CN102028933A - Medicinal composition containing lipid material nocathiacin antibiotic - Google Patents
Medicinal composition containing lipid material nocathiacin antibiotic Download PDFInfo
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- CN102028933A CN102028933A CN 201010548142 CN201010548142A CN102028933A CN 102028933 A CN102028933 A CN 102028933A CN 201010548142 CN201010548142 CN 201010548142 CN 201010548142 A CN201010548142 A CN 201010548142A CN 102028933 A CN102028933 A CN 102028933A
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Abstract
The invention belongs to a medicinal composition and particularly relates to a medicinal composition containing a lipid material nocathiacin antibiotic as well as a corresponding liposome, a noisome and a solid lipid nanoparticle form thereof. The invention discloses a medicinal composition containing a nocathiacin antibiotic which comprises the main medicine nocathiacin and a lipid material, wherein the lipid material is phospholipid or phospholipid. With the medicinal composition, a lipid containing nocathiacin, a noisome preparation or a solid lipid nanoparticle form can be prepared. The medicinal composition can obviously improve the solubility of nocathiacin, the preparation process is safe, the materials are economical, the equipment is simple and the process steps are few; and moreover, due to the remarkable drug-resistant bacteria activity of nocathiacin, the invention has important values in clinical application.
Description
Technical field
The invention belongs to pharmaceutical composition, be specifically related to contain the antibiotic pharmaceutical composition of Nocathiacin of matrix material, and corresponding liposome, class lipid vesicle and solid lipid nanoparticle dosage form.
Background technology
In the history of human and disease fight, bacterial infection always is and causes human dead first killer, when using more and more antibiotic therapy disease along with people, also tempered the drug resistance ability of antibacterial, so tachytelic evolution along with antibiotic abuse and pathogenic bacteria, increasing Resistant strain has appearred clinically, the bacterial strain such as the methicillin resistant staphylococcus aureus (MRSA) that particularly multiple antibiotic are all had resistance, penicillin-fast streptococcus pneumoniae (PRSP), so that recent " superbacteria " found, people often seem at a loss what to do in the face of the quick infection rate of these class 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 that a class is separated from soil and obtained, 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, form complex by 23S rRNA and L11 albumen with the big subunit of ribosome 50S, thereby influencing the proteinic conformation of L11 transforms, and then Profilin 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, in the level that is lower than μ g/ml just to most gram positive bacterias methicillin resistant staphylococcus aureus (MRSA) particularly, penicillin-fast streptococcus pneumoniae (PRSP), the enterococcus of vancomycin resistance (VRE) and have chemical sproof tubercule bacillus and superpower bactericidal activity is 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 presented 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, carried out studying at a series of chemistry and the bio-modification transformation of hydroxyl on its dehydroalanine side chain, indole and the pyridine ring in a large number, but all do not have successfully with factors such as causing safety issue because of preparing complexity (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 effective raising Nocathiacin, have significant values and meaning to strengthening its DEVELOPMENT PROSPECT and clinical practice.
Liposome is made up of phospholipid and cholesterol, has similar biomembranous bilayer structure, and insoluble drug is dissolvable in water in the interlayer of phospholipid bilayer, can dynamically increase the dissolubility of insoluble drug.Liposome have the favorable tissue compatibility, cellular affinity, targeting and and slow-releasing, therefore be widely used in the solubilising of insoluble drug, slow controlled release and targeting preparation, and existing a lot of successful cases (referring to: Int J Pharm, 2006,308 (1-2): 140-148; J Drug Target, 2008,16 (5): 357-365; Chinese patent application number 02153385.7; The patent No. is 02100554.0 Chinese invention patent; The patent No. is 98802737.2 Chinese invention patent).
Class lipid vesicle is conventional liposome to be improved and the new drug carrier that obtains, and than conventional liposome, the carrier material of class lipid vesicle does not contain phospholipid, thereby has avoided the degraded of phospholipid, makes preparation comparatively stable, work simplification, and cost reduces.Simultaneously, class lipid vesicle also has slow control property, toxicity mental retardation characteristic, thus as the carrier of multiple medicine by researcher favor both at home and abroad (referring to Langmuir, 2005,21 (24): 11034-11039; Int J Pharm, 2005,306 (1): 71-82; Drug Delivery, 2003,10 (4): 251-262; Application number is 200880016069.6 Chinese invention patent ublic specification of application; Application number is the Chinese invention patent ublic specification of application of 200710157581.X; Application number is 200910012314.2 Chinese invention patent ublic specification of application).
Solid lipid nanoparticle (SLN) is a kind of nano level drug-supplying system, he has had the high stability of polymer nanoparticle and the hypotoxicity of liposome concurrently, be that the new drug carrier that has development prospect at present is (referring to Adv Drug Del Rev, 2004,56 (1): 1257-1272; Recent Pat Drug Deliv Form μ l, 2008,2 (2): 120-35).In view of the good physiological compatibility of SLN, degradability, controlled capability and targeting, the SLN preparation of more and more medicines obtains development and application (referring to J Microencaps μ l, 2001,18 (3): 359-371; Int J Pharm, 1993,89:9-12; Int J Pharm, 1999,182:59-69; Int J Pharm, 2002,238:241-245).
But do not see about Nocathiacin being made the report of liposome, lipoid vesicle formation or solid lipid nanoparticle at present.
Summary of the invention
The object of the invention provides a kind of antibiotic pharmaceutical composition of Nocathiacin that contains matrix material, the material and the prescription that utilize economy to be easy to get, by simple technology, make the available clinically Nocathiacin pharmaceutical dosage form that contains matrix material, with increase Nocathiacin antibiotic dissolubility in the physiology dissolve medium, thereby solve the application limitations that its low aqueous solubility causes.
For achieving the above object, general plotting of the present invention is: with matrix material Nocathiacin is wrapped and carry, simultaneously under the assistance of emulsifying agent, solubilizing agent or cosolvent, Nocathiacin is realized solubilising and it finally be can be applicable to clinical, thereby represent its strong antibiotic activity.
For achieving the above object, the technical solution used in the present invention is: a kind of antibiotic pharmaceutical composition of Nocathiacin that contains, comprise principal agent Nocathiacin and matrix material, and described matrix material is selected from phospholipid or cholesterol.
Further in the technical scheme, the described antibiotic pharmaceutical composition of Nocathiacin that contains also comprises other pharmaceutic adjuvant additives, comprises antiseptic, correctives, analgesic, buffer agent, pH regulator agent, wetting agent, stabilizing agent, short penetrating agent and substrate; Described will be 0%～80% of drug regimen amount with its content of adjuvant additive, preferred 0%～20%.
Adopt aforementioned pharmaceutical compositions can prepare liposome, lipoid vesicle formation or the solid lipid nanoparticle dosage form that contains Nocathiacin.
Particularly, the present invention provides a kind of pharmaceutical composition that is used for preparing the liposome dosage form that contains Nocathiacin to comprise simultaneously: principal agent Nocathiacin, physiology dissolve medium and matrix material, and described matrix material comprises phospholipid and cholesterol, as pharmaceutical carrier; Described phospholipid is selected from: lecithin, cephalin, soybean phospholipid, synthetic phosphatidyl serine, DCP, egg yolk lecithin or other synthetic phospholipids; The mass ratio of principal agent Nocathiacin and phospholipid is 1: 1～1: 20; Preferred 1: 5～1: 10; The mass ratio of cholesterol and phospholipid is 1: 1～1: 10, preferred 1: 1～1: 4; The concentration of principal agent Nocathiacin is 4mg/ml～9mg/ml.
In the technique scheme, in the described pharmaceutical composition, more than the corresponding principal agent Nocathiacin of the every 1ml physiology dissolve medium 0.1mg, make the liposome dosage form after, the content of principal agent Nocathiacin is greater than its medicinal minimum effective dose; In the optimized technical scheme, make the liposome dosage form after, principal agent Nocathiacin concentration 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, described Nocathiacin (English general Nocathiacin by name) is selected from: Nocathiacin I, Nocathiacin II or Nocathiacin III, and the general structure of described 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, described Nocathiacin is Nocathiacin I.
In the technique scheme, described 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.
The above-mentioned pharmaceutical composition that is used for preparing the liposome dosage form that contains Nocathiacin can also comprise: the nonionic surfactant of the emulsifying agent oleic acid of physiology dissolve medium volume 0%～0.5% or physiology dissolve medium volume 0%～1%.
Further in the technical scheme, the described antibiotic pharmaceutical composition of Nocathiacin that contains also comprises other pharmaceutic adjuvant additives, comprises antiseptic, correctives, analgesic, buffer agent, pH regulator agent, wetting agent, stabilizing agent, short penetrating agent and substrate; Described will be 0%～80% of drug regimen amount with its content of adjuvant additive, preferred 0%～20%.
Adopt the method that the aforementioned pharmaceutical compositions preparation contains the liposome dosage form of Nocathiacin to be selected from: dispersion method, injection method or ultrasonic dispersing method, particularly:
1, described film dispersion method mainly may further comprise the steps: according to the prescription of aforementioned pharmaceutical compositions, the emulsifying agent oleic acid of phospholipid, cholesterol, principal agent Nocathiacin, physiology dissolve medium volume 0%～0.5% or the nonionic surfactant of physiology dissolve medium volume 0%～1% are dissolved in chloroform or the dichloromethane, with solution rotary evaporation in flask, make it on inwall, form thin film again; Subsequently phosphate buffer is added flask and continuous the stirring until forming homodisperse liposome solutions;
2, described injection method mainly may further comprise the steps: according to the prescription of aforementioned pharmaceutical compositions, the emulsifying agent oleic acid of phospholipid, cholesterol, principal agent Nocathiacin, physiology dissolve medium volume 0%～0.5% or the nonionic surfactant of physiology dissolve medium volume 0%～1% are dissolved in ether or the ethanol, again solution is slowly splashed in the phosphate buffer under stirring, constantly be stirred to till the volatilization to the greatest extent of ether or ethanol, by two sub-high pressure dispersing emulsification machines, promptly get homodisperse liposome solutions again;
3, described ultrasonic dispersing method mainly may further comprise the steps: according to the prescription of aforementioned pharmaceutical compositions, phosphate buffer is added in the chloroform or dichloromethane of nonionic surfactant of the emulsifying agent oleic acid that is dissolved with phospholipid, cholesterol, principal agent Nocathiacin, physiology dissolve medium volume 0%～0.5% or physiology dissolve medium volume 0%～1%, stir evaporation and remove organic solvent, residual liquid is through ultrasonic dispersing, isolate liposome, be suspended in again and promptly get homodisperse liposome solutions in the phosphate buffer;
In the technique scheme, described phosphate buffering liquid concentration is 0.01mol/L, and pH value is 6.0～7.5, preferred 7.0～7.4.
The present invention provides a kind of simultaneously and is used for preparation and contains Nocathiacin class lipid vesicle forms of pharmaceutical compositions, and comprising: principal agent Nocathiacin, membrane material, cholesterol, physiology dissolve medium or phosphate are slow; Described membrane material is selected from: the smooth or Polysorbate of nonionic surfactant fatty acid Pyrusussuriensis; Wherein, the mass ratio of principal agent Nocathiacin and membrane material is 1: 5～1: 10, preferred 1: 10; The mass ratio of cholesterol and membrane material is 1: 1～1: 4, preferred 1: 1～1: 2.
In the technique scheme, more than the corresponding principal agent Nocathiacin of every 1ml physiology dissolve medium or the phosphate buffer 0.1mg, make class lipid vesicle dosage form after, the content of principal agent Nocathiacin is greater than its medicinal minimum effective dose; In the optimized technical scheme, after making class lipid vesicle dosage form, the content of principal agent Nocathiacin can be up to about 9mg/ml, and those skilled in the art should know simultaneously, since the content of principal agent Nocathiacin can be up to about 9mg/mL, content also can be realized less than 9mg/mL so.
The method that adopts the aforementioned pharmaceutical compositions preparation to contain Nocathiacin class lipid vesicle dosage form is selected from: film dispersion method or injection method, particularly,
1, described film dispersion method mainly may further comprise the steps: according to the prescription of aforementioned pharmaceutical compositions, membrane material, cholesterol and principal agent are dissolved in chloroform or the dichloromethane, again with solution rotary evaporation in flask, make it form thin film on inwall; Add physiology dissolve medium or phosphate buffer in the flask subsequently and supersound process until forming homodisperse vesicle solution;
2, described injection method mainly may further comprise the steps: according to the prescription of aforementioned pharmaceutical compositions, membrane material, cholesterol and principal agent are dissolved in ether or the ethanol, again solution is slowly splashed in the physiology dissolve medium or phosphate buffer under stirring, constantly be stirred to till the volatilization to the greatest extent of ether or ethanol, by the high pressure dispersing emulsification machine, promptly get homodisperse vesicle solution again.
The present invention provides a kind of solid lipid nanoparticle forms of pharmaceutical compositions that contains the Nocathiacin dissolubility that is used for preparing simultaneously, comprising: principal agent Nocathiacin, physiology dissolve medium, matrix material and emulsifying agent; Described matrix material is selected from: one or more in satisfied fatty acid and glyceride thereof and the cholesterol, described satisfied fatty acid comprise stearic acid, lauric acid, mountain Yu acid, and described glyceride comprises monoester, two fat, three fat; Described emulsifying agent is selected from: the mixture of one or more in phospholipid, poloxamer, cholesterol, oleic acid, gelatin or the arabic gum (comprising two kinds); Wherein, the mass ratio of matrix material and principal agent is 5: 1～20: 1, preferred 5: 1～10: 1; The ratio of emulsifying agent and matrix material is 1: 1～1: 4.
In the technique scheme, described pharmaceutical composition can also comprise: gross mass is the co-emulsifier mannitol of 0mg～20mg in every 1ml pharmaceutical composition.
In the technique scheme, more than the corresponding principal agent Nocathiacin of the every 1ml physiology dissolve medium 0.1mg, make the solid lipid nanoparticle dosage form after, the content of principal agent Nocathiacin is greater than its medicinal minimum effective dose; In the optimized technical scheme, after making the solid lipid nanoparticle dosage form, the content of principal agent Nocathiacin can be up to about 9mg/ml, and those skilled in the art should know simultaneously, since the content of principal agent Nocathiacin can be up to about 9mg/mL, content also can be realized less than 9mg/mL so.
The method that adopts the aforementioned pharmaceutical compositions preparation to contain the solid lipid nanoparticle dosage form of Nocathiacin dissolubility is selected from: film dispersion method or emulsion-solvent evaporation method, particularly,
1, described film dispersion method mainly may further comprise the steps: according to the prescription of aforementioned pharmaceutical compositions, matrix material, fat-soluble emulsifier and principal agent are dissolved in chloroform or the dichloromethane, with solution rotary evaporation in flask, make it on inwall, form thin film again; The physiology dissolve medium that will contain co-emulsifier subsequently add in the flask and supersound process until forming homodisperse solid lipid nanoparticle solution;
2, described emulsion-solvent evaporation method mainly may further comprise the steps: according to the prescription of aforementioned pharmaceutical compositions, matrix material, fat-soluble emulsifier and principal agent are dissolved in ether or the ethanol, again solution is slowly splashed in the physiology dissolve medium that contains co-emulsifier under stirring, high-speed stirring mixes breast, or else disconnected stirring or ultrasonic till ether or ethanol volatilization to the greatest extent promptly gets homodisperse solid lipid nanoparticle solution.
Above-mentioned liposome, lipoid vesicle formation or the solid lipid nanoparticle dosage form that contains Nocathiacin can be for oral, external, an 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.
Because the technique scheme utilization, the present invention compared with prior art has following advantage:
1. the present both at home and abroad method of the raising Nocathiacin dissolubility of report, all based on chemical constitution transformation and biotransformation, 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, based on physical method, preparation process does not relate to a large amount of toxic reagents, material therefor economy is easy to get, used instrument and equipment is simple and safe, and processing step is few and easy to be capable, is the method for both economical simple raising Nocathiacin dissolubility.
2. the present method of the raising Nocathiacin dissolubility of report both at home and abroad, Nocathiacin is converted into enhanced derivant of various water solublity or prodrug, the antibacterial activity of medicine all decreases, and medicine is meeting generation 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, adopt the matrix material of safety in the preparation application process, can not cause toxicity, it is the 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 improves the Nocathiacin dissolubility at present more safely and effectively.
3. the present method of the raising Nocathiacin dissolubility of report both at home and abroad, to improve the dissolubility of chemical compound itself, do not carry out the dissolution and the interior dissolubility of preparation body of corresponding preparations and investigate, 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 to improve the preparation dissolubility of medicine, makes medicine improve intravital dissolubility under the form of preparation, and dissolubility raising ratio reaches nearly thousand times, more helps the clinical practice of medicine.
4. the method for the raising Nocathiacin dissolubility of 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: principal agent is than phosphatidase 11: 10, and cholesterol is than phosphatidase 11: 1 liposome
Prescription:
Soybean phospholipid 100mg; Cholesterol 100mg;
Nocathiacin I 10mg phosphate buffer (pH7.4) 1ml.
Preparation technology:
Phospholipid, cholesterol and the principal agent of recipe quantity are dissolved in the dichloromethane, centrifugal except that insoluble, with solution rotary evaporation below 30 ℃ in flask, make it on inwall, form thin film again; Subsequently phosphate buffer is added flask and continuous the stirring until forming homodisperse liposome solutions; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 6.96mg/ml; Solution does not have precipitation and separates out in the 72h after diluting 500～1000 times.
Embodiment two: principal agent is than phosphatidase 11: 10, and cholesterol is than phosphatidase 11: 2 liposome
Prescription:
Cephalin 100mg; Cholesterol 50mg;
Nocathiacin I 10mg; Phosphate buffer (pH7.4) 1ml.
Preparation technology:
Phospholipid, cholesterol and the principal agent of recipe quantity are dissolved in the ethanol, centrifugal except that insoluble, again solution is slowly splashed in the phosphate buffer under stirring, constantly be stirred to till the ethanol volatilization to the greatest extent, by two sub-high pressure dispersing emulsification machines, promptly get homodisperse liposome solutions again; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 7.61mg/ml; Solution does not have precipitation and separates out in the 72h after diluting 500-1000 times.
Embodiment three: principal agent is than phosphatidase 11: 10, and cholesterol is than phosphatidase 11: 4 liposome
Prescription:
Egg yolk lecithin 100mg; Cholesterol 50mg;
Oleic acid 3 μ l; Polyoxyethylene sorbitan monoleate 5 μ l;
Nocathiacin I 10mg; Phosphate buffer (pH7.4) 1ml.
Preparation technology:
Phosphate buffer is added in the chloroform or dichloromethane of the phospholipid, cholesterol, oleic acid, polyoxyethylene sorbitan monoleate and the principal agent that are dissolved with recipe quantity, stir evaporation and remove organic solvent, residual liquid is through ultrasonic dispersing, isolate liposome, be suspended in again and promptly get homodisperse liposome solutions in the phosphate buffer; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 7.98mg/ml; The solution dilution 500-1000 doubly interior nothing precipitation of back 72h separates out.
Embodiment four: principal agent is than phosphatidase 11: 5, and cholesterol is than phosphatidase 11: 2 liposome
Prescription:
Lecithin 50mg; Cholesterol 25mg;
Oleic acid 3 μ l; Polyoxyethylene sorbitan monoleate 5 μ l;
Nocathiacin I 10mg; Phosphate buffer (pH7.4) 1ml.
Preparation technology:
Phospholipid, cholesterol, oleic acid, polyoxyethylene sorbitan monoleate and the principal agent of recipe quantity are dissolved in the dichloromethane, centrifugal except that insoluble, with solution rotary evaporation below 30 ℃ in flask, make it on inwall, form thin film again; Subsequently phosphate buffer is added flask and continuous the stirring until forming homodisperse liposome solutions; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 8.74mg/ml; Solution does not have precipitation and separates out in the 72h after diluting 500-1000 times.
Embodiment five: membrane material is the vesicle (class lipid vesicle) of fatty acid Pyrusussuriensis smooth 80
Prescription:
The smooth 80 100 μ l of fatty acid Pyrusussuriensis; Cholesterol 100mg;
Nocathiacin I 10mg; 0.9% sodium chloride solution (pH7.4) 1ml.
Preparation technology:
The fatty acid Pyrusussuriensis of recipe quantity is smooth 80, cholesterol and principal agent are dissolved in chloroform or the dichloromethane, again with solution rotary evaporation in flask, make it form thin film on inwall; Subsequently 0.9% sodium chloride solution is added in the flask and supersound process until forming homodisperse vesicle solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 6.27mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment six: membrane material is the vesicle of fatty acid Pyrusussuriensis smooth 60
Prescription:
The smooth 60 100 μ l of fatty acid Pyrusussuriensis; Cholesterol 100mg;
Nocathiacin I 10mg; 0.9% sodium chloride solution (pH7.4) 1ml.
Preparation technology:
The fatty acid Pyrusussuriensis of recipe quantity is smooth 60, cholesterol and principal agent are dissolved in ether or the ethanol, again solution is slowly splashed in 0.9% sodium chloride solution under stirring, constantly be stirred to till the volatilization to the greatest extent of ether or ethanol, by the high pressure dispersing emulsification machine, promptly get homodisperse vesicle solution again; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 6.04mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment seven: membrane material is the vesicle of polysorbate 60
Prescription:
Polysorbate 60 100 μ l; Cholesterol 100mg;
Nocathiacin I 10mg; Phosphate buffer (pH7.4) 1ml.
Preparation technology:
Polysorbate 60, cholesterol and the principal agent of recipe quantity are dissolved in chloroform or the dichloromethane,, make it on inwall, form thin film again with solution rotary evaporation in flask; Subsequently phosphate buffer is added in the flask and supersound process until forming homodisperse vesicle solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 6.07mg/ml; Solution does not have precipitation and separates out in the 72h after diluting 500-1000 times.
Embodiment eight: polyoxyethylene sorbitan monoleate is as the vesicle of membrane material
Prescription:
Polyoxyethylene sorbitan monoleate 100 μ l; Cholesterol 100mg;
Nocathiacin I 10mg; 0.9% sodium chloride solution (pH7.4) 1ml.
Preparation technology:
Polyoxyethylene sorbitan monoleate, cholesterol and the principal agent of recipe quantity are dissolved in ether or the ethanol, again solution is slowly splashed in 0.9% sodium chloride solution under stirring, constantly be stirred to till the volatilization to the greatest extent of ether or ethanol, by the high pressure dispersing emulsification machine, promptly get homodisperse vesicle solution again; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 6.47mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment nine: the ratio of cholesterol and membrane material is 1: 2 a vesicle
Prescription:
Polyoxyethylene sorbitan monoleate 100 μ l; Cholesterol 50mg;
Nocathiacin I 10mg; 0.9% sodium chloride solution (pH7.4) 1ml.
Preparation technology:
Polyoxyethylene sorbitan monoleate, cholesterol and the principal agent of recipe quantity are dissolved in chloroform or the dichloromethane,, make it on inwall, form thin film again with solution rotary evaporation in flask; Subsequently 0.9% sodium chloride solution is added in the flask and supersound process until forming homodisperse vesicle solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 7.06mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment ten: the vesicle that contains two kinds of membrane materials
Prescription:
Polyoxyethylene sorbitan monoleate 50 μ l; The smooth 60 50 μ l of fatty acid Pyrusussuriensis;
Cholesterol 100mg; Nocathiacin I 10mg
0.9% sodium chloride solution (pH7.4) 1ml.
Preparation technology:
Polyoxyethylene sorbitan monoleate, the fatty acid Pyrusussuriensis of recipe quantity is smooth 60, cholesterol and principal agent are dissolved in chloroform or the dichloromethane, again with solution rotary evaporation in flask, make it form thin film on inwall; Subsequently 0.9% sodium chloride solution is added in the flask and supersound process until forming homodisperse vesicle solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 6.83mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment 11: the ratio of emulsifying agent and solid lipid material is 1: 1 a solid lipid nanoparticle
Prescription:
Stearic acid 100mg; Lecithin 100mg;
Mannitol 10mg; Nocathiacin I 10mg;
0.9% sodium chloride solution (pH7.4) 1ml.
Preparation technology:
Stearic acid, lecithin and the principal agent of recipe quantity are dissolved in chloroform or the dichloromethane,, make it on inwall, form thin film again with solution rotary evaporation in flask; 0.9% sodium chloride solution that will be dissolved with recipe quantity mannitol subsequently add in the flask and supersound process until forming homodisperse solid lipid nanoparticle solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 7.38mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment 12: the ratio of emulsifying agent and solid lipid material is 1: 2 a solid lipid nanoparticle
Prescription:
Glyceryl monostearate 100mg; Lecithin 50mg;
Poloxamer 10mg; Nocathiacin I 10mg;
0.9% sodium chloride solution (pH7.4) 1ml.
Preparation technology:
Glyceryl monostearate, lecithin and the principal agent of recipe quantity are dissolved in ether or the ethanol, again solution is slowly splashed in 0.9% sodium chloride solution that contains the recipe quantity poloxamer under stirring, high-speed stirring mixes breast, or else disconnected stirring or ultrasonic till ether or ethanol volatilization to the greatest extent promptly gets homodisperse solid lipid nanoparticle solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 7.68mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment 13: the ratio of emulsifying agent and solid lipid material is 1: 4 a solid lipid nanoparticle
Prescription:
Lauric acid triglyceride 100mg; Lecithin 25mg;
Mannitol 20mg; Nocathiacin I 10mg;
0.9% sodium chloride solution (pH7.4) 1ml.
Preparation technology:
Lauric acid triglyceride, lecithin and the principal agent of recipe quantity are dissolved in chloroform or the dichloromethane,, make it on inwall, form thin film again with solution rotary evaporation in flask; 0.9% sodium chloride solution that will be dissolved with recipe quantity mannitol subsequently add in the flask and supersound process until forming homodisperse solid lipid nanoparticle solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 7.10mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment 14: the ratio of solid lipid material and principal agent is 5: 1 a solid lipid nanoparticle
Prescription:
Mountain Yu acid triglyceride 50mg; Lecithin 25mg;
Mannitol 20mg; Nocathiacin I 10mg;
0.9% sodium chloride solution (pH7.4) 1ml.
Preparation technology:
Mountain Yu acid triglyceride, lecithin and the principal agent of recipe quantity are dissolved in ether or the ethanol, again solution is slowly splashed in 0.9% sodium chloride solution that contains recipe quantity mannitol under stirring, high-speed stirring mixes breast, or else disconnected stirring or ultrasonic till ether or ethanol volatilization to the greatest extent promptly gets homodisperse solid lipid nanoparticle solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 5.19mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Embodiment 15: the solid lipid nanoparticle that contains two kinds of solid lipid materials
Prescription:
Stearic acid 50mg; Glyceryl monostearate 50mg;
Lecithin 100mg; Poloxamer 10mg;
Nocathiacin I 10mg; 0.9% sodium chloride solution (pH7.4) 1ml.
Preparation technology:
Stearic acid, glyceryl monostearate, lecithin and the principal agent of recipe quantity are dissolved in chloroform or the dichloromethane,, make it on inwall, form thin film again with solution rotary evaporation in flask; 0.9% sodium chloride solution that will be dissolved with the recipe quantity poloxamer subsequently add in the flask and supersound process until forming homodisperse solid lipid nanoparticle solution; High performance liquid chromatography detects wherein, and the dissolubility of Nocathiacin I is 7.46mg/ml; Solution does not have precipitation and separates out in the 72h after 0.9% sodium chloride solution dilutes 500-1000 times.
Annotate: described Nocathiacin antibiotic, the need of its dissolubility detect with high performance liquid chromatography, and chromatographic condition is as follows:
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 acetonitrile
Gradient: gradient elution 32min, 30%～60%B
Column temperature: 40 ℃ of flow velocity: 1ml/min
Wavelength: 362nm sample size: 10 μ l.
Claims (7)
1. a pharmaceutical composition that is used for preparing the liposome dosage form that contains Nocathiacin comprises the physiology dissolve medium, it is characterized in that, also comprises: principal agent Nocathiacin and matrix material, and described matrix material comprises phospholipid and cholesterol, as pharmaceutical carrier; Described phospholipid is selected from: lecithin, cephalin, soybean phospholipid, synthetic phosphatidyl serine, DCP, egg yolk lecithin or synthetic phospholipid; The mass ratio of principal agent Nocathiacin and phospholipid is 1: 1～1: 20; The mass ratio of cholesterol and phospholipid is 1: 1～1: 10.
2. according to the described pharmaceutical composition of claim 1, it is characterized in that: described Nocathiacin is Nocathiacin I.
3. according to the described pharmaceutical composition of claim 1, it is characterized in that: described 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.
4. according to the described pharmaceutical composition of claim 1, it is characterized in that: described pharmaceutical composition also comprises: the nonionic surfactant of the emulsifying agent oleic acid of physiology dissolve medium volume 0%～0.5% or physiology dissolve medium volume 0%～1%.
One kind be used for the preparation contain Nocathiacin class lipid vesicle forms of pharmaceutical compositions, comprise membrane material, physiology dissolve medium or phosphate buffered solution, it is characterized in that, also comprise principal agent Nocathiacin and cholesterol; Described membrane material is selected from: the smooth or Polysorbate of nonionic surfactant fatty acid Pyrusussuriensis; Wherein, the mass ratio of principal agent Nocathiacin and membrane material is 1: 5～1: 10; The mass ratio of cholesterol and membrane material is 1: 1～1: 4.
6. one kind is used for preparing the solid lipid nanoparticle forms of pharmaceutical compositions that contains the Nocathiacin dissolubility, it is characterized in that, comprising: principal agent Nocathiacin, physiology dissolve medium, matrix material and emulsifying agent; Described matrix material is selected from: one or more in satisfied fatty acid and glyceride thereof and the cholesterol, described satisfied fatty acid comprise stearic acid, lauric acid, mountain Yu acid, and described glyceride comprises monoester, two fat, three fat; Described emulsifying agent is selected from: the mixture of one or more in phospholipid, poloxamer, cholesterol, oleic acid, gelatin or the arabic gum; Wherein, the mass ratio of matrix material and principal agent is 5: 1～20: 1, preferred 5: 1～10: 1; The ratio of emulsifying agent and matrix material is 1: 1～1: 4.
7. according to the described pharmaceutical composition of claim 6, it is characterized in that: described pharmaceutical composition can also comprise: gross mass is the co-emulsifier mannitol of 0mg～20mg in every 1ml pharmaceutical composition.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201010548142 CN102028933A (en) | 2010-11-18 | 2010-11-18 | Medicinal composition containing lipid material nocathiacin antibiotic |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010548142 CN102028933A (en) | 2010-11-18 | 2010-11-18 | Medicinal composition containing lipid material nocathiacin antibiotic |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3384921A4 (en) * | 2015-12-02 | 2019-08-14 | Nanjing Biotica Pharmaceutical Company | New use of thiopeptin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1309566A (en) * | 1998-07-16 | 2001-08-22 | 布里斯托尔-迈尔斯斯奎布公司 | Nocathiacin antibiotics |
| CN101401790A (en) * | 2008-11-14 | 2009-04-08 | 山东大学 | Lavo-ofloxacin liposome and preparation method thereof |
-
2010
- 2010-11-18 CN CN 201010548142 patent/CN102028933A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1309566A (en) * | 1998-07-16 | 2001-08-22 | 布里斯托尔-迈尔斯斯奎布公司 | Nocathiacin antibiotics |
| CN101401790A (en) * | 2008-11-14 | 2009-04-08 | 山东大学 | Lavo-ofloxacin liposome and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 《生物膜与脂质体技术》 19890531 刘文龙 张志鸿 《生物膜与脂质体技术》 , * |
| 《脂质体制备及其在生物医学中的应用》 19980430 张灵芝 脂质体制备及其在生物医学中的应用 , * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3384921A4 (en) * | 2015-12-02 | 2019-08-14 | Nanjing Biotica Pharmaceutical Company | New use of thiopeptin |
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Application publication date: 20110427 |