Aqueous pharmaceutical compositions containing borate-polyol complexes

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a multidose ophthalmic composition containing prostaglandin as a therapeutic ingredient, mannitol or sorbitol 0.15-0.5 wt/vol %, propylene glycol or glycerol 0.2-1.8, borate 0.25-0.5 wt/vol %, an antimicrobial preserving agent 0.0003-0.003 wt/vol % representing a polymer quaternary ammonium compound and water. Said composition has pH 6.4-7.2 and is benzalconium chloride free. Besides, the invention refers to the use of said ophthalmic composition for preparing a drug for treating glaucoma, eye infections, allergies and inflammations.

EFFECT: preparing the ophthalmic composition which exhibits improved antimicrobial preserving activity and improved buffer properties.

16 cl, 8 tbl, 21 ex

 

References to related applications

In this application claims the priority of provisional patent application U.S. No. 61/037,137, filed March 17, 2008.

The technical field

The present invention relates to pharmaceutical compositions that contain borate-polyol as one of the complexes to improve the preservation of the compositions. More specifically the present invention relates to aqueous pharmaceutical compositions (e.g., multi-dose ophthalmic compositions containing two or more different polyols in combination with borate, a preservative, or both.

The level of technology

The present invention is directed to pharmaceutical compositions, the composition of which is chosen in such a way as to provide sufficient antimicrobial activity that meets the performance requirements of preservatives in the United States Pharmacopeia ("USP") and similar regulatory documents of other countries. The achievement of the preservative properties is based on a unique combination of components of the drug and, in particular, the use of two or more different polyols in combination with borate.

Many pharmaceutical composition shall meet the requirements of sterility (i.e., they essentially must not contain bacteria, fungi and other pathogenic microorganisms). PR is measures such compositions include solutions and suspensions, intended for injection into the body of humans or other mammals; creams, lotions, solutions, or other topical preparations, which are applied to wounds, scrapes, burns, rashes, surgical incisions or other conditions associated with skin damage; and various types of compositions, which are applied either directly on the eye (e.g., artificial tears, solutions for washing and medicinal products), or applied to devices that come into contact with the eye (e.g., contact lenses).

Previously known types of compositions can be produced in sterile conditions by methods known to experts in this field. However, immediately after opening the package the product so that the composition contained in it, is exposed to the external environment and other sources of potential contamination by microorganisms (e.g., the patient's arm-person), the sterility of the product may be compromised. Such products typically used by the patient repeatedly, and therefore they are often referred to as the " products "multi-dose" type.

Because of the frequent, repeated exposure to the risk of contamination by microorganisms multi-dose products, it is necessary to use means to prevent such contamination. Such tools can be: (i) chemical agent to the second prevents microbial growth in the composition, which is referred to here as "antimicrobial preservative; or (ii) a packing system which prevents or reduces the risk of exposure of microorganisms in the pharmaceutical composition in the container.

Previously known multi-dose ophthalmic compositions in General contain one or more antimicrobial preservatives to prevent the growth of bacteria, fungi and other microorganisms. The contact of such compositions to the cornea can occur either directly or indirectly. The cornea are particularly sensitive to exogenous chemical agents. Therefore, to minimize the possibility of cases of adverse effects on the cornea, it is preferable to use an antimicrobial preservatives, which are relatively non-toxic to the cornea, and the use of such preservatives in relatively low concentrations.

Sometimes it is difficult to achieve a balance between antimicrobial effectiveness and potential Toxicological impact of antimicrobial preservatives. More specifically, the concentration of the antimicrobial component necessary to prevent contamination by microorganisms ophthalmic preparations may pose a risk of Toxicological effects on the cornea and/or other tissues of the eye. The lower con is entrace antimicrobial components in General helps to reduce the risks of such Toxicological effects, but lower concentrations may be insufficient to achieve the required level of biocidal efficacy (i.e. antimicrobial preservatives).

The use of antimicrobial preservative in inadequate concentrations may pose a risk of contamination by microorganisms. Such contamination is generally undesirable for most biological systems and particularly undesirable in the case of the human eye.

Thus, there is still a need for a tool that enhance the activity of antimicrobial components so as to provide the possibility of using low concentrations of components without increasing the risk of Toxicological effects or impact on the patients risk of contamination by microorganisms and the resulting ophthalmic infections.

Ophthalmic compositions in General are isotonic, buffered solutions. Particularly preferred ophthalmic compositions are those containing a borate or a borate-polyol as one of the complexes. Examples of such compositions are disclosed in U.S. patents 6503497; 6011062; 6849253; 5603929; 5653972; 5849792 and 5631287, the contents of which are fully incorporated here by reference.

It is known that the borate-polyol as one of the complexes can be used in ophthalmic compositions for increasing the deposits of antimicrobial activity in the presence of a preservative, such as polymeric Quaternary ammonium; see U.S. patent 5505953; 5811466; 6143799 and 6365636, the contents of which are fully incorporated here by reference. It was also shown that increasing the number of the polyol, such as sorbitol or mannitol, can significantly increase antimicrobial activity, even when using borate in a relatively low number. However, mannitol and sorbitol may also affect resistance to normalize the pH of tears after putting songs in the eye.

In General borate component (e.g., boric acid) of these systems can create significant resistance ophthalmic composition to normalize the pH of the tears. In the General case, it is desirable that these ophthalmic compositions retain at least some degree of buffer properties so that the natural pH of the compositions was not significantly changed in a long time. However, it is also possible that the composition can exhibit undesirable high degree of buffer properties, when used they can cause tearing and discomfort of the eyes, because the eyes will try to restore the natural pH. Thus, it is desirable to minimize the resistance of the compositions to normalize the pH of tears after application. The above-mentioned polyols, especially mannitol, sorbitol or the both, can significantly increase the resistance of the borate component to normalize to pH tears. Thus, with the aim of maintaining the required buffer properties, as a rule, it is desirable to provide a relatively low concentration of these polyols in the presence of borate. However, these lower concentrations may limit or reduce the antimicrobial activity of ophthalmic compositions.

Given the above, it seems particularly desirable that a ophthalmic composition which comprises a polyol-borate complex and which exhibits improved buffer properties, antimicrobial activity, preservative effectiveness, or any combination of these properties.

Brief description of the invention

The present invention relates to pharmaceutical compositions (e.g., multi-dose ophthalmic compositions). The composition typically includes two or more different polyols, which include the first polyol and the second polyol. In a preferred embodiment, the first polyol is selected from mannitol, or sorbitol, or combinations thereof, and the second polyol is selected from glycerol, or propylene glycol, or combinations thereof. The composition also typically includes an effective amount of Borat, where the effective amount is less than about 0.5 wt./vol.% the t of the composition. The composition is generally water, and preferably satisfies the requirements of Ph. Eur. A or Ph. Eur. B. composition Also typically includes a polymeric Quaternary ammonium compounds or other antimicrobial preservative.

Detailed description of the invention

The present invention is based on the fact that two or more different polyols in the presence of borate in the pharmaceutical compositions and, in particular, ophthalmic compositions, provide the required buffer properties and antimicrobial activity. Thus, the ophthalmic composition generally includes a first polyol, the second polyol different from the first polyol, and Borat. Ophthalmic composition also typically includes a preservative and may also include some other ingredients. It is assumed that the ophthalmic composition may be a solution for contact lenses (for example, the storage solution or rinsing contact lenses) or another type of ophthalmic compositions. In a preferred embodiment, the ophthalmic composition is a one - or multi-dose ophthalmic composition comprising a therapeutic component, and/or is provided in a form for topical application in the eye (such as drops directly into the eye).

If the ache is not marked, the percentages of these ingredients ophthalmic compositions of the present invention is expressed as a percentage by weight/volume (wt./vol.).

As used here, the term "borate" refers to boric acid, salts of boric acid, borate derivative, and other pharmaceutically acceptable borates or their combinations. The most suitable are boric acid, sodium borate, potassium borate, calcium borate, magnesium borate, manganese borate, and other such salts of borate. Borat interacts with polyols, such as glycerin, propylene glycol, sorbitol and mannitol, forming polyol-borate complexes. The type and content of these complexes depend on the number of OH groups of the polyol on adjacent carbon atoms that are not in the TRANS-position relative to each other. It should be clear that the percentage, expressed as mass/volume, polyol as one and borate components, their number, when they are part of a complex or without the formation of the complex.

As used here, the term "polyol" includes any compound having at least one hydroxyl group on each of two adjacent carbon atoms that are not in the TRANS-position is obtained with respect to each other. The polyols can be linear or cyclic, substituted or unsubstituted, or may represent a mixture of the above, but when the volume of the received complex should be water-soluble and pharmaceutically acceptable. Examples of such compounds include sugars, sugar alcohols, sugar acids and uronic acids. The preferred polyols are sugar, sugar alcohols and sugar acids, including without limitation: mannitol, glycerol, xylitol, sorbitol and propylene glycol.

The phrase "less than" in relation to a specified concentration (for example, 1 wt./vol.%) here is used to indicate that the specified component (e.g., antimicrobial preservative) or missing in the composition or is present at a concentration less than the specified limit (e.g., 1 wt./vol.%). The phrase "effective amount", as used here, means that the specified component is present in the composition in a quantity sufficient to show therapeutic activity, buffer properties, preservative and/or antimicrobial properties of the composition.

Compositions of the present invention, typically include a preservative. Potential preservatives without restrictions include: hydrogen peroxide, chlorine-containing preservatives, such as benzalkonium chloride or other. However, in accordance with a preferred aspect, the ophthalmic composition of the present invention essentially contains no chlorine-containing preservatives and, in particular, essentially does not contain benzalconi chloride. Preferred preservatives are included in of etimologically composition, are polymeric Quaternary ammonium compounds.

As used here, the phrase "essentially does not contain" in relation to ingredients ophthalmic compositions, means, as is implied that the ophthalmic solution may not contain a specific ingredient or to include only a nominal amount of this particular ingredient.

Polymeric Quaternary ammonium compounds used in the compositions according to the present invention are those exhibiting antimicrobial activity and which are ophthalmologist acceptable. Preferred compounds of this type are described in U.S. patents 3931319; 4027020; 4407791; 4525346; 4836986; 5037647 and 5300287 and PCT application WO 91/09523 (Dziabo et al.). The most preferred polymeric compound ammonium is polyquaternium-1, otherwise known as POLYQUAD.RTM or ONAMERM.RTM. with an average molecular weight from 2,000 to 30,000. Preferably the average molecular weight is between 3000 and 14000.

Polymeric Quaternary ammonium compounds in General are used in the compositions of the present invention in a quantity amounting to more than approximately within 0.00001 wt./vol.%, more preferably more than approximately 0,0003 wt./vol.% and even more preferably more than approximately 0,0007 wt./vol.% from ophthalmic whom is osili. In addition, polymeric Quaternary ammonium compounds in General are used in the compositions of the present invention in an amount that is less than about 3 wt./vol.%, more preferably less than about 0.003 units wt./vol.% and even more preferably less than about 0,0015 wt./vol.% from the ophthalmic composition.

As mentioned earlier, the ophthalmic composition will include a combination of two or more polyols, where the first polyol different from the second polyol. The first polyol preferably is such that substantially increases the resistance of the borate component to normalize to pH tears the instillation of ophthalmic composition in the eyes. In contrast, the second polyol is preferably not affected or only slightly increases this resistance borate component in ophthalmic compositions.

The first polyol may be a single polyol or polyols. Each of the polyols of the first polyol is preferably a sugar alcohol, which includes alkyl chain with a hydroxyl group (-OH group)attached to a significant amount (i.e., more than 50, 70 or 90% or all of carbons in the alkyl chain. Alkyl chains of each of the polyols of the first polyol, typically include 5 carbon is in (pentane), 6 hydrocarbons (hexane), 7 hydrocarbons (heptane) or any combination of them. Examples of suitable polyols for the first polyol include, without limitation, mannitol ((2R,3R,4R,5R)-hexane-1,2,3,4,5,6-hexol), sorbitol ((2R,3S,4S,5S)-hexane-1,2,3,4,5,6-hexol), combinations thereof or the like, Other possible suitable polyol for the first polyol may be xylitol ((2R,3R,4S)-pentane-1,2,3,4,5-pentanol). In a preferred embodiment, the first polyol is completely or essentially completely (i.e., at least 95% by weight) represents beckons, or sorbitol, or both. Most preferably, when the first polyol essentially consists entirely of mannitol.

As used here, the term "essentially completely" in relation ingredient[s], which is part of the ophthalmic composition, means, as it is assumed that the component consists entirely of one or more specific ingredient[s] or consists essentially entirely of the specified one or more specific ingredient[s] only a nominal quantity of the component that is different from the specified one or more specific ingredients.

The first polyol, typically, is at least about 0.01 wt./vol.%, more preferably at least about 0.15 wt./vol.% and even more preferably at least about 0.25 wt./vol.% from of etimologically composition. Also the first polyol, as a rule, is less than about 5 wt./vol.%, more preferably less than about 1.6 wt./vol.% and even more preferably less than about 0.5 wt./vol.% from the ophthalmic composition.

The second polyol may also be a single polyol or polyols. Each of the polyols of a second polyol, as the first polyol preferably is a sugar alcohol, which includes alkyl chain with hydroxyl groups (-OH groups)attached to a significant amount (i.e., more than 50, 70 or 90% or all) of the carbons in the alkyl chain. Alkyl chains of each of the polyols of a second polyol, typically include 2 carbon (ethane), 3 carbon (propane) or 4 C (butane). Examples of suitable polyols for the second polyol without restrictions include glycerol (propane-1,2,3-triol), propylene glycol (propane-1,2-diol) combinations thereof or the like In the preferred embodiment, the second polyol is completely or essentially completely (i.e., at least 95% by weight) composed of glycerol or propylene glycol, or both. Most preferably, when the second polyol essentially consists entirely of propylene glycol.

The second polyol, typically, is at least approximately of 0.015 wt./vol.%, more preferably at IU is greater least about 0.2 wt./vol.% and even more preferably at least about 0.3 wt./vol.% from the ophthalmic composition. Also the first polyol, as a rule, is less than about 7 wt./vol.%, more preferably less than about 5 wt./vol.%, even more preferably less than about 1.8 wt./vol.%, and even more preferably less than about 1.2 wt./vol.% from the ophthalmic composition.

In the General case it is assumed that the borate may be included in the ophthalmic compositions of the present invention in various amounts. However, it was found that a lower concentration of borate when used in combination with two or more different polyols can provide unexpectedly high antimicrobial activity, preserving the effectiveness of the required buffer properties or a combination of both. Generally, the present invention Borat is at least about 0.05 wt./vol.%, more preferably at least about 0.1 wt./vol.% and still more preferably at least about 0.25 wt./vol.% from the ophthalmic composition. In addition, mainly the borate may be less than about 0.75 wt./vol.%, more preferably less than about 0.5 wt./vol.% and still more preferably less than about 0.4 wt./vol.% and even possibly less than around 0.35 wt./vol.% from the ophthalmic compositions is AI. This, in particular, in the case of using a combination of polyols and borate in the presence of a preservative, such as polymeric Quaternary ammonium compounds (for example, polyquaternium-1).

Resistance to normalize the pH of the tears ophthalmic composition in the eye, generally is within the desired range. This resistance can be quantified by quantity or amount of a base or acid in the amount or volume of ophthalmic compositions, used to change the pH of the composition to a predetermined pH. The amount of base or acid required per unit volume of the ophthalmic composition to change the natural pH of the composition to pH tears (7,5), can be significant, because they can give the resistance of the composition to normalize the pH of tears after instillation of the composition in the eye. In particular, the present invention resisting normalization to pH tears can be quantified as the volume of 1 N NaOH (1 normal NaOH or 1 N HCl (1 normal HCl)required per unit volume of ophthalmic compositions, to change the natural pH of the composition to pH 7.5. For example, adding 10 microliters (ál) 1 N NaOH can change the pH of one milliliter (ml) ophthalmic composition from its natural pH (e.g. pH less than 7,0) to pH 7.5. To achieve pH 7.5 ophthalmic composition of the present invention may not be required NaOH or HCl. For conventional ophthalmic compositions of the present invention, generally require at least a 0.5 μl, more preferably at least 1.0 ml and even more preferably at least a 2.0 ál of 1 N NaOH to change the pH of one (1) ml of the ophthalmic composition to 7.5. Also typically, less than 20 μl, more preferably less than 15 ml and even more preferably less than 10 μl and even possibly less than 6,0 ál of 1 N NaOH can change the pH one (1) ml of the ophthalmic composition to 7.5. A few examples are given below, where the resistance to normalization to pH tears was expressed in Microlitre 1 N NaOH required to change the pH of one (1) ml of the ophthalmic composition to 7.5.

The present invention particularly relates to a multi-dose ophthalmic compositions with antimicrobial activity, sufficient for the composition to satisfy the requirements of the USP to the effectiveness of the preservative, and other standards on the effectiveness of the preservative for aqueous pharmaceutical compositions.

Performance standards preservative for multi-dose ophthalmic solutions in the U.S. and other countries/regions in the following table:

Criteria test the effectiveness of the preservative ("PET")
(The order log reduction of the microbial inoculum over time)
BacteriaMushrooms
USP 27The log reduction of 1 (90%) on day 7; log 3 (99,9%) to 14 days; and no increase after 14 daysComposition for the entire period of study should show no increase in the log of 0.5 or more, compared with the original inoculum
Japanlog 3 on day 14; and without increasing from 14 days to 28 daysNo increase in relation to the original number at 14 and 28 days
European Pharmacopoeia And1Reducing log 2 (99%) for 6 hours; log 3 for 24 hours; and no recovery after 28 daysReducing log 2 (99%) on day 7 and without subsequent increase
European PharmacopoeiaThe log reduction for 1 to 24 hours; log 3 to 7 days; and without subsequent increaseThe log reduction of 1 (90%) on day 14 and without subsequent increase
FDA/ISO 14730 A log reduction of 3 compared to the baseline indicator of contamination on day 14; and a log reduction of 3 after repeated contaminationWithout exceeding the original values to 14 days and without exceeding the values after repeated contamination on day 14 to 28 days
1In accordance with the European Pharmacopoeia, there are two standards on the effectiveness of preservatives: a and B.

The standards described above for the USP 27, is essentially identical to the requirements established in previous editions of USP, in particular USP 24, USP USP 25 and 26.

Described here are systems borate/polyol to increase antimicrobial activity and preservative properties of the compositions can be included in various types of pharmaceutical compositions, such as ophthalmic, for insertion into the ear cavity, nasal and dermatological compositions, but especially useful for their use in ophthalmic compositions. Examples of such compositions include: ophthalmic pharmaceutical compositions, such as local compositions used for the treatment of glaucoma, infections, allergies or inflammation; compositions for the treatment of contact lenses, such as cleansing products and products to improve eye comfort of patients wearing contact lenses; and various other types of etimologically compositions such as eye moisturizing products, artificial tears, funds suppress the secretion etc. Compositions can be aqueous or nonaqueous, but mostly water.

The compositions of the present invention can contain various types of therapeutic components. The invention may include nonionic therapeutic components. Also in the compositions can be used cationic therapeutic components, especially if the component is included in the composition in a free base form or in the form of a salt with a monovalent anion, such as hydrochloric salt.

Examples of therapeutic components that may be contained in the ophthalmic compositions of the present invention, include prostaglandin analogues (e.g., latanoprost, travoprost and unoprostone), hypotensive lipids (for example, bimatoprost) and glucocorticoids (e.g. prednisolone, dexamethasone and loteprednol). Examples in addition to, or as variants of the above without restrictions include timolol (e.g., timolol maleate), olopatadine (for example, olopatadine hydrochloride), brinzolamide, dorzolamide, brimonidine, emedastine, tandospirone, roscovitine, nepafenac, bradykinin, a PDE4 inhibitor, combinations thereof or the like

The present invention relates also to a multi-dose ophthalmic compositions d is I treat conditions, when the cornea or adjacent ocular tissues are irritated, or conditions requiring frequent use of the composition, such as for the treatment of patients with dry eye syndrome. The compositions of the present invention can be used as artificial tears, means for rinsing eyes and other compositions used for the treatment of conditions associated with dry eye syndrome, and other conditions associated with inflammation or discomfort of the eye. Also the composition can be used for the treatment of glaucoma.

In General the compositions of the present invention is made in the form of sterile aqueous solutions. The compositions of the present invention may also be compatible with the eye and/or other fabrics that will be exposed to songs. Ophthalmic compositions for direct application to the eye, should be prepared to have a pH and toychest compatible with the eye. This also implies that the composition can be in the form of suspensions or represent other types of solutions.

the pH of the compositions will normally be in the range of from 4 to 9, preferably from 5.5 to 8.5, and most preferably from 5.5 to 8.0. Particularly preferred pH ranges from 6.0 to 7.8, and more specifically from 6.4 to 7.2. Osmollnosti compositions will be from 200 is about 400 or 450 milliosmoles per kilogram (mOsm/kg), more preferably from 240 to 360 mOsm/kg

The compositions of the present invention can contain various types of pharmaceutical excipients, such as surfactants that modify the viscosity of the components (e.g., hydroxyethylcellulose (HEC), hypromellose (HPMC), or a combination) and so the Inclusion of surface-active substances, as a rule, it is desirable, but not mandatory, unless specified otherwise. Preferably, if the surfactant used in the present invention, it is a nonionic surfactant, derived from vegetable oils. Especially preferred are vegetable, seed and/or nut oil is subjected to hydrogenation, ethoxycarbonyl or a combination of these methods. Such surface-active substances derived from plant, seed and/or nut-oil, without limitation, include: babassu oil, almond oil, corn oil, palm kernel oil, castor oil, coconut oil, cottonseed oil, jojoba oil, linseed oil, mustard oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, sunflower oil and the oil of wheat germ, hydrogenated or ethoxylated derivatives or their com is inali. The preferred oils are castor oil, babassu oil, almond oil, corn oil and palm kernel oil, most preferably castor oil, and babassu oil, such as oil Crovol supplied by Croda Oleochemicals, England. For example nonionic surface-active substance polyoxyl-40-hydrogenated castor oil can be used to solubilize or stabilize the drug, such as travoprost.

Particularly preferred surfactants include polyoxyethylene (POE) (40) hydrogenated castor oil (or PEG-40 hydrogenated castor oil (HCO-40), POE (60) hydrogenated castor oil (HCO-60) and POE (200) hydrogenated castor oil (HCO-200).

Applicants emphasize that all documents, which are referenced in the description, is included in its entirety. Additionally, if the quantity, concentration, or other value or parameter is specified as a range, preferred range, or in the form of an enumeration of upper preferable values and lower preferable values, this should be understood as a specific disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or p is edocfile values, regardless of the specific disclosure of the range. If given the range of numerical values, unless otherwise specified, it is assumed that the range includes the endpoints and all integer and fractional values within the range. This should not be construed as limiting the claims to the invention the specific values that you specified when defining a range.

Other embodiments of the present invention will be obvious to the person skilled in the art based on the present description and experimental data of the present invention, disclosed here. It should be clear that the present description and examples should be considered illustrative in relation to the actual scope and intent of the invention defined in the following claims and its equivalents.

The Table below shows the approximate composition that is suitable as a preferred example of the preparation of ophthalmic compositions of the present invention, and the desired content of these components in percent, expressed as weight/volume.

TABLE A
ComponentThe percent wt./about.
Travoprost 0,004
POE-40 hydrogenated castor oil (HCO-40)of 0.5 or 0.1
Boric acid0,3
Propylene glycol0,75
Mannitol0,3
Sodium chloride0,35
Polymeric compound Quaternary ammonium0,001
NaOHSufficient to achieve a pH of 6.8
Purified waterq.s. 100

Assume that interest is expressed as mass/volume, in table A may vary on±10%, ±20%, ±30%, ±90% from the specified percentage values, expressed as weight/volume, or more, and that such deviations may, in particular, be used to generate ranges for the components of the present invention. For example, if the percentage of the component, expressed as weight/volume is 10% with a variation of ±20%, it means that the ingredient can be in the range of percentages expressed as weight/volume average of 8-12 wt./vol.%.

The following examples are provided for additionally the th disclosure of certain embodiments of the present invention. The drugs shown in the examples were prepared by methods known to experts in the field of ophthalmic pharmaceutical compositions.

The effectiveness of antimicrobial preservative, as confirmed by the examples was determined using the tests against contamination by microorganisms in accordance with the techniques described in the US Pharmacopoeia 24 (USP) for products of category 1A. Samples were inoculable known concentrations of one or more microorganisms selected from the gram-positive vegetative bacteria (Staphylococcus aureus ATCC 6538), gram-negative vegetative bacteria (Pseudomonas aeruginosa ATCC 9027 and E.coli ATCC 8739), yeast (Candida albicans ATCC 10231) and mould (Aspergillus niger ATCC 16404). Then the samples were observed during certain periods for setting system properties antimicrobial preservative in respect of destruction or inhibition of growth of organisms that are intentionally included in the product. The rate or concentration of the antimicrobial activity to determine compliance with the standards of the effectiveness of the preservative according to USP for these categories of products.

Table B
Standards for preservatives for products of category IA USA, represented as the logarithm of the reduction in the populations of microorganisms
The observation time6 hours24 hours7 days14 days28 days
for bacteria (S.aureus, P.aeruginosa and E.coli)
The European Pharmacopoeia (Ph. Eur. A)2,03,0NANANR
The European Pharmacopoeia (Ph. Eur. B)NA1,03,0NINI
USPNANA1,03,0NI
for fungi (C.albicans and A.niger)
Ph. Eur. ANANA2,0NANI
Ph. Eur. InNANANA1,0NI
USPNANANININI
NI = the Increase in this or any subsequent period of observation is missing
NA = This time interval is not required by the used standard (e.g., USP, Ph. Eur. B)
NR = No recovery of organisms

As shown in Table B, in accordance with the requirements for the study of antimicrobial effectiveness USP 27 products category IA containing compositions have sufficient antimicrobial activity to reduce the initial inoculation of approximately 105-106bacteria on the log (i.e. 90% reduction in microbial population) within seven (7) days and three log (i.e. reducing 99.9% of the population of microorganisms) within fourteen (14) days, and requirements also apply to the increase in microbial population was absent after the fourteen-day period.

Requirements of USP standards against fungi lies in the fact that the composition provided stasis (i.e. no growth) initial population inoculation during the entire 28-day study period. Product category IA represents an injection or other parenteral product, including the Aya emulsion, sterile products for introduction into the cavity of the ear or nose and eye product is water-based or media.

The allowable error in the calculation of the populations of microorganism is typically ±0,5 log. Accordingly, the term "stasis"is used here in relation to the above standards, USP, means that the initial population does not increase more than 0.5 order log compared to the original population.

EXAMPLES

The preparations of examples A-U is given here to illustrate possible variants of the present invention. In the examples shown antimicrobial activity and/or preservative effectiveness in ophthalmic compositions of the present invention containing the combination of two different polyols especially in combination with borate, polymeric Quaternary compound ammonium, or both. Specified in examples A-U percentage of ingredients is a percent, expressed as weight/volume.

Examples A-D

Table C presents the compositions A-D and data related to these compounds.

TABLE C
ExamplesAndB CD
TravoprostRequirements0,0040,0040,0040,004
HCO40on0,50,50,50,5
Sodium chloridePh. Eur. A0,720,690,66No
Propylene glycolNoNoNo1,8
Mannitol0,10,30,90,3
Boric acid0,30,30,30,3
Polyquaternium-10,0010,0010,0010,001
Sodium hydroxide, hydrochloric acidTo pH 6.5To pH 6.5To pH 6.5To pH 6.5
Purified waterUp to 100%Up to 100%Up to 100%Up to 100%
Resistance to normalization to a pH of tears, ál/ml3,67,2137,6
S.Aureus6 hours2,01,41,82,15,1
24 hours3,01,92,73,05,1
7 days5,15,15,15,1
14 days5,15,15,15,1
28 daysAll5,15,15,15,1
Pseudomonas A6 hours2,03,43,32,85,1
24 hours3,03,64,4the 3.85,1
7 days5,15,15,15,1
14 days5,15,15,15,1
28 daysAll5,15,15,15,1
E.coli6 hours2,02,54,52,45,1
24 hours3,05,15,1a 4.95,1
7 days5,15,15,15,1
14 days5,15,15,15,1
28 daysAll 5,15,15,15,1
Candida A.7 days2,01,01,31,4a 4.9
14 daysNI1,51,91,9a 4.9
28 daysNI1,92,32,5a 4.9
A.Niger7days3,03,03,73,5
14 daysNI3,53,73,63,7
28 daysNI3,7 a 3.9the 3.8a 3.9

All four examples A-D contain 0.001% of polyquaternium-1 and 0.3% boric acid. Examples a-C contain only one polyol, mannitol in a concentration of 0.1%, 0.3% or 0.9 percent. These three drugs only satisfy the requirements of Ph. Eur. B. they do not meet the requirements of the Ph. Eur. And in Candia Albican. In addition, examples A and B do not meet the requirements of Ph. Eur. And against Staph Aureus. Example D, which contains a combination of two polyols, 0.3% mannitol and 1.8% of propylene glycol, meets the requirements of Ph. Eur. A.

Examples of E-L

In tables D and E shows the compositions D and E, and data related to these compounds.

To a pH of 6.8 NI
TABLE D
ExamplesEFGH
Travoprost0,0040,0040,0040,004
HCO400,10,1 0,10,1
Sodium chloride0,350,350,350,35
Propylene glycol0,750,750,750,75
Mannitol0,30,30,3No
Boric acid0,30,3No0,3
Polyquaternium-10,001No0,0010,001
Sodium hydroxide, hydrochloric acidTo a pH of 6.8To a pH of 6.8To a pH of 6.8
Purified waterUp to 100%Up to 100%Up to 100%Up to 100%
Resistance to normalization to a pH of tears, ál/ml5,6-0,91,6
S.Aureus6 hours2,04,00,01,83,6
24 hours3,0a 4.90,02,05,0
7 daysa 4.90,55,05,0
14 daysa 4.92,15,05,0
28 daysAlla 4.94,45,05,0
Pseudomonas A6 hours2,05,00,22,6a 4.9
24 hours3,05,00,34,5a 4.9
7 days5,00,6a 4.9a 4.9
14 days5,00,9a 4.9a 4.9
28 daysAll5,01,2a 4.9a 4.9
E.cli 6 hours2,05,00,13,35,0
24 hours3,05,00,05,05,0
7 days5,00,05,05,0
14 days5,00,05,05,0
28 daysAll5,00,45,05,0
Candida A.7 days2,04,60,32,9a 4.9
14 daysa 4.90,34,3a 4.9
28 daysNIa 4.90,7a 4.9a 4.9
A.Niger7days2,03,03,00,11,1
14 daysNI3,63,60,61,1
28 daysNI3,62,90,61,0

5,0 4,8
TABLE E
ExamplesIJKL
Travoprost0,0040,0040,0040,004
HCO400,10,10,10,1
Sodium chloride0,350,66NoNo
Propylene glycolNoNoNo0,75
Mannitol2,30,34,62,3
Boric acid0,30,30,30,3
Polyquaternium-1 0,0010,0010,0010,001
Sodium hydroxide, hydrochloric acidTo a pH of 6.8To a pH of 6.8To a pH of 6.8To a pH of 6.8
Purified waterUp to 100%Up to 100%Up to 100%Up to 100%
Resistance to normalization to a pH of tears, ál/ml-6,22,58,7
S.Aureus6 hours2,02,72,0a 4.9a 4.9
24 hours3,0a 3.92,9a 4.9a 4.9
7 days a 4.9a 4.9a 4.9a 4.9
14 daysa 4.9a 4.9a 4.9a 4.9
28 daysAlla 4.9a 4.9a 4.9a 4.9
Pseudomonas A6 hours2,03,72,54,84,8
24 hours3,04,84,34,84,8
7 days4,85,04,84,8
14 days4,84,84,8
28 daysAll4,85,04,84,8
E.coli6 hours2,04,13,14,24,8
24 hours3,04,8a 4.94,84,8
7 days4,8a 4.94,84,8
14 days4,8a 4.94,84,8
28 daysAll4,8a 4.94,8
Candida A.7 days2,03,31,04,25,0
14 daysNI3,51,35,05,0
28 daysNI4,63,05,05,0
A.Niger7 days2,01,83,60,12,0
14 daysNI2,73,70,92,6
28 daysNI2,93,60,93,0

Example E present is employed, a typical example of the present invention. It contains low concentrations of boric acid (0.3%) and mannitol (0.3 percent). And has a preferred concentration of propylene glycol (0.75 percent). This drug also is isotonic and meets the requirements for conservation of Ph. Eur.A.

In the example F presents the same composition as in example E, except that it does not contain polyquaternium-1 and essentially any conventional preservative and antimicrobial activity rather is provided by the system, which comprises or essentially consists of borate and combinations of polyols. Although it does not satisfy the requirements for preservation by USP, Ph. Eur. B and Ph. Eur. As, however, shows good activity against A. Niger. Thus, the presence of polyquaternium-1 for the present invention it was found desirable.

In example G, the same composition as in example E, except that it does not contain boric acid. It meets the requirements of conservation for the USP, but does not meet the requirements of the Ph. Eur. B and Ph. Eur. A. the Absence of boric acid significantly affects microbial activity against A. Niger. It also reduces the activity against S. Aureus. Thus, preferably the presence of boric acid in ophthalmic compositions of the present invention.

In the example, N is the same composition as in example E, except that it does not contain mannitol. About the and meets the requirements for conservation USP and Ph. Eur. B, but does not meet the requirements for the conservation of Ph. Eur. A. the Absence of mannitol significantly affect microbial activity against A. Niger. It seems that mannitol itself does not have activity against A. Niger, as shown in example G. However, its complex with boric acid in a low concentration show significant activity against A. Niger. Thus, it is desirable that the ophthalmic composition of the present invention contain at least mannitol in low concentration.

Examples I, J and K do not contain propylene glycol. In the example I propylene glycol was replaced with additional mannitol. The increase in the ratio of mannitol relative to boric acid greatly increases the complexation and the ionization of boric acid. However, it is assumed that the activity of complex polyol and boric acid against A. Niger increases with decreasing level of ionization/complexation of boric acid and that activity begins to decrease with further increase in the complexation/ionization of boric acid. The result of microbial activity in the sample J against A. Niger was higher than in example H, but lower than in example E. the Composition in example I does not satisfy the requirements of the PET Ph. Eur. A. in Addition, with increasing ionization of boric acid increased resistance to normalize the pH of the tears, and traces the tion, this is undesirable. Thus, for the present invention in the General case, it is preferable that the concentration of mannitol was maintained below about 1.5%. Higher concentrations of mannitol, as a rule, is not desirable.

In example J propylene glycol was replaced with an additional quantity of sodium chloride. In this example, the absence of propylene glycol affects Candida albicans and Staph Aureus. However, activity against A. Niger did not change significantly. The composition meets the requirements of USP and Ph. Eur. B, but does not meet the requirements of the Ph. Eur. A.

In the example K and propylene glycol, and sodium chloride was replaced by mannitol. Thus, the composition contains mannitol in high concentrations (4.6 per cent). Such a high concentration of mannitol at 0.3% boric acid provides significantly increased the activity of polyquaternium-1 against Candida albicans and Staph Aureus, however, has a relatively weak activity against A. Niger. Thus, the high concentration of mannitol, as a rule, is not sufficient to meet the requirements for the conservation of Ph. Eur A or even Ph. Eur. B.

In example L sodium chloride was replaced with additional mannitol. Thus, the concentration of mannitol was 2.3%. The drug also contains 0,75% propylene glycol. He meets all the requirements for conservation of Ph. Eur. A. But its activity against A. Niger is slightly less than in example E with 0.3% boric key is lots. Thus, this confirms that the activity against A. Niger is reduced because a certain amount of mannitol forms a complex with higher amounts of boric acid. Thus, as a rule, it is preferable to keep the concentration of mannitol below 1.5 wt./vol.%.

Compared with the previously described example D, there is an additional amount of propylene glycol instead of sodium chloride. This drug satisfies Ph. Eur. A. and has good activity against A. Niger. Thus, unlike mannitol, it is shown that a higher concentration of propylene glycol as a rule, does not reduce microbial activity, since it does not form a complex with boric acid in such amounts.

Examples M-P

Table F shows the compositions of the P-M and data related to these drugs.

5,0
TABLE F
ExamplesMMOP
Travoprost0,0020,0020,0040,002
HCO400,10,10,10,1
Sodium chloride0,660,600,460,35
Propylene glycolNo0,250,50,75
Mannitol0,30,30,30,3
Boric acid0,30,30,30,3
Polyquaternium-10,0010,0010,0010,001
Sodium hydroxide, hydrochloric acidTo a pH of 6.8To a pH of 6.8To a pH of 6.8
Purified waterUp to 100%Up to 100%Up to 100%Up to 100%
Resistance to normalization to a pH of tears, ál/ml7,4--6,8
S.Aureus6 hours2,01,83,03,2a 4.9
24 hours3,03,04,2a 4.9a 4.9
7 daysa 4.9a 4.9a 4.9a 4.9a 4.9
14 daysa 4.9 a 4.9a 4.9a 4.9a 4.9
28 daysa 4.9a 4.9a 4.9a 4.9a 4.9
Pseudomonas A6 hours5,04,83,55,04,8
24 hours5,05,04,85,04,8
7 days5,05,04,85,04,8
14 days5,05,04,85,04,8
28 days5,05,04,84,8
E.coli6 hours2,32,84,44,54,8
24 hours4,6a 4.94,8a 4.94,8
7 daysa 4.9a 4.94,8a 4.94,8
14 daysa 4.9a 4.94,8a 4.94,8
28 daysa 4.9a 4.94,8a 4.94,8
Candida A.7 days1,32,45,05,05,0
14 days1,52,35,05,05,0
28 days2,62,45,05,05,0
A.Niger7 days3,13,73,03,72,0
14 days3,73,73,13,72,6
28 days3,13,73,13,63,0

In the examples M-P shows the effect of the concentration of propylene glycol. The results show that 0.25% propylene glycol improves preserving properties against Candida albicans. 0.5% propylene glycol additionally improves preservative St is istwa against Staph Aureus and Candida Albicans. Thus, the concentration of propylene glycol constituting 0.3% and above are usually required to obtain the desired results, and the concentration of propylene glycol, constituting 0.5% and above, generally preferred.

Example Q

Table G shows the composition of Q and the data related to this drug.

TABLE G
ExamplesQ
Travoprost0,004
HCO400,1
Sodium chloride0,35
Propylene glycol0,75
Mannitol0,3
Boric sour is and 0,3
Polyquaternium-10,001
Sodium hydroxide, hydrochloric acidTo pH 7.4
Purified waterUp to 100%
S.Aureus6 hours2,0a 4.9
24 hours3,0a 4.9
7 daysa 4.9
14 daysa 4.9
28 daysAll a 4.9
Pseudomonas A6 hours2,05,0
24 hours3,05,0
7 days5,0
14 days5,0
28 daysAll5,0
E.coli6 hours2,05,0
24 hours3,05,0
7 days5,0
14 days 5,0
28 daysAll5,0
Candida A.7 days2,0a 4.9
14 daysNIa 4.9
28 daysNIa 4.9
A.Niger7days2,02,8
14 daysNI3,4
28 daysNI2,8

As mentioned previously, the example E of table D is a typical example of the present invention. It contains a lower concentration of boric acid is you (0.3%) and mannitol (0.3 percent). It contains propylene glycol in a preferred concentration of 0.75%). In the example Q shows the same composition, except that the pH is 7.4 instead of a pH of 6.8. Drug Q also corresponds to the requirements for conservation of Ph. Eur. A.

Examples of R-U

Table N shows the compositions R-U and the data related to these drugs.

TABLE H
ExamplesRSTU
TravoprostRequirements Ph.Eur.A0,0040,0040,0040,004
Timolol maleate0,50,50,680,68
HCO400,10,10,10,1
Sodium chloride0,250,2 0,250,25
Propylene glycol0,750,750,750,75
Mannitol0,30,30,30,3
Boric acid0,30,30,30,3
Polyquaternium-10,0010,0010,0010,001
Sodium hydroxide, hydrochloric acidTo a pH of 6.2To pH 6.5To a pH of 6.8To pH 7.4
Purified waterUp to 100%Up to 100%Up to 100%Up to 100%
Resistance to normalization to a pH of tears, ál/ml --7,2-
S.Aureus6 hours2,01,52,02,83,7
24 hours3,02,43,04,25,0
7 days5,05,05,05,0
14 days5,05,05,05,0
28 daysAlla 4.9a 4.95,05,0
Pseudomonas A6 hours2,0a 3.94,9 5,05,0
24 hours3,0a 4.9a 4.95,05,0
7 daysa 4.9a 4.95,05,0
14 daysa 4.9a 4.95,05,0
28 daysAlla 4.9a 4.95,05,0
E.coli6 hours2,03,33,2a 3.94,4
24 hours3,04,0a 4.95,0 5,0
7 daysa 4.9a 4.95,05,0
14 daysa 4.9a 4.95,05,0
28 daysAlla 4.9a 4.95,05,0
Candida A.7 days2,04,84,8the 3.84,4
14 daysNI4,84,85,05,0
28 daysNI4,84,85,05,0
A.Nier 7days2,03,62,92,11,1
14 daysNI3,13,12,01,7
28 daysNI3,03,02,82,0

Example T analogous to example E except that it contains timolol maleate and a lower concentration of sodium chloride. The addition of timolol maleate, which contains polyvalent ions maleate resulted in slightly adverse effects on the characteristics of the preservative. However, it still meets the requirements of the activity on Ph. Eur. A. However, the drugs (R and U) at a pH of 6.2 and 7.4 corresponded to the Ph conditions. Eur. B, but did not meet the Ph requirements. Eur. And against Staph Aureus and Aspergillus Niger, respectively.

1. Multi-dose ophthalmic composition comprising: an effective amount of a therapeutic component, where therapeutic component is a prostaglandin;
the first floor is ol, where the first polyol selected from the group consisting of mannitol, sorbitol, or combinations thereof, where the first polyol is present in the composition at a concentration of at least about 0.15 wt./vol.%, but less than 0.5 wt./vol.% by weight of the composition;
the second polyol, where the second polyol selected from the group consisting of propylene glycol, glycerin, or combinations thereof, where the second polyol is present in a concentration of at least 0.2 wt./vol.%, but less than 1.8 wt./vol.% by weight of the composition;
an effective amount of borate in the composition, where the effective amount of the borate is at least 0.25 wt./vol.%, but less than 0.5 wt./vol.% by weight of the entire composition; and an antimicrobial preservative, where the antimicrobial preservative is a polymeric Quaternary ammonium compounds, while an antimicrobial preservative is present in a concentration of at least 0,0003, but less than 0,003 wt./vol.%; and water;
when this composition essentially contains benzalkonium chloride and the pH of the composition is in the range from 6.4 to 7.2.

2. The composition according to claim 1, where the preservative includes polyquaternium-1.

3. The composition according to claim 1, where the composition is essentially does not contain any chlorinated components.

4. The composition according to claim 1, where the composition is essentially not contain benzalkonium chloride.

5. The composition according to claim 1, further comprising a surfactant./p>

6. The composition according to claim 5, where the surfactant is a VAT-40.

7. The composition according to claim 6, where the VAT-40 is at least 0,03, but less than 0.5 wt./vol.% song.

8. The composition according to claim 1, where the resistance of the composition to normalize the pH of the tears after instillation in the eye is less than 15 µl per 1M NaOH per ml of composition.

9. The composition according to claim 1, where the resistance of the composition to normalize the pH of the tears after instillation in the eye is less than 10 1M NaOH per ml of composition.

10. The composition according to claim 1, where the first polyol is a mannitol.

11. The composition according to claim 1, where the second polyol is a propylene glycol.

12. The composition according to claim 7, further comprising sodium chloride.

13. The composition according to claim 1, where the pH of the composition is from 6.2 to 6.8.

14. The composition according to claim 1, where therapeutic component is travoprost.

15. The use of a composition according to any one of claims 1 to 14 for obtaining a medicinal product for the treatment of glaucoma, infections, allergies or inflammation of the eye.

16. The application indicated in paragraph 15, where the composition is obtained in the form of drops directly applied to the eye.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to biotechnology, specifically to obtaining modified IGF-1 proteins and can be used in medicine. Constructed is a polypeptide which contains a human IGF-1 precursor protein, wherein amino acids G1, P2 and E3 are removed as a result of deletion or amino acid E3 is removed as a result of deletion, and wherein amino acid R37 is replaced with alanine and amino acids R71 and R72 are removed as a result of deletion. The cleavage of the E-peptide from IGF-1 by a protease is reduced as a result of said modifications. The obtained polypeptide is used to treat a musculoskeletal disease, diabetes, conditions associated with neuron death, anaemia, chronic obstructive pulmonary disease and burn injury.

EFFECT: invention enables to obtain stabilised polypeptides containing a modified sequence of an IGF-1 precursor, in which the cleavage of the E-peptide from IGF1 which occurs in natural physiological conditions is reduced.

21 cl, 12 dwg, 1 tbl, 82 ex

FIELD: medicine.

SUBSTANCE: invention relates to veterinary science. A method involves in the fact that intramuscular injections of ferroglucinum 150 mg twice every four days are combined with crezacin 4 mg/kg a day of fed-on plan in the morning for 5 days and intramuscular injections of gamavit 0.03 ml/kg once a day in the morning for 5 days.

EFFECT: method enables normalising spontaneous erythrocyte aggregation in piglets, sanitising seed stock, reducing death loss, providing higher weight gain and high-quality meat products.

3 ex

FIELD: medicine.

SUBSTANCE: invention relates to veterinary science. A method involves the use of intramuscular injections of ferroglucinum 75 mg at 15 mg of iron per 1 kg of calf's body weight, once in a combination with feeding of glycopine 6.0 mg/day in the morning for 6 days starting simultaneously with injections of ferroglucinum 75.

EFFECT: method is high-effective in correction of blood antithrombin III activity.

1 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula possessing action on a BH4 sensitive condition.

EFFECT: invention refers to a pharmaceutical composition containing said compound to applying the compound for preparing a drug for treating the BH4 sensitive condition, such as a vascular disease, a psychoneurological disease, hyperphenylalaninemia.

12 cl, 31 dwg, 20 ex

FIELD: veterinary medicine.

SUBSTANCE: calves are injected intramuscularly as a single dose the solution of ferroglucine-75 on the basis of 15 mg of iron per 1 kg of live weight of a calf, and glicopin is fed 6.0 mg/day in the morning for 6 days, starting simultaneously with the injection of ferroglucine-75.

EFFECT: method enables to normalise the antioxidant activity of the liquid part of the blood of newborn calves with iron deficiency anemia, to increase the reactivity of the animal organism, to reduce the risk of thrombotic complications, promotes normal growth and development of calves.

2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to dihydropyrazolone derivatives or of formula (I), where R1 denotes a heteroaryl group of formulae given below, where * denotes the linkage point with the dihydropyrazolone ring, A in each individual occurrence denotes C-R4 or N, wherein at most two ring members A represent N at the same time, E denotes O or S, R2, R3 and R4 are as defined in the claim. The invention also relates to a method of producing said compounds.

EFFECT: compounds of formula (I) inhibit HIF-propylhydroxylase activity and can be used to treat and/or prevent diseases, as well as for producing medicaments for treating and/or preventing diseases, particularly cardiovascular and haematologic diseases, kidney diseases, and for promoting the healing of wounds.

10 cl, 10 tbl, 178 ex

FIELD: medicine.

SUBSTANCE: what is offered is using cyproheptadine as an agent preventing developing disorders in pulmonary tissue and blood system caused by the introduction of cytostatics. It is shown that cyproheptadine prevents alveoli infiltration, oedema of interalveoral septum, connective tissue development in lungs with reducing blood lymphocyte count and peripheral blood and bone marrow neutrophilic granulocyte count.

EFFECT: invention may be used for pharmacological correction of pulmonary fibrosis and blood system disorders developing with prescribing anticancer preparations.

1 dwg, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacology and medicine and concerns the use of dihydrobromide 9-(2-diethylaminoethyl)-2-(3,4-dioxyphenyl)imidazo[1,2-a]benzimidazole of formula as a biologically active compound possessing high antihypoxic, actoprotective, nootropic activities and having a positive effect on physical efficiency, and a based pharmaceutical composition.

EFFECT: preparing the compound possessing high antihypoxic, actoprotective, nootropic activities and having a positive effect on physical efficiency, and the based pharmaceutical composition.

2 cl, 8 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of veterinary. Method includes introduction of ferroglucinum-75 solution in dose 15 mg of iron per 1 kg of live weight of calf body, one time, intramuscularly and drinking of glicopin in dose 6.0 mg/day is the morning during 6 days, starting simultaneously with injection of ferroglucinum.

EFFECT: method makes it possible to stably normalise thrombotic hemostasis in newborn calves with iron-deficient anemia, ensures long-time support of thrombotic hemostasis in optimal mode of functioning, excludes risk of thrombotic complications and assists normal growth and development of calves.

2 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of veterinary. Method includes introduction of ferroglucinum-75 in dose 15 mg of iron per 1 kg of live weight of calf intramuscularly, one time and drinking of glicopin in dose 6.0 mg/day is the morning during 6 days, starting simultaneously with injection of ferroglucinum.

EFFECT: claimed method makes it possible to avoid vascular complications in newborn calves with iron-deficient anemia, make the herd healthier, reduce murrain, increase volume and quality of obtained meat and milk production, obtain healthy offspring from the animals.

2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a piperidine derivative of general formula (I)

,

where R1 denotes hydrogen or a substitute selected from the following (b)-(i): b) acrylic acid (including alkyl ester and hydroxyalkyl amide), (c) ureide, (d) alkenyl, (e) aminoalkyl which can be substituted with alkyl carbonyl or aminocarbonyl, (f) carbonyl alkyl, substituted with hydroxy, alkoxy or hydroxyalkylamino, (g) carbonyl, substituted with hydroxy, morpholino, alkoxy, hydroxyalkyl aminoalkoxy or cyclohexyloxy carbonyloxyalkoxy, (h) carbonylamino, substituted with alkyl or alkoxy, (i) aminocarbonyl which can be substituted with one or two substitutes selected from amino, hydroxy, alkoxy, alkenyl and alkyl (which can be substituted with halogen, thiol, piperidino, amino, alkoxy, alkoxycarbonyl, aminocarbonyl or one or two hydroxy); R2 denotes hydrogen or a substitute selected from the following (j)-(r): (j) cyano, (k) acrylic acid, (l) alkyl, substituted with hydroxy or piperidino, (m) carbonyl alkyl, substituted with hydroxy, alkoxy (which can be substituted with cyclohexyloxy carbonyloxy) or hydroxyalkylamino, (n) carbonyl, substituted with hydroxy or alkoxy, (o) carbonyl alkoxy, substituted with alkoxy, (p) carbonyl alkyl sulphanyl, substituted with hydroxy or alkoxy, (q) alkoxy, (r) halogen; and R3 denotes hydrogen or a substitute selected from the following (s)-(w): (s) alkyl which can be substituted with carboxy, cyano, pyrrolidyl, piperidino, alkoxy, alkyl sulphanyl or one or two hydroxy, (t) carbonyl, substituted with alkyl or alkoxy, (u) carbonyl alkoxyalkyl, substituted with hydroxy or alkoxy, (v) carbonyl alkyl, substituted with alkyl, alkoxy or alkylphenyl, (w) aminoalkyl, substituted with aminocarbonyl or alkane sulphonyl, where one of said R1 and R2 denotes a substitute other than hydrogen, A is unsubstituted or is an oxo, B denotes carbon or oxygen, one of X and Y denotes carbon and the other denotes sulphur, the dotted line denotes a single bond or a double bond, under the condition that when R2 denotes halogen or alkoxy, A is unsubstituted, R1 denotes a substitute other than hydrogen and B denotes oxygen. The invention also relates to an antihistamine which contains a compound of formula I and use of the described compound for treatment and production of a medicinal agent.

EFFECT: novel compounds having antagonistic action on histamine receptors are obtained and described and can be suitable as active ingredients of a pharmaceutical composition, especially an antihistamine composition.

17 cl, 40 ex, 21 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to method of obtaining said salts, to pharmaceutical composition, containing said salts, and to application of salt for preparation of medication for treatment, prevention or relief of one or several symptoms of disease, mediated by CRTH2, associated with eosinophils, basophils, where disease is selected from asthma, allergic asthma, asthma of physical effort, allergic rhinitis, atopic dermatitis, contact hypersensitivity and hyper IgE syndrome.

EFFECT: invention relates to novel pharmaceutically acceptable salts, containing pharmaceutically acceptable amine, selected from ethylenediamine, piperazine, benzathine or choline and {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidin-5yl}acetic acid.

43 cl, 21 dwg, 4 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel crystalline forms I, II and amorphous form of {4,6-bis(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzyl)pyrimidin-5-yl}acetic acid.

EFFECT: invention relates to pharmaceutical composition, containing crystalline form I of compound and to application of crystalline form I for treatment, prevention or relief of one or more symptoms of disease, mediated by CRTH2, associated with eosinophils, basophils, where disease is selected from asthma, allergic asthma, asthma, induced by physical effort, allergic rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity.

16 cl, 11 dwg, 8 tbl,11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a quinazoline derivative of general formula [1], or a pharmaceutically acceptable salt thereof [1], where R1-R6 assume values given claim 1, except compounds in which R5 is hydrogen and R6 is -NH2. The invention also relates to a pharmaceutical composition having the activity of an antipruritic agent, containing as an active ingredient said quinazoline derivative or pharmaceutically acceptable salt thereof.

EFFECT: obtaining a novel quinazoline derivative with low irritant action on skin and excellent action of significant suppression of scratching behaviour, as well as an antipruritic agent containing such a quinazoline derivative as an active ingredient.

9 cl, 250 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives having PGDS inhibiting properties. In formula (I): (I), R1 denotes phenyl or a 5- or 6-member heteroaryl containing 1-3 heteroatoms selected from N, O and S, each optionally having one or more of the following independent substitutes: halogen, (C1-C6)-alkyl, or (C1-C4)-haloalkyl; R2 denotes hydrogen or (C1-C6)-alkyl, which is optionally substituted with one or more halogens; R3 denotes hydrogen, (C1-C6)-alkyl or phenyl; R4 denotes C6-cycloalkyl, phenyl, a 6-member heterocyclyl containing one N heteroatom, a 6-member heteroaryl containing one N heteroatom, -C(=O)-NY1Y2, -C(=S)-NY1Y2, or -C(=O)-R5, where the phenyl, 6-member heteroaryl or 6-member heterocyclyl group optionally has one or more independent substitutes R6, or R3 and R4 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclyl containing one or two heteroatoms selected from N, O and S, a 6-member heterocyclenyl containing two or three N heteroatoms, a 5-member monocyclic or 9-member bicyclic heteroaryl containing one to three N heteroatoms, phenylheterocyclyl, where the heterocyclyl is 5- or 6-membered and contains one or two heteroatoms selected from N and O, each optionally having one or more independent substitutes R6. Values of R5, R6, Y1, Y2 are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds.

EFFECT: improved method.

15 cl, 227 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new benzimidazole derivatives of general formula (I) or to its pharmacologically acceptable salts wherein R1 represents a C6-aryl group which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), or a heterocyclic group which represents pyridyl, dihydrobenzofuranyl, 1,3-benzodioxolyl, tetrahydropyranyl, tetrahydrofuranyl which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), R2 represents a C1-C6 alkyl group, R3 represents a C6-aryl group which can be substituted by 1-2 groups optionally specified in a group of substitutes (a), Q represents a group represented by formula =CH-, or a nitrogen atom and a group of substitutes (a) represents a group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a carboxyl group, a C2-C7 alkylcarbonyl group, a C2-C7 alkoxycarbonyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, an amino group, a 4-morpholinyl group and a di-C1-C6 alkyl)amino group. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I), to a PPARγ activator/modulator based on the compound of formula (I), to using the compound of formula (I), to a method of reducing blood glucose, to a method of activating PPARγ, a method of treating and/or preventing said pathological conditions.

EFFECT: there are produced new benzimidazole derivatives showing PPARγ modulatory activity.

41 cl, 2 dwg, 6 tbl, 76 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 2,3-substituted pyrazine sulphonamides of formula (I), use thereof in treating allergic diseases, inflammatory dermatosis, immonological disorders and neurodegenerative disorders, as well as pharmaceutical compositions, having CRTH2 receptor inhibiting action and inhibiting chemoattractant receptor, homologous to the molecule expressed on T-helpers 2. in general formula .

A is selected from a group consisting of

, n denotes an integer independently selected from 0, 1, 2, 3 or 4; m equals 1 or 2; B is selected from a group consisting of phenyl or piperazinyl; R1 denotes hydrogen; R2 denotes phenyl, where R2 is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl; R3 is selected from a group consisting of (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl, where each of said (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, thioalkoxy and thioalkyl, or where said aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl can be condensed with one or more aryl, heteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl groups and can be substituted with one or more substitutes selected from a group consisting of (C1-C6)alkyl, alkoxy, aryl, heteroaryl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulphoxy, sulphonyl, sulphonamide and trihaloalkyl; R7 is selected from a group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, carboxyl, cyano, amino and hydroxy; aryl is selected from phenyl or naphthyl; and heteroaryl is selected from pyridyl, indolyl, 3H-indolyl, benzimidazolyl, quinolizinyl.

EFFECT: high efficiency of using the compounds.

4 cl, 10 dwg, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new acid dihydrogenphosphate of 2-(3-{6-[2-(2,4-dichlorophenyl)ethylamino]-2-methoxypyrimidine-4-yl}phenyl)-2-methylpropionic acid of formula optionally in a crystalline form exhibiting cAMP inhibitor properties. Also, the invention refers to a pharmaceutical composition.

EFFECT: compound can find application for treating the diseases associated with cell expression of prostaglandin D2 in such diseases, as allergic rhinitis, bronchial asthma, allergic conjunctivitis, etc.

3 cl, 12 dwg, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new compounds of formula (1) or its pharmaceutically acceptable salts, with properties of antagonist CXCR2 of human neutrophils receptor. In formula (1) R1 represents a group selected from C1-8alkyl; where this group is possibly substituted with 1 substituent, independently selected from phenyl or 5-6-unit heteroaryl, containing 1-2 heteroatoms selected from N, S; where phenyl and heteroaryl are possibly substituted by 1, 2 or 3 substitutors, independently selected from halogeno, cyano, -OR4, -COOR7, -SO2R10, C1-6alkyl; X represents -CH2-, oxygen, sulfur; R2 represents C3-7carbocyclil, possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4; or R2 represents 5-unit ring, containing 2 heteroatoms, selected from O, -NR8, and where this ring is possibly substituted with 1 substituent, independently selected from C1-3alkyl; or R2 represents group, selected from C1-8alkyla, where this group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-C1-6alkylcarbamoyl, N,N-di(C1-6alkyl)carbamoyl, carboxy, -NR8COR9 and -CONR5R6; R3 represents group -NR5R6, or R3 represents phenyl, possibly condensed with 6-unit heterocyclil, containing nitrogen, naphthyl, 4-8-unit monocyclic heterocyclil, containing 1-3 heteroatoms, selected from N, O, S, possibly condensed with benzole ring or 3-unit nitrogen-containing ring, where heteroring may be non-saturated, partially or fully saturated, and one or more than one circular atom of carbon may form carbonyl group, and where each phenyl or heterocyclil group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, phenyl, 5-6-unit heteroaryl, containing 1-2 atoms of nitrogen, -OR4, -NR5R6, -CONR5R6, -COR7, -COR20, -COOR7, -NR8COR9, -SO2R10, -SO2NR5R6 or C1-6alkyl [possibly additionally substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR20, -COOR20, -NR18R19, -CONR18R19, phenyl or 5-6-unit of monocyclic heteroaryl, containing 1-2 heteroatoms O, N, S, or 10-unit bicyclic heteroaryl, containing 1 heteroatom O, where heteroring may be partially or fully saturated, and where each phenyl or heteroaryl is group possibly substituted with 1 or 2 substituents, independently selected from halogeno, cyano, nitro, -OR20, -NR5R6, -COOR7, -NR8COR9, 6-unit heterocyclil, containing two heteroatoms, selected from O and N, 5-unit heteroaryl, containing 3 heteroatoms N, C1-6alkyl (possibly additionally substituted with 1 substituent, independently selected from halogeno, cyano, nitro, -OR20, -COOR20; or R3 represents group, selected from C3-7carbocyclil, C1-8alkyl, where this group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6; R4 represents hydrogen; R5 and R6 independently represent hydrogen or group, selected from C1-6alkyl and monocyclic 6-unit saturated heterocyclil containing 1 heteroatom N; where C1-6alkyl is possibly substituted with 1 substituent, independently selected from -NR15R16; or R5 and R6 together with atom of nitrogen, to which they are linked, form 4-7-unit saturated heterocyclic circukar system, possibly containing additional heteroatom, selected from oxygen, -SO(n)- (where n equals 0, 1 or 2) and atoms of nitrogen; R10 represents hydrogen or group, selected from C1-6alkyl; and each of R7, R8, R9, R15, R16, R17 independently represents hydrogen, C1-6alkyl; R18, R19 and R20 represent hydrogen or group, selected from C1-6alkyl, where this group is possibly substituted with 1 substituent, independently selected from -NR8R9, -CONR8R9.

EFFECT: production of new compounds, which may find application in production of medicinal agent for use in treatment of diseases and disorders mediated with chemokines, such as asthma, allergic rhinitis, chronic obstructive pulmonary disease, inflammatory intestine disease, irritable colon syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis or psoriasis, and also for treatment of cancer.

12 cl, 155 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I) or to its salts: , where R1 is ,, in which n is an integer ranging from 0 to 6; Y is aryl, where the said aryl is optionally substituted at a substitutable position with one or more substitutes selected from a group which consists of halogen or C1-6alkyl, optionally substituted with mono-, di- or trihalogen; R2 is hydrogen; R3 is hydrogen or halogen; and R4 is hydrogen. The invention also relates to derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I-i) or to its salts, to a drug, to use of compounds in paragraph 1, as well as to a drug in form of a standard single dosage.

EFFECT: obtaining new biologically active compounds, which are active towards CRTH2.

23 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of invention refers to ophthalmic compositions containing protease inhibition peptide substrates. The ophthalmic compositions contains a peptide substrate in a solution in the amount of approximately 0.01 wt/vol. % to 10 wt/vol. %, and said substrate is specified in a group consisting of gelatin, ovomacroglobulin, collagen and casein in an ophthalmically acceptable carrier. The composition additionally contains galactomannan and borate. The invention also describes a method for using the composition for treating dry eye.

EFFECT: group of invention provides higher viability and lower water loss of corneal epitheliocytes.

12 cl, 12 dwg, 11 ex

Up!