CN101472562A

CN101472562A - Pharmaceutical compositions for vein irritating drugs

Info

Publication number: CN101472562A
Application number: CNA2007800228020A
Authority: CN
Inventors: 陈献
Original assignee: Individual
Current assignee: Individual
Priority date: 2006-05-12
Filing date: 2007-05-11
Publication date: 2009-07-01
Also published as: EP2023895A2; CA2651988A1; WO2007133711A3; WO2007133711A2; TW200812608A; WO2007133711B1

Abstract

Non-vein irritating pharmaceutical formulations (e.g., oil-in-water emulsions, frozen formulations, and lyophilized formulations) of vancomycin and clarithromycin are provided. Also provided are methods for preparing and using such formulations.

Description

The pharmaceutical composition that is used for vein irritating drugs

Background

Technical field

The present invention relates to by and large and is used for the field that intravenous gives the pharmaceutical preparation of vein irritating drugs.Particularly, the present invention relates to be used to carry preparation such as the vein irritating antibiotic medicine of vancomycin and clarithromycin.

Description of Related Art

As everyone knows, the medicine of many intravenous injections causes venous stimulation or phlebitis at the injection site place.Vancomycin is one of them just.Vancomycin is important antibiotic medicine, it has activity and is effective to dangerous clinically reliable device especially most of gram-positive bacteriums, it comprises to methicillin-resistant staphylococcus aureus (Staphyloceccus aureus) and other multidrug resistant microorganism, to staphy lococcus infection and streptococcal infection in penicillin and the cephalosporin allergic patients, and to the clostridium difficile in the pseudomembranous colitis (Clostridumdifficile).Vancomycin can not be by good absorption when the oral administration administration, and intravenous injection is the main route of administration that is used for systemic infection.According to extensive report, vancomycin can cause phlebitis, and this is severe form (Clin Pharm.1988 October of venous stimulation and inflammation; 7 (10): 720-1), sickness rate is up to 13% (Archives of Pathology andLaboratory Medicine, in December, 2000 in the patient; 124 (2) 322-3).Make the totle drilling cost of vancomycin treatment significantly increase nearly 45% (Pharmacotherapy, in July, 1994-August to phlebitic prevention relevant and treatment with vancomycin; 14 (4): 438-45).

Present intravenous vancomycin product can use by two kinds of dosage forms.First kind of preparation is as aseptic vancomycin hydrochloride, USP list in American Pharmacopeia (United StatePharmacopoeia) (USP) in.It provides with the bottle form that contains lyophilizing (lyophilization) sterilized powder that is equivalent to 500mg or the active vancomycin hydrochloride of 1g vancomycin.Said preparation also can contain hydrochloric acid and/or sodium hydroxide and be used for the pH value adjusting.When recombinating with sterile water for injection (USP), its formation has the settled solution of the pH value of about 4.0 (2.5 to 4.5).Second kind of preparation be with contain respectively the 500mg that is the vancomycin hydrochloride form or 1g vancomycin (USP) freezing, etc. ooze aseptic, apyrogeneity, premixed 100mL or 200mL solution form provide.Every 100mL solution contains the 5g hydration glucose sugar of having an appointment, USP.The pH value of this solution is regulated with hydrochloric acid and/or sodium hydroxide.The solution that thaws has 3.0 to 5.0 pH value.Thawing to room temperature, this solution can be used for intravenous use.This preparation is packaged in the plastic containers (for example in GALAXY plastic containers (PL2040)

HCl only is used for intravenous use), also list among the USP.

Because vancomycin is easy to oxidized and hydrolytic degradation when solution state, so must be with its lyophilizing or freezing so that sufficiently long storage period to be provided.When solution state, it is more stable in sour environment than in neutrality or alkaline environment, so lyophilized formulations and frozen preparation all are adjusted to about pH4.

Although these simple pharmaceutical solutionses can keep the chemical integrity of vancomycin between the storage life, it can not prevent the phlebitis that caused by vancomycin.The vancomycin of dosage form must slowly give with the form of weak solution at present, and the transfusion site need be by turns with the frequency that reduces the venous stimulation that causes by vancomycin and seriousness (Product Description forSterile Vancomycin Hydrochloride, USP).

Clarithromycin is when intravenous administration, and it is another kind of vein irritating antibiotic.Present available intravenous Biaxin is from Abbott Labs's

, only granted in Britain and some other European countries, and do not obtain permission in the U.S..According to reports, the local tolerance of intravenous Biaxin is a problem.For example, people such as Zimmerman (Clinical Drug Investigation 21:527-36,2001) report from the intravenous clarithromycin (

) the various adverse events at injection site place of administration, it comprises phlebitis (50%), inflammation of vein (75%) and venous stimulation (100%).

Summary of the invention

But the invention provides the freeze-stable type oil in water emulsion of vancomycin and the freeze-dried type oil in water emulsion of vancomycin.In addition, also be provided at the freezing or freeze dried vancomycin formulations of stablizing and can be reassembled as submicron order Emulsion when storing.In addition, the oil in water emulsion of preparation vancomycin and the method for freezing or lyophilized formulations are provided.Similar approach can be used for preparing the oil in water emulsion and the freezing or lyophilized formulations of clarithromycin.Gained vancomycin and Biaxin can be used for treatment or reduce and infect and other disease.

On the one hand, provide freeze-stable type oil in water emulsion, it comprises: (i) concentration is about 0.1 weight % to the acceptable salt of medicine or the analog of the suitable vancomycin of the vancomycin of about 3 weight % or concentration; (ii) total concentration is about 2 weight % one or more liquid oil to about 4 weight %; (iii) total concentration is about 2 weight % to one or more phospholipid of about 5 weight %, and wherein all phospholipid are 0.5:1 at least to the weight ratio of whole liquid oil; (iv) about 5 weight % are to the dextrose of about 6 weight %; And (v) water.

In certain embodiments, these one or more liquid oil of this freeze-stable type vancomycin oil in water emulsion comprise soybean oil.

In certain embodiments, these one or more liquid oil of this freeze-stable type oil-in-water vancomycin Emulsion comprise vegetable oil and medium chain triglyceride.

In certain embodiments, these one or more phospholipid of this freeze-stable type vancomycin oil in water emulsion comprise lecithin.

In certain embodiments, described freeze-stable type oil in water emulsion comprises: (1) concentration is the vancomycin hydrochloride of about 0.5 weight %, (2) concentration is the soybean oil of about 1 weight % to about 2 weight %, (3) concentration is the medium chain triglyceride of about 1 weight % to about 2 weight %, (4) concentration is the lecithin of about 2 weight % to about 4 weight %, and (5) concentration is the dextroses of about 5 weight % to about 6 weight %.

In certain embodiments, described freeze-stable type oil in water emulsion comprises: (1) concentration is the vancomycin hydrochloride of about 0.5 weight %, (2) soybean oil and medium chain triglyceride, wherein the total concentration of soybean oil and medium chain triglyceride is about 2 weight %, the weight ratio of soybean oil centering chain triglyceride is between 2:1 to 1:1, (3) concentration is the lecithin of about 2 weight %, and (4) concentration is the dextrose of about 5 weight %.

In certain embodiments, the particle mean size of oil droplet is not more than about 200nm in the described freeze-stable type vancomycin oil in water emulsion, and PFAT5 is less than about 0.05.

In certain embodiments, described freeze-stable type oil-in-water vancomycin Emulsion does not further comprise the chemical compound of the amount of vancomycin in the oil droplet that can be increased in this Emulsion.

In certain embodiments, being lower than about 30% vancomycin is present in the oil droplet of this freeze-stable type oil in water emulsion.

On the other hand, provide frozen composition, it comprises: (i) concentration is the acceptable salt of medicine or the analog of the suitable vancomycin of the vancomycin of about 0.5 weight % or concentration; (ii) total concentration is about 2 weight % one or more liquid oil to about 4 weight %; (iii) total concentration is about 1 weight % one or more phospholipid to about 5 weight %; Wherein all phospholipid are 0.5:1 at least to the weight ratio of whole liquid oil; (iv) about 5 weight % are to the dextrose of about 6 weight %; And (v) water; Wherein when thawing, said composition forms oil in water emulsion, and wherein the average diameter of oil droplet is not more than about 200nm and PFAT less than about 0.05.

In certain embodiments, one or more liquid oil of this of described refrigerated vancomycin compositions comprise vegetable oil and medium chain triglyceride.

In certain embodiments, described refrigerated vancomycin compositions does not further comprise the chemical compound of the amount of vancomycin in the oil droplet that can increase the Emulsion that forms by this refrigerated vancomycin compositions of thawing.

In certain embodiments, when described refrigerated vancomycin compositions is thawed and formed oil in water emulsion, be lower than about 30% vancomycin and be present in the oil droplet of this oil in water emulsion.

On the other hand, provide the method that is used for the treatment of or reduces infection, it comprises that the patient to this method of needs gives the freeze-stable type vancomycin oil in water emulsion of describing of medicine effective quantity herein.

In related fields, be provided for treating or reducing the method for infection, it comprises that the patient to this method of needs gives the oil-in-water vancomycin Emulsion that refrigerated vancomycin compositions medicine effective quantity, that describe by thawing forms herein.

On the other hand, provide freeze-stable type oil in water emulsion, it comprises: (i) concentration is at least about the acceptable salt of medicine or the ester of the suitable clarithromycin of the clarithromycin of 0.5 weight % or concentration; (ii) total concentration is about 2 weight % one or more liquid oil to about 4 weight %; (iii) total concentration is about 1 weight % to one or more phospholipid of about 5 weight %, and wherein all phospholipid are 0.5:1 at least to the weight ratio of whole liquid oil; (iv) about 5 weight % are to the dextrose of about 6 weight %; And (v) water.

In certain embodiments, these one or more liquid oil of described freeze-stable type clarithromycin oil in water emulsion comprise soybean oil.

In certain embodiments, these one or more liquid oil of described freeze-stable type clarithromycin oil in water emulsion comprise vegetable oil and medium chain triglyceride.

In certain embodiments, these one or more phospholipid of described freeze-stable type clarithromycin oil in water emulsion comprise lecithin.

In certain embodiments, described freeze-stable type clarithromycin oil in water emulsion does not further comprise the chemical compound of the amount of clarithromycin in the oil droplet that can be increased in Emulsion.

In certain embodiments, being lower than about 30% clarithromycin is present in the oil droplet of described freeze-stable type clarithromycin oil in water emulsion.

In certain embodiments, described freeze-stable type oil in water emulsion comprises: (1) concentration is the clarithromycin of about 1 weight % to about 5 weight %; (2) soybean oil and medium chain triglyceride, wherein the total concentration of soybean oil and medium chain triglyceride is about 2 weight %, the weight ratio of soybean oil centering chain triglyceride is between 2:1 to 1:1; (3) concentration is that lecithin and (4) concentration of about 2 weight % are the dextrose of about 5 weight %.

In certain embodiments, the particle mean size of oil droplet is not more than about 200nm in the described freeze-stable type oil-in-water clarithromycin emulsion, and PFAT5 is less than about 0.05.

In another aspect, provide frozen composition, it comprises: (i) concentration is at least about the acceptable salt of medicine or the ester of the suitable clarithromycin of the clarithromycin of 0.5 weight % or concentration; (ii) total concentration is about 2 weight % one or more liquid oil to about 4 weight %; (iii) total concentration is about 1 weight % to one or more phospholipid of about 5 weight %, and wherein all the weight ratio of phospholipid and whole liquid oil is 0.5:1 at least; (iv) about 5 weight % are to about 6 weight % dextroses; And (v) water; Wherein when thawing, said composition forms oil in water emulsion, and wherein the average diameter of oil droplet is not more than about 200nm and PFAT5 less than 0.05.

In certain embodiments, one or more liquid oil of this of described refrigerated clarithromycin compositions comprise vegetable oil and medium chain triglyceride.

In another aspect, provide the method that is used for the treatment of or reduces infection, it comprises that the patient to this method of needs gives the type of the freeze-stable as described herein oil-in-water clarithromycin emulsion of medicine effective quantity.

In another aspect, provide to be used for the treatment of or to reduce the method that infects, it comprises that patient to this method of needs gives oil-in-water clarithromycin emulsion medicine effective quantity, that form by the refrigerated as described herein clarithromycin compositions of thawing.

On the one hand, but the invention provides the freeze-dried type oil in water emulsion, it comprises: (i) at least about 15mg/ml vancomycin or acceptable salt of its medicine or analog, (ii) total concentration is about 2 weight % one or more liquid oil to about 10 weight %, (iii) total concentration is about 1 weight % to one or more phospholipid of about 10 weight %, and (iv) concentration is at least about the dextrose of 10 weight %.

In certain embodiments, but these one or more liquid oil of described freeze-dried type vancomycin oil in water emulsion comprise soybean oil.

In certain embodiments, but these one or more phospholipid of described freeze-dried type vancomycin oil in water emulsion comprise lecithin.

In certain embodiments, but described freeze-dried type oil in water emulsion comprises concentration be about 1 weight % to vancomycin hydrochloride, the concentration of about 3 weight % be about 1 weight % to medium chain triglyceride, the concentration of about 5 weight % be about 1 weight % to vegetable oil, the concentration of about 5 weight % be the lecithin of about 1 weight % to about 4 weight %, and about 15 weight % are to the dextrose of about 25 weight %.

In certain embodiments, but the pH value of described freeze-dried type vancomycin oil in water emulsion is about 3 to about 8.

In certain embodiments, but in the described freeze-dried type vancomycin oil in water emulsion particle mean size of oil droplet less than about 250nm.

In certain embodiments, but in the described freeze-dried type vancomycin oil in water emulsion particle mean size of oil droplet less than the PFAT5 of about 200nm and this Emulsion less than about 0.05.

In certain embodiments, but described freeze-dried type vancomycin oil in water emulsion does not further comprise the chemical compound of the amount of vancomycin in the oil droplet that can be increased in Emulsion.

In certain embodiments, but be lower than about 30% vancomycin and be present in the oil droplet of described freeze-dried type vancomycin oil in water emulsion.

In another aspect, the invention provides freeze-dried composition, it comprises vancomycin or the acceptable salt of its medicine or analog, liquid oil (class), phospholipid (class) and dextrose, wherein said composition is to prepare by removing to anhydrate from oil in water emulsion described herein, said composition can the rehydrated Emulsion that is suitable for injecting with formation of water, and the average diameter of the Emulsion drop that forms again is not more than about 1 micron.

In certain embodiments, the average diameter of the Emulsion drop that forms again is not more than about 400nm.

In another aspect, the invention provides freeze-dried composition, it comprises: (i) concentration is vancomycin or its medicine acceptable salt or the analog of about 5 weight % to about 10 weight %, (ii) total concentration is about 10 weight % one or more liquid oil to about 20 weight %, (iii) total concentration is about 10 weight % one or more phospholipid to about 20 weight %, and (iv) concentration is the dextroses of 50 weight % to about 80 weight %.

In certain embodiments, when water was rehydrated, described freeze dried vancomycin compositions formed oil in water emulsion, and the average diameter of this Emulsion drop is not more than about 1 micron.

In certain embodiments, described freeze dried vancomycin compositions does not further comprise the chemical compound of the amount of vancomycin in the oil droplet that can increase the Emulsion of being recombinated by this freeze dried vancomycin compositions.

In certain embodiments, rehydrated when forming oil in water emulsion when described freeze dried vancomycin compositions water, be lower than about 30% vancomycin and be present in the oil droplet of this oil in water emulsion.

In certain embodiments, said composition forms oil in water emulsion when water is rehydrated, and the particle mean size of oil droplet is not more than about 200nm in this Emulsion, and the PFAT5 of Emulsion is less than about 0.05.

In another aspect, the invention provides the method that is used for the treatment of or reduces the risk that infects, but it comprises the freeze-dried type oil in water emulsion that the patient of this method of needs is given the vancomycin described herein of medicine effective quantity.

In related aspect, the invention provides the method that is used for the treatment of or reduces the risk that infects, its comprise patient to this method of needs give medicine effective quantity, by making the rehydrated oil in water emulsion that forms of freeze dried vancomycin compositions described herein.

In another aspect, but the invention provides the freeze-dried type oil in water emulsion, it comprises: (i) concentration is at least about clarithromycin or acceptable salt of its medicine or the ester of 1 weight %, (ii) total concentration is about 2 weight % one or more liquid oil to about 10 weight %, (iii) total concentration is about 1 weight % to one or more phospholipid of about 10 weight %, and (iv) concentration is at least about the dextrose of 10 weight %.

In certain embodiments, it is clarithromycin or its medicine acceptable salt or the ester of about 1 weight % to about 3 weight % that but described freeze-dried type oil in water emulsion comprises concentration, concentration is the medium chain triglyceride of about 1 weight % to about 5 weight %, concentration is the vegetable oil of about 1 weight % to about 5 weight %, concentration is the lecithin of about 1 weight % to 10 weight %, and the dextrose of about 15 weight % to 25 weight %.

But in some embodiment of the freeze-dried type oil in water emulsion of clarithromycin, the particle mean size of oil droplet is less than about 250nm in this Emulsion.

But in some embodiment of the freeze-dried type oil in water emulsion of clarithromycin, the particle mean size of oil droplet is less than about 200nm in this Emulsion, and the PFAT5 of this Emulsion is less than about 0.05.

But in some embodiment of the freeze-dried type oil in water emulsion of clarithromycin, this Emulsion does not further comprise the chemical compound of the amount of clarithromycin in the oil droplet that can increase Emulsion.

But in some embodiment of the freeze-dried type oil in water emulsion of clarithromycin, be lower than about 30% clarithromycin and be present in the oil droplet of this Emulsion.

In another aspect, the invention provides freeze-dried composition, it comprises clarithromycin or the acceptable salt of its medicine or ester, liquid oil (class), phospholipid (class) and dextrose, wherein said composition is to prepare by removing to anhydrate from the oil in water emulsion of clarithromycin described herein, said composition is can water rehydrated and form the Emulsion that is suitable for injecting, and the average diameter of the Emulsion drop that forms again is not more than about 1 micron.

In certain embodiments, the average diameter of oil droplet is not more than about 200nm in by the Emulsion of described freeze dried clarithromycin compositions reorganization.

In related fields, the invention provides freeze-dried composition, it comprises: (i) concentration is clarithromycin or its medicine acceptable salt or the esters of about 2 weight % to about 8 weight %, (ii) concentration is the liquid oil of about 10 weight % to about 20 weight %, (iii) concentration is about 10 weight % one or more phospholipid to about 20 weight %, and (iv) concentration is the dextroses of about 50 weight % to about 80 weight %.

In certain embodiments, when water was rehydrated, freeze dried clarithromycin compositions as herein described formed oil in water emulsion, and the average diameter of this Emulsion drop is not more than about 200nm.

In certain embodiments, when water was rehydrated, freeze dried clarithromycin compositions as herein described formed oil in water emulsion, and the PFAT of this Emulsion is less than about 0.05.

In certain embodiments, when water was rehydrated, freeze dried clarithromycin compositions as herein described formed oil in water emulsion, and the average diameter of this Emulsion drop is not more than about 200nm, and the PFAT of this Emulsion is less than about 0.05.

In certain embodiments, described freeze dried clarithromycin compositions does not further comprise the chemical compound of the amount of clarithromycin in the oil droplet that can increase the Emulsion of being recombinated by this freeze-dried composition.

In certain embodiments, when water was rehydrated, described herein freeze dried clarithromycin compositions formed oil in water emulsion, and was lower than about 30% clarithromycin and is present in the oil droplet of this Emulsion.

In another aspect, the invention provides the method that is used for the treatment of or reduces the risk that infects, but it comprises that the patient to this method of needs gives freeze-dried type oil in water emulsion medicine effective quantity, clarithromycin described herein.

In related fields, the invention provides the method that is used for the treatment of or reduces the risk that infects, it comprise patient to this method of needs give medicine effective quantity, by the rehydrated oil in water emulsion that forms of the freeze-dried composition that makes clarithromycin described herein.

Describe in detail

But the freeze-stable type oil in water emulsion and the freeze-dried type oil in water emulsion of vein irritating antibiotic vancomycin and clarithromycin are provided.Also be provided for preparing the method for described oil in water emulsion and frozen preparation or lyophilized formulations.The method directly preparation or be used for the treatment of or reduced infection by the oil in water emulsion of frozen preparation or lyophilized formulations reorganization of using also is provided.

Unless otherwise noted, otherwise the term that uses in a merogenesis of this description has identical implication in another merogenesis.

Freeze-stable type oil in water emulsion and frozen preparation

On the one hand, provide the freeze-stable type oil in water emulsion of vancomycin and clarithromycin.One or more during this class Emulsion can have the following advantages: it can keep stable through stored frozen and between the storage life (1), (2) it contains submicron oil droplet and method sterilization after filtration, (3) refrigerated Emulsion can be thawed to form the oil in water emulsion with submicron oil droplet again, and this Emulsion that forms again is method sterilization after filtration also, (4) directly preparation or the Emulsion that formed again by this refrigerated Emulsion are to wait the patient who opens and prepare need to be used to this treatment, (5) directly prepare or be that non-vein is irritating by the oil in water emulsion that refrigerated Emulsion forms again; And (6) described oil in water emulsion do not contain any additional compounds (for example, stabilizing agent) of the amount that can increase vancomycin in the oil droplet or clarithromycin, and this has been avoided any side effect of these additional compounds.

Vancomycin freeze-stable type preparation and frozen preparation

Vancomycin is trinucleated glycopeptide (its structure is as follows).In aqueous solution, it has limited stability and the most stable under the pH value of about 4.0-4.5; In order to make its stability maximization, (aseptic vancomycin hydrochloride is to be mixed with lyophilized form under pH4.0 to 4.5 USP) to the preparation that existing market is sold.Vancomycin can be moderately soluble in water (to about 1% to about 5%).Its dissolubility in sour environment or alkaline environment is bigger than the dissolubility in the pH neutral environment.Its dissolubility is issued to minima at about pH7.Along with pH value becomes pH7 (that is, pH value of blood) by pH4.0-4.5 (that is, the preparation pH value), the dissolubility of vancomycin descends about 40%.Therefore, after making the blended intravenous injection of the neutral blood of acidic formulation solution and pH, in vein, there is the probability of part drug precipitation.Such part drug precipitation may cause the factor of venous stimulation for causing the preparation of being sold by existing market.

The oil in water emulsion that provides herein is to be used for intravenous to carry the safe and efficient preparation of vancomycin to select.Although do not wish restricted, but the oil droplet of supposing the vancomycin oil in water emulsion is by the following venous stimulation that is used for preventing or reducing vancomycin: (1) disturbs vancomycin and venous endothelial bound, (2) a part of vancomycin molecule in the restriction Emulsion oil droplet, thereby minimizing contacts with the direct of venous endothelial, and/or (3) by the dissolubility that vancomycin is dissolved in improve vancomycin in the oil droplet and reduce that vancomycin is deposited in the blood flow and injection site place deposition or with the bonded probability of vein.

" oil in water emulsion " used herein is meant that liquid oil wherein is to be scattered in dispersion system of colloid in the aqueous medium (continuous phase is also called " water ") with droplet form (discontinuous phase is also called " oil phase ").

" acceptable salt of medicine or analog " used herein is meant chemicals relevant on salt or the structure, in the category of reliable medical judgment, it is applicable to and contact with human and zootic tissue and do not have unsuitable toxicity, stimulation, anaphylaxis and similar adverse consequences thereof, and can be effective in its treat or prevention infection in desired use.The acceptable salt of the medicine of vancomycin comprises hydrochlorate, sulfate, mesylate, acetate, citrate, Ascorbate, aspartate, benzene sulfonate, benzoate, caprate, caproate, caprylate, cyclamate, lauryl sulfate, formates, fumarate, gluceptate, glucuronate salt, glutamate, Glu, glutarate, oxyacetate, hydrobromate, lactate, lactobionate, maleate, malonate, nicotinate, nitrate, oleate, Orotate, oxalates, palmitate, embonate, phosphate, stearate, succinate, tartrate etc.The acceptable analog of the medicine of vancomycin is meant to have structure and the bioactive glycopeptide chemicals that is similar to vancomycin.The example of this class analog comprises LY333328 and BI 397 (Malabarba A, Ciabatti R.Glycopeptidederivatives (glycopeptide derivatives) .Curr Med Chem.2001; 8:1759-1773), teicoplanin (Teicoplanin) (was called teichmycin A2 (1), Salaria M.Teicoplanin.Indian Pediatr.2001 in the past; 38:372-375), (TLV) (DouchinK of Te Lawan star (Telavancin), Shaw J, Spencer E, Seroogy J, Barriere S, Wilbraham D.Single dosepharmacokinetics (PK) of telavancin (TLV) in healthy elderly subjects (the single dose of drug dynamic metabolism of Te Lawan star (TLV) in the healthy geriatric individuality) .ClinMicrobiol Infect.2004; 10:275), oritavancin (Oritavancin) (Internet pressrelease from Biospace Beat.Biotechnology and Pharmaceutical News), Targocid (Targocid) ( Http:// home.intekom.com/pharm/roussel/targocid.html) and norvancomycin (norvancomycin).

" concentration of calculating by weight " used herein is meant the ratio (in percentage ratio) of weight and the gross weight of said composition of the component (for example, vancomycin) of compositions (for example, vancomycin oil in water emulsion).

The concentration of the acceptable salt of medicine of vancomycin is for the concentration of the prescribed concentration of " being equivalent to " vancomycin, if under this concentration, then vancomycin salt contains the vancomycin free alkali with the vancomycin same amount of this prescribed concentration.For example, the 5.16mg/g vancomycin hydrochloride is equivalent to 5.0mg/g vancomycin free alkali.

The concentration of the acceptable analog of medicine of vancomycin is for the concentration of the prescribed concentration of " being equivalent to " vancomycin, if under this concentration, then the similar thing of vancomycin is the same equal effective with the vancomycin of this prescribed concentration in treatment or prevention infection.

In the freeze-stable type oil in water emulsion that provides in this article, vancomycin is to exist to the concentration of about 3 weight % with about 0.1 weight %, comprises any value of from 0.09% to 3.3%.

Be meant any value in 90% to 110% scope of designated value as employed term " about " in the disclosure.For example, about 0.1% be meant any percentage ratio of from 0.09% to 0.11%.

Term " liquid oil " is used for the disclosure with general meaning, be to refer under body temperature, that is, and about 37 ℃ down for liquid and be the acceptable hydrocarbon derivative of pharmacology, carbohydrate derivates in injectable formulation, or similar organic compound.This kind comprises vegetable oil, Animal fat and artificial oil, and by this class oil of chemical treatment and the fatty various liquid that obtain.

Term " oil ingredient " is meant the combination of the oily or multiple oil in the oil in water emulsion.

The oil ingredient of the oil in water emulsion that provides herein in certain embodiments, comprises monoglyceride, diglyceride, triglyceride or its mixture.In certain embodiments, this oil ingredient is included in the ester that forms between one or more fatty acids and the alcohol except that glycerol.

" vegetable oil " is meant the oil that derives from plant seed or nut.Exemplary vegetable oil includes but not limited to almond oil, borage oil, blackcurrant seed oil, Semen Maydis oil, safflower oil, soybean oil, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, olive oil, rapeseed oil, Oleum Cocois, Petiolus Trachycarpi oil, Canola oil etc.In certain embodiments, one or more liquid oil of this of oil in water emulsion comprise soybean oil.

Vegetable oil is generally " long chain triglyceride ", when three fatty acid (sources of depending on this oil, length is generally about 14 carbon to about 22 carbon, has different numbers and is in the unsaturated bond of diverse location) form this long chain triglyceride when forming ester bonds with three oh groups on the glycerol.In certain embodiments, the vegetable oil of high-purity rank (being also called " ultrapure purified ") is generally used for guaranteeing the safety and the stability of oil in water emulsion.

" medium chain triglyceride " is another kind of triglyceride oil (MCT), and it can be natural origin or synthetic.MCT is generally about 6 carbon to the fatty acid of about 12 carbon by length to make.The same with vegetable oil, MCT be widely used in the patient that need to be designed to parenteral absorption, in the Emulsion of injection as origin of heat.This oil can be commercially available, for from SASOLGmbH, the Miglyol 812 of Germany, from Parsippany, the CRODAMOL GTCC-PN of the Croda Inc. of New Jersey or from Boonton, the PVO International of New Jersey, the Neobees M-5 oil of Inc..In the Emulsion that other low-melting midchain oil also can be used for providing herein.

" Animal fat " is meant the oil that comes from animal origin.It also comprises triglyceride, but compares with vegetable oil, and the length of three fatty acid chains and unsaturated bond wherein change.From at room temperature processing to be liquid in case of necessity for the Animal fat in solid source (such as Adeps Bovis seu Bubali, Adeps Sus domestica etc.).The Animal fat that at room temperature is inherently other type of liquid comprises various fish oil etc.

It is about 2 weight % one or more liquid oil to about 4 weight % that the freeze-stable type oil in water emulsion that provides herein contains total concentration, comprises any value of from 1.8% to 4.4%.

In certain embodiments, the Emulsion that the combination of vegetable oil and MCT oil is used for providing herein.Such combination has long record that in Injectable Emulsion secure federation uses usually and provides advantages of excellent stability for Emulsion of the present invention.The concrete kind of employed vegetable oil (that is, soybean oil, Semen Maydis oil or Flos Carthami wet goods) and non-key, if its for safety, well tolerable, medicine is acceptable, chemically stable and the drop of the Emulsion with desired size range is provided.Usually, in the combination of vegetable oil and MCT, MCT oil is defined as 50 weight % at the most.

" phospholipid " used herein is meant glycerol and two fatty acids and three esters that phosphate anion forms.The exemplary phospholipid that the Emulsion that provides herein is provided includes but not limited to phospholipid acyl chlorides, lecithin (mixture of the cholinester of di(2-ethylhexyl)phosphate acylglycerol), PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, phosphatidic acid, its have about 4 to about 22 carbon atoms and being more typically have about 10 to about 18 carbon atoms and different saturations.The phospholipid fraction of Emulsion of the present invention can be the mixture of single phospholipid or some phospholipid.

The phospholipid that the Emulsion that provides herein is provided can be natural origin.The lecithin of natural origin is and the cholinester of phosphoric acid, is commonly referred to as phosphatidylcholine, the mixture of the stearic acid diglyceride of connection, Palmic acid diglyceride and Oleic acid diglyceride, and can derive from multiple source, such as egg and Semen sojae atricolor.Soybean lecithin and egg lecithin (hydrogenated form that comprises these chemical compounds) have permanent safety history, have the emulsifying and the dissolution properties of combination, and are easy to more promptly be decomposed into innocuous substance than most of synthetic surfactants.Commercially available soybean phospholipid is from Phospholipid GmbH, Germany with Central Soya, Phospholipon listing and the Centrophase that sells and Centrolex product, from Lipoid GmbH, the lipoid of Germany and from the EPIKURON of Degussa.

Be applicable to that phospholipid of the present invention can also be synthetic.Exemplary common synthetic phospholipid is listed in as follows:

DG

1,2-two Laurels acyl group-sn-glycerol (DLG)

1,2-two myristoyl-sn-glycerol (DMG)

1,2-two palmityls-sn-glycerol (DPG)

1,2-distearyl acyl group-sn-glycerol (DSG)

Phosphatidic acid

1,2-two myristoyl-sn-glycerol-3-phosphatidic acid, sodium salt (DMPA, Na)

1,2-two palmityls-sn-glycerol-3-phosphatidic acid, sodium salt (DPPA, Na)

1,2-distearyl acyl group-sn-glycerol-3-phosphatidic acid, sodium salt (DSPA, Na)

Phosphocholine

1,2-two Laurels acyl group-sn-glycerol-3-phosphocholine (DLPC)

1,2-two myristoyl-sn-glycerol-3-phosphocholine (DMPC)

1,2-two palmityls-sn-glycerol-3-phosphocholine (DPPC)

1,2-distearyl acyl group-sn-glycerol-3-phosphocholine (DSPC)

Phosphoethanolamine

1,2-two Laurels acyl group-sn-glycerol-3-phosphate ethanolamine (DLPE)

1,2-two myristoyl-sn-glycerol-3-phosphate ethanolamine (DMPE)

1,2-two palmityls-sn-glycerol-3-phosphate ethanolamine (DPPE)

1,2-distearyl acyl group-sn-glycerol-3-phosphate ethanolamine (DSPE)

Phosphoglycerol

1,2-two Laurels acyl group-sn-glycerol-3-phosphate glycerol, sodium salt (DLPG)

1,2-two myristoyl-sn-glycerol-3-phosphate glycerol, sodium salt (DMPG)

1,2-two myristoyl-sn-glycerol-3-phosphate-sn-1-glycerol, ammonium salt (DMP-sn-1-G, NH ₄)

1,2-two palmityls-sn-glycerol-3-phosphate glycerol, sodium salt (DPPG, Na)

1,2-distearyl acyl group-sn-glycerol-3-phosphate glycerol, sodium salt (DSPG, Na)

1,2-distearyl acyl group-sn-glycerol-3-phosphate-sn-1-glycerol, sodium salt (DSP-sn-1G, Na)

Phosphoserine

1,2-two palmityls-sn-glycerol-3-phosphate-L-serine, sodium salt (DPPS, Na)

Combination chain phospholipid

1-palmityl-2-oleoyl-sn-glycerol-3-phosphocholine (POPC)

1-palmityl-2-oleoyl-sn-glycerol-3-phosphate glycerol, and sodium salt (POPG, Na)

1-palmityl-2-oleoyl-sn-glycerol-3-phosphate glycerol, and ammonium salt (POPG, NH4)

Lysophosphatide

1-palmityl-2-haemolysis-sn-glycerol-3-phosphocholine (P-lyso-PC)

1-stearyl-2-haemolysis-sn-glycerol-3-phosphocholine (S-lyso-PC)

The phospholipid of Pegylation

N-(carbonyl-methoxy poly (ethylene glycol) 2000)-MPEG-2000-DPPE

1,2-two palmityls-sn-glycerol-3-phosphate ethanolamine, sodium salt

N-(carbonyl-methoxy poly (ethylene glycol) 5000)-MPEG-5000-DSPE

1,2-distearyl acyl group-sn-glycerol-3-phosphate ethanolamine, sodium salt

N-(carbonyl-methoxy poly (ethylene glycol) 5000)-MPEG-5000-DPPE

1,2-two palmityls-sn-glycerol-3-phosphate ethanolamine, sodium salt

N-(carbonyl-methoxy poly (ethylene glycol) 750)-MPEG-750-DSPE

1,2-distearyl acyl group-sn-glycerol-3-phosphate ethanolamine, sodium salt

N-(carbonyl-methoxy poly (ethylene glycol) 2000)-MPEG-2000-DSPE

1,2-distearyl acyl group-sn-glycerol-3-phosphate ethanolamine, sodium salt

In certain embodiments, these one or more phospholipid of freeze-stable type oil in water emulsion comprise lecithin, such as soybean lecithin or egg lecithin.

It is about 2 weight % one or more phospholipid to about 5 weight % that the freeze-stable type oil in water emulsion that provides herein comprises total concentration, is included in any value between 1.8% and 5.5%.

In the freeze-stable type oil in water emulsion that provides herein all phospholipid the weight ratio of whole liquid oil is 0.5:1 at least.In certain embodiments, whole phospholipid are 1:1 to the weight ratio of whole liquid oil.

The freeze-stable type oil in water emulsion that provides herein comprises the dextrose of about 5 weight % to about 6 weight %.

In most of embodiments, the freeze-stable type oil in water emulsion that provides herein is " wait and open " (can exchange with " isoosmotic " and use).When the osmotic pressure through measuring of oil in water emulsion equaled the osmotic pressure (it is about 296mOsm) of normal saline (0.9% sodium chloride), this oil in water emulsion was to wait to open.Typical case about the Emulsion sample measures transmutability for making an appointment with ± 10%; Therefore, think that the Emulsion with the osmotic pressure between 266mOsm and 326mOsm through measuring is isoosmotic or waits.

In certain embodiments, the oil droplet of freeze-stable type oil in water emulsion is a submicron order." submicron order drop " used herein is meant the oil droplet less than 1 micron average diameter that has by measuring such as the conventional determining size technologies of LASER Light Scattering Spectroscopy method in oil in water emulsion.For these drops safety in the blood capillary circulation is passed, need the submicron order oil droplet.Think that for intravenous injection diameter is unsafe greater than 5 microns drop, reason is that it can block blood capillary, causes pulmonary infarction.

In certain embodiments, the oil droplet of freeze-stable type oil in water emulsion has the average diameter less than 500nm, 450nm, 400nm, 350nm, 300nm or 250nm.

In certain embodiments, the oil droplet of freeze-stable type preparation has average diameter less than 0.2 micron (200nm) so that this Emulsion can be by sterilizing through 0.2 micron order membrane filtration.In certain embodiments, the oil droplet of compositions of the present invention has the average diameter less than about 175nm, 150nm, 125nm, 100nm or 75nm.

In certain embodiments, freeze-stable type oil in water emulsion also has the PFAT5 value less than 0.05." PFAT5 " is meant the percent by volume of diameter greater than fat drop or the oil droplet of 5 μ m.For intravenous Emulsion, PFAT5 less than 0.05% is preferred (Todd Canada, " Pathological Consequences From the Infusion of Unstable LipidEmulsion Admixtures in Guinea Pigs (in the Cavia porcellus body; import the pathology result of unsettled liplid emulsions mixture) " Nutrition in Clinical Practice, the 21st volume, the 6th phase, 2006636-637).The PFAT5 value can be also called optical particulate counting method (OPC) and measure, such as the AccuSizer 780 of Particle Sizing System by the method for individual particle optical sensor (SPOS).

In certain embodiments, freeze-stable type oil in water emulsion has that particle mean size is not more than the oil droplet of about 200nm and less than about 0.05 PFAT5.Low PFAT5 reduces or eliminates larger oil droplet and block microcirculatory probability.The little particle mean size of oil droplet allows this Emulsion to be filtered sterilization, and for vancomycin, because the sensitivity of its heat, light and oxygen, this is particularly preferred.These sensitivity make and other sterilizing methods expose such as autoclave, gamma-radiation or UV to the open air, can not carry out or more less preferred.

If at one freezing (under-20 ℃)-(under 4 ℃ or 25 ℃) all after dates that thaw, the increase of the average diameter of oil droplet is not more than 50% in oil in water emulsion, then this oil in water emulsion is " freeze-stable ".

In certain embodiments, the freeze-stable type oil in water emulsion that provides herein is at all after dates of 2,3,4 or 5 freeze-thaws, and the increase of the average diameter of oil droplet is not more than 50%.

In certain embodiments, at all after dates of 1,2,3,4 or 5 freeze-thaw, the increase of the average diameter of the oil droplet of the freeze-stable type oil in water emulsion that provides herein is not more than 40%, 30%, 30%, 20% or 10%.

In certain embodiments, at 1,2,3,4 or 5 freeze-thaw week after date, freeze-stable type oil in water emulsion keeps its mean oil droplet size to be not more than about 200nm and PFAT5 less than about 0.05.

As hereinafter in greater detail, when under freezing state (for example, under-20 ℃) time period of store prolonging is (for example, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months) time, freeze-stable type oil in water emulsion disclosed herein is stable.When storing under freezing state, freeze-stable type oil in water emulsion disclosed herein is also referred to as " frozen composition ", " freezing Emulsion " or " frozen preparation ".

In certain embodiments, the pH value of the freeze-stable type oil in water emulsion of vancomycin is about 3 to about 8.In certain embodiments, pH value is about 4 to about 7.

In certain embodiments, described freeze-stable type oil in water emulsion does not further comprise the chemical compound of the amount of vancomycin in the oil droplet that can increase oil in water emulsion.The example of this compounds comprises fatty acid, cholesterol sulfate, riboflavin-5-phosphoric acid ester, vitamin e succinate, and the mixture of two or more reagent in the mentioned reagent.According to Andrew, answer is a "No".

In some other embodiment, though described freeze-stable type oil in water emulsion can further comprise the chemical compound that can increase the amount of vancomycin in the oil droplet, the stability of this Emulsion (physical stability and/or chemical stability) does not need the existence of this chemical compound.

In certain embodiments, being lower than about 70% vancomycin is present in the oil droplet of described freeze-stable type oil in water emulsion.In certain embodiments, be lower than in the oil droplet that about vancomycin of 60%, 50%, 40%, 30% or 20% is present in described freeze-stable type oil in water emulsion.

In certain embodiments, for intravenous injection, some components in described freeze-stable type oil in water emulsion except that vancomycin or all components (for example, oil ingredient and phospholipid) are safety, well tolerable, and can be accepted by FDA.

If the component of oil in water emulsion does not cause the bad systemic reaction such as anaphylactic shock in the patient, think that then it is " safety ".

If the component of oil in water emulsion does not cause the untoward reaction of essence at the injection site place,, think that then it is " well tolerable " such as phlebitis, inflammation of vein or venous stimulation.

If when the application's the applying date, the component of oil in water emulsion is used for intravenous injection by the FDA approval, and is to use with the concentration that employed concentration is suitable in the product of FDA approval, to think that then this component is " can be accepted by FDA ".

In certain embodiments, some components in described freeze-stable type oil in water emulsion except that vancomycin or all components (for example, oil ingredient and phospholipid) are thought that by medicine Supervision Bureau (drug regulatory authority) it is safe being used for intravenous injection usually.

If when the application's the applying date, the component of oil in water emulsion has been used for the intravenous injection product through FDA or the approval of European medicine Supervision Bureau, and it is when using with the concentration that employed concentration is suitable in the product of U.S. FDA or the approval of European medicine Supervision Bureau, and then this component is " being thought that by medicine Supervision Bureau it is safe being used for intravenous injection usually ".

In certain embodiments, described freeze-stable type oil in water emulsion is that vein is nonirritating." vein non-irritating " is meant when through intravenous administration, do not cause the chemical compound of essence stimulation or the character of compositions at the injection site place, wherein this essence stimulates and for example shows as skin thickening, cutaneous necrosis, local rubescent, local swelling, has the venectasia that blood clotting forms, or the venous thrombosis with subcutaneous inflammation.This term can exchange with " non-vein anaphylaxis ", " non-vein zest " or similar terms and use.

In certain embodiments, freeze-stable type oil in water emulsion or its component are injectable." injectable " is meant that composition is that medicine authoritative institution (for example, US FDA) accepts, and allows it to be used for injectable drug.

In certain embodiments, freeze-stable type oil in water emulsion or its component are biocompatible." biocompatible " be meant with acceptable manner, that is, and and no inappropriate toxicity or deleterious physiology or pharmacotoxicological effect, in vivo or implement the ability of function on it.

Exemplary freeze-stable type oil in water emulsion of the present invention comprises: (1) concentration is the vancomycin hydrochloride of about 0.5 weight %, (2) concentration is the soybean oil of about 1 weight % to about 2 weight %, (3) concentration is the medium chain triglyceride of about 1 weight % to about 2 weight %, (4) concentration is the lecithin of about 2 weight % to about 4 weight %, and (5) concentration is the dextroses of about 5 weight % to about 6 weight %.

Another exemplary freeze-stable type oil in water emulsion of the present invention comprises: (1) concentration is the vancomycin hydrochloride of about 0.5 weight %, (2) soybean oil and medium chain triglyceride, wherein the total concentration of soybean oil and medium chain triglyceride is about 2 weight %, the weight ratio of soybean oil centering chain triglyceride is between 2:1 to 1:1, and (3) concentration is that lecithin and (4) concentration of about 2 weight % is the dextrose of about 5 weight %.

The present invention also is provided for preparing the method for the freeze-stable type oil in water emulsion of vancomycin described herein.Such emulsion composition can be prepared by following steps: (a) form and comprise (i) one or more liquid oil (for example, vegetable oil, or the combination of vegetable oil and medium chain triglyceride) and the (ii) mixture of one or more phospholipid; (b) form the vancomycin comprise (i) medicine effective quantity or the acceptable salt of its medicine or analog, the (ii) dextrose and the (iii) mixture of water; And (c) with step (a) and the formation of mixture (b) oil in water emulsion.

In certain embodiments, step (a) can be by being dissolved in liquid oil (class) and phospholipid (class) in the ethanol, removes ethanol (for example, passing through vacuum) then and be less than 1% of dry weight until the ethanol of remnants and carry out to obtain clarifying oil solution.

In certain embodiments, step (c) can be added into by the aqueous solution with step (b) in the mixture of step (a) and carry out to form primary emulsion.This aqueous solution can further contain buffer and/or tension regulator.The formation of this primary emulsion can be undertaken or promotes by using mechanically homogenise (for example, high shear mixing, high-pressure extrusion and Micro Fluid) or other suitable technology.In certain embodiments, the pH value of this primary emulsion is adjusted to about 4.Above-mentioned primary emulsion can be by further being made with extra care with the stable emulsion of the oil droplet size that obtains to have suitable homogeneous via the circulation of microjet homogenizer or similar device.The method sterilization after filtration of the purified Emulsion of gained, for example, through 0.22 micron sterilizing filter filtration sterilization.

The illustrative methods of the oil in water emulsion of preparation vancomycin hydrochloride is provided in embodiment 3 and embodiment 6.

Except ready-made oil in water emulsion, freeze-stable type vancomycin compositions of the present invention can also be frozen storage and thaw before administration period after a while.Frozen preparation prevents or reduces vancomycin and degrade rapidly owing to hydrolysis.

On the one hand, the application provides frozen composition, and it comprises vancomycin or the acceptable salt of its medicine or analog, liquid oil (class), phospholipid (class), dextrose and water.Described compositions can prepare by the freezing freeze-stable type oil in water emulsion that provides herein.Resulting composition can be thawed is suitable for the oil in water emulsion of administration (for example, injection) with formation.

" freezing Emulsion " for being lower than the Emulsion that (for example ,-20 ℃ to-10 ℃) under the temperature of ambient temperature stores, the water of this Emulsion crystallization (for example, form ice) wholly or in part under this temperature.

Exemplary frozen composition comprises: (i) concentration is the acceptable salt of medicine or the analog of the suitable vancomycin of the vancomycin of about 0.5 weight % or concentration; (ii) total concentration is about 2 weight % one or more liquid oil to about 4 weight %; (iii) total concentration is about 1 weight % to one or more phospholipid of about 5 weight %, and wherein all phospholipid are 0.5:1 at least to the weight ratio of whole liquid oil; (iv) about 5 weight % are to the dextrose of about 6 weight %; And (v) water.

Another exemplary frozen composition comprises: (1) concentration is the vancomycin hydrochloride of about 0.5 weight %, (2) concentration is the soybean oil of about 1 weight % to about 2 weight %, (3) concentration is the medium chain triglyceride of about 1 weight % to about 2 weight %, (4) concentration is the lecithin of about 2 weight % to about 4 weight %, and (5) concentration is the dextroses of about 5 weight % to about 6 weight %.

Another exemplary frozen composition comprises: (1) concentration is the vancomycin hydrochloride of about 0.5 weight %, (2) soybean oil and medium chain triglyceride, wherein the total concentration of soybean oil and medium chain triglyceride is about 2 weight %, the weight ratio of soybean oil centering chain triglyceride is between 2:1 to 1:1, (3) concentration is the lecithin of about 2 weight %, and (4) concentration is the dextrose of about 5 weight %.

In certain embodiments, when thawing, the average diameter that described frozen composition forms oil droplet again is not more than the oil in water emulsion of about 200nm.

In certain embodiments, when thawing, described frozen composition forms PFAT5 again less than about 0.05 oil in water emulsion.

In certain embodiments, when thawing, the average diameter that described frozen composition forms oil droplet again is not more than about 200nm and PFAT5 less than about 0.05 oil in water emulsion.

In certain embodiments, described frozen preparation at room temperature at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months be physically stable, chemically stable or not only physically stable but also chemically stable.

If frozen preparation can store one definite period under freezing state, and do not have to thaw by the frozen preparation after storing and the average droplet size of the oil in water emulsion that forms increases and surpasses 50%, the Emulsion that perhaps thaws does not have and is separated or the sign of oil droplet cohesion (coalescent), and then this frozen preparation is " physically stable ".In certain embodiments, with compare by its freeze-stable type oil in water emulsion that is prepared into frozen preparation of the present invention, the particle mean size of the oil droplet of the Emulsion that is formed again by this frozen preparation that stores under freezing state after at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months does not increase or increases and is no more than about 10%, 20%, 25%, 30% or 40%.

If store one definite period under suitable condition of storage, it is about 20% that the variation of the vancomycin concentration in the frozen preparation does not reach, and then said preparation is " chemically stable ".In certain embodiments, with compare by its freeze-stable type oil in water emulsion that is prepared into frozen preparation, vancomycin concentration does not change or concentration change does not reach about 5%, 10%, 15% or 20% in the Emulsion that is formed again by this frozen preparation that stores at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months under freezing state.

In certain embodiments, described one or more liquid oil of described frozen composition comprise vegetable oil and medium chain triglyceride.

In certain embodiments, described frozen composition does not further comprise the chemical compound of the amount of vancomycin in the oil droplet that can increase the Emulsion that forms by this frozen composition that thaws.

In certain embodiments, when described frozen composition was thawed with the formation oil in water emulsion, no more than about vancomycin of 70%, 60%, 50%, 40%, 30% or 20% was present in the oil droplet of this oil in water emulsion.

In related fields, also provide the oil in water emulsion of the vancomycin that forms again by thawing frozen preparation described herein.

In certain embodiments, the described oil in water emulsion that forms again has the above-mentioned chemical and physical properties identical with above-mentioned freeze-stable type oil in water emulsion.For example, in certain embodiments, the oil in water emulsion of Xing Chenging has the average diameter of the oil droplet that is not more than about 200nm again, and/or less than about 0.05 PFAT5.In certain embodiments, the oil in water emulsion that forms again is that grade is opened and is standby.In certain embodiments, the oil in water emulsion that forms does not again further comprise the chemical compound of the amount of vancomycin in the oil droplet that can increase the Emulsion that forms again.In certain embodiments, no more than about vancomycin of 70%, 60%, 50%, 40%, 30% or 20% is present in the oil droplet in the oil in water emulsion that forms again.

The vancomycin formulations of Miao Shuing can be used for treatment or prevents vancomycin that it is effectively infected (promptly herein, reduce or eliminate this infection risk), it comprises that treatment or prevention Gram-positive infect, treat the peritonitis relevant among the patient who suffers from end stagerenaldisease with peritoneal dialysis, treatment is owing to the pseudomembranous colitis or the staphylococcus aureus enterocolitis of clostridium difficile, surgical prophylaxis to penicillin or other beta-Lactam antibiotic patient hypersensitive, to standing gastrointestinal/apparatus urogenitalis program and to the ampicillin, the amoxicillin, penicillin or other beta-Lactam antibiotic patient's hypersensitive antibacterial endocarditis prevention, treatment meningitis or ventriculitis dock bacteremia prevention in the neonatal hospital that receives parenteral alimentation.

The individuality that vancomycin oil-in-water preparation of the present invention (directly preparation or formed again by frozen preparation) can be by all means needs said preparation with medicine effective quantity (for example, people or other mammal), wherein this approach includes but not limited to intravenous administration, intramuscular administration, intra-arterial administration, intrathecal drug delivery, eye drops, subcutaneous administration, intra-articular administration, intraperitoneal administration, oral administration, topical, intravaginal administration and dosing eyes.

" medicine effective quantity " is meant the amount of antibiotic (that is, vancomycin or the clarithromycin) oil in water emulsion that is enough to treat infection.

The vancomycin oil in water emulsion that provides herein can every day single dose or every day multidose come administration.Also can adopt other periodically therapeutic scheme.This treatment may need long term administration, for example a couple of days or about one thoughtful around.The amount of each dosage or administration total amount will depend on various factors, approach and frequency such as administration, the essence and the seriousness that infect, patient's age, sex, body weight and general health situation, and can determine according to known Therapeutic Principle in the field of antibiotics by the doctor.

In certain embodiments, the oil in water emulsion that provides herein can be divided into the daily dose of about 2 gram vancomycins per 6 hours about 500mg or per 12 hours about 1 grams give adult patient through intravenous.Other exemplary dose about the intravenous administration of the oil in water emulsion that provides herein comprises per 6 hours about 5mg to the 10mg vancomycins of per kilogram of body weight, or per 12 hours about 10mg to the 20mg vancomycins of per kilogram of body weight.

Clarithromycin freeze-stable type preparation or frozen preparation

" clarithromycin " be meant 6-O-methyl-erythromycin (referring to, United States Patent (USP) the 4th, 331, No. 803), it has structure as follows.

" clarithromycin " also refers to the semi-synthetic derivant (for example, acceptable salt of the medicine of clarithromycin and ester) of clarithromycin.

In another aspect of this invention, provide freeze-stable type oil in water emulsion, it comprises: (i) concentration is at least about the acceptable salt of medicine or the ester of the suitable clarithromycin of the clarithromycin of 0.5 weight % or concentration; (ii) total concentration is about 2 weight % one or more liquid oil to about 4 weight %; (iii) total concentration is about 1 weight % to one or more phospholipid of about 5 weight %, and wherein all phospholipid are 0.5:1 at least to the weight ratio of whole liquid oil; (iv) about 5 weight % are to the dextrose of about 6 weight %; And (v) water.

" acceptable salt of medicine and ester " be meant and be applicable in reliable medical judgment category and contact with human and zootic tissue and do not have unsuitable toxicity, stimulation, anaphylaxis and similar adverse consequences thereof, and can be effective to it in the chemotherapy of anti-microbial infection and the salt and the ester of the preventive use in preventing.The comparatively common acceptable salt of medicine of clarithromycin and ester are acetate/ester, support acid esters (estolate) (lauryl sulfate of propionic ester), ethyl succinate, gluceptate/ester (glucose enanthate/ester), Lactobionate/ester, stearate/ester and hydrochloride form.Employed other acid salt is as follows in field of medicaments: adipate, alginate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, citrate, camphorate, camsilate, cipionate, digluconate, lauryl sulfate, ethane sulfonate, fumarate, gluconate, glycerophosphate, Hemisulphate, enanthate, caproate, hydrobromate, hydriodate, 2-hydroxyl-ethane sulfonate, lactate, maleate, methane sulfonates, 2-naphthalene-sulfonate, nicotinate, oxalates, embonate, pantothenate, pectate, persulfate, 3-phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, tartrate, rhodanate, toluene fulfonate and hendecane hydrochlorate.The alkalescence nitrogen-containing group can be quaternized with following reagent, and this class reagent is elementary alkyl halide for example, such as methyl, ethyl, propyl group and butyl chloride, bromide and iodide; Dialkyl sulfate is as Dimethylsulfate, diethyl sulfide hydrochlorate, dibutyl sulfide hydrochlorate and diamyl sulfate; Long-chain halogenide is such as decyl, lauryl, myristyl and stearyl chlorination thing, bromide and iodide; Aralkyl halide is as benzyl bromide and phenethyl bromination thing and other.Thereby obtain water miscible or oil-soluble or dispersible products.

The concentration of the acceptable salt of medicine of clarithromycin is for the concentration of the prescribed concentration of " being equivalent to " clarithromycin, if under this prescribed concentration, clarithromycin salt contains the clarithromycin free alkali with the clarithromycin same amount of this prescribed concentration.

The concentration of the acceptable ester of medicine of clarithromycin is for the concentration of the prescribed concentration of " being equivalent to " clarithromycin, if under this prescribed concentration, the clarithromycin ester is the same equal effective with the clarithromycin of prescribed concentration in treatment or prevention infection.

In the freeze-stable type oil in water emulsion that provides in this article, clarithromycin is to exist with the concentration at least about 0.5%.In certain embodiments, clarithromycin is to exist with the concentration at least about 1%, 2% or 3%.

It is about 2 weight % one or more liquid oil to about 4 weight % that the freeze-stable type oil-in-water clarithromycin emulsion that provides herein contains total concentration, comprises any value of from 1.8% to 4.4%.

The oil ingredient of the oil-in-water clarithromycin emulsion that provides herein in certain embodiments, comprises monoglyceride, diglyceride, triglyceride or its mixture.In certain embodiments, this oil ingredient is included in the ester that forms between one or more fatty acids and the alcohol except that glycerol.

In certain embodiments, described one or more liquid oil of oil-in-water clarithromycin emulsion comprise vegetable oil, such as soybean oil.

In certain embodiments, the combination with vegetable oil and MCT oil is used for the present invention.Usually, in the combination of vegetable oil and MCT, MCT oil is defined as 50 weight % at the most.

In certain embodiments, described one or more phospholipid of freeze-stable type oil-in-water clarithromycin emulsion comprise lecithin, such as Semen Glycines lecithin or egg lecithin.

It is about 2 weight % one or more phospholipid to about 5 weight % that the freeze-stable type oil-in-water clarithromycin emulsion that provides herein comprises total concentration, is included in any value between 1.8% and 5.5%.

In the freeze-stable type oil-in-water clarithromycin emulsion that provides herein all phospholipid the weight ratio of whole liquid oil is 0.5:1 at least.In certain embodiments, whole phospholipid are 1:1 to the weight ratio of whole liquid oil.

The freeze-stable type oil-in-water clarithromycin emulsion that provides herein comprises the dextrose of about 5 weight % to about 6 weight %.

In most of embodiments, the freeze-stable type oil-in-water clarithromycin emulsion that provides herein is for wait opening, from but standby.

In certain embodiments, the oil droplet of freeze-stable type oil-in-water clarithromycin emulsion is a submicron order.In certain embodiments, the oil droplet of freeze-stable type oil-in-water clarithromycin emulsion has the average diameter less than about 500nm, 450nm, 400nm, 350nm, 300nm, 250nm, 200nm, 175nm, 150nm, 125nm, 100nm or 75nm.

In certain embodiments, freeze-stable type oil-in-water clarithromycin emulsion also has the PFAT5 value less than about 0.05.

In certain embodiments, freeze-stable type oil-in-water clarithromycin emulsion has that particle mean size is not more than the oil droplet of about 200nm and less than about 0.05 PFAT5.

In certain embodiments, the freeze-stable type oil-in-water clarithromycin emulsion that provides herein is at all after dates of 1,2,3,4 or 5 freeze-thaw, and the increase of the average diameter of its oil droplet is not more than about 50%.

In certain embodiments, the freeze-stable type oil-in-water clarithromycin emulsion that provides herein is at all after dates of 1,2,3,4 or 5 freeze-thaw, and the increase of the average diameter of its oil droplet is not more than about 40%, 30%, 30%, 20% or 10%.

In certain embodiments, at 1,2,3,4 or 5 freeze-thaw week after date, described freeze-stable type oil-in-water clarithromycin emulsion keeps its mean oil droplet size to be not more than about 200nm and PFAT5 less than about 0.05.

As more detailed description hereinafter, when under freezing state (for example, under-20 ℃) time period of store prolonging is (for example, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months) time, freeze-stable type oil-in-water clarithromycin emulsion disclosed herein is stable.

In certain embodiments, the pH value of the freeze-stable type oil in water emulsion of clarithromycin is about 3 to about 8 (for example, about 6 to about 8).In certain embodiments, pH value is about 4 or about 7.

In certain embodiments, described oil in water emulsion does not further comprise the chemical compound of the amount of clarithromycin in the oil droplet that can increase the clarithromycin oil in water emulsion.The example of this compounds comprises fatty acid, N-Methyl pyrrolidone and benzylalcohol.

In certain embodiments, no more than about vancomycin of 70%, 60%, 50%, 40%, 30% or 20% is present in the oil droplet of freeze-stable type oil-in-water clarithromycin emulsion.

In certain embodiments, for intravenous injection, some components in described freeze-stable type oil in water emulsion except that clarithromycin or all components (for example, oil ingredient and phospholipid) are safety, well tolerable, and can be accepted by FDA.

In certain embodiments, some components except that clarithromycin or all components (for example, oil ingredient and phospholipid) are thought that by medicine Supervision Bureau it is safe being used for intravenous injection usually in freeze-stable type oil in water emulsion.

In certain embodiments, freeze-stable type oil in water emulsion is that vein is nonirritating, injectable and/or biocompatible.

Exemplary freeze-stable type oil-in-water clarithromycin emulsion comprises: (1) concentration is the clarithromycin of about 1 weight % to about 5 weight %; (2) soybean oil and medium chain triglyceride, wherein the total concentration of soybean oil and medium chain triglyceride is about 2 weight %, and the weight ratio of soybean oil centering chain triglyceride is between 2:1 to 1:1; (3) concentration is the lecithin of about 2 weight %, and (4) concentration is the dextroses of about 5 weight % to about 6 weight %.

Another exemplary freeze-stable type oil-in-water clarithromycin emulsion comprises: (1) concentration is the clarithromycin of about 5 weight %, (2) concentration is the soybean oil of about 1 weight %, (3) concentration is the medium chain triglyceride of about 1 weight %, (4) concentration is the lecithin of about 2 weight %, and (5) concentration is the dextrose of about 5 weight %.

The present invention also provides the method for the freeze-stable type oil in water emulsion that is used to prepare clarithromycin as herein described.Such emulsion composition can be prepared by following steps: (a) form and comprise (i) one or more liquid oil (for example, vegetable oil, or the combination of vegetable oil and medium chain triglyceride) and the (ii) mixture of one or more phospholipid; (b) form the clarithromycin comprise (i) medicine effective quantity or the acceptable salt of its medicine or ester, the (ii) dextrose and the (iii) mixture of water; And (c) with step (a) and the formation of mixture (b) oil in water emulsion.

In certain embodiments, step (c) can be added into by the aqueous solution with step (b) in the mixture of step (a) and carry out to form primary emulsion.This aqueous solution can further contain buffer and/or tension regulator.The formation of this primary emulsion can be undertaken or promotes by using mechanically homogenise (for example, high shear mixing, high-pressure extrusion and Micro Fluid) or other suitable technology.In certain embodiments, the pH value of this primary emulsion is adjusted to about 5 to about 9 (for example, about 7).Above-mentioned primary emulsion can be by further being made with extra care with the stable emulsion of the oil droplet size that obtains to have suitable homogeneous via the circulation of microjet homogenizer or similar device.The method sterilization after filtration of the refining Emulsion of gained, for example, through 0.22 micron sterilizing filter filtration sterilization.

The illustrative methods of the oil in water emulsion of preparation clarithromycin is provided in embodiment 9.

Except ready-made oil in water emulsion, freeze-stable type clarithromycin compositions of the present invention can also be frozen storage and thaw before injection period after a while.

On the one hand, the application provides frozen composition, and it comprises clarithromycin or the acceptable salt of its medicine or ester, liquid oil (class), phospholipid (class), dextrose and water.This based composition can prepare by the freezing freeze-stable type oil in water emulsion that provides herein.The oil in water emulsion that resulting composition can be thawed and be suitable for injecting with formation.

Exemplary frozen composition comprises: (i) concentration is at least about the acceptable salt of medicine or the ester of the suitable clarithromycin of the clarithromycin of 0.5 weight % or concentration; (ii) total concentration is about 2 weight % one or more liquid oil to about 4 weight %; (iii) total concentration is about 1 weight % to one or more phospholipid of about 5 weight %, and wherein all phospholipid are 0.5:1 at least to the weight ratio of whole liquid oil; (iv) about 5 weight % are to the dextrose of about 6 weight %; And (v) water.

Another exemplary frozen composition comprises: (1) concentration is the clarithromycin of about 1 weight % to about 5 weight %, (2) soybean oil and medium chain triglyceride, wherein the total concentration of soybean oil and medium chain triglyceride is about 2 weight %, and the weight ratio of soybean oil centering chain triglyceride is between 2:1 to 1:1, (3) concentration is the lecithin of about 2 weight %, and (4) concentration is the dextroses of about 5 weight % to about 6 weight %.

Another exemplary frozen composition comprises: (1) concentration is the clarithromycin of about 5 weight %, (2) concentration is the soybean oil of about 1 weight %, (3) concentration is the medium chain triglyceride of about 1 weight %, and (4) concentration is the lecithin of about 2 weight %, and (5) concentration is the dextrose of about 5 weight %.

In certain embodiments, described frozen preparation at room temperature at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months was physically stable, chemically stable, or not only physically stable but also chemically stable.

In certain embodiments, with compare by its freeze-stable type oil in water emulsion that is prepared into disclosed frozen preparation among this paper, the particle mean size of the Emulsion that is formed again by this frozen preparation that stores under freezing state after at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months does not increase or increases and is no more than about 10%, 20%, 25%, 30% or 40%.

In certain embodiments, with compare by its freeze-stable type oil in water emulsion that is prepared into disclosed frozen preparation among this paper, clarithromycin concentration does not change or concentration change does not reach about 5%, 10%, 15% or 20% in the Emulsion that is formed again by this frozen preparation that stores at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months under freezing state.

In certain embodiments, described frozen composition does not further comprise the chemical compound of the amount of vancomycin in the oil droplet that can increase Emulsion.

In certain embodiments, when described frozen composition was thawed with the formation oil in water emulsion, no more than about clarithromycin of 70%, 60%, 50%, 40%, 30% or 20% was present in the oil droplet of this oil in water emulsion.

In related fields, also provide the frozen preparation of describing by thawing herein and the oil in water emulsion of the clarithromycin that forms again.

In certain embodiments, this oil in water emulsion that forms again has the above-mentioned chemical and physical properties identical with above-mentioned freeze-stable type oil in water emulsion.For example, in certain embodiments, the oil in water emulsion of Xing Chenging has the average diameter of the oil droplet that is not more than about 200nm again, and/or less than about 0.05 PFAT5.In certain embodiments, the oil in water emulsion that forms again is that grade is opened and is standby.In certain embodiments, the oil in water emulsion that forms does not again further comprise the chemical compound of the amount of clarithromycin in the oil droplet that can increase this Emulsion that forms again.In certain embodiments, no more than about clarithromycin of 70%, 60%, 50%, 40%, 30% or 20% is present in the oil droplet in the oil in water emulsion that forms again.

The Biaxin that provides herein can be used for treating clarithromycin it is effectively infected or reduce the risk of this infection, it comprises by bacterial infection, such as pneumonia, bronchitis, and ear infection, pulmonary infection, sinus infection, stomach infection, skin infection and throat infection.

The individuality that clarithromycin oil-in-water preparation of the present invention (directly preparation or formed again by frozen preparation) can be by all means needs said preparation with medicine effective quantity (for example, people or other mammal), wherein this approach includes but not limited to intravenous administration, intramuscular administration, intra-arterial administration, intrathecal drug delivery, eye drops, subcutaneous administration, intra-articular administration, oral administration, topical, intravaginal administration and intraperitoneal administration.

The clarithromycin oil in water emulsion that provides herein can every day single dose or every day multidose come administration.Also can use other periodically therapeutic scheme.This treatment may need long term administration, such as a couple of days or about one thoughtful around.The amount of each dosage or administration total amount will depend on various factors, approach and frequency such as administration, the essence and the seriousness that infect, patient's age, sex, body weight and general health situation, and can determine according to known Therapeutic Principle in the field of antibiotics by the doctor.For example, in certain embodiments, the oil in water emulsion that provides herein can per 12 hours about 250mg give adult patient through intravenous to the dosage of about 750mg.

But freeze-dried type oil in water emulsion and lyophilized formulations

In another aspect of this invention, but provide the freeze-dried type oil in water emulsion of vancomycin and clarithromycin.One or more during this class Emulsion can have the following advantages: it can store (1) and keep stable between the storage life through lyophilizing, (2) it contains submicron oil droplet and method sterilization after filtration, (3) described freeze-dried emulsion can be reassembled as the oil in water emulsion with submicron oil droplet, and the Emulsion that should recombinate is method sterilization after filtration also, (4) directly preparation or be that non-vein stimulates by the oil in water emulsion of described freeze-dried emulsion reorganization, and (5) described oil in water emulsion (does not for example contain any extra chemical compound, stabilizing agent), this has been avoided any side effect of this compounds.

When describing the oil in water emulsion that forms by freeze-dried composition, term " form again " can with " reorganization " exchange use.

But vancomycin freeze-dried type preparation and lyophilized formulations

On the one hand, but the invention provides the freeze-dried type oil in water emulsion, it comprises: (i) 15mg/ml vancomycin or acceptable salt of its medicine or analog at least, (ii) total concentration is about 2 weight % one or more liquid oil to about 10 weight %, (iii) total concentration is about 1 weight % to one or more phospholipid of about 10 weight %, and (iv) concentration is at least about the dextrose of 10 weight %.

In certain embodiments, acceptable salt of vancomycin or medicine or analog are to be present in the oil in water emulsion with the concentration at least about 16mg/ml, 17mg/ml, 18mg/ml, 19mg/ml, 20mg/ml, 21mg/ml, 22mg/ml, 23mg/ml, 24mg/ml, 25mg/ml, 30mg/ml, 35mg/ml, 40mg/ml, 45mg/ml, 50mg/ml.

But all the amount of oil ingredient can be at about 1 weight % to the scope of about 20 weight % (for example, about 2 weight % are to about 10 weight %) in the freeze-dried type vancomycin Emulsion that provides herein.In certain embodiments, the total concentration of described oil ingredient is about 2 weight %, 3 weight %, 4 weight %, 5 weight %, 6 weight %, 7 weight %, 8 weight %, 9 weight %, 10 weight %, 12 weight %, 15 weight %, 18 weight % or 20 weight %.

In certain embodiments, vegetable oil is calculated by weight at about 9:1 to the scope of about 1:1 the weight ratio of MCT oil in the described oil-in-water vancomycin Emulsion.In certain embodiments, vegetable oil is about 9:1,8:1,7:1,6:1,5:1,4:1,3:1,2:1 or 1:1 to the weight ratio of MCT oil.

Calculate by weight can be about 1% to about 10% scope for the amount of phospholipid in the vancomycin Emulsion that provides herein.In certain embodiments, the concentration of the phospholipid in described Emulsion is about 2 weight %, 3 weight %, 4 weight %, 5 weight %, 6 weight %, 7 weight %, 8 weight %, 9 weight % or 10 weight %.

But the freeze-dried type oil in water emulsion of vancomycin also comprises the dextrose that concentration is at least about 10 weight %.In certain embodiments, the concentration of dextrose is about 12 weight %, 14 weight %, 15 weight %, 18 weight %, 20 weight %, 22 weight %, 24 weight %, 25 weight %, 28 weight % or 30 weight % in described oil in water emulsion.

In the described oil in water emulsion, the existence of dextrose prevents that drop from forming agglutination body or be separated between lyophilizing and recombination stage, and allow the obtained freeze-drying preparation can water rapidly (for example, in about 5 minutes or shorter time) reorganization be not more than about 1 micron oil in water emulsion with the average diameter that forms drop again.In addition, because vancomycin is a high dose medicament, so in described oil in water emulsion, need a large amount of relatively cryoprotective agents after by lyophilizing, can be formed oil in water emulsion again by reorganization with micron order or submicron order drop to guarantee said preparation.When with big relatively amount intravenous administration, use dextrose as cryoprotective agent can avoid with such as other cryoprotective agents such as mannitol relevant safety or bioactive worry.

In certain embodiments, under suitable condition of storage (for example, under 2 ℃-8 ℃) store at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 9 days, 12 days, 15 days, 18 days, 20 days, 25 days or 30 days, but the increase of the particle mean size of the oil droplet of the freeze-dried type Emulsion that provides herein is not more than about 10%, 20%, 25%, 30%, 40%, 50%, 75%, 100%, 125%, 150%, 175% or 200%.

In certain embodiments, under suitable condition of storage (for example, under 2 ℃-8 ℃) store at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days or 10 days, but the rate of change of vancomycin concentration does not reach about 5%, 10%, 15% or 20% in the freeze-dried type Emulsion of the present invention.

In certain embodiments, but the oil droplet of the lyophilising composition that provides herein has the average diameter less than about 500nm, 450nm, 400nm, 350nm, 300nm, 250nm, 200nm, 175nm, 150nm, 125nm, 100nm, 75nm or 50nm.

In certain embodiments, this oil in water emulsion has the PFAT5 less than about 0.05.

In certain embodiments, this oil in water emulsion has less than the average diameter of the oil droplet of about 200nm and less than about 0.05 PFAT5.

In certain embodiments, this oil in water emulsion is sterilized.For example, the oil in water emulsion with the mean oil droplet diameter that is not more than about 200nm can be sterilized by 0.2 μ m filter.

In certain embodiments, the pH value of the oil in water emulsion of vancomycin is about 3 to about 8.In certain embodiments, this pH value is about 7 or about 7.5.

In certain embodiments, but described freeze-dried type oil in water emulsion does not further comprise the chemical compound of the amount of vancomycin in the oil droplet that can increase this Emulsion.

In some other embodiment, though but described freeze-dried type oil in water emulsion may further comprise the chemical compound that can increase the amount of vancomycin in the oil droplet, the stability of this Emulsion (physical stability and/or chemical stability) does not need the existence of this compounds.

In certain embodiments, being lower than about vancomycin of 70%, 60%, 50%, 40%, 30% or 20% is present in the oil droplet of described oil in water emulsion.

" but freeze-dried type oil in water emulsion " is meant can be by the oil in water emulsion (" initial oil in water emulsion ") of lyophilizing to form lyophilized products (lyophile), and compare with this initial oil in water emulsion, do not increase 50% by the mean oil droplet size of the oil in water emulsion of this lyophilized products reorganization.

In certain embodiments, by lyophilizing with form lyophilized products and subsequently by this lyophilized products reorganization after, but should freeze-dried type oil in water emulsion keep its mean oil droplet size to be not more than about 200nm and PFAT5 less than about 0.05.

But another exemplary freeze-dried type oil in water emulsion comprises: concentration is the vancomycin hydrochloride of about 1 weight % to about 3 weight %; Concentration is the medium chain triglyceride of about 1 weight % to about 5 weight %; Concentration is the vegetable oil of about 1 weight % to about 5 weight %; Concentration is the lecithin of about 1 weight % to 4 weight %; And the dextrose of about 15 weight % to 25 weight %.

But the present invention also provides the method for the freeze-dried type oil in water emulsion that is used to prepare the vancomycin of describing herein.This class emulsion composition can be prepared by following steps: (a) form and comprise (i) one or more liquid oil (for example, vegetable oil, or the combination of vegetable oil and medium chain triglyceride) and the (ii) mixture of one or more phospholipid; (b) form the vancomycin comprise (i) medicine effective quantity or the acceptable salt of its medicine or analog, the (ii) dextrose and the (iii) mixture of water; And (c) with step (a) and the formation of mixture (b) oil in water emulsion.

In certain embodiments, step (c) can be added into by the aqueous solution with step (b) in the mixture of step (a) and carry out to form primary emulsion.This aqueous solution can further contain buffer, stabilizing agent and/or tension regulator.The formation of this primary emulsion can be undertaken or promotes by using mechanically homogenise (for example, high shear mixing, high-pressure extrusion and Micro Fluid) or other suitable technology.In certain embodiments, the pH value of this primary emulsion is adjusted to about 6 to about 8 (for example, about 7.4).Above-mentioned primary emulsion can be by further refining with the stable emulsion of the oil droplet size that obtains to have suitable homogeneous via the circulation of microjet homogenizer or similar device.The method sterilization after filtration of the refining Emulsion of gained, for example, through 0.22 micron sterilizing filter filtration sterilization.

The illustrative methods of the oil in water emulsion of preparation vancomycin hydrochloride is provided in example 1.

Except ready-made oil in water emulsion, but the freeze-dried type vancomycin compositions that provides herein can also be by lyophilizing and is being recombinated to form oil in water emulsion again by dilute with water at the preceding of injection period after a while subsequently.As lyophilized products, prevent vancomycin because hydrolysis and degraded rapidly according to the preparation of vancomycin of the present invention, this hydrolysis takes place in the presence of water.

On the other hand, the application provides freeze-dried composition, and it comprises vancomycin or the acceptable salt of its medicine or analog, liquid oil (class), phospholipid (class) and dextrose.Said composition can be by preparing by removing to anhydrate in the above-mentioned oil in water emulsion.Resulting composition can water or buffer solution rehydrated and form the oil in water emulsion that is suitable for injecting.The average diameter of the Emulsion drop that this forms again is not more than about 1 micron.

In certain embodiments, the average diameter of this Emulsion drop that forms again is not more than about 1000nm, 900nm, 800nm, 700nm, 600nm, 500nm, 450nm, 400nm, 350nm, 300nm, 250nm, 200nm, 175nm, 150nm, 125nm, 100nm, 75nm or 50nm.

In certain embodiments, but with compare by its freeze-dried type oil in water emulsion that is prepared into lyophilized formulations of the present invention, this lyophilized formulations under suitable condition of storage (for example, under-20 ℃) store at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 14 months, 16 months, 18 months, 20 months, after 22 months or 24 months, be not more than about 10% by the increase of the particle mean size of the oil droplet of the Emulsion of this lyophilized formulations reorganization, 20%, 25%, 30%, 40%, 50%, 75%, 100%, 125%, 150%, 175% or 200%.

In certain embodiments, described lyophilized formulations does not further comprise the chemical compound of the amount of vancomycin in the oil droplet that can increase the Emulsion of being recombinated by this lyophilized formulations.

In certain embodiments, when described lyophilized formulations was recombinated with the formation oil in water emulsion, no more than about vancomycin of 70%, 60%, 50%, 40%, 30% or 20% was present in the oil droplet of this oil in water emulsion.

In certain embodiments, but with compare by its freeze-dried type oil in water emulsion that lyophilized formulations that provides among this paper is provided, this lyophilized formulations under suitable condition of storage (for example, under-20 ℃) store at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 14 months, 16 months, 18 months, 20 months, 22 months or after 24 months, do not reach about 5%, 10%, 15% or 20% by the rate of change of vancomycin concentration in the Emulsion of this lyophilized formulations reorganization.

In certain embodiments, the application provides freeze-dried composition, it comprises: (i) concentration is vancomycin or acceptable salt of its medicine or the analog of about 5 weight % to 10 weight %, (ii) total concentration is one or more liquid oil of about 10 weight % to 20 weight %, (iii) total concentration is one or more phospholipid of about 10 weight % to 20 weight %, and (iv) concentration is the dextrose of 50 weight % to 80 weight %.

Freeze dried vancomycin formulations of the present invention can by adopt any suitable freeze drying technology (for example, adopting cabinet type freeze dryer) lyophilizing as described herein oil in water emulsion prepare.

" lyophilizing " or " lyophilization " removes the process of anhydrating by this product after being frozen and placing under the vacuum at product, it allows ice directly to become steam by solid without liquid phase.This process is made up of three independences, uniqueness and complementary process: freezing, first drying (distillation) and second drying (desorption).

Described lyophilized formulations can contain the vancomycin of medicine effective concentration or the oil in water emulsion of acceptable salt of its medicine or analog to form with the aqueous solution of appropriate amount (for example, water, buffer solution or have aqueous solution such as other additives such as tension regulators) reorganization again." medicine effective concentration " be meant when with the oil in water emulsion administration, is enough to treat vancomycin or the acceptable salt of its medicine or analog for effectively infecting or the vancomycin other disease, in this oil in water emulsion or the concentration of acceptable salt of its medicine or analog.

In certain embodiments, under suitable condition of storage (for example, under 2 ℃-8 ℃) store at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days or 12 days, the increase of the mean oil droplet size of the oil in water emulsion of described reorganization is not more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 70%, 80%, 90% or 100%.

In certain embodiments, under suitable condition of storage (for example, under 2 ℃-8 ℃) store at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days or 12 days, the rate of change of vancomycin concentration does not reach 5%, 10%, 15% or 20% in the oil in water emulsion of described reorganization.

In certain embodiments, the oil in water emulsion of described reorganization is the non-vein zest.

In certain embodiments, the oil in water emulsion of described reorganization has about 6 to about 8 pH value (for example, about 7 or about 7.5).

In certain embodiments, but the oil in water emulsion of described reorganization has the above-mentioned chemical and physical properties identical with above-mentioned freeze-dried type oil in water emulsion.For example, in certain embodiments, the oil in water emulsion of described reorganization has the average diameter of the oil droplet that is not more than about 200nm, and/or less than about 0.05 PFAT5.In certain embodiments, the oil in water emulsion of described reorganization is that grade is opened and is standby.In certain embodiments, the oil in water emulsion of described reorganization does not further comprise the chemical compound of the amount of vancomycin in the oil droplet of understanding the Emulsion that increases this reorganization.In certain embodiments, no more than about vancomycin of 70%, 60%, 50%, 40%, 30% or 20% is present in the oil droplet in the oil in water emulsion of described reorganization.

But the freeze-dried type vancomycin formulations that provides herein and can be used for treatment or prevention vancomycin to its effective infection by the oil in water emulsion of lyophilized formulations reorganization.More particularly, the individuality that they can be by all means need them with medicine effective quantity (for example, people or other mammal), wherein this approach includes but not limited to intravenous administration, intramuscular administration, intra-arterial administration, intrathecal drug delivery, eye drops, subcutaneous administration, intra-articular administration, intraperitoneal administration, oral administration, topical, intravaginal administration and dosing eyes.

But clarithromycin freeze-dried type preparation and lyophilized formulations

On the other hand, but provide the freeze-dried type oil in water emulsion, it comprises: (i) concentration is at least about clarithromycin or suitable acceptable salt of its medicine or the ester of concentration of 1 weight %, (ii) total concentration is about 2 weight % one or more liquid oil to about 10 weight %, (iii) total concentration is about 1 weight % to one or more phospholipid of about 10 weight %, and (iv) concentration is at least about the dextrose of 10 weight %.

In certain embodiments, clarithromycin or the acceptable salt of its medicine or ester are to be present in this oil in water emulsion with the concentration at least about 0.5 weight %.In certain embodiments, the concentration of clarithromycin or acceptable salt of its medicine or ester is about 1%, 1.5%, 2%, 2.5%, 3%, 4% or 5% in this Emulsion.

All the content of oil ingredient can be at about 1 weight % to the scope of about 20 weight % (for example, about 2 weight % are to about 10 weight %) in the freeze dried clarithromycin emulsion that provides herein.In certain embodiments, the total concentration of oil ingredient is about 2 weight %, 3% weight %, 4% weight %, 5% weight %, 6% weight %, 7% weight %, 8% weight %, 9% weight %, 10% weight %, 12% weight %, 15% weight %, 18 weight % or 20 weight %.

In certain embodiments, vegetable oil is calculated by weight at about 9:1 to the scope of about 1:1 the weight ratio of MCT oil in this oil in water emulsion.In certain embodiments, vegetable oil is about 9:1,8:1,7:1,6:1,5:1,4:1,3:1,2:1 or 1:1 to the weight ratio of MCT oil.

Calculate by weight can be about 1% to about 10% scope for the amount of phospholipid in the described freeze dried clarithromycin emulsion that provides herein.In certain embodiments, the concentration of the phospholipid in the described Emulsion is about 2 weight %, 3 weight %, 4 weight %, 5 weight %, 6 weight %, 7 weight %, 8 weight %, 9 weight % or 10 weight %.

The lyophilizing oil in water emulsion of described clarithromycin also comprises the dextrose that concentration is at least about 10 weight %.In certain embodiments, the concentration of dextrose is about 12 weight %, 14 weight %, 15 weight %, 18 weight %, 20 weight %, 22 weight %, 24 weight %, 25 weight %, 28 weight % or 30 weight % in this oil in water emulsion.

In certain embodiments, for intravenous injection, some components in the described oil in water emulsion except that clarithromycin or acceptable salt of its medicine or ester or all components are (for example, oil ingredient, phospholipid, stabilizing agent and tension regulator) be safe, well tolerable, and can be accepted by FDA.

In certain embodiments, some components in described oil in water emulsion except that clarithromycin or acceptable salt of its medicine or ester or all components (for example, oil ingredient, emulsifying agent, stabilizing agent and tension regulator) are thought that by medicine Supervision Bureau it is safe being used for intravenous injection usually.

In certain embodiments, but the freeze-dried type oil-in-water clarithromycin emulsion that provides herein is that vein is nonirritating, injectable and/or biocompatible.

In certain embodiments, but the freeze-dried type oil-in-water clarithromycin emulsion that provides herein is physically stable, chemically stable, or not only chemically stable but also physically stable.

In certain embodiments, under suitable condition of storage (for example, under-20 ℃ or 2 ℃-8 ℃) store at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 9 days, 12 days, 15 days, 18 days, 20 days, 25 days or 30 days, but the increase of the particle mean size of the oil droplet of the freeze-dried type oil-in-water clarithromycin emulsion that provides herein is not more than about 10%, 20%, 25%, 30%, 40%, 50%, 75%, 100%, 125%, 150%, 175% or 200%.

In certain embodiments, under suitable condition of storage (for example, under-20 ℃ or 2 ℃-8 ℃) store at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days or 10 days, but the rate of change of clarithromycin concentration does not reach about 5%, 10%, 15% or 20% in the freeze-dried type oil-in-water clarithromycin emulsion that provides herein.

In certain embodiments, but the oil droplet of the freeze-dried type oil-in-water clarithromycin emulsion that provides herein has the average diameter less than about 500nm, 450nm, 400nm, 350nm, 300nm, 250nm, 200nm, 175nm, 150nm, 125nm, 100nm, 75nm or 50nm.

In certain embodiments, but described freeze-dried type oil-in-water clarithromycin emulsion is sterilized.For example, the described oil in water emulsion with the mean oil droplet diameter that is not more than about 200nm can be sterilized by 0.2 μ m filter.

In certain embodiments, but the pH value of described freeze-dried type oil-in-water clarithromycin emulsion is about 3 to about 8.In certain embodiments, this pH value is about 7 or about 7.5.

In certain embodiments, but described freeze-dried type oil in water emulsion does not further comprise the chemical compound of the amount of clarithromycin in the oil droplet that can increase this Emulsion.

In certain embodiments, but no more than about clarithromycin of 70%, 60%, 50%, 40%, 30% or 20% be present in the oil droplet of described freeze-dried type oil in water emulsion.

In certain embodiments, by lyophilizing with form lyophilized formulations and subsequently by this lyophilized formulations reorganization after, but the freeze-dried type oil in water emulsion keeps its mean oil droplet size to be not more than about 200nm and PFAT5 less than about 0.05.

In certain embodiments, but described freeze-dried type oil in water emulsion comprises concentration be about 1 weight % to clarithromycin, the concentration of about 3 weight % be about 1 weight % to medium chain triglyceride, the concentration of about 5 weight % be about 1 weight % to vegetable oil, the concentration of about 5 weight % be the lecithin of about 1 weight % to 10 weight %, and the dextrose of about 15 weight % to 25 weight %.

But the present invention also is provided for preparing the method for the freeze-dried type oil in water emulsion of the clarithromycin of describing herein.This emulsion composition can be prepared by following steps: (a) form and (for example comprise (i) one or more liquid oil, vegetable oil, or the combination of vegetable oil and medium chain triglyceride) and (ii) the mixture of one or more phospholipid, (b) form the clarithromycin comprise (i) medicine effective quantity or the acceptable salt of its medicine or ester, (ii) dextrose, the (iii) mixture of water, and (c) form oil in water emulsion with step (a) and (b) mixture.

In certain embodiments, step (c) can be added into by the aqueous solution with step (b) in the mixture of step (a) and carry out to form primary emulsion.This aqueous solution can further contain buffer, stabilizing agent and/or tension regulator.The formation of this primary emulsion can be undertaken or promotes by using mechanically homogenise (for example, high shear mixing, high-pressure extrusion and Micro Fluid) or other suitable technology.In certain embodiments, the pH value of this primary emulsion is adjusted to about 6 to about 8 (for example, about 7.4).Above-mentioned primary emulsion can be by further being made with extra care with the stable emulsion of the droplet size that obtains to have suitable homogeneous via the circulation of microjet homogenizer or similar device.The method sterilization after filtration of the refining Emulsion of gained, for example, through 0.22 micron sterilizing filter filtration sterilization.

The illustrative methods of preparation clarithromycin oil in water emulsion is provided in example 2.

But freeze-dried type clarithromycin compositions of the present invention also can be prepared as lyophilized formulations, this lyophilized formulations can recombinated period after a while and the injection before dilute with water to form oil in water emulsion again.

On the one hand, the application provides freeze-dried composition, and it comprises clarithromycin or the acceptable salt of its medicine or ester, liquid oil (class), phospholipid (class) and dextrose.Said composition can be by preparing by removing to anhydrate in the above-mentioned oil in water emulsion.Resulting composition can water or buffer solution rehydrated and form the oil in water emulsion that is suitable for injecting.The average diameter of the Emulsion drop of this formation is not more than about 1 micron again.

In certain embodiments, described lyophilized formulations at room temperature at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 14 months, 16 months, 18 months, 20 months, 22 months or 24 months was physically stable, chemically stable or is the chemically stable again of physically stable.

In certain embodiments, but with compare by its freeze-dried type oil in water emulsion that lyophilized formulations that provides among this paper is provided, this lyophilized formulations under suitable condition of storage (for example, under-20 ℃) store at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 14 months, 16 months, 18 months, 20 months, after 22 months or 24 months, be not more than about 10% by the increase of the particle mean size of the oil droplet of the clarithromycin emulsion of this lyophilized formulations reorganization, 20%, 25%, 30%, 40%, 50%, 75%, 100%, 125%, 150%, 175% or 200%.

In certain embodiments, described lyophilized formulations does not further comprise the chemical compound of the amount of clarithromycin in the oil droplet that can increase the Emulsion of recombinating.

In certain embodiments, when lyophilized formulations was thawed with the formation oil in water emulsion, no more than about clarithromycin of 70%, 60%, 50%, 40%, 30% or 20% was present in the oil droplet of this oil in water emulsion.

In certain embodiments, but with compare by its freeze-dried type oil in water emulsion that lyophilized formulations that provides among this paper is provided, this lyophilized formulations under suitable condition of storage (for example, under-20 ℃) store at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 14 months, 16 months, 18 months, 20 months, 22 months or after 24 months, do not reach about 5%, 10%, 15% or 20% by the rate of change of clarithromycin concentration in the oil in water emulsion of this lyophilized formulations reorganization.

In certain embodiments, the invention provides freeze-dried composition, it comprises: (i) concentration is clarithromycin or acceptable salt of its medicine or the ester of about 2 weight % to 8 weight %, (ii) concentration is the liquid oil of about 10 weight % to 20 weight %, (iii) concentration is one or more phospholipid of about 10 weight % to 20 weight %, and (iv) concentration is the dextrose of 50 weight % to 80 weight %.

Described freeze dried Biaxin can comprise the clarithromycin of medicine effective concentration or the oil in water emulsion of acceptable salt of its medicine or ester to form with the aqueous solution of appropriate amount (for example, water, buffer solution or have aqueous solution such as other additives such as tension regulators) reorganization again.In certain embodiments, this oil in water emulsion that forms again (for example under 2 ℃-8 ℃) under the suitable condition of storage at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days or 12 days for physically stable, chemically stable, or not only physically stable but also chemically stable.

In certain embodiments, the described oil-in-water clarithromycin emulsion that forms again is that non-vein is irritating.

In certain embodiments, the described oil-in-water clarithromycin emulsion that forms again has about 6 to about 8 pH value (for example, about 7 or about 7.5).

In certain embodiments, but the oil in water emulsion of described reorganization has the above-mentioned chemical and physical properties identical with above-mentioned freeze-dried type oil in water emulsion.For example, in certain embodiments, the oil in water emulsion of described reorganization has the average diameter of the oil droplet that is not more than about 200nm, and/or less than about 0.05 PFAT5.In certain embodiments, the oil in water emulsion of described reorganization is that grade is opened and is standby.In certain embodiments, the oil in water emulsion of described reorganization does not further comprise the chemical compound of the amount of clarithromycin in the oil droplet of understanding the Emulsion that increases this reorganization.In certain embodiments, no more than about clarithromycin of 70%, 60%, 50%, 40%, 30% or 20% is present in the oil droplet in the oil in water emulsion of described reorganization.

Biaxin of the present invention can be used for treating clarithromycin it is effectively infected or reduce the risk of this infection.More particularly, but described freeze-dried type clarithromycin oil-in-water preparation or the individuality that can be by all means needs them with medicine effective quantity by the oil in water emulsion of lyophilized formulations reorganization are (for example, people or other mammal), wherein this approach includes but not limited to intravenous administration, intramuscular administration, intra-arterial administration, intrathecal drug delivery, eye drops, subcutaneous administration, intra-articular administration, oral administration, topical, intravaginal administration and intraperitoneal administration.

Embodiment

Embodiment 1

But preparation freeze-dried type vancomycin Emulsion and freeze dried vancomycin Emulsion

By preparing 1000g vancomycin Emulsion in batches following the composition:

Component	The supplier	％(w/w)	g/1000g
Component	The supplier	％(w/w)	g/1000g	Vancomycin hydrochloride, USP	Hospira?Inc.	2	20
Soybean lecithin, EP	American?lecithin company	4	40	Vancomycin hydrochloride, USP	Hospira?Inc.	2	20
Soybean lecithin, EP	American?lecithin company	4	40	Medium chain triglyceride, USP	Sasol	1.5	15
Soybean oil, USP	Corda	2.5	25	Medium chain triglyceride, USP	Sasol	1.5	15
Soybean oil, USP	Corda	2.5	25	Dextrose, USP	Roquette	20	200
Water, deionization is through being added into		100	1000	Dextrose, USP	Roquette	20	200

Prepare Emulsion by following steps:

(1) weighing soybean lecithin, medium chain triglyceride and soybean oil and they are combined in the mixer;

(2) ethanol of interpolation appropriate amount obtains settled solution with the dissolving all components;

(3) use vacuum removing ethanol, until the ethanol of remnants be less than dry weight 1% to obtain clarifying oil solution;

(4) vancomycin HCl, dextrose and water are joined in another container, fully mix to dissolve these solids to obtain clarifying aqueous solution;

(5) be added into this aqueous solution in this oil solution and use high-shear homogenizing machine (for example, IKAUltra Turrax blender) to obtain primary emulsion (oil-in-water);

(6) pH value with this primary emulsion is adjusted to 7.4 ± 0.1;

(7) make this primary emulsion have the submicron Emulsion of the average droplet size of about 77 nanometers for 3-5 time with acquisition by high pressure homogenizer (for example Micro Fluid machine 110L that under 100psi inlet air pressure, operates);

(8) make this Emulsion through 0.2 micron sterilising filter (Nalgene) but to obtain freeze-dried type Emulsion;

(9) with 25g in the Emulsion of sterilization is packed the aseptic bottle of each 50mL into (each bottle 500mg vancomycin HCl); And

(10) use cabinet type freeze dryer (for example, the Advantage type of Virtis) to carry out lyophilizing to obtain freeze dried vancomycin Emulsion.

As follows to this freeze dried vancomycin Emulsion test:

The lyophilized products outward appearance

Through observation, the freeze-dried emulsion in the described bottle is canescence, uniform pie, porous block thing.

Reorganization

Under the blended situation of gentleness, the freeze-dried emulsion of each bottle is recombinated about 1-5 minute to obtain white, homogeneous and translucent to opaque Emulsion (" Emulsion of Xing Chenging again ") with 15.4g water.The Emulsion of Xing Chenging again

Under optical microscope, observe this Emulsion that forms again, do not observe crystal, visible drop or solid matter with 400 * amplification.Through measuring, the pH value of the Emulsion that this forms again is 7.1.Measured by LASER Light Scattering Spectroscopy instrument (770 types of Particle Sizing Systems), the average droplet size of the Emulsion that this forms again is 82nm.Determine amount and the integrity of vancomycin HCl in this Emulsion that forms again by HPLC.

The stability of the Emulsion of Xing Chenging again

This Emulsion that forms again is diluted with water to 10mg/mL and further is diluted to 1mg/mL with 5% dextrose solution, and stable testing is lasted 7 days.Under-20 ℃, 5 ℃ and 25 ℃, the stability of the Emulsion of the dilution of discovery 1mg/mL kept 1 day at least, and the stability of 10mg/mL Emulsion kept 7 days at least.

Venous stimulation

Use rabbit edge ear vein model, by test the venous stimulation of this vancomycin Emulsion that forms again with continuous 7 days slow infusions of every day 5mg/mL and 10mL/kg.Compare with negative control sample (5% dextrose solution), outward appearance and histopathology check do not show any unusual of vein tissue.Can conclude that this vancomycin Emulsion is that non-vein is irritating.

Embodiment 2

But preparation freeze-dried type clarithromycin emulsion and freeze dried clarithromycin emulsion

By preparing 1000g vancomycin Emulsion in batches following the composition:

Component	The supplier	％(w/w)	g/1000g
Component	The supplier	％(w/w)	g/1000g	Clarithromycin, USP	Teva	1.5	15
Soybean lecithin, EP	American?lecithin?company	4	40	Clarithromycin, USP	Teva	1.5	15
Soybean lecithin, EP	American?lecithin?company	4	40	Medium chain triglyceride, USP	Sasol	1.5	15
Soybean oil, USP	Corda	2.5	25	Medium chain triglyceride, USP	Sasol	1.5	15
Soybean oil, USP	Corda	2.5	25	Dextrose, USP	Roquette	20	200
Water, deionization is through being added into		100	1000	Dextrose, USP	Roquette	20	200

Prepare Emulsion by following steps:

(3) use vacuum with remove ethanol until the ethanol of remnants be less than dry weight 1% to obtain clarifying oil solution;

(4) clarithromycin, dextrose and water are joined in another container, fully mix and add hydrochloric acid to about pH2.3 to dissolve these solids to obtain clarifying aqueous solution;

(5) be added into this aqueous solution in this oil solution and use high-shear homogenizing machine (for example, IKAUltra Turrax blender) to obtain primary emulsion;

(6) pH value with this primary emulsion is adjusted to 6.0-6.2;

(7) make this primary emulsion have the submicron Emulsion of the average droplet size of about 170 nanometers for 5 times with acquisition by high pressure homogenizer (for example Micro Fluid machine 110L that under 100psi inlet air pressure, operates);

(8) make this Emulsion through 0.2 micron sterilising filter (Millipak-20 of Millipore) but to obtain freeze-dried type Emulsion;

(9) with 16.7g in the Emulsion of sterilization is packed the aseptic bottle of each 50mL into (each bottle 250mg clarithromycin); And

(10) use cabinet type freeze dryer (for example, the Advantage type of Virtis) to carry out lyophilizing to obtain freeze dried clarithromycin emulsion.

As follows to this freeze dried clarithromycin emulsion test:

The lyophilized products outward appearance

Through observation, the freeze-dried emulsion in the described bottle is canescence, the even sugary porous block thing of Cotton Gossypii.

Reorganization

Under the blended situation of gentleness, the freeze-dried emulsion of each bottle is recombinated about 2-5 minute to obtain white, homogeneous and opaque Emulsion (" Emulsion of Xing Chenging again ") with 11.78g water.

The Emulsion of Xing Chenging again

Under optical microscope, observe this Emulsion that forms again, do not observe crystal, visible drop or solid matter with 400 * amplification.

Through measuring, the pH value of this Emulsion is 6.4.

Measured by LASER Light Scattering Spectroscopy instrument (the zetasizer type of Malvern Instruments), the average droplet size of this Emulsion is 157-180nm.

Determine the amount of clarithromycin in this Emulsion that forms again by HPLC.

Embodiment 3

Freeze-stable, etc. the exploitation of vancomycin Emulsion that open and submicron

By preparing 1g each vancomycin Emulsion in batches following the composition:

Mg/g	F30	F31	F32	F33	F34	F35	F36	F37
Mg/g	F30	F31	F32	F33	F34	F35	F36	F37	Vancomycin HCl	5.16 ^*	5.16	5.16	5.16	5.16	5.16	5.16	5.16
Soybean lecithin, EP	10	10	10	10	10	10	10	10.00	Vancomycin HCl	5.16 ^*	5.16	5.16	5.16	5.16	5.16	5.16	5.16
Soybean lecithin, EP	10	10	10	10	10	10	10	10.00	Soybean oil, USP	6.25	6.25	6.25	6.25	6.25	6.25	6.25	6.25

Medium chain triglyceride, USP	3.75	3.75	3.75	3.75	3.75	3.75	3.75	3.75
Medium chain triglyceride, USP	3.75	3.75	3.75	3.75	3.75	3.75	3.75	3.75	Dextrose, USP	50	60	70	80	90	100	50	60
Glycerol, USP							4.5		Dextrose, USP	50	60	70	80	90	100	50	60
Glycerol, USP							4.5		Deionized water is settled to	1000	1000	1000	1000	1000	1000	1000	1000
pH	4	4	4	4	4	4	4	7.00	Deionized water is settled to	1000	1000	1000	1000	1000	1000	1000	1000
pH	4	4	4	4	4	4	4	7.00	All oily	10	10	10	10	10	10	10	10
Lecithin is to the ratio of oil	1:1	1:1	1:1	1:1	1:1	1:1	1:1	1:1	All oily	10	10	10	10	10	10	10	10

^*Be equivalent to 5.0mg/g vancomycin free alkali

Prepare Emulsion by following steps:

(1) weighing soybean lecithin, soybean oil and medium chain triglyceride and they are combined in the suitable vessel;

(3) use vacuum with remove ethanol until the ethanol of remnants be less than dry weight 2% to obtain clarifying oil solution;

(4) vancomycin HCl, dextrose, glycerol and water are joined in another container, fully mix to dissolve these solids to obtain clarifying aqueous solution;

(5) this aqueous solution is added in this oil solution;

(6) use the mixture 10 seconds of mini pearl mill formula grinder (mini-beadbeater) vigorous stirring aqueous solution and oil solution with the formation primary emulsion;

(7) the record pH value is adjusted to 4.0+/-0.2 or 7.0+/-0.2 with 0.1N HCl/NaOH with pH value also if desired;

(8) use same mini pearl mill formula grinder that this primary emulsion is stirred 200 seconds to obtain final Emulsion;

(9) make this Emulsion by 0.2 micron filter (Spin-X); And

(10) freezing this filtering Emulsion under-20 ℃.

As follows to this refrigerated Emulsion test:

PH value and osmotic pressure

Preparation	Osmotic pressure (mOsm)	pH
Preparation	Osmotic pressure (mOsm)	pH	F30	261.8	3.80
F31	314.5	4.00	F30	261.8	3.80
F31	314.5	4.00	F32	357.0	3.95
F33	415.7	3.90	F32	357.0	3.95
F33	415.7	3.90	F34	471.8	3.94
F35	522.3	3.96	F34	471.8	3.94
F35	522.3	3.96	F36	325.6	4.07
F37	315.0	6.98	F36	325.6	4.07

Measure with laser scattering method by Malevrn Zetasizer particle size measuring instrument Average droplet size (nm)

The above results shows:

(1) dextrose concentration is for about 5% and provided in about 6% o'clock etc. and to ooze Emulsion (F30, F31, F36 and F37); (2) F30, F31, F36 and F37 also are presented at all its drop sizes of after date of two freeze-thaws does not have significant change; And (3) show, submicron Emulsion can pH4 or 7 times with about 0.5% vancomycin, about 1% oil, about 1% lecithin, about 5% or about 6% dextrose prepare, and this Emulsion is freeze-stable.

Embodiment 4

By preparing another group vancomycin Emulsion following the composition:

mg/g	F-30	F38	F39	F40	F41	F42	F43	F44	F45	F46	F47	F48	F49
mg/g	F-30	F38	F39	F40	F41	F42	F43	F44	F45	F46	F47	F48	F49	Vancomycin HCl	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16
Soybean lecithin, EP	10	20	30	50	20	30	50	20	30	50	20.0	30	50	Vancomycin HCl	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16
Soybean lecithin, EP	10	20	30	50	20	30	50	20	30	50	20.0	30	50	Soybean oil, USP	6.25	12.5	18.75	31.25	12.5	18.75	31.25	12.5	18.75	31.25	12.5	18.75	31.25
MCT，USP	3.75	7.5	11.25	18.75	7.5	11.25	18.75	7.5	11.25	18.75	7.5	11.25	18.75	Soybean oil, USP	6.25	12.5	18.75	31.25	12.5	18.75	31.25	12.5	18.75	31.25	12.5	18.75	31.25
MCT，USP	3.75	7.5	11.25	18.75	7.5	11.25	18.75	7.5	11.25	18.75	7.5	11.25	18.75	Dextrose, USP	50	50	50	50	60	60	60	50	50	50	60	60	60
Glycerol, USP								4.5	4.5	4.5				Dextrose, USP	50	50	50	50	60	60	60	50	50	50	60	60	60
Glycerol, USP								4.5	4.5	4.5				Deionized water is settled to	1000	1000	1000	1000	1000	1000	1000	1000	1000	1000	1000	1000	1000
pH		4	4	4	4	4	4	4	4	4	7	7	7	Deionized water is settled to	1000	1000	1000	1000	1000	1000	1000	1000	1000	1000	1000	1000	1000
pH		4	4	4	4	4	4	4	4	4	7	7	7	All oily	10	20	30	50	20	30	50	20	30	50	20	30	50
Lecithin is to the ratio of oil	1:1	1:1	1:1	1:1	1:1	1:1	1:1	1:1	1:1	1:1	1:1	1:1	1:1	All oily	10	20	30	50	20	30	50	20	30	50	20	30	50

This Emulsion is to prepare and test according to the operating procedure of describing among the embodiment 3 and method.

The average droplet size (nm) that records with laser scattering method

This result shows, pH4 or have for 7 times about 1% to about 5% oil, about 1% to about 5% soybean lecithin, and about 5% to about 6% dextrose, or the lecithin of about 5% dextrose and about 0.45% glycerol is the submicron Emulsion of the preparation formation freeze-stable of 1:1 to the ratio of oil.

Embodiment 5

By preparing another group vancomycin Emulsion following the composition:

mg/g	F-50	F-51	F-52	F-53	F-54	F-55	F-56	F-57	F-58	F-59	F-60	F-61
mg/g	F-50	F-51	F-52	F-53	F-54	F-55	F-56	F-57	F-58	F-59	F-60	F-61	Vancomycin HCl	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16
Egg lecithin	12			12			12			12			Vancomycin HCl	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16	5.16
Egg lecithin	12			12			12			12			Soybean lecithin is from Lipoid		12			12			12			12
Soybean lecithin is from Phospholipid Co.			12			12			12			12	Soybean lecithin is from Lipoid		12			12			12			12
Soybean lecithin is from Phospholipid Co.			12			12			12			12	Soybean oil, USP	100	100	100	75	75	75	50	50	50	50	50	50
Dextrose, USP	50	50	50	50	50	50	50	50	50	50	50	50	Soybean oil, USP	100	100	100	75	75	75	50	50	50	50	50	50
Dextrose, USP	50	50	50	50	50	50	50	50	50	50	50	50	Deionized water is settled to	1000	1000	1000	1000	1000	1000	1000	1000	1000	1000	1000	1000
pH	4	4	4	4	4	4	4	4	4	7	7	7	Deionized water is settled to	1000	1000	1000	1000	1000	1000	1000	1000	1000	1000	1000	1000
pH	4	4	4	4	4	4	4	4	4	7	7	7	All oily	100	100	100	75	75	75	50	50	50	50	50	50
Lecithin is to the ratio of oil	0.12:1	0.12:1	0.12:1	0.16:1	0.16:1	0.16:1	0.24:1	0.24:1	0.24:1	0.24:1	0.24:1	0.24:1	All oily	100	100	100	75	75	75	50	50	50	50	50	50

This Emulsion is to prepare and test according to the operating procedure of describing in the example 3 and method.

As seen the outward appearance of drop and microscopic

Preparation	Outward appearance	Microscopic
Preparation	Outward appearance	Microscopic	F50	No Emulsion forms
F51	No Emulsion forms		F50	No Emulsion forms
F51	No Emulsion forms		F52	No Emulsion forms
F53	Thick Emulsion	A large amount of visible drop (〉 5 μ m)	F52	No Emulsion forms
F53	Thick Emulsion	A large amount of visible drop (〉 5 μ m)	F54	Thick Emulsion	A large amount of visible drop (〉 5 μ m)
F55	Thick Emulsion	A large amount of visible drop (〉 5 μ m)	F54	Thick Emulsion	A large amount of visible drop (〉 5 μ m)

F56	Thick Emulsion	A large amount of visible drop (〉 5 μ m)
F56	Thick Emulsion	A large amount of visible drop (〉 5 μ m)	F57	Thick Emulsion	A large amount of visible drop (〉 5 μ m)
F58	Thick Emulsion	A large amount of visible drop (〉 5 μ m)	F57	Thick Emulsion	A large amount of visible drop (〉 5 μ m)
F58	Thick Emulsion	A large amount of visible drop (〉 5 μ m)	F59	Thick Emulsion	A large amount of visible drop (〉 5 μ m)
F60	Thick Emulsion	A large amount of visible drop (〉 5 μ m)	F59	Thick Emulsion	A large amount of visible drop (〉 5 μ m)
F60	Thick Emulsion	A large amount of visible drop (〉 5 μ m)	F61	Thick Emulsion	A large amount of visible drop (〉 5 μ m)

The result shows that the method for describing in the use-case 3 does not form submicron Emulsion with about 0.5% vancomycin, about 1.2% lecithin and about 10% soybean oil.The compositions of test is similar to conventional lipomul in this research,, has about 5% to about 10% oil and about 1.2% lecithin that is.They are failed to form submicron Emulsion and show high oil concentration (〉 about 5%) be unfavorable for forming submicron Emulsion, and form submicron Emulsion need lecithin to the ratio of oil greater than 0.24:1.

Embodiment 6

Prepare 16g each vancomycin Emulsion in batches according to following composition:

Mg/g	F-62	F-63	F-64	F-65
Mg/g	F-62	F-63	F-64	F-65	Vancomycin HCl	5.16	5.16	5.16	5.16
Egg lecithin, EP	8.26	12.38	16.51	20.12	Vancomycin HCl	5.16	5.16	5.16	5.16
Egg lecithin, EP	8.26	12.38	16.51	20.12	Soybean oil, USP	50	100	100	100
Dextrose, USP	50	50	50	50	Soybean oil, USP	50	100	100	100
Dextrose, USP	50	50	50	50	Deionized water is settled to	1000	1000	1000	1000
pH	4	4	4	4	Deionized water is settled to	1000	1000	1000	1000
pH	4	4	4	4	All oily	50	100	100	100
Lecithin is to the ratio of oil	0.17:1	0.12:1	0.17:1	0.20:1	All oily	50	100	100	100

Prepare Emulsion by following steps:

(1) weighing egg lecithin and soybean oil and they are combined in the suitable vessel;

(5) this aqueous solution is added in this oil solution;

(6) record pH value and if desired the time is adjusted to 4.0+/-0.2 with 0.1N HCl/NaOH with pH value;

(7) by manually shaking the mixture that stirs aqueous solution and oil solution;

(8) record pH value and if desired the time is adjusted to 4.0+/-0.2 or 7.0+/-0.2 with 0.1N HCl/NaOH with pH value;

(9) use high-shear homogenizing machine, for example, IKA Ultra Turrax blender is to obtain primary emulsion (oil-in-water);

(10) make this primary emulsion by high pressure homogenizer (for example Micro Fluid machine 110L that under 100psi inlet air pressure, operates) 3-5 all over to obtain submicron Emulsion.

(11) make this Emulsion by 0.2 micron sterilising filter (Sartoruis, CE); And

(12) at-20 ℃ of freezing down Emulsions that are somebody's turn to do through sterilization.

As follows to this freezing Emulsion test:

Average droplet size (nm) with laser scattering method

Preparation	Before the filtration	After the filtration	-20 ℃, 1 day (a freeze-thaw cycle)	25 ℃, 1 day
Preparation	Before the filtration	After the filtration	-20 ℃, 1 day (a freeze-thaw cycle)	25 ℃, 1 day	F62	192.5	171	185	216
F63	186.8	186	195	184	F62	192.5	171	185	216
F63	186.8	186	195	184	F64	191	177	208	184
F65	167	164	178	162	F64	191	177	208	184

Observe visible drop (〉 5 μ M at microscopically)

Preparation	Before the filtration	After the filtration	-20 ℃, 1 day (a freeze-thaw cycle)	25 ℃, 1 day
Preparation	Before the filtration	After the filtration	-20 ℃, 1 day (a freeze-thaw cycle)	25 ℃, 1 day	F62	Not	Not	Be	Be
F63	Be	Be	Be	Be	F62	Not	Not	Be	Be
F63	Be	Be	Be	Be	F64	Be	Be	Be	Be
F65	Be	Be	Be	Be	F64	Be	Be	Be	Be

This studies show that in the use-case 6 preparation method of describing, and when lecithin pair and oily ratio were 0.17:1 (F62), the oil with about 5% may make submicron Emulsion.Yet this Emulsion is not freeze-stable.

Big drop (〉 5 μ m) existence shows follows low lecithin that the oil (about 10%) of the high % of the ratio (0.12:1,0.17:1 or 0.2:1) of oil is unfavorable for forming submicron Emulsion.

Embodiment 7

mg/g	F66	F67	F68	F69	F70
mg/g	F66	F67	F68	F69	F70	Vancomycin HCl	5.16	5.16	5.16	5.16	5.16
Egg lecithin, EP	8.26	12.38	16.51	20.12		Vancomycin HCl	5.16	5.16	5.16	5.16	5.16
Egg lecithin, EP	8.26	12.38	16.51	20.12		Soybean lecithin, EP					12.38
Medium chain triglyceride, USP	25.0	50.0	50.0	50.0	50.0	Soybean lecithin, EP					12.38
Medium chain triglyceride, USP	25.0	50.0	50.0	50.0	50.0	Soybean oil, USP	25.0	50.0	50.0	50.0	50.0
Dextrose, USP	50.0	50.0	50.0	50.0	50.0	Soybean oil, USP	25.0	50.0	50.0	50.0	50.0
Dextrose, USP	50.0	50.0	50.0	50.0	50.0	Deionized water is settled to	1000	1000	1000	1000	1000
PH	4	4	4	4	4	Deionized water is settled to	1000	1000	1000	1000	1000
PH	4	4	4	4	4	All oily	50	100	100	100	100
Lecithin is to the ratio of oil	0.17:1	0.12:1	0.17:1	0.20:1	0.12:1	All oily	50	100	100	100	100

This Emulsion is to prepare and test according to the operating procedure of describing in the example 6 and method.

Observe big drop (〉 5 μ m at microscopically)

Preparation	Before the filtration	After the filtration	-20 ℃, 1 day (a freeze-thaw cycle)	25 ℃, 1 day
Preparation	Before the filtration	After the filtration	-20 ℃, 1 day (a freeze-thaw cycle)	25 ℃, 1 day	F66	Be	Be	Be	Be
F67	Be	Be	Be	Be	F66	Be	Be	Be	Be
F67	Be	Be	Be	Be	F68	Be	Be	Be	Be
F69	Be	Be	Be	Be	F68	Be	Be	Be	Be
F69	Be	Be	Be	Be	F70	Be	Be	Be	Be

This determines to have and follows low lecithin (about 5mg/mL vancomycin compositions of＜0.2:1) high oil concentration (〉=about 5%) is unfavorable for forming submicron Emulsion-for the combination of independent soybean oil or soybean oil and medium chain triglyceride, or for egg lecithin or soybean lecithin to the ratio of oil.

Embodiment 8

mg/g	F-38	F-71	F-72	F-73
mg/g	F-38	F-71	F-72	F-73	Vancomycin HCl	5.16	5.16	5.16	5.16
Soybean lecithin, EP	20	20	20	20	Vancomycin HCl	5.16	5.16	5.16	5.16
Soybean lecithin, EP	20	20	20	20	Soybean oil, USP	12.5	18.8	25.0	10.0
Medium chain triglyceride, USP	7.5	11.3	15.0	10.0	Soybean oil, USP	12.5	18.8	25.0	10.0
Medium chain triglyceride, USP	7.5	11.3	15.0	10.0	Dextrose, USP	50	50	50	50
Deionized water is settled to	1000	1000	1000	1000	Dextrose, USP	50	50	50	50
Deionized water is settled to	1000	1000	1000	1000	pH	4	4	4	4

All oily	20	30	40	20
All oily	20	30	40	20	Lecithin is to the ratio of oil	1:1	0.67:1	0.5:1	1:1

PH value

The average droplet size (nm) that records with laser scattering method

Observe big drop (〉 5 μ m at microscopically)

By Accusizer380 measure in time-0 o'clock greater than 5 microns fat Percentage ratio (that is, PFAT5)

(％)	F-38	F-71	F-72	F-73
(％)	F-38	F-71	F-72	F-73	AVG	0.002	0.003	0.004	0.003
Std?Dev	0.001	0.001	0.002	0.003	AVG	0.002	0.003	0.004	0.003

The result shows, uses the Micro Fluid method, reaches the Emulsion that the ratio of oil has been obtained submicron order and freeze-stable greater than the lecithin of about 0.5:1 with the oil concentration that is not more than about 4%.After storing 3 days under-20 ℃ or 25 ℃, for all four kinds of preparations, do not observe the significant change of pH value or particle diameter.According to average droplet size and microscopic, F38 and F73 show as preferable preparation, wherein in F38 and F73 than the big drop that observes in other preparation still less.

Embodiment 9

Refrigerated, etc. the preparation of the clarithromycin emulsion of opening

mg/g	F-74	F-75
mg/g	F-74	F-75	Clarithromycin	5.0	5.0
Soybean lecithin, EP	20	20	Clarithromycin	5.0	5.0
Soybean lecithin, EP	20	20	Soybean oil, USP	12.5	10.0
Medium chain triglyceride, USP	7.5	10.0	Soybean oil, USP	12.5	10.0
Medium chain triglyceride, USP	7.5	10.0	Dextrose, USP	50	50
Deionized water is settled to	1000	1000	Dextrose, USP	50	50
Deionized water is settled to	1000	1000	pH	7	7

All oily	20	20
All oily	20	20	Lecithin is to the ratio of oil	1:1	1:1

Prepare Emulsion by following steps:

(4) clarithromycin, dextrose and water are joined in another container, fully mix to dissolve these solids to obtain clarifying aqueous solution;

(5) this aqueous solution is added in this oil solution;

(6) record pH value and if desired the time is adjusted to 7.0+/-2 with 0.1N HCl/NaOH with pH value;

(8) record pH value and if desired the time is adjusted to 7.0+/-2 with 0.1N HCl/NaOH with pH value;

(10) make this primary emulsion by high pressure homogenizer (for example Micro Fluid machine 110L that under 100psi inlet air pressure, operates) 3-5 all over to obtain submicron Emulsion;

(11) make this Emulsion by 0.2 micron sterilising filter (Sartoruis, CE); And

Above-mentioned various embodiment can be combined so that other embodiment to be provided.Mentioned all United States Patent (USP)s, U.S. Patent Application Publication, U.S. Patent application, foreign patent, foreign patent application and non-patent disclosure is in by reference its full content being incorporated herein in this description.The various aspects of these embodiments can be modified, and adopt various patents, application and disclosed notion that other embodiment is provided in case of necessity.

Can make these and other change to described embodiment according to above detailed description.Generally speaking, in following claim, employed term should not be construed as and makes this claim be limited to disclosed particular in this specification and claims book, and is understood to include whole equivalency range that all possible embodiment and these claim are authorized.Therefore, described claim is not subject to the disclosure.

Claims (according to the modification of the 19th of treaty)

1. oil in water emulsion, it comprises:

(i) concentration is about 0.1 weight % to the acceptable salt of medicine or the analog of the suitable vancomycin of the vancomycin of about 3 weight % or concentration;

(ii) total concentration is about 2 weight % one or more liquid oil to about 4 weight %;

(iii) total concentration is about 2 weight % to one or more phospholipid of about 5 weight %, and wherein said whole phospholipid are 0.5:1 at least to the weight ratio of described whole liquid oil;

(iv) about 5 weight % are to the dextrose of about 6 weight %; And

(v) water,

The particle mean size of oil droplet is not more than about 200nm in the wherein said Emulsion, and the PFAT5 of described Emulsion is less than about 0.05.

2. Emulsion as claimed in claim 1, wherein said one or more liquid oil comprise soybean oil.

3. Emulsion as claimed in claim 1, wherein said one or more liquid oil comprise vegetable oil and medium chain triglyceride.

4. as the described Emulsion of arbitrary claim in the claim 1 to 3, wherein said one or more phospholipid comprise lecithin.

5. Emulsion as claimed in claim 1, it comprises:

(1) concentration is the vancomycin hydrochloride of about 0.5 weight %,

(2) concentration is the soybean oil of about 1 weight % to about 2 weight %,

(3) concentration is the medium chain triglyceride of about 1 weight % to about 2 weight %;

(4) concentration is the lecithin of about 2 weight % to about 4 weight %; And

(5) concentration is the dextroses of about 5 weight % to about 6 weight %.

6. Emulsion as claimed in claim 1, it comprises:

(1) concentration is the vancomycin hydrochloride of about 0.5 weight %,

(2) soybean oil and medium chain triglyceride, wherein the total concentration of soybean oil and medium chain triglyceride is about 2 weight %, and the weight ratio of soybean oil centering chain triglyceride is between 2:1 to 1:1;

(3) concentration is the lecithin of about 2 weight %; And

(4) concentration is the dextrose of about 5 weight %.

7. as the described Emulsion of arbitrary claim in the claim 1 to 6, wherein said Emulsion does not further comprise the chemical compound of the amount of vancomycin in the described oil droplet that can increase described Emulsion.

8. as the described Emulsion of arbitrary claim in the claim 1 to 6, wherein be less than about 30% vancomycin and be present in the described oil droplet of described Emulsion.

9. frozen composition, it comprises:

(iv) about 5 weight % are to the dextrose of about 6 weight %; And

(v) water;

Wherein when thawing, described compositions forms oil in water emulsion, and the average diameter that described oil in water emulsion has an oil droplet that is not more than about 200nm reaches the PFAT less than about 0.05.

10. compositions as claimed in claim 9, it comprises the acceptable salt of medicine or the analog of the suitable vancomycin of vancomycin that concentration is about 0.5 weight % or concentration.

11. as claim 9 or the described compositions of claim 10, wherein said one or more liquid oil comprise vegetable oil and medium chain triglyceride.

12. as the described compositions of arbitrary claim in the claim 9 to 11, wherein said compositions does not further comprise the chemical compound of the amount of vancomycin in the described oil droplet that can increase described Emulsion.

13., wherein when thawing, be less than about 30% vancomycin and be present in the described oil droplet of described oil in water emulsion as the described compositions of arbitrary claim in the claim 9 to 11.

14. the method that treatment or minimizing are infected, described method comprise the described Emulsion of arbitrary claim in the claim 1 to 8 of medicine effective quantity is needed described treatment or reduces the patient who infects.

15. the method that treatment or minimizing are infected, described method comprise oil in water emulsion medicine effective quantity, that form by the described frozen composition of arbitrary claim in the claim 9 to 13 of thawing is needed described treatment or reduces the patient who infects.

16. oil in water emulsion, it comprises:

(i) concentration is at least about the acceptable salt of medicine or the ester of the suitable clarithromycin of the clarithromycin of 0.5 weight % or concentration;

(iii) total concentration is about 1 weight % to one or more phospholipid of about 5 weight %, and wherein said whole phospholipid are 0.5:1 at least to the weight ratio of described whole liquid oil;

(iv) about 5 weight % are to the dextrose of about 6 weight %; And

(v) water;

17. Emulsion as claimed in claim 16, wherein said one or more liquid oil comprise soybean oil.

18. Emulsion as claimed in claim 16, wherein said one or more liquid oil comprise vegetable oil and medium chain triglyceride.

19. as the described Emulsion of arbitrary claim in the claim 16 to 18, wherein said one or more phospholipid comprise lecithin.

20. as the described Emulsion of arbitrary claim in the claim 16 to 19, wherein said Emulsion does not further comprise the chemical compound of the amount of clarithromycin in the described oil droplet that can be able to increase described Emulsion.

21., wherein be less than about 30% clarithromycin and be present in the described oil droplet of described Emulsion as the described Emulsion of arbitrary claim in the claim 16 to 19.

22. Emulsion as claimed in claim 16, it comprises:

(1) concentration is the clarithromycin of about 1 weight % to about 5 weight %,

(2) soybean oil and medium chain triglyceride, wherein the total concentration of soybean oil and medium chain triglyceride is about 2 weight %, the weight ratio of soybean oil centering chain triglyceride is between 2:1 to 1:1;

(3) concentration is the lecithin of about 2 weight %; And

(4) concentration is the dextrose of about 5 weight %.

23. frozen composition, it comprises:

(iv) about 5 weight % are to the dextrose of about 6 weight %; And

(v) water;

Wherein when thawing, described compositions forms oil in water emulsion, and the average diameter that described oil in water emulsion has an oil droplet that is not more than about 200nm reaches the PFAT5 less than about 0.05.

24. compositions as claimed in claim 23, wherein said one or more liquid oil comprise vegetable oil and medium chain triglyceride.

25. the method that treatment or minimizing are infected, described method comprise the described Emulsion of arbitrary claim in the claim 16 to 22 of medicine effective quantity is needed described treatment or reduces the patient who infects.

26. the method that treatment or minimizing are infected, described method comprise oil in water emulsion medicine effective quantity, that form by the described frozen composition of claim 23 or claim 24 that thaws is needed described treatment or reduces the patient who infects.

27. oil in water emulsion, it comprises:

(i) at least about 15mg/ml vancomycin or suitable acceptable salt of its medicine or the analog of concentration,

(ii) total concentration is about 2 weight % one or more liquid oil to about 10 weight %;

(iii) total concentration is about 1 weight % one or more phospholipid to about 10 weight %, and

(iv) concentration is at least about the dextrose of 10 weight %.

28. oil in water emulsion as claimed in claim 27, wherein said one or more liquid oil comprise soybean oil.

29. oil in water emulsion as claimed in claim 27, wherein said one or more phospholipid comprise lecithin.

30. oil in water emulsion as claimed in claim 27, it comprises concentration be about 1 weight % to vancomycin hydrochloride, the concentration of about 3 weight % be about 1 weight % to medium chain triglyceride, the concentration of about 5 weight % be about 1 weight % to vegetable oil, the concentration of about 5 weight % be the lecithin of about 1 weight % to about 4 weight %, and concentration is the dextroses of about 15 weight % to about 25 weight %.

31. oil in water emulsion as claimed in claim 27, the pH value of wherein said Emulsion are about 3 to about 8.

32. as the described oil in water emulsion of arbitrary claim in the claim 27 to 31, the particle mean size of oil droplet is less than 250nm in the wherein said Emulsion.

33. oil in water emulsion as claimed in claim 32, the particle mean size of oil droplet is not more than about 200nm described in the wherein said Emulsion, and the PFAT5 of described Emulsion is less than about 0.05.

34. as the described oil in water emulsion of arbitrary claim in the claim 27 to 33, wherein said Emulsion does not further comprise the chemical compound of the amount of vancomycin in the described oil droplet that can increase described Emulsion.

35. as the described oil in water emulsion of arbitrary claim in the claim 27 to 33, wherein no more than about 30% vancomycin is present in the described oil droplet of described oil in water emulsion.

36. freeze-dried composition, it comprises vancomycin or the acceptable salt of its medicine or analog, liquid oil (class), phospholipid (class) and dextrose, wherein

Described compositions is to prepare by removing to anhydrate in the described oil in water emulsion of arbitrary claim in the accessory rights requirement 27 to 35,

Described compositions can the rehydrated Emulsion that is suitable for injecting with formation of water, and

The average diameter of the described Emulsion drop that forms again is not more than about 1 micron.

37. freeze-dried composition as claimed in claim 36, the average diameter of the wherein said Emulsion drop that forms again is not more than about 400nm.

38. freeze-dried composition, it comprises:

(i) concentration is vancomycin or concentration suitable its medicine acceptable salt or the analog of about 5 weight % to about 10 weight %,

(ii) total concentration is about 10 weight % one or more liquid oil to about 20 weight %,

(iii) total concentration is one or more phospholipid of about 10 weight % to 20 weight %, and

(iv) concentration is the dextroses of about 50 weight % to about 80 weight %.

39. freeze-dried composition as claimed in claim 38, wherein when water was rehydrated, described compositions formed oil in water emulsion, and the average diameter of oil droplet is not more than about 1 micron in the described oil in water emulsion.

40. as claim 38 or the described freeze-dried composition of claim 39, wherein said compositions does not further comprise can increase the chemical compound that makes the amount of vancomycin in the oil droplet of the rehydrated oil in water emulsion that forms of described compositions by water.

41. as claim 38 or the described freeze-dried composition of claim 39, wherein when water is rehydrated, described compositions forms oil in water emulsion, and is less than about 30% vancomycin and is present in the oil droplet of described Emulsion.

42. as the described freeze-dried composition of arbitrary claim in the claim 38 to 41, wherein when water is rehydrated, described compositions forms oil in water emulsion, and the particle mean size of oil droplet is not more than about 200nm in the described Emulsion, and the PFAT5 of described Emulsion is less than about 0.05.

43. the method that treatment or minimizing are infected, described method comprise the described oil in water emulsion of arbitrary claim in the claim 27 to 35 of medicine effective quantity is needed described treatment or reduces the patient who infects.

44. treatment or the method that reduce to infect, described method comprise with medicine effective quantity, needs the patient of described treatment or minimizing infection by making the rehydrated oil in water emulsion that forms of the described freeze-dried composition of arbitrary claim in the claim 36 to 42.

45. oil in water emulsion, it comprises:

(i) concentration is at least about clarithromycin or suitable acceptable salt of its medicine or the ester of concentration of 1 weight %,

(ii) total concentration is about 2 weight % one or more liquid oil to about 10 weight %,

(iv) concentration is at least about the dextrose of 10 weight %.

46. oil in water emulsion as claimed in claim 45, it comprises concentration be about 1 weight % to clarithromycin, the concentration of about 3 weight % be about 1 weight % to medium chain triglyceride, the concentration of about 5 weight % be about 1 weight % to vegetable oil, the concentration of about 5 weight % be the lecithin of about 1 weight % to about 10 weight %, and about 15 weight % are to the dextrose of about 25 weight %.

47. as claim 45 or the described oil in water emulsion of claim 46, the particle mean size of oil droplet is less than about 250nm in the wherein said Emulsion.

48. oil in water emulsion as claimed in claim 47, the particle mean size of oil droplet is not more than about 200nm described in the wherein said Emulsion, and the PFAT5 of described Emulsion is less than about 0.05.

49. as the described oil in water emulsion of arbitrary claim in the claim 45 to 48, wherein said Emulsion does not further comprise the chemical compound of the amount of clarithromycin in the described oil droplet that can increase described Emulsion.

50. as the described oil in water emulsion of arbitrary claim in the claim 45 to 48, wherein no more than 30% clarithromycin is present in the described oil droplet of described Emulsion.

51. freeze-dried composition, it comprises clarithromycin or the acceptable salt of its medicine or ester, liquid oil (class), phospholipid (class) and dextrose, wherein

Described compositions is to prepare by removing to anhydrate in the described oil in water emulsion of arbitrary claim in the accessory rights requirement 45 to 50,

52. freeze-dried composition as claimed in claim 51, the average diameter of the wherein said Emulsion drop that forms again is not more than about 200nm.

53. freeze-dried composition, it comprises:

(i) concentration is clarithromycin or concentration suitable its medicine acceptable salt or the esters of about 2 weight % to about 8 weight %,

(ii) concentration is the liquid oil of about 10 weight % to about 20 weight %,

(iii) concentration is about 10 weight % one or more phospholipid to about 20 weight %, and

(iv) concentration is the dextroses of about 50 weight % to about 80 weight %.

54. freeze-dried composition as claimed in claim 53, wherein when water was rehydrated, described compositions formed oil in water emulsion, and the average diameter of described Emulsion drop is not more than about 200nm.

55. freeze-dried composition as claimed in claim 54, wherein when water was rehydrated, described compositions formed oil in water emulsion, and the PFAT5 of described Emulsion is less than about 0.05.

56. as the described freeze-dried composition of arbitrary claim in the claim 53 to 55, wherein when water is rehydrated, described compositions forms oil in water emulsion, and described compositions does not further comprise the chemical compound of the amount of clarithromycin in the described oil droplet that can increase described Emulsion.

57. as the described freeze-dried composition of arbitrary claim in the claim 53 to 55, wherein when water is rehydrated, described compositions forms oil in water emulsion, and is less than about 30% clarithromycin and is present in the described oil droplet of described Emulsion.

58. the method for infection risk is infected or reduces in treatment, described method comprises needs described treatment to infect or reduce the patient of infection risk the described oil in water emulsion of arbitrary claim in the claim 45 to 50 of medicine effective quantity.

59. treatment is infected or is reduced the method that infects, described method comprise with medicine effective quantity, needs the patient of described treatment infection or minimizing infection risk by making the rehydrated oil in water emulsion that forms of the described freeze-dried composition of arbitrary claim in the claim 51 to 57.

Claims

1. oil in water emulsion, it comprises:

(iv) about 5 weight % are to the dextrose of about 6 weight %; And

(v) water,

5. Emulsion as claimed in claim 1, it comprises:

(1) concentration is the vancomycin hydrochloride of about 0.5 weight %,

(2) concentration is the soybean oil of about 1 weight % to about 2 weight %,

(4) concentration is the lecithin of about 2 weight % to about 4 weight %; And

(5) concentration is the dextroses of about 5 weight % to about 6 weight %.

6. Emulsion as claimed in claim 1, it comprises:

(1) concentration is the vancomycin hydrochloride of about 0.5 weight %,

(3) concentration is the lecithin of about 2 weight %; And

(4) concentration is the dextrose of about 5 weight %.

9. frozen composition, it comprises:

(i) concentration is the acceptable salt of medicine or the analog of the suitable vancomycin of the vancomycin of about 0.5 weight % or concentration;

(iv) about 5 weight % are to the dextrose of about 6 weight %; And

(v) water;

10. compositions as claimed in claim 9, wherein said one or more liquid oil comprise vegetable oil and medium chain triglyceride.

11. as claim 9 or the described compositions of claim 10, wherein said compositions does not further comprise the chemical compound of the amount of vancomycin in the described oil droplet that can increase described Emulsion.

12., wherein when thawing, be less than about 30% vancomycin and be present in the described oil droplet of described oil in water emulsion as claim 9 or the described compositions of claim 10.

13. the method that treatment or minimizing are infected, described method comprise the described Emulsion of arbitrary claim in the claim 1 to 8 of medicine effective quantity is needed described treatment or reduces the patient who infects.

14. the method that treatment or minimizing are infected, described method comprise oil in water emulsion medicine effective quantity, that form by the described frozen composition of arbitrary claim in the claim 9 to 12 of thawing is needed described treatment or reduces the patient who infects.

15. oil in water emulsion, it comprises:

(iv) about 5 weight % are to the dextrose of about 6 weight %; And

(v) water;

16. Emulsion as claimed in claim 15, wherein said one or more liquid oil comprise soybean oil.

17. Emulsion as claimed in claim 15, wherein said one or more liquid oil comprise vegetable oil and medium chain triglyceride.

18. as the described Emulsion of arbitrary claim in the claim 15 to 17, wherein said one or more phospholipid comprise lecithin.

19. as the described Emulsion of arbitrary claim in the claim 15 to 18, wherein said Emulsion does not further comprise the chemical compound of the amount of clarithromycin in the described oil droplet that can increase described Emulsion.

20., wherein be less than about 30% clarithromycin and be present in the described oil droplet of described Emulsion as the described Emulsion of arbitrary claim in the claim 15 to 18.

21. Emulsion as claimed in claim 15, it comprises:

(2) soybean oil and medium chain triglyceride, wherein the total concentration of soybean oil and medium chain triglyceride is about 2 weight %, the weight ratio of soybean oil centering chain triglyceride is between 2: 1 to 1: 1;

(3) concentration is the lecithin of about 2 weight %; And

(4) concentration is the dextrose of about 5 weight %.

22. frozen composition, it comprises:

(iii) total concentration is about 1 weight % one or more phospholipid to about 5 weight %, and wherein said whole phospholipid are at least 0.5: 1 to the weight ratio of described whole liquid oil;

(iv) about 5 weight % are to the dextrose of about 6 weight %; And

(v) water;

23. compositions as claimed in claim 22, wherein said one or more liquid oil comprise vegetable oil and medium chain triglyceride.

24. the method that treatment or minimizing are infected, described method comprise the described Emulsion of arbitrary claim in the claim 15 to 21 of medicine effective quantity is needed described treatment or reduces the patient who infects.

25. the method that treatment or minimizing are infected, described method comprise oil in water emulsion medicine effective quantity, that form by the described frozen composition of claim 22 or claim 23 that thaws is needed described treatment or reduces the patient who infects.

26. oil in water emulsion, it comprises:

(iv) concentration is at least about the dextrose of 10 weight %.

27. oil in water emulsion as claimed in claim 26, wherein said one or more liquid oil comprise soybean oil.

28. oil in water emulsion as claimed in claim 26, wherein said one or more phospholipid comprise lecithin.

29. oil in water emulsion as claimed in claim 26, it comprises concentration be about 1 weight % to vancomycin hydrochloride, the concentration of about 3 weight % be about 1 weight % to medium chain triglyceride, the concentration of about 5 weight % be about 1 weight % to vegetable oil, the concentration of about 5 weight % be the lecithin of about 1 weight % to about 4 weight %, and concentration is the dextroses of about 15 weight % to about 25 weight %.

30. oil in water emulsion as claimed in claim 26, the pH value of wherein said Emulsion are about 3 to about 8.

31. as the described oil in water emulsion of arbitrary claim in the claim 26 to 30, the particle mean size of oil droplet is less than 250nm in the wherein said Emulsion.

32. oil in water emulsion as claimed in claim 31, the particle mean size of oil droplet is not more than about 200nm described in the wherein said Emulsion, and the PFAT5 of described Emulsion is less than about 0.05.

33. as the described oil in water emulsion of arbitrary claim in the claim 26 to 32, wherein said Emulsion does not further comprise the chemical compound of the amount of vancomycin in the described oil droplet that can increase described Emulsion.

34. as the described oil in water emulsion of arbitrary claim in the claim 26 to 32, wherein no more than about 30% vancomycin is present in the described oil droplet of described oil in water emulsion.

35. freeze-dried composition, it comprises vancomycin or the acceptable salt of its medicine or analog, liquid oil (class), phospholipid (class) and dextrose, wherein

Described compositions is to prepare by removing to anhydrate in the described oil in water emulsion of arbitrary claim in the accessory rights requirement 26 to 34,

36. freeze-dried composition as claimed in claim 35, the average diameter of the wherein said Emulsion drop that forms again is not more than about 400nm.

37. freeze-dried composition, it comprises:

(iv) concentration is the dextroses of about 50 weight % to about 80 weight %.

38. freeze-dried composition as claimed in claim 37, wherein when water was rehydrated, described compositions formed oil in water emulsion, and the average diameter of oil droplet is not more than about 1 micron in the described oil in water emulsion.

39. as claim 37 or the described freeze-dried composition of claim 38, wherein said compositions does not further comprise can increase the chemical compound that makes the amount of vancomycin in the oil droplet of the rehydrated oil in water emulsion that forms of described compositions by water.

40. as claim 37 or the described freeze-dried composition of claim 38, wherein when water is rehydrated, described compositions forms oil in water emulsion, and is less than about 30% vancomycin and is present in the oil droplet of described Emulsion.

41. as the described freeze-dried composition of arbitrary claim in the claim 37 to 40, wherein when water is rehydrated, described compositions forms oil in water emulsion, and the particle mean size of oil droplet is not more than about 200nm in the described Emulsion, and the PFAT5 of described Emulsion is less than about 0.05.

42. the method that treatment or minimizing are infected, described method comprise the described oil in water emulsion of arbitrary claim in the claim 26 to 34 of medicine effective quantity is needed described treatment or reduces the patient who infects.

43. treatment or the method that reduce to infect, described method comprise with medicine effective quantity, needs the patient of described treatment or minimizing infection by making the rehydrated oil in water emulsion that forms of the described freeze-dried composition of arbitrary claim in the claim 35 to 41.

44. oil in water emulsion, it comprises:

(iv) concentration is at least about the dextrose of 10 weight %.

45. oil in water emulsion as claimed in claim 44, it comprises concentration be about 1 weight % to clarithromycin, the concentration of about 3 weight % be about 1 weight % to medium chain triglyceride, the concentration of about 5 weight % be about 1 weight % to vegetable oil, the concentration of about 5 weight % be the lecithin of about 1 weight % to about 10 weight %, and about 15 weight % are to the dextrose of about 25 weight %.

46. as claim 44 or the described oil in water emulsion of claim 45, the particle mean size of oil droplet is less than about 250nm in the wherein said Emulsion.

47. oil in water emulsion as claimed in claim 46, the particle mean size of oil droplet is not more than about 200nm described in the wherein said Emulsion, and the PFAT5 of described Emulsion is less than about 0.05.

48. as the described oil in water emulsion of arbitrary claim in the claim 44 to 47, wherein said Emulsion does not further comprise the chemical compound of the amount of clarithromycin in the described oil droplet that can increase described Emulsion.

49. as the described oil in water emulsion of arbitrary claim in the claim 44 to 47, wherein no more than 30% clarithromycin is present in the described oil droplet of described Emulsion.

50. freeze-dried composition, it comprises clarithromycin or the acceptable salt of its medicine or ester, liquid oil (class), phospholipid (class) and dextrose, wherein

Described compositions is to prepare by removing to anhydrate in the described oil in water emulsion of arbitrary claim in the accessory rights requirement 44 to 49,

51. freeze-dried composition as claimed in claim 50, the average diameter of the wherein said Emulsion drop that forms again is not more than about 200nm.

52. freeze-dried composition, it comprises:

(ii) concentration is the liquid oil of about 10 weight % to about 20 weight %,

(iv) concentration is the dextroses of about 50 weight % to about 80 weight %.

53. freeze-dried composition as claimed in claim 52, wherein when water was rehydrated, described compositions formed oil in water emulsion, and the average diameter of described Emulsion drop is not more than about 200nm.

54. freeze-dried composition as claimed in claim 53, wherein when water was rehydrated, described compositions formed oil in water emulsion, and the PFAT5 of described Emulsion is less than about 0.05.

55. as the described freeze-dried composition of arbitrary claim in the claim 52 to 54, wherein when water is rehydrated, described compositions forms oil in water emulsion, and described compositions does not further comprise the chemical compound of the amount of clarithromycin in the described oil droplet that can increase described Emulsion.

56. as the described freeze-dried composition of arbitrary claim in the claim 52 to 54, wherein when water is rehydrated, described compositions forms oil in water emulsion, and is less than about 30% clarithromycin and is present in the described oil droplet of described Emulsion.

57. the method for infection risk is infected or reduces in treatment, described method comprises needs described treatment to infect or reduce the patient of infection risk the described oil in water emulsion of arbitrary claim in the claim 44 to 49 of medicine effective quantity.

58. treatment is infected or is reduced the method that infects, described method comprise with medicine effective quantity, needs the patient of described treatment infection or minimizing infection risk by making the rehydrated oil in water emulsion that forms of the described freeze-dried composition of arbitrary claim in the claim 50 to 56.