Peptide composition containing propylene glycol optimal for manufacturing and application in injection devices

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to pharmaceutical compositions containing a peptide and propylene glycol, to methods of preparing such compositions, and also concerns methods of reducing contamination of injection devices by a peptide composition and reducing sediment formation in the production equipment during manufacturing of the peptide composition. The agonist GLP-1 is used as said peptide in the composition.

EFFECT: reduced contamination of the injection devices during injection.

23 cl, 6 ex, 7 dwg

 

The technical FIELD

The present invention relates to pharmaceutical compositions containing the peptide and propylene glycol, to methods of preparing such compositions and to the use of such compositions for the treatment of diseases and conditions for which illustrates the application of the peptide contained in these compositions. The present invention also relates to methods of reducing the clogging of the injection device peptide composition and reduce sediment production equipment in the manufacturing process of the peptide composition.

PRIOR art

Including means providing isotonicity, pharmaceutical compositions containing the peptides, widely known, and one of the most commonly used in such compositions isotonic means is mannitol. However, the authors of the present invention have observed that mannitol causes problems in the production process of the peptide compositions, because it crystallizes, forming precipitation in industrial equipment and in the final product. Such precipitation increase the need for cleaning equipment in the production process of the composition, resulting in reduced production capacity. In addition, such precipitation can lead to reduced yield of the final product, as you may need to discard vials/ampoules containing peptide composition, if they will be present in the particles. Finally, the authors present invention have observed that the presence of mannitol in the peptide compositions intended for administration by injection, leads to clogging of the injection device.

Accordingly, it is desirable to find an isotonic agent, an alternative to mannitol, for inclusion in the compositions containing the peptides, and more specifically for inclusion in the peptide composition introduced by injection.

The INVENTION

The authors of the present invention found that the peptide compositions containing propylene glycol concentrations in some form less precipitation in industrial equipment and in the final product, and less litter injection device. Compositions according to the present invention can be prepared using any of the peptide, and they are also physically and chemically stable, which ensures their stability during storage and suitability for invasive (e.g., via injection, subcutaneous injection, intramuscular injection, intravenous injection or infusion) and noninvasive (e.g., nasal, oral, pulmonary, transdermal or transmucosal, e.g. buccal) techniques.

Thus, the present invention relates to pharmaceutical is some compositions, containing the peptide and propylene glycol, which contains propylene glycol at a concentration of 1-100 mg/ml, and the pH of the composition is in the range from 7 to 10. In a preferred embodiment of the invention the pharmaceutical composition according to the present invention also includes a buffering agent and a preservative.

The present invention also relates to methods of manufacturing pharmaceutical compositions according to the present invention.

In one of the embodiments of the present invention, the method of preparation of the peptide composition includes:

a) preparing a first solution by dissolving the preservative, propylene glycol, and a buffering agent in water;

b) preparing a second solution by dissolving the peptide in water;

C) mixing the first and second solutions; and

g) adjusting the pH of the mixture obtained in stage b), until the desired pH values.

In another embodiment of the present invention, the method of preparation of the peptide composition includes:

a) preparing a first solution by dissolving the preservative and buffer substances in the water;

b) adding propylene glycol to the first solution;

C) mixing the first solution with the second solution containing the peptide dissolved in water; and

g) adjusting the pH of the mixture obtained in stage b), until the desired pH values.

In the following embodiment of the present invention, the method of preparation of the peptide composition includes:

a) preparation of a solution by dissolving the preservative, a buffering agent and propylene glycol in water;

b) adding the peptide to the solution obtained in stage a); and

C) regulation of the pH of the solution obtained in stage b), until the desired pH values.

The present invention also relates to methods of treatment using the pharmaceutical compositions according to the present invention, in which the composition is introduced in a quantity effective to combat the disease, condition or disorder, which shows the introduction of the peptide contained in the composition.

In addition, the present invention relates also to a method of reducing deposits on the surfaces of production equipment in the manufacturing process of the peptide composition, which instead means to ensure isotonicity, previously used in such compositions, introducing propylene glycol at a concentration of from 1 to 100 mg/ml

In one of the embodiments of the present invention, the degree of reduction of deposits on the surfaces of production equipment in the manufacturing process of the composition containing propylene glycol, compared to the sediments is, observed when using the composition containing the previously used tool to ensure isotonicity, measured in the experiment on the model of the filling of such equipment.

The present invention also relates to a method of reducing sludge formation in the final product in the manufacturing process of the peptide composition, which instead means to ensure isotonicity, previously used in such compositions, introducing propylene glycol at a concentration of from 1 to 100 mg/ml

In one of the embodiments of the present invention, the degree of reduction of sludge formation in the final product is measured by the decrease in the number of vials and/or vials with a composition containing propylene glycol, which must be destroyed because of the presence of precipitation, compared with the number of vials and/or vials with a composition containing the previously used tool to ensure isotonicity, which must be destroyed because of the presence of precipitation.

The present invention also relates to a method of reducing the clogging of the injection device peptide composition, which instead means to ensure isotonicity, previously used in such compositions, the composition is administered propylene glycol at a concentration of from 1 to 100 mg/ml

In one embodiment, the implementation of this and is gaining a degree of reducing the clogging of the injection device composition, contains propylene glycol, compared with the contamination observed in the case of the composition containing the previously used tool to ensure isotonicity, measured in the experiment on the model of the use of such a device.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 shows a photograph of dried slides drops compositions placebo (containing no peptide), representing (from left to right): composition not containing means to ensure isotonicity (i.e. containing only water, preservative and buffering agent), the composition containing as a means to ensure isotonicity mannitol, sorbitol, xylitol, sucrose or glycerol, and the right glass contains mannitol with peptide Arg34, Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-GLP-1(7-37).

Figure 2 presents svetotekhnicheskoe image several dried drops compositions placebo containing as a means to ensure isotonicity (left to right) mannitol, arginine, Inositol, or glycerol.

Figure 3 presents svetotekhnicheskoe image clogged needles filled compositions placebo containing as a means to ensure isotonicity of the myo-Inositol, maltose or glycerin.

Figure 4 presents svetotekhnicheskoe image clogged needles filled compositions placebo containing as a means to ensure isotonicity glycine, lactose or mannitol.

Figure 5 shows a photograph of the water-filling equipment after a 24-hour experiment on the model filling equipment composition on the basis Arg34, Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-GLP-1(7-37), containing myo-Inositol.

Figure 6 presents pictures of sediments filling-bottling equipment after a 24-hour experiment on the model filling equipment placebo composition containing mannitol.

Figure 7 presents pictures of deposits on the needle, filled compositions based Arg34,Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-GLP-1(7-37)containing mannitol (upper figure) and propylene glycol (bottom figure).

INFORMATION CONFIRMING the POSSIBILITY of carrying out the INVENTION

The present invention relates to pharmaceutical compositions containing the peptide or mixture of peptides and propylene glycol, and the final concentration of propylene glycol in the composition is from 1 to 100 mg/ml and the final pH value of the composition is in the range from 7 to 10.

It is shown that the pharmaceutical compositions according to the present invention are optimal for the production process, because they produce fewer sieges is economical in production equipment in comparison with compositions, containing other means to ensure isotonicity, the results of measurements in experiments on models fill the equipment described in the Examples, moreover, found that the pharmaceutical compositions according to the present invention is optimal for use in injection devices, as they help reduce clogging of the injection device in comparison with compositions containing other means to ensure isotonicity, the results of measurements in experiments on models use injection devices described in the Examples.

Compositions according to the present invention can be prepared using any peptide, examples of such peptides include, but are not limited to, glucagon, human growth hormone (hGH), insulin, Aprotinin, Factor VII, tissue activator of plasminogen (TPA), Factor VIIa, FFR Factor VIIa, heparinase, ACTH, heparinase protein, corticotropin-releasing factor, angiotensin, calcitonin, and the like peptide-1, like peptide-2, insulin-like growth factor-1, insulin-like growth factor-2, fibroblast growth factors, gastric inhibitory peptide, hormone-releasing factor, growth hormone, peptide, activates the pituitary adenylate cyclase, secretin, enterogastrone, somatostatin, somatomedin, parathyroid the th hormone thrombopoietin, erythropoietin, hypothalamic releasing factors, prolactin, thyroid-stimulating hormone, endorphins, enkephalins, vasopressin, oxytocin, opioids, DPP IV (dipeptidyl peptidase IV), interleukins, immunoglobulins, inhibitors of complement inhibitors semipretioase, cytokines, receptors, cytokines, platelet-derived growth factor (PDGF), tumor necrosis receptor factors, tumor necrosis, growth factors and their analogues and derivatives, with each of these peptides is an alternative implementation of the present invention.

In this application the definition of "similar" is used to denote a peptide in which one or more amino acid residues of the original peptide is replaced by other amino acid residues and/or to the original peptide has one or more amino acid residues. This addition can take place either at the N-terminal end or the C-terminal end of the original peptide, or at both ends. In a typical case of "similar" is a peptide in which 6 or less amino acids substituted and/or added and/or removed from the original peptide, more preferably a peptide in which 3 or less amino acids substituted and/or added and/or removed from the original peptide, and most preferably a peptide in which one aminoxy the lot replaced, and/or added and/or removed from the original peptide.

In this application, the term "derivative" is used to refer to peptide or its counterpart, which is chemically modified by introducing an organic substituent, for example ester, alkyl or lipophilic functional group at one or more amino acid residues of the peptide or its equivalent.

In one form of implementation of the present invention the peptide is intended for inclusion in the composition according to the present invention is an agonist of GLP-1 like peptide-1), under "agonist GLP-1" is understood as any peptide that is fully or partially activate the receptor for GLP-1 person. In a preferred embodiment of the invention, the agonist of GLP-1 is any peptide that binds to a receptor LGP-1, preferably with an affinity constant (KD) or effective concentration (EC50) less than 1 μm, for example less than 100 nm, the results of measurement methods known in the art (see, for example, WO 98/08871), and detects insulinotropic activity, and insulinotropic activity can be measured in vivo or in vitro using assays known to specialists in this field of technology. For example, the agonist of GLP-1 may be introduced to the animal, and after some time can be measured insulin concentration.

Methods of identifying agonists of GLP-1 is described in WO 93/19175 (Novo Nordisk A/S), and examples of suitable analogues and derivatives of GLP-1, which can be used according to the present invention, include the examples described in WO 99/43705 (Novo Nordisk A/S), WO 99/43706 (Novo Nordisk A/S), WO 99/43707 (Novo Nordisk A/S), WO 98/08871 (analogues with lipophilic substituents) and in WO 02/46227 (analogues, merged with serum albumin or Fc fragment of Ig) (Novo Nordisk A/S), WO 99/43708 (Novo Nordisk A/S), WO 99/43341 (Novo Nordisk A/S), WO 87/06941 (The General Hospital Corporation), WO 90/11296 (The General Hospital Corporation), WO 91/11457 (Buckley et al.), WO 98/43658 (Eli Lilly & Co.), EP 0708179-A2 (Eli Lilly & Co.), EP 0699686-A2 (Eli Lilly & Co.), WO 01/98331 (Eli Lilly & Co.).

In one of the embodiments of the present invention, the agonist of GLP-1 is selected from the group consisting of GLP-1(7-36)-amide, GLP-1(7-37), analogue of GLP-1(7-36)-amide, an analogue of GLP-1(7-37) or derivatives of any of these substances.

In one of the embodiments of the invention, the agonist of GLP-1 is a derivative of GLP-1(7-36)-amide, GLP-1(7-37), analogue of GLP-1(7-36)-amide, or analog of GLP-1(7-37), which contains a lipophilic Deputy.

In this embodiment of the present invention derived GLP-1 preferably contains three lipophilic substituent, more preferably two lipophilic substituent, and most preferably one lipophilic Deputy attached to the original peptide (i.e. GLP-1(7-36)-amide, GLP-1(7-37), analogue of GLP-1(7-36)-amide, or an analog, GLP-1(7-7)), each lipophilic Deputy preferably contains 4-40 carbon atoms, more preferably 8-30 carbon atoms, even more preferably 8-25 carbon atoms and most preferably 14 to 18 carbon atoms.

In one variant of the invention, the lipophilic Deputy contain partially or fully hydrogenated cyclopentanophenanthrene skeleton.

In one variant of the invention, the lipophilic Deputy is unbranched or branched alkyl group.

In one variant of the invention, the lipophilic Deputy is an acyl group, an unbranched or branched fatty acids. Preferably lipophilic Deputy is an acyl group having the formula CH3(CH2)nCO-, where n is an integer from 4 to 38, preferably an integer from 12 to 38, and most preferably has the formula CH3(CH2)12CO, CH3(CH2)14CO, CH3(CH2)16CO, CH3(CH2)18CO, CH3(CH2)20CO - or CH3(CH2)22WITH-. In a more preferred variant of the invention, the lipophilic Deputy is the deletion. In the most preferred embodiment of the invention the lipophilic mixture is ielem is hexadecanol.

In one of the embodiments of the present invention the lipophilic substituent has a negatively charged group such as a carboxylic acid group. For example, lipophilic Deputy may be acyl group, an unbranched or branched alkane-α,ω-dicarboxylic acid, with formula noos(CH2)mCO-, where m is an integer from 4 to 38, preferably an integer from 12 to 38, and most preferably has the formula HOOC(CH2)14CO-, HOOC(CH2)16CO-, HOOC(CH2)18CO-, HOOC(CH2)20CO - or noos(CH2)22WITH-.

In derivatives of GLP-1 according to the present invention the lipophilic substituent (or substituents) contains a functional group that can be attached to one of the following functional groups of the amino acids of the original GLP-1 peptide:

(a) to the amino group that is connected to the alpha carbon atom of the N-terminal amino acids;

(b) to the carboxyl group connected to the alpha carbon atom of the C-terminal amino acids;

(C) to the Epsilon-amino group of any of the residues Lys;

(g) to the carboxyl group of the R group of any of the residues Asp and Glu;

(d) to the hydroxyl group of the R group of any of the residues Tyr, Ser and Thr;

(e) to the amino group of the R group of any of the residues Trp, Asn, Gln, Arg and His, or

(W) to the thiol group of the R group of any of the Cys residues.

In one the m variant of the invention, the lipophilic Deputy attached to the carboxyl R-group of any residue Asp or Glu.

In one variant of the invention, the lipophilic Deputy attached to the carboxyl group connected to the alpha carbon atom of the C-terminal amino acids.

In the most preferred embodiment of the invention the lipophilic Deputy attached to the Epsilon-amino group of any of the residues Lys.

In a preferred embodiment of the present invention lipophilic Deputy attached to the original GLP-1 peptide by means of the intermediate group (spacer). Intermediate group must contain at least two functional groups, one of which is connected with the functional group of the lipophilic substituent, and the other functional group of the original GLP-1 peptide.

In one of the embodiments of the invention, the intermediate group is an amino acid residue except Cys or Met, or a dipeptide, such as Gly-Lys. In the context of the present invention, the phrase "dipeptide, for example, - Gly-Lys" means any combination of two amino acids except Cys or Met, preferably dipeptide in which the C-terminal amino acid residue is Lys, His, or Trp, preferably Lys, a N-terminal amino acid residue is Ala, Arg, Asp, Asn, Gly, Glu, Gln, lle, Leu, Val, Phe, Pro, Ser, Tyr, Thr, Lys, His, or Trp. Preferably the amino group of the original peptide forms an amide bond with carboxyl the Noah group of amino acid residue or dipeptide spacer, and the amino group of amino acid residue or dipeptide spacer forms an amide bond with a carboxyl group of the lipophilic substituent.

Preferred intermediate groups (spacers) are lysine, glutamic, aspartic, glycine, beta-alanine and gamma-aminobutanol groups, each of which represents a different variant embodiment of the invention. The most preferred spacers are glutamine and beta-alanine group. If the spacer is Lys, Glu or Asp, its carboxyl group may form an amide bond with the amino group of amino acid residue and the amino group may form an amide bond with a carboxyl group of the lipophilic substituent. If the spacer is used Lys, in some cases between the ε-amino group of Lys and lipophilic Deputy may be introduced by another spacer. In one form of implementation of the present invention such additional spacer is succinic acid, which forms an amide bond with the ε-amino group of Lys and the amino group present in the lipophilic substituent. In another form of implementation of such further spacer is Glu or Asp which forms one amide bond with the ε-amino group of Lys and another amide bond with a carboxyl group present in the lipophilic for whom istitle, that is lipophilic Deputy is Nε-acylated residue lysine.

In one of the embodiments of the invention the spacer is a group of unbranched alkane-α,ω-dicarboxylic acids containing from 1 to 7 methylene groups, and the spacer forms a bridge between the amino group of the original peptide and the amino group of lipophilic substituent. Preferably the spacer is succinic acid.

In one variant of the invention, the lipophilic Deputy together with the attached spacer is a group having the formula CH3(CH2)pNH-(CH2)qCO-, where p is an integer from 8 to 33, preferably from 12 to 28, and q is an integer from 1 to 6, preferably 2.

In one variant of the invention, the lipophilic Deputy together with the attached spacer is a group having the formula CH3(CH2)rCO-NHCH(COOH)(CH2)2CO-, where r is an integer from 4 to 24, preferably from 10 to 24.

In one variant of the invention, the lipophilic Deputy together with the attached spacer is a group having the formula CH3(CH2)sCO-NHCH((CH2)2COOH)CO-, where s is an integer from 4 to 24, preferably from 10 to 24.

In one of the in the of the ways the invention, the lipophilic Deputy is a group, having the formula COOH(CH2)tCO-, where t is an integer from 6 to 24.

In one variant of the invention, the lipophilic Deputy together with the attached spacer is a group having the formula-NHCH(COOH)(CH2)4NH-(CH2)uCH3where u is an integer from 8 to 18.

In one variant of the invention, the lipophilic Deputy together with the attached spacer is a group having the formula CH3(CH2)vCO-NH-(CH2)zWITH, where v is an integer from 4 to 24, a z is an integer from 1 to 6.

In one variant of the invention, the lipophilic Deputy together with the attached spacer is a group having the formula-NHCH(COOH)(CH2)4NH-COCH((CH2)2COOH)NH-CO(CH2)wCH3where w is an integer from 10 to 16.

In one variant of the invention, the lipophilic Deputy together with the attached spacer is a group having the formula-NHCH(COOH)(CH2)4NH-CO(CH2)2CH(COOH)NHCO(CH2)xCH3where x is zero or an integer from 1 to 22, preferably from 10 to 16.

In one of the embodiments of the present invention is an agonist of GLP-1 is Arg34, Lys26(Nε-(γ-Glu(Nα-Gex is decanoyl)))-GLP-1(7-37).

In one of the embodiments of the present invention, the agonist of GLP-1 is selected from the group consisting of Gly8-GLP-1(7-36)-amide, Gly8-GLP-1(7-37), Val8-GLP-1(7-36)-amide, Val8-GLP-1(7-37), Val8Asp22-GLP-1(7-36)-amide, Val8Asp22-GLP-1(7-37), Val8Glu22-GLP-1(7-36)-amide, Val8Glu22-GLP-1(7-37), Val8Lys22-GLP-1(7-36)-amida, Val8Lys22-GLP-1(7-37), Val8Arg22-GLP-1(7-36)-amide, Val8Arg22-GLP-1(7-37), Val8His22-GLP-1(7-36)-amide, Val8His22-GLP-1(7-37), their analogues and derivatives of any of these substances.

In another one of the embodiments of the present invention, the agonist of GLP-1 is selected from the group consisting of Arg26-GLP-1(7-37); Arg34-GLP-1(7-37); Lys36-GLP-1(7-37); Arg26,34Lys36-GLP-1(7-37); Arg26,34-GLP-1(7-37); Arg26,34Lys40-GLP-1(7-37); Arg26Lys36-GLP-1(7-37); Arg34Lys36-GLP-1(7-37); Val8Arg22-GLP-1(7-37); Met8Arg22-GLP-1(7-37); Gly8His22-GLP-1(7-37); Val8His22-GLP-1(7-37); Met8His22-GLP-1(7-37); His37-GLP-1(7-37); Gly8-GLP-1(7-37); Val8-GLP-1(7-37); Met8-GLP-1(7-37); Gly8Asp22-GLP-1(7-37); Val8Asp22-GLP-1(7-37); Met8Asp22-GLP-1(7-37); Gly8Glu22-GLP-1(7-37); Val8Glu22-GLP-1(7-37); Met8Glu22-GLP-1(7-37); Gly8Lys22-GLP-1(7-37); Val8Lys22-GLP-1(7-37); Met8Lys22-GLP-1(7-37); Gly8Arg22-GLP-1(7-37); Val8Lys22His 37-GLP-1(7-37); Gly8Glu22His37-GLP-1(7-37); Val8Glu22His37-GLP-1(7-37); Met8Glu22His37-GLP-1(7-37); Gly8Lys22His37-GLP-1(7-37); Met8Lys22His37-GLP-1(7-37);Gly8Arg22His37-GLP-1(7-37); Val8Arg22His37-GLP-1(7-37); Met8Arg22His37-GLP-1(7-37); Gly8His22His37-GLP-1(7-37); Val8His22His37-GLP-1(7-37); Met8His22His37-GLP-1(7-37); Gly8His37-GLP-1(7-37); Val8His37-GLP-1(7-37); Met8His37-GLP-1(7-37); Gly8Asp22His37-GLP-1(7-37); Val8Asp22His37-GLP-1(7-37); Met8Asp22His37-GLP-1(7-37); Arg26-GLP-1(7-36)-amide; Arg34-GLP-1(7-36)-amide; Lys36-GLP-1(7-36)-amide; Arg26,34Lys36-GLP-1(7-36)-amide; Arg26,34-GLP-1(7-36)-amide; Arg26,34Lys40-GLP-1(7-36)-amide; Arg26Lys36-GLP-1(7-36)-amide; Arg34Lys36-GLP-1(7-36)-amide; Gly8-GLP-1(7-36)-amide; Val8-GLP-1(7-36)-amide; Met8-GLP-1(7-36)-amide; Gly8Asp22-GLP-1(7-36)-amide; Gly8Glu22His37-GLP-1(7-36)-amide; Val8Asp22-GLP-1(7-36)-amide; Met8Asp22-GLP-1(7-36)-amide; Gly8Glu22-GLP-1(7-36)-amide; Val8Glu22-GLP-1(7-36)-amide; Met8Glu22-GLP-1(7-36)-amide; Gly8Lys22-GLP-1(7-36)-amide; Val8Lys22-GLP-1(7-36)-amide; Met8Lys22-GLP-1(7-36)-amide; Gly8His22His37-GLP-1(7-36)-amide; Gly8Arg22-GLP-1(7-36-amide; Val8Arg22-CLP-1(7-36)-amide; Met8Arg22-GLP-1(7-36)-amide; Gly8His22-GLP-1(7-36)-amide; Val8His22-GLP-1(7-36)-amide; Met8His22-GLP-1(7-36)-amide; His37-GLP-1(7-36)-amide; Val8Arg22His37-GLP-1(7-36)-amide; Met8Arg22His37-GLP-1(7-36)-amide; Gly8His37-GLP-1(7-36)-amide; Val8His37-GLP-1(7-36)-amide; Met8His37-GLP-1(7-36)-amide; Gly8Asp22His37-GLP-1(7-36)-amide; Val8Asp22His37-GLP-1(7-36)-amide; Met8Asp22His37-GLP-1(7-36)-amide; Val8Glu22His37-GLP-1(7-36)-amide; Met8Glu22His37-GLP-1(7-36)-amide; Gly8Lys22His37-GLP-1(7-36)-amide; Val8Lys22His37-GLP-1(7-36)-amide; Met8Lys22His37-GLP-1(7-36)-amide; Gly8Arg22His37-GLP-1(7-36)-amide; Val8His22His37-GLP-1(7-36)-amide; Met8His22His37-GLP-1(7-36)-amide; and their derivatives.

In another one of the embodiments of the present invention, the agonist of GLP selected from the group consisting of Val8Trp19Glu22-GLP-1(7-37), Val8Glu22Val25-GLP-1(7-37), Val8Tyr16Glu22-GLP-1(7-37), Val8Trp16Glu22-GLP-1(7-37), Val8Leu16Glu22-GLP-1(7-37), Val8Tyr18Glu22-GLP-1(7-37), Val8Glu22His37-GLP-1(7-37), Val8Glu22lle33-GLP-1(7-37), Val8Trp16Glu22Val25lle33-GLP-17-37), Val8Trp16Glu22lle33-GLP-1(7-37), Val8Glu22Val25lle33-GLP-1(7-37), Val8Trp16Glu22Val25-GLP-1(7-37), their analogues and derivatives of any of these substances.

In another one of the embodiments of the present invention is an agonist of GLP-1 is the basis 4 basis 3, the analogue of basis 4 or basis 3 or a derivative of any of these substances.

Examples of Akindinov and their analogs, derivatives and fragments, which can be included in the present invention, is described in WO 97/46584, US 5424286 and WO 01/04156. In the US 5424286 described method of stimulation of insulin secretion by using the polypeptide of the basis. Described polypeptides exendin include HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGX, where X=P or Y, and HX1X2GTFITSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS where HH=SD (basis 3) or GE (basis 4)). In WO 97/46584 described truncated variants of the peptide of the basis. Described peptides enhance the secretion and biosynthesis of insulin, but reduce the secretion and biosynthesis of glucagon. In WO 01/04156 described analogs and derivatives of the basis 4 and obtaining these molecules. Analogues of basis 4, stabilized by fusion to serum albumin or Fc fragment of Ig, described in WO 02/46227.

In one of the embodiments of the present invention similar to the basis 4 is HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-amide.

If the peptide is intended for inclusion in the composition according to this is the overarching invention, is an agonist of the GLP-1 agonist GLP-1 is contained in the composition at a concentration from about 0.1 mg/ml to about 100 mg/ml, more preferably in a concentration from about 0.1 mg/ml to about 50 mg/ml and most preferably in a concentration from about 0.1 mg/ml to about 10 mg/ml

In one embodiment of the present invention the peptide is designed to be incorporated into the composition according to the present invention, is insulin "insulin" refers to human insulin [while under the "human insulin" understand insulin having the amino acid sequence shown in the work D.S.H.W. Nicol and LF. Smith: Nature, (1960) 4736:483-485, which is incorporated in this application by reference], analogues of human insulin, a derivative of human insulin or mixtures thereof, with examples of analogs and derivatives of insulin described in EP 0792290 (Novo Nordisk A/S), EP 0214826 and EP 0705275 (Novo Nordisk A/S), US 5,504,188 (Eli Lilly), EP 0368187 (Aventis), U.S. patents 5,750,497 and 6,011,007, EP 375437 and EP 383472, and these insulins may include (but are not limited to NPH-insulin, Lys β29 (Nε-deletion) (B30)-human insulin, LysB29-(Nε-(γ-glutamyl-Nα-lithocholyl) (B30)-human insulin, NB29-actinomycosis, a mixture in a ratio of 30/70 fast-acting insulin-zinc (SemiLente®) insulin-zinc long-acting (Ultralente®), which is sold under the trade name Lnte®, insulin glargin (Lantus®) or insulin-zinc long-acting (Ultralente®), LysB28 ProB29 human insulin (Humalog®), AspB28 human insulin, insulin aspart (Novolog®), or a mixture in the ratio 30/70 insulin aspart and insulin aspart Protamine (NovoMix®).

In one of the embodiments of the invention the insulin is a derivative of human insulin or insulin analogue and derivative contains at least one lysine residue, and lipophilic Deputy attached to the Epsilon-amino group of lysine residue.

In one of the embodiments of the invention, the lysine residue that is attached lipophilic Deputy, is in position B28 peptide of insulin.

In an alternative embodiment of the present invention, the lysine residue that is attached lipophilic Deputy, is in position V peptide of insulin.

In another one of the embodiments of the present invention lipophilic Deputy is an acyl group corresponding carboxylic acid having at least 6 carbon atoms.

In another preferred embodiment of the present invention lipophilic Deputy is an acyl group, a branched or unbranched, which corresponds to a carboxylic acid having a chain of carbon atoms in length from 8 to 24 atoms.

In the following a preferred embodiment of the present invention lipophilic Deputy is an acyl group corresponding to a fatty acid having at least 6 carbon atoms.

In the following a preferred embodiment of the present invention lipophilic Deputy is an acyl group corresponding to a linear saturated carboxylic acid having from 6 to 24 carbon atoms.

In the following a preferred embodiment of the present invention lipophilic Deputy is an acyl group corresponding to a linear, saturated carboxylic acid having from 8 to 12 carbon atoms.

In the following a preferred embodiment of the present invention lipophilic Deputy is an acyl group corresponding to a linear, saturated carboxylic acid having from 10 to 16 carbon atoms.

In the following a preferred embodiment of the present invention lipophilic Deputy is oligoastrocytomas group containing up to 10, preferably up to 5, oxyethylene monomers.

In the following a preferred embodiment of the present invention lipophilic Deputy is oligoastrocytomas group containing up to 10, preferably up to 5, oxypropylene monomer is.

In one of the preferred embodiments the invention relates to a derivative of human insulin in which the B30 amino acid residue is deleted or is any amino acid residue which can be encoded by the genetic code except Lys, Arg and Cys; amino acid residues A21 and B3 are, independently from each other, residues of any amino acids that can be encoded by the genetic code except Lys, Arg and Cys; PheB1can be removed; the ε-amino group of LysB29has lipophilic Deputy, which contains at least 6 carbon atoms; and 2-4 ion Zn2+can be associated with each insulin hexameron, provided that, when B30 is Thr or Ala, A21 and B3 are simultaneously Asn, a PheB1not deleted, 2-4 zinc ions associated with each hexameron derived insulin.

In one of the preferred embodiments the invention relates to a derivative of human insulin in which the B30 amino acid residue is deleted or is any amino acid residue which can be encoded by the genetic code except Lys, Arg and Cys; amino acid residues A21 and B3 are, independently from each other, residues of any amino acids that can be encoded by the genetic code except Lys, Arg and Cys, with the proviso that when the amino acid residue B30 is Aa or Thr, at least one of the residues A21 and B3 is Asn; PheB1can be removed; and the ε-amino group of LysB29has lipophilic Deputy, which contains at least 6 carbon atoms.

In one of the preferred embodiments the invention relates to a derivative of human insulin in which the B30 amino acid residue is deleted or is any amino acid residue which can be encoded by the genetic code except Lys, Arg and Cys; amino acid residues A21 and B3 are, independently from each other, residues of any amino acids that can be encoded by the genetic code except Lys, Arg and Cys; PheB1can be removed; the ε-amino group of LysB29has lipophilic Deputy, which contains at least 6 carbon atoms; and 2-4 ion Zn2+can be associated with each insulin hexameron.

When a peptide designed to be incorporated into the composition according to the present invention, is insulin, the insulin contained in the composition at a concentration from about 0.5 mg/ml to about 20 mg/ml, more preferably in a concentration from about 1 mg/ml to about 15 mg/ml

In another embodiment of the present invention the peptide is designed to be incorporated into the composition according to the present invention, is hGH or Met-hGH.

If the peptide designation is significant for inclusion in the composition according to the present invention, is hGH or Met-hGH, hGH or Met-hGH contained in the composition at a concentration from about 0.5 mg/ml to about 50 mg/ml, more preferably in a concentration from about 1 mg/ml to about 10 mg/ml

In the following embodiment of the present invention the peptide is designed to be incorporated into the composition according to the present invention is a GLP-2 or an analogue or derivative.

If a peptide designed to be incorporated into the composition according to the present invention is a GLP-2, or equivalent, or derivative, GLP-2, or equivalent, or derivative contained in the composition at a concentration from about 1 mg/ml to about 100 mg/ml, more preferably in a concentration from about 1 mg/ml to about 10 mg/ml

In yet another embodiment of the present invention the peptide is designed to be incorporated into the composition according to the present invention is a Factor VII or Factor VIIa or an analogue or derivative.

If a peptide designed to be incorporated into the composition according to the present invention is a Factor VII or Factor VIIa, or its analogue, or derivative, the Factor VII or Factor VIIa, or its analogue, or derivative contained in the composition at a concentration from about 0.1 mg/ml to about 10 mg/ml, more preferably in a concentration from about 0.5 mg/ml to about 5 mg/ml

which one of the embodiments of the present invention the final concentration of propylene glycol in the compositions according to the present invention is from about 1 to about 50 mg/ml

In another of the embodiments of the present invention the final concentration of propylene glycol in the compositions according to the present invention is from about 5 to about 25 mg/ml

In the following embodiment of the present invention the final concentration of propylene glycol in the compositions according to the present invention is from about 8 to about 16 mg/ml

In the following embodiment of the present invention the final concentration of propylene glycol in the compositions according to the present invention is from about 13 to about 15 mg/ml

In the following embodiment of the present invention the final concentration of propylene glycol in the compositions according to the present invention is from about 13.5 to about 14.5 mg/ml

In another embodiment of the present invention, the composition has a pH in the range from about 7.0 to about 9.5 to where the term "about"used in relation to pH, mean + or - 0.1 of a pH unit from the specified number.

In the following embodiment of the present invention, the composition has a pH in the range from about 7.0 to about 8.0 in.

In the following embodiment of the present invention, the composition has a pH ranging from about 7.2 to about 8.0 in.

In the following embodiment, this is about the invention the composition has a pH in the range from about 7.0 to about 8.3 in.

In the following embodiment of the present invention, the composition has a pH in the range of from about 7.3 to about 8,3.

In a preferred embodiment of the invention the composition contains, in addition to peptide and propylene glycol, a buffering agent and/or preservative.

When the composition according to the present invention must include a buffering agent, a buffering agent selected from the group consisting of sodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine, lysine, arginine, sodium dihydrophosphate, disodium hydrogen phosphate, sodium phosphate, and Tris(hydroxymethyl)-aminomethane or mixtures thereof. Each of these specific buffers is an alternative implementation of the present invention. In a preferred embodiment of the present invention, the buffer substance is glycylglycine, sodium dihydrophosphate, the disodium hydrogen phosphate, sodium phosphate or mixtures thereof.

If the compositions according to the present invention must include pharmaceutically acceptable preservative, preservative selected from the group consisting of phenol, m-cresol, methyl p-hydroxybenzoate, propyl-p-hydroxybenzoate, 2-Phenoxyethanol, butyl p-hydroxybenzoate, 2-phenylethanol, benzyl alcohol, chlorobutanol and thimerosal or mixtures thereof. Each of these Conques is to maintain preservatives represents an alternative implementation of the present invention. In a preferred embodiment of the present invention the preservative is phenol or m-cresol.

In the following embodiment of the present invention the preservative is contained in the composition at a concentration from about 0.1 mg/ml to about 50 mg/ml, more preferably in a concentration from about 0.1 mg/ml to about 25 mg/ml and most preferably in a concentration from about 0.1 mg/ml to about 10 mg/ml

The use of preservative in pharmaceutical compositions is well known to a person skilled in the art. For convenience, we give a link to Remington: The Science and Practice of Pharmacy, 19thedition, 1995.

In the following embodiment, the present invention composition may also contain chelate forming reagent, and chelate forming reagent may be selected from salts of ethylenediaminetetraacetic acid (EDTA), citric acid and aspartic acid or mixtures thereof. Each of these specific chelat forming reagent is an alternative implementation of the present invention.

In the following embodiment, the present invention chelate forming reagent is contained in the composition in a concentration from 0.1 mg/ml to 5 mg/ml In the following embodiment, the present invention chelate forming reagent is contained in the composition at the end of the ation from 0.1 mg/ml to 2 mg/ml In the following embodiment, the present invention chelate forming reagent is contained in the composition at a concentration of 2 mg/ml to 5 mg/ml

Use chelat forming reagent in pharmaceutical compositions is well known to a person skilled in the art. For convenience, we give a link to Remington: The Science and Practice of Pharmacy, 19thedition, 1995.

In the following embodiment of the present invention the composition may also contain a stabilizer selected from the group of high molecular weight polymers or low molecular weight compounds, such stabilizers may include, but are not limited to, polyethylene glycol (e.g. PEG 3350), polyvinyl alcohol (PVA), polyvinylpyrrolidone, carboxymethyl cellulose, various salts (e.g. sodium chloride), L-glycine, L-histidine, imidazole, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine or mixtures thereof. Each of these specific stabilizers is an alternative implementation of the present invention. In a preferred embodiment of the present invention the stabilizer is selected from the group consisting of L-histidine, imidazole or arginine.

In the following embodiment of the present invention, high molecular weight polymer contained in the composition in a concentration from 0.1 mg/ml to 50 mg/ml in the Following embodiment of the present invention, high molecular weight polymer contained in the composition in a concentration from 0.1 mg/ml to 5 mg/ml In the following embodiment of the present invention, high molecular weight polymer contained in the composition at a concentration of 5 mg/ml to 10 mg/ml In the following embodiment of the present invention, high molecular weight polymer contained in the composition at a concentration of 10 mg/ml to 20 mg/ml In the following embodiment of the present invention, high molecular weight polymer contained in the composition at a concentration of 20 mg/ml to 30 mg/ml In the following embodiment of the present invention, high molecular weight polymer contained in the composition at a concentration of 30 mg/ml to 50 mg/ml

In the following embodiment, the present invention is a small molecule compound contained in the composition in a concentration from 0.1 mg/ml to 50 mg/ml In the following embodiment, the present invention is a small molecule compound contained in the composition in a concentration from 0.1 mg/ml to 5 mg/ml In the following embodiment, the present invention is a small molecule compound contained in the composition at a concentration of 5 mg/ml to 10 mg/ml In the following embodiment, the present invention is a small molecule compound contained in the composition at a concentration of 10 mg/ml to 20 mg/ml In the following embodiment, the present invention is a small molecule compound contained in the compo is icii at a concentration of 20 mg/ml to 30 mg/ml In the following embodiment, the present invention is a small molecule compound contained in the composition at a concentration of 30 mg/ml to 50 mg/ml

The use of the stabilizer in pharmaceutical compositions is well known to a person skilled in the art. For convenience, we give a link to Remington: The Science and Practice of Pharmacy, 19thedition, 1995.

In the following embodiment of the present invention, the composition according to the present invention may also contain a surfactant, and the surfactant may be selected from a detergent, ethoxylated castor oil, poliglecaprone of glycerides, acetylated monoglycerides, esters of fatty acids and of sorbitol, poloxamer, for example 188 and 407, esters of fatty acids and polyoxyethylenesorbitan derivatives, polyoxyethylene, such as alkyl and alkoxycarbonyl derivatives (twins, such as tween-20 or tween-80), monoglycerides or ethoxylated derivatives, diglycerides or polyoxyethylene derivatives, glycerin, holeva acid or its derivatives, lecithins, alcohols and phospholipids, glycerophospholipids (lecithins, kefallinos, phosphatidylserine), glyceroglycolipids (galactopyranoside), sphingophospholipids (sphingomyelin) and sphingoglycolipids (ceramides, Gan is Leonidov), DSS (sodium docusinate, docusinate calcium, docusinate potassium), SDS (sodium dodecyl sulphate or sodium lauryl), dipalmitoylphosphatidyl acid, kaprilat sodium, bile acids and their salts and conjugates with glycine and taurine, ursodeoxycholic acid, cholate sodium, desoxycholate sodium, taurocholate sodium, glycocholate sodium, N-hexadecyl-N,N-dimethyl-3-ammonium-1-propanesulfonate, anionic (alkyl-aryl-sulfonates) monovalent surfactants, palmitoylethanolamide-L-serine, lysophospholipids (for example, 1-acyl-sn-glycero-3-phosphate esters of ethanolamine, serine or threonine), alkyl, alkoxyalkyl ester, alkoxyalkyl simple ester derivatives of lysophosphatidyl and phosphatidylcholines, for example lauroleic and monitoring derivatives of the effective absorption with added, dipalmitoylphosphatidylcholine and modifications of the polar head groups, that is, choline, ethanolamine, phosphatidic acid, serine, threonine, glycerol, Inositol, and the positively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and dispostition, amphoteric ionic surfactants (for example, N-alkyl-N,N-dimethylammonio-1-propanesulfonates, 3 hollida-1-propyltrimethylammonium-1-propanesulfonate, dodecylphosphocholine, myristoyltransferase, lysolecithin chicken eggs), cationic surface-Akti is different agents (Quaternary ammonium bases) (for example, cetyltrimethylammonium bromide, cetylpyridinium chloride), non-ionic surfactants, block copolymers of polyethylene oxide/polypropyleneoxide (Pluronics/Tetronics, Triton X-100, dodecyl-β-D-glucopyranosid) or polymeric surfactants (tween-40, tween-80, Brij-35), the derivatives fuseboy acid (for example, Tauro-dihydropyridine sodium and the like), long-chain fatty acids from C6 to C12, and their salts (for example, oleic acid and Caprylic acid), acylcarnitines and their derivatives, Nα-acylated derivatives of lysine, arginine or histidine, or acylated at the side chain derivatives of lysine or arginine, Nα-acylated derivatives of dipeptides containing any combination of lysine, arginine or histidine and a neutral or acidic amino acid, Nα-acylated derivatives of tripeptides containing any combination of a neutral amino acid and two charged amino acids, or the surfactant may be selected from the group of imidazoline derivatives, or mixtures thereof. Each of these specific surfactants form an alternative embodiment of the invention.

The use of surfactants in pharmaceutical compositions is well known to a person skilled in the art. For convenience, we give a link to Remington: The Science and Pracice of Pharmacy, 19thedition, 1995.

Compositions according to the present invention can be prepared using standard techniques, e.g. as described in Remington's Pharmaceutical Sciences, 1985 or in Remington: The Science and Practice of Pharmacy, 19thedition, 1995, and these standard methods in the pharmaceutical industry include dissolving and mixing the ingredients to obtain the desired end product.

As described above, in the preferred embodiment of the invention the composition according to the present invention contain, in addition to peptide and propylene glycol, a buffering agent and/or preservative.

In one of the embodiments of the present invention a method of preparation of such peptide composition includes:

a) preparing a first solution by dissolving the preservative, propylene glycol, and a buffering agent in water;

b) preparing a second solution by dissolving the peptide in water;

C) mixing the first and second solutions; and

g) adjusting the pH of the mixture obtained in paragraph (b), until the desired pH value.

In another of the embodiments of the present invention a method of preparation of such peptide composition includes:

a) preparing a first solution by dissolving the preservative and buffer substances in the water;

b) relax the of propylene glycol to the first solution;

C) mixing the first solution with the second solution containing the peptide dissolved in water; and

g) adjusting the pH of the mixture obtained in stage b), until the desired pH values.

In the following embodiment of the present invention, the method of preparation of the peptide composition includes:

a) preparation of a solution by dissolving the preservative, a buffering agent and propylene glycol in water;

b) adding the peptide to the solution obtained in stage a); and

C) regulation of the pH of the solution obtained in stage b), until the desired pH values.

Compositions according to the present invention is optimal for the manufacture and use of injection devices because they produce fewer deposits on the surfaces of production equipment and less litter injection device, the above methods of preparation can be used for the manufacture of peptide compositions suitable for the manufacture and use of injection devices.

Compositions according to the present invention suitable for administration to mammals, preferably humans. By introducing the compositions according to the present invention may be any route, which effectively transports the peptides contained in the composition to the appropriate or desired site of action is via, for example, oral, nasal, buccal, pulmonary, transdermal or parenteral administration.

Due to the ability of propylene glycol to reduce clogging of injection devices compared with other means to ensure isotonicity, in particular compared with mannitol, in a preferred embodiment of the present invention the compositions according to the present invention it is possible to enter a needy patient parenterally. Parenteral administration can be performed by subcutaneous, intramuscular or intravenous injection with a syringe using a syringe-pens. Alternatively, parenteral administration can be performed using an infusion pump.

The next option is a composition which may be in the form of powder or liquid, for administration of the composition in the form of a nasal or pulmonal spray. As the next variant, the composition may also be introduced transdermal, for example, the patch may informationstore patch, or transmucosal, such as buccal. The above possible ways of introduction of the compositions according to the present invention should not be considered as limiting the scope of invention.

Certainly it is clear that depending on the peptide or peptides included in the composition according to Nast is ademu the invention, the composition can be used in methods of treatment of diseases or conditions under which illustrates the use of the peptide. Specialist in the art should understand that when using such methods of treatment composition should be introduced in a quantity effective to treat the condition or disease, the purpose of which introduced the peptide, and "effective amount" or "amount effective..." should be understood as the dose is sufficient for treatment of a patient with the disease or condition to be treated, was effective compared with treatment without injection of this dose. It should be understood that "an effective amount" is an effective dose, which should be determined by a qualified medical practitioner, which can change dosage to achieve the desired reaction. Factors that must be considered when determining the dose are the efficacy, bioavailability, desirable pharmacokinetic/pharmacodynamic profiles, condition or disease to be treated (for example, diabetes, obesity, weight loss, stomach ulcers), factors associated with the patient (e.g., weight, health condition, age etc), the presence of simultaneously injected drugs (such as insulin), time of introduction or other factors known to the practitioner.

In one of the embodiments of the present invention, the reduction of sediment production equipment during production of the propylene-containing composition, in comparison with the sediments observed in the case of the composition containing the previously used tool to give isotonicity, measured in the experiment on the model filling equipment, as described in the Examples.

Means for imparting isotonicity, instead of which use propylene glycol is a sorbitol, sucrose, glycine, mannitol, lactose monohydrate, arginine, myo-Inositol and dimethyl sulfone.

In the following embodiment, the present invention instead of the tools to give isotonicity, previously used in the above composition, using the propylene glycol at a concentration of from about 1 to about 50 mg/ml

In the following embodiment, the present invention instead of the tools to give isotonicity, previously used in the above composition, using the propylene glycol at a concentration of from about 5 to about 25 mg/ml

In the following embodiment, nastoyascheevremya instead to give isotonicity, previously used in the above composition, using the propylene glycol at a concentration of from about 8 to about 16 mg/ml

In one of the embodiments of the present invention a composition comprising propylene glycol, has a pH in the range from about 7.0 to about 9.5 to.

In one of the embodiments of the present invention a composition comprising propylene glycol, has a pH in the range from about 7.0 to about 8.0 in.

In one of the embodiments of the present invention a composition comprising propylene glycol, has a pH in the range from about 7.2 to about 8.0 in.

In one of the embodiments of the present invention a composition comprising propylene glycol, has a pH in the range from about 7.0 to about 8.3 in.

In one of the embodiments of the present invention a composition comprising propylene glycol, has a pH in the range of from about 7.3 to about 8,3.

The present invention relates also to a method of reducing sludge formation in the final product during the manufacture of the peptide composition, which instead means to ensure isotonicity, previously used in such compositions, the composition is administered propylene glycol at a concentration of from 1 to 100 mg/ml

In one of the embodiments of the present invention, the reduction of education to adcav in the final product is measured by the decrease in the number of vials and/or vials of the propylene-containing composition, be liquidated due to the presence of precipitation, compared with the number of vials and/or vials with a composition containing the previously used tool to give isotonicity to be liquidated due to the presence of precipitation.

Means for imparting isotonicity, instead of which use propylene glycol is a sorbitol, sucrose, glycine, mannitol, lactose monohydrate, arginine, myo-Inositol and dimethyl sulfone.

In the following embodiment, the present invention instead of the tools to give isotonicity, previously used in the above composition, using the propylene glycol at a concentration of from about 1 to about 50 mg/ml

In the following embodiment, the present invention instead of the tools to give isotonicity, previously used in the above composition, using the propylene glycol at a concentration of from about 5 to about 25 mg/ml

In the following embodiment, the present invention instead of the tools to give isotonicity, previously used in the above composition, using the propylene glycol at a concentration of from about 8 to about 16 mg/ml

In another embodiment of the present invention a composition comprising propylene glycol, has a pH in the range from about 7.0 to about 9.5 to.

In the trail of the General embodiment, the present invention composition, contains propylene glycol, has a pH in the range from about 7.0 to about 8.0 in.

In the following embodiment of the present invention a composition comprising propylene glycol, has a pH in the range from about 7.2 to about 8.0 in.

In the following embodiment of the present invention a composition comprising propylene glycol, has a pH in the range from about 7.0 to about 8.3 in.

In the following embodiment of the present invention a composition comprising propylene glycol, has a pH in the range of from about 7.3 to about 8,3.

The present invention relates also to a method of reducing the clogging of the injection device, in which instead of a means to ensure isotonicity, previously used in such compositions, the composition is administered propylene glycol at a concentration of from 1 to 100 mg/ml

In one of the embodiments of the present invention reduce the clogging of the injection device, the propylene-containing composition compared with clogging observed using the composition containing the previously used tool to give isotonicity, measured in the experiment on the model of the use of the injection device, as described in the Examples.

In one of the embodiments of the present invention the means for imparting isotonicity, instead of the fact that use propylene glycol, selected from the group consisting of Inositol, maltose, glycine, lactose and mannitol.

In the following embodiment, the present invention instead of the tools to give isotonicity, previously used in the above composition, using the propylene glycol at a concentration of from about 1 to about 50 mg/ml

In the following embodiment, the present invention instead of the tools to give isotonicity, previously used in the above composition, using the propylene glycol at a concentration of from about 5 to about 25 mg/ml

In the following embodiment, the present invention instead of the tools to give isotonicity, previously used in the above composition, using the propylene glycol at a concentration of from about 8 to about 16 mg/ml

In another form of implementation of the present invention a composition comprising propylene glycol, has a pH in the range from about 7.0 to about 9.5 to.

In the following embodiment of the present invention a composition comprising propylene glycol, has a pH in the range from about 7.0 to about 8.0 in.

In the following embodiment of the present invention a composition comprising propylene glycol, has a pH in the range from about 7.2 to about 8.0 in.

All scientific publications and patent documents, proci is new in this application included in it by reference. The following examples illustrate various aspects of the invention, but in no way limit the scope of the invention.

DESCRIPTION of embodiments of the INVENTION

Example 1

Experiments on the model fill the drip test and test for contamination when replacing mannitol

Since laboratory experiments have shown that the composition without peptides ("placebo") in relation to the clogging of the needle and the formation of deposits on the needles give the same results as the composition with peptides at a concentration of 0.3-5.0 mg/mg, screening studies in Example 1 were performed using a placebo, except in those cases where otherwise noted.

The preparation of compositions with various means to ensure isotonicity

Preservative (5,5 mg/l phenol) and a buffering agent (1.24 mg/ml disodium phosphate dihydrate) was dissolved in water and with stirring was added a tool to ensure isotonicity. the pH was brought to pH 7,9 using sodium hydroxide and/or hydrochloric acid. In conclusion, the composition was filtered through a filter with a pore diameter of 0.22 μm. Means to ensure isotonicity, tested in each song, and their concentrations are shown in Table 1.

Table 1
The composition of the tested compositions
no songsThe modifier toychest
1.Glucose monohydrate (38,0 mg/ml)
2.Lactose monohydrate (65,0 mg/ml)
3.Maltose (67,2 mg/ml)
4.Glycine (15,1 mg/ml)
5.Polyethylene glycol 400 (77,5 mg/ml)
6.L-arginine (24.6 mg/ml)
7.Myo-Inositol (35.2 mg/ml)
8.Propylene glycol (13,7 mg/ml)
9.The dimethyl sulfone (18 mg/ml)
10.Mannitol (35,9 mg/ml)
11.Sorbitol (to 39.6 mg/ml)
12.Xylitol (to 39.5 mg/ml)
13.Sucrose (79,1 mg/ml)
14.Glycerin (16 mg/ml)

OS is pay attention

Was determined osmolarity of various compositions placebo, and the results are shown in Table 2.

Isotonic solution has an osmolarity of about 0,286 osmol/L. As can be seen from Table 2, three songs (with PEG 400, sucrose and xylitol) differed from isotonicity more than 20% (0,229-0,343 osmol/l), however, in these experiments, the osmolarity did not affect the results, although further experiments toychest compositions should be adjusted.

Table 2
The results of measurements of osmolarity songs
no songsThe means to ensure isotonicityOsmolarity
1.Glucose monohydrate (38,0 mg/ml)0,315
2.Lactose monohydrate (65,0 mg/ml)0,283
3.Maltose (67,2 mg/ml)0,306
4.Glycine (15,1 mg/ml)0,286
5.On etilenglikol 400 (77,5 mg/ml) 0,370
6.L-arginine (24.6 mg/ml)0,318
7.Myo-Inositol (35.2 mg/ml)0,285
8.Propylene glycol (13,7 mg/ml)0,268
9.The dimethyl sulfone (18 mg/ml)0,274
10.Mannitol (35,9 mg/ml)0,284
11.Sorbitol (to 39.6 mg/ml)0,310
12.Xylitol (to 39.5 mg/ml)0,351
13.Sucrose (79,1 mg/ml)0,346
14.Glycerin (16 mg/ml)0,262

Drip test

A drop of each of the compositions were placed on a glass slide and allowed it to dry. The sediment was examined visually with the naked eye and using a light microscope.

Photography dried drops of some of the compositions are given in figure 1. On pictures well what about the shows what mannitol forms a precipitate on a glass slide after drying. Was not observed precipitation in the case of sorbitol, xylitol, sucrose and glycerol. The right drop contains mannitol and Arg34, Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-CLP-1(7-37).

Figure 2 presents the substance that gave the highest precipitation (mannitol, arginine, Inositol) on a glass slide. Shown for comparison glycerin, which does not give rain.

Test for contamination

In this test, with each composition was tested on 10 syringe-pens NovoPens® 1.5 ml with needle NovoFine 30® G (needle gauge 30), 5 of which were placed in a vertical position and 5 in the horizontal. System syringe-pens in the intervals between the tests was kept at room temperature. Every day needle examined for sludge formation and before injection into the tissue did blow with compressed air. Noted the degree of resistance and clogging if they were. Injections were made daily by the same needle and did so within 9 working days with all the songs.

Test results clogging presented in Table 3.

From Table 3 and Figure 3 shows that Inositol and maltose were gummed up the needle. For comparison, figure 3 shows the glycerin, which does not contaminate the needle. From Figure 4 and Table 3 it can be seen that compositions containing glycine, lactose and Mann is t, formed large deposits on the needle. In the case of glycine deposits represented the drops dry on the rod tip, whereas in the case of lactose and mannitol deposits were observed on the tip of the needle.

Model filling equipment

1 l of each composition were used for the experiment on the model of the filling, which lasted 24 hours. After 24 hours the equipment was inspected for the presence of deposits.

Based on the results of research on the model fill (data not shown) compositions placebo can be divided into three categories:

1. Means to ensure isotonicity, which does not form deposits on the water-filling equipment: xylitol, glycerin, glucose monohydrate, maltose, PEG 400 and propylene glycol.

2. Means to ensure isotonicity, which form a little fat and have better properties when filling than mannitol: sorbitol, sucrose and glycine.

3. Means to ensure isotonicity, which is comparable to mannitol or worse: mannitol, lactose monohydrate, arginine, myo-Inositol and dimethyl sulfone.

Conclusion

In the experiment on the model of the filling, it was found that xylitol, glycerin, glucose, maltose, PEG 400, propylene glycol, sorbitol, sucrose and glycine are good candidates for replacement of mannitol. However, since glucose is the Voss is anuliuosis the saccharide and therefore may cause undesired decomposition of the components of the composition, this modifier toychest was rejected. In addition, was rejected maltose due to clogging of the needle. This led to the following choice: glycerin, xylitol, sorbitol, sucrose, glycine, propylene glycol and PEG 400, which according to the results of the drip test, contamination of needles and model filling properties were found suitable for use as candidates for replacement of mannitol peptide compositions.

However, on the basis of the following considerations as a means to ensure isotonicity for further research by comparing with mannitol of all candidates was selected propylene glycol:

a) it was shown that propylene glycol does not affect the physical and chemical stability of the compositions containing Arg34, Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-CLP-1(7-37);

b) it was shown that propylene glycol does not affect the testing of antimicrobial preservatives; and

C) the use of propylene glycol does not require additional toxicity studies.

Example 2

Comparison of compositions placebo containing mannitol and propylene glycol, in experiments on the model filling and model application

The preparation of compositions

Preservative and a buffer substance was dissolved in water and with stirring was added a tool to ensure isotonicity. LV delivered and to the desired value using sodium hydroxide and/or hydrochloric acid. In conclusion, the composition was filtered through a filter with a pore diameter of 0.22 μm. Formulations of the compositions were as follows:

Disodium phosphate dihydrate:of 1.42 mg/ml
Phenol:5,5 mg/ml
Propylene glycol or mannitol:13,7 or 35,9 mg/ml
Water for injection:To 1.0 ml
pH:of 7.90

The experiment on the model filling

The experiment on the model of the filling, which lasted 24 hours, was carried out as described in Example 1, and after 24 hours the water-filling equipment was inspected for the presence of sediments. In the case of the composition containing the propylene glycol was not detected deposits on the equipment. For comparison, using the composition containing mannitol, after 24 hours on the equipment were discovered large deposits (see Fig.6).

The experiment on the model application

For the experiment on the model application was tested for contamination as described in Example 1. The same needle was used during the entire study period, equal to ten working days, and daily needle smatr the Wali for the presence of sediments. Figure 7 shows pictures of needles filled with compositions containing propylene glycol (top row) or mannitol (bottom row). When used as a means to ensure isotonicity of mannitol deposits on the needles were found in 48% of cases, whereas when used as a means to ensure isotonicity of propylene glycol deposits were found.

Example 3

Comparison of propylene glycol and mannitol compositions containing Arg34, Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-GLP-1(7-37)

The preparation of compositions

Preservative, a means to ensure isotonicity (mannitol or propylene glycol) and a buffering agent was dissolved in water and brought the pH to the desired value. Arg34, Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-GLP-1(7-37) was dissolved in water with slow stirring. Then the two solutions were mixed and brought the pH to the desired value using sodium hydroxide and/or hydrochloric acid. In conclusion, the composition was filtered through a filter with a pore diameter of 0.22 μm. Formulations of the compositions were as follows:

Arg34, Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-GLP-1(7-37) (6.25 mg/ml),

Dinatriumfosfaatti dehydrate (of 1.42 mg/ml),

Phenol (5.5 mg/ml),

Mannitol or propylene glycol (35,9 or 14.0 mg/ml),

Water for injection (1.0 ml),

R is: 8,15

The experiment on the model application

For the experiment on the model application was tested for contamination as described in Example 1, except that was used needle gauge G31. The same needle gauge G31 used during the entire study period, equal to ten working days, and daily needle examined for the presence of sediments. Figure 7 shows pictures of needles that do not contain fat, if they were filled with compositions containing propylene glycol (bottom row), and needles were found in the sediments if they were filled with compositions containing mannitol (top row).

In the case of compositions containing mannitol, clogging of the needle was observed in 1 of 10 cases per Day, 4 in 2 out of 10 cases - in Day 5, in 3 of 10 cases per Day 8 and 4 out of 10 cases per day 9. For comparison, in the case of compositions containing propylene glycol, was not observed clogging of the needle.

It is assumed that the results are similar to results obtained when applying the above composition containing the propylene glycol can be obtained if the pH is brought to 7.40, 7,70 or of 7.90. In addition, additional compositions that can be tested are the composition of the following composition:

Buffer substances: glycylglycine (1,32 mg/ml), L-histidine (of 1.55 mg/ml), HEPES (HEPES - 2-[4-(2-hydroxyethyl)-1-piperazinil]-ethanal the background acid) (2.38 mg/ml) or bicin (1,63 mg/ml)

Preservatives: phenol (5.0 or 5.5 mg/ml), benzyl alcohol (18 mg/ml) or a mixture of m-cresol and phenol (2,5/2,0 mg/ml)

Propylene glycol: 14,0 or 14.3 mg/ml

Water for injection to 1.0 ml

pH: 7,70, of 7.90 or 8,15

Example 4

The effect of the concentration of peptide in the clogging of needles

Compositions containing Arg34, Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-GLP-1(7-37), were prepared as described in Example 3, using concentrations of peptide, varieeruvusi in the range 0-5 mg/ml Arg34, Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-GLP-1(7-37). Formulations of the compositions were as follows:

Liraglutide: 0, 0,3, 3 and 5 mg/ml

Dinatriumfosfaatti dehydrate: 0,71 mg/ml

Sodium dihydrophosphate dehydrate: to 0.62 mg/ml

Mannitol: 36,9 mg/ml

Phenol: 5.0 mg/ml

Water for injection (1.0 ml)

pH: 7,40

The experiment on the model application was carried out as in Example 3, except that was used needle gauge G30, and the results (data not shown) showed that the effect of clogging the needle compositions containing mannitol, compared with the absence of clogging compositions containing propylene glycol, did not depend on the concentration of the peptide.

Example 5

Clogging of needles compositions containing Lys β29 (Nε-deletion) (B30)-human insulin or NovoMix 30 and mannitol

The preparation of compositions

Composition containing Lys β2 (Nε-deletion) (B30)-human insulin, was prepared as follows:

a) was first prepared a solution by dissolving a buffering agent, sodium chloride, preservatives (phenol and m-cresol) in water;

b) was prepared with the second solution Lys β29 (Nε-deletion) (B30)-human insulin and zinc acetate in water;

C) Containing the peptide solution prepared in stage b), was added to the solution prepared in stage a); and

d) the pH of the solution was brought to the desired pH values.

Composition containing Lys β29 (Nε-deletion) (B30)-human insulin, prepared by the above method, had the following composition: Lys β29 (Nε-deletion) (B30)-human insulin (2400 nmol), phenol (1,80 mg/ml), m-cresol (of 2.06 mg/ml), mannitol (30.0 mg/ml), disodium phosphate dehydrate (0,890 mg/ml), sodium chloride (1,17 mg/ml), zinc acetate (65,6 µg/ml), water for injection (1.0 ml), pH: 7,4.

Composition containing NovoMix 30, was prepared as follows:

a) Prepared a solution by dissolving a buffering agent, sodium chloride, phenol, mannitol and sodium hydroxide in water.

b) Prepared in a solution of sodium chloride, phenol and mannitol in water.

C) Prepared in a solution of Protamine sulfate in the water.

C) Prepared in a solution of insulin, hydrochloric acid and zinc in the water.

g) Mixed solutions of b), C) and d).

d) was Added to a solution of (e) to the solution, the floor is built at the stage a).

e) Adjusted the pH of the solution to the desired pH values and has led to the solution at room temperature.

g) Prepared a solution by dissolving m-cresol, phenol and mannitol in water.

C) the Solution g) was added to the crystalline fraction obtained in stage e); and

and Adjusted the pH of the solution to the desired pH values.

Composition containing NovoMix 30 and prepared by the above method, had the following composition: insulin aspart (100 units/ml), Protamine sulfate (approximately 0.33 mg/ml), phenol (1.50 mg/ml), m-cresol (1,72 mg/ml), mannitol (30.0 mg/ml), disodium phosphate dehydrate (1.25 mg/ml), sodium chloride (0,58 mg/ml), zinc (at 19.6 µg/ml), water for injection (1.0 ml), pH: 7,3.

Results

The experiment on the model application was carried out as in Example 3, using a needle gauge G31, with 20 needles were investigated in 20 days. The following results were obtained: clogging of the needles were found in the case of Lys β29 (Nε-deletion) (B30)-human insulin on Day 2 (5%), day 3 (70%) and Day 4 (100%). Clogging of the needles in the case of NovoMix 30 was detected at Day 3 (5%), Day 4 (10%), Day 5 (35%), Day 6 (40%), Day 8 (50%), Day 9 (55%) and Day 10 (80%). Therefore, the effect of mannitol on the clogging of the needle does not depend on the type of peptide included in the composition as a comparable effect of clogging was observed when using Arg34, Lys26(Nε α-hexadecanoyl)))-GLP-1(7-37), Lys β29 (Nε-deletion) (B30)-human insulin and NovoMix 30.

Example 6

The test compositions containing Lys β29 (Nε-deletion)des(B30)-human insulin or NovoMix 30 and propylene glycol

Preparation and compositions containing Lys β29 (Nε-deletion) (B30)-human insulin or NovoMix 30 are the same as described in Example 5, except that mannitol is replaced by propylene glycol in concentrations provided isotonicity. The experiment on the model application were carried out as described in Example 5.

On the basis of the fact that clogging compositions containing Lys β29 (Nε-deletion) (B30)-human insulin or NovoMix 30 and mannitol, was similar to the contamination observed in the case of compositions containing Arg34, Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-GLP-1(7-37) and mannitol, it can be assumed that the effect of propylene glycol on the clogging of needles compositions containing Lys β29 (Nαthe deletion) (B30)-human insulin or NovoMix 30 and propylene glycol, is similar to the action of compositions containing Arg34, Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-GLP-1(7-37) and propylene glycol.

1. Pharmaceutical composition comprising at least one agonist of GLP-1 and propylene glycol, and propylene glycol contained in the composition in a concentration of from approx the RNO 8 mg/ml to about 50 mg/ml, and the composition has a pH of about 7.3 to about 8,3, where agonist GLP-1 is a derivative of GLP-1(7-36) or GLP-1(7-37), or the analog of GLP-1(7-36)-amide, or an analog of GLP-1(7-37), and specified derivative contains a lysine residue and lipophilic Deputy attached to the Epsilon-amino group of the specified lysine by using a spacer or no spacer.

2. The composition according to claim 1, characterized in that the concentration of propylene glycol is from about 8 mg/ml to about 25 mg/ml

3. The composition according to claim 1, characterized in that the concentration of propylene glycol is from about 8 mg/ml to about 16 mg/ml

4. The composition according to claim 1, characterized in that it further comprises a preservative.

5. The composition according to claim 4, characterized in that the content of the preservative is from 0.1 to 20 mg/ml

6. The composition according to claim 1, characterized in that it further comprises a buffering agent.

7. The composition according to claim 6, wherein the buffer substance is selected from the group consisting of glycylglycine, L-histidine, 2-[4-(2-hydroxyethyl)-1-piperazinil]-econsultancy acid, bicine and dinatriumfosfaatti dihydrate.

8. The composition according to claim 7, characterized in that the lipophilic Deputy containing 8 to 40 carbon atoms.

9. The composition according to claim 8, characterized in that the spacer is an amino acid.

10. The composition according to claim 9, wherein the agonist of GLP-1 t is aetsa Arg 34,
Lys26(Nε-(γ-Glu(Nα-hexadecanoyl)))-GLP-1(7-37).

11. The composition according to claim 1, wherein the agonist of GLP-1 is selected from the group consisting of Gly8-GLP-1(7-36)-amide, Gly8-GLP-1(7-37), Val8-GLP-1(7-36)-amide, Val8-GLP-1(7-37), Val8ASP22-GLP-1(7-36)-amide, Val8ASP22-GLP-1(7-37), Val8Glu22-GLP-1(7-36)-amide, Val8Glu22-GLP-1(7-37), Val8Lys22-GLP-1(7-36)-amide, Val8Lys22-GLP-1(7-37), Val8Arg22-GLP-1(7-36)-amide, Val8Arg22-GLP-1(7-37), Val8His22-GLP-1(7-36)-amide, Val8His22-GLP-1(7-37), Arg34GLP-1(7-37), Arg26,34, Lys36GLP-1(7-36), Arg26GLP-1(7-37) and Gly8, Arg26, 34, Glu37, Lys38GLP-1(7-38), their analogues and derivatives of any of these substances.

12. The method of preparation of the pharmaceutical composition according to claim 1, suitable for use in an injection device, comprising preparing a composition according to claim 1, containing an agonist of GLP-1 and propylene glycol, and possibly, a buffering agent and a preservative, where propylene glycol is contained in the composition in a concentration of from about 8 mg/ml to about 50 mg/ml, where the preparation of the composition includes the following stages:
a) preparing a first solution by dissolving propylene glycol and, possibly, preservative and buffering agents in the water;
b) preparing a second solution by dissolving agonist of GLP-1 in water;
C) mixing the first and second solutions; and
g) bring the pH of the mixture, extracting the Noah on stage), to a pH of from about 7.3 to about 8,3.

13. The method according to item 12, wherein the concentration of propylene glycol is from about 8 mg/ml to about 25 mg/ml

14. The method according to item 12, wherein the concentration of propylene glycol is from about 8 mg/ml to about 16 mg/ml

15. The method of reducing the formation of deposits on the production equipment in the manufacturing process of the pharmaceutical composition according to claim 1, containing an agonist of GLP-1, which is a derivative of GLP-1(7-36) or GLP-1(7-37), or the analog of GLP-1(7-36)-amide, or an analog of GLP-1(7-37), and specified derivative contains a lysine residue and lipophilic Deputy attached to the Epsilon-amino group of the specified lysine by using a spacer or no spacer, in which instead of a means to ensure isotonicity, previously used in such compositions, introducing propylene glycol at a concentration of from 8 to 50 mg/ml

16. The method according to item 15, wherein the reduced formation of deposits on the production equipment in the manufacturing process propilenglikolstearat composition, compared to the amount of sediment observed in the case of the composition containing the previously used tool to ensure isotonicity, measured in the experiment on the model of the fill.

17. The method according to item 15, wherein the means for providing isot is lichnosti, instead use propylene glycol selected from the group consisting of sorbitol, sucrose, glycine, mannitol, lactose monohydrate, arginine, myo-Inositol and dimethyl sulfone.

18. A method of reducing sludge formation in the final product in the process of manufacturing the pharmaceutical composition according to claim 1, containing an agonist of GLP-1, which is a derivative of GLP-1(7-36) or GLP-1(7-37), or the analog of GLP-1(7-36)-amide, or an analog of GLP-1(7-37), and specified derivative contains a lysine residue and lipophilic Deputy attached to the Epsilon-amino group of the specified lysine by using a spacer or no spacer, in which instead of a means to ensure isotonicity, previously used in such compositions, introducing propylene glycol at a concentration of in the range from 8 to 50 mg/ml

19. The method according to p, characterized in that the reduction of sludge formation in the final product is measured by the reduction in the number of vials and/or vials propilenglikolstearat composition, which must be destroyed because of the presence of precipitation, compared with the number of vials and/or vials with a composition containing the previously used tool to ensure isotonicity, which must be destroyed because of the presence of precipitation.

20. The method according to p, characterized in that the means to ensure isotonicity, instead use the form propylene glycol, selected from the group consisting of sorbitol, glycerol, sucrose, glycine, mannitol, lactose monohydrate, arginine, myo-Inositol and dimethyl sulfone.

21. The way to reduce clogging of injection devices pharmaceutical composition according to claim 1, containing an agonist of GLP-1, which is a derivative of GLP-1(7-36) or GLP-1(7-37), or the analog of GLP-1(7-36)-amide, or an analog of GLP-1(7-37), and specified derivative contains a lysine residue and lipophilic Deputy attached to the Epsilon-amino group of the specified lysine by using a spacer or no spacer, in which instead of a means to ensure isotonicity, previously used in such compositions, introducing propylene glycol at a concentration in the range of 8-50 mg/Jr.

22. The method according to item 21, in which the reduction of clogging of the injection device propilenglikolstearat composition, compared with the contamination observed in the case of the composition containing the previously used tool to ensure isotonicity, measured in the experiment on the model application.

23. The method according to item 21, wherein the means to provide isotonicity, instead of which use propylene glycol selected from the group consisting of Inositol, maltose, glycine, lactose and mannitol.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to medicine, and concerns a method of body weight reduction, diabetes treatment, HbAlC level decrease or plasma glucose level decrease on an empty stomach by the use of exendin or an exendin agonist analogue.

EFFECT: invention provides a specific plasma level (170 pg/ml to 290 pg/ml) of exendin or its agonist analogue for at least 1 month.

19 cl, 1 ex, 3 dwg, 3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology and endocrinology, and concerns treating the patients with chronic cardiac failure compromised by type 2 diabetes. That is ensured by the additional introduction of the selective β1 adrenoceptor antagonist nebivolol in a single dose 5-7.5 mg/day within 12 months with underlying ACE inhibitor and diuretic therapy in the patients with a higher level of basal glycemia by more than 4.5 mmol/l and preserved LVEF by more than 52 %.

EFFECT: method provides effective treatment in the given group of patients due to ability of nebivolol to improve nitrogen oxide synthesis by a vascular endothelium and to provide normalising haemodynamic, metabolic, anti-ischemic and immune-correcting action.

1 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: invention is related to alimentation, in particular - to a method and composition for improvement of glucose and insulin balance. Proposed is a compound that includes: a protein source, a fat source and a carbohydrate source, the protein source to the fat source ratio being approximately 1:1:1, each source accounting for 15% - 45% of the total calorie content of the compound. The fat source accounts for approximately over 2% of the total calorie content of the composition in the form of linoleic acid (18:2). According to an alternative version, the food compound for normalisation of insulin and glucose in the organism contains a protein source, a fat source and a carbohydrate source at a ratio of 1:1:1, each of these components accounting for approximately a third of the total calorie content of the compound. Additionally proposed are a diet for enhancement of sensitivity to insulin, a method to reduce resistivity to insulin, a method to reduce insulin levels in the plasma during after dinner time, a method to delay occurrence of insulin in one's blood and a method to increase fat clearance during after dinner time envisaging usage of the above food compound.

EFFECT: invention allows to improve glucose regulation and insulin effect.

68 cl, 34 dwg, 38 tbl

FIELD: medicine.

SUBSTANCE: in formula (I) , the ring A represents 6-members aryl or 5-6-members heteroaryl containing 1-2 heteroatoms selected from nitrogen and sulphur; Q means C3-8 cycloalkyl, 5-6-members heterocycle containing 1 heteroatom selected from oxygen, nitrogen or sulphur, C1-6 alkyl or C2-6 alkenyl; the ring T represents 5, 6, 9 or 10-members heteroaryl or 9-members heterocycle optionally additionally substituted by 1-3 heteroatoms independently selected from nitrogen or sulphur. The values of other substitutes are specified in the patent claim. Also, the invention refers to methods for preparing oxime derivatives of general formula (I), to pharmaceutical compositions containing the compound of the invention as an active ingredient and to applications of the compounds of the invention in preparing a drug.

EFFECT: compounds of the invention exhibit properties of a glucokinase activator.

33 cl, 1499 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds - benzoquinone derivatives of formula (I): , where each of R1 and R2 is O-C(O)phenyl; where the phenyl is substituted with 1 substitute selected from halide, nitro, C1-C6 alkyl or C1-C6 alkoxy, and pharmaceutically acceptable salts thereof.

EFFECT: low activity of pancreatic lipase based on compounds of the said formula.

6 cl, 3 tbl, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is application of biologically active substance for production of medication for treatment of syndrome of resistance to insulin, diabetes, including type I diabetes and type II diabetes, syndrome of ovary polycystosis, treatment or reduction of probability of atheroslerosis development, arterioslerosis, obesity, hypertension, hyperlipidemia, fatty infiltration of liver, nephropathy, neuropathy or retinopathy, feet ulceration or cataracts associated with diabetes, where medication represents compound of formula , as well as corresponding treatment method, pharmaceutical composition and biologically active substance of the same purpose.

EFFECT: increase of compound activity: 75% reduction of glucose level with loading in contrast to 10% reduction for analogues known before, as well as reduction of level of triglycerides in blood serum.

17 cl, 1 dwg, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein Q together with carbon and nitrogen atoms whereto attached forms a 5-6-members monocyclic heteroaromatic ring; or Q together with carbon and nitrogen atoms whereto attached forms a 9-10-members bicyclic heterocycle; R1 and R2 independently mean hydrogen, halogen, alkyl, alkyl substituted by one or more halogen, alkoxygroup, alkoxygroup substituted by alkoxygroup, alkylthiogroup, sulphonyl, free or etherified carboxygroup, carbamoyl, sulohamoyl, morpholinyl or pyridinyl; or R2 is absent; R3 means (C3-C6)cycloalkyl; R4 means hydrogen, halogen, lower alkyl or lowest alkyl substituted by one or more halogen; R5 means (C3-C6cycloalkyl, (C6-C10) aryl, (C3-C10)heterocyclyl or (C1-C6)alkyl optionally substituted by (C1-C6)alkoxygroup, (C3-C7)cycloalkyl, (C6-C10)aryl or (C3-C10)heterocyclyl; R6 means free or etherified carboxygroup; and n is an integer equal to 1-6; or to its enanthiomer, or a mixture of its enanthiomers, or its pharmaceutically acceptable salt. Besides, the invention refers to a method of glucokinase activation in mammals, to a method of treating pathological conditions associated with glucokinase activation in mammals and impaired glucose tolerance, as well as to a pharmaceutical composition based on these compounds and to application of said compositions for preparing a drug.

EFFECT: there are produced and described new compounds which are activators and can be used as therapeutic agents for treating the glucokinase mediated pathological conditions.

31 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound having structure

, radicals are as described in the formula of invention, as well as pharmaceutically-acceptable salt, prodrug, tautomer and stereoisomer thereof. The invention also relates to a composition, a set for modulating PPAR based on said compound, a method of treating a patient suffering from a disease or condition or at risk of a disease or condition, for which PPAR modulation is therapeutically useful.

EFFECT: novel compounds which are active towards PPAR are obtained and described.

41 cl, 622 ex, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula

where X represents OR1, SR1 or NR1R2 where R1 and R2 independently represent C1-C5 lower alkyl, and R1 and R2 in NR1R2 can form a 5-7-members ring including an O heteroatom; or to its stereoisomer, to a pharmaceutically acceptable salt, hydrate or solvate. Besides, the invention refers to a method for making thereof and to a based pharmaceutical composition exhibiting DPP-IV inhibitor activity.

EFFECT: new compounds which can find application in medicine for prevention or treatment of the DPP-IV associated diseases, such as diabetes or obesity are produced.

12 cl, 1 tbl, 2 dwg, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention aims at a pharmaceutical composition in the form of a clear solution or a water mixture, a suspension or a semisolid composition containing at least one peptide compound of water solubility more than 1 mg/ml at room temperature and pH value within 4.0 to 6.0 selected from the group consisting of hGLP-1 (7-36)-NH2, as well as its analogues and derivatives, hGLP-1 (7-37)-OH, as well as its analogues and derivatives and/or exendin-4, as well as its analogues and derivatives, zinc and a solvent where less than 95 % of said peptide compound are dissolved by the solvent.

EFFECT: invention provides a long-term effect of the preparation with lower initial plasma concentrations.

20 cl, 1 dwg

FIELD: medicine.

SUBSTANCE: in formula (I) , the ring A represents 6-members aryl or 5-6-members heteroaryl containing 1-2 heteroatoms selected from nitrogen and sulphur; Q means C3-8 cycloalkyl, 5-6-members heterocycle containing 1 heteroatom selected from oxygen, nitrogen or sulphur, C1-6 alkyl or C2-6 alkenyl; the ring T represents 5, 6, 9 or 10-members heteroaryl or 9-members heterocycle optionally additionally substituted by 1-3 heteroatoms independently selected from nitrogen or sulphur. The values of other substitutes are specified in the patent claim. Also, the invention refers to methods for preparing oxime derivatives of general formula (I), to pharmaceutical compositions containing the compound of the invention as an active ingredient and to applications of the compounds of the invention in preparing a drug.

EFFECT: compounds of the invention exhibit properties of a glucokinase activator.

33 cl, 1499 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds - benzoquinone derivatives of formula (I): , where each of R1 and R2 is O-C(O)phenyl; where the phenyl is substituted with 1 substitute selected from halide, nitro, C1-C6 alkyl or C1-C6 alkoxy, and pharmaceutically acceptable salts thereof.

EFFECT: low activity of pancreatic lipase based on compounds of the said formula.

6 cl, 3 tbl, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are offered a prolonged release composition for regional depot fat reduction containing a therapeutically effective amount of at least one glucocorticosteroid in the form of a crystalline microparticle suspension, and a therapeutically effective amount of at least one selective beta-2-adrenergic receptor agonist and a respective combined preparation of the same purpose.

EFFECT: glucocorticosteroid reduced beta-adrenergic receptor desensitisation to provide a synergetic action with the beta-2-adrenergic receptor agonist (eg, with formoterol) to enable fat amount reduction.

18 cl, 11 dwg, 5 tbl, 7 ex

FIELD: food industry.

SUBSTANCE: invention relates to therapy and prevention of obesity and may be used for reduction of body weight with both humans and animals. The mammal body weight reduction method envisages addition of a biologically active substances concentrate produced of aspen wood by way of water extraction to the basic ration. For mice the food additive efficient quantity is 0.43-1.71 mg of dry substance of the aspen biologically active substances concentrate (administered daily in two separate doses during a month) per 1 g of live weight. For humans the food additive efficient quantity is 3.6 mg of dry aspen biologically active substances concentrate (administered daily in two separate doses during a month).

EFFECT: invention enables to reduce weight smoothly and without side effects and to maintain a lower body weight achieved through weight loss.

3 cl, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula

where X represents OR1, SR1 or NR1R2 where R1 and R2 independently represent C1-C5 lower alkyl, and R1 and R2 in NR1R2 can form a 5-7-members ring including an O heteroatom; or to its stereoisomer, to a pharmaceutically acceptable salt, hydrate or solvate. Besides, the invention refers to a method for making thereof and to a based pharmaceutical composition exhibiting DPP-IV inhibitor activity.

EFFECT: new compounds which can find application in medicine for prevention or treatment of the DPP-IV associated diseases, such as diabetes or obesity are produced.

12 cl, 1 tbl, 2 dwg, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof where R1 and R2 together denote a group selected form groups of formula (III-1): , where R9 denotes 1) a lower alkyl group, optionally substituted with a halogen atom or lower alkoxy group, 2) an aryl group, 3) an aralkyl group, 4) a heteroarylalkyl group, 5) a heteroaryl group, where the aryl, aralkyl, heteroarylalkyl and heteroaryl groups can be substituted with a halogen atom, lower alkyl group, optionally substituted with a lower alkoxy group or 1-3 halogen atoms, lower alkoxy group, optionally substituted with 1-3 halogen atoms, cyano group, hydroxy group, alkylsulphonyl group, cycloalkylsulphonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanoyl amino group, alkyl amino group or dialkylamino group; R10 denotes a lower alkyl group, optionally substituted with 1-3 halogen atoms, or a lower alkylsulphonyl group; X9-X12 denotes a carbon atom or a nitrogen atom, where the carbon atom can be independently substituted with a lower alkyl group, optionally substituted with a halogen atom or a lower alkoxy group, lower alkoxy group, optionally substituted with a halogen atom, or a cyano group or a halogen atom; R3 denotes a) a group of formula (II-1): (ii-U where R4 and R5, taken together with a nitrogen atom, form a 5- or 6-member monocyclic ring, where the monocyclic ring may contain a substitute in form of a lower alkyl group, m1 equals 3; or b) a group of formula (II-2): , where R6 denotes a lower alkyl group or cycloalkyl group; m2 equals 1 or 2; X1-X4 all denote carbon atoms, or one of X1-X4 denotes a nitrogen atom and the rest denote carbon atoms; and where "heteroaryl" in each case relates to a 5- or 6-member aromatic ring containing 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and a sulphur atom. The invention also relates to a histamine H3 receptor antagonist or inverse agonist, as well as a preventive or medicinal agent.

EFFECT: obtaining novel biologically active compounds, having histamine H3 receptor antagonist or inverse agonist activity.

11 cl, 8 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) where R1 is chosen from a group consisting of phenyl, unsubstituted or substituted by one or two groups independently chosen from (lower) alkyl, (lower) phenylalkyl wherein a phenyl ring can be unsubstituted or substituted by one or two groups independently chosen from halogen; R2 represents hydrogen; or R1 and R2 together with nitrogen atom whereto attached, form a saturated 5- or 6-members heterocyclic ring optionally containing an additional oxygen heteroatom, said saturated heterocyclic ring is unsubstituted or substituted by one, two or three groups independently chosen from (lower) alkyl, halogen; R3 is chosen from a group consisting of hydrogen, (lower) alkyl, (lower) hydroxyalkyl, (lower) alkoxyalkyl, (lower) haloalkyl, (lower) cycloalkylalkyl, (lower) cyanoalkyl, (lower) alkylsulfonyl, phenyl unsubstituted or substituted by one or two groups independently chosen from halogen; R4 represents hydrogen or halogen; R5 represents a group chosen from where m represents 0 or 1; n represents 0,1 or 2; X represents CR13R13'; R6, R6', R7, R7', R8,R8', R13, R13' are independently chosen from a group consisting of hydrogen, (lower) alkyl, halogen; p represents 0 or 1; R9 is chosen from (lower) alkyl, cycloalkyl, (lower) cycloalkylalkyl; q represents 0 or 1; R10 represents (lower) alkyl; and to their pharmaceutically acceptable salts, as well as to a pharmaceutical composition exhibiting histamine 3 receptor antagonistic and/or antagonistic activity and based on the compounds of formula I.

EFFECT: there are prepared and described new compounds which can be effective in treatment and/or prevention of the diseases associated with H3 receptor modulation.

24 cl, 34 ex

FIELD: medicine.

SUBSTANCE: invention refers to the compound 3-{[5-(azetidine-1-ylcarbonyl)pyrazine-2-yl] oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazine-5-yl)benzamide or to its pharmaceutically acceptable salt. Also, it refers to a pharmaceutical composition for treating insulin-independent diabetes or obesity containing said compound.

EFFECT: there is produced and described a new compound which can be effective in treating insulin-independent diabetes and obesity.

5 cl, 64 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed are: nutrient composition, which contains 0.5-20 wt % of phospholipids, 0.1-20 wt % of sphingolipids and 0.005-10 wt % of cholesterol from total lipid content, protein and carbohydrates, intended for child form 36 months for prevention of obesity and/or diabetes, its application for treatment of type two diabetes and/or nutrient regulation of type two diabetes, as well as its application for prevention of disorder development, when age of mentioned child exceeds 36 months, said disorder is selected from group, which consists of type two diabetes, hyperglycemia at starvation, insulin immunity, visceral obesity, hyper-insulinemia, hypertension, cardiovascular diseases, cerebral vessel diseases, arthrosclerosis, dislipidemia, hyperuricemia, fatty liver dystrophy and sleep apnea.

EFFECT: reduction of insulin level in blood plasma after introduction of claimed composition against introduction of standard composition for children nutrition, which indicates increased sensitivity to insulin, which favours obesity prevention in more mature age.

10 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I): wherein R means dihydrosubstituted C2-C6alkyl group, and Cy represents spiro[4.5]dec-6-yl, spiro[2.5]oct-4-yl, spiro[3.5]non-5-yl, 3,3-dimethylbicyclo[2.2.1]hept-2-yl or 1-spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropane)-3-yl-group. Said compounds act as nociceptive receptor antagonists, and are applied e.g. as agents improving acceptability of narcotic analgesics, relieving narcotic analgesic dependence or narcomania; as an analgesic intensifier; antiobesity agents or appetite suppressants; agents for treating decreasing cognition and senile dementia /amnesia; agents for treating developing cognition disorder; therapeutic agents in schizophrenia; agents for treating neurodegenerative diseases; antidepressants or therapeutic agents in affective disorder; therapeutic or prophylactic agents in diabetes insipidus; therapeutic or prophylactic agents in polyuria; and therapeutic agents in hypotension and similar.

EFFECT: preparation of the compounds acting as nociceptive receptor antagonists.

11 cl, 5 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: offered invention refers to medicine, namely to surgery, and can be used for prevention of inconsistency of anastomoses of hollow organs in gastrointestinal tract surgery. That is ensured by the oral introduction of 5-oxymethyluracil pills of the weight 1.5 g and diameter 7-7.5 mm on the 2nd postoperative day in the following proportions: 5-oxymethyluracil - 0.5 g, 5 % spirit-acetone acetylphthalylcellulose - 3 layers, 10 % hexane solution of low-molecular polyethylene - 1-3 layers, biological adhesive Sulphacrylate - 1-3 layers.

EFFECT: introduction of 5-oxymethyluracil in said dosage form provides stimulation of repair regeneration ensured by selective maximum concentration of the preparation in gastrointestinal segments where the anastomosis has been created, and reduced ischemic disorders.

1 ex, 1 dwg

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