Conjugates polymyxin b

 

(57) Abstract:

The invention can be used in pharmacy and medicine for the preparation of drugs used in the treatment of syndrome of systemic inflammatory response and septic shock. Water-soluble conjugate or its salt contains polymyxin b or its salt and dextran. He has antiendotoxin activity is higher than the original polymyxin b C. the ratio IC50polymyxin b to the IC50its conjugate is greater than 1.0. The claimed method of obtaining conjugate. Polymyxin b or its salt is subjected to interaction with dextran in aqueous medium of pH from 9.3 to 10. The temperature from 30 to 35°C. the requested farmcampsite containing the claimed water-soluble conjugate. The conjugate has a higher antiendotoxin activity, the method is the best reproducibility. The activity of the conjugate is 125% or more of the activity of natural polymyxin b C. 3 C. and 10 C.p. f-crystals, 3 tables.

The invention relates to a method for producing water-soluble conjugates (or their salts) polymyxin b B (PMB) or their salts and acid by the interaction of polymyxin b B or its salt with the acid in an aqueous medium at a pH of from about 9.3 to about 10, preferably from about 9.5 to sustained fashion variant of the method involves the interaction of polymyxin b sulfate B with oxidized dextran at a temperature of about 32oC covalent joining of molecules polymyxin b B to dextran via an amine linkage. Improved conjugates (or their salts) obtained by the method of the present invention, easily and firmly reproducible and show significantly improved pharmacological properties, such as higher potency and antiendotoxin activity, which is greater than antiendotoxin activity of unconjugated polymyxin b B.

The invention also includes a water-soluble conjugates (or their salts) containing polymyxin B or its salt and dextran, and conjugates (or their salts) are more antiendotoxin activity than antiendotoxin activity of unconjugated polymyxin b B.

The need of medicine in an effective therapy for the syndrome of systemic inflammatory response (SIRS) and septic shock are widely recognized, and the client base is large. It is more than 100000 critical cases of SIRS/sepsis in developed countries, requiring intensive care, and almost 1 million patients with a high risk of sepsis, which could benefit from prevention.

Based on the research of a large group of people and animals endotoxin is recognized as the main initialising approach to sepsis. Endotoxins or lipopolysaccharides are structural molecules in the cell walls of gram-negative bacteria. When introduced into the bloodstream, they can interfere with the regulation of body temperature and cause fever. They also have toxic effects, leading to cardiac, pulmonary and renal disorders. Associated with endotoxin diseases are the leading cause of death among patients in intensive care units.

Unique among antibiotics is the ability of PMB to neutralize endotoxin, which is achieved by linking with a plot of lipid A endotoxin molecules. PMB from Bacillus polymyxa (B. aerosporus) is vysokopatogennym amphiphilic cyclic peptidoglycan. It is also useful in the fight against various fungal infections, especially those that occur in individuals at risk for diseases of the immune system. However, the PMB has some properties that make it not so ideal antibiotic. First, he has a short half-life in the body that require repeated doses to be effective. Secondly, when passing through the kidneys it can cause extensive damage. Third, at high doses, it has neurotoxic properties, fixed molecules, for example, separate (Sepharose) [Issekutz, J. Immunol. Methods, 61(1983), 275-281]. These conjugates useful in the methods of cleaning, not suitable for therapeutic use in vivo.

One approach to achieve pharmacological activity, increased duration or reduced toxicity for the body was to attach drugs to macromolecules of high molecular weight, such as dextran, polyethylene glycol or polyvinylpyrrolidine. Attempts in this direction polymeric conjugation, however, had only limited success. For example, the conjugated form of procainamide hydrochloride (antiarrhythmic drug) was less active and showed a shorter half-life than native procainamide [Schact et al., Ann N. Y., Acad. Sci. 416 (1985), 199-211]. Similarly, a prostaglandin analog B245 associated with the media was less effective (by several orders of magnitude) than the native molecule [Bamford et al., Bioch. Biophys. Acta 886 (1986). 109-118]. Reduction in the power of biological activities have been described for conjugated forms of kallikrein, Aprotinin, bradykinin [Odya et al., Biochem. Pharmacol. 27 (1978), 173-179], anticancer drugs daunorubicin [Hurwitz et al., J. AppI. Biochem. 2 (1980), 25-35] , and mitomycin C [Takakura et al., Cancer Res. 44 (1984), 2505-2510]. Conjugated enzymes availability of substrate [Blomhoff et al. , Biochem. Biophys. Acta 757 (1983), 202-208; Marshall et al., J. Biol. Chem. 251(4) [1976], 1081-1087; R. L. Foster, Experimentia 31(7) [1975] , 772-773: Wileman et al., J. Pharm. Pharmacol. 35 (1983). 762-765]. There are, however, examples of improvement half-life in the bloodstream after conjugation [Wileman, previously; Kaneo, Chem. Pharm. Bull. 37 (1) [1989], 218-220].

It would be desirable to develop a form PBM, which would remain in the bloodstream longer and/or would not have neuro - or nephrotoxicity at therapeutic doses. Described [USP 5177059 and its analogues in other countries, such as EP 428486] conjugates polymyxin b B a polysaccharide such as dextran or gidroxiatilkrahmal, proteins such as albumin, and polymers, such as polyvinylpyrrolidone, polyethylene glycol and polyvinyl alcohol. This patent specifically describes how chemical conjugation polymyxin b B dextran interaction of materials at room temperature (i.e. about 25oC or less) and pH 8.5, and 9.0. The conjugates described in this patent, are less toxic than unconjugated polymyxin B and have antiendotoxin activity, which is not explicitly expressed, but is less than or equal to the activity of unconjugated polymyxin b B.

The method of the present invention is a y is its salts and dextran, which have unexpectedly improved properties compared to known PMB conjugates/dextran, in particular higher antiendotoxin activity than unconjugated polymyxin B, greater efficiency, better reproducibility and better pharmacological properties. Particularly unexpected is the fact that the new conjugates PMB/dextran (or their salts) of the present invention possess firmness and reproducibly higher antiendotoxin activity than unconjugated PMB. While the molecular basis for this unexpected new properties are not fully understood, it is likely that in the reaction conditions applied in the present invention to obtain conjugates, the change in pH alters the distribution of the protons on the basic side chains. At higher pH values, one or more amino groups of the side chain can be made more accessible for connection to a dextran via reductive amination. As each amino group of the side chain will have a characteristic pKa, a higher pH will release each time the same amine. If this amine gives particularly favorable connection (from the point of view of the strength of the conjugate), then there is more than ur. This structure gives the conjugates steadfastly reproducible method activity level, which is higher than the level of activity of natural PMB, such as 125% or more of the activity of natural PMB.

The present invention includes an improved method of obtaining water-soluble conjugate (or its salts) polymyxin b B and dextran, which is useful in the treatment of fungal and bacterial infections and prevention of diseases caused by bacterial endotoxin. Specifically, the present invention relates to a method for producing a water-soluble conjugate polymyxin B/acid (or its salts), which lies in the interaction of polymyxin b B or its salt with the acid in an aqueous medium at a pH of from about 9.3 to about 10 and a temperature of from about 30oC to approximately 35oC. PMB is an antibiotic peptide and a recognized pharmaceutical agent with moderate antibiotic activity. It is clinically used for more than 40 years for local and parenteral applications. The development of bacterial resistance to PMB very rarely. PMB binds endotoxin with an affinity of about 10-6M and can neutralize the biological effects of endotoxin from all clinically value is that to neutralize endotoxin. In addition, in vivo PMB protects against pathology of bacterial sepsis in many animal models, such as acidosis and hypotension with enterobacterial infections, and mortality caused by gram-negative sepsis in dogs, rabbits, rats and mice. It also has potential in the prevention of sepsis in humans, such as in patients with burns.

PMB used to obtain the conjugate of the present invention, commercially available. PMB can be obtained by fermentation polymyxa (Prazmowski) Migula. PMB consists of a mixture of several related Decapeptide. This invention is suitable PMB or its pharmaceutically acceptable salt (such as polymyxin b sulfate B, and the like).

The dextran used in the method of the present invention may be any conventional pharmaceutically acceptable dextrans. Preferably, when the dextran is chemically modified for covalent binding with peptides, for example, is oxidized with an oxidant, such as periodates sodium. The acid should preferably be srednevekovoy molecular weight of from about 25,000 to about 500000; more preferably from about 50,000 to about 200,000; more preferably from about 63000 to what adresine. The most preferred acid is produced by fermentation with Leuconostoc mesenteroides (NRRL B-512). It includes units of glucose, which are [1-6]-related in a long side chain with approximately 5% [1-3] branch. From the side chains of about 85% is from 1 to 2 units of glucose, and the remaining 15% in average of 33 units.

A General method of obtaining PMB conjugates and dextran in aqueous medium is described in USP 5177059 and it is applicable to the present invention. In the preferred embodiment of the present invention, partially oxidized dextran is produced by interaction with an oxidant, such as periodate sodium (NaIO4). This treatment leads to the formation of aldehydes via oxidative cleavage of the adjacent diols on the monomers glucose. Under the influence of PMB or its salt, partially oxidized dextran formed of Chiffony Foundation. Obtaining conjugates in the framework of the present invention requires careful control of pH from about 9.3 to about 10, preferably from about 9.5 to about 10, more preferably from about 9.5 to about 9,7, during the interaction between PMB and dextran, especially at the stage of formation of Chippewa Foundation. the pH is preferably supported using borate buffer, pH is th salt and dextran support from about 30oC to approximately 35oC, more preferably about 32oC. Subsequent introduction of sodium borohydride (NaBH4) restores Chiffony base and the remaining aldehydes and provides a stable, covalent bond, preferably through one or more amine linkages, between PMB and dextran. The conjugate is preferably purified by ultrafiltration, e.g., using membrane, cut-off molecular weight of 10,000 to remove residual PMB, inorganic by-products (such as borates) and potential low molecular weight cleavage products. Before cleaning the pH of the aqueous medium is preferably adjusted to from about 5 to about 7.

The preferred embodiment of the method of the present invention, thus, includes:

a) get partially oxidized dextran interaction of dextran with periodates sodium;

b) subjecting the interaction of polymyxin B or its salt obtained with partially oxidized dextran in aqueous medium at a pH of from about 9.3 to about 10 and a temperature of from about 30oC to approximately 35oC;

d) add sodium borohydride to the resulting aqueous environment; and

g) clean the obtained conjugate polymyxin B/dextran.

Yixing B or its pharmaceutically acceptable salt and dextran, moreover, these conjugates have a higher antiendotoxin activity than antiendotoxin activity of unconjugated polymyxin b B, for use in the prevention or healing treatment of syndrome of systemic inflammatory response and septic shock. It also includes such conjugates and their pharmaceutically acceptable salts) obtained by the method as defined above, and such conjugates and their pharmaceutically acceptable salts), whenever obtained by the process as described above: pharmaceutical compositions containing the water-soluble conjugate (or its pharmaceutically acceptable salt) polymyxin b B or its pharmaceutically acceptable salt and dextran, as defined above, together with at least one pharmaceutically acceptable carrier or diluent; and the application of these conjugates (or their pharmaceutically acceptable salts) upon receipt of the medication for use in the prevention and healing treatment of syndrome of systemic inflammatory response and septic shock.

In the method of the present invention, as well as in the conjugates obtained by this method, the molecular ratio PMB or its salts to the acid is from about 1: 15 to primer the ol polymyxin b B preferably is a pharmaceutically acceptable salt PMB. The conjugate should be considered as water-soluble if it has a solubility in water at 20oC about 25 mg/ml or more, preferably about 50 mg/ml or more; more preferably about 60 mg/ml or more, most preferably about 65 mg/ml or more at 20oC.

Conjugates PMB/dextran (or their salts) obtained by the present invention can be used in a way consistent with the use of the PMB, namely, they can be used either alone, for example as an antibiotic for bacterial or fungal infections, or in combination with other antibacterial and/or anti-inflammatory drugs. You can enter them in any of the forms, which usually do native PMB, for example intramuscularly, intravenously, vnutriobolochechnoe, subcutaneously or topically. Thus, the compositions for intramuscular injections typically contain an effective amount of the conjugate PMB/acid (or its pharmaceutically acceptable salt) in sterile water, saline solution or about 1% HCl. Intravenous formulations typically contain an effective amount of the conjugate in 15% dextrose and sterile water. Vnutriobolochechnoe compositions typically include an effective amount of conjugate mixed with water or saline solution, and perhaps glycerin, and copper sulfate eye drops, or it may be made in the form of ointments or suspensions. Creams for topical application, especially for the burnt surface, typically contain an effective amount of the conjugate PMB/acid (or its pharmaceutically acceptable salt) on the basis of inactive ingredients, such as liquid petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene and emulsifying wax.

Purified conjugates PMB/dextran (or their pharmaceutically acceptable salts) of the present invention is essentially non-toxic. The amount of the conjugate of the present invention, which should be used can be determined based on the number of native PMB, which is usually prescribed to a particular patient, taking into account factors such as passtoyanie and the age and weight of the patient, and the specific activity of the conjugate. Due to the increased effective activity of the conjugate of its low toxicity and its extended duration of action, the dose can be reduced by half or more compared with native PMB.

Molecular weight conjugates of the present invention can be determined, for example, using liquid chromatographically laser scattering) in relation to dextranomer standard having srednevekovoy molecular weight (MW) 79800. The conjugates of the present invention preferably have srednevekovoy molecular weight (MW) from about 55,000 to about 80000; more preferably from about 60,000 to about 80000: most preferably from about to about 63000 76000.

Improved conjugates of the present invention have better reproducibility compared to conjugates known in the prior art, and have a higher antiendotoxin activity than antiendotoxin activity of unconjugated polymyxin b B. Conjugates of the present invention have improved antiendotoxin activity, namely, the ratio of unconjugated polymyxin b B to conjugates of the invention is greater than 1.0; more preferably, less than 1.25 or 1.3; more preferably greater than about 1.4. Here it means the concentration of polymyxin b B, as measured by analysis of the c carbocyanine dye, which cancels 50% shift of optical density carbocyanine dye at 450 nm in the presence of 0.05 mg of endotoxin from E. coli. Here activity (%) is defined as follows:

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Analysis carbocyanine dye represents a biochemical analysis in the. This analysis represents modificatio from the previous message [Ogava and Kanoh, Environ. Immunol. 28 (1984), 1313-1323: Zey and Jackson, Applied Environ. 26 (1973), 129-133] , and it is optimized for use in microtiter plates. In this analysis, the conjugate or unconjugated PMB (positive standard) competes with carbocyanine dye (small cationic compound that changes the spectrophotometric optical density at the binding of endotoxin) endotoxin.

Preparation of reagents for carbocyanines analysis carried out as follows:

1) prepare a 0.15 M solution of sodium acetate and 0.15 M solution of acetic acid. Both unite (40,2 ml of 0.15 M sodium acetate and 159,8 ml of 0.15 M acetic acid) to give 0.03 M acetate buffer;

2) 8.0 mg carbocyanine dye dissolved in 12.5 ml of ethanol. It's all diluted to 37.5 ml of acetate buffer. The result is the final dye solution at 160 μg/ml in 25% ethanol. He was kept on ice in the dark and stirred for at least 30 min;

3) the serial cultivation PMB or each conjugate prepared in 40 mm phosphate buffer (pH of 7.4). Each dilution was six times more than his final concentration test;

4) prepared from, frozen main concentration of 1.0 mg/ml of 0.9% saline solution.

Establish tablets and analyze with the addition of first sample or buffer in the wells of microtiter tablet as follows:

a) control: 100 µl of saline solution and 50 μl of 40 mm phosphate buffer (pH 7,4) in triplicate;

b) positive standard: 100 µl of endotoxin and 50 μl of 40 mm phosphate buffer (pH 7,4) in triplicate;

C) samples PMB: 100 µl of endotoxin and 50 ál of the samples PMB, in triplicate;

g) negative standards: 100 µl of saline solution and 50 ál of conjugate samples, in triplicate;

d) experimental: 100 µl of endotoxin and 50 ál of conjugate samples, in triplicate.

Tablets rotate within a few minutes. In each well, add 150 ál of the dye, the tablet is wrapped in foil and kept on ice in the dark for 60 minutes, the Wells are mixed using a multichannel pipette and read immediately at 450 nm using a tablet reader. Produce calculations reed-turns into a hissing drone to assess IC50.

The invention is illustrated by the following non-limiting examples. All temperatures are in degrees Celsius.

ode for injection and 150 g of dextran. The mixture was stirred at 21-24oC at 140 rpm. /min to dissolve. Add a solution of 3.9 g of periodate of sodium in 60 ml of water for injection (weakly ectothermic, about 1oC). Funnel for adding the wash solution 30 ml of water for injection. The resulting mixture is maintained at 21-24oC for 1 h, This solution is filtered under vacuum through a cellulose acetate membrane filter Corning (Corning, 0.22 μm, 90 mm membrane) and heated to 30-32oC and maintain at this temperature.

B) Obtaining a solution of polymyxin b sulfate B/borate buffer

Getting the start for 45 min before the end of the oxidation of dextran, filtering and heating, as described above in A). A 12-liter, 4-necked round-bottom flask is charged 3,00 l borate buffer with a pH of 9.7 and bring the temperature of the buffer up to 32oC. Then add 45 g of polymyxin b sulfate B, and the resulting suspension stirred at 32oC for 45 minutes Measure the pH of the mixture (originally 9.4) and adjusted to a pH of 9.7 when the 32oWith the addition of 30 ml of 5N NaOH.

Borate buffer was prepared as follows: heated in a 5-liter round-bottom flask is charged 114.3 g desativado of sodium tetraborate and 2,906 l (2.90 kg) of water for injection. The solution is heated to 32oC and the initial cellulose acetate filter Corning (Corning, 0.22 μm, 90 mm membrane) and stored.

C) Interaction of polymyxin b sulfate B with oxidized dextran

Preheated (30-32oC) a solution of oxidized dextran (from stage A) add as quickly as possible to stir the mixture of polymyxin b sulfate B in borate buffer at 32oC (from the stage). After the addition is complete, measure the pH of the mixture (originally 9,5) and adjusted to a pH of 9.7 by adding 18 ml of 5N NaOH. The mixture was stirred at 32oC for 1 h To this heterogeneous mixture is added a solution of 3.6 g of sodium borohydride in 50 ml of water for injection. This mixture was stirred at 32oC for 2 hours To the mixture add another freshly prepared solution of 3.6 g of sodium borohydride in 50 ml of water for injection. The mixture is stirred for 2 h at 32oC. To this mixture add a solution of 3.6 g of sodium borohydride in 50 ml of water. Heating stopped and the reaction mixture is allowed to cool down to room temperature, stirring for 14 hours Measure the pH of the reaction mixture (10,0) and pH adjusted to 5.7 by the addition of 1.27 ml of 1N HCl. The resulting mixture was stirred for 10 min after acidification and filtered under vacuum through a sterile 0.22 μm cellulose acetate membrane filter Corning obtaining for 6.81 g of races is th

The conjugate solution polymyxin B/dextran (from the stage) clean using pre-processed Amicon CH2PRS blocks ultrafiltration membrane cartridges S1Y10. The purified product is removed from the filtration unit and stored frozen at -25oC.

Analysis of the conjugate showed that this product has the following characteristics:

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activity = of 124.7%

the content of the dextran = 65,37 mg/ml

the total content of polymyxin b B = 2,47 mg/ml

the content of free polymyxin b B = 0,65%

attitude PMB/dextran = 37,71 mg PMB/g dextran.

It turns out that at the reaction temperature 32oC and a pH of 9.5, the obtained reaction product is an activity, which is about 125% of the activity of unconjugated PMB.

Example 2

Repeating the method of example 1 and receive conjugate polymyxin B/dextran that has the following characteristics:

< / BR>
activity = for 125.8%

the content of the dextran = 65,30 mg/ml

the total content of polymyxin b B = 2,49 mg/ml

the content of free polymyxin b B = 0,67%

attitude PMB/dextran = 38,06 mg PMB/g dextran

Again, when the reaction temperature 32oC and a pH of 9.5 was obtained conjugate has about 126% activity compared the AI with the method of example 1 (except as indicated) to determine the effect of reaction temperature PMB with dextran at pH of 9.7. Payload (mg PMB/g dextran), medium (μg/ml) and activity (%) is determined. The results are presented in table. 1.

From example 3, it is obvious that when the reaction temperature is reduced to 10oC at a pH of 9.7 resulting product has a low activity.

Example 4

Conjugates polymyxin B/dextran receive in accordance with the method of example 1 (except as indicated) to determine the influence of pH interaction PMB with dextran. Payload (mg PMB/g dextran), mean (ál/ml) and activity (%) is defined as in example 3. The results are presented in table. 2.

The data in the table. 2 show that lowering the reaction temperature to 32oC at a pH of between 9.5 and 9.7 still enables to obtain a conjugate with the activity, which is higher than the activity unrelated PMB (examples 4m, o and 4P), while further increase of pH up to pH 10, not particularly profitable (example 4P).

Example 5

Conjugates polymyxin B/dextran get as in example 1 (except as indicated) and measure their antiendotoxin activity. The results are presented below in table. 3.

Results table. 3 further confirm that optimal conditions are created when the reaction temperature is about 32oC and pH from 1-5 show thus, the use of reaction temperatures from about 30oC to approximately 35oC, preferably about 32oC, and a pH of from about 9.3 to about 10, preferably from about 9.5 to about 9,7, resulting in improved conjugates of the present invention.

1. The method of obtaining water-soluble conjugate (or its salts) polymyxin b or its salts and dextran, in which polymyxin b or its salt is subjected to interaction with dextran in aqueous medium at a pH from 9.3 to 10 and a temperature between 30 and 35oC.

2. The method according to p. 1, wherein the pH is from about 9.5 to about 9,7.

3. The method according to p. 1, characterized in that the temperature is about 32oC.

4. The method according to p. 1, characterized in that the salt of polymyxin b is a sulfate polymyxin b Century.

5. The method according to p. 1, characterized in that the molecular ratio of polymyxin b or its salts to the acid is from about 1:15 to about 200: 1.

6. The method according to p. 1, wherein the dextran has srednevekovoy molecular weight of from about to about 63000 76000.

7. The method according to p. 1 characterized in that use is partially oxidized dextran.

the B. p. 8, characterized in that the borate buffer contains sodium tetraborate.

10. The method according to p. 1, which includes a subsequent interaction with sodium borohydride.

11. The method according to p. 1, to obtain a water-soluble conjugate (or its salts) polymyxin b or its salts and dextran, in which: a) receive and partially oxidized dextran interaction of dextran with periodates sodium; b) subjecting the interaction of polymyxin b or its salt obtained with partially oxidized dextran in aqueous medium at a pH from 9.3 to 10 and a temperature between 30 and 35oC; C) add sodium borohydride to the resulting aqueous mixture; and d) purify the resulting conjugate.

12. Water-soluble conjugate (or its pharmaceutically acceptable salt) polymyxin b or its pharmaceutically acceptable salt and dextran obtained by the method according to p. 1 or 11.

13. Pharmaceutical composition containing water-soluble conjugate (or its pharmaceutically acceptable salt) polymyxin b or its pharmaceutically acceptable salt and dextran, as defined in paragraph 12, in conjunction with at least one pharmaceutically acceptable carrier or diluent.

 

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