System of medication delivery

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine. System of medication delivery includes, at least, one compartment, which contains loaded with medicinal substance heart-shaped layer from thermoplastic polymer, loaded with medicinal substance intermediate layer from thermoplastic polymer and non-containing medicinal substances coating from thermoplastic polymer, which covers intermediate layer. Heart-shaped layer is loaded with crystals of first compound, in particular with pharmaceutically active compound. Intermediate layer is loaded with crystals of second compound, in particular with pharmaceutically active compound. Both active compounds are loaded over their corresponding concentration of saturation. Described is method of contraception, application of delivery system for application in contraception or hormone-substituting therapy, application of system for production of contraception set and method of producing three-layer system of medication delivery.

EFFECT: ensuring independent speed of release of active compounds.

15 cl, 7 ex, 8 tbl, 26 dwg

 

The SCOPE of the INVENTION

The present invention relates to medicine, in particular for reproductive medicine, such as female contraception, hormone replacement therapy, regulation of ovarian function and so on.

The present invention relates to a system (device) drug delivery for the simultaneous release of two or more active substances, and the system releases the active substance is essentially in a constant ratio over an extended period of time. The delivery system of drugs can be in various forms, such as the implant, intrauterine system (IUS), screw spiral spring and, in particular, the annular intravaginal delivery system of drugs. When the invention relates to a product for drug delivery for intravaginal use, its application is focused on the typical female medical conditions, such as contraception and hormone replacement therapy. In one embodiment, the product in accordance with the invention has in particular the shape of the ring, which will be referred to as a vaginal ring.

The prior art INVENTIONS

Vaginal rings are known. The prior art in this regard includes the following patent documents

U.S. patent No. 3995633 and 3995634 describe separate, preferably spherical or cylindrical containers, comprising a different active substances that link in specially designed holders.

U.S. patent No. 4237885 describes a tube or a spiral of polymer material, which is divided into sections by many "strips"provided in the tube, after which each of the individual sections of the tube fill with different active substances in the silicone fluid, and both ends of the tube are subsequently connected to each other. However, in this system release takes place transfer (diffusion) of the active material from one container to another through the wall of the tube, especially during long-term storage, so consider a pre-set fixed value release between the active substances will change over time.

Publication of the European patent 0050867 discloses a two-layer vaginal ring containing pharmacologically acceptable supporting ring, covered with two layers preferably a silicone elastomer, whereby the inner layer is a silicone elastomer loaded with active substance.

U.S. patent No. 4292965 describes a three-layer annular intravaginal delivery system, izgotovlennoe of silicone elastomers.

U.S. patent No. 4596576 describes triple vaginal ring, in which each compartment contains a different active substances. In order to achieve an acceptable ring with a constant ratio of release between the various active substances, the ends of branches fasten through glass tubes.

Patent publication WO 97/02015 describes a two-chamber device with the first unit, consisting of a core containing a medicinal substance medium layer and not containing the medicinal substance of the outer layer, and a second branch consisting of containing the medicinal substance core and not containing the medicinal substance of the outer layer.

EP 876815 reveals vaginal ring (Nuvaring®), developed for the simultaneous release of progestin-only steroid compounds and estrogenic steroid compounds in a fixed physical relationship for an extended period of time. System drug delivery includes one compartment containing a core of a thermoplastic polymer having in its composition a mixture of progestin-only and estrogenic compounds, and a shell of thermoplastic polymer, and progestin-only connection at the beginning of the polymer dissolved in the core material at a relatively low degree of saturation.

Patent publication WO 2004/103336 describes a system of drug delivery, including at least one division, consisting of the loaded drug core of a thermoplastic polymer, loaded drug substance intermediate layer of a thermoplastic polymer and does not contain medicinal substances sheath of thermoplastic polymer covering the intermediate layer. The intermediate layer is loaded with crystals progestin-only connection and estrogenic compound in dissolved form. The core load estrogenic compound in dissolved form.

Patent publication WO 2005/089723 reveals the ring with one or more branches, where one branch includes a core in which progestin-only connection dissolved to a concentration below the saturation level at 25°C. the Core also contains estrogenic compound. In addition, the Department includes a membrane that is permeable for injectables and estrogenic compounds.

From the above disclosure it is clear that, for example, the material layers and separation are all aspects that play a role in improving the device rings.

Usually all alternatives to pick with the intention to obtain the model of a permanent release, which is difficult, to the Yes are two or more active substances. The latter is especially important in the field of contraception, because with this purpose they used a combination of progestin and estrogen, model release which leads to a contraceptive effect. Also in hormone replacement therapy may be desirable to have the ring, delivering a combination of drugs.

Among the above disclosures EP 876815, WO 2005/089723 and WO 2004/103336 clearly set the standard; they use a single chamber design of the ring, they eliminate the need for elasticum the polymer through the use of combinations of ethylene vinyl acetate (EVA), and they release two or more active substances in essentially constant ratio to each other over an extended period of time.

However, as with any technology product at all times, the latter may, however, be improved. Device drug delivery described in EP 876815, WO 2005/089723 and WO 2004/103336, require that all active compounds were present in the dissolved state (EP 876815 and WO 2005/089723) or to all connections except the one (WO 2004/103336) was present in the dissolved state. This prerequisite strictly limits the amount of medicinal substance, which can be loaded into a polymer matrix. The increase in the concentration of drugs definitely above the critical threshold (J. van Laarhoven et al, Journal of Controlled Release, 82, 2002, p 309-317) will inevitably lead to crystallization of the drug in the polymeric matrix. Therefore, the system of drug delivery, as disclosed in EP 876815 and WO 2005/089723 and WO 2004/103336, are unsuitable in the case of the use of two pharmaceutically active compounds, both of which are present in the solid state. This can happen when the active compounds have a relatively low solubility in the polymers, such as EVA polymers, and/or require a relatively high loading in the polymer matrix in order to obtain the desired model release. When both medicinal substances are present in crystalline form, the concentration of both dissolved substances is by definition the concentration of saturation of each connection. Therefore, it is impossible to adjust the rate of release of one of such pharmaceutically active compounds independently of the other, by changing the concentration of active compounds, because their concentration will be equal to their concentration saturation. Changing the shell thickness also will not contribute to the regulation of the speed of release of one of such pharmaceutically active compounds independently of the other, because the increase or decrease of the thickness of the glasses will affect the release of both compounds in the same direction.

Consequently, the aim of the present invention is the provision of a system of drug delivery, in which the rate of release of the two compounds which are partly in the solid state and partly in a dissolved state, can be adjusted independently from each other.

The INVENTION

This problem resolved by the invention through a system of drug delivery, comprising at least one compartment, which contains (i) the loaded drug core layer of a thermoplastic polymer, (ii) the loaded drug substance intermediate layer of a thermoplastic polymer and (iii) not containing medicinal substances sheath of thermoplastic polymer covering the intermediate layer, and specified the core layer is loaded with crystals of the first connection, in particular pharmaceutically active compounds, and the specified intermediate layer is loaded with crystals of a second connection, in particular pharmaceutically active compounds.

In the first embodiment of the invention the core layer forms the core of the system of drug delivery. In an alternative embodiment, the delivery system of drugs includes additional non-containing drugs is the R substances core, which covered the core layer.

In accordance with the invention, the system of drug delivery may also include more layers than the above-mentioned core, intermediate and top layers. The layers form a three - or mnogopolnoe fiber, which is used to form the delivery system. The delivery system may be in the form of a ring, implant, intrauterine system (IUS), a spiral or helical spring.

The delivery system of drugs of the invention preferably is a single-chamber system, which means that the whole system consists of the same segment, which is made from the same type of the loaded drug depot, for example fiber. The fiber may consist of three, four or more layers, of which at least two layers loaded active ingredient in crystalline form.

Thus, the claimed system drug delivery resolves the above problem, since it allows you to adjust, independently from each other, the rate of release of the two active compounds, in particular pharmaceutically active compounds that are present in the polymer in the crystalline state, for example, because they have relatively low solubility in EVA polymers and/or require otnositelnosti download medicinal substance in a polymer matrix, to obtain the desired release profile.

The present invention relates to drug delivery, formed of fiber, which consists of at least three coaxial layers. The outer layer of medicinal substances does not, however, at least two of the inner layers of the loaded drug substance, which is in crystalline form.

Fig illustrates a variant embodiment of the invention in which the system of drug delivery contains three layers, of which the core and the intermediate shell loaded active compounds a and B, respectively. Both active compounds ("active substances a and B") is loaded in excess of its saturation concentration, and both are partly present in the crystalline state.

Immediately after manufacturing the delivery system will begin internal diffusion, leading to the redistribution of active compounds. The fraction of active substances a and B will dissolve in the polymer until then, until you reach the saturation concentration, and internal diffusion simultaneously will not equalize the internal concentration gradient. The diffusion process resulting in the alignment of the internal difference of concentration submitted for the active substance And Fig. Time t8 corresponds to the moment when the system is and reaches equilibrium.

The fraction of active substances a and B, which are present in the crystalline state, however, will not diffuse and, therefore, will not be redistributed in the system. As a result, the crystals of the active substances a and B will remain in the core and the intermediate shell, where they were originally loaded in manufacturing. This spatial separation of the crystals of the active substances a and B leads to a special pathway for these compounds, which are illustrated in Fig. When the device deliver drugs introduced into the environment either in vitro or in vivo will immediately begin outer diffusion. In the intermediate phase the dissolved portion of the compounds a and B, close to the surface of the device, it will be very quickly to diffuse out of the system, leading to the initial explosion. At the same time starts to increase the internal concentration gradient, and the steady state situation is illustrated in Fig.

Without being limited to theory, it is expected that in the process of liberation of the concentration of the active substance at the heart of it will be equal or very close to the saturation concentration. The outer diffusion from the core will lead to a local decrease of the concentration in the core, which is a consequence of the driving force for dissolution in the polymer matrix of the Cristallo is, distributed throughout the core. Thus, the decrease in the concentration of dissolved active substance As a result of diffusion is easily balanced by the crystals start to dissolve, and the concentration gradient will be aligned as in the intermediate layer and the shell.

Based on similar arguments, it is expected that the active ingredient will align the concentration gradient only in the shell. Therefore, in steady state, the diffusion length for the active substance and the active substance In an individual, and the variation of parameters and/or composition of the shell and the intermediate layer will provide a means for regulating the absolute speed of release, and the ratio in which the active substances a and B are released by the system.

Thus, the claimed invention provides a three-layer system design drug delivery, of which two active compounds, in particular pharmaceutically active compounds, can be released independently from each other. The invention is particularly suitable for the simultaneous release of two pharmaceutically active compounds, which have a relatively low solubility in thermoplastic polymers (such as EVA polymers) and require considers the super high loading in the polymeric matrix, to obtain the desired model release, inevitably present, therefore, in its solid (crystalline) form in the polymer matrix.

Another objective of the claimed invention is to increase the effectiveness of drugs used in the system of drug delivery, and minimization of residues of medicinal substances used in the system.

Due to one of its aspects the present invention provides a method that uses a system of drug delivery to the invention, in particular vaginal ring.

Due to one of its aspects the present invention provides a method of hormone replacement therapy, which uses a system of drug delivery to the invention, in particular vaginal ring.

In accordance with another embodiment, it provided a way to provide both contraception and treatment, or prevention of sexually transmitted diseases.

Also provided by another aspect of the invention, a method of manufacturing a three-layer system drug delivery inventions.

BRIEF DESCRIPTION of DRAWINGS

Figa, 1B and 1C show a cross-section of the three-layer fiber options A, B and C, respectively, as described in the examples.

Figure 2 shows the release profiles in vitro nomegestrol acetate (referred to hereinafter as NOMAc) structures of the rings variant A1-A4.

Figure 3 shows the release profiles in vitro Estradiol (E2) structures of the rings variant A1-A4.

Figure 4 shows the release profiles in vitro NOMAc and Estradiol (E2) designs rings options B1 and B2.

Figa and 5B show the release profiles in vitro NOMAc designs of the rings variant B3-B11.

Figa and 6B show the release profiles in vitro Estradiol (E2) structures of the rings variant B3-B11.

Fig.7 shows the release profiles in vitro NOMAc designs of the rings variant C1-C4.

Fig shows the release profiles in vitro Estradiol (E2) structures of the rings variant C1-C4.

Fig.9 shows the release profiles in vitro NOMAc designs rings option C5-C7.

Figure 10 shows the release profiles in vitro Estradiol (E2) structures of the rings variant C5-C7.

11 shows the definition of the point of exhaustion, used to calculate the efficiency of drug substances, profile release in vitro NOMAC design options ring B3.

Fig shows the definition of the point of exhaustion, used to calculate the efficiency of drug substances, profile release in vitro Estradiol (E2) design variant of the C5 ring.

Fig demonstriruet the impact of changes in the concentration of Etonogestrel on the release profile of two-layer system, having in its composition only dissolved steroids (NuvaRing® and ring, as described in WO 2005/089723).

Fig shows a schematic cross section of a three-layer fiber.

Fig shows the graph redistribution and equalization of the internal concentration gradient of the fiber Fig.

Fig is an illustration of a fully-edged concentration gradient in stable condition.

Fig shows the release profiles in vitro Drosperinone (DPN) designs rings option D1-D3.

Fig shows the release profiles in vitro Estradiol (E2) designs rings option D1-D3.

Fig shows the release profiles in vitro Levonoguestrela (LNG) designs rings option F1-F3.

Fig shows the release profiles in vitro Estradiol (E2) designs rings option F1-F3.

Fig shows the release profiles in vitro Etonogestrel (ETO) structures of the rings variant G1-G3.

Fig shows the release profiles in vitro Estradiol (E2) structures of the rings variant G1-G3.

Fig shows the release profile in vitro of Mirtazapine from device a three-layer ring having in its composition also Risperidone.

Fig shows the release profile in vitro of Risperidone from the device a three-layer ring having in its composition also Mirtazapine.

Fig shows a system that includes not containing medicinal substances the core layer (white), covered downloaded medicinal substance medullary layer (dark gray), loaded drug substance intermediate layer (light grey) and not containing the medicinal substance shell (white).

Fig shows a system that includes downloaded the drug core layer (dark gray), not containing drug substance intermediate layer (white), loaded drug substance intermediate layer (light grey) and not containing medicinal substances shell (white).

DETAILED description of the INVENTION

The claimed invention provides a drug delivery comprising at least one division, consisting of three layers: (i) based on the polymer core layer, (ii) based on the polymer intermediate layer and (iii) based on the polymer membrane covering the intermediate layer, in which the specified core layer contains crystals of the first pharmaceutical compounds (drug substance or active substance)and the specified intermediate polymer layer contains crystals of the second pharmaceutical compounds.

In the first embodiment of the invention the core with the Oh forms the core of the system of drug delivery. In an alternative embodiment, the delivery system of drugs includes additional, not containing medicinal substances the core, which is covered with medullary layer.

Thus, in the process of making crystals of medicinal substances are not distributed in a single layer, but the crystals of active substances a and B is divided in two separated layers. The fraction of active substances a and B will dissolve in the polymer until then, until it reaches the saturation concentration and the internal diffusion does not align to the internal gradients of concentrations. The crystals of the active compounds a and B are fixed, and therefore, the crystals of the active substances a and B remain spatially separated in layers, in which they were originally loaded.

The kinetics of release delivery system of drugs intended for the simultaneous release of two active compounds, differs in two main significant features; the absolute speed with which the two compounds are released from the delivery system, and the mutual relation in which these substances are released. The absolute rate of release of active substances a and B of the delivery system can be configured by adjusting the thickness of the shell. The ratio, in what oterom released data connection, however, will remain essentially unchanged due to changes in shell thickness, because the thickness adjustment of the shell affects the diffusion path of compounds a and B in equal measure.

Known solutions (EP 876815, WO 2005/089723 and WO 2004/103336) for independent regulation of the release of the two connections from the same Department are not appropriate, as these solutions are based on the distinctive trait that at least one connection is completely dissolved in the delivery system. Obviously, this is not the case system in accordance with the purpose of the invention, comprising two active ingredients, both of which are partly present in crystalline form. For this reason, should be considered a new and an alternative mechanism for regulating the mutual ratio of the release.

In the new concept of independent regulation of the release of two active substances from the same separation is achieved by creating a path of individual diffusion to the active substances a and B. To this end a and B are loaded into the same compartment in two separate coats. In the delivery system with the crystals of the active compounds a and B loaded in the core layer and the intermediate layer, respectively, the connection will align the concentration gradient as in promezhutochnoyee, and in the shell, while the active ingredient will align the concentration gradient only in the shell. Different duration of diffusion of the compounds a and B provides a means to independently adjust the ratio in which these compounds are released from the system.

The duration of diffusion connections loaded in the core layer, can be regulated by changing the thickness of the intermediate layer. Thus, by changing the thickness of the intermediate layer, the rate of release of connections loaded in the core layer, can be adjusted up and down, by reducing or increasing the thickness of the intermediate layer. However, the diffusion path connections loaded in the intermediate layer essentially remains unchanged and, therefore, the rate of release also remains essentially not affected by the change. Thus, the rate of release of drug compounds loaded in the core layer can be changed without impact on the rate of release of drug compounds loaded in the intermediate layer, and, hence, the ratio of release can be adjusted in the direction of the desired ratio. When the desired ratio of release is obtained, the absolute speed released the I can be adjusted by selecting a suitable thickness of the shell.

Another opportunity to radically change the ratio of the release is to swap the loading of drug in the core layer and the intermediate layer. Instead of loading the active substance in the core layer, and B in the intermediate layer B can be loaded into the core layer and the intermediate layer. Additional means for regulating the ratio of the release is the implementation of the use of different classes of polymers used for the intermediate layer.

The diffusion path of medicinal substance loaded in the core layer, leads through the intermediate layer and the shell. However, the composition of the intermediate layer is not constant. During use or testing release in vitro the size and concentration of solid particles loaded in the intermediate layer will gradually decrease relative to the size of the source content and particle size. Unexpectedly, it was found that the rate of release of drug compounds loaded in the core, which diffuses through the layer of variable composition, changes only slightly and remains essentially zero order.

Another aim of the invention is to improve the effectiveness of the system of drug delivery, which means lower residual soda is the content of the medicinal substance in the system after use. The residual content after use as a medicinal substance as well As drug substance B in the delivery system of the invention may be limited to less than 20-40% of the mass. the requested quantities. This is a very significant improvement compared with the delivery system of the previous prior art, comprising a medicinal substance exclusively in the dissolved form (EP 876815, NuvaRing®and WO 2005/089723), or systems that contain at least one completely dissolved active substance (WO 2004/103336). For example, the residual content of drug substance after using NuvaRing®approximately 78% of the mass. and 88% of the mass. for etonogestrel and ethinyl estradiol, respectively. Three rings, which are described in WO 2004/103336, the effectiveness of drug substances (fully) dissolved compounds not improved compared with NuvaRing®.

't bother yourself by theory, the improved efficiency of the delivery system in accordance with the purpose of the invention can be understood in terms of stable concentration gradient in the delivery system. The new delivery system is composed of crystals of both compounds, and therefore, the decrease in the concentration of both dissolved drugs, due to diffusion from the system will be balanced at the expense beginners RA is to Dvoretsa crystals. This means that the concentration gradient during the (semi) stable release remains essentially unchanged up until the dissolution rate of the crystals is in connection with the transportation of medicinal substances from the system.

The essence of this new three-layer system drug delivery of the claimed invention is to provide control of the speed of release of two pharmaceutically active compounds independently from each other, despite the fact that both compounds used in the claimed invention, are present in its solid (crystalline) state in the polymer matrix, because they have relatively low solubility in thermoplastic polymers and/or require relatively high load in the polymeric matrix in order to obtain the desired ratio of release and/or rate of release, inevitably present, therefore, in the crystalline state.

The fiber may consist of three layers, but may also contain one or more additional layers. An example of an additional layer can be a not containing medicinal substances core, covered containing the medicinal substance medullary layer. Not containing medicinal substances core may predstavljati an advantage for the effectiveness of the system of drug delivery. The core is aimed mainly at giving its fiber predetermined thickness, which means that the core contains a large amount of. A large depot core (sandwich) must contain a medicinal substance at this level, so that the crystalline material was left over. This should mean that required a large excess of medicinal substances. In the case of not containing medicinal substances core (fourth layer), the inner containing the medicinal substance layer should contain a medicinal substance with a high concentration, without affecting the speed of release. Due to this high concentration, the average diffusion path is shorter, and the rate of release can be even more permanent. Thus, the higher efficacy of medicinal substances can be achieved without significant impact on the release profiles.

In yet another embodiment, additional layers may be included between containing the medicinal substance layers. This can be used as an additional means to differentiate diffusion paths for connections loaded in the core layer and the intermediate shell.

In accordance with the tvii with the invention, there are various other configurations, provided that at least two layers contain the medicinal substance, and that the active compounds in these layers at least partially located in the solid state.

System drug delivery of the claimed invention can be used for any mammal, specifically for the female mammal. In a separate embodiment, the mammal is a human female.

The delivery system of drugs of the invention can be provided in various forms, made of multi - or three-layer fiber, which includes containing the medicinal substance core layer containing the drug substance intermediate layer not containing medicinal substances shell. The core layer may be a core or may not cover containing medicinal substances the core. Suitable forms are, essentially annular shape, sticks, T-shape, etc.

The term "essentially annular form" must be understood as covering in addition to having a ring shaped devices any other essentially ring-shaped structure, suitable for vaginal administration, such as, for example, helicoidal curly spiral and annular eliminate the STV, having a curvilinear surface. Implants are usually Blockoban form, whereas intrauterine system, generally T-shaped.

The desired ratio of release depends on the indications on the basis of which should be applied device drug delivery of the claimed invention, such as, but not limited to, contraception or hormone replacement therapy.

Provide fiber, which is used in the system of drug delivery to the claimed invention, accompanied by (1) loading fiber core first (pharmaceutically) active compound in the solid (crystalline) form and (2) loading of the intermediate layer fiber second pharmaceutically active compound in solid form, thereby providing fiber, in which both compounds are physically separated and are present in solid form in two separate layers, i.e. the core and the intermediate layer. The dissolved part of both pharmaceutically active compounds are present throughout the fibers in all layers, after equilibrium is reached. The hard part of both drugs remains divided.

In a separate embodiment of the claimed invention (pharmaceutically) active compounds have a relatively low solubility in thermoplastic in which imarah, such as EVA polymers, and require relatively high load in the polymeric matrix in order to obtain the desired ratio of the release. In a specific embodiment of the invention both pharmaceutically active compounds are steroids.

However, the invention can be used to release other active compounds, which must be entered at the same time and in a particular ratio.

As an example, a preferred variant of the invention, the following passages relate to vaginal rings and steroids, although the claimed invention also provides non-steroidal compounds and other forms of system drug delivery.

On the release of steroids from the ring is influenced by the solubility and diffusion coefficient of the steroid in the polymer. In the specific case of steroids, which have a relatively low solubility in the polymer matrix and that require relatively high load in the polymeric matrix in order to obtain the desired model release, steroids will be incorporated into the matrix in its solid form and will dissolve in the polymer matrix until then, until it reaches saturation. In such a system, the concentration of dissolution cannot be chosen freely, but equal concentrations of us is the same.

Therefore, steroid load cannot be used to regulate the release to the desired speed, because the variation of the steroid load will not lead to a higher or lower concentration of dissolved steroids, since the concentration of steroids will be equal to the saturation concentration. Change the thickness of the shell will have a limited contribution to the regulation of the speed of release of more than one of such pharmaceutically active compounds independently from each other, because the increase or decrease in the shell thickness will in General affect the release of both substances in the same direction.

Once the ring is placed in the sink, the steroid will begin to diffuse out of the ring, and the concentration of steroid dissolved in the polymer matrix will slightly fall. As a consequence, the solid steroid will begin to dissolve. Thus, the decrease of the concentration gradient by diffusion movement of the ring is balanced due to the dissolution of the steroid present in solid form.

Therefore, the concept of three-layered vaginal ring of the invention is to load: (1) the core of the first steroid (A), which has relatively low solubility in EVA polymers and requires a relatively high zagrosek is in the polymeric matrix, in order to achieve the desired release profile; and loading (2) an intermediate layer second steroid (B), which has relatively low solubility in EVA polymers and requires a relatively high load in the polymeric matrix in order to achieve the desired release profile. Thus, as the compound a and compound B are present in the polymeric matrix in the solid state.

It is necessary to take into account that the required rate of release of steroid and steroid B receive by hosting compounds separately in two separate layers. The rate of release can be further adjusted by varying the thickness and/or by changing the class EVA polymer of the intermediate layer.

Three-layered vaginal ring of the invention can be designed with the flexibility to provide different ratios between the average speed of release of compound a and compound B. the ratio between the average speed of release of steroid compounds can be influenced by varying the location of the connections, i.e. by downloading the connection And in the core, and B in the intermediate layer or Vice versa. The ratio of release can be further adjusted by changing the thickness of the intermediate layer and/or posredstvennaia class of polymers of the intermediate layer.

Additionally, optimization of the ring intended for the simultaneous release of two compounds, in the direction of certain pre-established technical release characteristics, requires regulatory capacity as a relative ratio, in which two compounds of medicinal substances (A and B) are released, and the possibility of regulation of the absolute velocity, with which the daily released the connection.

If, on the other hand, both steroid with relatively low solubility in the polymer matrix would be loaded in a relatively large extent, together, in a single layer (i.e. in the intermediate layer or in the core), therefore, both being present in their solid (crystalline) state, the rate of release could be driven mainly by the solubility and diffusion coefficient of steroids in the polymeric matrix. In this case, the desired ratio of liberation could be achieved only by coincidence shift.

The vaginal ring of the claimed invention can be produced by known extrusion process, such as co-extrusion and/or mixed extrusion. Downloaded the drug core, loaded drug substance intermediate layer not containing medicinal ve the EU ETS outer layer together ekstragiruyut. Thus obtained fiber is cut into pieces of desired length and each part is collected in the annular device in any suitable way. The rings are then packaged, for example, in a suitable package, optional after sterilizacii or disinfection.

The vaginal ring of the claimed invention may also be produced through the application of multi-stage injection molding (Woolfson et al. (1999), J of Contr. Release 61: 319-328; Malcolm et al. (2003), J. Contr. Release 91: 355-364; Woolfson et al. (2003), J. Contr. Release 91: 465-476).

Thermoplastic polymer that can be used for carrying out the invention in practice, may in principle be any thermoplastic polymer or elastomer material, suitable for pharmaceutical applications, such as low density polyethylene, ethylene-vinyl acetate copolymers, poly(ether urethane), Sterol-butadiene-Sterol copolymers and polysiloxane. In a separate embodiment, the ethylene-vinyl acetate copolymer (poly-EVA) is used due to its excellent mechanical and physical properties. Material poly-EVA can be used for the core, intermediate layer, and also shell, and may be any commercially available ethylene-vinyl acetate copolymer, such as the product available under the trade name Elvax, Evatane, Lupolen, Movriton, Ultra the subject, Ateva and Vestypar.

In one embodiment, the core and the intermediate layer are made of one and the same class of polymers. In yet another embodiment, the core and the intermediate layer is not made from the same class of polymers. Careful selection of different classes of polymers for the core and the intermediate layer provides a means of regulating the speed of release of the compounds of medicinal substances from your system drug delivery and provides fine adjustment of the flexibility of the system of the invention.

Vaginal ring in accordance with the invention can be manufactured in any size as needed. The same applies to other forms.

In one embodiment, the ring has an outer diameter (outer circumference) between 50 and 60 mm, and in yet another embodiment, between 52 and 56 mm; the diameter of the cross-section is between about 2.5 and 6.0 mm, in a separate embodiment, between approximately 3.0 and 4.5 mm, in another embodiment between about 3.5 and 4.0 mm, in another embodiment, the diameter of the cross-section vaginal ring is 4.0 mm

The implant has a length equal to from 1 to 6 cm and a diameter of 1-4 mm, preferably a length equal to 1-5 cm, and the diameter of Rawa is 1-3 mm, more preferably the length is 2-5 cm, and the diameter of the cross section is from 1.5 to 2.5 mm

Intrauterine system (IUS) is a medicated intrauterine device. They can take various forms. In one embodiment, the downloaded hormone part consists of a fiber in accordance with the invention. In an additional embodiment, the system is T-shaped. The hormone can then be loaded into the barrel and/or shoulders of the system. In addition, similar to the intrauterine system may contain a vector, which is composed loaded hormone fiber.

Capacity settings medicinal substance IUS usually vary between 1 and 3.6 cm in length with a diameter equal to from 1 to 4.5 mm, preferably a length equal to from 1 to 3.6 cm and a diameter equal to from 1.5 to 3.6 mm, more preferably a length equal to from 2 to 3.6 cm and a diameter equal to from 1.5 to 2.5 mm, even more preferably a length equal to from 2.5 to 3.1 mm, and a diameter of from 2.0 to 2.3 mm Each or both parts of T can contain a medicinal substance.

Another objective of the present invention is to increase the effectiveness of drugs used in drug delivery, such as the vaginal ring, and to minimize the residual content of drug substance used in the system is E. The residual content of both drug substances And and medicinal substance B in the annular system of the invention after use can be minimized to approximately 45% of the mass. or less from the loaded quantity. Specifically, it can be reduced to approximately 20-35% of the mass.

The purpose of the claimed invention is to provide an improved vaginal ring, in which the intermediate layer and/or core, in addition to steroids, for example, contraception or gormonozavisimye also contains antimicrobials, for example, for the simultaneous treatment and/or prevention of sexually transmitted diseases (STD)such as HIV, herpes, chlamydia and gonorrhea.

In the embodiment, the ring of the claimed invention, the surface (outer surface of the ring is greater than 800 mm2and in yet another embodiment, more than 1000 mm, and is typically about 1700-2200 mm2although some of essentially annular forms, for example helicoidal curled spirals, possible much larger surface, provided that the design (physical parameters) vaginal ring does not cause discomfort for the patient, human or animal.

Sometimes it may require adding a second branch, which is submitted is a compartment for placebo or Department, loaded with one or more other medicinal substances. Such additional separation may be necessary to introduce, in addition to steroids, antimicrobial drugs for treatment and/or prevention of sexually transmitted diseases such as AIDS, chlamydia, herpes and gonorrhea.

Any antimicrobial drug can be included in system drug delivery, in particular the vaginal ring, the claimed invention (in the intermediate layer and/or in the core and/or in the additional section). Antimicrobial drug substance may be any antibacterial medicinal substance, such as any antibiotic any antiviral agent, any antifungal agent or any antibacterial agent. An example of antimicrobial medicinal substances provided for inclusion in the vaginal ring of the claimed invention is a condensation polymer almond acid (Zanefeld et al. (2002), " Fertility and Sterility 78(5): 1107-1115). Another example is dapivirine (4-[[4-[2,4,6-trimetilfenil)amino-2-pyrimidinyl] amino]benzonitrile).

Vaginal ring and all other systems of drug delivery in accordance with the invention are physically stable.

As used is in this application physically stable system drug delivery (such as ring) is a system that can be stored at approximately 18°C-40°C for at least about six months to one year without the formation of steroid crystals on the surface membrane of the vaginal ring.

Vaginal ring in accordance with the invention is primarily designed for contraceptive use, however, under certain conditions, the ring can also be used in HRT (hormone replacement therapy), regulation of ovarian function and so on. Implants are also suitable for contraceptive use and can be even more convenient because they can remain in the body for several years without the need for a daily, weekly or monthly reconciliation with the timetable for the introduction.

The delivery system of drugs of the invention, in particular vaginal ring, can also be used to provide both contraception and combating disease of bacterial origin. Microbial infections are subject to treatment and/or prophylaxis may be any bacterial, viral, fungal or protozoal infection. Specifically, sexually transmitted diseases, such as HFV, chlamydia, gonorrhea, or Germany, the EU, can be treated by incorporating antimicrobial agents into the system of the claimed invention.

An additional object of the invention is to provide a method of contraception, which includes the deployment stage system drug delivery of the claimed invention within the vaginal tract of a woman and preservation of the system within the vaginal tract for a long period of time. The implant is not set in the vaginal tract, but is injected subcutaneously, for example in the arm. The method with the implant contains, therefore, the stage of placement of the drug delivery of the claimed invention females subcutaneously, and conservation system inside females for a long period of time.

As used in this application, "long time" for the ring system may be any time from about 7 to about 365 days. In one embodiment, the period of time is approximately 21 days. In yet another embodiment, the period is approximately 24 days. In yet another additional embodiment, the period may correspond to a calendar month and to make or 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 days depending on the particular calendar month, and t is bamogo period without rings (which will in General vary from 0 to a maximum of 7 days).

In other embodiments, the implementation period is approximately 7, 14, 22, 23, 25, 26, 27, 28, 29, 30, 31, 42, 48, 59, 60, 61, 62, 63, 72, 84, 90, 91, 92, 96, 105, 120, 126, 144, 147, 151, 152, 153, 168, 181, 182, 184, 189, 192, 210, 212, 213, 214, 216, 231, 240, 252, 264, 273, 274, 288, 294, 304, 305, 312, 315, 334, 335, 336, 357, 360, 365 or 366 days.

To implant a long period of time may be significantly longer and vary between 7 days and 5 years, in particular from 7 days to 1 year, or from 7 days to 2 years, or from 7 days to 3 years, or from 7 days to 4 years, or from 7 days to 5 years.

For IUS "long time" can vary between 7 days and 5 years, in particular from 7 days to 1 year, or from 7 days to 2 years, or from 7 days to 3 years, or from 7 days to 4 years, or from 7 days to 5 years.

For use in the vaginal tract, the device deliver drugs of the invention is in particular annular, such as rings, screw helix and springs, or T-shaped, in particular IUS. The implants used subcutaneously, in particular in the hand.

The invention additionally provides a method of contraception, which includes the deployment stage system drug delivery of the claimed invention within the vaginal tract of a woman and preservation of the system within the vaginal tract for at least about 21 days.

The invention additionally provides a method of contraception that VK is uchet stage system drug delivery of the claimed invention within the vaginal tract of a woman and preservation of the system within the vaginal tract for at least about 24 days.

The invention additionally provides a method of contraception, which includes the deployment stage system drug delivery of the claimed invention within the vaginal tract of a woman and preservation of the system within the vaginal tract for at least about 28 days.

The invention additionally provides a method of contraception, which includes the deployment stage system drug delivery of the claimed invention within the vaginal tract of a woman and preservation of the system within the vaginal tract for at least about one calendar month (ranging from 28 to 31 days depending on the calendar month).

Another objective of the claimed invention is to provide a method of simultaneously providing contraception and treating or preventing sexually transmitted diseases, which includes the deployment stage system drug delivery of the claimed invention within the vaginal tract of a woman and preservation of the system within the vaginal tract for at least about 21 days.

Another objective of the claimed invention is to provide a method of simultaneously providing contraception and treating or profile the tick diseases sexually transmitted diseases, which includes the deployment stage system drug delivery of the claimed invention within the vaginal tract of a woman and preservation of the system within the vaginal tract for at least about 24 days.

The invention additionally provides a method for simultaneously providing contraception and treating or preventing sexually transmitted diseases, which includes the deployment stage system drug delivery of the claimed invention within the vaginal tract of a woman and preservation of the system within the vaginal tract for at least about 28 days.

The invention additionally provides a method for simultaneously providing contraception and treating or preventing sexually transmitted diseases, which includes the deployment stage system drug delivery of the claimed invention within the vaginal tract of a woman and preservation of the system within the vaginal tract for at least about one calendar month (ranging from 28 to 31 days depending on the calendar month).

In one embodiment, the delivery system of drugs, in particular vaginal ring or any other ring on the merits F. the RMU, which is placed in the vaginal tract, remove after approximately 21 days for a period of approximately one week to allow menstruation. In yet another embodiment, the delivery system of medicinal substances are removed after approximately 24 days for a period of approximately 4 days to allow menstruation.

In other embodiments, implementation of the system of drug delivery are removed after approximately 22, 23, 25, 26, 27, 28, 29, 30, 31, 42, 48, 59, 60, 61, 62, 63, 72, 84, 90, 91, 92, 96, 105, 120, 126, 144, 147, 151, 152, 153, 168, 181, 182, 184, 189, 192, 210, 212, 213, 214, 216, 231, 240, 252, 264, 273, 274, 288, 294, 304, 305, 312, 315, 334, 335, 336, 357, 360, 365 or 366 days, for a period to allow menstruation. After a period to allow menstruation new system of drug delivery of the claimed invention is injected into the woman's vagina to provide contraception in the next menstrual cycle or cycles.

In other embodiments, implementation of the system of drug delivery replace immediately, without making allowances for the period to allow menstruation.

In a separate embodiment, the delivery system of drugs claimed invention can be used in the calendar mode, as described in WO 2007/001888, which is incorporated in this application by reference.

Another is ariante implementation system drug delivery of the claimed invention can be used in the extended mode, i.e. after removing the ring, later, for example, 21 or 24 days, the next ring is administered on the following day, without making allowances for the period of menstruation. Such stretched modes are well known in the art (see, for example, Davies et al., Contraception 46, 269-278 (1992)).

The claimed invention additionally provides drug delivery of the claimed invention for the manufacture of contraceptive set.

The claimed invention further includes the use of a system of drug delivery of the claimed invention for the manufacture of medical devices for hormone replacement therapy.

The claimed invention also provides the use of a system of drug delivery of the claimed invention for the manufacture of a combined preparation for the provision of contraception and the treatment and/or prevention of sexually transmitted diseases, such as, for example, AIDS, herpes, chlamydia and gonorrhea.

In one embodiment of the claimed invention both pharmaceutically active compounds are steroids. In a separate embodiment of the invention one of the steroid compounds is a progestin-only steroid compound, and the other steroid compound is an estrogen article is Rodnoe connection.

Progestin-only steroid compound of the claimed invention may be any suitable progestogen that has a relatively low solubility in thermoplastic polymers, such as EVA polymers, and require relatively high load in the polymeric matrix in order to achieve the desired ratio of the release. Examples of such progestin-only steroid compounds include, but are not limited to, nomegestrol acetate (NOMAc), natural progesterone, Dydrogesterone, Medrogestone, Medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, ciproteron acetate, Gestonorone caproate, Demeester, promegestone, nestorone, trimegestone, Norethisterone (= norethindrone), norethisterone acetate, lynestrenol, ethynodiol acetate, norethynodrel, Norgestrel, norgestimate, Dienoguesta, Etonogestrel, Levonorgestrel, Drospirenone, or any other suitable steroid connection with progestin-only activity.

Estrogenic steroid compound of the claimed invention may be any suitable estrogen that has a relatively low solubility in EVA polymers and require relatively high load in the polymeric matrix in order to achieve the desired ratio of the release. Examples like the s estrogenic steroid compounds include, but not limited to, Estradiol (E2), ethinyl estradiol (EE), Estriol, Asteralm (E4) or its esters, its pseudopolymorphs, its pharmaceutically acceptable solvate, hydrate or its hemihydrate, such as, but not limited to, oestradiol hemihydrate or any other suitable steroidal compound with estrogenic activity.

In a separate embodiment of the claimed invention progestogen is nomegestrol acetate (NOMAc), and estrogen is an estradiol (E2) or its hydrate, such as estradiol hemihydrate.

In one embodiment of the claimed invention, the progestogen is present in the intermediate layer at about 10-70% by weight, and estrogen is present in the core, how about 3-70% by weight. In a specific embodiment of the claimed invention, nomegestrol acetate (NOMAc) is present in the intermediate layer at approximately 20-60% by weight. In yet another embodiment, nomegestrol acetate (NOMAc) is present in the intermediate layer at about 35-60% by weight. In another embodiment, estradiol (E2) is present in the core as approximately 3-20% by weight. In yet another embodiment, estradiol (E2) is present in the core as approximately 4.5 to 9 mass%.

Prophetic one embodiment of the claimed invention, the estrogen present in the intermediate layer at about 3-70% by weight, and the progestogen is present in the core as about 5-70% by weight. In a specific embodiment of the claimed invention estradiol (E2) is present in the intermediate layer at approximately 3-27% by weight. In yet another embodiment, estradiol (E2) is present in the intermediate layer at approximately 9 to 27% by weight. In another embodiment, estradiol (E2) is present in the intermediate layer at about 4-15% by weight. In yet another embodiment, nomegestrol acetate (NOMAc) is present in the core as approximately 5-35% by weight. In a specific embodiment, nomegestrol acetate (NOMAc) is present in the core at about 35% by weight. In yet another embodiment, nomegestrol acetate (NOMAc) is present in the core as approximately 5-15% by weight.

Three-layered vaginal ring of the invention can be designed with the flexibility to provide different ratios between the average velocities release progestin-only steroid compounds and estrogenic steroid compounds. The ratio between the average velocities of the release can have a significant impact by varying the location of the steroid compounds, i.e. by loading a progestogen in the heart and estrogen in the intermediate text by the second or Vice versa. In a specific embodiment, the progestogen is nomegestrol acetate (NOMAc), estrogen is an estradiol (E2), and the average ratio of release between nomegestrol acetate (NOMAc) and estradiol (E2) can vary up to between approximately 0.6 and approximately 28.

In addition to steroids, in the delivery system of drugs of the invention may also be included nonsteroidal compounds, in particular for the introduction of two or more active compounds in special value.

The claimed invention also provides a method of manufacturing a three-layer fiber, which is used for manufacturing systems drug delivery of the claimed invention by:

(i) get loaded (containing the medicinal substance) homogeneous polymer granulate core,

(ii) obtaining loaded (containing the medicinal substance) homogenous polymer intermediate layer granulate; and

(iii) co-extrusion of the granules of the core and the intermediate layer granulate with granulate polymer shell for forming a three-layer fiber.

Getting loaded (containing the medicinal substance) homogeneous polymer granulate core includes:

a) grinding the core polymer;

b) mix the dry powder of the crushed polymer with the active compounds, be loaded into the core;

c) mixed extrusion of the resulting mixture of powders stage (b);

d) cutting the resulting loaded polymer strands into granules, receiving, thereby granulate core;

e) lubricating the granules core lubricant.

Getting loaded (containing the medicinal substance) homogenous polymer intermediate layer granulate includes:

a) grinding the polymer of the intermediate layer;

b) mixing a dry powder powdered polymer with the active compounds to be loaded in the intermediate layer;

c) mixed extrusion of the resulting mixture of powders stage (b);

d) cutting the resulting loaded polymer strands into granules, receiving, thereby, the intermediate layer granulate;

e) lubrication of the intermediate layer granulate with a lubricant.

The present invention is additionally described in the following examples which are in no way intended to limit the scope of the legal claims of the claimed invention.

EXAMPLES

EXAMPLE 1 - Obtain a three-layer ring

Got a great variety of three-layer fibers (A1-A4, B1-B11, and C1-C7). The fiber was stretched to 4.0 mm from only 3.6 mm capillary.

To blend homogeneity in the polymer act the main ingredients of nomegestrol acetate (NOMAc) and estradiol hemihydrate, had two successive stages of mixing. The first stage was performed by mixing a dry powder with the active compounds and polymer (EVA 28 or 33) powder. The active compound was mixed with the polymer powder in the drum of stainless steel, using Rhonrad (Principle Hoop barrels) with a fixed speed of approximately 47 rpm for 60 minutes. The first stage of mixing powders was performed by mixing the polymer and the active connections for the various active layers. Subsequently homogenized mixture of powders was extrudible with mixing, using a 25 mm twin screw extruder for mixing with screws rotating in the same direction (Berstorff ZE25), and the resulting containing the medicinal substance polymer strands were cut into pellets using a pelletizer IPS (system design pressure). In accordance with this process have produced eight (8) servings active granulate.

After pelleting all portions except granulate V were treated with 0.1% of the mass. the stearate in order to facilitate a triple co-extrusion. Portion V produced by mixing 50 wt%. granulate U with 50 wt%. placebo EVA 28. The composition of the portions of the granules, which are used for the manufacture of three-layer fiber, using the process of joint extra is AI, described in Tables 1A and 1B below.

Table 1A
Composition active granulate made from EVA 28 polymer
MaterialActive granulate SActive granulate TActive granulate UActive granulate V
GoalThe granulate or the core or intermediateIntermediate granulateThe granulate or the core or intermediateThe granulate core
Nomegestrol acetate35% of the mass.60% of the mass.--
Estradiol--9% of the mass.4,5% of the mass.
EVA 2864,9% of the mass.39.9% of the mass.90,9% of the mass.95,45% of the mass.
Stearate mA is of 0.1% of the mass.0.1% of the mass.0.1% of the mass.0.05% mass.
Total100% of the mass.100% of the mass.100% of the mass.100% of the mass.

Table 1B
Composition active granulate made from EVA 33 polymer
MaterialActive granulate WActive granulate XActive granulate YActive granulate Z
GoalIntermediate granulateThe granulate or the core or intermediateThe granulate or the core or intermediateIntermediate granulate
Nomegestrol acetate35% of the mass.35% of the mass.--
Estradiol9% of the mass. -9% of the mass.27% of the mass.
EVA 3355,9% of the mass.64,9% of the mass.90,9% of the mass.72,9% of the mass.
Magnesium stearate0.1% of the mass.0.1% of the mass.0.1% of the mass.0.1% of the mass.
Total100,0% of the mass.100,0% of the mass.100,0% of the mass.100,0% of the mass.

Three-layer co-extrusion

Used extruder Fourne Trico (18/18/15 mm screws) for three-layer co-extrusion fiber. Two 18 mm extruder was treated core and the intermediate material, whereas 15 mm extruder is used for processing a layer of the shell. Three of the extruder was connected to the 3-chamber spinning unit with 3 separate spinning pumps. These pumps are used to control the volumetric flow rate of the three polymer melts. By controlling the volumetric flow rate regulating a layer thickness of all three layers. Three of flow of polymer melts were combined in filiere to form a 3-layer fiber. Used capillary, equal ,6 mm The planned fiber diameter was 4.0 mm and all fibers were extrudible at 110°C with a speed of 1 m/min

The parameters of the fiber (outer diameter, an intermediate thickness, and the thickness of the shell) were measured in 6 parts of fiber. The outer diameter was determined by means of laser equipment for thickness determination. The thickness of the layers was determined using a microscope (Jena).

Made the following portions of the fiber:

Table 2
Parameters fiber
OptionShell thickness (µm)Sheath material (placebo)The thickness of the intermediate layer (μm)Intermediate materialThe core materialThe fiber diameter (mm)
A150EVA 28100WEVA 28 (Placebo)4,00
A2150EVA 28100W EVA 28 (Placebo)4,00
A350EVA 15100WEVA 28 (Placebo)4,00
A450EVA 9100WEVA 28 (Placebo)4,00
B150EVA 28100XY4,00
B2150EVA 28100XY4,00
B3100EVA 2875SU4,00
B4100EVA 28100SU 4,00
B5100EVA 28400SU4,00
B6100EVA 28800SU4,00
V7150EVA 2875SU4,00
B8150EVA 28100SU4,00
B9250EVA 2875SU4,00
10100EVA 2875SV4,00
B11 100EVA 28100TU4,00
C150EVA 28100YX4,00
C2150EVA 28100YX4,00
C350EVA 28200YX4,00
C4150EVA 28100ZX4,00
C5100EVA 28100US4,00
C6100EVA 2840 US4,00
C7100EVA 28800US4,00

Pictures of typical examples of three-dimensional cross-sections of options A, B and C provided on Figa, Figv and 1C, respectively.

Cutting and Assembly

After co-extrusion of a portion of a three-layer fiber A1-A4, B1, B2, C1-C4 cut into pieces of equal 157 mm Ring formed by bonding of the ends of the fibers together using bonding polyolefin set Loctite (Loctite 406 + Loctite 770).

Portions of the three-layer fiber B3-B11, and C5-7 cut into pieces of equal 157 mm, after which they were welded Poplawski welding machines (CCM) when the welding temperature is 115°C and welding time is 17 seconds.

EXAMPLE 2 - the Speed of release of NOMAc and Estradiol In vitro

Speed of release In-vitro

The results of the release in vitro for rings, partially made of EVA 33, shown in Table 3 and figure 2-4, 7 and 8. Figure 2 shows the release profiles NOMAc in vitro designs rings option A. Figure 3 shows the release profiles of Estradiol in vitro designs rings option A. Figure 4 shows the profiles of visvobodi the Oia NOMAc and Estradiol in vitro designs rings options B1-B2. Fig.7 shows the release profiles NOMAc in vitro designs rings variants C1-C4. Fig shows the release profiles of Estradiol in vitro designs rings variants C1-C4. Table 3A shows the speed of release of the four (4) samples of ring options And, two (2) samples of ring options B and four (4) samples ring option C.

1955
Table 3A
Speed of release of NOMAc and Estradiol In vitro in water/sodium Laureth sulphate (SLS) (0.9%) in systems with EVA 33
PortionRelease NOMAc [µg/day]The release of Estradiol (E2) [µg/day]
Day 1On an average day (2-13)Day 13Day 1On an average day (2-13)Day 13
A16504414630092545932151
A23151210519111106374
A3139511151075799686600
A4376309328165144135
B15337351028731254611611
B22573180117441200393376
C13294223922141925943489
C22207143214011094 608523
C325031629159620081210919
C4212412451228977577565

The results of the release in vitro for rings, composed of EVA 28, shown in Table 3B and figure 5, 6, 9 and 10. 5 and 5B show the release profiles NOMAc in vitro designs rings options B3-B11. Figa and 6B show the release profiles of Estradiol in vitro designs rings options B3-B11. Fig.9 shows the release profiles NOMAc in vitro designs rings options C5-C7. Figure 10 shows the release profiles of Estradiol in vitro designs rings options C5-C7. Table 3B shows the rate of release of the nine (9) samples of ring option B, composed of EVA 28, and three (3) samples ring option C, composed of EVA 28.

Table 3B
Speed of release of NOMAc and Estradiol In vitro in the de/sodium Laureth sulphate (SLS) (0.9%) in systems with EVA 28
PortionRelease NOMAc [µg/day]The release of Estradiol (E2) [µg/day]
Day 1On an average day (2-14)Day 14Day 1On an average day (2-14)Day 14
B33500208814951294408378
B43556214517291087347331
B5397722031792797148118
B64026218617852687859
V7 2666168014001294348317
B82714170814691067294275
B91929114610321152263231
103482209715091761418363
B113703241920831043253248
C53308151213621419603451
C62096667 6061588620518
C710213613191868637528

The ratio of release between NOMAc and Estradiol

The ratio between the two drug substances for options A, B and C given in Tables 4 and 4B. For rings in Table 4A, the ratio between the two medicinal substances was determined by dividing the average velocities release in vitro (day 2-5) NOMAc on the average rate of release of Estradiol. For rings in Table 4B (completely made of EVA (28) the ratio determined by dividing the average velocities release for 2-14 days.

Table 4A
The ratio of release between the speed of release of NOMAc and Estradiol in vitro in the ring, made of EVA 33
PortionThe average release NOMAc for 2-5 days [µg/day]The average release of Estradiol in 2-5 days [µg/day]The ratio between NOMA and Estradiol
A1509520302,5
A2226015311,5
A311817391,6
A43131462,1
B140506256,5
B218334044,5
C1224512561,8
C214697222,0
C3166414901,1
C412745992,1

Table 4B
The ratio of release between the speed of release of NOMAc and Estradiol in vitro in the ring, completely made of EVA 28
PortionThe average release NOMAc for 2-14 days [µg/day]The average release of Estradiol for 2-14 days [µg/day]The ratio between NOMAc and Estradiol (release for 2-14 days)
B320884085,1
B421453476,2
B5220314814,9
B621867828,1
V716803484,8
B817082945,8
B91146263 4,4
1020974185,0
B1124192539,5
C515126032,5
C66676201,1
C73616370,6

Design ring groups B and C represent the finished form in which the crystals NOMAc and Estradiol physically/spatially separated and are in two separate layers. In embodiments B1-B11 intermediate layer loaded NOMAc, while the core is loaded by Estradiol. In embodiments, C1-C7 intermediate layer loaded by Estradiol, whereas the core is loaded NOMAc. In both groups, the active ingredients are in their solid (crystalline) state. In the options group B the ratio of the average rate of release between NOMAc and Estradiol may be increased to 28.1, whereas the ratio in group C remains below 2.5 and can be essentially reduced to 0.6 by increasing the thickness of the districts of the intermediate layer.

The stabilizing effect device drug delivery inventions

Once the ring is placed in the sink, steroids begin to diffuse out of the ring and the concentration of steroid dissolved in the polymeric matrix, slightly falls. As a consequence, the solid steroids begin to dissolve. Thus, the decrease of the concentration gradient by diffusion movement of the ring is balanced by dissolving the steroid present in solid form. Figure 2-10 illustrate this stabilizing effect. The slope of the release curve for option B2 for NOMAc and options B1 and B2 for Estradiol (E2) in figure 4, for options C1 C4 figure 7 and for variants with C3 on C4 on Fig essentially flat, i.e. indicates that the release is almost zero order, i.e. the rate of release of steroid can be maintained until such time as not to dissolve the solid phase.

In the examples, in which EVA 28 used for the dissolution of NOMAC and Estradiol was detected a similar trend. In variants B profile release of Estradiol on 6 was close to zero order in all examples (B3-B11). Portions B7, B8 and B9 in the Figure 5 showed also essentially flat release profiles for NOMAc, and other portions, although a little less constantly, also showed acceptable persistent profiles h is obozrenie. In variants C (C5-C7), the release profiles NOMAc on Fig.9 very flat even for relatively high speeds release.

EXAMPLE 3 - the Effectiveness of drug substances, devices, drug delivery inventions

If the active compounds are present mainly in its solid state, the effectiveness of drug substances rings can be much improved. The rate of release can be maintained up until the solid phase will not fail. Determining the point at which begins the depletion of one of the steroids is shown at 11 and 12. The release profile shows the mode (almost) steady state up until the curve will not deviate (S-curve) to another mode. The point where the two tangent lines of these modes cross each other, is defined as the point of exhaustion.

Table 5 demonstrates the effectiveness of drug substances for multiple portions (portions B3, B4, B7, and C5).

Table 5
The effectiveness of drugs of some examples servings
PortionThe point of depletion (days) [drug]Download medicinal substance [mg]/td> The effectiveness of the medicinal substance
B314 [NOMAc]4470
B419 [NOMAc]5868
V718 [NOMAc]4170
C514 [Estradiol]1278

From the data in Table 5 it can be established that the release is essentially supported until then, until you are released approximately 65-80% of the drug substance. The resulting residue content after use is only 20-35% by weight.

DISCUSSION of EXPERIMENTAL RESULTS

Speed of release in vitro and the ratio of release between NOMAc and Estradiol

Alternatives A1 through A4 show that by loading both steroid compounds in a single layer, the ratio of the release of NOMAc and Estradiol restricted within narrow regions in comparison with a wide range of ratios of release, which can be obtained with the vaginal ring of the claimed invention. Some and the change in the ratio of release is observed when comparing examples A1, A2, A3 and A4; however, the change of properties of the shell (thickness and/or polymer) does not provide a practical means for regulating the release of two compounds independently from each other. A small variation of the ratio of the release (between 1.5 and 2.5)observed for alternatives A1 through A4 are not related to the absolute rate of release of both steroid compounds of the rings (table 4A). Therefore, by changing properties of the shell it is impossible to get, unless you explicitly match required for optimal performance of the simultaneous release, which include the optimal relative release and optimal absolute rate of release.

The physical separation of the two crystalline steroids (by placing them in two separate layers - options B and C), provides the ability to control independently the speed of release of the two steroids. This is illustrated using options B and C, which show that the ratio of release between NOMAC and E2 can be adjusted in a considerable range in both directions (up or down).

As for the thickness of the intermediate layer, the thickness of the shell and classes of polymers, rings A1, B1 and C1 are identical except for the location where you downloaded the crystals of drug vexes the VA (table 2). Similar calculations for options A2, B2 and C2. Rings A1 and A2 represent the standard ring, in which the crystals as NOMAc and E2 loaded in the intermediate layer and, thus, the crystals of the drug substance are not separated spatially. In respect of the rings B1 and B2, if these rings would work the ideal way, the rate of release of Estradiol from the rings B1 and B2 compared with standard rings would be essentially really reduced due to the fact that Estradiol is loaded into the core, increasing, thus, the diffusion length for this connection. On the other hand, the release of NOMAc would remain the same (identical duration of diffusion). In practice, work options B1 and B2 is approaching, apparently, to perfect the work. When the release of Estradiol rings B1 and B2 are compared with the standard release of the rings, the results (table 4A) demonstrate that the average rate of release of Estradiol actually fell really significantly, approximately 69% for B1 compared to the A1 and approximately 74% for B2 compared to A2. For comparison, the average rate of release of NOMAc was less affected, showing a moderate decline of about 15-20% for B1 vs A1 and B2 vs. A2. It has a great effect on the ratio is svobodne, and the results in Table 4A show that the separation of crystals of drugs NOMAc and Estradiol in different layers significantly increases the possibility of increasing the ratio of the release. Speed of release of NOMAC portions C1 and C2 is significantly lower compared to A1 and A2, which is a consequence of a longer duration of diffusion. Speed of release of Estradiol also lower (see Table 4A), despite comparable duration of diffusion. This shows that there is interaction between the two steroids, the steroid from the core diffuses into the intermediate layer. Since the reduction in the rate of release was comparable for both steroids, the ratio of the release is about 2.

Example C3 demonstrates the concept of ratio control release in the other direction (low ratio). Moreover, this example demonstrates that changing the thickness of the intermediate layer in combination with the spatial separation of the crystals of drugs represents a practical means for regulating the speed of release and the ratio of release between the two compounds. The ring C3 is similar to ring C1 except that the intermediate layer is twice as thick and, consequently, the duration of diffusion for NOMAc more the tion increased. This additionally increases the duration of diffusion for NOMAc, which leads to an additional reduction in the rate of release of NOMAc and, thus, the ratio of the release which is close to 1. This is further exemplified by the examples C5, C6 and C7. Due to the significant increase in the thickness of the intermediate layer, the ratio decreases to 0.6. In these examples, the rate of release of E2 remains constant, whereas the rate of release of NOMAC is significantly reduced.

Similar effects were observed in the rings of option B, which was entirely composed of EVA 28. By increasing the thickness of the intermediate (NOMAC) layer, preserving, at the same time, shell thickness, the ratio between NOMAC and Estradiol increased from 5.1 to 28.1 (portion B3-B6), not being a hindrance to the absolute speed of release of NOMAC. By increasing only the shell thickness (samples B3, B7 and B9) ratio was maintained within a narrow bandwidth (4,4-5,1). However, the absolute speed of release is actually substantially dependent on changes in the thickness of the shell.

Everywhere the type of EVA polymer, selected for distribution of the active substances (EVA 28 against EVA 33), does not have a strong effect on the ratio of release between the two steroids (comparison of B2 to B8).

The stabilizing effect of the delivery Device of lekarstvennyie inventions

No action download medicinal substance (after reaching the saturation concentration) of course confirmed by the examples. The variation of the load of Estradiol or in the intermediate layer (C2 vs. C4) or in the core (B3 against B10) is not affected significantly either on the absolute rate of release, as well as does not affect the relative ratio, in which the released connection (NOMAc and Estradiol). Changes in the concentration of NOMAc, essentially no effect on the absolute rate of release, although some effect on the ratio can be seen.

The effect of increasing the loading of drug substances (above the point where the connection is present in the solid state) are illustrated portions C2 and C4. Estradiol concentration in the intermediate layer portions C2 and C4 is 9% of the mass. and 27 wt. -%, respectively (in both examples, Estradiol is present in the solid state). Although the loading of medicinal substances Estradiol significantly increase (the portion C2 vs. C4), the increase does not affect significantly either the absolute rate of release of Estradiol, as it does not affect the relative rate of release (the ratio of release between NOMAc and Estradiol). This example certainly demonstrates that the rate of release can be controlled by the concentration of RA is solved medicinal substance, which in both cases will be essentially equal to the saturation concentration of Estradiol in the polymer, and that the additional increase in load medicinal substance is not an effective tool to influence the rate of release of compounds present in the solid state.

Comparison of portions B3 and B10 in which the loading of Estradiol in the core is reduced from 9% of the mass. up to 4.5% of the mass. (in both examples, Estradiol is present in the solid state), confirms that the release of estradiol cannot be regulated by changing the boot medicinal substances above levels Estradiol appears in the matrix. The inability to essentially use boot medicinal substance for regulating the release of further underlined by the comparison of example B3 to B11. In this case, the loading of medicinal substances NOMAc in the intermediate layer increases from 35% of the mass. (B3) up to 60% of the mass. (B11), and this increase has only a negligible effect on the rate of release of NOMAc. The rate of release of E2 decreases (B3 against B11), and without linking yourself by theory, this may be the result of an increase of the diffusion resistance in the intermediate layer, which is composed of approximately 60% of the mass. the crystals of the drug substance that is essentially impermeable to diffusion forefront of the l medicinal substance, and, therefore, it also increases the duration of diffusion due to high sinuosity diffusion path.

The effectiveness of drug substances, devices, drug delivery inventions

The residual content after using the device for drug delivery to the invention is only 20-35% by weight, which is considerably lower than the residual content available in rings, described in the previous prior art (US 5989581; WO 2004/103336). For rings, in which steroids are in the dissolved form (EP 876815, and WO 2005/089723), a large depot (the core and the intermediate layer) is necessary for the conclusion of a certain concentration of steroid in order to achieve a specific absolute speed of release in combination with an acceptable plane of the profile. In the case of a smaller dissolution of the steroid absolute rate of release may, however, be achieved by selecting the appropriate thickness of the membrane and/or membrane material. However, the observed release profile will be steeper (see Fig). The location in the ring more steroid in combination with maintaining the speed of release (for example, adjusting the thickness of the shell) leads to a lower efficiency of the ring. Three-layer ring, described in WO 2004/103336 suitable for simultaneously released the I two or more compounds, is composed of at least one active compound which is completely dissolved in the polymeric matrix. Similarly NuvaRing® this dissolved the connection needs to be loaded with a large excess in order to obtain a sufficiently persistent profiles and, therefore, like NuvaRing®, this leads to sub-optimal efficacy of medicinal substances for at least one active pharmaceutical ingredients loaded in the ring.

EXAMPLE 4 to Obtain a three-layer ring

Got a great variety of three-layer fibers (D1-D3, F1-F3, G1-G3). The fiber was stretched to 4.0 mm from only 3.6 mm capillary.

To mix the active ingredients is homogeneous along the polymer had two successive stages of mixing. The first stage was performed by mixing the dry powders of the active compounds and polymer (EVA 28) powder. The active compound was mixed with the polymer powder in the drum of stainless steel, using Rhonrad (Principle Hoop barrels) with a fixed speed of approximately 47 rpm for 60 minutes First stage mixing powders was performed by mixing the polymer and the active connections for the various active layers. Subsequently homogenized mixture of powders was extrudible with mixing, using a 25 mm twin screw extruder is La mix (Berstorff ZE25) with augers, rotating in one direction, and the resulting containing the medicinal substance polymer strands were cut into pellets using a pelletizer IPS. In accordance with this process produced four servings active granulate.

After granulation, all the portions were treated with 0.1% of the mass. the stearate in order to facilitate joint extrusion. The composition of the portions of the granules, which are used for the manufacture of three-layer fiber by using a co-extrusion process described in Table 6A below.

Table 6A
MaterialThe active ingredientThe content of the active substanceClass EVA
Active granulate JDrosperinone (DPN)20% of the mass.EVA 28
Active granulate KLevonorgestrel (LNG)20% of the mass.EVA 28
Active granulate LEtonogestrel (ETO)11% of the mass.EVA 28
Active granulate MEstradiol (E2)10% of the mass.EVA 28

Three-layer co-extrusion

The extruder Fourne Trico (18/18/15 mm screws) used for three-layer co-extrusion fiber. Two 18 mm extruder was treated core and the intermediate material, whereas 15 mm extruder is used for processing a layer of the shell. Three of the extruder was connected to the 3-chamber spinning unit with 3 separate spinning pumps. These pumps are used to control the flow rate of the three polymer melts. By controlling the volumetric flow rate regulating a layer thickness of all three layers. Three of flow of polymer melts were combined in filiere to form a 3-layer fiber. Used the capillary is 3.6 mm, the Planned fiber diameter was 4.0 mm, and all fibers were extrudible at a speed equal to 1-2 m/min

The parameters of the fiber (outer diameter, an intermediate thickness, and the thickness of the shell) were measured in 6 parts of fiber. The outer diameter was determined using laser equipment to determine the thickness. The thickness of the layers was determined using a microscope (Jena).

The portion of fiber that have been made are listed in Table 6B.

Table 6B
OptionThe shell thickness [µm]Sheath material (placebo)The thickness of the intermediate layer [μm]Intermediate materialThe core material
D1100EVA 28600JM
D250EVA 28600JM
D350EVA 28300JM
F1100EVA 15500KM
F2100EVA 15250KM
F350EVA 15KM
G1300EVA 15600LM
G2300EVA 15200LM
G3150EVA 15200LM

Cutting and Assembly

Portions of the three-layer fiber cut into parts equal to 157 mm, after which they were welded neoplasm welding machine during the welding temperature to 125°C.

EXAMPLE 5 - Speed release in-vitro

Speed of release in vitro from the received vaginal rings was determined in 0.45% of SLS. In tables 7A-7C lists the average release in vitro portions of the D-G.

Table 7A
Serving size:The release of drosperinone [mg/day]The release of Estradiol (E2) [mg/day]
On an average day (2-28)Day 28Day 1On an average day (2-28)Day 28
D11,730,9430,7400,4020,1240,103
D22,941,240,8800,470of 0.1330,113
D32,991,230,8701,0780,2380,211

The design of the ring Portions D are prepared, in which the crystals DPN and E2 physically/spatially separated and are in two separate layers. The results of the release in vitro (Fig and 18) D1 and D2 show that the release of DPN can be increased, whereas the release of E2 remains largely unchanged. Comparison of D2 and D3 demonstrates controversial behavior. Release DPN remains unchanged, whereas the release of E2 increases the I. This demonstrates that through the physical separation of the two active compounds, the rate of release of both compounds can otregulirovat independently.

Table 7B
Serving size:Release levonoguestrela [mg/day]The release of Estradiol (E2) [mg/day]
Day 1On an average day (2-28)Day 28Day 1On an average day (2-28)Day 28
F10,1070,0700,0670,1770,0930,082
F20,1070,0700,0650,3550,1260,110
F30,223was 0.1380,1240,5860,176 0,152

The design of the ring Portions F are prepared in which the crystals LNG and E2 physically/spatially separated and are in two separate layers. The results of the release in vitro (Fig and 20) F1 and F2 show that the release of E2 can be increased by reducing the thickness of the intermediate layer, whereas the release of LNG remains unchanged. F3 shows that the release of LNG can be increased by reducing the thickness of the shell.

Table 7C
Serving size:Release etonogestrel [mg/day]The release of Estradiol (E2) [mg/day]
Day 1On an average day (2-28)Day 28Day 1On an average day (2-28)Day 28
G10,7850,200of) 0.1570,0530,0500,042
G20,581 0,1770,1560,2370,0640,051
G30,8830,3400,2930,4090,1130,094

The design of the ring Portions G are prepared in which the crystals ETO and E2 physically/spatially separated and are in two separate layers.

The ratio of release

Tables 8A-8C show that the present invention provides the opportunity for a wide variety of ratios of release.

Table 8A
PortionThe average release of DPN for 2-28 days [mg/day]The average release of E2 for 2-28 days [mg/day]The ratio between DPN and E2 (release for 2-28 days)
D10,9430,1247,60
D21,24of 0.133to 9.32
D 1,230,2385,17

Table 8B
PortionThe average release of LNG for 2-28 days [mg/day]The average release of E2 for 2-28 days [mg/day]The relationship between LNG and E2 (release for 2-28 days)
F10,0700,0930,75
F20,0700,1260,56
F3was 0.1380,1760,78

Table 8C
PortionThe average release of ETO for 2-28 days [mg/day]The average release of E2 for 2-28 days [mg/day]The relationship between ETO and E2 (release for 2-28 days)
G10,2000,050,00
G20,1770,0642,77
G30,3400,1133,01

EXAMPLE 6 - Four-layer fiber not containing medicinal substances core

The fiber may consist of three layers, but may also include one or more additional layers. An example of an additional layer may be desterrado drug core that is covered containing the medicinal substance medullary layer. Nicodemia drug core can be beneficial for the effectiveness of the system of drug delivery. The core mainly acts to provide fiber predetermined thickness, which means that the core contains a large amount of. A large depot core (sandwich) must contain a medicinal substance at this level, so that the crystalline material was left over. This should mean that required a large excess of medicinal substances. In the case of not containing medicinal substances core (a fourth layer), the inner containing lekarstvennogo layer should contain a medicinal substance with a high concentration, no discernable impact on the speed of release. Due to this high concentration, the average diffusion path is shorter, and the rate of release can be even more permanent. Higher efficacy of medicinal substances can thus be achieved without significant impact on the release profiles. This is illustrated by means of the release profile ring made of four-layer fiber, which is similar to the release profile of the three-layered fiber.

EXAMPLE 7 - Application of the invention for non-steroid active connections

The present invention is not limited to the use of steroids. Fig and Pig respectively show the release of Mirtazapine (MIR) and Risperidone (RIS) of three-layer controlled release device with the thickness of the shell EVA 33 is equal to 50 microns, with an intermediate layer of EVA 33 equal to 150 μm, comprising 60% of the Risperidone, and EVA core 33, comprising 60% of Mirtazapine. The ratio and magnitude of the velocity of release of Mirtazapine and Risperidone can be adjusted independently by controlling the various materials and thicknesses of the layers.

1. System drug delivery, comprising at least one compartment, which contains (i) the loaded drug core with the Oh of thermoplastic polymer, (ii) the loaded drug substance intermediate layer of a thermoplastic polymer and (iii) not containing medicinal substances sheath of thermoplastic polymer covering the intermediate layer, and specified the core layer is loaded with crystals of the first connection, in particular pharmaceutically active compound and the specified intermediate layer is loaded with crystals of a second connection, in particular pharmaceutically active compound, both active compound loaded in excess of its saturation concentration.

2. The system of drug delivery according to claim 1, characterized in that the core layer forms the core systems of drug delivery; or the presence of additional non-containing medicinal substance core, which is covered with medullary layer; or the presence of additional non-containing drug substance intermediate layer between the core layer and the loaded drug substance intermediate layer.

3. The system of drug delivery according to any one of claims 1 or 2, characterized in that the delivery system has the form of a ring, implant, intrauterine system (IUS), a helical coil or spring; or the delivery system has an essentially annular shape and is designed to VA is analnogo introduction.

4. The system of drug delivery according to claim 1, in which the specified first pharmaceutically active compound is a progestogen and said second pharmaceutically active compound is an estrogen.

5. The system of drug delivery according to claim 1, in which the specified first pharmaceutically active compound is an estrogen and a specified second pharmaceutically active compound is a progestogen.

6. The system of drug delivery according to any one of claims 4 or 5, in which the progestogen is nomegestrol acetate, and estrogen is a estradiol or estradiol those hydrate.

7. The system of drug delivery according to claim 1 or 2, characterized in that at least the shell, but not necessarily also the core layer and the intermediate layer contains the ethylene-vinyl acetate copolymer as thermoplastic polymer.

8. The system of drug delivery according to any one of claims 4 or 5, characterized in that the estrogen present in the intermediate layer in an amount of about 3-70% by weight and the progestogen is present in the core layer in an amount of about 5-70% by weight; or the progestogen is present in the intermediate layer in an amount of about 10-70% by weight and estrogen is present in the middle is Celine in the amount of about 3-70% by mass.

9. System drug delivery of claim 8, wherein the progestogen is nomegestrol acetate and is present in the core layer in an amount of about 5-35% by weight; or he is present in the intermediate layer in an amount of about 20-60% by weight.

10. System drug delivery of claim 8, wherein the estrogen is a estradiol and he is present in the core layer in the amount of approximately 3-20% by weight; or he is present in the intermediate layer in the amount of approximately 3-27% by mass.

11. The method, which involves the following stages (i) placement of drug delivery according to claims 1 or 2 within the vaginal tract of a woman and (ii) the preservation of the system within the vaginal tract for a long period.

12. The birth control method that includes a step (i) placement of drug delivery according to claims 1 or 2 within the vaginal tract of a woman on digital date 'n'+'x' months and (ii) the preservation of the system within the vaginal tract to digital date 'n' next month, where 'n' is a digital date month 1 to 28, 'x' is 3, 4, 5, 6 or 7, and when this method is carried out for at least two cycles.

13. The system of drug delivery according to any one of claims 1 and 2, for the use in contraception or hormone replacement therapy.

14. The application of drug delivery according to claim 1 or 2 for the manufacture of contraceptive set.

15. A method of manufacturing a three-layer system of drug delivery according to claim 1 or 2, including:
(i) obtaining loaded homogeneous polymer granulate core;
(ii) obtaining loaded homogenous polymer intermediate layer granulate; and
(iii) co-extrusion of the granules of the core and the intermediate layer granulate with granulate shell for forming the three-layer system of drug delivery.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition contains as a first active agent, 6β, 7β; 15β, 16β-dimethylenene-oxo-17α-pregn-4-ene-21,17-carbolactone (drospirenone) in an amount according to a daily dose after the administration of the composition and making approximately 2 to approximately 4 mg, and as a second active agent, 17a-ethinylestradiol (ethinylestradiol) in an amount according to a daily dose and making approximately 0.01 mg to approximately 0.05 mg together with one or more pharmaceutically acceptable carriers or additives. The composition contains drospirenone applied on inert carrier particles. A method for preparing a pharmaceutical composition involves spraying of the drospirenone and ethinylestradiol solution on the inert carrier particles. The pharmaceutical preparation according to the invention contains a number of separately packed and individually taken daily dosage units of the described compositions in a single package used for oral administration for at least 21 days running with said daily dosage units containing the combination of drospirenone and ethinylestradiol. The composition may additionally contain 7 and less daily dosage units containing no active agent, or containing ethinylestradiol only.

EFFECT: invention provides higher oral bioavailability of drospirenone.

20 cl, 5 dwg, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely pharmacy and may be used for creating an oral solid dosage form. The dosage form contains a pharmaceutically acceptable salt of an alkaline-earth metal of 5-methyk-(6S)-tetrahydrofolic acid and granules containing progestogen, oestrogen and microcrystalline cellulose. What is also presented is a pharmaceutical kit for females for providing the concentrations or treating the diseases, conditions or symptoms associated with endogenous oestrogen deficiency.

EFFECT: group of inventions provides the good storage stability of tetrahydrofolic acid, and at the same time provides rapid and reliable release of oestrogen and progestogen being parts of the composition.

13 cl, 3 dwg, 4 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a diacetate of racemic 18-ethyl-gona-1,3,5(10),8(9)-tetraene-3,17β-diol, having anti-implantation and antioxidant activity with low uterotropic action. Presence of antioxidant activity in said steroid is essential since compounds with such action can be agents for preventing oestrogen-dependent breast cancer.

EFFECT: compounds exhibit anti-implantation and antioxidant activity with low uterotropic action, which is an advantage over agents used in practice.

1 cl, 1 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: as a first active agent a pharmaceutical composition contains drospirenone in the amount equal to a daily dose when administering the composition and making 2 to 4 mg, and as a second active agent - ethinylestradiol in the amount equal to a daily dose and making 0.01 mg to 0.05 mg, together with one or more pharmaceutically acceptable carriers or additives. Drospirenone as a part of the pharmaceutical composition has a particle surface area more than 10000 cm2/g. Preferentially, drospirenone is fine-grained or sprayed from a drospirenone solution by inert carrier particles. The preparation contains a number of separately packed and individually taken daily dosage units in a single package used for oral administration for at least 21 days running with said daily dosage units containing a combination of drospirenone and ethinylestradiol. The preparation may additionally contain 7 and less daily dosage units containing no active agent, or containing ethinylestradiol only.

EFFECT: combination of drospirenone and ethinylestradiol provides reliable contraceptive activity ensured by the use of a maximum dose of drospirenone which causes no side effects, particularly, excess diuresis.

29 cl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry and relates in particular to medication for women, which has contraceptive and protective action against inflectional diseases: herpes, HIV infections, viral disease. Medication for vaginal application, possessing contraceptive and protective against inflectional diseases action contains actively-acting components and target base. As actively-acting components medication contains contraceptive, bactericidal, anti-inflammatory preparations, and as target base it contains gel-forming biocompatible polymers and L-lysin hydrochloride with specified component ratio per 1 g. Medication presents gel, ointment, cream, liniment.

EFFECT: medication not only has contraceptive action, but also makes it possible to simultaneously prevent sexually transmitted infection diseases.

3 cl, 6 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to gynaecology, and can be used for female contraception. Inventions include methods of female contraception. That is ensured by the multiple administration of a dosage form started in a day of month marked either by 'n+3', or 'n+4', or 'n+5', or 'n+6' date and taken out in a day marked by 'n' number of the next month for at least two cycles where 'n' is a date either within 1 to 25, or 1 to 24, or 1 to 23, or 1 to 22 respectively. Also, the inventions involve female contraception kits containing at least two dosage forms and patient information leaflets according to the declared modes of contraception. Besides, the inventions comprise a dosing regimen reminder system adjusted in such a manner that it allows to choose one specific date either within 1 to 25, or within 1 to 24, or within 1 to 23, or within 1 to 22 regardless of a month, as a date when the dosage form is always taken out and a date when a new dosage form shall be used either through three, or through four, or through five, or through six days thereafter respectively.

EFFECT: inventions provide convenient administration of contraceptives with maintained efficacy of contraception and its increase in certain cases.

1 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: multiphase pharmaceutical preparation for ovulation inhibition in mammal contains a number of individually packed and individually removed daily units placed in a single package, and used for oral administration for at least 21 days running; specified daily units contain a combination of oestradiol and drospirenone. A daily unit contains 0.5 to 4 mg of oestradiol and 2 to 4 mg of drospirenone. At least 70% of specified drospirenone are released from specified unit within 30 minutes.

EFFECT: invention provides higher oral bioavailability of drospirenone.

6 cl, 5 dwg, 5 ex

FIELD: medicine.

SUBSTANCE: there is claimed application of ethinylestradiol and chlormadinone acetate combination for obtaining medication applied simultaneously for treatment of androgen-induced disorders, for substitution hormonotherapy, for treatment of dismenorea, for stabilisation of menstrual cycle, for treatment of illnesses dependent on menstrual cycle and for women's contraception, said medication being obtained in form of at least 21 hormone-containing day dose, and said combination of hormones contains from 5 to 20 mcg of ethinylestradiol and from 1 to 5 mg of chlormadinone acetate in day dose, if necessary in combination with 7-3 day doses which do not contain hormone.

EFFECT: it is demonstrated that reduction in claimed medication of ethinylestradiol amount does not influence cycle stabilisation, but it can be continuously introduced to women in pre- and perimenopause in order to achieve simultaneously all said aims, as well as for reduction of high blood pressure.

11 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to steroids with (11β)-[4-(aza-aryl)phenyl] substitutes which modulate progesterone receptors, or pharmaceutically acceptable salts and/or hydrated form, and/or prodrug thereof.

EFFECT: compounds exhibit combined activity profile of PR agonist and PR antagonist which makes them suitable for contraception and treating gynaecological disorders.

30 cl, 28 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention distinguishes 28-day and 91-day modes of taking combined oral contraceptives, possibly in combination with antidepressant (fluoxetine hydrochloride) in which full disappearance of estrogen from preparation does not take place. This presupposes that shorter influence of peaks and drops of endogenic progesterone protects against premenstrual disphoric disorder (PMDD) and against symptoms of mood disturbance in women with PMS.

EFFECT: application of estrogen and progesterone for manufacturing medication for contraception, treatment of premenstrual syndrome (PMS) or syndrome of estrogen cessation (versions), respective preparation (versions) and method of pregnancy prevention.

91 cl, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is a composition for nicotinic immunonanotherapy containing synthetic nanocarriers having a polymeric surface conjugated with a variety of nicotine residues with the variety of the nicotinic residues on the nanocarrier form an immunogenic surface providing a low affinity, a high-avidity binding of the nicotinic residues to the surfaces of an antigen presenting cell (APC) compared with an antibody binding, and a pharmaceutically acceptable excipient. The invention provides the nanocarriers capable to stimulate an immune response in T-cells and/or B cells and to produce the antinicotin antibodies with the humoral and cellular response to be achieved in the absence of an exogenous adjuvant.

EFFECT: invention provides the absence of the non-specific response on an inflammation caused by an adjuvant.

17 cl, 37 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is a composition for nicotinic immunonanotherapy containing synthetic nanocarriers having a polymeric surface conjugated with a variety of nicotine residues with the variety of the nicotinic residues on the nanocarrier form an immunogenic surface providing a low affinity, a high-avidity binding of the nicotinic residues to the surfaces of an antigen presenting cell (APC) compared with an antibody binding, and a pharmaceutically acceptable excipient. The invention provides the nanocarriers capable to stimulate an immune response in T-cells and/or B cells and to produce the antinicotin antibodies with the humoral and cellular response to be achieved in the absence of an exogenous adjuvant.

EFFECT: invention provides the absence of the non-specific response on an inflammation caused by an adjuvant.

17 cl, 37 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a pharmaceutical composition the form of an oral suspension consisting of valsartan or a pharmaceutically acceptable salt thereof and at least one or two or more ingredients specified in glycerol or a syrup or a mixture thereof, a preserving agent, a buffer system, a suspending/stabilising agent and anti-foaming agent. The buffer system is specified in sodium citrate, potassium citrate, sodium bicarbonate, sodium dihydrophosphate and potassium dihydrophosphate, and maintains pH of the composition within the range of 3.0 to 5.0. Further, the present invention refers to using the pharmaceutical composition for preparing a drug.

EFFECT: orally administered valsartan suspension provides high bioavailability and reduced variability of response to the administered dose when administered to different subjects or one subject.

10 cl, 4 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine and describes a solid pharmaceutical composition applicable for oral administration and containing: S1P receptor modulator which represents 2-amino-2-[2-(4-octylphenylethyl)]propane-1,3-diol in the free form or in the form of a pharmaceutically acceptable salt or a phosphate thereof and monocrystalline cellulose in the absence of a sugar alcohol.

EFFECT: invention provides higher storage stability of the composition.

9 cl, 40 ex, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine and describes a solid pharmaceutical composition applicable for oral administration and containing: S1P receptor modulator which represents 2-amino-2-[2-(4-octylphenylethyl)]propane-1,3-diol in the free form or in the form of a pharmaceutically acceptable salt or a phosphate thereof and monocrystalline cellulose in the absence of a sugar alcohol.

EFFECT: invention provides higher storage stability of the composition.

9 cl, 40 ex, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine and describes a solid pharmaceutical composition applicable for oral administration and containing: S1P receptor modulator which represents 2-amino-2-[2-(4-octylphenylethyl)]propane-1,3-diol in the free form or in the form of a pharmaceutically acceptable salt or a phosphate thereof and monocrystalline cellulose in the absence of a sugar alcohol.

EFFECT: invention provides higher storage stability of the composition.

9 cl, 40 ex, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine and describes a solid pharmaceutical composition applicable for oral administration and containing: S1P receptor modulator which represents 2-amino-2-[2-(4-octylphenylethyl)]propane-1,3-diol in the free form or in the form of a pharmaceutically acceptable salt or a phosphate thereof and monocrystalline cellulose in the absence of a sugar alcohol.

EFFECT: invention provides higher storage stability of the composition.

9 cl, 40 ex, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine and describes a solid pharmaceutical composition applicable for oral administration and containing: S1P receptor modulator which represents 2-amino-2-[2-(4-octylphenylethyl)]propane-1,3-diol in the free form or in the form of a pharmaceutically acceptable salt or a phosphate thereof and monocrystalline cellulose in the absence of a sugar alcohol.

EFFECT: invention provides higher storage stability of the composition.

9 cl, 40 ex, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and medicine, particularly it is used for treating various forms and localisation of tuberculosis.

EFFECT: medicine under the present invention containing sodium aminosalicylate and dextran, and provides the effective treatment of multidrug-resistant pulmonary tuberculosis.

3 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a solution for preparing a chitosan material, methods for preparing the haemostatic material of the solution and a medical device with using chitosan fibres. The solution consists of the following ingredients in ratio of total amount of the solution, wt %: dry chitosan with a degree of deacetylation - not less than 80%: 4-8 at dry basis, an aqueous solution of a polymer or a mixture of polymers: 1-10 at dry basis, an aqueous solution of an organic acid or a mixture of organic acids in the concentration of 50 - 80% - the rest. The method for preparing the haemostatic material of the aqueous-acidic solution containing a polyelectrolyte complex of chitosan and a water-soluble polymer comprising the electrochemical treatment of the chitosan solution in an electric field with a conductive substrate. The electrospun fibres have the following characteristics: viscosity - 1.4-2.5 Pa·s, surface tension - 31-35 mN/m and electrical conductivity no more than 2.3 mSm/cm due to the use of a viscoelastic solution.

EFFECT: method enables the chitosan fibre of a thinner diameter.

45 cl, 20 dwg, 6 tbl, 16 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine. An intrauterine contraceptive device comprises a bearing body and an active metal alloy of formula ZnxCuyMnzAuk (I) or ZnxCuyMnzAgk (II) in which x+y+z+k=100 wt %, x varies within the range approximately 18 to 30 wt %, z varies within the range approximately 0.5 to 3 wt %, and k varies within the range approximately 3 to 12 wt %, and y makes the rest.

EFFECT: group of inventions provides shorter and less intensive menstruation, and reduces a risk of abdominal contamination.

9 cl, 1 dwg

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