtained fibers were cut into pieces of desired length, of which any suitable way collected annular device. The rings are then Packed into suitable sachets, then it need not sterilized or disinfected.

Thermoplastic polymer that can be used in the practical implementation of the invention in principle can be any thermoplastic polymer or elastomer material, suitable for pharmaceutical applications, such as polyethylene low density copolymers of ethylene and vinyl acetate, block copolymers of styrene and butadiene with alternating blocks (copolymers of polystyrene-polybutadiene-polystyrene). In a preferred embodiment, the copolymer of ethylene and vinyl acetate (poly-EVA) is used because of its excellent mechanical and physical properties (i.e. solubility of the steroid in the material). The material is poly-EVA is used as the core and the intermediate layer and the shell can be any commercially available copolymer of ethylene and vinyl acetate, such as the products available under the trade name Elvax, Evatane, Lupolen, Movriton, Ultrathene, Ateva and Vestypar.

In one embodiment, both the core and the intermediate layer is made of a polymer of one species. In another embodiment, the core and the intermediate layer is made of polymers of different varieties, to get the more flexible the ring. Choosing polymers of different classes for the core and the intermediate layer, it is possible to achieve fine adjustment of the flexibility of the ring.

Vaginal ring in accordance with the invention can be made of any desired size. In one embodiment, the ring has an outer diameter (the outer circumference) between 50 and 60 mm and in another embodiment between 52 and 56 mm, cross-sectional diameter between 2.5 and 5 mm; in a preferred embodiment, between 3.0 and 4.5 mm, and in another embodiment between 3.5 and 4.0 mm, and in one embodiment is 4.0 mm

Also the task of the invention to provide an improved vaginal ring, in which the intermediate layer and/or the core, and in addition, steroids for contraception or gormonozavisimye also contain antimicrobial components, i.e. the treatment and/or protection from sexually transmitted diseases (STD's), such as HIV, herpes, chlamydia and gonorrhea, accompany.

The surface of the core according to the invention is more than 800 mm2in another embodiment, more than 1000 mm2and the typical will be in the range from 1700 to 2200 mm2, although there are significantly large surface area, such construction (physical dimensions) vaginal ring is inconvenient for the above tasks. This design can sometimes require adding the second Department, which is a placebo-Il Department the Department, filled with one or more medicinal substance. This additional section may be necessary, for example, for the implementation of hormone replacement therapy, where the level of progestin and estrogen differs from the level that is appropriate for contraception. Such additional Department may also be necessary to introduce in addition to steroid antimicrobial drugs for treatment and/or protection from sexually transmitted diseases (STD's), such as AIDS, chlamydia, herpes and gonorrhea.

Any antimicrobial drug may be enclosed in a vaginal ring according to the invention (in the intermediate layer and/or in the nucleus and/or in the additional section). Antimicrobial drug may be any antimicrobial drug, such as any antibiotic any anti-virus agent, any antifungal agent or any Antiprotozoal agent. An example of an antimicrobial drug that is intended for insertion into a vaginal ring according to the invention, is a polymer almond acid (Zanefeld et al. (2002), " Fertility and Sterility 78(5): 1170-1115), another example is dapivirine (4-[[4-[2,4,6-trimetilfenil)amino-2-pyrimidinyl]amino]benzonitrile).

Figure 5 shows a schematic description of a vaginal ring according to the invention. R1is the diameter of the three-layer fiber. R2is the radius of the nucleus together with the intermediate layer and R 3is the radius of the nucleus. The ratio R1/R2and R2/R3described in this figure is defined as the following:

NomenclatureR1/R2R2/R3
Option 11,0075-2,00001,0075-2,0000
Option 21,0100-1,50001,0200-1,5000
Option 31,0300-above 1.30001,0200-1,5000
Option 41,0400-1,18001,0200-1,5000
Option 51,0300-1,20001,0100-1,0900

The term "room temperature"used here refers to a temperature in the range from about 18°With up to about 30°C.

The term "physical stability"used here means that the system of drug delivery (ring), which can be stored at temperatures from about 18°With up to about 30°With at least a year and a half (1.5 years) without the formation of crystals of the steroid on the surface membrane of the vaginal ring.

Vaginal ring in accordance with the invention was originally designed for use for the purposes of contraception, but, as mentioned above, can also be used under certain conditions to check the Denia HRT (hormone replacement therapy).

Vaginal ring according to the invention, as mentioned above, can also be used for simultaneous updates and contraception and disease caused by germs. Microbial infection that can be treated and/or prevented, is any bacterial, viral, fungal or protozoal infection. In particular sexually transmitted diseases such as HIV, chlamydia, gonorrhea or herpes, can be treated by the introduction of antimicrobial agent in the ring according to the invention.

Further, the object of the invention is a method that includes the steps of placing an object of the invention is a system of drug delivery into the woman's vagina and hold it in the vagina for at least 21 days.

Another object of the invention is a method that can provide both contraception and treatment of or protection from sexually transmitted diseases, which includes the steps of placing a system of drug delivery according to the invention inside a woman's vagina and retention system inside the vagina for at least 21 days.

In one embodiment, the delivery system of the drug is removed after approximately 21 days for approximately one week, the period of menstruation. In other embodiments, the delivery system drug adelaideacl approximately 42, 63, 84, 105, 126, 147, 186, 189, 210, 231, 252, 273, 294, 315, 336 or 357 days approximately one week for the period of menstruation. After approximately week period menstruation a new system of drug delivery according to the invention is placed inside a woman's vagina to provide contraception in the next cycle or cycles in women.

Further, the object of the invention is the application of the system of drug delivery for the manufacture of contraceptive sets.

Further, the object of the invention is the application of the system of drug delivery for the manufacture of a medicinal product intended for conducting hormone replacement therapy.

The object of the invention is also the method of delivery of medicinal substance for the manufacture of a combined preparation for and contraception, and treatment and/or protection from sexually transmitted diseases, such as AIDS, herpes, chlamydia and gonorrhea.

Progestogenic steroid compound according to the invention can be any suitable progestogen, such as desogestrel, etonogestrel, levonorgestrel, norgestimate, gestodene or any other steroid substance with progestogenic activity. Estrogenic steroid substance can be any suitable estrogen, such as estradiol, estriol, mestranol and ethinylestradiol. In a preferred embodiment of the invention, the progestogen is etonogestrel. In another preferred variant of the invention, the estrogen for use in contraception is ethinyl estradiol. In another preferred embodiment of the invention estradiol is estrogen for use in HRT (hormone replacement therapy).

In one embodiment of the invention levonorgestrel is in the intermediate layer and in the core of the approximate amount of 0.05-1.5% of the total mass. In other embodiments, levonorgestrel is in the intermediate layer and the core in the amount of approximately 0.08 to 0.5% of the total mass, approximately in the amount of 0.09-0.20 per cent of the total, approximately in the amount of 0.09 to 0.18% by weight of the total or approximately the number of 0,09-0,15% of the total mass.

In the next version of the invention etonogestrel is in an intermediate layer about the number 6-80% of the total mass. In other embodiments, etonogestrel is in an intermediate layer about the number 6-70% of the total mass, the approximate number 10-53% of the total mass, approximately in the amount of 10-30% by weight of the total, approximately in the amount of 10-15% by weight of the total or in the amount of approximately 10-12% of the total mass.

The object of the invention is also a method of obtaining a three-layer system shortcuts the Cai medicinal substance by using:

(i) receipt of a completed (drug substance) of a homogenous polymer core granulate and filled (drug substance) homogenous polymer intermediate layer in the form of granules.

(ii) the joint extrusion of the nucleus in the form of granules and the intermediate layer in the form of granules for forming the three-layer system of drug delivery.

Getting filled (drug substance) homogenous polymer core granulate and filled (drug substance) homogenous polymer intermediate layer in the form of granules, includes:

(a) grinding the polymer;

(b) mixing the crushed polymer with the active substance in the form of a dry powder to fill the intermediate layer;

(c) mixing the crushed polymer with the active substance in the form of a dry powder to fill core;

(d) the combination of extrusion on the steps (b) and (C) mixtures in powder form;

(e) cutting the obtained filled polymer filaments granules with obtaining, thus, the kernel in the form of granules and the intermediate layer in the form of pellets;

(f) lubrication the lubricant is a kernel in the form of granules and the intermediate layer in the form of pellets; where steps (b) and (C) are interchangeable.

The present invention is further illustrated by the following examples, which prove that n does not limit the invention.

Examples

Example 1. Obtaining a three-layer ring

Were made eight (8) three-layer fiber (A1-A4 and B1-B4). The fibers were stretched to 3.5 mm (I) and 4.0 mm (Ah) from a single capillary (4.1 mm).

To mix the active ingredients etonogestrel (a steroid) and ethinylestradiol (steroid), there were two subsequent mixing with getting completely homogeneous polymer. In the first phase was the mixture in the form of dry powder by mixing finely ground active compounds and polymer powder. These micronized compounds were mixed with the polymer powder in the drum stainless steel Röhnrad (principle loops Barrel (Burrel - hoop principle)with a fixed speed of about 26 rpm for 60 minutes. When performing the first step of obtaining a mixture in powder form of the polymer and the active substance was mixed for kernel (powder polymer and fine ethinyl estradiol)and intermediate layer (polymer powder, fine levonorgestrel and fine etonogestrel). Next gomogenizirovannogo mixture powder was subjected to a combined extrusion (blendstrup) using 25 mm blendercoders (Berztorff ZE25) with a double auger rotating in one direction, and the resulting polymer filament, impregnated drug in the society, were cut into pellets using a pelletizer Scheer. In accordance with this method was a series of nuclei in the form of granules and a series of intermediate layers in the form of granules. After granulation these series were lubricated with magnesium stearate to facilitate the next phase (co-extrusion). The granular composition series, which was used to obtain three-layer fiber using the method of co-extrusion is described below in Table 1.

Table 1
MaterialTrack
The core in the form of granulesThe intermediate layer in the form of granules
Etonogestrel-10,3%
Levonorgestrel0,095%0,092%
Eaten 28-25 (Evatane 28-25)99,8%89,5%
Magnesium stearate0,1%0,1%
Total100,0%100,0%

Three-layer co-extrusion

To conduct a triple co-extrusion were used extruder co-extrusion (15/18 mm) Plactic Machinenebau (plastic machinenbau) in combination with the extruder Fourné (10 mm). To get the kernel and Premiata the aqueous layer were used extruders for co-extrusion of 15 mm and 18 mm Plactic Machinenebau (plastic machinenbau) and, respectively, for receiving the shell (outer layer) of 10 mm extruder Fourné . Three of the extruder was connected to the spinning unit, consisting of three units with three separate spinning pumps (Ankutec, Germany) (to control flow rate) (melt viscosity) of each layer). Three of the molten flow (melt) were combined in a multi-channel mouthpiece (extruder) to obtain the resulting three-layer fiber. Was used capillary 4,1 mm All fibers were extruded at a temperature of extrusion 110°C.

To obtain the expected diameter of the fiber as 3.5 mm and 4.0 mm was selected speed molding, the expected thickness of the shell and the intermediate layer was obtained by adjusting the spinning pumps. Each option three-layer fiber was obtained using an appropriate rate of formation and control of spinning pumps (full options 2×4, A1-A4 and B1-B4). After about 20 minutes of holding three-layer co-extrusion of each option three-layer fiber was wound (assembled) on the coil from stainless steel for 30 minutes. The outer diameter of the fiber was measured online (on-line) (permanent operation) using a laser micrometer and recorded. At the beginning and at the end of this 30 minute period of time were measured and recorded the fiber diameter, the thickness of the middle layer, the thickness of the shell.

Filled fibers were subjected to the s extrusion at a speed of 3 m/min for options a and 3.9 m/min for variants Century Except for option 3, which was obtained at 1.0 m/min for fiber A3 and 1.3 m/min for fiber B3.

Measurement of fiber

Measurement of fiber (outer diameter, the thickness of the intermediate layer and the shell thickness) were carried out directly after receiving 10 collected rings. The external diameter was determined by means of a laser device to measure the thickness (Mitutoyo). The thickness of the intermediate layer and the shell were determined by means of a microscope (Jena). The results of a completed series are given in Table 2A and 2b.

Table 2A

Measure 4 mm are filled with fibers obtained by extruding speed of 3 m/min (except A3, which was obtained at a speed of 1 m/min)
OptionThe fiber diameter (mm)The intermediate layer (μm)Shell (μm)The polymer shellR1/R2R2/R3
A14,006766Evatane 1020 VN31,03411,0359
A24,006181Evatane 1020 VN31,04221,0328
A33,9967294Evatane 1040 VN41,1728/td> 1,0410
A44,005180Evatane 1020 VN31,04171,0273

Table 2b

Measuring 3.5 mm filled fibers obtained by extruding speed of 3.9 m/min (except B3, which was obtained at a speed of 1.3 m/min)
OptionThe fiber diameter (mm)The intermediate layer (μm)Shell (μm)The polymer shellR1/R2R2/R3
B13,495458Evatane 1020 VN31,03441,0331
B23,515273Evatane 1020 VN31,04341,0319
B33,5059261Evatane 1040 VN41,17531,0413
B43,504870Evatane 1020 VN31,04171,0294

The concentration of the active components in the core and the intermediate layer was identical for all rings (10,3% ENG, 0,092% in the intermediate layer and 0,095% of ITS kernel). Concentration 0,092 and 0,095% for intermediate what about the layer and the core, respectively, is (almost) identical.

Speed of release In vitro

The results of the speed of release in vitro is shown in Table 3, shown in Figures 1-4 and Figures 6-13.

In Figures 1 and 2 shows the rate of release of etonogestrel from the tested one sample of each type of rings. In Figures 3 and 4 show the rate of release of levonorgestrel from one sample of each species tested rings. In Figures 6-13 shows the rate of release of etonogestrel and ethinyl estradiol from one sample tested rings of each type (A1-A4 and B1-B4). Table 3 shows the rate of release is calculated according to six (6) samples of each species tested rings.

Table 3

Speed of release in vitro for all of the series at t=0
SeriesSpeed of release in vitro etonogestrel (µg/day/ring)Speed of release in vitro EE (µg/day/ring)
Day 1The average daily value (2-21)Rsd (%)Day 21Day 1The average daily value (2-21)Rsd (%)Day 21
A1258-2641941177-180 22-2214111-12
A2216-2251621149-15219-2012110-10
A3179-1841190113-11425-251108-9
A4213-2211561130-13219-2012110-10
B1223-2321881157-16319-2113210-11
B2191-1971581139-14318-191119-10
B3168-1721171110-11226-261018-8
B4182-1961452104 to 11117-191129-9

Speed visw is bogdania in the 1st and 21st day represented as a sequence of individual results 6 rings (see minimum and maximum estimates).

The average daily value of the speed of release of 2-21 days shows the average rate of release from the 2nd day through the 21st day. Given an average score of 6 rings.

Assembly

4 mm series (Ax) were chopped into pieces with a length of 157 mm and welded at the welding temperature 130°and a weld time of 15 seconds using TWI mono welding installation.

3.5 mm fibers were chopped into pieces with a length of 157 mm and the ends were connected together using a binder, Loctite (Loctite) (type 406770; catalysts room 40621 and 77012).

Thus was obtained a new design of a three-layer ring with layers ranging from 50 to 300 μm, limited by the thickness of the shell and the thickness of the intermediate layer.

Example 2. Physical stability

The storage stability of NuvaRing® under normal storage temperature (up to 30° (C) is limited by the formation of crystals of the steroid on the surface membrane of the vaginal ring, which leads to an increase in the allocation of on-set, the so-called explosive release (explosive rate of release), and thus, lowers physical stability. The explosive rate of release (the rate of release of the 1st day) 8 series object of the invention - rings were tested at time zero and after 12, 18 and 24 months of storage at 30°C/75% relative humidity in a closed sachet, laminarian the m aluminum foil (WO 99/30976). The explosive rate of release of 3 representative series NuvaRing®also tested at time zero after 12, 18 and 24 months of storage at 30°C/75% relative humidity in a closed sachet, laminated aluminum foil. The rate of release at time zero was determined by examination of 12 rings series, and the rate of release after 12, 18 and 24 months of storage was determined using studies 6 rings series. The results of these studies are shown in Tables 4, 5 and 6. Explicit explosive rate of release of all three series NuvaRing® increases after 12 months of storage at 30°C. Except A3, all seven series of the object of the invention is a ring - showed constant or low explosive speed release after storage at 30°C. Visual examination of the rings series A3, showed that the increase the explosive speed of release is not dependent on the formation of crystals of the steroid on the surface of the ring. Indeed, increase the explosive speed of release of series A3 does not depend on the formation of crystals on the surface of the ring, which also demonstrated a slight difference observed in the course of the experiment between individual test results and evaluation RSD (relative standard deviation (CCA), which indicates relatively low on klonnie from standard CCA.

Table 4

Day 1, the rate of release at time zero and after 12 months of storage at 30°C/75% relative humidity
NuvaRing®On-set
Individual results t=0Rsd (%)Individual results t=12 monthsRsd (%)
N1186,4, 193,2, 186,6, 185,5, 189,9, 188,5, 187,8, 187,6, 189,6, 184,4, 188,3, 190,21,3210,6, 191,0, 179,5, 178,6, 171,8, 205,98,3
N2197,4, 199,0, 199,3, 198,2, 199,7, 198,3, 205,1, 200,5, 200,4, 200,1, 200,3, 198,31,0188,5, 190,5, 194,4, 195,4, 215,3, 200,1a 4.9
N3194,6, 197,5, 197,0, 193,8, 198,3, 197,5, 198,3, 199,4, 198,7, 204,5, 211,6, 201,82,4255,1, 325,3, 276,3, 215,0, 505,9, 222,536,6
The object of the invention - ring
A1260,7, 264,9, 263,7, 260,3, 263,6, 261,6, 265,2, 264,7, 263,7, 261,7, 265,5, 258,40,9210,2, 207,1, 220,7, 217,2, 209,3, 209,22,5
A2219,5, 221,6, 219,5, 219,2, 219,4, 225,0, 222,5, 221,7, 215,8, 223,6, 218,0, 221,21,1184,2, 181,1, 176,9, 179,9, 177,3, 177,01,6
A3181,0, 180,8, 180,, 182,2, 179,3, 180,7, 180,5, 181,5, 181,2, 182,1, 180,7, 193,60,6198,7, 194,0, 197,7, 202,5, 199,0, 199,51,4
A4217,9, 213,4, 216,3, 216,9, 215,1, 219,2, 220,1, 220,6, 221,1, 218,0, 217,9, 219,21,1169,1, 171,1, 176,6, 176,6 175,0, 169,32,0
B1222,9, 230,0, 225,5, 227,8, 230,5, 229,4, 229,5, 226,8, 226,4, 231,9, 232,3, 226,61,2181,6, 178,4, 180,8, 181,8, 178,1, 179,00,9
B2194,8, 194,5, 194,3, 197,3, 190,9, 195,2, 194,9, 192,8, 191,5, 192,6, 194,2, 194,00,9154,1, 152,5, 151,0, 154,3, 154,1, 153,70,8
B3171,3, 171,3, 170,1, 171,4, 168,8, 172,0, 171,5, 171,5, 169,7, 169,7, 167,5, 167,90,9179,0, 177,8, 176,6, 183,2, 179,1, 178,91,2
B4188,2, 189,9, 195,8, 185,9, 189,9, 181,7, 194,3, 192,2, 191,5, 182,5, 189,7, 193,62,3155,1, 150,6, 148,8, 150,4, 151,6, 148,31,6

Table 5

Day 1, the rate of release at time zero and after 18 months of storage at 30°C/75% relative humidity
NuvaRing®On-set
Individual results t=0Rsd (%)Individual results t=18 monthsRsd (%)
N1186,4, 193,2, 186,6, 185,5,189,9, 188,5, 187,8, 187,6, 189,6, 184,4, 188,3, 190,21,3188,6, 237,0, 301,8, 252,6, 234,0, 186,418,5
N2197,4, 199,0, 199,3, 198,2, 199,7, 198,3, 205,1, 200,5, 200,4, 200,1, 200,3, 198,31,0210,8, 183,0, 261,6, 202,1, 241,8, 249,413,7
N3194,6, 197,5, 197,0, 193,8 198,3, 197,5, 198,3, 199,4, 198,7, 204,5, 211,6, 201,82,4479,6, 560,2, 510,2, 483,0, 579,4, 477,98,6
The object of the invention - ring
A1260,7, 264,9, 263,7, 260,3, 263,6, 261,6, 265,2, 264,7, 263,7, 261,7, 265,5, 258,40,9205,5, 209,1, 201,9, 207,5, 199,0, 198,32,2
A2219,5, 221,6, 219,5, 219,2, 219,4, 225,0, 222,5, 221,7, 215,8, 223,6, 218,0, 221,21,1172,5, 174,0, 174,0, 180,5, 177,0, 174,51,7
A3181,0, 180,8, 180,0, 182,2, 179,3, 180,7, 180,5, 181,5, 181,2, 182,1, 180,7, 193,60,6194,0, 203,4, 197,9, 201,5, 190,2, 197,912,5
A4217,9, 213,4, 216,3, 216,9, 215,1, 219,2, 220,1, 220,6, 221,1, 218,0, 217,9, 219,21,1166,9, 163,2, 165,7, 168,1, 159,4, 166,41,9
B1222,9, 230,0, 225,5, 227,8, 230,5, 229,4, 229,5, 226,8, 226,4, 231,9, 232,3, 226,61,2171,8, 169,7, 167,6, 173,3, 171,6, 169,41,3
B2194,8, 194,5, 194,3, 197,4 190,9, 195,2,194,9, 192,8, 191,5, 192,6, 194,2, 194,00,9147,6, 146,1, 146,0, 146,8, 142,9, 143,71,3
B3171,3, 171,3, 170,1, 171,4, 168,8, 172,0, 171,5, 171,5, 169,7, 169,7, 167,5, 167,90,9172,3, 170,9, 171,7, 172,0, 169,5, 177,11,5
B4188,2, 189,9, 195,8, 185,9, 189,9, 181,7, 194,3, 192,2, 191,5, 182,5, 189,7, 193,62,3147,5, 146,5, 142,4, 127,3, 145,6, 145,5of 5.4

Table 6

Day 1, the rate of release at time zero and after 24 months of storage at 30°C/75% relative humidity
NuvaRing®On-set
Individual results t=0Rsd (%)Individual results t=24 monthsRsd (%)
N1186,4, 193,2, 186,6, 185,5, 189,9, 188,5, 187,8, 187,6, 189,6, 184,4, 188,3, 190,21,3199,0, 175,9, 219,9, 188,9, 206,9, 184,88,2
N2197,4, 199,0, 199,3, 198,2, 199,7, 198,3, 205,1, 200,5, 200,4, 200,1, 200,3, 198,31,0247,0, 275,7, 297,3, 371,9, 215,6, 269,019,0
N3194,6, 197,5, 197,0, 193,8 198,3, 197,5, 198,3, 199,4, 198,7, 204,5, 211,6, 201,82,4271,3, 262,2, 268,1, 247,2, 436,6, 329,423,6
The object of the invention - ring
A1260,7, 264,9, 263,7, 260,3, 263,6, 261,6, 265,2, 264,7, 263,7, 261,7, 265,5, 258,40,9206,4, 208,6, 201,8, 203,7, 209,9, 213,72,1
A2219,5, 221,6, 219,5, 219,2, 219,4, 225,0, 222,5, 221,7, 215,8, 223,6, 218,0, 221,21,1179,1, 172,1, 173,4, 179,8, 179,8, 172,82,0
A3181,0, 180,8, 180,0, 182,2, 179,3, 180,7, 180,5, 181,5, 181,2, 182,1, 180,7, 193,60,6197,7, 195,8, 196,8, 197,8, 197,7, 204,91,6
A4217,9, 213,4, 216,3, 216,9, 215,1, 219,2, 220,1, 220,6, 221,1, 218,0, 217,9, 219,21,1170,1, 163,6, 163,5, 168,2, 164,6, 166,91,6
B1222,9, 230,0, 225,5, 227,8, 230,5, 229,4, 229,5, 226,8, 226,4, 231,9, 232,3, 226,61,2171,3, 170,3, 172,1, 175,9, 168,2, 171,81,5
B2194,8, 194,5, 194,3, 197,4 190,9, 195,2, 194,9, 192,8, 191,5, 192,6, 194,2,194,00,9143,5, 145,8, 146,8, 148,0, 150,0, 148,81,6
B3171,3, 171,3, 170,1, 171,4, 168,8, 172,0, 171,5, 171,5, 169,7, 169,7, 167,5, 167,90,9173,9, 173,0, 173,9, 177,4, 175,4, 175,90,9
B4188,2, 189,9, 195,8, 185,9, 189,9, 181,7, 194,3, 192,2, 191,5, 182,5, 189,7, 193,62,3145,0, 145,6, 144,9, 143,9, 142,6, 143,40,8

Example 3. Superior three-layer ring, version, opican the I in US 4,292,965

This example illustrates the advantages of object - improved three-layer ring relative to the three-layered rings, described in US 4,292,965.

In the US 4,292,965 two steroid entered (acomodaron) in the intermediate layer; steroid is not present in the kernel.

The essence of the improved three-layer ring is that the rate of release of two or more steroids can be adjusted independently from each other, and that the ring can maintain the rate of release over an extended period of time, maintaining physical stability at room temperature. This example demonstrates the advantages of the improved three-layered rings, which also filled the kernel, before ring design with the kernel, not impregnated with pharmaceutical substances, as described in US 4,292,965.

It is impossible to fill the intermediate layer more than one steroid in crystalline form with independent rate of release. When regulating the speed of release of the two (or more) of steroids from one Department only one steroid is in the crystalline phase and the other(s) are in the dissolved phase. In the case of steroid And partially in the crystalline phase, the steroid in the crystal lattice will be in dynamic equilibrium with the dissolved steroid. At a certain pre-concentration erased the IDA And the rate of release of steroid And can be adjusted by selecting the proper thickness of the shell. Is obvious that the thickness of the shell is a tool that is already applied to control the speed of release of the steroid And the rate of release of the second component of the steroid can also be picked up only by selecting the desired concentration. Since a steroid, is only in the dissolved form, more steroid can be incorporated (introduced) into the ring (while maintaining the same level of concentration gradient across the membrane) by increasing the volume of the tank (kernel). Thus, the volume of the tank is determined by the amount of dissolved steroid In that can fill the ring.

For an object of the present invention, the ring A2 (see example 1) - volume of the intermediate layer and the reservoir kernel can be computed as follows. Measurement of the fiber ring A2 are approximate; the length of 15.7 cm, diameter 4 mm, the thickness of the intermediate layer is about 60 μm and a shell of about 80 μm and the volume of the intermediate layer of the core is approximately Vint(prom)=0,11 ml and Vcore)=1,71 ml, the density and the core, and an intermediate layer that is relatively close to 1 g/ml and, therefore, the mass of the core and the intermediate layer is approximately 1,71 g and 0.11 g, respectively. ITS concentration in the core and the intermediate layer is approximately 0,095% m/m and, therefore, the core contains priblizitel the 1620 but µg HER and the intermediate layer contains approximately 106 µg HER. Thus, in this particular case (A2) can be entered more than IT improved three-layer construction, compared with a ring, which is not impregnated drug core, about more than 15 times.

The rate of release HER from the ring A2, as a function of time, represented in the Figure 3, can be used as an illustration of the advantages of the kernel, filled HER. Pseudoleucite condition of release (release within 2-21 days) is between 15 and 10 µg/day, and the contents of only one intermediate layer (106 g) may not be sufficient to maintain a relatively constant rate of release over a period of more than a few days. In this case, after less than 7 days, intermediate layer can be almost completely depleted and the rate of release will considerably fall after a few days.

Furthermore, the design of the ring, such as in the US 4,292,965, internal difundieran in the core network nonequilibrium state and, therefore, ITS concentration in the intermediate layer decreases, resulting in pharmacological product with unstable release profile. However, when ITS concentration in the nucleus is the same as in the intermediate layer, the desired equilibrium state.

This pseudoleucite state when the internal diff is Ziya (also called reverse diffusionism) inherent in the three-layer structure in accordance with US 4,292,965, while improved design eliminates these unwanted effects.

Example 4. Production of three-layered rings containing additional Department

Were made twenty (20) additional three-layer fibers (a-h). Options fibers have a size of 4 mm (E-V), 3 mm (option W) and 5 mm (option X). All fibers were produced from a single capillary (3.6 mm). Pellet nuclei and granules of the intermediate layer (C1-C4 and D1-D2, respectively) were prepared using mostly the same way as described in Example 1, with the following minor changes:

Granules C4, D1 and D2 were mixed in the drum of stainless steel, using Rhönrad (principle loops Barrel (Barrel-hoop principle)with a fixed speed of approximately 47 rpm for 60 minutes.

Table 7

The composition of the pellet cores
OptionEtonogestrelLevonorgestrelAtewa A (Ateva2820A)Magnesium stearateTotal
C1--0,16%99,7%0,1%100,0%
C2--0,13%99,8%0,1%100,0%
C3--0,20%99,7% 100,0%
C40,33%0,16%99,4%0,1%100,0%

Table 8

The composition of the granules in the intermediate layer
OptionEtonogestrelLevonorgestrelAtewa A (Ateva A)Magnesium stearateTotal
D110,5%0,16%89,2%0,1%100,0%
D252,5%0,16%47,2%0,1%100,0%

Three-layer co-extrusion

To obtain a three-layer fiber was used extruder for carrying out the triple co-extrusion Fourné (25/18/18). The extruder of 25 mm was used to obtain nuclear/inner layer, while the two extruder 18 mm were used to obtain the intermediate layer and the shell (outer layer), respectively. Three of the extruder was connected to the spinning unit, consisting of three units with three separate spinning pumps (Ankutec, Germany) (to control flow rate) (melt viscosity) of each layer). Three of the molten flow (melt) were combined in a multi-channel mouthpiece (extruder) with the teaching in the three-layer fiber. Was used capillary 3,6 mm All fibers were extruded at a temperature of extrusion 110°C.

To obtain the expected diameter of the fiber as 3.4 mm or 5.0 mm was adjusted speed molding. The expected thickness of the shell and the intermediate layer was obtained by adjusting the spinning pumps. Each option three-layer fiber was obtained using an appropriate rate of formation and control of spinning pumps (full options-h). After about 20 minutes of holding three-layer co-extrusion of each option three-layer fiber was wound (assembled) on the coil from stainless steel for 120 minutes. The outer diameter of the fiber was measured online (on-line) using a laser micrometer and recorded. At the beginning and at the end of this 120 minute period of time were measured and recorded the fiber diameter, the thickness of the middle layer, the thickness of the shell. Options W and X were collected within only 30 minutes. Filled fibers were obtained by extruding speed of 2.0 m/min for options E-V, 3,59 m/min for option W, and when 1,28 m/min for option X.

Measurement of fiber

The thickness of the intermediate layer and the shell thickness were determined for each variant parts of the fiber from 4 samples during the process of triple co-extrusion. The external diameter was determined for every what about the variant parts of the fiber from the 6 samples during the process of triple co-extrusion of the fibers. The external diameter was determined using a laser device to measure the thickness (Zumbach). The thickness of the intermediate layer and the shell were determined by means of a microscope (Jena). The results of a completed series are shown in Table 9a and 9b.

Table 9a

Measure 4 mm are filled with fibers obtained by extruding speed of 3 m/min (except A3, which was obtained at a speed of 1 m/min)
OptionThe fiber diameter (mm)The composition engineThe intermediate layer (μm)The composition of the intermediate layer (μm)Shell (μm)R1/R2R2/R3The polymer Shell
E4,01C161D11101,05801,0333Aveta 1070
F4,01C360D11001,05251,0325Aveta 1070
Gas 4.02C363D11261,06691,0346Aveta 1070
Has 4.02C253D1 941,04911,0284Aveta 1070
I4,04C262D11231,06481,0338Aveta 1070
Jas 4.02C1148D11101,05791,0845Aveta 1070
K4,00C128D21111,05881,0150Aveta 1070
L4,03C467D11121,05891,0365Aveta 1070
M4,01C161D11461,07801,0339Aveta 1231
N4,03C260D11331,07011,0329Aveta 1231
O4,01C263D11671,09091,0355Aveta 1231
Pas 4.02C363D11321,07031,0347Aveta 1231
Q as 4.02C360D11611,08711,0335Aveta 1231
R4,04C170D13151,18481,0428Aveta 1231
S4,05C269D12771,15851,0411Aveta 1231
Tas 4.02C268D13351,20001,0423Aveta 1231
U4,04C367D12981,17311,0405Aveta 1231
V4,04C365D13341,19811,0401Aveta 1231

Table 9b

Measure 3 mm filled fibers obtained by extruding speed 3,59 m/min
OptionThe fiber diameter (mm)The composition engineThe intermediate layer (μm)The composition of the intermediate layerShell (μm)R1/R2 R2/R3The polymer shell
W3,03C145D1831,05801,0324Aveta1070

Table 9c

Measuring 5 mm are filled with fibers obtained by extruding speed of 1.28 m/min
Vari antThe fiber diameter in mmThe composition engineThe intermediate layer (μm)The composition of the intermediate layerShell mcmR1/R2R2/R3The polymer shell
X5,00C174D11381,05841,0323Aveta1070

Speed of release in vitro,

The results of the speed of release in vitro is shown in Table 10 and shown in Figures 14-21, which illustrate the speed of release of etonogestrel and ethinyl estradiol all fibers (E-W). In Table 10 and Figures 14-21 shows the speed of release, calculated according to six (6) samples of each species tested rings.

131
Table 10

Speed of release in vitro all the series at t=0
SeriesSpeed of release in vitro etonogestrel (µg/day, ring)Speed of release in vitro IT (µg/day/ring)
Day 1Average daily rate (2-21)Rsd (%)Day 21Day 1Average daily rate (2-21)Rsd (%)Day 21
E140-15394189-9023-2414312-13
F153-162108299-10429-3019217-18
G125-13182176-7924-2515212-14
H148-157106297-10120-2113310-12
I122-12782176-7917-181048-9
J208-214101191-93 23-2414212-13
K123-13595288-9321-2313311-12
L178-18798287-9121-2313311-11
M187-1971231113-11734-3519216-17
N193-1981331121-12530-3117214-15
O165-171106198-10126-2814211-12
P182-2081381127-13139-4425222-23
Q170-1801121103-10738-4021219-19
R186-2031181109-11326-2919215-17
S226-2361123-12636-3818214-15
T190-1971101102-10527-2915212-12
U218-2241251116-11941-4424220-22
V181-1931111103-10730-3222219-19
W120-12296183-8521-2113211-12
X134-14484377-8421-2212310-12

Speed of release of the 1st and 21st days were represented as a sequence of individual results 6 rings (see minimum and maximum estimates).

The average daily value of the speed of release of 2-21 days shows the average rate of release from the 2nd day through the 21st day. Given an average score of 6 rings.

Assembly

4 mm fiber (E-V) were chopped into pieces with a length of 157 mm and welded at the welding temperature 130°and in which the time of welding 17 seconds on the SMS (Centrum voor Constructie " en Mechatronica, The Netherlands) Assembly machine. Fiber W and X were manually cut 157 mm and the ends of the threads were connected together using a binder, Loctite (Loctite adhesive) (type 406 and 770; catalysts room 40621 and 77012).

1. The delivery system is intended for vaginal administration of a drug comprising at least one unit consisting of (i) the kernel of thermoplastic polymer filled with a medicinal substance, (ii) an intermediate layer of thermoplastic polymer filled with a medicinal substance, (iii) a sheath of thermoplastic polymer covering the intermediate layer and not containing medicinal substances, where specified intermediate layer filled in (a) crystals of the first pharmacologically active compound and (b) a second pharmacologically active compound in dissolved form, and where the specified core filled with the specified second compound in dissolved form.

2. The system of drug delivery according to claim 1, which is physically stable at temperatures of approximately 18-30°C.

3. The system of drug delivery according to claim 1, where the specified second connection in the nucleus is in the same concentration as in the intermediate layer.

4. The system of drug delivery according to claim 1, characterized by the fact that systems for the delivery, essentially has the shape of a ring and is intended for vaginal administration.

5. The system of drug delivery according to claim 1, where the specified first active compound is a steroid, and a specified second compound is a steroid.

6. The system of drug delivery according to claim 5, where said first active steroid is a progestogen.

7. The system of drug delivery according to claim 5, where the specified second active steroid is estrogen.

8. The system of drug delivery according to claim 7, where the estrogen is ethinyl estradiol.

9. The system of drug delivery according to claim 6, where the progestogen is etonogestrel.

10. The system of drug delivery according to claim 1, where the first active connection is etonogestrel, and the second active compound is ethinyl estradiol.

11. The system of drug delivery according to claim 1, characterized in that at least the shell, and not necessarily, the core and the intermediate layer contains as thermoplastic polymer is a copolymer of ethylene and vinyl acetate.

12. The system of drug delivery according to claim 11, characterized in that the core and the intermediate layer contains as thermoplastic polymer is a copolymer of ethylene and vinyl acetate of the same class.

13. System dostavka the medicinal substance according to claim 11, characterized in that the core and the intermediate layer contains as thermoplastic polymer is a copolymer of ethylene and vinyl acetate of different varieties.

14. The system of drug delivery according to claim 1, characterized in that the core is additionally filled with the first substance.

15. The system of drug delivery of claim 8, where the ethinyl estradiol is in the intermediate layer and the core in the amount of about 0.05-1.5% of the total mass.

16. The system of drug delivery according to § 15, where levonorgestrel is in the intermediate layer and the core in the amount of approximately 0.08 to 0.5% of the total mass.

17. The system of drug delivery according to clause 16, where levonorgestrel is in the intermediate layer and the core in the amount of approximately 0,09-0,18% of the total mass.

18. The system of drug delivery by 17, where ethylestradiol is located in the intermediate layer and the core in the amount of approximately 0,09-0,15% of the total mass.

19. The system of drug delivery according to clause 16, where levonorgestrel is in the intermediate layer and the core in the amount of approximately 0,09-0,20% of the total mass.

20. The system of drug delivery according to claim 9, where etonogestrel is located in the intermediate layer in the amount of approximately 6-80% of the total mass.

21. The delivery system drug vexes the VA in claim 20, where etonogestrel is located in the intermediate layer in the amount of approximately 6-70% of the total mass.

22. The system of drug delivery according to item 21, where etonogestrel is located in the intermediate layer in the amount of approximately 10-53% of the total mass.

23. The system of drug delivery according to article 22, where etonogestrel is located in the intermediate layer in the amount of approximately 10-30% of the total mass.

24. The system of drug delivery according to item 23, where etonogestrel is located in the intermediate layer in the amount of approximately 10-15% of the total mass.

25. The system of drug delivery according to paragraph 24, where etonogestrel is located in the intermediate layer in the amount of approximately 10-12% of the total mass.

26. The system of drug delivery according to claim 1, where the ratio R1/R2is approximately between 1,0075-2,0000, and the ratio R2/R3is approximately between 1,0075-2,0000.

27. The system of drug delivery by p, where the ratio R1/R2is approximately between 1,0100-1,5000, and the ratio R2/R3is approximately between 1,0200-1,5000.

28. The system of drug delivery according to item 27, where the ratio R1/R2is approximately between 1,0300-above 1.3000, and the ratio R2/R3is approximately between 1,0200-1,000.

29. The system of drug delivery by p, where the ratio R1/R2is approximately between 1,0400-1,8000, and the ratio R2/R3is approximately between 1,0200-1,0500.

30. The system of drug delivery according to claim 1, where the ratio R1/R2is approximately between 1,0300-1,2000, and the ratio R2/R3is approximately between 1,0100-1,0900.

31. The system of drug delivery on pp.5-30, characterized in that the intermediate layer further comprises an antimicrobial agent.

32. The system of drug delivery on pp.5-30, characterized in that the core further comprises an antimicrobial agent.

33. The system of drug delivery according to claim 1, characterized in that the device comprises two sections.

34. The system of drug delivery by p where the second division contains an antimicrobial agent.

35. The system of drug delivery by p, where the antimicrobial agent is a polymer condensed almond acid.

36. The system of drug delivery by p, where the antimicrobial agent is a polymer condensed almond acid.

37. The system of drug delivery according to § 34, where the antimicrobial agent is a polymer condensed mihalenko.

38. The method includes the following steps: (i) placement system of drug delivery according to claims 1-30 into the woman's vagina and (ii) the presence of the system into the woman's vagina for at least about 21 days.

39. The way of concentration, including the following stages: (i) placement system of drug delivery according to claims 1 to 30 in a woman's vagina, (ii) the presence of the system into the woman's vagina for at least 21 days and (iii) removing the system for approximately one week during menstruation.

40. The method of the simultaneous holding of contraception and the treatment of or protection from sexually transmitted diseases, which includes the following steps: (i) placement system of drug delivery by PP-37 into the woman's vagina and (ii) the presence of the system into the woman's vagina for at least 21 days.

41. The system of simultaneous contraception and the treatment of or protection from sexually transmitted diseases, which includes the following steps: (i) placement system of drug delivery by PP-37 into the woman's vagina, (ii) the presence of the system into the woman's vagina for at least 21 days and (iii) removing the system for approximately one week during menstruation.

42. The application delivery system of Lekarstvo the th substance according to claims 1 to 30 for receiving contraceptive set.

43. The application of the system of drug delivery according to claims 1 to 30 for receiving medicinal products for hormone replacement therapy.

44. The application of the system of drug delivery by p-37 to obtain the combination of the drug providing contraception and the treatment and/or protection from sexually transmitted diseases.

45. The application of item 44, where the disease is AIDS.

46. The application of item 44, where the disease is herpes.

47. The application of item 44, where the disease is chlamydia.

48. The application of item 44, where the disease is gonorrhea.

49. A method of obtaining a three-layer system of drug delivery according to claim 1, including:

(iii) receipt of a completed homogenous polymer core granulate and filled with a homogenous polymer intermediate layer granulate;

(iv) joint extrusion of the nucleus in the form of granules and the intermediate layer in the form of granules, polymer-coated pellets to obtain a three-layer system of drug delivery.

50. The method according to § 49, where step (i) includes:

(a) grinding the polymer;

(b) mixing the crushed polymer with the active substances in the form of a dry powder to fill the intermediate layer;

(c) mixing the crushed polymer with active substances the AMI in the form of a dry powder to fill the core;

(d) conducting a combined extrusion process from steps (b) and (C) mixtures in powder form;

(e) cutting the obtained filled polymer fibres, granules, obtaining thus the kernel in the form of granules and the intermediate layer in the form of pellets;

(f) lubrication the lubricant is a kernel in the form of granules and the intermediate layer in the form of pellets; where steps (b) and (C) are interchangeable.

51. The delivery system is intended for vaginal administration of a drug containing at least one unit consisting of (i) the kernel of thermoplastic polymer filled with a medicinal substance, (ii) an intermediate layer of thermoplastic polymer filled with a medicinal substance, and (iii) a sheath of thermoplastic polymer covering the intermediate layer and not containing medicinal substances, where specified intermediate layer is filled with crystals of the first pharmacologically active substance, and where the specified core filled in the second pharmacologically active substance in dissolved form.



 

Same patents:

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to immunology and biotechnology. Described is polypeptide of protein P17 of HIV virus with amino acid sequence, consisting of peptide, corresponding to neutralising epitope of protein p17 of HIV, and peptide, corresponding to positions 23-32 of protein p17 of HIV. Peptide is bound to peptide of neutralising in carboxy-terminal position of epitope and makes it soluble. Described are vaccine compositions based on polypeptide, versions of polypeptide application such as, for preparation of medication against HIV, and as specific reagent in test on detecting neutralising anti-p-17-antibodies. Described are monoclonal and polyclonal anti-p 17-antibodies, able to recognise neutralising polypeptide epitope in specific way and neutralise its biological activity. Described is application of said antibodies to polypeptide for detecting p17 in biological material and for preparation of medication inhibiting p17 protein activity in HIV-infected people. Application of invention allows to induce neutralising anti- p17-antibodies and inhibit p17 activity which can be applied in medicine for preparation of vaccine of injection material against HIV.

EFFECT: obtaining composition which can be applied in medicine for preparation of vaccine or injection material against HIV.

17 cl, 9 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine and viral infection treatment, particularly combined antiviral agent with anti-HIV action, namely the combined antiviral agent, comprising the composition of (2R, cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolane-5-yl)-1H-pyrimidine-2-on (lamivudine) and 5'-H-phosphonate-3'-azido-3'-desoxythymidine sodium salt (phosphazide) in 250:1 to 1:250 weight ratio, and the treatment for HIV-infection method.

EFFECT: producing of combined antiviral agent with anti-HIV action, providing the increase in treatment effectiveness along with significant reduction of toxic manifestations.

12 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention concerns a crystal of 6-(3-chlor-2-fluorbenzyl)-1-[(S)-1-hydroxynethyl-2-methylpropyl]-7-metoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid featuring specific x-ray diffraction spectre with characteristic diffraction peaks at diffraction angles of 2Θ (°), measured at an x-ray diffractometre. Also the invention describes a pharmaceutical composition with active integrase inhibition, antiviral and anti-HIV properties.

EFFECT: excellent physical and chemical stability of the obtained crystal.

10 cl, 8 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to compounds with general formulae (I) and (II) and their pharmaceutical salts, their use as inhibitors of HIV-integrase and to pharmaceutical salts based on them. In formula (I) , R1 represents H or NR2R5; R2 represents CH3; R5 represents 1) C(O)CH2SO2CH3, 2) C(O)C(O)N(CH3)2, 3) SO2N(CH3)2 or 4) SO2R20 where R20 represents , , or ; or alternatively, R2 and R5 together with a nitrogen atom, to which they are bonded, form or , R3 represents hydrogen; R4 represents 1) n-fluorobenzyl, 2) 4-fluro-3-methylbenzyl, 3) 3-chlorobenzyl or 4) 3-chloro-4-methylbenzyl; R12 and R14 both represent H, except that, when R5 represents C(O)C(O)N(CH3)2 and R4 represents n-fluorobenzyl, and n equals 1, then R12 and R14 both represent H, or both represent CH3; and n is an integer, equal to 0, 1 or 2.

EFFECT: compounds can be used for treating HIV-infection.

12 cl, 5 dwg, 1 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to medical products and concerns combination for HIV-infection treatment, containing (a) therapeutically effective amount of HIV-protease inhibitor by formula or its pharmaceutically accepted salt or ester and (b) effective amount of rhytonavir or its pharmaceutically accepted salt or ester. Besides, method of improved pharmacokinetics of HIV-protease inhibitor by formula (4) or its pharmaceutically accepted salt or ester, including introduction to an individual requiring such treatment, therapeutically effective amount of rhytonavir or its pharmaceutically accepted salt or ester with therapeutically effective amount of specified HIV-protease inhibitor by formula (4) is described.

EFFECT: offered combination has synergetic action if taken in any molar ratios.

33 cl, 6 dwg, 9 tbl, 4 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to new compounds of and formula: I II those developing antiviral activity allowing application in pharmaceutical formulations and for antiviral medicines production.

EFFECT: new compounds have useful biological properties.

5 cl, 3 dwg, 6 tbl, 3 ex

FIELD: medicine, molecular biology, antibodies.

SUBSTANCE: invention relates to an antibody raised against CCR5 and comprising: (i) two light chains wherein each light chain comprises product of plasmid expression and designated as pVK:HuPRO140-VK (ATCC - PTA-4097), and (ii) two heavy chains wherein each heavy chain comprises product of plasmid expression and designated as pVg4:HuPRO140 HG2-VH (ATCC - PTA-4098), or plasmid designated as pVg4:HuPRO140 (mut B+D+I)-VH (ATCC - PTA-4099), or fragment of such antibody binding with CCR5 on a human cell surface. Invention relates to nucleic acid encoding light and heavy chains of antibody, expression vector, cell-host transformed with at least one vector, and a method for preparing antibody. Antibody is used as an active component in composition used for inhibition of infection of cells CD4 + HIV-1, and to a pharmaceutical composition used in treatment of a patient with HIV-1 infection. Also, invention relates to antibody conjugate against CCR5 and its using. Use of antibodies provides enhancing effectiveness of prophylaxis and treatment of HIV-1 infection.

EFFECT: valuable medicinal properties of antibody.

31 cl, 23 dwg, 3 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to novel 5'-phosphonates of 3`-azido-3`-deoxythymidine of the general formula (I) possessing anti-HIV activity, and to using 5'-phosphonates of 3`-azido-3`-deoxythymidine as an active component for preparing drugs possessing anti-HIV activity. In compound of the general formula (I): at n = 0-2; R1 means (wherein X means -CH2, -NH, O); R2 means -NH-C(O)- (wherein R2 means H, (C1-C6)-alkyl, (C5-C7)-cycloalkyl), -HO(CH2)k- (wherein k = 2-4); at n = 0 R1 means -Cl3C; at n = 1-6 R1 means Cl-, Br-, J-, and at n = 2-6 R3 means -C(O)O- (wherein R3 means (C1-C6)-alkyl) at n = 2-6.

EFFECT: valuable medicinal properties of compounds.

3 cl, 2 tbl, 10 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: pharmaceutical composition comprises abacavir and alovudin taken in the ratio = (1-10):(200-800) and a pharmaceutical carrier for them. Package designated for a patient for treatment of poly resistant HIV comprises alovudin and abacavir and information instruction for using both alovudin and abacavir in combination. Use of abacavir in common with alovudin for treatment of polyresistant HIV wherein use involves simultaneous, combined or successive administration of alovudin and abacavir. Invention provides more inhibition of virus, suppression of virus for longer period, limiting safety for arising mutations and development of polyresistant HIV, and decreasing toxicity of drugs.

EFFECT: valuable properties and enhanced effectiveness of drugs.

10 cl, 1 tbl, 3 dwg, 2 ex

FIELD: medicine, polymers.

SUBSTANCE: invention relates to conjugates consisting of a water-soluble polymer of molecular mass from 200 to 20000 Da and representing polyethylene glycol or alkyl chain to which two molecules of synthetic peptides, not less, are bound by reactive functional group and wherein each peptide comprises amino acid sequence originating from region HR1 or HR2 of human immunodeficiency virus (HIV) gp41. Invention relates to methods for using these conjugates for delivery inhibition of to HIV target-cell by addition of indicated conjugates in the amount providing effective inhibition of cell infection with indicated virus. Also, invention relates to methods for preparing conjugates by functional adding of each molecule of synthetic peptide to polymer through reactive functional group.

EFFECT: valuable biological properties of conjugates.

27 cl, 2 dwg, 6 tbl, 6 ex

FIELD: chemistry, immonology.

SUBSTANCE: hybrid protein includes 936 protein sequence from Neisseria meningitides or protein with sequence identical to the mentioned protein sequence by 90% or more, and 741 protein sequence from Neisseria meningitides or protein with sequence identical to the mentioned protein sequence by 90% or more. The sequences can be linked by N- and/or C-end to histidine labels, with or without a linker. Linker is selected out of group of polyglycine linker, histidine labels and GSGGGG linker. A nucleic acid encoding this protein is displayed. Invention also claims composition for treatment and/or prevention of disease caused by Neisseria meningitides bacterium, based on hybrid protein and one or more proteins of the following group: 287, 741, ORF46.1, 961, NH2-A-[X-L-]n-B-COOH, where n=2, X1=287, and X2 is selected out group of: 953, 919, 961, 741. Invention claims application of composition in production of medicine for treatment of disease caused by Neisseria.

EFFECT: efficient treatment and prevention of disease.

13 cl, 5 dwg, 28 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of formula (I) and their pharmaceutically acceptable salts as β-lactamase inhibitors, method of their production, pharmaceutical composition based on them, and methods of treatment involving the claimed compounds. In the general formula (I) one of A and B is hydrogen, while the other is optionally substituted condensed bicyclic heteroaryl group; if aromatic ring part of bicyclic heteroaryl group is imidazole, non-aromatic ring part does not include S atom adjacent to head carbon atom of bridge group; X is S; R5 is H, C1-C6-alkyl or C5-C6-cycloalkyl; or its pharmaceutically acceptable salt where bicyclic heteroaryl group is (1-A) , where one of Z1, Z2 and Z3 is independently S, while the others are CR2 or S, if one of Z1-Z3 is carbon and is linked to the rest of molecule; W1, W2 and W3 are independently CR4R4, S, O or N-R1, if it does not form S-S, O-O, or S-O link with saturated ring system; t=1-4; R1 is H, C1-C6-alkyl, C5-C7-cycloalkyl, -C=O-aryl, -C=O(C1-C6)-alkyl, -C=O(C5-C6)-cycloalkyl, aryl-C1-C6-alkyl, optionally substituted C1-C6-alkoxy; heteroalkyl- C1-C6-alkyl or C=O(heteroaryl), where heteroaryl is 6-member ring containing 1 nitrogen atom, R2 is hydrogen, C1-C6-alkyl, R4 ir H, C1-C6-alkyl.

EFFECT: efficient application in bacterial infection treatment.

29 cl, 3 tbl, 58 ex

FIELD: medicine.

SUBSTANCE: invention relates to veterinary and medicine, particularly substances with cytostatic and bactericidal properties; it can be applied in pharmaceutical industry. The water-soluble composition includes, in wt %: 0.007 to 0.7 metronidazole, 0.0085 to 0.85 silver hexamethylenetetramine nitrate, 0.0284 to 2.84 sodium thiosulphate, water or physiological solution to 100.

EFFECT: obtaining of composition with cytostatic and bactericidal activity, lowered toxicity, and expanded storage time; it is inexpensive, can be prepared in the field, and moreover effective in therapy for leucosis in cattle

4 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, particularly to abdominal surgery, and applied to treatment for extensive peritonitis. To do it during operative intervention the peritonitis source is eliminated, and abdominal cavity sanation is performed. Then 3% methylcellulose gel, preliminary saturated with 1200 mg/l sodium hypochlorite solution in proportion 3:1, is introduced.

EFFECT: preventing of parietal and visceral peritoneum mesothelium injury by microbial exo- and endotoxins, anti-microbial effect prolongation of sodium hypochlorite, and preventing inactivation of sodium hypochlorite by peritoneal toxic effluent.

1 ex

FIELD: medicine; pharmacology.

SUBSTANCE: essence of the invention includes selection of the damaged organs from the dead nutrias from the local epidemical centre from which prepare suspension, perform bacterial inoculation in differenrial diagnostic mediums, separate pure cultures of originators of colibacillosis, salmonellosis and enterococcus infections, separately grow up cultures Escherichia coli. Salmonella typhimurium and Streptococcus, fecalis in a meat infusion agar with addition of 0.2% of a glucose with titer 4-5 billion microbic cells in 1 cm3, inactivate by entering of formalin to 0.4-0.6 % final concentration, condition at temperature 37°C within 72-96 hours, admix cultures in equal parities, then bring a solution of a aluminium hydroxide in amount of 20% to the volume, carefully admix, pack up and cork.

EFFECT: increase of an adjuvanticity of a vaccine.

1 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: agent possessing wound-healthing, antiinflammatory, antibacterial, immunomodulating, anaesthetising and antitumoral activity on a basis of terpenoids, contains a capsule extract of plants of Pinaceae bloodline exposed to short-term stressful influence, enriched with monoterpenes, obtained from a capsule extract. The pharmaceutical composition possessing wound-healthing, antiinflammatory, antibacterial, immunomodulating, anaesthetising and antitumoral activity, contains the above described agent in effective quantity and the target additive. Application of the above described agent for preparation of a medicinal preparation for treatment of pyoinflammatory diseases.

EFFECT: increased wound-healthing; antiinflammatory; antibacterial; immunomodulating; anaesthetising and antitumoral activities.

8 cl, 1 dwg, 6 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: agent contains Rifabutin sorbated in polymeric nanoparticles matrix, potassium cholesterylphosphate, or sodium glycocholate, or hexadecyl dihydrogen phosphate, or a-tocopheryl succinate, water-soluble polymeric stabiliser and bulking agents. Polymeric nanoparticles sized 100-800 nm include lactic acid polymer/polymers and/or lactic and glycolic acid copolymer/copolymers at glycolic acid content in specified copolymers up to 50 mole %. Molecular weight of specified polymers and copolymers is 5 to 300 kDa. Molecular weight of water-soluble polymeric stabiliser is no more than 70 kDa and is selected from the group including polyvinyl alcohol, polyvinylpyrrolidone, polysorbate and seralbumin.

EFFECT: new agent provides durable action of Rifabutin; higher bioavailability of Rifabutin and efficiency of bacterial infection treatment.

3 dwg, 1 tbl, 7 ex

FIELD: medicine; veterinary science.

SUBSTANCE: preparation consists of viral-bacterial polyvalent blood serum for diarrhea with antibody titre 1:300-1:600 and sodium hypochlorite solution concentrated 300-350 mg/l at ratio of serum: sodium hypochlorite 7:3. Additionally contains serum maral blood preparation in ratio 2:1, where 2 portions are serum maral blood preparation. Method implies that preparation is injected in dosage 4 ml preventively. Therapeutically preparation is injected intramuscularly in dose 4-5 ml per 10 kg 2 or 3 times every 48 or 48, 72 hours respectively.

EFFECT: medical product and application method allow for lowered consumption of hyperimmune serum while preserving high medical preventive efficiency.

4 cl, 4 tbl, 1 ex

FIELD: medicine; dermatovenerology.

SUBSTANCE: daily before each injection of benzylpenicillin sodium salt a patient gets intravenously within 15 minutes osmotic diuretic mannitol in the dosage 2 g/kg of patient's body weight. In 30 minutes after its completion they administer intravenously 12 million units of benzylpenicillin sodium salt, the course of treatment is 10 days. At this penetration of benzylpenicillin to the arachnoid cavity increases in the conditions of temporary osmotic burst of the hematoencephalic barrier by means of mannitol effect, also sanitation of the nervous system is provided.

EFFECT: method allows to increase efficiency of the specific therapy of advanced neurosyphilis; to minimise side effects; is easy in production and is widely available in hospitals.

4 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention concerns topica of antimicrobic action for infected dermhelminthiasis and blennosis treatment. The declared antimicrobial agent contains compounding of fluoroquinolones group, metronidazole, 0.05-0.2% solution of chlorhexidine bigluconate and organosilicone glycerohydrigel with the composition Si(C3H7O3)4·xC3H8O3·yH2O, where 3≤x≤10, 20≤y≤40 as the basis. As antibacterial agent of fluoroquinolones group, it contains pefloxacine or ofloxacine or cyprofloxacine or norfloxacine or lomefloxacine or levofloxacine or moxifloxacine orsparfloxacine or enoxacine. The agent has broad spectrum of application, strong therapeutic impact and doesn't have frank side effects. The agent is characterised by strength, convinient storage and administration.

EFFECT: creation of effective antimicrobial agent.

2 cl, 11 ex, 1 tbl, 2 dwg

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention refers to pharmacology and medicine and concerns ethonogestrel new esters of formula 1 , 2 , 3 , applied for male and female contraception. Compositions are characterised by improved disposition profile.

EFFECT: production of composition with improved disposition profile.

3 cl, 2 dwg, 1 ex

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