Soluble dosage forms containing cephem derivatives applicable for parenteral administration

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to new dosage forms of cephem compounds effective for treating bacterial infections.

EFFECT: dosage forms are stable; they show the improved solubility and are especially applicable for parenteral administration.

9 cl, 29 tbl, 8 ex

 

This application claims priority to provisional application U.S. No. 60/974,194, filed September 21, 2007, the full contents of which are introduced in this application by reference.

The SCOPE TO WHICH the INVENTION RELATES.

The present invention relates to novel dosage forms of the compounds cafema, useful for the treatment of bacterial infections. Dosage forms stable, exhibit improved solubility and are particularly appropriate, for example, for parenteral administration.

BACKGROUND of INVENTION

U.S. patent No. 6,417,175 discloses derivatives phosphonoacetate, with excellent antibacterial activity against a broad spectrum of gram-positive and gram-negative bacteria. These compounds have the General formula:

where R1-R4, Q, X, Y and n are as defined in this patent. One of these compounds is a 7β-[2(Z)-amoxiillin-2-(5-postname-1,2,4-thiadiazole-3-yl)acetamido]-3-[4-(1-methyl-4-pyridinio)-2-thiazolino]-3-cefem-4-carboxylate. U.S. patent No. 6,417,175 discloses methods of obtaining this compound (see, for example, Examples 1, 2, 5 and 6), and in General discloses compositions of the compounds described in this patent.

U.S. patent No. 6,906,055 discloses compounds of the formula:

in which X, not only is et a CH 3COOH, CH3CH2COOH or CH3CN, and n is 0-5. One of these compounds (in which X represents CH3COOH, and n is 1) is (6R,7R)-7-[[2(Z)-amoxiillin-[5-(postname)-1,2,4-thiadiazole-3-yl] acetyl]amino]-3-[[4-(1-methylpyridinium-4-yl)thiazol-2-yl]sulfanyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]Oct-2-ene-2-carboxylate monoacetate monohydrate, which is also known as pyridine, 4-[2-[[(6R,7R)-2-carboxy-7-[[2(Z)-amoxiillin-[5-(postname)-1,2,4-thiadiazole-3-yl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]Oct-2-EN-3-yl]thio-4-thiazolyl]-1-methyl-, inner salt, monoacetate, monohydrate (molecular formula C22H21N8O8PS4. C2H4O2. H2O, molecular weight 762,75). Name drug on the Formulary national nonproprietary names US for this connection is ceftaroline rosamel.

Proposed international nonproprietary name (WHO Drug Information vol 21, No. 2, 2007) ceftaroline rosamel applies to the following compound: 4-[2-[[(6R,7R)-2-carboxy-7-[[2(Z)-amoxiillin-[5-(postname)-1,2,4-thiadiazole-3-yl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]Oct-2-EN-3-yl]thio-4-thiazolyl]-1-methyl-, inner salt. INN name ceftaroline thozamile refers to ceftaroline thozamile adjusted anhydrous, free from acetate base (molecular formula C22H21 8O8PS4molecular weight 684,68)

When parenteral (such as intravenous, intramuscular or subcutaneous administration), proletarienne means, such as 7β-[2(g)-amoxiillin-2-(5-postname-1,2,4-thiadiazole-3-yl)acetamido]-3-[4-(1-methyl-4-pyridinio)-2-thiazolino]-3-cefem-4-carboxylate and ceftaroline rosamel (USAN and INN), develop with the help of body fluids in active antibacterial residue ceftaroline (molecular formula C22H22N8O5S4molecular weight 604,71)

Antibacterial compounds can be administered in several ways, including parenterally, for example, via intravenous (IV) bolus, IV infusion and by intramuscular (IM) injection. Adsorption of drug depends on its bioavailability. Drugs that are administered intravenously, directly enter the systemic circulation and is typically assumed as such, which are 100% bioavailable. However, medicines that are injected intramuscularly, may pass through one or more biological membranes in order to reach the systemic circulation. It is desirable that all parenteral dosage forms have identical bioavailability (i.e., the same area under the curve (AUC) for all p is renderlng dosage forms. However, the pharmacokinetic profiles for CENTURIES and VM compositions may vary, and obtain desired values of bioavailability (i.e., AUC) after intramuscular injection is difficult. For example, the perfusion (blood flow to 1 gram of tissue) significantly affects the capillary adsorption of small molecules with intramuscular injection. Thus, the site of adsorption can affect the rate of absorption. In addition, adsorption of drugs after VM introduction may be delayed or wrong for slightly soluble salts of bases and acids. In addition, VMS composition or dosage form must have sufficient solubility to be able to deliver the required dose in a small injection volume with minimal local irritation. These limitations should be addressed when developing compositions for VM introduction. VM introduction is necessary in some cases, for example, first aid and nursing homes, where the infusion is not feasible.

In addition, for drugs with a short half-life introduction CENTURIES boles typically leads to rapid excretion of drugs from the system of the patient. Rapid IV infusion dosage forms may be desirable in some cases. Though the dosage form must be stable and compatible with CC liquid (for example, to represent 0.9% sodium chloride solution or 5% sugar solution) to carry out treatment. Thus, there is also a need to develop dosage forms with improved solubility, for use in CENTURIES the introduction, when the introduction of large volumes of infusion solution is not desirable, for example, when BB introduction to infants, children and the elderly.

In line with this, there is still a need for new dosage forms, containing a compound cafema that are stable, bioavailable and demonstrate acceptable pharmacokinetic parameters with the introduction of, for example, parenteral.

The applicants were developed dosage forms containing the compound cafema, such as ceftaroline rosamel having high solubility, which is acceptable for parenteral, for example, VV and VM introductions. Dosage forms are stable and exhibit excellent pharmacokinetic parameters with the introduction of, for example, intramuscularly or intravenously.

SUMMARY of the INVENTION

The present invention relates to novel dosage forms of the compounds cafema, in which the active agent has a high solubility. Dosage forms are particularly acceptable for parenteral (e.g. the measures intravenous and intramuscular) injection.

In one embodiment described dosage forms containing ceftaroline or its pharmaceutically acceptable salt and/or MES, and/or Palekastro form and solubilizers agent, where both molarity solubilizing agent in the aqueous solution dosage forms is greater than approximately 0.1 M

In additional embodiments are described dosage forms containing ceftaroline or its pharmaceutically acceptable salt and/or MES, and/or Palekastro the form in which the active agent has a solubility greater than about 40 mg/ml

In some embodiments of the dosage form includes Palekastro form ceftaroline, for example, ceftaroline rosamel.

In additional embodiments are described dosage forms containing from about 223 to about 2005 mg ceftaroline fosamine, where a single dose of parenteral dosage forms provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 10650 ng hour/ml

In additional embodiments are described dosage forms containing from about 223 to about 2005 mg ceftaroline fosamine, where a single dose of IV tubing dosage forms provide Ecevit obtaining in vivo profile in plasma for ceftaroline, characterized by a mean AUC0-∞more than approximately 10650 ng hour/ml, and an average value of Cmaxless than approximately 39500 ng/ml.

In additional embodiments are described dosage forms containing from about 223 to about 2005 mg ceftaroline fosamine, where a single dose of VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 10650 ng hour/ml, an average value of Cmaxless than approximately 39500 ng/ml, and the average value of Tmaxabout 1 or more hours.

Describes the methods of treatment using soluble dosage forms.

DETAILED description of the INVENTION

The present invention relates to novel dosage forms of the compounds cafema that are stable, exhibit improved solubility, and are particularly well-suited for, for example, parenteral (e.g., BB, BM) introduction.

Ceftaroline is an active antibacterial compound useful to treat a wide spectrum of gram-positive and gram-negative bacteria. However, the solubility in water ceftaroline limited (~2-3 mg/ml) and is thus too low to allow the direct application is ceftaroline in compositions for parenteral administration. For example, the maximum dosage ceftaroline, which can be entered from a volume of 100 ml package to IV infusion, is only about 200-300 mg.

Ceftaroline rosamel, proletarienne form ceftaroline has a higher solubility in water (approximately 36 mg/ml). Despite the fact that the solubility proletarienne form is greater than for active rest ceftaroline, solubility in water ceftaroline fosamine is still insufficient to allow ceftaroline thozamile be used directly for VM introduction, where the input quantities are typically 5 ml or less on the site of the injection. For example, the maximum dosage ceftaroline fosamine, which may be injected intramuscularly using 5 ml of solution is only about 180 mg to the site of the injection.

Applicants have found that can be obtained vysokodetalnye dosage forms containing the compound cafema, such as ceftaroline rosamel. Soluble dosage forms are, therefore, useful for parenteral (as BB and BM) introduction to allow you to enter a higher dose of the active ingredient when using smaller volumes of solution. Dosage forms include connection cafema, for example, ceftaroline or its pharmaceutically acceptable salt and/what does MES, and/or Palekastro form as the active agent and solubilizers agent, where solubilizers agent present at polyarnosti such that the solubility of the active agent increases. For example, the solubility of the active agent is increased compared with the corresponding dosage form that does not contain solubilizing agent.

In one aspect the present invention relates to dosage forms containing ceftaroline or its pharmaceutically acceptable salt, and/or MES, and/or Palekastro form (for example, ceftaroline rosamel) and solubilizers agent, where solubilizers agent is present at polyarnosti, greater than approximately 0.1 M

In additional embodiments solubilizers agent is present at polyarnosti, greater than about 0.2 M, greater than about 0.3 M, greater than about 0.4 M, greater than about 0.5 M, greater than approximately 0.6 M, greater than approximately 0.7 M, greater than about 0.8 M, greater than about 0.9 M, greater than about 1.0 M, greater than about 1.1 M, greater than about 1.2 M, greater than about 1.3 M, greater than about 1.4 M, greater than about 1.5 M, greater than about 1.75 M, greater than about 2.0 M, bol is further than approximately 2.3 M or greater than approximately 2.5 M

In additional embodiments solubilizers agent is attended by polyarnosti about 0.5 M, about 0.6 M, about 0.7 M, about 0.8 M, about 0.9 M, about 1.0 M, about 1.1 M, approximately 1.2 M, approximately 1.3 M, approximately 1.4 M, about 1.5 M, about 1.6 M, 1.7 M, about 1.8 M, about 1.9 M, about 2.0 M, approximately 2.3 meters, or approximately 2.5 M for Example, solubilizers agent is present at polyarnosti about 0.5 M, about 1.0 M, about 1.5 M, approximately 2.0 M or approximately 2.3 M

Acceptable solubilizing agents include, but are not limited to, acids such as carboxylic acids, amino acids. For example, solubilizers agent may be selected from saturated carboxylic acids, unsaturated carboxylic acids, fatty acids, ketoacids, aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids, α-hydroxy acids, amino acids and combinations thereof.

Specific solubilizing agents that can be used include, but are not limited to, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, Caproic acid, enanthic acid, Caprylic acid, pelargonium Ki the lot, capric acid, lauric acid, stearic acid, acrylic acid, docosahexaenoic acid, eykozapentaenovuyu acid, pyruvic acid, benzoic acid, salicylic acid, eldarovoy acid, oxalic acid, malonic acid, malic acid, succinic acid, glutaric acid, adipic acid, citric acid, lactic acid, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, praline, serine, threonine, tryptophan, tyrosine, valine, and combinations thereof (including their salts and/or individual stereoisomers, and/or a mixture of their stereoisomers).

In some embodiments solubilizers agent is selected from acetic acid, its salts and their combinations (for example, acetic acid/sodium acetate), citric acid, its salts and their combinations (for example, citric acid/sodium citrate), DL arginine, L-arginine, and histidine. In one embodiment solubilizers agent is a DL-arginine. In one embodiment solubilizers agent is an L-arginine. In one embodiment solubilizers agent is an acetic acid/sodium acetate. In one embodiment solubilizers agent is a citric acid/sodium citrate.

In additional embodiments, R is stoimosti active agent in the dosage form is greater than about 40 mg/ml, such as greater than about 50 mg/ml, greater than about 75 mg/ml, greater than about 100 mg/ml, greater than about 125 mg/ml, greater than about 150 mg/ml, greater than about 175 mg/ml, greater than about 200 mg/ml or greater than about 250 mg/ml, when measured, for example, in water at 25°C.

In additional embodiments, the solubility of the active agent in the dosage form is from about 100 to about 250 mg/ml, from about 150 to about 250 mg/ml, from about 180 to about 200 mg/ml, or from about 200 to about 250 mg/ml, when measured, for example, in water at 25°C.

In some embodiments of the dosage form includes Palekastro form ceftaroline, for example ceftaroline rosamel. Examples of acceptable dosage forms are presented in Tables 1-4.

Table 1:
Dosage forms containing L-arginine
IngredientInterval (mg)The preferred interval (mg)Example 1* (mg)Example 2** (mg)Example 3*** (mg)
Ceftaroline rosamela100-2200200-1400668668668
L-arginine26-135050-800400348174
* 2.3 M L-arginine; ** 2.0 M L-arginine; *** 1.0 M L-arginine
andDose of about 668 mg ceftaroline fosamine (USAN) is equivalent to a dose of approximately 530 mg ceftaroline

Table 2:
Dosage forms containing DL-arginine
IngredientInterval(mg)The preferred interval (mg)Example 1* (mg)Example 2** (mg)Example 3*** (mg)
Ceftaroline rosamela100-2200200-1400668668668
DL-arginine26-135050-800400348174

* 2.3 M DL-arginine; ** 2.0 M DL-arginine; *** 1.0 M DL-arginine
andDose of about 668 mg ceftaroline fosamine (USAN) is equivalent to a dose of approximately 530 mg ceftaroline

Table 3:
Dosage forms containing acetic acid/sodium acetate
IngredientInterval (mg)The preferred interval (mg)Example 1* (mg)Example 2** (mg)
Ceftaroline rosamela100-2200200-1400668668
Acetic acid/sodium acetate10-55024-30016482
* 2.0 M acetic KIS the PTA/acetate; ** 1.0 M acetic acid/acetate
andDose of about 668 mg ceftaroline fosamine (USAN) is equivalent to a dose of approximately 530 mg ceftaroline

Table 4:
Dosage forms containing citric acid/sodium citrate
IngredientInterval (mg)The preferred interval (mg)Example 1* (mg)Example 2** (mg)
Ceftaroline rosamela100-2200200-1400668668
Citric acid/sodium citrate40-55080-1200588294
* 2.0 M citric acid/citrate; ** 1.0 M citric acid/citrate
andDose of about 668 mg ceftaroline fosamine (USAN) is equivalent to a dose of approximately 530 mg ceftaroline

Dosage forms may be obtained, for example, by mixing proletarienne forms of active Agay is that (for example, ceftaroline fosamine) and solubilizing agent (for example, DL arginine, L-arginine, citric acid/sodium citrate, acetic acid/sodium acetate) in a device for mixing under conditions of sterility until a homogeneous mixture. Pre-sterilized vials can then be filled with appropriate amount of sterile mixture. A predetermined quantity of a sterile mixture can then be mixed with the solvent, for example, water, saline solution, sugar solution at a concentration of approximately 5-10% (e.g., glucose, dextrose) and their combination before the introduction. In addition, the solution can be frozen and activitise before additional processing.

Solubilizers agent can be used in solid form or in the form of a solution. If you use a solid form, solubilizers agent and proletarienne form of the active ingredient (for example, ceftaroline rosamel) can be mixed together as described above, after which the solvent is added prior to parenteral administration. If you use the form of a solution, proletarienne form of the active ingredient (for example, ceftaroline rosamel) can be mixed with a solution solubilizing agent before making parenteral administration.

Additional waples the deposits dosage form includes from about 177 to about 2005 mg ceftaroline or its pharmaceutically acceptable salt, and/or MES, and/or proletarienne form, for example, from about 177 mg to about 1337 mg ceftaroline or its pharmaceutically acceptable salt, and/or MES, and/or proletarienne form, for example, from about 353 to about 891 mg ceftaroline or its pharmaceutically acceptable salt, and/or MES, and/or proletarienne form, for further example, from about 353 mg to about 668 mg ceftaroline or its pharmaceutically acceptable salt, and/or MES, and/or proletarienne form.

In additional embodiments of the dosage form includes from about 223 to about 2005 mg ceftaroline fosamine, for example, from about 223 mg to about 1337 mg ceftaroline fosamine, for example, from about 446 to about 891 mg ceftaroline fosamine, for further example, from about 446 mg to about 668 mg ceftaroline thozamile. For example, ceftaroline fosamine (USAN) (molecular formula C22H21N8O8PaS4. C2H4O2. H2O, molecular weight 762,75).

In one embodiment of the dosage form contains about 223 mg ceftaroline thozamile. In one embodiment of the dosage form contains about 446 mg ceftaroline thozamile. In one embodiment of the dosage form contains the approximately 557 mg ceftaroline thozamile. In one embodiment of the dosage form contains about 668 mg ceftaroline thozamile. In one embodiment of the dosage form contains approximately 891 mg ceftaroline thozamile. In one embodiment of the dosage form contains about 1114 mg ceftaroline thozamile. In one embodiment of the dosage form contains about 1337 mg ceftaroline thozamile. In one embodiment of the dosage form contains about 2005 mg ceftaroline thozamile. For example, ceftaroline fosamine (USAN) (molecular formula C22H21N8O8PS4. C2H4O2. H2O, molecular weight 762,75).

In one embodiment of the dosage form contains about 200 mg ceftaroline thozamile. In one embodiment of the dosage form contains about 400 mg ceftaroline thozamile. In one embodiment of the dosage form contains about 500 mg ceftaroline thozamile. In one embodiment of the dosage form contains about 600 mg ceftaroline thozamile. In one embodiment of the dosage form contains about 800 mg ceftaroline thozamile. In one embodiment of the dosage form contains about 1000 mg ceftaroline thozamile. In one embodiment of the dosage form contains about 1200 mg ceftaroline thozamile. In one embodiment of the dosage form contains p is blithedale 1800 mg ceftaroline thozamile. For example, ceftaroline fosamine (INN) (calculated on the anhydrous, free from acetate based, molecular formula C22H21N8O8PS4molecular weight 684,68).

In additional embodiments of the dosage form includes from about 177 to about 1589 mg ceftaroline, for example, from about 177 mg to about 1060 mg ceftaroline, for example, from about 353 to about 706 mg ceftaroline, for further example, from about 353 mg to about 618 mg ceftaroline, for further example, from about 353 mg to about 530 mg ceftaroline. In additional embodiments of the dosage form contains about 177 mg ceftaroline, approximately 353 mg ceftaroline, approximately 442 mg ceftaroline, approximately 530 mg ceftaroline, approximately 618 mg ceftaroline, approximately 706 mg ceftaroline, approximately 883 mg ceftaroline, approximately 1060 mg ceftaroline or approximately 1589 mg ceftaroline. For example, ceftaroline, molecular formula C22H22N8O5S4molecular weight 604,71.

In one embodiment of the dosage form contains about 668 mg ceftaroline fosamine (USAN). In one embodiment of the dosage form contains about 600 mg ceftaroline fosamine (INN).

In one oplemenjivanja form contains approximately 446 mg ceftaroline fosamine (USAN). In one embodiment of the dosage form contains about 400 mg ceftaroline fosamine (INN).

In one embodiment of the dosage form contains about 530 mg ceftaroline.

In additional embodiments of the dosage form contains approximately 353 mg ceftaroline.

In a clinical study of anti-infective drugs the choice of dose, dosing regimen, duration of therapy will be to take into account the biopharmaceutical, pharmacokinetic and pharmacodynamic properties of anti-infective drugs/medicinal product. See, for example, "Developing Antimicrobial Drugs - General Considerations for Clinical Trials," U. S. Department of Health and Human Services, Food and Drug Administration, Draft Guidance for Industry, July 1998.

Pharmacodynamics can establish a relationship between the dose of anti-infective drug and its antimicrobial activity. Combined pharmacokinetic/pharmacodynamic (PK/PD) assessment includes the correlation of concentrations of drugs in plasma with in-vitro sensitivity of microorganisms to target and/or clinical outcomes. Usually the concentration of drug in plasma are associated with the minimum inhibitory concentration (MIC). In addition, the concentration profile of the medicinal product-the time can be converted to produce a single is serenia impact (for example, the area under the curve (AUC) or the time above the minimum inhibitory concentration (T > MIC) and contact microbiological and/or clinical output to determine the optimal dosing regimen. The choice pharmacodynamic variable (e.g., AUC/MIC, the peak concentration in plasma (Cmax)/MIC, T > MIC) depends on mechanisms of antimicrobial effect.

AUC is a measure of the overall impact of antibiotic drugs in the circulation system during the period of time. The concentration of antibiotic funds in serum and the period of time during which the concentration of the antibiotic means is above the MIC, are the pharmacokinetic properties of antimicrobial agents. The product of these two factors is represented by the area under the curve concentration in the serum-time (AUC). Thus, the destruction of bacteria is a function of AUC.

For the development of antibacterial drugs dosage form that is acceptable for parenteral (e.g., VMS) introduction, should have AUC values observed after VM injection dosage forms similar AUC values observed for drugs, when the dosage form is administered intravenously. In addition, must be met acceptable MIC criterion for VM introduction medicine is nogo tool was effective.

Parenteral dosage forms described in this application, provide the following pharmacokinetic parameters.

In intramuscular observed time of maximum concentration in plasma (Tmaxfor ceftaroline (active rest) patients, representing people, about 1 or more hours (e.g., approximately 1.5 hours or more). In additional embodiments of the observed value of Tmaxceftaroline (active rest) patients, representing the people, which ranges from about 1 to about 4 hours, for example, from about 1 to about 3 hours, for example, from about 1.5 to about 2 hours. In other embodiments observed value of Tmaxfor ceftaroline fosamine (proletarienne tool) patients, representing people, about 0.05 or more hours. The time to maximum concentration in plasma is measured after the end of infusion.

(a) In one aspect the present invention relates to a dosage form containing from about 223 mg to about 2005 mg ceftaroline fosamine (USAN), where a single dose for parenteral dosage forms provides obtaining in vivo profile in plasma for ceftaroline characterized by average AU 0-∞more than approximately 10650 ng hour/ml

(b) In one embodiment of the dosage form includes from about 223 mg to about 2005 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by an average value of Cmaxless than approximately 39500 ng/ml.

(c) In another embodiment of the dosage form includes from about 223 mg to about 2005 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 10650 ng hour/ml, and an average value of Cmaxless than approximately 39500 ng/ml.

(d) In an additional embodiment of the dosage form includes from about 223 mg to about 2005 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 10650 ng hour/ml, an average value of Cmaxless than approximately 39500 ng/ml, and the average value of Tmaxabout 1 or more hours.

(e) In another aspect the present izobreteyonija to the dosage form, containing approximately 223 mg ceftaroline fosamine (USAN), where a single dose for parenteral dosage forms provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 10650 ng hour/ml

(f) In one embodiment of the dosage form includes about 223 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by an average value of Cmaxless than approximately 4900 ng/ml.

(g) In another embodiment of the dosage form includes about 223 mg ceftaroline fosamine (USAN), where a single dose continue VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 10650 ng hour/ml, and an average value of Cmaxless than approximately 4900 ng/ml.

(h) In an additional embodiment of the dosage form includes about 223 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 10650 ng hour/ml, an average value is receiving C maxless than approximately 4900 ng/ml, and the average value of Tmaxabout 1 or more hours.

(i) In another aspect the present invention relates to a dosage form containing approximately 446 mg ceftaroline fosamine (USAN), where a single dose for parenteral dosage forms provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 21350 ng hour/ml

(j) In one embodiment of the dosage form includes approximately 446 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by an average value of Cmaxless than approximately 9800 ng/ml.

(k) In another embodiment of the dosage form includes approximately 446 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 21350 ng hour/ml, an average value of Cmaxless than approximately 9800 ng/ml.

(l) In an additional embodiment of the dosage form includes approximately 446 mg ceftaroline fosamine (USAN), where a single dose for VM introduction of dozirovanno the sixth form provides obtaining in vivo profile in plasma for ceftaroline, characterized by a mean AUC0-∞more than approximately 21350 ng hour/ml, an average value of Cmaxless than approximately 9800 ng/ml, and the average value of Tmaxabout 1 or more hours.

(m) In another aspect the present invention relates to a dosage form containing approximately 557 mg ceftaroline fosamine (USAN), where a single dose for parenteral dosage forms provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 25800 ng hour/ml

(n) In one embodiment of the dosage form includes approximately 557 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by an average value of Cmaxless than approximately 11100 ng/ml.

(o) In another embodiment of the dosage form includes approximately 557 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 25800 ng hour/ml, and an average value of Cmaxless than approximately 11100 ng/ml.

(p) In an additional embodiment of dosiro the fair form includes approximately 557 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 25800 ng hour/ml, an average value of Cmaxless than approximately 11100 ng/ml, and the average value of Tmaxabout 1 or more hours.

(q) In another aspect the present invention relates to a dosage form containing about 668 mg ceftaroline fosamine (USAN), where a single dose for parenteral dosage forms provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 28800 ng hour/ml

(r) In one embodiment of the dosage form includes about 668 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by an average value of Cmaxless than approximately 12000 ng/ml.

(s) In another embodiment of the dosage form includes about 668 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than rough is about 28800 ng hour/ml, and average value of Cmaxless than approximately 12000 ng/ml.

(t) In an additional embodiment of the dosage form includes about 668 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 28800 ng hour/ml, an average value of Cmaxless than approximately 12000 ng/ml, and the average value of Tmaxabout 1 or more hours.

(u) In another aspect the present invention relates to a dosage form containing approximately 891 mg ceftaroline fosamine (USAN), where a single dose for parenteral dosage forms provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 49,000 ng hour/ml

(v) In one embodiment of the dosage form includes approximately 891 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by an average value of Cmaxless than approximately 17750 ng/ml.

(w) In another embodiment of the dosage form includes approximately 891 mg ceftaroline fosamine (USAN), where a single dose on the VM I injection dosage form provides obtaining in vivo profile in plasma for ceftaroline, characterized by a mean AUC0-∞more than approximately 49,000 ng h/ml and an average value of Cmaxless than approximately 17750 ng/ml.

(x) In an additional embodiment of the dosage form includes approximately 891 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 49,000 ng hour/ml, an average value of Cmaxless than approximately 17750 ng/ml, and the average value of Tmaxabout 1 or more hours.

(y) In another aspect the present invention relates to a dosage form containing approximately 1114 mg ceftaroline fosamine (USAN), where a single dose for parenteral dosage forms provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 66000 ng hour/ml

(z) In one embodiment of the dosage form includes approximately 1114 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by an average value of Cmaxless than approximately 22500 ng/ml.

(aa) In another embodiment of dozer the private form includes approximately 1114 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 66000 ng hour/ml, and an average value of Cmaxless than approximately 22500 ng/ml.

(bb) In an additional embodiment of the dosage form includes approximately 1114 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 66000 ng hour/ml, an average value of Cmaxless than approximately 22500 ng/ml, and the average value of Tmaxabout 1 or more hours.

(cc) In another aspect the present invention relates to a dosage form containing approximately 1337 mg ceftaroline fosamine (USAN), where a single dose for parenteral dosage forms provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 79500 ng hour/ml

(dd) In one embodiment of the dosage form includes about 1337 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for Sept rolina, characterized by an average value of Cmaxless than approximately 26500 ng/ml.

(ee) In another embodiment of the dosage form includes about 1337 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 79500 ng hour/ml, and an average value of Cmaxless than approximately 26500 ng/ml.

(ff) In an additional embodiment of the dosage form includes about 1337 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than approximately 79500 ng hour/ml, an average value of Cmaxless than approximately 26500 ng/ml, and the average value of Tmaxabout 1 or more hours.

(gg) In another aspect the present invention relates to a dosage form containing about 2005 mg ceftaroline fosamine (USAN), where a single dose for parenteral dosage forms provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than about 126000 ng hour/ml

(hh) In one embodiment to the new form includes about 2005 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by an average value of Cmaxless than approximately 39500 ng/ml.

(ii) In another embodiment of the dosage form includes about 2005 mg ceftaroline fosamine (USAN), where a single dose continue VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than about 126000 ng h/ml and an average value of Cmaxless than approximately 39500 ng/ml.

(jj) In an additional embodiment of the dosage form includes about 2005 mg ceftaroline fosamine (USAN), where a single dose for VM injection dosage form provides obtaining in vivo profile in plasma for ceftaroline characterized by a mean AUC0-∞more than about 126000 ng hour/ml, an average value of Cmaxless than approximately 39500 ng/ml, and the average value of Tmaxabout 1 or more hours.

In additional embodiments of the dosage form of any of the embodiments described above (for example, embodiments of the aa-jj), may include a corresponding number ceftaroline fosamine (INN) or ceftaroline.

Any expert recognizes that a dose of approximately 223 mg CEFTA is oline fosamine (USAN) is equivalent to a dose of approximately 200 mg ceftaroline fosamine (INN), which is equivalent to a dose of approximately 177 mg ceftaroline.

Dose of approximately 446 mg ceftaroline fosamine (USAN) is equivalent to a dose of about 400 mg ceftaroline fosamine (INN), which is equivalent to a dose of approximately 353 mg ceftaroline.

Dose approximately 557 mg ceftaroline fosamine (USAN) is equivalent to a dose of approximately 500 mg ceftaroline fosamine (INN), which is equivalent to a dose of approximately 442 mg ceftaroline.

Dose of about 668 mg ceftaroline fosamine (USAN) is equivalent to a dose of about 600 mg ceftaroline fosamine (INN), which is equivalent to a dose of approximately 530 mg ceftaroline.

Dose approximately 891 mg ceftaroline fosamine (USAN) is equivalent to a dose of about 800 mg ceftaroline fosamine (INN), which is equivalent to a dose of approximately 706 mg ceftaroline.

Dose approximately 1114 mg ceftaroline fosamine (USAN) is equivalent to a dose of approximately 1000 mg ceftaroline fosamine (INN), which is equivalent to a dose of approximately 883 mg ceftaroline.

Dose approximately 1337 mg ceftaroline fosamine (USAN) is equivalent to a dose of about 1200 mg ceftaroline fosamine (INN), which is equivalent to a dose of approximately 1060 mg ceftaroline.

Dose priblisitelno mg ceftaroline fosamine (USAN) is equivalent to a dose of approximately 1800 mg ceftaroline fosamine (INN), which is equivalent to a dose of approximately 1589 mg ceftaroline.

In some embodiments of the dosage forms provide such pharmacokinetic parameters parenteral. In one embodiment of the dosage forms provide such pharmacokinetic parameters for intramuscular introduction. In another embodiment of the dosage forms provide such pharmacokinetic parameters of intravenous. For example, with intramuscular injection at a concentration of approximately 228 mg ceftaroline fosamine (INN)/ml In another example, and intramuscular injection at a concentration of approximately 165 mg ceftaroline fosamine (INN)/ml In another example, when administered intravenously at a concentration of from about 1.2 to about 12 mg ceftaroline fosamine (INN)/ml.

In one embodiment of the dosage form includes ceftaroline rosamel and L-arginine. In another embodiment of the dosage form substantially consists of ceftaroline thozamile and L-arginine. In an additional embodiment of the dosage form consists of ceftaroline thozamile and L-arginine.

In one embodiment of the dosage form includes ceftaroline rosamel and DL-arginine. In another embodiment of the dosage form substantially consists of ceftaroline thozamile and DL-arginine. In an additional embodiment of the dosage form consists of after the Lin thozamile and DL-arginine.

In one embodiment of the dosage form includes ceftaroline rosamel and acetic acid/sodium acetate. In another embodiment of the dosage form substantially consists of ceftaroline thozamile and acetic acid/sodium acetate. In an additional embodiment of the dosage form consists of ceftaroline thozamile and acetic acid/sodium acetate.

In one embodiment of the dosage form includes ceftaroline rosamel and citric acid/sodium citrate. In another embodiment of the dosage form substantially consists of ceftaroline thozamile and citric acid/sodium citrate. In an additional embodiment of the dosage form consists of ceftaroline thozamile and citric acid/sodium citrate.

In some embodiments of the dosage form is a dry powder. In additional embodiments of the dosage form additionally comprises a solvent, such as water, saline, glucose or dextrose at a concentration of from about 5% to about 10%, and combinations thereof.

In some embodiments of the dosage form includes about 668 mg ceftaroline thozamile and approximately 400 mg of L-arginine, about 668 mg ceftaroline thozamile and approximately 348 mg of L-arginine, about 668 mg ceftaroline thozamile and approximately 174 mg of L-arginine.

In some embodied the s dosage form includes about 668 mg ceftaroline thozamile and approximately 400 mg DL-arginine, about 668 mg ceftaroline thozamile and approximately 348 mg DL-arginine, about 668 mg ceftaroline thozamile and approximately 174 mg DL-arginine.

In some embodiments of the dosage form includes about 668 mg ceftaroline thozamile and approximately 164 mg acetic acid/sodium acetate, about 668 mg ceftaroline thozamile and approximately 120 mg acetic acid/sodium acetate, about 668 mg ceftaroline thozamile and approximately 82 mg acetic acid/sodium acetate.

In some embodiments of the dosage form includes about 668 mg ceftaroline thozamile and approximately 558 mg citric acid/sodium citrate, about 668 mg ceftaroline thozamile and approximately 440 mg citric acid/sodium citrate, about 668 mg ceftaroline thozamile and about 294 mg citric acid/sodium citrate.

In some embodiments of the dosage form includes approximately 446 mg ceftaroline thozamile and approximately 267 mg of L-arginine, approximately 446 mg ceftaroline thozamile and approximately 230 mg of L-arginine, approximately 446 mg ceftaroline thozamile and approximately 116 mg of L-arginine.

In some embodiments of the dosage form includes approximately 446 mg ceftaroline thozamile and approximately 267 mg DL-arginine, approximately 446 mg ceftaroline and approximately 230 mg DL-arginine, approximately 446 mg ceftaroline thozamile and approximately 116 mg DL-arginine.

In some embodiments of the dosage form includes approximately 446 mg ceftaroline thozamile and approximately 110 mg acetic acid/sodium acetate, approximately 446 mg ceftaroline thozamile and approximately 82 mg acetic acid/sodium acetate, approximately 446 mg ceftaroline thozamile and approximately 55 mg acetic acid/sodium acetate.

In some embodiments of the dosage form includes approximately 446 mg ceftaroline thozamile and approximately 374 mg citric acid/sodium citrate, includes approximately 446 mg ceftaroline thozamile and approximately 293 mg citric acid/sodium citrate, about 446 mg ceftaroline thozamile and approximately 197 mg citric acid/sodium citrate.

In some embodiments, the drug (ceftaroline) or proletarienne form (for example, ceftaroline rosamel) and solubilizers agent are in the form of a solid substance (e.g., dry powder). In other embodiments, the drug or proletarienne tool and solubilizers agent are in the form of a solution. In additional embodiments, the drug (ceftaroline) or proletarienne form (for example, ceftaroline rosamel) and solubilizers agent are in the form with PENSIONNOGO solution.

In some embodiments solubilizers(s) agent(s) is in a liquid form. Drug (ceftaroline) or proletarienne form (for example, ceftaroline rosamel) can be mixed with liquid solubilization agent (either by adding or without adding additional solvent) prior to parenteral administration.

Methods of treatment

Ceftaroline rosamel (USAN, molecular formula C22H21N8O8PS4. C2H4O2. H2O) and ceftaroline rosamel (INN, anhydrous, free from acetate molecular formula C22H21N8O8PS4molecular weight 684,68) represent N-phosphoramide proletarienne means ceftaroline (molecular formula C22H22N8O5S4). Ceftaroline demonstrates a wide range of efficacy against aerobic and some anaerobic gram-positive and gram-negative bacteria. In particular, ceftaroline has excellent activity against many staphylococci are resistant to medicines, including Staphylococcus aureus (MSRA), methicillin-resistant S. aureus moderate sensitivity to vancomycin (VISA), resistant to vancomycin S. aureus (VSRA) and coagulase-negative staphylococci, methicillin-resistant or having an average degree of h is stateliest to vancomycin (MR-CoNS or VI-CoNS). Their in vitro antibacterial spectrum also includes etiologic pathogens involved in respiratory and other hospital-acquired infections, such as streptococcal (including resistant to penicillin Streptococcus pneumoniae [PRSP]) resistant to ampicillin we did Haemophilus influenzae, Monraxella catarrhalis, the majority of pathogenic enteric bacilli, and selected anaerobic species. Minimum inhibitory concentration that inhibits 90% of microbial strains of these species (MIC90), is usually ≤2 mg/ml In accordance with this, the dosage forms of the present invention can be used to treat a wide range of bacterial infections in patients, such as respiratory infections and urinary tract infections.

In an additional aspect, the present invention relates to methods for treating bacterial infections by injecting the patient who needs it, dosage forms in accordance with one or more embodiments above. In any case, in additional embodiments of the dosage form is introduced parenterally (e.g. intravenously, intramuscularly) in the form of a solution or suspension in a solvent such as water, saline solution, sugar solution in a concentration of from about 5% to about 10% (e.g., glucose, dextrose and combinations thereof.

Definition

If not decree what about the other all technical and scientific terms used in this application, generally have a common value to a person skilled in the art to which this invention.

The term "about" or "approximately" as used in this application means the interval of acceptable errors for private values, as is determined by the average expert in the art, which will depend on how it is measured or determined value, that is, from the limitations of the measuring system. For example, "about" can mean 1 or more than 1 standard deviation, in accordance with practices in the art. Alternatively, "about" can mean interval up to 20%, and preferably up to 10% of this value.

The term "bioavailability" refers to the extent to which the active ingredient or active rest is absorbed from a drug product and becomes systemically available.

The term "effective amount" means the amount of dosage form that when administered to a patient (e.g. a mammal) for treating a disease contains sufficient amounts of the active ingredient in order to carry out such treatment of the disease in order to achieve the purposes of this invention. The term "effective number is the amount" will vary depending on the connection, the disease and its severity, the age, weight, physical condition and sensitivity, etc. of the patient, which is subjected to the treatment.

Pharmacokinetic parameters described in this application include the area under the curve concentration in plasma-time (AUC0-tand AUC0-∞), the maximum concentration in plasma (Cmax), and time to maximum concentration in plasma (Tmax). Can also be provided for the final elimination half-life (T1/2). The time of maximum concentration, Tmax, is defined as the time corresponding to Cmax. The area under the curve concentration in the blood plasma of the time up until the time corresponding to the latest capable of measuring the concentration (AUC0-t), are estimated by numerical integration using the linear trapezoid, as shown below:

AUC0-t=i=2n0.5(Ci+Ci-1)(ti-ti-1)Ypandin n.1

where Cirepresents the concentration of memantine in time corresponding sampling tia n represents the number of time points up to and including the last concentration that can be measured.

The final half-life (T1/2) calculate using the following equation:

T1/2=0.693λzYpandinn.2

where λzis a constant final speed of elimination.

The area under the curve concentration in the blood plasma of the time from time 0 to infinity, calculated in accordance with the following equation:

AUC0-=AUC0-t+Clastλz(Ypandinn.3)

the de C lastis the latest capable of measuring concentration.

The terms "treat" and "treatment" refer to one of the following:

(a) relief or mitigation of at least one symptom in the subject, including, for example, allergic and inflammatory disorders, such as asthma and COPD;

(b) the relief or decrease in the intensity and/or duration of the disorder manifestations experienced by the subject, including, but not limited to, those that occur in response to the stimulus (e.g., pressure, tissue damage, low temperature, and so on);

(c) the relief of, delaying the onset (i.e. the period prior to clinical manifestation of the disorder) and/or reducing the risk of developing or worsening of the disorder.

The subject or patient which the introduction of therapeutic compound is an effective therapeutic regime for the disease or disorder, preferably is a human, but can be an animal, including a laboratory animal in the context of laboratory experiments or screening or activity experiment. Thus, as is clear to a person skilled in the art, the methods, compounds and compositions in accordance with the present invention are particularly well-suited for the introduction of any animal, in the hour of the activity to a mammal, and shall include, but without limitation, humans, domestic animals such as cats or dogs, farm animals, such as, but without limitation, cows, horses, goats, sheep and pigs, wild animals (or living in the wild or in zoos), laboratory animals such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats and so on, various kinds of birds, such as chickens, turkeys, songbirds, and so on, for veterinary medical use.

Pharmaceutically acceptable salts include those obtained by reaction of the primary connection, which functions as the base, with an inorganic or organic acid with the formation of salts, for example salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, Hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, Mandelieu acid and carbonic acid. Pharmaceutically acceptable salts also include those in which the primary connection functions as an acid and reacts with reasonable grounds to education, for example, salts of sodium, potassium, calcium, magnesium, ammonium and choline. A qualified specialist in this field of technology as well I what is known, that salt accession acid can be obtained by reaction of compounds with acceptable inorganic or organic acid by using a number of known ways. Alternatively, salts of alkaline and alkaline earth metals can be obtained by performing the reaction of the compounds with reasonable Foundation using a number of known methods. Below are examples of acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adipate, alginates, citrates, aspartate, benzoate, bansilalpet, bisulfate, butyrate, camphorate, digluconate, cyclopentanepropionate, dodecylsulfate, econsultancy, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic, lactates, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalates, palmoate, pectinate, persulfates, 3-phenylpropionate, picrate, pivalate, propionate, succinate, the tartratami, thiocyanates, tozilaty, mesylates and undecanoate.

The term "proletarienne agent" means a connection representing a drug precursor which, when administered to a subject undergoes a chemical transformation through metabolic or chemical processes with getting active is the STATCOM connection. Acceptable proletarienne means ceftaroline include, for example, ceftaroline rosamel (USAN, INN) and 7β-[2(Z)-amoxiillin-2-(5-postname-1,2,4-thiadiazole-3-yl)acetamido]-3-[4-(1-methyl-4-pyridinio)-2-thiazolino]-3-cefem-4-carboxylate.

The solvate compounds can be formed when the molecule(s) of the solvent is embedded(are) in the structure of the crystal lattice of the molecules of compound, for example, during the crystallization process. Acceptable solvate include, for example, hydrates (monohydrate, sesquihydrate, dihydrate), a solvate with an organic compound (for example, CH3CO2H, CH3CH2CO2H, CH3CN) and their combinations.

EXAMPLES

The present invention will be further described using the following limitiruesh examples. When using the disclosure of these examples it should be borne in mind that the examples are for illustrating the present invention and may not be treated as such, which limit the invention in any way, because a large number of variations and equivalents that are encompassed by the present invention will be understood by a person skilled in the art after reading the present disclosure.

Ceftaroline rosamel can be obtained as described in U.S. patent No. 6,906,055.

Example 1: pH solubility profile ceftaroline thozamile

One-hour and trench Savoy kinetic solubility ceftaroline thozamile was measured at room temperature (25°C) by adding excess ceftaroline thozamile to various USP buffers with pH, the value of which ranged from 1.2 to 9.0 at 0.05 M. the Results are presented in Table 5.

TABLE 5:
the pH solubility profile ceftaroline fosamine (0.05 M)
pHSolubility in 1 hour (mg/ml)The solubility of 3 hours(mg/ml)
1,266
1,999
2,92727
3,73629
5,32626
5,93429
7,32524
8,02924
9,01612

Fluctuations in the composition of the USP buffers: pH=1-2: HClKCl; pH=3-5: sodium acetate; pH=6-9: sodium phosphate

As can be seen from Table 5, the solubility ceftaroline thozamile ranged from approximately 25 mg/ml to about 36 mg/ml within a wide range of pH (from about 3 to about 8, 0.05 M).

Example 2: solubility of ionic compounds ceftaroline fazael-acetic acid/sodium acetate

The impact of polyarnosti acetate ion on the one-hour kinetic solubility ceftaroline thozamile was measured at room temperature (25°C) by adding excess ceftaroline thozamile to various USP buffers with pH value, which ranged from 1.2 to 9.0, at ionic strength acetate ion, which ranged from 0.1 M to 2.0 M. the Results are presented in Tables 6-9.

TABLE 6:
the pH solubility profile of ion mixtures ceftaroline fazael-acetic acid/sodium acetate (0.1 M)
pHSolubility in 1 hour(mg/ml)
3,020
the 3.835
4,636
6,036
6,731
8,231
9.434

Fluctuations in the composition of the USP buffers: pH=1-1: HCl/KCl; pH=3-5: sodium acetate; pH=6-9: sodium phosphate

TABLE 7:
the pH solubility profile of ion mixtures ceftaroline fazael-acetic acid/sodium acetate (0.5 M)
pHSolubility in 1 hour (mg/ml)
3,1126
4,2158
the 4.7156
5,6123
6,8133
8,2125
8,950

Fluctuations in the composition of the USP buffers: pH=1-2: HCl/KCl; pH=3-5: sodium acetate; pH=6-9: sodium phosphate

TABLE 8:
the pH profile of the solubility of ionic compounds C is Carolyn fazael-acetic acid/sodium acetate (1.0 M)
PHSolubility in 1 hour (mg/ml)
2,9213
a 3.9237
pHSolubility in 1 hour (mg/ml)
4,8235
the 5.7212
6,9207
7,7205
8,9102

Fluctuations in the composition of the USP buffers: pH=1-2: HCl/KCl; pH=3-5: sodium acetate; pH=6-9: sodium phosphate

TABLE 9:
the pH solubility profile of ion mixtures ceftaroline fazael-acetic acid/sodium acetate (2.0 M)
PHSolubility in 1 hour(mg/ml)
3.2152
a 3.9273
the 4.7 271
5.9244
6,9225
7,8212
9,0159

Fluctuations in the composition of the USP buffers: pH=1-2: HCl/KCl; pH=3-5: sodium acetate; pH=6-9: sodium phosphate

As can be seen from Tables 6-9, the solubility ceftaroline thozamile significantly increased with increasing ionic strength acetate ion (for example, solubility is greater than 200 mg/ml, with concentrations of acetate 1.0 M and above).

Example 3: solubility of ionic compounds ceftaroline fazael-citric acid/sodium citrate

The impact of polyarnosti citrate ion in a one-hour kinetic solubility ceftaroline thozamile was measured at room temperature (25°C) by adding excess ceftaroline thozamile to various USP buffers with different ionic strength ion citrate, which ranged from 0.05 M to 1.0 M. the Results are presented in Table 10.

TABLE 10:
Profile solubility of ionic compounds ceftaroline fazael-citric acid/sodium citrate
The both molarityDissolve the spine after 1 hour (mg/ml)
0,05121
0,1159
0,5240
1,0245

As can be seen from Table 10, the solubility ceftaroline thozamile significantly increased with increasing ionic strength citrate ion (for example, solubility is greater than 200 mg/ml, with concentrations of citrate, 0.5 M and above).

Example 4: solubility of mixtures ceftaroline fazael - DL arginine

The impact of polyarnosti DL arginine during the one-hour kinetic solubility ceftaroline thozamile was measured at room temperature (25°C) by adding excess ceftaroline thozamile to various USP buffers with different ionic strength DL arginine, which ranged from 0.05 M to 2.0 M. the Results are presented in Table 11.

TABLE 11:
Profile solubility of mixtures ceftaroline fazael - DL arginine
The both molaritySolubility in 1 hour(mg/ml)
0,0513
0,10,5142
1,0233
2,0226

As can be seen from Table 11, the solubility ceftaroline thozamile significantly increased with increasing ionic strength DL arginine (for example, solubility is greater than 200 mg/ml, with concentrations of DL arginine 1.0 M and above).

Example 4: solubility of mixtures ceftaroline fazael - L-arginine

The impact of polyarnosti L-arginine during the one-hour kinetic solubility ceftaroline thozamile was measured at room temperature (25°C) by adding excess ceftaroline thozamile to various USP buffers with different ionic strength L-arginine, which ranged from 0.05 M to 0.5 M. the Results are presented in Table 12.

TABLE 12:
Profile solubility of mixtures ceftaroline fazael - L-arginine
The both molaritySolubility in 1 hour (mg/ml)
0,0539
0,182
0,5 226

As can be seen from Table 12, the solubility ceftaroline thozamile significantly increased with increasing ionic strength L-arginine (for example, solubility is greater than 200 mg/ml, with concentrations of L-arginine 0.5 M and above).

Example 5: solubility of mixtures ceftaroline fazael-histidine

The impact of polyarnosti histidine at one-hour kinetic solubility ceftaroline thozamile was measured at room temperature (25°C) by adding excess ceftaroline thozamile to various USP buffers with different ionic strength histidine, which ranged from 0.05 M to 1.0 M. the Results are presented in Table 13.

TABLE 13:
Profile solubility of mixtures ceftaroline fazael-histidine
The both molaritySolubility in 1 hour(mg/ml)
0,0543
0,175

As can be seen from Table 13, the solubility ceftaroline thozamile significantly increased with increasing ionic strength of histidine. Solubility ceftaroline fosamine at concentrations of histidine above 0.1 M cannot be determined because of the e insolubility of histidine in the mixture.

Example 6: Stability of solutions containing ceftaroline rosamel/L-arginine

Preparing a composition containing 668 mg ceftaroline thozamile and 400 mg of L-arginine. The stability of the aqueous composition (at a concentration of 338 mg ceftaroline thozamile anhydrous, in terms of free acetate base per ml) was determined under the following conditions: (i) 25°C and (ii) 2-8°C. the Results of these studies are presented in Tables 14 and 15, respectively.

TABLE 14:
The stability of the solution ceftaroline rosamel/L-arginine at 25°C
Time (hours)% active from source
Source100
0,5100
199
397
696
2483

As can be seen from Table 14, the solution ceftaroline rosamel/L-arginine is stable at room temperature for more than 6 hours, and, therefore, is acceptable is m for VM injection.

TABLE 15:
The stability of the solution ceftaroline rosamel/L-arginine at 2-8°C
Time (hours)% active from source
Source100
24106
48102
168(7 days)96
336 (14 days)71

The stability of the solution ceftaroline rosamel/L-arginine 250 ml package for infusion was determined under the following conditions: (i) 25°C and relative ambient humidity (RH) and (U) 2-8°C when RH environment. The results are presented in Tables 16 and 17, respectively.

TABLE 16:
The stability of the solution ceftaroline fosamine (≡530 mg ceftaroline) in 250 ml package for infusion at 25°C
Time (hours)% active from source
Source 107
3106
6105
24101
4892
7285

TABLE 17:
The stability of the solution ceftaroline fosamine (≡530 mg ceftaroline) in 250 ml package for infusion at 2-8°C
Time (hours)% active from source
Source107
6106
24110

Time (hours)% active from source
48107
72105

As can be seen from Tables 16 and 17, the solution ceftaroline rosamel/L-arginine is stable at room temperature for several days, and thus the om, is acceptable to IV infusion.

Chemical stability of the mixture ceftaroline rosamel/L-arginine in 0.9% sodium chloride solution in packages for the IV tubing was determined at concentrations ceftaroline thozamile approximately 5 mg/ml in freezing conditions (2-8°C) for 24 or 48 hours, after which the solution was placed for 6 hours in the conditions of room temperature (25°C and at room lighting). The results are presented in Table 18.

TABLE 18:
Chemical stability
The initial (t=0)24 hours at 2-8°C, then 6 hours at 25°C48 hours at 2-8°C, then 6 hours at 25°C
AppearanceClear, colorlessTransparent, slightly yellowTransparent, yellow
PH6,126,136,16
Content (% of initial)10097,2697,87

As can be seen from the Tables is 18, the pH value of the solution in the research process was not changed. Thus, the solution can be used for intravenous injection.

Example 7: Getting songs that are acceptable to the VM and VV introductions

Examples of compositions that are acceptable to the VM and VV introductions, are provided in Tables 19-22.

TABLE 19:
IngredientExample 1 (mg)Example 2 (mg)Example 3 (mg)
Ceftaroline rosamel*668446223
L-Arginine400267133
* 668 mg ceftaroline fosamine (USAN) is equivalent to approximately 530 mg ceftaroline; 446 mg ceftaroline fosamine (USAN) is equivalent to approximately 353 mg ceftaroline; 223 mg ceftaroline fosamine (USAN) is equivalent to 176 mg ceftaroline.

TABLE 20:
IngredientExample 1 (mg) Example 2 (mg)Example 3 (mg)
Ceftaroline rosamel*668446223
DL-Arginine400267133
* 668 mg ceftaroline fosamine (USAN) is equivalent to approximately 530 mg ceftaroline; 446 mg ceftaroline fosamine (USAN) is equivalent to approximately 353 mg ceftaroline; 223 mg ceftaroline fosamine (USAN) is equivalent to approximately 176 mg ceftaroline.

TABLE 21:
IngredientExample 1 (mg)Example 2 (mg)Example 3 (mg)
Ceftaroline rosamel*668446223
Citric acid/Na citrate440293147
* 668 mg ceftaroline fosamine (USAN) is equivalent to approximately 530 mg ceph is arolina; 446 mg ceftaroline fosamine (USAN) is equivalent to approximately 353 mg ceftaroline; 223 mg ceftaroline fosamine (USAN) is equivalent to approximately 176 mg ceftaroline.

TABLE 22:
IngredientExample 1 (mg)Example 2 (mg)Example 3 (mg)
Ceftaroline rosamel*668446223
Acetic acid/Na acetate1208241
* 668 mg ceftaroline fosamine (USAN) is equivalent to approximately 530 mg ceftaroline; 446 mg ceftaroline fosamine (USAN) is equivalent to approximately 353 mg ceftaroline; 223 mg ceftaroline fosamine (USAN) is equivalent to approximately 176 mg ceftaroline.

Solutions with new strength, acceptable to VM or IV tubing, can be obtained from a mixture of ceftaroline rosamel/L-arginine Example 1 of Table 19 (i.e., 668 mg ceftaroline fosamine (USAN) is equivalent to 530 mg ceftaroline) and 400 mg of L-arginine), in compliance and with the following procedures:

223 mg ceftaroline fosamine (USAN) for VM introduction:

Added about 2 ml of sterile water for injection to the mixture. The resulting solution (2.6 ml) had a concentration equivalent to approximately 228 mg ceftaroline anhydrous, in terms of free acetate base /ml was Injected approximately 0,88 ml is equivalent to approximately 177 mg ceftaroline).

446 mg ceftaroline fosamine (USAN) for VM introduction

Added about 2 ml of sterile water for injection to the mixture. The resulting solution has a concentration of about 228 mg ceftaroline anhydrous, in terms of free acetate base/ml was Injected approximately 1.75 ml (equivalent to approximately 353 mg ceftaroline).

668 mg ceftaroline thozamile CUSAN) for VM introduction

Added about 3 ml of sterile water for injection to the mixture. The resulting solution (approximately 3.6 ml) had a concentration of approximately 165 mg ceftaroline anhydrous, in terms of free acetate base/ml is equivalent to approximately 530 mg ceftaroline).

668 mg ceftaroline fosamine (USAN) for VM introduction

Added about 2 ml of sterile water for injection to the mixture. The resulting solution has a concentration of about 228 mg ceftaroline anhydrous, in terms of free acetate base/ml was Injected approximately what part of 2.6 ml (equivalent to approximately 530 mg ceftaroline).

1114 mg ceftaroline fosamine (USAN) for VM introduction

Added about 2 ml of sterile water for injection to two vials containing mixture. The resulting solution has a concentration of about 228 mg ceftaroline anhydrous, in terms of free acetate base/ml was Injected an estimated 4.4 ml (equivalent to approximately 883 mg ceftaroline).

For the introduction of higher doses, for example, a 2005 mg ceftaroline fosamine (USAN), injection can be carried out in two intramuscular site of the patient.

223 mg ceftaroline fosamine (USAN) in a 250 ml infusion for IV tubing

Added about 20 ml of sterile water for injection to the mixture. Transferred approximately 6,67 ml package for CENTURIES infusion, for example, 250 ml of sterile 0,9% saline or 5% dextrose (which is equivalent to approximately 177 mg ceftaroline).

446 mg ceftaroline fosamine (USAN) in a 250 ml infusion for IV tubing

Added about 20 ml of sterile water for injection to the mixture. Transferred approximately 13.3 ml package for CENTURIES infusion, for example, 250 ml of sterile 0,9% saline or 5% dextrose (which is equivalent to approximately 353 mg ceftaroline).

668 mg ceftaroline fosamine (USAN) in a 250 ml infusion for IV tubing

Added about 20 ml of sterile water for injects the th to the mixture. Transferred content (20 ml) in a package for CENTURIES infusion, for example, 250 ml of sterile 0,9% saline or 5% dextrose (which is equivalent to approximately 530 mg ceftaroline).

1337 mg ceftaroline thozamile in a 250 ml infusion for IV tubing

Added about 20 ml of sterile water for injection to the mixture when using two bottles. Transferred the contents of the package to IV infusion, for example, 250 ml of sterile 0,9% saline or 5% dextrose (which is equivalent to approximately 1060 mg ceftaroline).

2005 mg ceftaroline thozamile in a 250 ml infusion for IV tubing

Added about 20 ml of sterile water for injection to mixtures using three vials. Transferred the contents of the package to IV infusion, for example, 250 ml of sterile 0,9% saline or 5% dextrose (which is equivalent to approximately 1589 mg ceftaroline).

EXAMPLE 8: a Randomized, two-part study of single and multiple doses ceftaroline fosamine, parenteral introduced by intramuscular injection and intravenous injection of healthy people

It was a randomized, two-part study of single and multiple doses to determine the pharmacokinetics ceftaroline thozamile and active rest, ceftaroline, notarymobile parenteral (intramuscular injection and intravenous injection).

Part a of the study was a study with a single dose without placebo control. Part In the research was a study of multiple doses.

Part a

Twenty-four subjects (six subjects per treatment group) were randomly assigned to one of four treatment groups (A-D): Introduced next dose when using vials containing 668 mg ceftaroline fosamine (USAN, molecular formula C22H21N8O8PS4. C2H4O2. H2O, molecular weight 762,75).

Group A: Day 1 - Single VM injection 400 mg ceftaroline fosamine (anhydrous, in terms of free acetate-based, 228 mg/ml) (≡53 mg ceftaroline)

Group B: Day 1 - Single VM injection 600 mg ceftaroline fosamine (anhydrous, in terms of free acetate-based, 165 mg/ml) (≡530 mg ceftaroline)

Group C: Day 1 - Single VM injection 600 mg ceftaroline fosamine (anhydrous, in terms of free acetate-based, 228 mg/ml) (≡530 mg ceftaroline)

Day 8 - Single VM injection (within 60 minutes) 600 mg ceftaroline fosamine (anhydrous, in terms of free acetate base) (≡530 mg ceftaroline)

The subjects of group treatment received BB infusion Day 8

Group D: Day 1 - Single VM injection 1000 mg setrole is and fosamine (anhydrous, in terms of free acetate-based, 228 mg/ml) (≡883 mg ceftaroline)

20 Part b

Eighteen subjects were randomly assigned to one of two treatment groups. VM injection was carried out alternately in different directions, gluteal muscle of each subject.

Group E: Days 1-4 - VM injection 600 mg ceftaroline fosamine (anhydrous, 25 terms of free acetate basics, 228 mg/ml) (≡530 mg ceftaroline) every 12 hours

Day 5 - single VM injection 600 mg ceftaroline fosamine (anhydrous, in terms of free acetate-based, 228 mg/ml) (≡530 mg ceftaroline) 12 hours after the last dose of the Day 4

The control group F: Days 1-4 - VM injection of cefepime hydrochloride 1000 mg every 12 hours

Day 5 - single VM injection of cefepime hydrochloride 1000 mg every 12 hours after the last dose of the Day 4 was used as the control group

The duration of the study for treatment groups E and F was 11 days (Days 1 to 10). The amount of fluid for each intramuscular injection podamirowo in Table 23. Dosing solutions for VM injection ceftaroline was prepared using sterile water for injection.

TABLE 23:
Volumes for VM injections
The treatment groupVM ceftaroline rosamel (USAN) injected dose*Equivalent dose ceftaroline fosamine (INN)Concentration (calculated on the anhydrous, free from acetate basis INN, mg/ml)Approximate injection volume (ml)
And446 mg400 mg2281,8
In668 mg600 mg1653,6
668 mg600 mg2282.6
D1114 mg1000 mg2284.4
E668 mg600 mg2282,6
* 668 mg ceftaroline fosamine (USAN) is equivalent to approximately 530 mg ceftaroline; 446 mg ceftaroline fosamine (USAN) is equivalent to approximately 353 mg ceftaroline and 1114 mg ceftaroline fosamine (USAN) is equivalent to approximately 883 mg ceftaroline.

Pharmacokinetic parameters ceftaroline thozamile and ceftaroline was determined using the standard analysis. Blood for research pharmacokinetic parameters were taken from all subjects as described below:

The first blood sample was taken approximately 5 minutes (approximately 0.06 to hours) after injection. The measurement was considered to be substantially equal to zero up to this point.

Part a: 5, 15, and 30 minutes and 1, 2, 4, 6, 8, 12, 18, 24, 36 and 48 hours after injection. In addition, blood was taken from the subjects who received BB infusion immediately before injection of the drug in day 8 and through 20,40, 60 (just before the end of infusion of the investigational medicinal product), 65 and 75 minutes, and 1, 5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours after the start of infusion of the drug in Day 8.

Part b: injection of a drug on days 1 and 5 after 5, 15, and 30 minutes and 1, 2, 4, 6, 8 hours after the first injection on Day 1, immediately before (within 15 minutes) injection of the morning dose on Day 4, after 12 hours after administration of the morning dose on Day 4 (before the introduction of the evening dose) and after 5, 15 and 30 minutes and 1, 2, 4, 6, 8, 12, 24, 36 and 48 hours after the last injection (morning) Day 5.

Pharmacokinetic parameters ceftaroline thozamile obtained in part a of this study are presented in Table 24.

TABLE 24:
The average pharmacokinetic parameters for ceftaroline thozamile INN (proletarienne medium)
RK parameter for ceftaroline fosamine(INN)Treatment With 600 mg (INN) BB (Day 8)Treatment With 600 mg (INN) BM (Day 1) (228 mg/ml)Treatment of A 400 mg (INN) BM (228 mg/ml)Treatment B 600 mg (INN) BM (165 mg/ml)Treatment D 1000 mg (INN) BM (228 mg/ml)
Cmax(ng/ml)3549±4651492±2751113±4182722±5572239±657
Tmax(h)0,67 (0,33-0,98)of 0.50 (0.08 to 1.0 in)to 0.29 (0.08 to 1.0 in)0,75 (0,25-1,0)0,38 (0,08-1,0)
AUC0-t(h ng/ml)2734±3403060±4751950±4014846±9755791±2795
AUC0-∞(h ng/ml)2744±344 3242±4862144±4215118±9856229±2829
T1/2(h)0,07±0,03of 1.57±0.411,21±0.491,06±0,331,87±0,90

AUC0-∞and Cmaxvalues were increased and decreased proportionally with dosage ceftaroline thozamile. Thus, a qualified expert in the art given this disclosure can easily determine the pharmacokinetic parameters for any specific dosage ceftaroline fosamine (or other proletarienne forms ceftaroline) used in a private form of dosage in accordance with the invention. Proletarienne tool in the blood is rapidly converted to the active balance ceftaroline.

Pharmacokinetic parameters for ceftaroline obtained from part a of this study are presented in Table 25.

TABLE 25:
The average pharmacokinetic parameters for ceftaroline (molecular formula C22H22N8O5S4active rest)
RK pair of the ETP for ceftaroline (active rest) Treatment With 600 mg (INN) BB (Day 8)Treatment With 600 mg (INN) BM (Day 1) (228 mg/ml)Treatment And 400 mg (INN) BM (228 mg/ml)Treatment with 600 mg (INN) BM (165 mg/ml)Treatment D 1000 mg (INN) BM (228 mg/ml)
Cmax(ng/ml)19685±22648510±16916971±161614651±329915997±3739
Tmax(h)1,0(1,0-1,0)2,0(1,2-2,0)1.5(1.0 to 2.0)2,0(1,0-2,0)2,0(1,0-2,0)
AUC0-t(h ng/ml)44587±502647466±400635285±615573439±12080109893±31345
AUC0-∞(h ng/ml)44987±504148108±384635611±613173826±12031110265±31283
T1/2(h)2.13±0,312,55±0.492,36±0,22 2,27±0,162,68±0,31
Bioavailability (%)NA107±7,1NANANA

Injected dose when using vials containing 668 mg ceftaroline Fazail (USAN, molecular formula C22H21N8O8PS4. C2H4O2. H2O, molecular weight 762,75). As can be seen from Table 25, systemic exposure (AUC0-∞) ceftaroline (active rest) after a dose of 600 mg ceftaroline fosamine (INN) (≡530 mg ceftaroline) by VM injection at a concentration of 228 mg/ml, defined in Table 23 (Day 1), is approximately equivalent systemic exposure after CENTURIES infusion equivalent to 600 mg ceftaroline fosamine (INN) (≡530 mg ceftaroline) (Day 8), which resulted in an absolute bioavailability of approximately 100%. The value of Cmaxceftaroline for VM injections in the treatment group was approximately 57% lower than the value of Cmaxafter CENTURIES of infusion. Tmaxafter VM injection was approximately 1 to 2 hours, while Nmaxafter CENTURIES infusion was determined around the time of the end of infusion (~1 hour).

In addition, as can be seen from Table 25, the concentration in the blood plasma after VM injection when is ispolzovanie bottles, contains 668 mg ceftaroline fosamine (USAN, molecular formula C22H21N8O8PS4. C2H4O2. H2O, molecular weight 762,75, which is equivalent to 600 mg ceftaroline fosamine (INN) (≡530 mg ceftaroline) at a concentration of 165 mg/ml (as defined in Table 23), was greater than after VM injection 600 mg ceftaroline fosamine (INN) (≡530 mg ceftaroline) at a concentration of 228 mg/ml (as defined in Table 23), which resulted in obtaining values of Cmaxand AUC of approximately 72% and 56%. VM solution containing the equivalent of 600 mg ceftaroline fosamine (INN) at a concentration of 165 mg/ml (as defined in Table 23) is 50% more bioavailable than BB solution with the same power. This is an unexpected result.

Linearly calculated pharmacokinetic parameters for ceftaroline after VM injection single dose ceftaroline thozamile when using vials containing 668 mg ceftaroline fosamine (USAN) at a concentration of 228 mg/ml, as defined in Table 23, are presented in Table 26.

TABLE 26:
Linearly calculated pharmacokinetic parameters for ceftaroline
Dose ceftaroline fosamine (USAN) Equivalent dose ceftarolineThe average value of Cmax(ng/ml)The average AUC0-∞(ng/ml*h)The average value of Tmax(h)
223 mg177 mg3486178061,5
446 mg353 mg6971356111,5
557 mg442 mg7899431632
668 mg530 mg8510481082
891 mg706 mg12570818032
1114 mg883 mg159771102652
1337 mg1060 mg18798133323 2
2005 mg1589 mg281402106032
*Nachine ceftaroline to 177, 442, 706, 1060 and 1589 mg calculated on the basis of the linear terms

Linearly calculated pharmacokinetic parameters ceftaroline fosamine (INN) after the introduction of the VM injection ceftaroline thozamile USAN (at a concentration of ceftaroline fosamine (anhydrous, in terms of free acetate-based, 228 mg /ml, as defined in Table 23) is shown in Table 27.

TABLE 27:
Linearly calculated pharmacokinetic parameters for ceftaroline fosamine (INN)
Ceftaroline Fazail (USAN)Equivalent dose ceftaroline Fazail (INN)The average value of Cmax(ng/ml)The average AUC0-∞(ng/ml*h)The average value of Tmax(h)
22320048411620,3
446400111321440,29
557500121029050,5
668600149232420,5
891800193646480,5
11141000223862290,5
13371200290469720,5
200518004356104580,5

The dose ratio of the number ceftaroline, for example, 668 mg ceftaroline fosamine (USAN) is equivalent to 530 mg ceftaroline. Values for ceftaroline fosamine (USAN) 223, 557, 891, 1337 2005 and mg calculated on the basis of the linear terms.

Pharmacokinetic parameters of the La ceftaroline, obtained from part b of this study are presented in Table 28.

TABLE 28:
The mean values of pharmacokinetic parameters for ceftaroline (molecular formula: C22H22N8O5S4)
RK parameter ceftaroline (active rest)Treatment is 600 mg (INN) VM (Day 1) 228 mg/mlTreatment is 600 mg (INN) VM (Day 5) q 12 h 228 mg/ml
Cmax(ng/ml)11557±341612960 1361
Tmax(h)2,0 (1,0-2,02)2,0 (1,0-2,02)
AUC0-t(h ng/ml)55289±1107665407±11807
T1/2(h)2,54±0,63of 2.51±0.45

The dose ratio of the number ceftaroline, for example, 668 mg ceftaroline fosamine (USAN) is equivalent to 530 mg ceftaroline

Pharmacokinetic parameters for ceftaroline thozamile obtained from part b of this study are presented in Table 29.

TABLE 29:
The mean values of pharmacokinetic parameters ceftaroline fosamine (INN)
RK parameter ceftaroline fosamine (INN)Treatment is 600 mg (INN) BM (Day 1) 228 mg/mlTreatment is 600 mg (INN) VM (Day 5) q 12 h 228 mg/ml
Cmax(ng/ml)1575±5072223±497
Tmax(h)of 0.50 (0.08 to 1.0 in)of 0.50 (0.08 to 1.0 in)
AUC0-t(h ng/ml)3096±8504067±782
T1/2(h)1,17±0,521,11±0,35

The dose ratio of the number ceftaroline, for example, 668 mg ceftaroline fosamine (USAN) is equivalent to 530 mg ceftaroline

Although the invention has been reflected and described by reference to a typical embodiment of the invention, such reference shall be construed as limiting the invention, and no such limitation is not assumed. The invention can be subjected to considerable modification, alteration and use of equivalents in respect of army and functions as will be clear to the average person skilled in the art are familiar with this disclosure. Shown and described embodiments of the invention are only examples and are not exhaustive for the scope of invention. Therefore, the invention is limited only by the spirit and scope of the attached claims, giving full consideration to equivalents in all respects.

Full disclosure of all patents, patent applications and publications cited in this application are entered into it by reference.

1. Dosage form for parenteral administration, containing ceftaroline rosamel or its pharmaceutically acceptable salt, and solubilizers agent, where both molarity solubilizing agent in the aqueous solution dosage forms is greater than about 1.0 M, and where ceftaroline rosamel is ceftaroline rosamel monohydrate (USAN) or ceftaroline fazael-anhydrous-free acetate (INN), and where ceftaroline rosamel has a solubility in water greater than approximately 100 mg/ml

2. Dosage form for parenteral administration according to the point 1, where ceftaroline rosamel has a solubility in water greater than about 200 mg/ml

3. Dosage form for parenteral administration according to the point 1, where solubilizers agent is an L-arginine.

4. Dosage form for parenteral administration according to the point 1, containing approximately 668 mg ceftaroline fosamine (USAN) and approximately 400 mg of L-arginine, where ceftaroline rosamel has a solubility in water greater than approximately 100 mg/ml

5. Dosage form for parenteral administration according to the point 1, containing approximately 668 mg ceftaroline fosamine (USAN) and approximately 348 mg of L-arginine, where ceftaroline rosamel has a solubility in water greater than approximately 100 mg/ml

6. Dosage form for parenteral administration according to the point 1, containing approximately 668 mg ceftaroline fosamine (USAN) and approximately 174 mg of L-arginine, where ceftaroline rosamel has a solubility in water greater than approximately 100 mg/ml

7. Dosage form for parenteral administration according to the point 1, containing approximately 446 mg ceftaroline fosamine (USAN) and approximately 267 mg of L-arginine, where ceftaroline rosamel has a solubility in water greater than approximately 100 mg/ml

8. Dosage form for parenteral administration according to the point 1, containing approximately 446 mg ceftaroline fosamine (USAN) and approximately 230 mg of L-arginine, where ceftaroline rosamel has a solubility in water greater than approximately 100 mg/ml

9. Dozorova the Naya form for parenteral administration in accordance with p. 1, containing approximately 446 mg ceftaroline fosamine (USAN) and approximately 116 mg of L-arginine, where ceftaroline rosamel has a solubility in water greater than approximately 100 mg/ml



 

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4 cl, 2 ex, 6 tbl, 7 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a topical composition containing a combination of natural salt or pure sodium chloride and glucose mixed in ratio 1:1-30 (wt/wt) as an active ingredient in an amount effective for treating bacterial vaginosis caused by Cardnerella vaginalis together with a pharmaceutically acceptable carrier.

EFFECT: invention provides the higher pharmacological activity.

4 cl, 4 ex, 5 tbl

FIELD: medicine.

SUBSTANCE: as active ingredients, a formulation contains fenoterol hydrobromide and ipratropium bromide monohydrate; the excipients are absolute ethanol, triethylcitrate, propellant 1,1,1,4 tetrafluoroethane (HFA-134a) and/or 1,1,1,2,3,3,3-heptafluoropropane (HFA-227ea) and a pharmaceutically acceptable acid specified in hydrochloric, orthophosphoric and citric acids.

EFFECT: increasing the respirable fraction and obtaining an optimised particle release profile.

2 dwg, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics and represents method of treating prostate cancer, which includes introduction to patient of composition, which contains degarelix lyophilisate or its pharmaceutically acceptable salt and excipient, dissolved in solvent, in initial dose 200-300 mg of degarelix in concentration 20-80 mg of degarelix per ml of solvent with the following after 14-56 days after initial dose supporting dose 320-55 mg of degarelix in concentration 50-80 mg of degarelix per ml of solvent, possibly with one or more than one following additional supporting dose 320-550 mg of degarelix in concentration 50-80 mg of degarelix per ml of solvent, introduced with interval from 56 days to 112 days between each supporting dose.

EFFECT: invention provides long release of degarelix from obtained depot of medication without increase of occurrence of side effects.

11 cl, 1 ex, 2 dwg, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and represents a gel biologically active composition for topical application containing chitosan hydrochloride in an amount of 10-20 wt %, an organic acid in an amount of 1-10 wt %, distilled water - the rest. The above organic acid is specified in acetic, ascorbic, glycolic, lactic, citric or succinic acids.

EFFECT: providing a lower toxicity and a wider spectrum of biological action of the composition ensured by the synergetic effect of a reaction of chitosan hydrochloride and the organic acid.

11 ex, 11 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention represents method of preparing viscoelastic protector of corneal endothelium, including dissolution of initial therapeutic component with excessive viscosity in phosphate buffer, filtration and sterilisation until required viscosity value is obtained, characterized by the fact that as initial therapeutic component used is 3% solution of native hyaluronic acid, after dissolution 1% peptide complex, consisting of amino acid desmosine and following short-chained peptides-oligopeptides: GlyTrpIle; IleAspIle; PheArgPro; GlnHisHis; ProHisTyr; ThrTrpTrp; LysPheThr; LysArgMet; PheCysMet; IleIle; AspLysLys; TrpPro; GluThr, is introduced, and sterilisation is carried out by ionizing radiation in the range of radioactive radiation from 78×107 Mrad to 11×108 Mrad.

EFFECT: recovery of biochemical processes in endothelial layer of cornea with constant eye cornea moistening and increase of biocompatibility, which contributes to fast rehabilitation after traumas or surgery.

2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a cefdinir acid salt, represented by formula I, where M represents Na+, K+, NH4+, or Cs+; Y represents SO42- or PO43-, and 1) if Y represents SO42-: if m=1, then n=1; if m=0.5, then n=1.5; and 2) if Y represents PO43-: if m=1, then n=2. Also claimed is a method of obtaining the cefdinir acid salt of formula (I), including preparation of a homogeneous mixture of cefdinir with a solvent, drop introduction into the homogenous mixture of cefdinir of a solution with an equimolar quantity of acid from the group: sulphuric acid, phosphoric acid, with further addition to the obtained transparent solution of an ammonium compound from the group: ammonium acetate, ammonium propionate, gaseous ammonia, aqueous ammonia solution, or with further addition to the obtained transparent solution of a compound of alkali metal from the group: sodium, potassium, cesium; or into the homogenous cefdinir mixture introduced by drop introduction is an equimolar amount of ammonium hydrosulphate or hydrosulphate of alkali metal from the group: sodium, potassium, or ammonium dihydrophosphate or alkali dihydrophosphate of alkali metal from the group: sodium, potassium, after which the obtained product of reaction, taking place for 15 minutes, is concentrated, crystallised, filtered and dried. In case, if acid or the compound contains a sulphate group, the obtained product is cefdinir acid salt, and if acid or the compound contains a phosphate group, the obtained product is cefdinir phosphate salt.

EFFECT: cefdinir acid salt, possessing high solubility.

8 cl, 2 tbl, 48 ex

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