Liquid preparation containing tobramycine

FIELD: medicine.

SUBSTANCE: sterile aqueous inhalation solution containing active substance Tobramycine. Preparation of invention is offered with high content of active substance (approximately 80 to 120 mg/ml Tobramycine). Preparation also contains acid adjuvant and has low content of sodium chloride (maximum approximately 2 mg/ml). Preparation can be injected or introduced as aerosol with e.g. common sprays.

EFFECT: suitable for application in combination with recent sprays with vibrating membrane and gives the chance for application of an individual therapeutic dose.

24 cl, 1 tbl, 7 ex

 

The technical field to which the invention relates.

The invention relates to liquid preparations, which contain the antibiotic tobramycin and which can be introduced in the form of pharmaceutical drugs by injection or aerosol form, namely in the lungs or nasal. In addition, the invention relates to pharmaceutical kits comprising two components, which can be prepared liquid preparations for administration of tobramycin. In addition, the invention relates to the use of drugs in pharmaceutical products that can be introduced into the lungs or nasal via atomizer and which can be used for the treatment of cystic fibrosis or other diseases of the respiratory tract.

Prior art

The tobramycin is an aminoglycoside antibiotic having the chemical name O-3-amino-3-deoxy-α-D-glyukopiranozil(1→4)-O-[2,6-diamino-2,3,6-trideoxy-α-D-RIBO-hexopyranosyl-(1→6)]-2-deoxystreptamine, which is used systemically or topically for the treatment of severe infections. Systemic treatment is carried out by injection or infusion; it is shown in the case of severe infections many sensitive to tobramycin gram-negative bacteria, in particular in the case of septicemia, infections of the lower respiratory tract, michaelbailey, intraperitoneal infections, skin infections, soft tissue and bone, osteomyelitis, septic arthritis, bacterial endocarditis, meningitis caused by gram-negative bacteria and infections in patients with immunosuppression.

In the case of severe infections of the respiratory tract the tobramycin can be entered by inhalation. For example, in Germany there is a drug TOBI (supplied on the market Chiron), which contains tobramycin in the form of an aqueous solution without antioxidants and which can be entered by inhalation in aerosol form. In this form, the active agent can be used to treat infections of the lower respiratory tract, caused by Pseudomonas aeruginosa. patients suffering from mucoviscidosis or cystic fibrosis. Additional applications for which carry out clinical tests include the treatment of bacterial infections in cases of bronchiectasis and in patients with artificial ventilation of the lungs, and also in cases of tuberculosis.

Cystic fibrosis (or cystic fibrosis) is one of the most common congenital metabolic disorders. It is autosomal-recessive hereditary multi-organ syndrome caused by loss of transmembrane regulatory protein cystic fibrosis (cystic fibrosis transmembrane regutator, CFTR), represents the future of a regulatory protein transport chloride across cell membranes, increase in the viscosity of the secrets of the body. The defect of the enzyme is localized on chromosome 7. The genetic defect affects, in particular, glands of external secretion, resulting in many organs form a viscous mucus that blocks the lungs, pancreas and biliary tract. Approximately 90 percent of the problems associated with the respiratory system. Chronic pneumonia often occurs when viscous mucus prevents the destruction of bacteria. In particular Pseudomonas aeruginosa tends to infect the lungs of patients with cystic fibrosis. This causes a sort of vicious circle: the growth and reproduction of bacteria increase mucus secretion and result in infection and inflammation of the respiratory tract, and it becomes increasingly difficult to ensure the access of oxygen to the respiratory tract. Many patients suffering from cystic fibrosis, chronic inflammation of the lungs results in progressive destruction of lung tissues and severe disorders respiratory, which in the end, over 90% of patients die.

The state of the art

The treatment of patients suffering from cystic fibrosis, by introducing into the lungs active agent tobramycin currently carried out mainly with the use of a drug TOBI. In contrast to injecor is subject to the preparations of tobramycin TOBI does not contain a stabilizing additive antioxidants, which inhalation can trigger coughing or asthma.

TOBI spray in aerosol form and ingaliruut via atomizer. Depending on the design and type sprayer reach very different results. The effectiveness of pulmonary introduction depends, in particular, the particle size of the obtained aerosol, which varies considerably depending on the device used. A pharmaceutical manufacturer, Chiron particularly recommends for treatment with TOBI jet nebulizer PARI LC PLUSTMin combination with the compressor Pari MasterTM(both are available on the market PARI).

The literature describes other preparations of tobramycin for inhalation. In U.S. patent 5508269 described preparation containing approximately 200 mg to 400 mg of tobramycin in approximately 5 ml. as excipients, giving isotonicity, it contains sodium chloride in the amount of approximately 0,225%, and the pH of the drug increased to approximately 5.5 to 6.5. For administration of the drug should be sprayed through a jet or ultrasonic nebulizer with obtaining aerosol having a particle size of from 1 to 5 microns.

In U.S. patent 6083922 described in somewhat similar drugs active agent tobramycin, which, however, is used to treat infections caused by Mycobacterium tubrculosis. Approximately 80 to 300 mg of active agent is added in a single dose to a volume of approximately 3 to 5 ml of the pH Value was adjusted to 5.5-7.0 and to give isotonicity again using sodium chloride.

The drug tobramycin described in U.S. patent 6387886, also has a very similar composition. It contains approximately from 250 to 350 mg of active agent in 5 ml of sodium chloride solution, the pH is again adjusted to 5.5-6.5. Intended application is the treatment of chronic bronchitis caused by susceptible to tobramycin pathogens.

In WO 03/004005 described preparation having a content of tobramycin 75 mg/ml and the concentration of sodium chloride of 0.45%. In contrast to the above cited documents, according to this publication requires a pH of from 4.0 to 5.5. As another sign indicated the osmotic pressure in the range from 250 to 450 mosmol/L. In the preferred embodiment, the preparation has a pH of 5.2 and an osmotic pressure of from 280 to 350 mosmol/L.

In the practical use of all these drugs tobramycin exhibit various disadvantages. First, their portability is not particularly satisfactory. This is probably caused by the active agent and is compounded by the affective state of the respiratory tract of patients with cystic fibrosis. Second, patients need prolonged inhalation of one on the PS active agent (currently the most common is the inhalation of 300 mg of tobramycin in 5 ml of liquid), namely, for about 15-20 minutes when using the inkjet dispenser (depending on device). This is particularly difficult for critically ill patients. Another disadvantage of conventional drugs is their taste, which many patients perceive as bad; of course, this is mainly caused by the active agent, i.e. drops of aerosol that fall into the oral cavity and larynx, and then mixed with the saliva and reach the taste buds of the tongue. This occurs with significant inhalation aerosol droplets.

To solve at least the problems of long time of inhalation, and the resulting burden for patients in WO 02/094217 proposed the use of a more concentrated solution of tobramycin in which a single dose can be Invalidovna faster due to the smaller volume. Applied amount should be reduced to no more than 4, preferably up to not more than 3.5 ml the concentration of the active agent, in turn, must be reduced to approximately 200 mg/ml, which is achieved by the time of inhalation is less than 10 minutes. Especially preferred concentration of the active agent from 90 to 120 mg/ml and the time of inhalation is less than approximately 6 minutes. However, the latter should be achieved by used the I instead of the usual spray of modern devices with particularly high emissions of aerosol. For example, recommended a stronger compressors, which can be connected with the conventional spray nozzles or piezoelectric atomizers, which thanks to the principle of his actions demonstrate better performance. However, in a more detailed discussion of the examples in this document describes only one drug that has a concentration of active agent in more than 60 mg/ml, namely preparation containing 420 mg tobramycin in 3.5 ml, which corresponds to the concentration of the active agent 120 mg/ml At the same time, this product contains non-specific excipient to bring the pH to 6.0±0,5 and 0,225% sodium chloride. However, it turned out that this drug cannot be used effectively with the selected tools that have been optimized for short-time inhalation. In clinical research the number of active agent found in plasma and saliva, was no more than after inhalation of 300 mg of tobramycin in the form of medicines TOBI. Thus, the time of inhalation can be reduced compared to TOBI (300 mg) from 18.1 to 9.7 minutes, but only at the expense of bioavailability.

One of the disadvantages of the known preparations of tobramycin for inhalation is suboptimal tolerability in the respiratory tract. Compared with the use of a sprayed solution is lacebo reaction, such as cough and respiratory tract irritation, more frequent inhalation of TOBI or known experimental preparations of tobramycin. Still not been fully clarified whether this effect is only active agent, which can hardly be influenced, or a combination with some conventional auxiliary substances contributing to the incompatibility or can contribute to its reduction.

Description of the invention

Thus, there is a need in the preparations of tobramycin for effective, acceptable to the patient an effective and tolerable inhalation. In particular, there is a need for drugs of this active agent that can be introduced quickly and efficiently using highly-effective inhalers and well tolerated and which does not possess the disadvantages of the known drugs. The objective of the invention is to provide such an improved drugs.

This problem is solved by proposing preparations according to claim 1 of the claims. An additional problem solution will become apparent from the other claims and from the following description. Drugs can improve pulmonary antibiotic therapy of patients suffering from cystic fibrosis; however, they can also be used as solutions for injection or for matnog the treatment of infections affecting the upper part of the respiratory tract.

Declared sterile liquid medication in the form of an aqueous solution for injection or inhalation, which contains approximately 80 to 120 mg of tobramycin per ml, and optionally acidic excipient and the concentration of sodium chloride to a maximum of approximately 2 mg/ml

In this context, an aqueous solution means a solution or a colloidal solution in which the solvent consists wholly or mainly of water. Sterile means that the product meets, in respect of its sterility, the relevant requirements of the European Pharmacopoeia (Pharm. Eur.). The tobramycin is a substance O-3-amino-3-deoxy-α-D-glyukopiranozil(1→4)-O-[2,6-diamino-2,3,6-trideoxy-α-D-RIBO-hexopyranosyl-(1→6)]-2-deoxystreptamine, including its salts, complexes, conjugates, and derivatives. Installed a concentration of approximately from 80 to 120 mg/ml, however, refers to the basis of tobramycin. It should be noted that in practice of course there are slight deviations from the nominal concentration, which is absolutely normal and acceptable. Thus, for example, for a drug with an estimated concentration of 80 mg/ml, the actual concentration of 78.5 mg/ml may be within product specifications. Accordingly, the pharmacist is logically permissible deviation of the concentration of the active agent in the range from 80 to 120 mg/ml is included in the scope of the invention.

Acidic excipient is a physiologically acceptable acid or acidic salt, which brought the pH of the drug. In accordance with the invention, sodium chloride, or not present at all or present only in concentrations up to 2 mg/ml using the same portability as the active agent.

It was found that the drugs prepared in accordance with claim 1, perfect for spraying in conventional sprayers. Aerosols can be Invalidovna quickly and efficiently. In particular, in combination with possible features, which are described below, can be achieved greatly improved, acceptable to the patient, treatment of pulmonary infections in cases of cystic fibrosis.

In order to achieve comfortable, safe, and effective inhalation of a therapeutic dose of tobramycin should take into account various parameters, some of which are associated with the drug. One of the crucial parameters is the concentration of the active agent in inhalation solution. Market the product TOBI at a concentration of 300 mg/5 ml is clearly a lower concentration of the active agent than that required in accordance with the present invention. Due to the low concentration it is hardly possible to enter inhalation solution TOBI for Korotkov the time of inhalation. Although, apparently, preferably the time of inhalation, comprising a maximum of approximately 6-8 minutes, and particularly preferably the time of inhalation, comprising a maximum of 4-5 minutes, to achieve a high degree of patient compliance regime and regimen for inhalation 5 ml TOBI in combination with spray recommended in the instructions for use, requires at least approximately 15-20 minutes. Even if you ignore this recommendation and to use a more powerful spray, and is unlikely to be achieved in the desired time inhalation because of the low concentration of the active agent should be sprayed a relatively large amount of liquid.

Unexpectedly, it was found that the concentration of the active agent should not choose arbitrarily high within the solubility of the active agent and that should not be exceeded is approximately 120 mg/ml Thus, it was found that with increasing concentrations of tobramycin surface tension of the solution can be maintained within the desired range of approximately 70 to 76 mn/m, but the dynamic viscosity, which is equally important for dispersion increases significantly and has a negative effect on the spray. Thus, aqueous solutions of tobramycin, having a pH of from 6.0 to 6.5, have 50% more viscosity of around 2.9 MPa· (C) when the concentration of the active agent 180 mg/ml compared with a solution having a concentration of 100 mg/ml (approximately 1.8 MPa·). Comparable solutions having a concentration of tobramycin 120 mg/ml, have a viscosity of approximately 2.1 MPa·and they can still spray with almost the same efficiency as solutions having a concentration of 100 mg/ml under standard conditions prescribed by the present invention have a viscosity of about 1.4 to 2.3 MPa·and preferably a viscosity in the range from about 1.6 to 2.0 MPa·c. The most preferred viscosity of approximately 1.8 MPa·C.

The choice and amount of agent that gives isotonicity, has a special impact on local tolerability. The sodium chloride contained in products supplied to the market product TOBI, also used or recommended for use in almost all of the preparations described in the literature, for example in WO 03/004005, where the use of 0.45% (wt./about.) sodium chloride, and in WO 02/094217 where it is preferable to use 0,225% (wt./vol.). However, experiments by inhalation, carried out by the inventors have demonstrated that a low concentration of sodium chloride from 0.0 to 0.2% (wt./about.) is less annoying and optimally compatible with other required and possible ingredients. In one preferred is oplasty of the invention, sodium chloride is present at a concentration of less than 0.2% (wt./vol.), preferably at a concentration of 0.17% (wt./vol.). In yet another embodiment, the sodium chloride is not present, except ubiquitary quantities of sodium chloride, which may also be contained in pharmaceutical water quality. In yet another embodiment of the drug as an agent, giving isotonicity, contains essentially neutral salt, which is sodium chloride, such as sodium sulfate or sodium phosphate. However, in this case, salts other than salts of sodium, even more preferred. So, for some salts of calcium and magnesium is known that they can have a positive or a subsidiary effect of inhalation solutions of active agents, perhaps because they counteract local irritation caused by introduction, and have a bronchodilator effect, which is currently postulated in the clinical literature (for example, see R. Hughes et al., Lancet. 2003; 361 (9375):2114-7), and/or because they inhibit the adhesion of microorganisms to proteoglycans of the mucous membrane of the respiratory tract, so indirectly supported mucociliary clearance as a natural protective mechanism of the body against microbes (.W.Tsang et al., Eur. Resp. 2003, 21, 932-938). Particularly preferred magnesium sulfate, which has excellent pulmonary portability and can be inhalieren without the claim of any problems, and calcium chloride (1-10 mmol). If the last action should be strengthened, consideration may be given heparin or phytohemagglutinin, although these substances can certainly not provide the contribution to osmollnosti, which was described for mineral salts.

As an alternative to neutral mineral salts, as agents, giving isotonicity, can be used physiologically acceptable organic excipients. Particularly useful water-soluble substances with a relatively low molecular weight, for example a molecular weight less than 300, or, even better, less than 200, and with correspondingly high osmotic activity. Examples of such excipients are sugars and sugar alcohols, in particular mannitol and sorbitol.

The number of the selected agent, giving isotonicity must be defined in order to obtain osmollnosti from about 150 to 350 mosmol/l, whereas the content of tobramycin and acidic excipients and the content of other possible auxiliary substances in the product. Moreover, the preferred osmollnosti in the range from approximately 200 to 300 mosmol/L. In another embodiment, the drug has osmollnosti from about 230 to 280 mosmol/HP/p>

Acidic excipient in the drug simultaneously serves several objectives. First, it brings the pH to the range that is physiologically well tolerated (aqueous solution of tobramycin base gives the main reaction, which is unfavorable for inhalation). For portability, the pH of the drug, however, must be brought to values approximately from 5.0 to 7.0, preferably to a pH of from 5.5 to 6.5. Secondly, in relation to physico-chemical and chemical properties of the drug, particularly with respect to chemical stability of the contained active agent, especially a favorable pH in the above range from 5.0 to 7.0, or from 5.5 to 6.5. If desired compromise between a particularly high stability and acceptable tolerability, can also be selected pH in the acidic region to approximately pH 4.0. The use of acidic excipients ensures that the active agent tobramycin was present in the product at least partially in the form of salts.

Especially useful excipients to lower pH values represent a strong inorganic acid, in particular sulfuric acid and hydrochloric acid. Additionally, there may be used inorganic or organic acid, with an intermediate force is also acid salt, for example, phosphoric acid, citric acid, tartaric acid, succinic acid, fumaric acid, lysine, methionine, sour hydrogen phosphate, sodium or potassium, lactic acid, and so forth. However, the most preferred sulfuric acid and hydrochloric acid.

The drug may contain a surfactant as an excipient. To stabilize the dispersed solid or liquid particles or to colloidal solubilisate usually poorly soluble active agent, for example, in the form of micelles or in the form of so-called microemulsions, liquid pharmaceutical preparations using surface-active substances. To achieve the specific surface tension can be used surfactants that are particularly important for optimal and reproducible spray.

In the preferred embodiment of the preparation according to the invention has a surface tension at standard conditions, i.e. at room temperature and under normal pressure of approximately from 70 to 76 mn/m In yet another embodiment, the drug has a surface tension of about 72 mn/m, These surface tension facilitates effective dispersion by conventional sprayers with a high proportion of respirable droplets, having the appropriate diameter to a maximum of 5 μm. This can also be achieved without the addition of surface-active substances.

However, if the drug must be adapted for use in a particular type of spray, the surface tension can be reduced to values below about 70 mn/m, possibly even up to values below about 55 mn/m at room temperature. Even when the type of surfactant, the surface tension should be not less than approximately 30-35 mn/m Surface tension is reduced by surface-active substances, may be useful in improving the ability to spray aerosols in the lungs, which in turn can have a positive impact on the efficiency of the application.

As it has been unexpectedly discovered by the inventors that the addition of surfactants may have an additional beneficial effect: sensory quality, that is, in particular, the taste of the drug during inhalation can be improved by the addition of suitable surface-active substances. However, the surfactants must be pharmaceutically acceptable and suitable for application by introducing into the lungs. Examples of such surfactants are Tween®(in particular, Tween®80), tyloxapol, vitamin E D-alfatek is freelolitamovies 1000 succinate (vitamin E TPGS) and phospholipids, such as hydrogenated lecithins.

The amount used depends on the intended effect: if in the first place it is supposed superior ability to spray in the lungs, particularly useful application of Tween®80 and phospholipids in relatively high concentrations, comprising from about 0.01 to 0.1% (wt./vol.). If, in addition, must be masked by the taste of the active agent should preferably be the use of higher concentrations of the components, for example, from about 0.2 to 2% (wt./vol.). Especially preferred combination of tyloxapol and phospholipid, such as dimyristoylphosphatidylcholine (DMPC), and the concentration of tyloxapol should be approximately from 0.5 to 1.5% (wt./vol.), most preferably approximately 1.0% (wt./vol.), and the concentration of DMPC or comparable phospholipid should be approximately from 0.2 to 1.0% (wt./vol.), particularly preferably about 0.5% (wt./vol.). It was unexpectedly found that the combination of surface-active substances does not result in an increase, but rather decrease local irritation in the respiratory tract or bronchostenosis.

The combination of tyloxapol and phospholipid, in particular DMPC, together with the active agent tobramycin is particularly useful from the point of view of galenical preparations. The tee is akapol has only limited compatibility with the active agent, that is within the desired concentration ranges of tyloxapol and tobramycin resulting in the deposition. However, this incompatibility can be reduced or eliminated by combining with DMPC.

Depending on the type and configuration of the spray density of the drug may also affect the effectiveness of the spray. It should be in the range from approximately 1.0 to 1.2 g/ml, preferably approximately from 1.05 to 1.1 g/ml, for example 1.07 g/ml

The preparation according to the invention can be carried out, for example, by dissolving one by one acidic excipients, the active agent and the agent, giving isotonicity, under aseptic conditions in a measured amount of water for injection. Depending on whether or not surface-active substances, and which surfactants are used, after the addition can be carried out stage homogenization. In the preferred embodiment of the method of preparation includes a cooling solution during the dissolution of the active agent in the aqueous phase or in close temporal relationship with the dissolution of the active agent in the aqueous phase. Through this active agent may be further stabilized and protected from destruction. Stability can also be favorably Provo is whether treatment in a protective atmosphere.

The filling is preferably carried out under aseptic conditions in a single dose or mnogorazovye containers. Suitable primary packaging represents, for example, polypropylene or polyethylene bottles (PP/PE bottles) and cycloolefine copolymer blister (SOS blisters). Sealed plastic containers, such as PP or PE bottles, can be produced, filled and sealed, for example, preferably by technology blow-fill-seal (blow fill seal method) in a single process. Produced in this way, the container is particularly suitable for liquid products having a volume from about 0.2 ml In a particularly favorable for the patient embodiment they can be produced with a cap that can be removed by turning or bending. Thus obtained hole through which can be extracted liquid contents may be designed so that it can be connected to the connector Luer or connector with Luer lock. The hole may be circular and have a diameter that essentially corresponds to the external diameter of the inserted connector Luer. Thus, a conventional syringe connector Luer can be tightly attached to the container, for example, to select the contents of the container and transfer it into the sprayer is whether to to mix the contents of the container with the contents of the syringe, and then transfer them into the sprayer. As another alternative, a plastic container may be designed so that after removal of the closing element, you can attach tightly enough to the connecting element for input of liquid in appropriately adapted dispenser, whereby the reservoir of the nebulizer can be directly filled with the drug.

Plastic containers of this type have advantages because they can be easily applied embossing. This makes unnecessary the presence of paper labels, which is desirable in order to avoid migration of the components of glue, paper or printing ink through the wall of the container in the drug. In addition, using this embossing important information may become available for patients with impaired vision. Embossing can contain various information, such as the designation of the party, the expiry date, the designation of the product, instructions for use and one or more than one markup doses. Especially in the case of patients-children, when it is often desirable flexible dosing depending on age and growth, many of the markings of the volume can facilitate the extraction of the desired dose without additional medium is in, whereby can be reduced the risk of dosing errors.

In yet another embodiment of the invention proposed pharmaceutical kits which contain two liquid component or, alternatively, a solid and a liquid component in a separate immediate packings with a common secondary packaging in which the contents of the components are adjusted so that by combining and mixing can be prepared drug tobramycin according to the invention, as described above, which is ready for use. The liquid component or one of the liquid component contains a solvent and possibly additional contained excipients, whereas the solid component (or another liquid component) contains the active agent (tobramycin) in a concentrated and stable form. Such kits may have the advantage that they are particularly high pharmaceutical stability and the ability to store, but the ease of handling, and thus to facilitate easy handling for the patient. Alternatively, the kits can be designed so that medical or pharmaceutical trained personnel (for example, in a hospital pharmacy) can be prepared from them the drugs ready for use.

In accordance with another variant of the invention the proposed mogogos the new containers, which contains the above product and are designed with the possibility of aseptic extract per dose. Thus, mnogorazovyj the container may be a glass or plastic container such as a vial or bottle for infusion elastomer cover which can be punctured by a syringe, or it may represent a complex container equipped with a device for dispensing and retrieval.

One of the particular advantages of parenteral multi-dose containers in relation to the preparations of tobramycin for inhalation is flexibility, which makes it easy to adjust the dose according to individual needs without losing significant quantities of the drug, as may be the case in single dose containers after opening. In hospitals and medical institutions patients thus can be treated in a most effective and potentially cost-effective by the selection of an individual dose. Also can easily be taken into account special therapeutic requirements of individual patients.

In principle, any spray used to treat, can be used for spraying of the drug. Tested inkjet nozzles in principle as useful as a more modern ultrasonic or piezoelectric dispensers, but they are bladud gap with regard to the time of inhalation. The advantage of inkjet nozzles is that they are already widely available and can be profitably produced. Many patients are already accustomed to using conventional spray nozzles. In some modern jet nebulizers (e.g. PARI LC PLUS®and PARI LC STAR®are mechanisms by which the spray is regulated in accordance with the type of respiration of the patient, so that inhalation is available the maximum possible share of the generated aerosol.

Especially preferred aerosolize drug through modern piezoelectric atomizer, in particular by spray-type eFlowTMPARI. A special advantage for patients using this device (or similar device) is in a relatively shorter time compared with alternative ways. This device not only sprays the quantity of liquid per unit time, but also creates an aerosol of high quality with a high proportion of small respirable aerosol droplets.

Therapeutically favorable result is highly dependent on reliable and adequate availability of an active agent in the lungs. Achieving this within a reasonable period of time promotes patient compliance with the regimen and the regimen. Patients FAV is reading short periods of inhalation and inhalation, comprising more than about 6-8 minutes, may adversely affect the patient's compliance regime and regimen. Particularly desirable time of inhalation, comprising more than about 10 minutes. In contrast, from the point of view of the patient, particularly preferably time inhalations is less than approximately 5-6 minutes.

Traditional treatment tobramycin drug TOBI, which contains 300 mg of tobramycin in 5 ml of an aqueous solution is sprayed through a jet nebulizer recommended in the instructions for use, including a device PARI LC PLUS®which in practice requires a sufficiently long period of time, approximately 15-20 minutes. The fraction of the inhaled aerosol droplets having a diameter less than 5 μm, in this treatment, approximately 60% of the generated aerosol (measured by laser diffraction using a MasterSizer X, Malvern). Taking into account all the losses of active agent occurring in the atomizer, with the exhalation of the patient and the settling of aerosol in the upper part of the respiratory tract, it can be assumed that only approximately 60-80 mg of tobramycin reach the patient's lungs (respirable dose, RD).

In contrast, the preparations according to the present invention in combination with piezoelectric is Kim spray reach significantly higher speeds of ejection. This applies in particular to spray using a spray gun with a vibrating membrane type eFlowTM, which at the same time produce large fraction of the inhaled aerosol droplets, namely approximately 75%. In addition, design-related losses within the device is less than in the case of inkjet dispenser. Thus, a smaller amount of active agent sufficient to cook the same amount of active agent delivered into the lungs. Thus, we can assume, for example, on the basis of in vitro data that the drug of the present invention, contains only 200 mg of tobramycin in 2 ml solution for inhalation, when spraying with the use of the device eFlowTMresults in the availability of approximately 70-80 mg of active agent in the lungs (respirable dose, RD), then there must be biologically equivalent to the usual treatment with 5 ml of TOBI 300 mg of Particular advantage for patients is in a shorter period of time required for inhalation 2 ml of the preparation according to the present invention using the eFlow deviceTMin experimental in vitro it takes approximately 3-4 minutes, whereas in practice it takes about 4-5 minutes, but in any case less than 6 minutes, which represents a significant difference in cf is the ranking with conventional treatment.

Thus, in accordance with the present invention, it is preferable to prepare the drug in relation to its pharmaceutical and, in particular, physico-chemical parameters for optimalnoe sputtering using a piezoelectric atomizer or nebulizer with the vibrating membrane, such as the eFlow deviceTMso as to provide a particularly significant benefit for patients from the point of view of the significantly reduced time inhalation.

In yet another embodiment, the preparation adapted for use in aerosol form for the treatment of upper respiratory tract. In this case, it is also possible topical treatment of infections caused by sensitive to tobramycin pathogens. In particular, the mucous membrane of the nasal and oral cavity, as well as the mucous membrane of the sinuses, the maxillary and frontal sinuses in principle amenable aerosol treatment. Most easily the aerosol reaches the mucous membranes of the mouth and the nasal cavity. In this case, can be used mechanical sprayers, such as sprayers, often used for nasal and oral sprays. Especially adapted jet, ultrasonic or piezoelectric dispensers, however, can be used to significantly improved hydration of the mucous membrane of the oral or nasal cavity is asalaamu drug.

Effective use of the spray in relation to the less well-ventilated cavities of the upper respiratory tract is more complex. However, the frontal and paranasal sinuses are often the site of infection. Typically, these infections tend to treat otharkivajushchimi and anti means that it is not always beneficial. Severe cases additionally treated with systemic antibiotic therapy, which, however, is not tolerated by all patients well.

Simple nasal inhalation drug sprayed active agent leads him to the area of the sinuses; however, the majority of aerosol passes the openings of the sinuses (the mouth) no penetration of any significant share in the sinus.

However, recently became available especially adapted inkjet nozzles, through which the sinuses can be achieved much better than previously. These sprayers have nasal tip to the flow direction of the spray in the nose. If inhalation aerosol uses only one nostril, the other nostril should be closed using a suitable device. In addition, these dispensers are characterized by the fact that they create a spray with pulsating pressure. Pulsating pressure results in increased ventilation of the sinuses, so the simultaneous inhalation aerosol may RA is which are gathering dust more effectively in these cavities. Examples of such dispensers are described in DE 10239321 B3. In the preferred embodiment of the preparation according to the present invention used to prepare drugs for use by one of these devices for the treatment of infections of the upper respiratory tract, in particular, by using the device type of the PARI Sinus.

Examples

The following examples serve to illustrate the invention by means of a number of selected embodiments.

Example 1: Preparation of solutions for inhalation containing 100 mg/ml of tobramycin

11,08 g of tobramycin, 5,41 g of sulfuric acid (96%), 0.2 g of sodium chloride and 90,95 g of water for injection is used as the starting materials. All stages carried out in aseptic conditions and in an atmosphere of nitrogen gas. First, take water, which is added to the sulfuric acid. Then add the sodium chloride and the active agent. The mixture is stirred until complete dissolution of all solid components, which is determined visually. This gives approximately 100 ml of a solution which has a pH of approximately 6,0, osmollnosti approximately 0.22 Osmol/l dynamic viscosity of approximately 1.9 IPA·and a surface tension of approximately 71 mn/m, This solution is sterile filtered and filled into a bottle for infusion volume of 100 ml This bottle tightly closed amenable procelian the Yu elastomeric stopper and cover aluminum cover.

Example 2: the Spraying of the solution for inhalation containing 100 mg/ml tobramycin, piezoelectric nebulizer

2 ml of the solution prepared in accordance with Example 1, taken aseptically with a sterile needle and syringe and add to the reservoir of the piezoelectric sprayer eFlowTM(PARI). This device operates in accordance with instructions for use to create the aerosol. The aerosol test of fitness for inhalation by means of laser diffraction (Malvern MasterSizer X) and the cascade impactor Andersen. For spraying requires 3.2 minutes. The fraction of particles up to 5 microns, as determined by laser diffraction, was 75%, fraction up to 5 μm, determined using a cascade impactor, was 77%.

Example 3: Preparation of a solution of tobramycin for inhalation containing surfactant

10,88 g of tobramycin, 5,41 g of sulfuric acid (96%), 0.2 g of sodium chloride, 0.1 g Tween®80 and 90,95 g of water for injection is used as the starting materials. All stages carried out in aseptic conditions and in an atmosphere of nitrogen gas. First, take water, which is added to the sulfuric acid. Then add tobramycin and dissolved at room temperature. To this solution add sodium chloride and Tween®. The mixture is stirred until the image is of a transparent solution. This gives approximately 100 ml of a solution that has a pH of about 6.2, osmollnosti approximately 0.22 Osmol/l dynamic viscosity of approximately 1.9 IPA·and a surface tension of about 43 mn/m, the Solution is sterile filtered and aseptically filled into single dose plastic containers of 2 ml each.

Example 4: preparation of a solution of tobramycin for inhalation with two surfactants

10,88 g of tobramycin, 5,41 g of sulfuric acid (96%), 0.2 g of sodium chloride, 0.45 g of dimyristoylphosphatidylcholine (DMPC), of 0.91 g of tyloxapol and 89,59 g of water for injection is used as the starting materials. First, water is dispersed DMPC and tyloxapol. Then this mixture is homogenized at high pressure 150 MPa (1500 bar) to obtain opalescense solution. Then add sulfuric acid and the active agent, which first leads to the formation of sludge, which however is not observed after stirring for 24 h at room temperature, when the mixture is at least opal. Finally, add the sodium chloride, the solution is sterile filtered and filled into single dose containers. The solution has a pH of about 6.2, the surface tension of approximately of 36.5 mn/m, dynamic viscosity of about 2.07 MPa·and osmollnosti approximately 0,otmal/L.

Example 5: preparation of a solution of tobramycin for inhalation with the addition of CaCl2

10,88 g of tobramycin, 5,41 g of sulfuric acid (96%), 0.2 g of sodium chloride, 0.07 g of calcium chloride and 90,95 g of water for injection is used as the starting materials. First take water, which add sulfuric acid. Then add the active agent, and then the sodium chloride with calcium chloride. The mixture is stirred until complete dissolution of all solids, as determined visually. The addition of salts can result in temporary sedimentation, which is not observed after stirring for 12 hours. The solution is sterile filtered and filled into single dose containers. The drug has a value of approximately pH of 6.0, a surface tension of approximately 70,2 mn/m, a viscosity of approximately 1,87 MPa·and osmollnosti approximately 0.24 Osmol/kg

Example 6: Preparation of a solution of tobramycin for inhalation with the addition of MgSO4

10,88 g of tobramycin, 5,41 g of sulfuric acid (96%), 0.2 g of sodium chloride, 0.12 g of the heptahydrate of magnesium sulfate and 90,95 g of water for injection is used as the starting materials. Preparation of the solution is carried out, as in Example 5. The solution is sterile filtered and filled into single dose containers. The preparation has a pH value of approximately 6,1, surface tension when listello 69,8 mn/m, viscosity is about to 1.86 MPa·and osmollnosti approximately 0.24 Osmol/kg

Example 7: the Spraying of the solution of tobramycin for inhalation with ispolzovaniem atomizer with a vibrating membrane and characterization of the aerosol in the cascade impactor and the breathing simulator

1,4 ml of tobramycin according to the invention, prepared as in Example 1, selected and sprayed using a piezoelectric atomizer (atomizer with vibrating membrane) type eFlowTM(PARI GmbH), and the aerosol is characterized by using a cascade of Andersen impactor (ACI) and the breathing simulator type PARI COMPASTM(15 breaths/min, 500 ml of respiratory volumes, the ratio of inhalation:exhalation 1:1) and compared with the dispersion of a commercially available solution of tobramycin (TOBITM300, 5 ml) in the jet spray type PARI LC PLUS®. In addition, the geometrical distribution of the droplet size of the aerosol was determined by photon correlation spectroscopy (PCS) using a Malvern MasterSizer X. the Results are shown in the Table.

Abbreviations:

MMD:mean mass diameter
GSD:the geometric standard deviation
FPF:fine fraction is less than 5 microns
TOR:the total rate of emission
MMAD:mean mass aerodynamic diameter
DD:delivered dose
RD:the inhaled dose
DDR:extent of delivery medicine
RDDR:the degree of delivery of inhaled medication

1. Sterile liquid medication in the form of an aqueous solution for use in the form of a solution for injection or in the form of an aerosol containing approximately 80 to 120 mg/ml of tobramycin and acidic excipient, characterized in that the preparation contains not more than 2 mg/ml sodium chloride.

2. The preparation according to claim 1, essentially free from sodium chloride.

3. The preparation according to claim 2, containing at least one essentially neutral agent, giving isotonicity.

4. The preparation according to claim 3, where the agent gives isotonicity, is a salt of magnesium, calcium salt, sugar or sugar alcohol.

5. Preparation according to one of claims 1 to 4, having a pH from about 5.5 to about 6.5.

6. The preparation according to claim 1, where the acid excipient is a sulfuric acid or hydrochloric acid.

7. The preparation according to claim 1, containing at least one surface-active auxiliary substance.

8. The preparation according to claim 7, where the surface of the active auxiliary substance is a phospholipid.

9. The preparation of claim 8, containing tyloxapol as an additional surface-active excipients.

10. The preparation according to claim 1, having a dynamic viscosity at room temperature of approximately from 1.6 to 2.0 MPa·and osmollnosti approximately from 200 to 300 mosmol/L.

11. The preparation according to claim 1, having osmollnosti from about 230 to 280 mosmol/L.

12. The preparation according to claim 1, where the drug is in the form of measured single dose in the primary packaging.

13. The drug is indicated in paragraph 12, where the primary packaging has the form of a plastic container including a removable closing element.

14. The drug is indicated in paragraph 13, where the destruction of the closing element, leads to the formation of round holes in a plastic container, the diameter of which corresponds approximately to the inner diameter of the adapter is inserted Luer lock.

15. The drug is indicated in paragraph 13 or 14, where the plastic container after removal of the closing element can be attached very tightly to the connecting device of the dispenser, intended for the introduction of fluid.

16. The drug is indicated in paragraph 13, where a plastic container provided with at least one embossed lettering, which is a designation product code, lot code, expiry date and/or marking of the volume or dose.

17. Set for making PR the preparations according to one of claims 1 to 16, includes (a) a liquid or solid component containing an active agent, and (b) a liquid component, free of active agent.

18. Use of the preparation according to one of claims 1 to 16 or set at 17 for the preparation of drugs for intravenous, intraarterial, subcutaneous or intramuscular injection.

19. Use of the preparation according to one of claims 1 to 16 or set at 17 for the preparation of medicaments for use in the form of an aerosol.

20. The application of claim 19 for insertion into the lungs through the jet, ultrasonic or piezoelectric atomizer.

21. The application of claim 20, where the piezoelectric atomizer is a device type eFlow™ PARI.

22. Use item 21 for nasal introduction by mechanical spray or jet, ultrasonic or piezoelectric atomizer.

23. The application of article 22 for introduction into the mucous membranes of the sinuses and/or frontal sinus.

24. The application of article 22 for insertion through a jet nebulizer, including nasal tip to enter aerosol in one or both nostrils of the patient, and the output of the aerosol which is carried out under pulsed pressure.



 

Same patents:

FIELD: medicine; phthisiology.

SUBSTANCE: invention use for treatment of infiltrative and disseminated pulmonary tuberculosis. Perform chemotherapy providing introduction of preparations of Isoniazidum, Rifampicin, Pyrazinamidum, and also Ethambutolum or Streptomycin. In addition prescribe Populin vegetative preparation.

EFFECT: rising of efficiency of treatment and reduction of by-effects of chemotherapy.

FIELD: medicine; phthisiology.

SUBSTANCE: against spent complex antituberculous therapy carry out lymphotropic administration of the admixture consisting of Isoniazidum in a dose of 10 mg/kg of mass of a body, a heparin of 2.5-5 thousand UN and 0.25 % of a solution of Novocainum in volume of 5-7 ml. Admixture interawned intervals of 1-4 thoracal vertebra administer subcutaneously consistently on one zone in day in postensiform, bulbar, parasternal zone, in addition including in a combination of zones of administration. Then the administration zone is exposed to an electromagnetic irradiation of the highest frequency with a wavelength by of 5.6 mm within 10 minutes in a continuous regimen of 3-5 times in a week. The quantity of lymphotropic introductions on course of treatment makes 20-60 injections.

EFFECT: increase of efficiency of treatment of patients with infiltrative tuberculosis at the expense of substantial growth of concentration of Isoniazidum in a pulmonary tissue.

4 ex

FIELD: medicine.

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

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

3 dwg, 1 tbl, 7 ex

FIELD: medicine; pharmacology.

SUBSTANCE: composition displays tuberculostatic activity in respect of isoniazid-resistant M. Tuberculosis and amplifies specific pharmacological effect of isoniazid and ethambuthol hydrochloride due to its synergism. The composition is made in the form of granules with the components in the following quantities, g: isoniazid - 0.3000, ethambuthol hydrochloride - 0.3000, pectin - 0.3000.

EFFECT: high tuberculostatic activity; low toxicity and reduced side effects of the components.

2 cl, 4 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically to phthisiology, and can be used for pulmonary tuberculosis treatment. For this purpose antibacterial treatment according is applied according to standard modes. In addition 5% unithiol solution in amount 5 ml per 200 ml of 0.9% sodium chloride solution is introduced intravenously. Unithiol introduction is alternated to contrical in amount 10 th.unit per 200 ml of 0.9% sodium chloride solution is introduced intravenously for the next day. Treatment course is 10 injections of each preparation. Invention widens range of pulmonary tuberculosis treatment, improving treatment efficiency due to reduction of abacillation time and degradation cavity closure, prevention of by-effects reactions of antitubercular preparations, removal of tubercular intoxication symptoms.

EFFECT: development of effective method of pulmonary tuberculosis treatment.

3 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, phthisiology. Antibacterial therapy is carried out under standard conditions. From first day of treatment transcoetaneous analgesic electric stimulator of nerves is applied at frequency 77 Hz. Points 4 GI, 5 TR, 6 MC, 14 VG and also pulmonary frontal projection are exposed by posterior midline, right and left paravertebral lines. Total exposure is 30-35 minutes. Treatment course is 20 sessions. Method reduces abacillation time and destruction cavity closure time.

EFFECT: reduced abacillation time and destruction cavity closure time.

2 ex, 2 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to medicinal agents containing combined inhibitor of dipeptidylpeptidase IV (DPPIV) and biguanide agent. Offered application of pharmaceutical agent implies production of preventive and therapeutic agent and method of intensified effects of active circulating GLP-1 and/or active circulating GLP-2. Besides, invention concerns method of prevention or treatment of disease connected with active circulating GLP-1 and/or active circulating GLP-2, specifically diabetes, obesity, hyperlipidemia, gastrointestinal diseases. Combined inhibitor DPPIV of formula (I) and biguanide agent, specifically phenformine, methformin or buformine stimulates action of active circulating glucagon-like peptide-1 (GLP-1) and/or active circulating glucagon-like peptide -2 (GLP-2) and, therefore inhibits destruction of GLP-1 and GLP-2, with their levels raised up with biguanide agent.

EFFECT: agent has improved efficiency.

17 cl, 12 tbl, 425 ex

FIELD: medicine; pharmacology.

SUBSTANCE: to produce composition of common agent, substance or combination of substances, copolymer of lactic and glycolic acid, polysorbate 80 and dimethyl sulfoxide taken in specified ratio are heated at 50÷60°C and mixed to produce homogeneous transparent liquid, which is cooled to room temperature and watered. Produced suspension containing nanoparticles sized 200-400 nm is used according to its intended purpose.

EFFECT: provided technologically available production method of medicinal agents of new generation based on common high-performance and almost non-toxic substances.

4 cl, 4 ex, 5 tbl, 1 dwg

FIELD: medicine.

SUBSTANCE: antibacterial therapy is conducted in accordance to standard conditions. 1 tablet vobenzim TID 30 minutes before a meal, is included into the complex treatment of pulmonary tuberculosis starting from the first day. Also, the daily transcutaneous electroneurostimulation (TENS) is performed in direct pulmonary plane above the area of pathologic focus and in the central universal zone - along the median line, right and left paravertebral lines, at comfort energetic mode with frequency 77 Hz, total exposure time 30-35 min and 20 sessions of treatment course.

EFFECT: method improves a microcirculation in body organs and tissues, provides the anti-inflammatory and analgesic effect, increases the immune response and resistance to infectious agents, normalizes the balance and enhances the production of endorphins, cortisone, dopamine, provides the spasmolytic and anti-edema action.

2 tbl, 2 ex

FIELD: medicine; pharmacology.

SUBSTANCE: medicine for treatment of tuberculosis, contains the 30% alcoholic tincture of medicinal plants: knotgrass (Polygonum aviculare) herb, garden violet (Viola tricolor) herb, aspen (populus tremula) rind, agrimony (Agrimonia) herb, agrimony (Agrimonia) roots, rough-fruited cinquefoil (Potentilla recta) herb, golden thoroughwax (Bupleurum) herb, medic hop (Medicago lupulina) cone, Adonis vernalis herb, late red bartsia (Odontites vulgaris) herb, Betula leaf, bird cherry (Prunus padus) tree rind, common peony (Paeonia officinalis) root, common burdock (Arctium lappa) roots, foxtail clover (Trifolium rubens) bloom, cowberry (Comarum palustre) roots, Inula root, wheat grass (Agropyron) root, garden angelica (Angelica officinalis) root, coltsfoot herb, snowdrop anemone (Anemone sylvestris) herb, snowdrop anemone (Anemone sylvestris) root, locoweed semilunar (Astragalus) herb, arborescent aloe (Arborescence aloe) succus, swallowwort (Chelidonium majus) herb, black current (Ribes nigrum) leaf, garlic (Allium sativum) bulb, greater burnet (Sanguisorba officinalis) root, lady's finger (Lathyrus pratensis) herb, dandelion (Taraxacum officinale) root, stringing nettle (Urtica dioica) herb, common origanum (Origanum vulgare) herb, ginger plant (Tanacetum vulgare) herb, bottle brush (Equisetum arvense) herb, common wormwood (Artemisia absinthium) herb, crystal tea ledum (Ledum palustre) herb, common juniper (Juniperus communis) needle, parnassia herb, mother-of-thyme herb, flat-leaved snakeroot (Eryngium) herb, shinleaf (Ramischia secunda) herb, willow herb root and field pennycress (Thlaspi arvense) herb taken in specific proportion and added by 3 volume percent of 10% propolis tincture.

EFFECT: tincture shows efficiency in treating tuberculosis.

3 tbl

FIELD: medicine.

SUBSTANCE: antibacterial and rehydration therapies are combined with prescribed sorbents, symptomatic therapy. From first day of disease prescribed is infusion herb collection consisting of silverweed rhizome, salvia leaves, milfoil herb, St. John's wort herb, inula rhizomes with roots, tickseed herbs, mint leaves, fennel fruits and buckthorn bark at ratio of components 2:2:2:2:2:2:2:2:1. Infusion is taken up dosed 1\3 glass 3 times a day, 30 min before meal within 10 days. Then within three weeks after basic therapy appoint infusion from silverweed rhizome, salvia leaves, milfoil herb.

EFFECT: provides accelerated normalisation of clinical-laboratory indicators, and prevention of infectious complications without by-effects.

2 cl, 1 tbl, 1 ex

FIELD: medicine; biotechnologies.

SUBSTANCE: strain Lactobacillus casei FERM BP-100059 (FERM P-19443), possessing probiotic properties; grow up in the presence of any from one to four amino acids as a source of the nitrogen necessary for growth. At planting in suitable cultural to medium, the final value pH makes 4.0 or lower, and the highest acidity makes 1.5% or above. The strain resistable is to 5% salts of cholic acids. The strain produces an antibiotic. On the basis of the strain as the active beginning, the lactobacillus preparation of probiotic action for humans, animals and plants and the preventive or therapeutic agent against human, animal and plant infections.

EFFECT: ability to colonise and breed in the centres chronic the infections, steady against treatment, strong clearing action and destruction causing a bacterium infection.

12 cl, 5 dwg, 56 tbl, 34 ex

FIELD: medicine; pharmacology.

SUBSTANCE: peroral pharmaceutical dosed out form for treatment of the conditions bound to secretion of acid in a stomach, includes an acid-sensible inhibitor of the proton pump and antagonist of H2-molecular switchers, with the delayed and-or prolonged liberation of the proton pump acid-sensible inhibitor, and fast liberation of antagonist of H2-molecular switchers.

EFFECT: maximum suppression of acid in a stomach after the first dose and throughout all course of treatment.

69 cl, 4 dwg, 7 ex

FIELD: medicine; veterinary science.

SUBSTANCE: vaccine includes inactivated adhesive antigens E.coli K88, E.coli K99, E.coli F-41, E.coli 987P and an adjuvant - aluminum hydrate. As the inactivated adhesive antigens E.coli use inactivated filamentous adhesive antigens E.coli K88 ab, E.coli K88 ad, E.coli K88 ad, E.coli K99, E.coli F-41, E.coli Att-25, E.coli 987P with activity level in reaction of the passive hemagglutination peer as 1:2048-4096; 1:1024-2048; 1:256-512; 1:1024-2056; 1:1024-2056; 1:32-64; 1:256-512, accordingly, at a following parity of components, wt. %: inactivated filamentous adhesive antigens E.coli K88 ab, E.coli K88 ad, E.coli K88 ad, E.coli K99, E.coli F-41, E.coli Att-25, E.coli 987P, taken in mass parities 1:(0.8-1.2:(0.8-1.2:(0.8-1.2:(0.8-1.2:(0.8-1.2:(0.8-1.2, accordingly - 55-65, 5.8-6.2%-s' aluminium hydrate the rest.

EFFECT: rising of safety of livestock of agricultural animals.

2 cl, 1 tbl, 8 ex

FIELD: medicine; pharmacology.

SUBSTANCE: perform processing of an elevated part and roots of the primrose plant (Primula macrocalyx Bge.) with an organic dissolvent - ligroin or hexane with the subsequent extraction with acetone and allocation of a target product using chromatography.

EFFECT: increase of output of the product.

4 ex, 2 dwg

FIELD: medicine; pharmacology.

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

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

51 cl, 21 dwg, 10 tbl, 4 ex

FIELD: chemistry, immonology.

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

EFFECT: efficient treatment and prevention of disease.

13 cl, 5 dwg, 28 tbl, 1 ex

FIELD: chemistry.

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

EFFECT: efficient application in bacterial infection treatment.

29 cl, 3 tbl, 58 ex

FIELD: medicine.

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

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

4 tbl, 6 ex

FIELD: medicine.

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

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

1 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention represents a composition including micronised particles of biologically active substance of respirable size in a combination with coarsely dispersed, unrespirable particles of the inert carrier where glutarilhistamine is used as biologically active substance. The composition contains biologically active substance, namely glutarilhistamine, and possesses with expressed antiinflammatory, antiallergic, antiasthmatic and antiviral action.

EFFECT: invention provides the maximum value of size respirable fraction at inhalation.

8 ex, 2 dwg

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