TW200835523A - Cephalosporin derivative formulation - Google Patents

Abstract

The present invention relates to a freeze-dried formulation for cephalosporin derivatives having increased stability and a method for preparing such a formulation using certain excipients for stabilizing the formulation.

Description

200835523 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to freeze-dried formulations of cephalosporin and its derivatives with increased stability and the use of specific 5 excipients to stabilize the formulation. A method of preparing this formulation. [Prior Art] Active pharmaceutical ingredients (API) are contained in the formulation according to their own and external factors.

Easy to degrade. The factors themselves depend on the interaction of the ingredients used in the formulation and its final form with the API in accordance with various external factors. Additional variables for the freeze-dried formulation itself include during manufacturing and after reconstitution

The pH, the amount of acidic and basic components (excipients) used, and their interaction with the API. Specific external factors include processing conditions during manufacturing, environmental conditions during storage or prior to use, and length of time after reconstruction. Examples of processing conditions include temperature, pressure, and the time taken to freeze, sublimate, and dry the formulation. Examples of environmental conditions include temperature, oxygen, humidity, and duration of stress, especially during stability studies. The copending formulation of the cephalosporin derivative of the present invention is described in the patent application EP 1087980. PCT Application No. 06/050631 (Stable cephalosporin Derivative, East Dry § Weekly Formulation) describes a freeze-dried formulation of the cephalosporin derivative of the present invention having increased stability, a solution obtained, and A method for preparing the formulation, and a method for stabilizing a cephalosporin derivative in a freeze-dried formulation 5 200835523 Inconsistent results Gan "Winter mandarin, sound" The use of a specific compound. According to the invention, used as a stabilizer The compound of the agent is preferably mannitol, trehalose and pVp. The advantages and disadvantages of using the special excipient in the freeze-dried formulation have been discussed, and the conclusion is that the stability of the active ingredient of the medicinal ingredient is on the subject. f provides the opposite of the poor news i and can not also get the information on the relationship between the structure of the green object and its stability. Similarly, the role of polyol (such as sugar, alcohol) ^ amino acid (alone Or a combination) cannot be described according to the nature of a set of generalized ^ but based on API research and the amount of the agent used

【Contents】 The present invention is a cold-riding-face and a charm of the charm;

Ming will also step out the exclusion of the ingredients already in the previous formulation. Surprisingly, it has been found that the stability of the formulation of the flavonoid derivative with or without specific ingredients is unexpectedly directed to the proven ability to improve the stability of the formulation during the lingering period. The addition of cephalosporin 200835523 The present invention relates to freeze-dried formulations comprising cephalosporins and their derivatives and a buffer system. The cephalosporin derivative is an anthracene selected from the group consisting of ceftobiprole or its form. The term "form" refers to a pharmaceutically acceptable salt, stereoisomer, tautomer, crystal, isomorph, amorphous, solvate, hydrate, ester present in the formulations of the present invention. , prodrugs or metabolites. The A PI contained in the formulation of the present invention may be a single living component or may be combined with additional antimicrobial or antiviral chemical (small molecule), protein (molecular) or non-proteinaceous active ingredients. Furthermore, the API can be a natural, semi-synthetic or synthetic source, including combinations of these sources. The cephalosporin derivative of the present invention is a ceftobiprole of formula (1) 'an anti-methicillin-resistant S. aureus izwrewsXMRSA) injectable cephalosporin, which is also effective against other important leathers. Lange positive and Gram-negative bacteria,

Wherein R1 is argon, Cu alkyl, optionally fluoro or 〇3_6 cycloalkyl; R 2 is hydrogen or a group selected from the group consisting of -CH2C(=CHR)_C00R, -CH20C0R, -CH(R)0C0R, 20

-CH(R)0C00R, -CH(0C0R)0C0R, CH2COCH2OCOR 7 200835523

R3 is hydrogen or a group selected from the group consisting of -CH2C(=CH2)-COOR, -COOCH2C(=CHR)-COOR, -COOCH2OCOR, -COOCH(R)OCOR, -COOCH(R)OCOOR, -COOCH(OCOR) OCOR,

Cooch2coch2ocor and its constraints are that one of R2 and R3 is hydrogen and the other 112 and R3 are not hydrogen or CV6 alkyl; hydrogen or hydroxy; hydrogen or ω-alkyl; Χ is CH or hydrazine; Its form. Examples of the compound of the formula (1) include (6R,7RKH(Z)-2-(amino-[12,4] σ 塞 、, yl)-2-transiminoamino-ethenylamino]-3-[ (E)-(3,R,5,R)_5,_-based fluorenyl-l,-(5-mercapto-2-keto-[1,3]dioxol-4-ylindole Alkoxy-l-yl-2-keto-[1,3,]diπ-pyridyl-3-ylidene] keto-5-喽-1, aza-bicyclo[4·2· 0] oct-2-ene-2-carboxylic acid or a form thereof, wherein R1, I, R4 and R5 are all hydrazine; 8 200835523

R is a methyl group. Examples of the compound of the formula (I) include a cephalosporin (la) prodrug form or a form thereof (also referred to as ceftobiprole medocaril) which is a highly water-soluble aminic acid group, thus making the formula (la) Suitable for parenteral applications. In solution, the rate at which the prodrug (la) or its form is degraded to the cephalosporin metabolite (Ib) or its form depends on the pH and temperature. As the pH and temperature increase, the rate of degradation increases. In plasma, the prodrug (Ia) is cleaved into a cephalosporin metabolite (lb) (active group) which occurs rapidly. 10 (la):

Examples of compounds of formula (I) also include cephalosporin metabolites of formula (Ib) or forms thereof, bubosin free acid formula (IC) or forms thereof, and cephalosporin trihydrate hydrochloride salt form (Id) or forms thereof: Formula (lb):

9 15 200835523 Formula (Ic):

Prior art formulations provide the prodrug form as sterile; the Donggan product, which is reconstituted using water for injection or other suitable infusion vehicle. In a previously reconstructed prior art example, the prodrug form (333.3 mg) was adjusted to pH 4.5 with citric acid (5·25 mg, 10 mM) and sodium hydroxide and then reconstituted and diluted for intravenous injection. . In a second reconstituted prior art example, the prodrug form (666.6) was adjusted to pH 4.5 using # citric acid (10.5 mg, 10 mM) and sodium strontium oxide, then reconstituted and diluted for intravenous use. In prior art embodiments, prior art formulations comprise a prodrug form, mannitol, and a citrate buffer. In the formulations of the present invention, we have found that mannitol is not desired and that removal of it can improve embodiments of this technique. An example of such a prior art formulation includes water for injection or other suitable infusion vehicle, prodrug form (333.3 mg), mannitol (15% w/w 200835523 amount), and # citric acid monohydrate (5·25) Formulation (1) prepared by mg) and pH-adjusted sodium hydroxide. Another embodiment of this prior art formulation includes water for injection or other suitable infusion vehicle, prodrug form (666.6 mg), mannitol (丨 5% by weight/weight), and # citrate monohydrate (1〇) • 5 mg) and a pH adjusted sodium hydroxide prepared from the formulation (II). These formulations were then similarly reconstituted and diluted for intravenous injection. 10 15 20 In prior art embodiments, this prior art formulation requires a reconstitution diluent for prior art formulations, water for injection, 1 mg/mL dextrose (glucose), 8.4 mg /mL of citric acid monohydrate (4 〇 and withstand pH to 5 〇 sodium hydroxide. In the formulation of the present invention, I have found that a buffer system is used in the compounding mixture, in the freezing Pre-drying addition can improve this prior art embodiment. Due to the complexity of the chemical structure and properties of formula (1), the previous formula (la) exhibits a stability of = based on compatibility with the excipients of the formulation towel, / It is still difficult to predict, especially in biologically compatible formulations and classes. These know-how challenges the general techniques and practices of this technology. It is related to the preparation of immediate medical use. The use of green prodrugs and daily observance depends on the characteristics of the formulation, such as biocompatibility, stability under II conditions or as close as possible to the surrounding conditions, long-term (four): duration, with reconstruction capacity ^ Sex and dry in or around the situation, 40% A predetermined reconstitution solution. This object can be achieved in the present invention by balancing the enthalpy of the formulation, the buffer concentration, and the buffering of the compound mixture at the cold beam. Therefore, there is still a need for a method of formulation and reconstruction, 11 200835523 for preparation These formulations provide the desired properties and characteristics, such as those indicated above. In the practice of the prior art, the formulation (1) is obtained by containing the buccal botanic, mannitol, citrate buffer and water in the vial. The 2.5 mL solution was made by cold/east drying. The prior art formulation (II) was likewise produced by freeze-drying 5 mL of the solution. Prior art freeze-drying methods for prior art formulations, including The aqueous solution or suspension of the mash and the excipient is placed in a sales container, and the lyophilization is carried out by freezing the solution or suspension and then lowering the pressure in the freezer for a period of time. The filled formulation (1) (2.5 The volume of mL) and the formulation (11) (5 mL) must be placed in the shipping container before freezing. The initial drying step removes water vapor from the frozen material by sublimation and gives a semi-dried mass. The temperature is then raised for a period of time for a second dryness to remove residual water from the semi-dried agglomerate. The sales container is then sealed. The prior art lyophilized formulation is then stored and then reconstituted to reconstitute the solvent. Reconstitution 'where the solvent has a high buffer concentration (40 mM) or buffering capacity and sodium hydroxide to obtain a pH of 5 after reconstitution. The 'previous technical formulation (1) and the formulation (II) as described above have several disadvantages. PCT application WO 06/050631 describes the use of stabilizers such as amino acids, carbohydrates, polyols and polyvinylpyrrolidone (pvp), including mannitol, trehalose and PVP. Understanding the effect of excipients on the stabilization of Αρι usually It is not true science but technology. In general, those skilled in the art must conduct detailed design studies to clarify the interaction between various excipients and API combinations, as the nature of the excipients in the composition is 12 200835523 3 2 for the final cold-drying The effect of product stability. Therefore, = towel, polymorph, (iv) is the interaction of mannitol. This is based on a generalized nature, but no results have been observed based on the amount of excipient used in API Study 5. We have found that the use of mannitol in the Donggan formulation causes the formation of the young (10) prodrug a after reconstitution, thus rendering the prodrug form inactive and limiting the shelf life of the product. Therefore, the use of mannitol is contraindicated. Formula (le):

10 15 When using a commercially available vehicle such as water for injection or 5% dextrose injection, the prior art formulation (I) and the formulation (IIXpH .·, 5 ' are used during manufacturing after reconstitution. 1 mM citrate buffer) formed an opal or 2 turbid solution. This turbidity is an undesirable property and requires the use of a specific reconstitution solvent with high buffering force and sodium hydroquinone to obtain a pH 5.0 after reconstitution and to produce a clear reconstituted solution. ^^ The formulation of the present invention provides a buffer system that is added to the formulation mixture prior to lyophilization, which produces a higher post-reconstitution pH range and a higher buffer concentration, thus providing improved appearance and stability of the reconstituted and infusion solution. Sex, so it is not necessary to first technically rebuild solvents. 13 200835523 Furthermore, prior art reconstitution formulations (I) and formulations (II) have essentially lower buffering capacity, thus making the formulation very sensitive to pH shifts in commercially available infusion vehicles. From the standpoint of stability, this sensitivity is also an undesirable characteristic, and it is not until this time that the reconstitution solvent using a high buffering capacity is used. However, even with the high buffering capacity of the reconstitution solvent, the prior art reconstitution of the pH sensitivity of the formulation (I) and the formulation (II) significantly reduces the pot life and allows the infusion solution to have only a short processing time. A prior art freeze-drying method in which a liquid volume formulation (1) (2.5 mL) and a formulation (11) (5 mL) are placed in a sales container 10 prior to freezing by using a bulk lyophilization method It may then be advantageous and more effective to fill the dry powder aseptically into a shipping container. By manufacturing a sterile formulation by bulk beam drying, the manufacturing throughput can be significantly increased. Formulations of the present invention include ingredients which increase the stability of the final form during manufacture, storage and reconstitution prior to use. 15 The present invention provides a composition in the form of a lyophilized formulation comprising a compound of formula (la) and a buffer system. The present invention provides a composition in the form of a lyophilized formulation comprising a trihydrate hydrochloride salt of a compound of formula (Id) and a buffer system. The present invention provides a composition in the form of a bulk lyophilized formulation comprising a compound of formula (la) and a buffer system. The present invention provides a composition in the form of a bulk lyophilized formulation comprising a trihydrate hydrochloride salt of formula (Id) and a buffer system. The term "formulation" or "composition" means a product containing one or more compounds of formula (I), formula (la), formula (lb), formula (Ic), formula (Id) or a form thereof (Example 14) 200835523 A specific component of a product, and any product produced by a direct or indirect composition. The term composition ^ is used by L for the father, so it is desirable that the two terms have similar meanings to the two (10), and it is desirable to adopt the skill of the present invention: 忿 the invention of the invention can be further included - ❹ (4) When the extra-head component of t疋 provides a stabilizing effect of the formulation, “: 医::: 二 々 is commonly used in cold-baked dry form: = followed by excipients. Also familiar with the preparation of pharmaceutical preparations Whitening additives such as flavoring or dyeing agents can also be used. None, sexual phase infusion systems contain - or a variety of acids selected from acids, tests and compliance. Acid, single, multiple or multiple acid Or the additional buffer system of the present invention can also be used alone (including hydrates) and in any combination thereof, the final two: ==== Cognition by those skilled in the art = generating a buffer system compatible with AH and its salts. Embodiments of the column and the vertical compound include a buffer system which comprises a deuterium, a salt, an acetate salt, Acetic acid, arginine, ascorbic acid 20 200835523 salt, ascorbic acid, bicarbonate, carbonic acid , carbonic acid, citrate, citric acid, glutamate, glutamic acid, glycine, histidine, hydrochloric acid, hydrogencarbonate, lactate, lactic acid, maleate, maleic acid, phosphate, Phosphoric acid, potassium dihydrogen phosphate, potassium hydroxide, dipotassium phosphate, sodium bismuth oxide, succinic acid 5 salt, succinic acid, tartrate, tartaric acid, tris(hydroxydecyl)aminomethane (TRIS), and combinations thereof. Embodiments of the compounds of the present invention further include a buffer system comprising an acid, a base, and a salt selected from the group consisting of a base and a salt: acetate, acetic acid, arginine, ascorbate, ascorbic acid, bicarbonate, citrate , lemon 10 acid, glutamate, glutamic acid, glycine, histidine, hydrochloric acid, lactate, lactic acid, acid salt, acid, acid bismuth, potassium argon, acid Sodium citrate, succinate, succinic acid, tartrate, tartaric acid, and combinations thereof. Embodiments of the compounds of the present invention also include a buffer system comprising an acid selected from the group consisting of citrate, citric acid, glutamic acid, hydrochloric acid, 15 phosphate, phosphoric acid, and combinations thereof. Examples of compounds of the invention include buffer systems comprising a combination of acids, bases, and salts selected from the group consisting of potassium dipotassium phosphate, phosphate/citrate, sodium dihydrogen phosphate, tartrate/citrate, and the like. . An example of the invention is a buffer system comprising an acid, a base and a salt, wherein the 20 acid is selected from the group consisting of citric acid, glutamic acid, hydrochloric acid, phosphoric acid, and combinations thereof; and wherein the base is selected from the group consisting of potassium hydroxide or hydroxide Sodium and combinations thereof. Another example of the present invention is a buffer system comprising an acid, a base, and a salt, wherein the acid is an acid-like acid, and wherein the test is a gas-oxidized nano. The concentration (mM) of the buffer system in the examples of the present invention is determined by the solubility and compatibility of the acids, bases and salts used in 16 200835523. For cold-dried formulations, another factor determining the concentration depends on the ability of the buffer system to freeze dry. Embodiments of the invention include a buffer system concentration of about 1 mM, or 5 about 10 mM, or about 25 mM, or from about 10 mM to about 25 mM, or

From about 10 mM to about 35 mM, or from about 10 mM to about 40 mM, or from about 10 mM to about 50 mM, or from about 10 mM to about 100 mM, or from about 25 mM to about 35 mM, or From about 25 mM to about 40 mM, or from about 25 mM to about 50 mM, or from about 25 mM to about 100 mM, ίο or from about 25 mM to about 200 mM, or from about 50 mM to about 200 mM Within the scope. Embodiments of the invention include a buffer system concentration of about 25 mM, or from about 10 mM to about 50 mM, or from about 25 mM to about 50 mM, or from about 25 mM to about 200 mM, or from about 50 mM to about Within the range of 15 mM 200 mM. Examples of the invention also include buffer system concentrations in the range of about 25 mM, or from about 10 mM to about 50 mM. An example of the invention additionally includes a buffer system concentration in the range of about 25 mM. 20 Embodiments of the invention include leavening agents such as, but not limited to, cellobiose, cyclodextrin, gelatin, gentian disaccharide, isomaltose, isoflavone, iso-trehalose, lactose, maltodextrin, Maltose, melibiose, PVP, sorbose, sucralose, sucrose or trehalose or turanose. The ratio of the leavening agent to the A PI in the examples of the present invention is determined by the solubility of the leavening 17 200835523 agent. In the case of cold; east dry formulations, another factor determining the ratio depends on the ability of the leavening agent to cool. A consistent embodiment of the present invention includes a weight/weight (W/W) ratio of a leavening agent ·ρι (a leavening agent to API) of about 〇:1, or about 1:5, or about 1:1 〇, Or about 5:3:100, or from about 1:10 to about 〇:1, or from about 丨:1〇 to about 1:1〇〇, or from about 1:100 to about 5:100, or from about 1 : 2 〇〇 to about 1:8 〇〇, or from about 1:250 to about 1:600, or from about 1:1 〇〇 to about 1:15 。. Embodiments of the invention additionally include a leavening agent: the ratio of (w/w) of the API is from about 1:100 to about 5:100, or from about 1:2 to about 1:8, or from 10 from about 1:250 to about 1:600, or about 3:100. Embodiments of the invention also include a leavening agent: Αρι is in the range of about 3:100. Embodiments of the invention include surfactants such as, but not limited to, phosphonium (e.g., egg s), sorbitol, poloxamer (e.g., 15 polyoxyethylene) (20) sorbitan monooleate or stearic acid-40-polyoxyl ester), tyloxapol, polyoxyethylene polyoxypropanol copolymer (eg, Pluronic surfactant),丨2_polyoxyethylene ester of stearic acid (such as Solutol surfactant), cholesterol ethoxylate (such as diglyceride or dialkyl glyceride), bile salt (such as sodium cholate), sucrose ester (eg sucrose 20 monolaurate or sucrose monooleate) or polyvinyl alcohol (PVA) and analogues thereof. Examples of the invention include cephalosporins and derivatives thereof and analogs in the form of pharmaceutically acceptable salts. For medical use, the "medical acceptable salt" of the cephalosporin derivative of the present invention means a non-toxic acid/anion or an assay / 18 200835523 cationic salt form. A combined salt form includes an acid addition salt, which may be, for example, by a member of the invention? l 溶液 奸 生物 biological solutions and acids such as acetic acid, adipic acid, benzoic acid, phenolic acid, citric acid, fumaric acid, glycolic acid, hydrochloric acid, maleic acid, propylene glycol, phosphoric acid, saccharin acid, amber A solution of an acid, sulfuric acid, tartaric acid, trifluoroacetic acid, and the like is mixed to form. Further, when the cephalosporin derivative of the present invention is combined with an acidic group, the salt of the salt may include a metal salt such as a sodium salt or a salt, and a metal salt such as a calcium salt or a magnesium salt. And salts formed with suitable organic ligands such as quaternary amine salts. Therefore, its representative salts and alkali or alkaline earth metal salts, including the following: acetate, adipate, benzenesulfonate, benzoate, hydrogencarbonate, barium sulfate, hydrogen tartrate , borate, bromide, calcium salt, bar moon salt (camsylate or camphosulphonate), carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate (edentate), fumarate, gluconate, glutamate, glycolate, hydrabamine, hydrobromide, hydrochloride, hydrazine, isosulfonate, lactate, malate , maleate, malonate, mandelate, carboxate, nitrate, oleate, pamoate, palmitate, phosphate/diphosphate, sugarate, Salicylate, stearate, sulfate, succinate, tartrate, tosylate, trichloroacetate, trifluoroacetate, and the like. Examples of the invention include salts such as, but not limited to, acetates, bicarbonates, chlorides, glutamates, hydrochlorides or sodium salts; alkali metal sodium 19 200835523 salts such as edetate (EDTA) Four nano-), multi-base g salt ((jocusate) (i, 4-bis(2-ethylhexyl) phosphorus succinate), potassium bicarbonate or potassium carbonate; or alkaline earth metal salts such as magnesium stearate and Hydrates of the foregoing. Embodiments of the invention include preservatives such as, but not limited to, methyl and 5 propyl p--basic formate, benzethonium chloride, sodium thiomersal (sodium) Mercurothiolate, phenylmercuric nitrate, benzyl alcohol, phenol, and m-cresol. Embodiments of the invention include cosolvent systems such as, but not limited to, alcohols (eg, sterols, ethanol, propanol, third Butanol), glycerides, polyethylidene alcohol, propylene glycol, vegetable oil, and the like. Embodiments of the present invention include cephalosporins and derivatives thereof and analogs thereof having solubility-increasing properties via their own dissolution mechanism. The formulation of the present invention can be added by adding A suitable solvent or suitable reconstitution/pool is reconstituted into a liquid form for administration via a parenteral, intramuscular or oral route, or administered directly to the subject via an oral route. Additionally, liquid or dry formulation The cephalosporin derivative of the present invention includes its form, for example, including a drug and a prodrug form thereof. 2 () Shuming - Examples include dissolution of the material, sublimation, and lining buffer a derivative of the cephalosperm, thereby buffering the pH of the reconstituted substance to prevent precipitation and degradation of the cephalosporin derivative. "The present invention also includes the use of the metabolite of the formula (10) as a provenance. (la) a cephalosporin prodrug to maintain the degree of resolution of the prodrug during the lv administration. Thus, the formulation of the invention may comprise - or a plurality of formula (1), formula 20 200835523 (la), formula (lb), formula (Ic) A compound of the formula (Id) and mixtures thereof. An example of the invention comprises a compound of the formula (la), a compound of the formula (Ib) and mixtures thereof. The cephalosporin metabolite of the formula (lb) is a solvated prodrug of the formula (Ia) The original 5 10 15 degradation product, this metabolite is also present after the donor The active metabolite in the living body of the therapist. The presence of the "species source" metabolite, after the reconstruction of the Donggan formulation, regulates the degradation of the solvated prodrug by maintaining the solubility of the prodrug. Increased the solubility of the cephalosporin prodrug and increased the time of significant degradation of the prodrug in the liquid. In the buffer system, the cephalosporin metabolite of formula (lb) was provided as a "species source for the invention" at 25〇c The stability of the post-reconstruction is as high as 24-30 hours and the stability after reconstitution is at least the ligand. Zhou-Η excludes the injury that clearly reduces the stability of the final form. In particular, the use of _· and the use of Lai will increase the rate of degradation of cephalosporin = = the existence of the deposit - only need to adjust the water, the solution of the sister amount of the derivative derivative The problem of the agent. Previously adjusted to 〜 疋 疋 迁 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属 金属One or more cephalosporin derivatives and mono-derivative formulations are selected for one or more cephalosporin derivatives of lyophilized cephalosporins including a buffer system. The present invention is derived from cephalosporin or a form thereof. 21 20 200835523 Embodiments of the invention include a sporomycin derivative selected from the group consisting of a cephalosporin prodrug and a metabolite thereof. The cephalosporin derivative of the present invention may be, for example but not limited to, a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a crystal, a homomorph, an amorphous, a solvate, a hydrate. , ester, prodrug or generation form. The present invention encompasses all such cephalosporin derivatives in the form of mixtures thereof. The term "isolated form" means that the cephalosporin derivative of the present invention may exist in an essentially pure state such as, but not limited to, a mirror image isomer, a racemic mixture, a regioisomer (for example, cis or Mixtures of stereoisomers and their analogs. The present invention encompasses all such cephalosporin derivative forms and mixtures thereof. The present invention includes various isomers of cephalosporin derivatives and mixtures thereof. The term "isomer" refers to a cephalosporin derivative which has the same composition and molecular weight but differs in physical properties and/or chemical properties. These materials have the same number and type of atoms but differ in structure. The difference may be in construction (regional isomers) or in the ability to rotate the polar plane (optical isomers). 9 The term "stereoisomers" refers to atoms having the same molecular formula and the same covalent bond atomic sequence. Isomers with different spatial orientations. The π optical isomers mean that the isomers of the same structure differ only in the arrangement of the groups of the groups. The optical isomers rotate in different directions. The term "optically active" refers to the angle at which the optical isomer rotates the polar plane. The term "racemate" or "racemic mixture" refers to a molar mixture of two mirrors 22 200835523 isomers, Among them, the auroral plane is turned off, so that the mixture is missing in the opposite direction. The term "mirror isomer" refers to the shoulder of the term "radiation (four) structure ^. The term "pair of palm" refers to having no. "In contrast to the non-palphaite molecule, it can be divided into two different mirror images of the opponent's two molecules. The way it is based on it is also called left-handed (left-handed), abbreviated L, or right-handed abbreviation D. The symbols "R" and "S" represent 疋 (right-handedness) ' 10 15 20 ′′ representing the configuration of a group surrounding a stereoscopic carbon atom. Examples of separation of the enantiomer-rich form from a racemic mixture include right-handed The mirror image isomer's towel composition does not contain a levorotin. In this context, substantially no levo isomer is included, and the range may be less than 25° according to the following formula. Mixture, less than 1%, less than 5%, less than 2% or 1% mixture: % left-handed = (left-handed)_X 1〇〇 (dextrorotatory) + (left-handed) Similarly, examples of separation of the enantiomer-rich form from the racemic mixture include left-handed mirroring An isomer, wherein the mixture is substantially free of a dextrorotatory isomer. In this context, substantially no dextrorotatory isomer is included, and a range of less than 25% of the mixture may be included according to the following formula, low Mixture of 10%, less than 5%, less than 2% or less than 1%: 23 25 200835523 % dextrorotatory X 100 丄 right condensate) (dextrorotatory amount) + (left-handed amount) term "regional isomer "" refers to the orientation of the substituent atom and the related obstacle-carbon double bond, Wei-based ring or isomers different from the bridged Shuangxian. Substituents (other than hydrogen) on each side of the Shihu-carbon double bond can be in the £ or 2 configuration. In the configuration, the 'substituent' is on the opposite side of the associated carbon-carbon double bond. In the "z" configuration, i replaces the secret toward the _carbon·money bond. The substituent atom (other than hydrogen) to which the medium is attached may be cis or trans =. In the "cis" configuration, the substituents are in the phase configuration of the relevant ring plane, and the substituents are in the cephalosporin and "trans" mixture of the relevant cephalosporins. _ The biological atomic configuration is called "cis/trans". The purity of the substance and the isomer description symbol ("R "s "7 15 20 configuration and as defined in the literature (", s. Further drumming, by formulating the isomers with the appropriate materials, the isomers of the isomers of the vinegar or the enriched amine (subsequently using the heterogeneous mixture of the auxiliaries) or the intermediate or the final The product is heterozygous; Further, the cephalosporin derivative of the present invention may have a _ a foreign form or an amorphous crystal form, and the like is intended to be included in the range of 25 200835523. Furthermore, the cephalosporin derivative may form a solvate with water (i.e., hydrate) or a common organic solvent (e.g., an organic ester such as glycolate and the like), and the solvates are also encompassed by the present invention. Within the scope. The term "stable" or "stable prodrug formulation" means a formulation that satisfies the desired properties as described herein or an equivalent thereof, which is not a custom formulation and is prepared as a conventional method of manufacture. The time helmet method is reached. An embodiment of the invention is a pharmaceutically acceptable composition comprising a compound of formula (I) and a buffer system. One embodiment of the invention is a pharmaceutically acceptable composition comprising a compound of formula (la) and a buffer system. One embodiment of the invention is a pharmaceutically acceptable composition comprising a compound of formula (lb) and a buffer system. One embodiment of the invention is a pharmaceutically acceptable composition comprising a compound of formula (Ic) and a buffer system. One embodiment of the invention is a pharmaceutically acceptable composition comprising a compound of formula (Id) and a buffer system. The present invention further relates to a method for improving, treating or preventing a chronic or acute disease caused by an anti- oxicillin-resistant Staphylococcus aureus, a Gram-positive bacteria or a Gram-negative bacteria in a subject in need thereof, It includes a bundle of the present invention that is reconstituted to the subject in an effective amount. The invention also relates to one or more compounds of formula (I), formula (la), formula (lb), formula (ic), formula (Id) or a form thereof and a buffer system for the manufacture, improvement or treatment of - Use of methicillin-resistant Staphylococcus aureus, Gram-positive bacteria 25 200835523 or Gram-negative bacteria for chronic or acute diseases 0 Terminology "Reconstructed bead dry formulation" means an effective amount One or more compounds of the formula (I), formula (la), formula (lb), formula (Ic), formula (Id) or a form thereof and a buffering system; an east dry formulation. The term "administering" in relation to the method of the invention means treating, ameliorating or preventing a disease as described herein with a reconstituted lyophilized formulation. The method comprises administering a reconstituted lyophilized formulation at a different time or simultaneously in a therapeutic time course. The method further comprises administering a reconstituted lyophilized formulation with one or more agents at different times or simultaneously in a 10 treatment session. The term "pre-lean" refers to a metabolic precursor of a compound of formula (la). In general, Lu, a functional derivative of a compound, is inactive when administered to a subject, but rapidly converts to an active metabolite in a living body. 15 The term "active metabolite" means a metabolite of a compound of formula (1) which is effective for the amelioration, treatment or prevention of Staphylococcus aureus, Gram-positive or Gram-negative bacteria which are resistant to methicillin. Caused by chronic or acute illness. The term "subject" as used herein refers to an animal, mammal, or 20 human being that is the target of treatment, observation, or experiment, and has S. aureus, Gram-positive bacteria that develop resistance to anti-valving. The risk of chronic or acute disease caused by Gram-negative bacteria (easy to suffer) or already has this, chronic or acute disease. The term "observation or experiment" includes, but is not limited to, testing, analytical testing, and model analysis of a tissue. 26 200835523 The term "effective amount" means an active compound or dose that is sought by a researcher, veterinarian, physician or other clinician to cause biological or medical treatment in a patient's tissue system, animal or human body. The reaction comprises preventing, treating or ameliorating the symptoms of a chronic or acute disease. 5 Λ Method towel Qiu Zhi's effective amount of reconstituted sago is from about 250 mg to about 500 mg. ...the term "pharmaceutical" means a compound of formula (1), formula (Ia), formula (lb), formula (Ic), formula (Id) used as a prophylactic, therapeutic or ameliorating chronic or acute disease in a product. Or its form. 10 Animals The molecular entities and components used in the text are of sufficient purity and quality to prevent harmful, allergic or other undesired reactions in the formulation, composition or pharmaceutical product when administered to the field. The formulation group 5 or the pharmaceutical product of the present invention is "pharmaceutically acceptable". Because both human use (clinical or over-the-counter) and veterinary use are equally included in the scope of the present invention, formulations, compositions or pharmaceuticals that are acceptable for use are for human or veterinary use. The term "combination therapy" refers to the use of a formulation, composition or medicament of the invention in combination with one or more therapeutic agents for the prevention, treatment or amelioration of a chronic or acute condition and advantageously facilitates the use of lower formulations of the invention. An effective dose of a composition or a pharmaceutical and/or therapeutic agent, rather than an amount recommended for the prevention, treatment or amelioration of a chronic or acute condition. Accordingly, it is contemplated that the formulations, compositions, or pharmaceuticals of the present invention can be used prior to, during, or after treatment with a particular therapeutic agent. The term "therapeutic agent" refers to an antibacterial agent used to ameliorate, treat or prevent chronic or acute diseases caused by Staphylococcus aureus, Gram-positive bacteria or Gram-negative sputum by the resistance of 曱西西27 200835523 林林. Agent. Am The term "improving, treating or preventing" means, but is not limited to, helping to eradicate or inhibit chronic or acute diseases caused by anti-methylin-resistant Staphylococcus aureus, Gram-positive or Gram-negative bacteria. deterioration. The present invention is directed to a pharmaceutically acceptable composition comprising a compound of formula (Ia) and a buffer system. The invention also relates to a freeze-dried cephalosporin derivative formulation comprising one or more cephalosporin derivatives and a buffer system, wherein the cephalosporin is a compound of formula (la) and optionally exists ( Ic) a compound. The amount of the compound of formula (la) and optionally the compound of formula (Ic) contained in the pinning container is selected from the group consisting of 333.3 mg (250 mg dose) or 666.6 mg (500 mg dose). The lyophilized formulation is supplied as a shipping container, typically a vial for intravenous injection. Although the invention is not limited to a particular container form or design, it is acceptable as long as the container is acceptable for its intended use. A consistent embodiment of the present invention provides a cold-dried dry formulation, preferably a tubular vial, contained in a vial. The lyophilized formulation of the present invention can be reconstituted with a vehicle and further diluted as needed to give a composition in the form of a solution that is immediately available for intravenous injection. The actual amount of reconstitution vehicle used is not limited by the examples of the present invention. By way of illustration, and not limitation, examples of reconstitution vehicles for the lyophilized formulations of the present invention include water for injection (WFI), deionized water, demineralized water, and the like. Water 1 is in the range of about 10 ml, or from about 1 mi to about 2 ml, or from about 1 ml to 28 200835523 about 5 ml, or from about 5 ml to about 0 ml. An example of a reconstituted lyophilized formulation of the invention provides that the concentration of the compound of formula (Ia) and optionally the compound of formula (Ic) is at about 13.3 mg/ml, or about 66.7 mg/m or about 33 • 3 mg/πύ, or about 150.0 mg/m b or from about 13·3 mg/ml to about 199·5 mg/ml. An example of a reconstituted lyophilized formulation of the invention provides that the concentration of the compound of formula (Ia) and optionally the compound of formula (Ic) is in the range of about 66. 7 mg/ml. 10 15 20 If the embodiment of the invention is further diluted as needed, this dilution is not a limitation of the invention. This dilution, as desired, is preferably carried out in an aqueous system, typically 5% dextrose (glucose) or 09% sodium chloride or lactated Ringer's. Depending on the concentration of Αρι in the solution and the desired final concentration of the formulation, the reconstituted solution may be diluted as needed. γ Embodiments of the freeze-drying method of the present invention comprise dispensing material in the form of a bulk solution. Recording _ _ _ _ The solution pH is in the range of about pH 4.5 to about pH 5.6. ^ : After the order is completed, the dry powder is added to the lock container in a weight ratio. Wang is compared to the prior art (in a bulk solution system). The dry method of the present invention allows the head in the solution to be corrected by the irradiance and reduces the filling amount of the sales container. The method of the present invention allows the manufacture of bulk solutions to be carried out at a higher concentration. 29 200835523 [Embodiment] Example 1 Paper composition The composition with various buffers was prepared by filling a liquid in a vial, or lyophilized in bulk and the powder was filled into a vial. The reference solution contains the compound of formula (la) (666.6 mg), mannitol (about 15% w/w dry cake weight), citric acid (1 mM mM), bismuth oxide steel solution (force to solution to pH 4.5) and WFI (added to the solution to 5 ml). The formula (1) contains a compound of the formula (la) (666.6 mg), citric acid (25 mM), a sodium hydroxide solution (added to a solution to pH 4.8), and WFI (to a solution of 5 ml). Test Formulation (2) contains a compound of formula (la) (666.6 mg), citric acid (1 〇-50 mM), sodium hydroxide or potassium hydroxide solution (added to solution to pH 4.8) and WFI (added to solution to 5 ml) . Test Formulation (3) contains a compound of formula (la) (666.6 mg), hydrogen phosphate dehydrogenation (10-200 mM), citric acid (10_5 mM mM), sodium aroxide or potassium hydroxide solution (added to solution to become 1) 114.8 ) and the boundaries? 1 (added to the solution to be 51111). Test Formulation (4) contains a compound of formula (la) (666·6 mg), potassium hydrogen phosphate (10-200 mM), citric acid (10-50 mM), sodium hydroxide or potassium hydroxide solution (added to solution to pH) 4.8), phosphoric acid (added to solution to 48) and WFI (added to solution to 5 ml). The test formulation (5) contains a compound of the formula (la) (666 6 mg), histidine (1〇-50 mM), can acid (added to the solution to pH 4 8), hydrochloric acid (added to the solution to pH 4.8) and WFI (added to the solution to 5 ml). 30 200835523 Test formulation (6) contains compound of formula (la) (666·6 mg), glutamic acid (10-50 mM), sodium hydroxide or potassium hydroxide solution (added to solution to 4.8) and WFI (added to solution 5 ml). The test formulation (7) contained a compound of the formula (?a) (666·6 mg), arginine (10-50 mM), phosphoric acid (added to a solution of ρΗ4·8), and WFI (added to a solution of 5 ml). The test formulation (8) contains a compound of the formula (la) (666·6 mg), glycine (1〇_50 mM), phosphoric acid (added to a solution to become ρΗ4.8), hydrochloric acid (added to ρΗ4·8), and WFI ( Add to the solution to become 5 ml).彳彳 test formulation (9) contains compound of formula (la) (666 6 mg), sucrose (M0%), citric acid (10-50 mM), sodium hydroxide or potassium cesium hydroxide solution (added to solution to become ρΗ4·8 ) and WFI (added to the solution to 5 ml). Test formulation (10) containing a compound of formula (la) (666 6 mg), lactose (M0%), citric acid (10-50 mM), sodium hydroxide or potassium strontium oxide solution (added to solution to pH 4.8) and WFI (added to the solution to 5 ml). The test formulation (11) contains a compound of the formula (la) (666·6 mg), cyclodextrin dl〇%), citric acid (10-50 mM), sodium hydroxide or a hydroxide solution to the solution J to the solution to pH 4.8) and WFI (added to the solution to 5 ml). Test Formulation (12) may contain a compound of formula (la) (666.6 mg), trehalose citrate (10-50 mM), sodium hydroxide or potassium hydroxide solution (added to solution to pH 4.8) and WFI (added to solution to become 5 ml) ). The test formulation (13) may contain a compound of the formula (la) (666 6 mg), trichlorostea (M0%), citric acid (10_5 mM mM), sodium hydroxide or a hydroxide solution (added to the solution to pH) 4·8) and WFI (added to the solution to 5 ml). 31 200835523 Female test formula (14) contains compound of formula (h) (666.6 mg), ionic and nonionic, surfactant (eg sodium lauryl phosphate or polysorbate, X 1CU), 彳 棣 棣 (10_50 mM), sodium hydroxide or potassium hydroxide solution (added to the solution to pH 48) and WFI (added to the solution to 5 ml). . Formula X (15) contains a compound of formula (la) (666.6 mg), gelatin S, ^°, 彳 citric acid (1〇-50 mM), sodium hydroxide or potassium hydroxide solution (addition / combination) Become pH 4.8) and WFI (add 5 ml to the solution). Formula (16) contains a compound of formula (Ia) (666.6 mg), an ionic and nonionic surfactant (such as sodium lauryl phosphate or polysorbate 108) (M〇%), a chelating agent (0.1]%), citric acid (10-50 mM), sodium hydroxide or potassium hydroxide solution (added to the solution to pH 4.8) and WFI (added to the solution to 5 ml). The lyophilization method of the present invention is carried out by filling the bulk solution into a vial, reducing the temperature of the solution to 1 (rc below the time of about 4 hours, 15, and preliminary drying for about 38 hours, then The second drying is carried out for about 10 hours. After the contents of the vial are dried, the vial is sealed = stored in -20. (: in the refrigerated storage area. The stability sample is stored at 5 ± 3 c Temperature. The reference and test formulations were stable at 5 ° C. Results After '0 ^ WFI reconstruction, the turbid solution was formed with reference to the formulation. After reconstitution, the test formulation (1) was clarified (turbid Degree less than 16 NTU) Test Formulation (1) Stability Results - The stability results of the test formulation (1) under various stable conditions are shown in Table i. 32 200835523 Table 1 Initial 5 ° C 3 Months 25 ° C /60〇/〇25°C/60% 40°C/75% 40°C/75% 1 month 3 months 14 days 1 month Appearance conforming to conform to meet the conforming to the reconstructed pH 4.8 4.9 4.8 4.8 4.8 4.7 turbidity Degree (< 16 NTU) 2 2 2 2 3 2 particulate matter (25 μΜ<6000) 790 320 890 442 648 2362 particles Quality (10 μΜ<6000) 362 4 38 16 38 146 Water (%<3·0) 2.6 0.7 0.7 0.8 0.6 0.9 Formula (la) % area 93.0 92.4 90.9 89.1 87.5 86.6 Formula (Ic) (% area 〇·〇 1.2 1.2 1.5 1.7 1.8 2.0 Adduct (% area 0.0) 1.1 1.1 1.5 2.2 2.7 3.0 TRS (% area 512.0) 5.3 6.0 7.1 8.5 10.0 10.9 Reconstituted pH results after 5 months of storage at 5QC, will be reconstructed after WFI The pH results were compared to formulations with a 25 mM citric acid buffer system and a 10 mM citric acid buffer system. The results are shown in Table 2 and verified that the 25 mM formulation provided better buffering capacity, thus Maintain a stable post-reconstitution pH. 33 200835523 Table 2

The pH of the formulation begins at pH 10 mM (P014A) 4.3 4.4 10 mM (P014B) 4.3 4.4 10 mM (P014C) 5.2 4.9 10 mM (P014D) 5.6 5.3 25 mM (P015A) 4.3 4.3 25 mM (P015B) 4.5 4.5 25 mM (P015C) 4.8 4.8 25 mM (P015D) 5.3 5.3 When the foregoing description provides an example for the purpose of teaching the principles of the invention, it is understood that the practice of the invention encompasses all common variations, modifications, and modifications. The scope of the following patent application and its equivalents are within the scope 5. Throughout the application, various publications are cited. The disclosures of these publications are hereby incorporated by reference in their entirety to the extent of the extent of the disclosure of the disclosure. 34

Claims (1)

200835523, the scope of patent application:, tautomers, crystals, isomorphs, amorphous, solvates, hydrates, esters, prodrugs or metabolites: 2. The formulation of claim 1, wherein the cephalosporin-derived compound is selected from the group consisting of a compound of formula (I) or a pharmaceutically acceptable salt thereof, stereoisomer 10 wherein ^2 is hydrogen, Ci-6 alkyl, Requires a fluorine group or a cycloalkyl group; is hydrogen or a group selected from -CH2C(=CHR)_COOR, -CH2OCOR_CH (8) OCOR, -CH (8) OCOOR _CH(OC〇R)OCOR, CH2COCH2OCOR and 〇 , 〇 Rs is hydrogen or a group selected from -CH2C(=CH2)-COOR, -COOCH2C(=CHR)-COOR, -COOCH2OCOR, -COOCH(R)OCOR, -COOCH(R)OCOOR, -COOCH( OCOR)OCOR, 35 200835523 COOCH2COCH2OCOR and its constraints are that one of r2 and r3 is hydrogen and the other r2 and r3 are not rats, 5 R is hydrogen or Cu alkyl; r4 is hydrogen or hydroxy; R5 is hydrogen or ω-hydroxyalkyl; X is CH or hydrazine. 3. The formulation of claim 2, wherein Ri, R2, R4 and R5 are all nitrogen; R3 is 1; and R is a thiol group. 15 4. The formulation of claim 1 wherein the compound of formula (I) is (6R,7RK7-[(Z)-2-(amino-[1,2,4]thiazol-3-yl) -2-hydroxyimino-ethenylamino]-3-[pentyl]-(3'-, 5'1〇-5'-hydroxyindolyl-1'-(5-mercapto-2-one --[1,3]dioxol-4-pyridyloxycarbonyl-2-keto-[1,3']dipyrrolidinyl-3-ylidene]-8-one 5--5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid or a pharmaceutically acceptable salt, stereoisomer, tautomer, crystal, homomorph 5. Amorphous, solvate, hydrate, ester, prodrug or metabolite. 5. The formulation of claim 1, wherein the compound of formula (I) is selected from a compound of formula (la) or a pharmaceutical thereof Acceptable salts, stereoisomers, mutual 36 20 200835523 metamers, crystals, isomorphs, amorphouss, solvates, hydrates, esters, prodrugs or metabolites: 6. The formulation of claim 1, wherein the compound of formula (I) is selected from the group consisting of a compound of formula (lb) or a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, a crystal, a homomorphic , amorphous, solvate, hydrate, ester, prodrug or metabolite: 10. The formulation of claim 1, wherein the compound of formula (I) is selected from the group consisting of a compound of formula (Ic) or a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, a crystal, a homomorphic , amorphous, solvate, hydrate, ester, prodrug or metabolite: 37 200835523 Inter-water s. The formulation of claim 1, wherein the compound of the formula (1) is a compound or a pharmaceutically acceptable salt thereof, a stereoisomer, a cross-structure, a crystal, and a zebra , amorphous, solvate, hexyl, ester, prodrug or metabolite: 5 Formulation wherein the compound is trihydrate 9 · The hydrochloride salt of the compound of claim 8 is as claimed. Wherein the freeze-dried formulation is cold; the east dry formulation wherein the cold-dried formulation is 10. The formulation of the second item of claim II is prepared by bulk lyophilization. η· The formulation of item 5 of the patent application is prepared by bulk lyophilization. 12. The formulation of claim 8 is prepared by bulk lyophilization. 13. The formulation of claim 9 in the scope of patent application, wherein the cold; the East Dry is prepared by bulk lyophilization to prepare the formulation of the '1, 15 20 formulation 14H material range, wherein the formulation is further selected by the following Additional optional ingredients: leavening solvent = agent, salt, preservative, antioxidant or alternatives. The formulation of the patent system, including the 2008 20082323 acid, salt. 16. The formulation of claim 1, wherein the acid or base is monoacid, single, polyacid or multiple. 17. The formulation of claim 15, wherein the acid, base and salt system 5 are selected from the group consisting of acetate, acetic acid, arginine, ascorbate, ascorbic acid, bicarbonate, carbonate, carbonic acid, citrate , citric acid, glutamate, glutamic acid, glycine, histidine, hydrochloric acid, hydrogencarbonate, lactate, lactic acid, maleate, maleic acid, phosphate, phosphoric acid, dihydrogen phosphate , Hydroxide dehydration, acid dihydrogen sodium, sodium hydroxide, spironic acid salt, 10 succinic acid, tartrate, tartaric acid, tris(hydroxydecyl)aminodecane, and combinations thereof. 18. The formulation of claim 17, wherein the acid, base and salt are selected from the group consisting of acetate, acetic acid, arginine, ascorbate, ascorbic acid, bicarbonate, citrate, citric acid, glutamine Acid salt, glutamic acid, glycine 15 amino acid, histidine acid, hydrochloric acid, lactate, lactic acid, phosphate, phosphoric acid, potassium dibasic potassium phosphate, potassium hydroxide, sodium dihydrogen phosphate, succinate, crotonic acid , tartrate, tartaric acid and combinations thereof. 19. The formulation of claim 17, wherein the acid, base, and salt are selected from the group consisting of citrate, citric acid, glutamic acid, hydrochloric acid, phosphate, phosphoric acid 20, and combinations thereof. 20. The formulation of claim 17, wherein the acid, base and salt are selected from the group consisting of potassium dihydrogen phosphate, phosphate/citrate, sodium dihydrogen phosphate or tartrate/lime acid, A combination of a base and a salt. 21. The formulation of claim 17, wherein the acid is selected from the group consisting of lemon 39 200835523 acid, glutamic acid, hydrochloric acid, phosphoric acid, and combinations thereof; and wherein the base is selected from potassium hydroxide or sodium hydroxide And their combinations. 22. The formulation of claim 17, wherein the acid is citric acid; and wherein the base is sodium hydroxide. 5 23. The formulation of claim 15, wherein the buffer system is at about 1 mM, or about 10 mM, or about 25 mM, or from about 1 〇 mM to about 25 mM ' or from about 1 〇 mM to about 35 mM, or from about 1 〇 to about 40 mM ' or from about 1 〇 mM to about 50 mM, or from about 1 〇 mM to about 100 mM, or from about 25 mM to about 35 mM, or from about 25 mM to about ίο 40 mM Or, from about 25 mM to about 50 mM, or from about 25 mM to about 100 mM, or from about 25 mM to about 200 mM, or from about 5 mM to about 200 mM. 24. The formulation of claim 23, wherein the buffer system is at about 25 mM, or from about 1 mM to about 50 mM, or from about 25 gua to 15 about 5 mM, or from about From 25 mM to about 200 mM, or from a concentration ranging from about 50 mM to about 200 mM. 25. The formulation of claim 23, wherein the buffer system is present at a concentration of about 25 mM, or from about i mM to about 50 mM. 26. The formulation of claim 23, wherein the buffer system is present in a concentration range of about 2 mM. 27. The formulation of claim 14, wherein the leavening agent is selected from the group consisting of cellobiose, cyclodextrin, gelatin, gentian disaccharide, isomaltose, isoflavone, iso-trehalose, lactose, wheat Budextrin, maltose, melibiose, PVP, sorbose, sucralose, vegetable sugar or trehalose or turanose. 200835523 28. The formulation of claim 27, wherein the leavening agent is about ,: 1, or about 1:5, or about 1:10, or about 3:100, or from about to about 0. :1, or from about 1:10 to about 1:100, or from about 1:100 to about 5:1 〇〇, or from about 1:200 to about 1:800, or from about 1:25 〇 to about 1:6 〇〇, or a weight/weight ratio of the leavening agent in the range of from about 1:100 to about 1:15 对 to the compound of claim 2 is present. 29. The formulation of claim 27, wherein the leavening agent is from about 1:100 to about 5·1, or from about ι··200 to about 1:8, or from The ratio of the leavening agent in the range of from about 1:25 Torr to about 1:600, or in the range of about 3:100, is present in the weight/weight ratio of the compound of claim 2. 30. The formulation of claim 27, wherein the leavening agent is present in a weight/weight ratio of the leavening agent in the range of about 3:100 to the compound of claim 2 in the scope of application. 31. The formulation of claim 14, wherein the surfactant is selected from the group consisting of phospholipids (eg, lecithin), polysorbates, and poloxamers (eg, polyoxyethylene (20) Sorbitan monooleate or hard lauric acid -40-polyoxyacetate), tyloxapol (cut (10) squeak, polyoxyethylene poly-propanol copolymer (eg Pluronic surfactant) , 12-based hard hydroxy phthalic acid polyoxyethylene | (such as S〇lut〇i surfactant), cholesterol ethoxylate (such as diglyceride or dialkyl glyceride), bile salts (such as gall a sodium sulphate, a sucrose ester (such as sucrose monolaurate or sucrose monooleate) or a polyvinyl alcohol (PVA). 32. The formulation of claim n, wherein the salt is selected from the group consisting of acetate, Bicarbonate, vapor, glutamate, hydrochloride or sodium salt; selected 200835523 from edetate (EDTA tetrasodium), docusate (d〇cusate) (l, 4# (2-B) A metal salt of a hexanyl group, a strontium carbonate or a carbonic acid clock; or an alkaline earth metal salt selected from magnesium stearate and a hydrate thereof. The formulation of claim 14 wherein the preservative is selected from the group consisting of 5 methyl and propyl p-hydroxybenzoate, benzethonium chloride, s〇diurn mercurothiolate, stone Phenylmercuric nitrate, phenyl sterol, phenol, and m-cresol. 34. The formulation of claim 14, wherein the cosolvent system is selected from the group consisting of alcohols (eg, sterol, ethanol, C) Alcohol, tert-butanol), glycerol ester, monoterpene polyethylene glycol, propylene glycol, vegetable oil, and the like. 35. The formulation of claim 15 wherein the buffer system is dissolved in dried beads a cephalosporin derivative. 3 6 · A formulation according to the scope of claim 5, wherein the buffer system is in the freeze-dried adjustment of the bulk solution 1) 11 to about 1) 11 4 · 5 to about pH 5 6 The scope of the 15 is around. 37. The formulation of claim 3, wherein the cephalosporin derivative is a compound of claim 5 of the patent application scope, and the compound of claim 6 is as claimed in claim 6 A compound of the formula, such as a compound of claim 8 of the patent scope, a compound of claim 9-20, and mixtures thereof. 38. For example, if the cephalosporin is derived from the cephalosporin, the cephalosporin-derived compound, such as the compound of the fifth paragraph of the patent application, (6) the patent of claim 1, the patent of the sixth item, such as the patent application Compounds of the scope of item 8, such as the compounds of claim 9 and mixtures thereof. 42 200835523 39. = The formulation of claim 1 of the patent scope, wherein the formulation is weighted by 4〇==== The composition, wherein the post-reconstitution formulation has a stability of 48 hours. The mosquito of the day or the generation exhibits at least 41.^_ the scope of the formulation of item 37, wherein the adjustment __ 42 · as claimed in the scope of the item μ At 25 〇C, it is as high as 24 _3 ;;; raw = after reconstruction, the stability of the formulation is stable. Read or in the generation exhibits at least 43. = patent scope, item 38, wherein the formulation is heavy 44. If you apply for the scope of the patent, item 43 ★ 15 20 at 25. 〇 shows up to 24_3 () hours. "2 stability after 48 hours of reconstitution. Knowing, defamatory, or exhibiting at least the first item in 5〇C, including the compound of the patent scope 2, and the scope of the patent application. A formulation in which the =heavy range/46 formulation's (4) post-reconstitution formulation exhibits a stability of 24_3 hrs at 25 C or a stability of at least 48 hours in the generation. 48.=Application for patent scope! The formulation of the item comprises a compound as claimed in claim 5 and a buffer system as in claim 15 of the patent application. 43 200835523 4 9. The formulation of claim 4, wherein the formulation has been reconstituted. 50. The formulation of claim 49, wherein the reconstituted formulation exhibits a stability of 24-30 hours in the south at 25 C or a stability of at least 48 hours at 5 °C. 51. The formulation of claim </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; 52. The formulation of claim 5, wherein the formulation is reconstituted. 53. The formulation of claim 52, wherein the reconstituted formulation exhibits a stability of up to 24-30 hours at 25 C or a stability of at least 48 hours at 5 °C. 54. The formulation of claim 1 of the patent application, comprising a compound as claimed in claim 7 and a buffer system as in claim 15 of the patent application. 55. The formulation of claim 54, wherein the formulation is constructed. 56. The formulation of claim 55, wherein the reconstituted formulation exhibits a stability of up to 24-30 hours at 25 C or a stability of at least 48 hours at 5.夕 57· = The formulation of the scope of the patent application is a compound containing the compound of claim 8 and the buffer system of claim 15 of the patent application. 58. The formulation of claim 57, wherein the formulation is graded. 59. The formulation of claim 58 of the patent application, wherein the post-reconstruction formulation 44 200835523 exhibits a stability of 24-3 hrs at 25 C or at least 48 hours at 5 〇 c. The formulation of the first paragraph of the patent scope includes the compound of claim 9 and the buffer system of item 5 of the patent application. 61. The formulation of claim 4, wherein the formulation is reconstituted. 62. The formulation of claim 6 wherein the reconstituted formulation exhibits a stability of up to 24_3 hours at 25 C or at 5. . Shows stability for at least 48 hours. 63. The formulation of claim 1 of the patent application, further comprising a compound as claimed in claim 5, one or more additional optional ingredients as in claim 14 of the patent application, as claimed in claim 15 Buffering system and &gt; main shot water. 64. The formulation of claim 63, wherein the buffer system comprises citric acid and sodium hydroxide or potassium strontium oxide. 65. The formulation of claim 63, wherein the buffer system comprises citric acid and sodium hydroxide. 66. The formulation of claim 63, wherein the buffer system comprises citric acid, potassium dipotassium phosphate, and sodium hydroxide or potassium hydroxide. 67. The formulation of claim 63, wherein the buffer system comprises citric acid, sodium dihydrogen phosphate, phosphoric acid, and sodium hydroxide or hydroxide. 68. The formulation of claim 63, wherein the buffer system comprises histidine, phosphoric acid and hydrochloric acid. 69. The formulation of claim 63, wherein the buffer system is a package of 45 200835523 containing glutamic acid and f-sodium oxide or hydrogenation. 7〇. 3 t circumference of the formulation of item 63, wherein the buffer system comprises arginine and scaly acid. 71 · ^申# Patent Closed Item 63, wherein the buffer system comprises glycine, phosphoric acid and hydrochloric acid. 72. The application of the scope of claim 63, wherein the additional component is a sugar, and the system comprises a citric acid and sodium hydroxide or hydroxide. 73. The formulation of claim 63, wherein the additional component is 10 15 lactose, and wherein the buffer system comprises citric acid and sodium hydroxide or potassium hydroxide. 74. The formulation of claim 63, wherein the additional component is a % dextrin; and wherein the buffer system comprises citric acid and sodium hydroxide or ruthenium oxide. 75. The formulation of claim 63, wherein the additional ingredient is sea bath sugar; and wherein the buffer system comprises citric acid and sodium bismuth oxide or potassium hydroxide. 76. The formulation of claim 63, wherein the additional component is trichlorostea; and wherein the buffer system comprises citric acid and sodium or potassium hydroxide. 77. The formulation of claim 63, wherein the additional component is alum; and wherein the buffer system comprises citric acid and sodium or potassium hydroxide. 78. The formulation of claim 63, wherein the additional component is 46 20 200835523 anionic or nonionic surfactant; and wherein the buffer system comprises a holding acid and sodium hydroxide or hydroxide Potassium. 79. The formulation of claim a, wherein the additional component is a sub- or non-ionic surfactant and a chelating agent; and wherein the buffer system comprises citric acid and sodium hydroxide or cesium Potassium oxide. 80. A pharmaceutical composition for use in a subject in need thereof for the improvement, treatment or prevention of chronic acid-induced Staphylococcus aureus, Gram-positive bacteria or Gram-negative bacteria caused by anti-methylin resistance Or an acute disease comprising a formulation effective as set forth in claim 39 of the patent application. 81. The pharmaceutical composition of claim 8 wherein the effective amount of the formulation of claim 39 is from about 250 mg to 500 mg. 82. The pharmaceutical composition of claim 8 wherein the effective amount of the formulation of claim 41 is from about 25 0 m g to 500 m g. 83. The pharmaceutical composition of claim 8 wherein the effective amount of the formulation of claim 43 is from about 250 mg to 500 mg. 84. The pharmaceutical composition of claim 80, wherein the effective amount of the formulation of claim 46 is from about 250 mg to 500 mg. 85. The pharmaceutical composition of claim 8 wherein the effective amount of the formulation of claim 49 is from about 250 mg to 500 mg. 86. The pharmaceutical composition of claim 80, wherein the effective amount is from about 250 mg to 500 mg of the formulation of claim 52 of the patent scope. 87. The pharmaceutical composition of claim 80 of the Shenqing Patent Range, wherein the effective amount is from about 250 mg to 500 mg as defined in claim 55 of the scope of the patent application. 88. The pharmaceutical composition of claim (10), wherein the effective amount is, for example, 47 200835523, the formulation of the 58th patent of the patent application range is from about 250 mg to 500 mg. 89. The pharmaceutical composition of claim 8 wherein the effective amount is from about 25 mg to 5 mg, as defined in the scope of claim 61. 90. The formulation of claim </ RTI> wherein the cephalosporin-derived 5 is about mg/ml, or about 66.7 mg/ml, or about 133.3 mg/ml' or about i5 〇.〇 mg/ m Bu is present in the range from ^913 3π^/ιη1 to about 199 5 mg/ml. 91. The formulation of claim 9 wherein the cephalosporin derivative is present at a level of about 13.3 mg/ml, or about 66.7 mg/ml, or about 133.3 mg/ml. 92·: The use of a compound such as a full-time 丨 丨 item is used to manufacture, improve, treat or prevent Staphylococcus aureus, Gram-positive bacteria or Gram-negative A drug that is chronic or acutely afflicted by bacteria. 15 The application of the scope of claim 92, wherein the cephalosporin derivative is a compound of the patent application No. 2, such as a compound of the patent scope, such as a compound of claim 6 4 The compound of claim 7 of the patent scope, as claimed in claim 8 of the patent application, the compound of claim 9 and mixtures thereof. 2〇94·^Application of the scope of application of the 93rd item, wherein the cephalosporin derivative is a compound of the fifth item of the patent range of the U.S. patent, and the compound of the patent scope== Compounds of the formula, such as the compounds of claim 9 and mixtures thereof. 48 200835523 VII. Designation of representative representatives: (1) The representative representative of the case is: (No). (2) A brief description of the symbol of the representative figure: None 10 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 15 Formula (I) 4