CN102008436B - Nocathiacin antibiotic medicament composition containing emulsifying agent - Google Patents
Nocathiacin antibiotic medicament composition containing emulsifying agent Download PDFInfo
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Abstract
The invention belongs to a medicament composition, and particularly relates to solution of a nocathiacin antibiotic-containing medicament composition. The invention particularly discloses a nocathiacin antibiotic-containing medicament composition, which comprises nocathiacin, medicament carrier, water-soluble emulsifying agent and fat-soluble emulsifying agent, wherein the medicament carrier consists of an aqueous phase and an oil phase; the water-soluble emulsifying agent is selected from one or mixture of poloxamer and povidone; the fat-soluble emulsifying agent is selected from one or mixture of two of lecithin, yolk phospholipid and soya bean phospholipid; the total mass of the water-soluble emulsifying agent and the fat-soluble emulsifying agent in each 1 milliliter of composition is 30 to 50 milligrams; and the mass ratio of the water-soluble emulsifying agent to the fat-soluble emulsifying agent is 2-1:1. The provided medicament composition can obviously improve the dissolubility of the nocathiacin, the preparation process is safe, the used materials are economic, the used equipment is simple, and the process steps are a few; and the nocathiacin has remarkable medicament-resistant bacteria activity resistance, so the medicament composition has important clinical application value.
Description
Technical field
The invention belongs to pharmaceutical composition, be specifically related to contain emulsifying dosage form, submicron emulsion dosage form, nanometer microemulsion type, the microsphere of the antibiotic pharmaceutical composition of Nocathiacin of emulsifying agent.
Background technology
In the history of human and disease fight; Bacterial infection always is and causes human dead first killer; In the time of Along with people's applied more and more antibiotic therapy disease, also tempered the drug resistance ability of antibacterial, so along with the tachytelic evolution of antibiotic abuse and pathogenic bacteria; Increasing Resistant strain has appearred clinically; Particularly multiple antibiotic is all had bacterial strain such as methicillin resistant staphylococcus aureus (MRSA), the penicillin-fast streptococcus pneumoniae (PRSP) of resistance, so that " superbacteria " found recently, people often seem at a loss what to do in the face of the quick infection rate of this type pathogenic bacterium.In addition, along with increasing gradually of the gram positive bacteria of vancomycin resistance clinically, the last-ditch status that the antibiotic of glycopeptide classes such as vancomycin is used as antimicrobial agent all the time also becomes precarious.So the medicine of seeking and develop some novel structures, active significant novel anti fastbacteria has become the focus and the difficult point of new drug research.
Nocathiacin is one type to be separated from soil and obtains; Novel drug-resistance bacteria medicine with novel structure and significant antibacterial activity; He is a member of having potential applicability in clinical practice in the sulfur peptide antibiotics most (referring to J.Antibiot.2003,26:232～242).Nocathiacin has the unique chemical structure; 23S rRNA and L11 albumen through with the big subunit of ribosome 50S form complex; Thereby influencing the proteinic conformation of L11 transforms; And then CKIs matter synthetic and reach powerful bactericidal action (referring to Nat Prod Rep, 1999,16 (2): 249～263).Nocathiacin is as the sulfur peptide antibiotics of latest find; The level that is lower than μ g/ml just to most gram positive bacterias particularly methicillin resistant staphylococcus aureus (MRSA), penicillin-fast streptococcus pneumoniae (PRSP), vancomycin resistance enterococcus (VRE) and have chemical sproof tubercule bacillus and superpower bactericidal activity arranged (referring to J.Antibiot.2003; 56:226～231); And there is report to point out Nocathiacin because it has unique dimethylamino sugar ring residue; Thereby the mouse model of infection of staphylococcus aureus has also been demonstrated significant curative effect (referring to Antimicrob Agents Chemother; 2004,48 (10): 3697～3701).
As the common trait of sulfur peptide antibiotics, the similar antibiotic with other of Nocathiacin is the same to have special strong-hydrophobicity multiring structure, causes the water solublity of its extreme difference, thereby has limited its medical value.In order to improve the water solublity of Nocathiacin; A large amount of a series of chemistry and bio-modification Research for reconstruction have been carried out to hydroxyl on its dehydroalanine side chain, indole and the pyridine ring; But all do not have successfully with factors such as causing safety issue because of preparing complicacy (referring to: J Org Chem; 2002,67 (24): 8699～8702; J Nat Prod, 2005,68 (4): 550～553; Bioorg Med Chem Lett, 2004,14 (14): 3743～3746).So, seek the water miscible method of more how more effective raising Nocathiacin, to enlarge its DEVELOPMENT PROSPECT and clinical practice with imperative.
In the prior art; Emulsification preparation is the clinical preparation type commonly used that increases the insoluble drug dissolubility at present, improves drug bioavailability; Than the solution with high-load cosolvent, Emulsion is little to the venous zest, thereby safety and the scope of application all have sizable raising (referring to J Parenter EnterNutr; 1981,5:230-235).In recent years along with The Usage of Surfactant and the technological improvement of system breast; The emulsion droplet particle diameter is littler; Preparation more stable, better submicron emulsion of dissolving out capability and nano-emulsion have obtained significant progress, and existing a lot of successful examples are able to application (referring to Eur J Pharm Biopharm; 2007,66 (2): 227-243; Pharmazie, 2008,63 (7): 516-519; Int J Pharm, 2003,254 (2): 99-107; J Collodi Inetrface Sci, 2007,315 (2): 637-647; The patent No. is 96198137.7 Chinese patent).At present, do not see common Emulsion, submicron emulsion dosage form, the nanometer microemulsion type report of the Nocathiacin that contains emulsifying agent.
In addition; Microsphere is a kind of emerging drug-loading system; It can disperse insoluble drug or be embedded in the carrier material and form spherical entity; Confirmed at present it have advantages such as reduce adverse effect, improve drug selectivity, curative effect is lasting (referring to J Surg Res, 2000,92:165-170).The exploitation of this new drug carrier and application have great significance to developing slow controlled release and targeting drug delivery system.Therefore, report also rich in the research in this field both at home and abroad, and a lot of launch products have been arranged (referring to Int J Pharm, 2006,307 (1): 9-15; J Pharm Pharmacol, 1997,49 (8): 737-742; Int J Pharm, 1994,106:41-49; J Control Releas, 2002,81 (4): 263-280; The Chinese invention patent of the patent No. 02145144.3).Do not see at present the microsphere dosage form report of the Nocathiacin that contains emulsifying agent yet.
Summary of the invention
The object of the invention provides a kind of antibiotic pharmaceutical composition of Nocathiacin that contains emulsifying agent; The material and the prescription that utilize economy to be easy to get; Through simple technology; Process emulsifying dosage form, submicron emulsion dosage form or the microsphere dosage form of available Nocathiacin clinically,, thereby solve the application limitations that its low aqueous solubility causes with increase Nocathiacin antibiotic dissolubility in the physiology dissolve medium.
For achieving the above object, general plotting of the present invention is: select suitable emulsifying agent as decentralized photo, Nocathiacin is better disperseed and dissolving.
For achieving the above object, the technical scheme that the present invention adopts is: a kind of antibiotic pharmaceutical composition of Nocathiacin that contains, comprise Nocathiacin and pharmaceutical carrier, and also comprise emulsifying agent.
Aforementioned pharmaceutical compositions can prepare the Nocathiacin medicament of common Emulsion, submicron emulsion dosage form, nanometer microemulsion type or microsphere dosage form.
Particularly; The present invention provides a kind of pharmaceutical composition that is used for preparing the Nocathiacin Emulsion of common Emulsion, submicron emulsion dosage form or nanometer microemulsion type simultaneously; Comprise: water soluble emulsifier, water, fat-soluble emulsifier, oil phase and principal agent Nocathiacin; Wherein, the volume ratio of water and oil phase is 50～95: 5～50; Said water soluble emulsifier is selected from one or both the mixture in poloxamer or the polyvidone, and said fat-soluble emulsifier is selected from: the mixture of one or more in lecithin, egg yolk lecithin or the soybean phospholipid; Wherein, in every 1ml pharmaceutical composition, the gross mass of water soluble emulsifier and fat-soluble emulsifier is 30～50mg; Said every 1ml pharmaceutical composition is meant the mixed 1ml pharmaceutical composition of all components.
In the technique scheme, every 1mL pharmaceutical composition contains the above principal agent Nocathiacin of 0.1mg, process Emulsion after, the content of principal agent Nocathiacin is greater than its medicinal minimum effective dose; In the optimized technical scheme, process Emulsion after, the content of principal agent Nocathiacin can be up to about 9mg/mL, simultaneously, since it will be understood by those skilled in the art that the content of principal agent Nocathiacin can be up to about 9mg/mL, content also can be realized less than 9mg/mL so.
In the technique scheme, pharmaceutical carrier is made up of water and oil phase, and the volume ratio of water and oil phase is preferably 70～80: 20～30; Said water is the physiology dissolve medium of pH4～9; Be preferably the physiology dissolve medium of pH7.0～7.5; Particularly, said physiology dissolve medium is selected from: purified water, water for injection, sterilized water for injection, medicinal water, mass fraction are that 0.9% sodium chloride solution or mass fraction are a kind of in 5% the glucose solution; Said oil phase is selected from: soybean oil, fish oil, Camellia oil, medium chain triglyceride (MCT), Oleum Arachidis hypogaeae semen, olive oil, Oleum Gossypii semen, Oleum Ricini, liquid paraffin or stearic acid.
In the technique scheme, water soluble emulsifier and fat-soluble emulsifier promote principal agent in pharmaceutical carrier, to disperse and dissolve; In the optimized technical scheme, the mass ratio of water soluble emulsifier and fat-soluble emulsifier is 2～1: 1.
In the technique scheme, said principal agent Nocathiacin (English general Nocathiacin by name) is selected from:
Nocathiacin I, Nocathiacin II or Nocathiacin III, the general structure of said Nocathiacin is as follows:
Wherein, among the Nocathiacin I, R
1=OH,
Among the Nocathiacin II, R
1=H,
Among the Nocathiacin III, R
1=OH, R
2=OH; In the optimized technical scheme, said Nocathiacin is Nocathiacin I.
In the technique scheme, the said pharmaceutical composition that is used for preparing the Nocathiacin Emulsion of common Emulsion, submicron emulsion dosage form or nanometer microemulsion type also comprises: the mixture of one or more in the co-emulsifier oleic acid of the cosolvent ethanol of pharmaceutical composition cumulative volume 0%～10%, the surfactant Polysorbate of pharmaceutical composition cumulative volume 0%～5% or pharmaceutical composition cumulative volume 0%～0.5% (comprising two kinds); Wherein, the volume preferred pharmaceutical compositions cumulative volume 0%～5% of surfactant.
In the technique scheme, said pharmaceutical composition cumulative volume refers to all components is mixed volume afterwards.
Further in the technical scheme; The said pharmaceutical composition that is used for preparing the Nocathiacin Emulsion of common Emulsion, submicron emulsion dosage form or nanometer microemulsion type also comprises other pharmaceutic adjuvant additives, comprises antiseptic, correctives, analgesic, buffer agent, pH regulator agent, wetting agent, stabilizing agent, short penetrating agent and substrate; Said its content of adjuvant additive that will use is mass fraction 0%～80%, preferred 0%～20%.
When adopting aforementioned pharmaceutical compositions to prepare the Nocathiacin Emulsion of common Emulsion, submicron emulsion dosage form or nanometer microemulsion type, can adopt polishing, Mechanical Method or ultrasonic method preparation; Particularly,
Said polishing mainly may further comprise the steps: according to the prescription of aforementioned pharmaceutical compositions; Water soluble emulsifier is scattered in aqueous phase to grind well; To contain the cosolvent of fat-soluble emulsifier, principal agent Nocathiacin, Nocathiacin Emulsion cumulative volume 0%～10%, the surfactant of Nocathiacin Emulsion cumulative volume 0%～5%, the co-emulsifier of Nocathiacin Emulsion cumulative volume 0%～0.5% or the oil phase of other pharmaceutic adjuvant additives again adds; Firmly stir and process colostrum, add water again the colostrum dilution is quantitatively promptly got homodisperse Emulsion.
Said Mechanical Method mainly may further comprise the steps: according to the prescription of aforementioned pharmaceutical compositions; The cosolvent of oil phase, water, fat-soluble emulsifier, water soluble emulsifier, principal agent, Nocathiacin Emulsion cumulative volume 0%～10%, the surfactant of Nocathiacin Emulsion cumulative volume 0%～5%, co-emulsifier or other pharmaceutic adjuvant additives mixing back of Nocathiacin Emulsion cumulative volume 0%～0.5% are prepared with high-speed homogenization machine or high pressure homogenizer, promptly get homodisperse Emulsion.
Said ultrasonic method mainly may further comprise the steps: according to the prescription of aforementioned pharmaceutical compositions; Water soluble emulsifier is soluble in the aqueous phase; The cosolvent of fat-soluble emulsifier, principal agent Nocathiacin, Nocathiacin Emulsion cumulative volume 0%～10%, the surfactant of Nocathiacin Emulsion cumulative volume 0%～5%, co-emulsifier or other pharmaceutic adjuvant additives of Nocathiacin Emulsion cumulative volume 0%～0.5% are dissolved in oil phase; Supersound process makes each component be dissolved in each phase fully; Oil phase is dropwise added to the aqueous phase of continuous stirring, supersound process is until forming homodisperse Emulsion more again.
That the Nocathiacin Emulsion of above-mentioned common Emulsion, submicron emulsion dosage form or nanometer microemulsion type can supply is oral, external, drip ear, eye drip, intramuscular injection, subcutaneous injection and intravenous injection; Can be used for treating clinically the infection and acute accordingly, the chronic inflammatory reaction that cause by various gram positive bacterias and fastbacteria.
The present invention provides a kind of Nocathiacin microsphere forms of pharmaceutical compositions that contains emulsifying agent that is used for preparing simultaneously, comprising: principal agent Nocathiacin, pharmaceutical carrier and emulsifying agent; Said pharmaceutical carrier is selected from: the mixture of one or more in gelatin, methylcellulose, arabic gum, chitosan, polylactic acid (PLA) and the polylactic acid-glycolic guanidine-acetic acid copolymer (PLGA) (comprising two kinds); Said emulsifying agent is selected from: Polysorbate, polyvinyl alcohol, poloxamer or lecithin; Wherein the mass ratio of pharmaceutical carrier and principal agent Nocathiacin is 2: 1～10: 1.
In the technique scheme, preferred 5: 1～10: 1 of the mass ratio of pharmaceutical carrier and principal agent Nocathiacin.
In the technique scheme, every 1mL pharmaceutical composition contains the above principal agent Nocathiacin of 0.1mg, process microspheres agent after, the content of principal agent Nocathiacin is greater than its medicinal minimum effective dose; In the optimized technical scheme, process microspheres agent after, the content of principal agent Nocathiacin can be up to about 9mg/mL; Simultaneously; Since it will be understood by those skilled in the art that the content of principal agent Nocathiacin can be up to about 9mg/mL, content also can be realized less than 9mg/mL so.
In the technique scheme, saidly be used for preparing the Nocathiacin microsphere forms of pharmaceutical compositions that contains emulsifying agent and also comprise: the mixture of one or more in cross-linking agent, plasticizer, cosolvent ethanol or the co-emulsifier oleic acid (comprising two kinds);
When adopting the aforementioned pharmaceutical compositions preparation to contain the Nocathiacin microsphere dosage form of emulsifying agent, when containing cross-linking agent in the said pharmaceutical composition, can adopt emulsion-crosslinking method; Said pharmaceutical composition comprises: 5%～15% cross-linking agent, the plasticizer of pharmaceutical composition cumulative volume 0～15%, the cosolvent ethanol of pharmaceutical composition cumulative volume 0～10% or the co-emulsifier oleic acid of pharmaceutical composition cumulative volume 0～0.3% of principal agent Nocathiacin, pharmaceutical carrier, physiology dissolve medium, emulsifying agent, oil phase, pharmaceutical composition cumulative volume; The preparation process mainly may further comprise the steps: by the prescription of aforementioned pharmaceutical compositions; Principal agent Nocathiacin and pharmaceutical carrier are dissolved in the physiology dissolve medium under ultransonic condition as water; Stir in the oleic oil phase of co-emulsifier of the cosolvent ethanol that joins the plasticizer that contains emulsifying agent, pharmaceutical composition cumulative volume 0～15%, pharmaceutical composition cumulative volume 0～10% down or pharmaceutical composition cumulative volume 0～0.3%; Mix to continue stirring and emulsifying, it is crosslinked to form 5%～15% the cross-linking agent that adds the pharmaceutical composition cumulative volume after the stable emulsion again, separates oil removing; Isopropyl alcohol or acetone dehydrate promptly get the microsphere of medicine carrying; In the optimized technical scheme, the consumption of cross-linking agent is 8%～11% of a pharmaceutical composition cumulative volume; Said cross-linking agent is selected from: formaldehyde or glutaraldehyde; Said plasticizer is selected from: polyvinyl alcohol (PVA) or glycerol.
In the technique scheme, when emulsifying agent was solid, the consumption of emulsifying agent was 3%～15% of a drug regimen amount; When emulsifying agent was liquid, the consumption of emulsifying agent was 3%～15% of a pharmaceutical composition volume.
In the technique scheme, said pharmaceutical composition volume refers to all components is mixed volume afterwards.
In the technique scheme, the volume ratio of water and oil phase is 6～8: 2～4.
When not containing cross-linking agent in the said pharmaceutical composition, can adopt intra-liquid desiccation method; Said pharmaceutical composition comprises: the co-emulsifier oleic acid of the plasticizer of principal agent Nocathiacin, pharmaceutical carrier, emulsifying agent, physiology dissolve medium, pharmaceutical composition cumulative volume 0～15%, the cosolvent ethanol of pharmaceutical composition cumulative volume 0～10% or pharmaceutical composition cumulative volume 0～0.3%; Particularly; The preparation process mainly may further comprise the steps: husky star of principal agent Rocca and pharmaceutical carrier are dissolved in chloroform or the dichloromethane; Join again in the oleic physiology dissolve medium of co-emulsifier of cosolvent ethanol or pharmaceutical composition cumulative volume 0～0.3% of the plasticizer that contains emulsifying agent, pharmaceutical composition cumulative volume 0～15%, pharmaceutical composition cumulative volume 0～10%; Carry out emulsifying with high-speed homogenization machine or high pressure homogenizer or ultransonic method; Form and stir behind the stable emulsion or organic facies is removed in ultrasonic volatilization, promptly get the microsphere of medicine carrying.
In the technique scheme, said pharmaceutical composition volume refers to all components is mixed volume afterwards.
Because the technique scheme utilization, the present invention compared with prior art has advantage:
1, improving the method for Nocathiacin dissolubility in the prior art, is main with chemical constitution transformation and biotransformation all, process relate to a large amount of toxic reagents and complex process, consuming time, cost is high, efficient is low; The method of raising Nocathiacin dissolubility provided by the present invention; With physical method is main, and the preparation process does not relate to a large amount of toxic reagents, and material therefor economy is easy to get; Used instrument and equipment is simple and safe; Few and the easy row of processing step is the present most economical method (less than 0.01mg/ml, the dissolubility of Nocathiacin can improve hundreds and thousands of times to the Nocathiacin of one pack system among the present invention at the dissolubility in the physiology dissolve medium) that the most simply improves the Nocathiacin dissolubility.
2, improving the method for Nocathiacin dissolubility in the prior art, is main Nocathiacin is converted into enhanced derivant of various water solublity or prodrug, and the antibacterial activity of medicine all decreases, and medicine can produce toxic and side effects in the metabolism way; The method of raising Nocathiacin dissolubility provided by the present invention; With Nocathiacin I body is principal agent; Without any chemical modification; Can not produce any influence to the antibacterial activity and the metabolic way of medicine, can not cause toxicity in the preparation application process, be the method that the most effectively improves the Nocathiacin dissolubility at present.
3, improving the method for Nocathiacin dissolubility in the prior art, is main with the dissolubility that improves chemical compound itself, does not carry out the dissolution and the interior dissolubility of preparation body of corresponding preparations and investigates, and it is little that the dissolubility of medicine improves ratio, can not guarantee effect; The method of raising Nocathiacin dissolubility provided by the present invention is main with the preparation dissolubility that improves medicine, makes medicine under the form of preparation, improve intravital dissolubility, and dissolubility raising ratio reaches nearly thousand times, more helps the clinical practice of medicine.
The method of the raising Nocathiacin dissolubility of 4, reporting both at home and abroad at present is owing to existing safety issue not have application example; The method of raising Nocathiacin dissolubility provided by the present invention, onset is rapid, and is easy to use, and route of administration is extensive, has greatly improved the using value of Nocathiacin.
The specific embodiment
Below in conjunction with embodiment the present invention is further described:
Embodiment one: common Emulsion
Prescription:
Soybean oil 200 μ l; Lecithin 10mg;
Poloxamer 20mg; 0.9% sodium chloride solution (pH7.4), 800 μ l;
Nocathiacin I 10mg.
Preparation technology:
The poloxamer of recipe quantity is scattered in 0.9% sodium chloride solution grinds well, will contain the phospholipid of recipe quantity and the oil phase of principal agent again and add, firmly stir and process colostrum, add 0.9% sodium chloride solution again the colostrum dilution is quantitatively promptly got homodisperse Emulsion; HPLC detects wherein, and the dissolubility of Nocathiacin I is 4.13mg/ml; Solution does not have deposition and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment two: common Emulsion
Prescription:
Soybean oil 500 μ l; Lecithin 10mg;
Poloxamer 10mg; 0.9% sodium chloride solution (pH7.4), 500 μ l;
Nocathiacin I 10mg.
Preparation technology:
The poloxamer of recipe quantity is scattered in 0.9% sodium chloride solution grinds well, will contain the phospholipid of recipe quantity and the oil phase of principal agent again and add, firmly stir and process colostrum, add 0.9% sodium chloride solution again the colostrum dilution is quantitatively promptly got homodisperse Emulsion; HPLC detects wherein, and the dissolubility of Nocathiacin I is 2.175mg/ml; Solution does not have deposition and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment three: submicron emulsion
Prescription:
MCT 200 μ l; Egg yolk lecithin 20mg;
Poloxamer 10mg; Polyvidone 10mg;
Oleic acid 3 μ l; 0.9% sodium chloride solution (pH7.4), 800 μ l;
Nocathiacin I 10mg.
Preparation technology:
The polyvidone and the poloxamer of recipe quantity are dissolved in 0.9% sodium chloride solution; Egg yolk lecithin, oleic acid and principal agent are dissolved in MCT; Supersound process makes each components dissolved in each phase; Centrifugal except that insoluble, again oil phase is dropwise added to the aqueous phase of continuous stirring, the ultrasonic again 30min of place is until forming homodisperse Emulsion; HPLC detects wherein, and the dissolubility of Nocathiacin I is 5.27mg/ml; Solution does not have deposition and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment four: nano-emulsion
Prescription:
Oleum Arachidis hypogaeae semen 200 μ l; Soybean phospholipid 20mg;
Poloxamer 20mg; Polyvidone 10mg;
Oleic acid 3 μ l; Ethanol 100 μ l;
Nocathiacin I 10mg; 0.9% sodium chloride solution (pH7.4), 700 μ l.
Preparation technology:
Oleum Arachidis hypogaeae semen, 0.9% sodium chloride solution, polyvidone, poloxamer, soybean phospholipid, oleic acid, ethanol and the principal agent of recipe quantity are mixed the back with high-speed homogenization machine 10000r/min shearing 3 times, and each 20min prepares, and promptly gets homodisperse Emulsion; HPLC detects wherein, and the dissolubility of Nocathiacin I is 7.31mg/ml; Solution does not have deposition and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment five: nano-emulsion
Prescription:
Camellia oil 200 μ l; Soybean phospholipid 10mg;
Poloxamer 10mg; Polyvidone 10mg;
Oleic acid 3 μ l; Ethanol 100 μ l;
Polyoxyethylene sorbitan monoleate 50 μ l; 0.9% sodium chloride solution (pH7.4), 700 μ l;
Nocathiacin I 10mg.
Preparation technology:
Camellia oil, 0.9% sodium chloride solution, polyvidone, poloxamer, soybean phospholipid, oleic acid, ethanol, polyoxyethylene sorbitan monoleate and the principal agent of recipe quantity are mixed the back with high-speed homogenization machine 10000r/min shearing 3 times; Each 20min prepares, and promptly gets homodisperse Emulsion; HPLC detects wherein, and the dissolubility of Nocathiacin I is 8.02mg/ml; Solution does not have deposition and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment six: gelatine microsphere
Prescription:
Soybean oil 700 μ l; Oleic acid 3 μ l;
Lecithin 10mg; Ethanol 100 μ l;
Gelatin 30mg; Arabic gum 30mg;
Formaldehyde 100 μ l; 0.9% sodium chloride solution (pH7.4), 200 μ l;
Nocathiacin I 10mg.
Preparation technology: gelatin, arabic gum and the principal agent of recipe quantity are dissolved in 0.9% sodium chloride solution under ultransonic condition as water; Stir and to join down in the oleic acid that contains recipe quantity, lecithin, the alcoholic acid soybean oil; Mix lasting stirring and emulsifying, add formaldehyde crosslinking again after the formation stable emulsion, separate oil removing; Isopropyl alcohol or acetone dehydrate promptly get the microsphere of medicine carrying; HPLC detects wherein, and the dissolubility of Nocathiacin I is 4.79mg/ml; Solution does not have deposition and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment seven: the gelatine microsphere of plasticizer-containing
Prescription:
Camellia oil 700 μ l; Oleic acid 3 μ l;
Polyoxyethylene sorbitan monoleate 5 μ l; Glycerol 100 μ l;
Gelatin 30mg; Methylcellulose 30mg;
Glutaraldehyde 100 μ l; 5% glucose solution (pH7.4), 200 μ l;
Nocathiacin I 10mg.
Preparation technology: gelatin, methylcellulose and the principal agent of recipe quantity be dissolved under ultransonic condition in 5% the glucose solution as water; Stir in the Camellia oil that joins the oleic acid that contains recipe quantity, polyoxyethylene sorbitan monoleate, glycerol down; Mix lasting stirring and emulsifying, add glutaraldehyde cross-linking again after the formation stable emulsion, separate oil removing; Isopropyl alcohol or acetone dehydrate promptly get the microsphere of medicine carrying; HPLC detects wherein, and the dissolubility of Nocathiacin I is 4.50mg/ml; Solution through 5% glucose solution dilution 500-1000 doubly in the 72h of back nothing precipitate and separate out.
Embodiment eight: chitosan microball
Prescription:
Soybean oil 700 μ l; Oleic acid 3 μ l;
Lecithin 10mg; Ethanol 100 μ l;
Chitosan 100mg; Formaldehyde 100 μ l;
Nocathiacin I 10mg; 0.9% sodium chloride solution (pH7.4), 200 μ l.
Preparation technology: the chitosan and the principal agent of recipe quantity are dissolved in 0.9% sodium chloride solution under ultransonic condition as water; Stir and to join down in the oleic acid that contains recipe quantity, lecithin, the alcoholic acid soybean oil; Mix lasting stirring and emulsifying, add formaldehyde crosslinking again after the formation stable emulsion, separate oil removing; Isopropyl alcohol or acetone dehydrate promptly get the microsphere of medicine carrying; HPLC detects wherein, and the dissolubility of Nocathiacin I is 4.32mg/ml; Solution does not have deposition and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment nine: carrier material and 10: 1 polymer microballoon of principal agent ratio
Prescription:
PLGA 100mg； PVA 10mg；
Nocathiacin I 10mg; 0.9% sodium chloride solution (pH7.4) 1ml.
Preparation technology: the principal agent and the PLGA of recipe quantity are dissolved in chloroform or the dichloromethane; Join again in 0.9% sodium chloride solution that contains recipe quantity PVA; Ultrasonic emulsification forms and stirs behind the stable emulsion or organic facies is removed in ultrasonic volatilization, promptly gets the microsphere of medicine carrying; HPLC detects wherein, and the dissolubility of Nocathiacin I is 4.01mg/ml; Solution does not have deposition and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment ten: carrier material and 5: 1 polymer microballoon of principal agent ratio
Prescription:
PLGA 50mg； PVA 5mg；
Nocathiacin I 10mg; 0.9% sodium chloride solution (pH7.4) 1ml.
Preparation technology: the principal agent and the PLGA of recipe quantity are dissolved in chloroform or the dichloromethane; Join again in 0.9% sodium chloride solution that contains recipe quantity PVA; Ultrasonic emulsification forms and stirs behind the stable emulsion or organic facies is removed in ultrasonic volatilization, promptly gets the microsphere of medicine carrying; HPLC detects wherein, and the dissolubility of Nocathiacin I is 4.20mg/ml; Solution does not have deposition and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment 11: carrier material is the polymer microballoon of PLA
Prescription:
PLA 100mg； PVA 10mg；
Nocathiacin I 10mg; 0.9% sodium chloride solution (pH7.4) 1ml.
Preparation technology: the principal agent and the PLA of recipe quantity are dissolved in chloroform or the dichloromethane, join in 0.9% sodium chloride solution that contains recipe quantity PVA again, ultrasonic emulsification forms and stirs behind the stable emulsion or organic facies is removed in ultrasonic volatilization, promptly gets the microsphere of medicine carrying; HPLC detects wherein, and the dissolubility of Nocathiacin I is 4.33mg/ml; Solution does not have deposition and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment 12: the polymer microballoon that contains two kinds of emulsifying agents
Prescription:
PLGA 100mg； PVA 5mg；
Nocathiacin I 10mg; Poloxamer 5mg;
0.9% sodium chloride solution (pH7.4) 1ml;
Preparation technology: the principal agent and the PLGA of recipe quantity are dissolved in chloroform or the dichloromethane; Join again in 0.9% sodium chloride solution that contains recipe quantity PVA and poloxamer; Ultrasonic emulsification forms and stirs behind the stable emulsion or organic facies is removed in ultrasonic volatilization, promptly gets the microsphere of medicine carrying; HPLC detects wherein, and the dissolubility of Nocathiacin I is 4.46mg/ml; Solution does not have deposition and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Annotate: above-mentioned Nocathiacin antibiotic detects its dissolubility with efficient liquid-phase chromatography method, and described efficient liquid-phase chromatography method is characterized in that chromatographic condition is:
Chromatographic column: Waters Symmetry, 150mm * 4.6mm, 5 μ m.
Mobile phase: A: contain 0.05%TFA in the distilled water; B: contain 0.05%TFA in the nitrile.
Gradient: gradient elution 32min, 30%～60%B.
Column temperature: 40 ℃ of flow velocity: 1ml/min
Wavelength: 362nm sample size: 10 μ l.
Claims (9)
1. pharmaceutical composition that is used for preparing the Nocathiacin Emulsion of common Emulsion, submicron emulsion dosage form or nanometer microemulsion type; Comprise water and oil phase; It is characterized in that; Also comprise: water soluble emulsifier, fat-soluble emulsifier and principal agent Nocathiacin, wherein, the volume ratio of water and oil phase is 50～95: 5～50; Said water soluble emulsifier is selected from one or both the mixture in poloxamer or the polyvidone, and said fat-soluble emulsifier is selected from: the mixture of one or more in lecithin, egg yolk lecithin or the soybean phospholipid; Wherein, in every 1ml pharmaceutical composition, the gross mass of water soluble emulsifier and fat-soluble emulsifier is 30～50mg.
2. according to the said pharmaceutical composition of claim 1; It is characterized in that; Said water is the physiology dissolve medium of pH4～9, and said physiology dissolve medium is selected from: purified water, water for injection, sterilized water for injection, mass fraction are that 0.9% sodium chloride solution or mass fraction are a kind of in 5% the glucose solution; Said oil phase is selected from: soybean oil, fish oil, Camellia oil, medium chain triglyceride, Oleum Arachidis hypogaeae semen, olive oil, Oleum Gossypii semen, Oleum Ricini, liquid paraffin or stearic acid.
3. according to the said pharmaceutical composition of claim 1, it is characterized in that the mass ratio of water soluble emulsifier and fat-soluble emulsifier is 2～1: 1.
4. according to the said pharmaceutical composition of claim 1, it is characterized in that said Nocathiacin is Nocathiacin I.
5. according to the said pharmaceutical composition of claim 1; It is characterized in that said pharmaceutical composition also comprises: the mixture of one or more in the co-emulsifier oleic acid of the cosolvent ethanol of pharmaceutical composition cumulative volume 0%～10%, the surfactant Polysorbate of pharmaceutical composition cumulative volume 0%～5% or pharmaceutical composition cumulative volume 0%～0.5%.
6. according to the said pharmaceutical composition of claim 1, it is characterized in that said pharmaceutical composition also comprises other pharmaceutic adjuvant additives, comprise antiseptic, correctives, analgesic, buffer agent, pH regulator agent, wetting agent, stabilizing agent, short penetrating agent and substrate; Said its content of pharmaceutic adjuvant additive is pharmaceutical composition gross mass 0%～80%.
7. one kind is used for preparing the Nocathiacin microsphere forms of pharmaceutical compositions that contains emulsifying agent, it is characterized in that, comprising: principal agent Nocathiacin, pharmaceutical carrier and emulsifying agent; Said pharmaceutical carrier is selected from: the mixture of one or more in gelatin, methylcellulose, arabic gum, chitosan, polylactic acid and the polylactic acid-glycolic guanidine-acetic acid copolymer; Said emulsifying agent is selected from: Polysorbate, polyvinyl alcohol, poloxamer or lecithin; Wherein the mass ratio of pharmaceutical carrier and principal agent Nocathiacin is 2: 1～10: 1.
8. be used for preparing the Nocathiacin microsphere forms of pharmaceutical compositions that contains emulsifying agent according to claim 7 is said, it is characterized in that said pharmaceutical composition comprises: principal agent Nocathiacin, pharmaceutical carrier, emulsifying agent; Said pharmaceutical composition also comprises: 5%～15% cross-linking agent, the plasticizer of pharmaceutical composition cumulative volume 0～15%, the cosolvent ethanol of pharmaceutical composition cumulative volume 0～10% or the co-emulsifier oleic acid of pharmaceutical composition cumulative volume 0～0.3% of physiology dissolve medium, oil phase, pharmaceutical composition cumulative volume; Said cross-linking agent is selected from: formaldehyde or glutaraldehyde; Said plasticizer is selected from: polyvinyl alcohol or glycerol; When emulsifying agent was solid, the consumption of emulsifying agent was 3%～15% of a drug regimen amount; When emulsifying agent was liquid, the consumption of emulsifying agent was 3%～15% of a pharmaceutical composition volume; Wherein, in every 1ml pharmaceutical composition, the quality of pharmaceutical carrier is 45～105mg.
9. be used for preparing the Nocathiacin microsphere forms of pharmaceutical compositions that contains emulsifying agent according to claim 7 is said, it is characterized in that said pharmaceutical composition comprises: principal agent Nocathiacin, pharmaceutical carrier, emulsifying agent; Said pharmaceutical composition also comprises: the co-emulsifier oleic acid of the plasticizer of physiology dissolve medium, pharmaceutical composition cumulative volume 0～15%, the cosolvent ethanol of pharmaceutical composition cumulative volume 0～10% or pharmaceutical composition cumulative volume 0～0.3%; Wherein, in every 1ml pharmaceutical composition, the quality of pharmaceutical carrier is 45～105mg.
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| CN102274180B (en) * | 2011-09-09 | 2013-04-17 | 南京正科制药有限公司 | Prulifloxacin nano spheres and preparation method thereof |
| CN104244712A (en) * | 2012-03-05 | 2014-12-24 | 阿彻丹尼尔斯米德兰德公司 | Microemulsions and uses thereof as delivery systems |
| CN107469068B (en) * | 2017-08-04 | 2021-06-22 | 南京碧迪可医药科技有限公司 | Pharmaceutical composition of thiopeptocyclines |
| CN108669272A (en) * | 2018-06-01 | 2018-10-19 | 黑龙江福和制药集团股份有限公司 | A kind of dandelion tea bag and preparation method thereof |
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