CN107019700B - A kind of pediatric pharmaceuticals compositions and preparation - Google Patents

A kind of pediatric pharmaceuticals compositions and preparation Download PDF

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CN107019700B
CN107019700B CN201710259887.XA CN201710259887A CN107019700B CN 107019700 B CN107019700 B CN 107019700B CN 201710259887 A CN201710259887 A CN 201710259887A CN 107019700 B CN107019700 B CN 107019700B
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cholesterol
nao
oxos
ene
sulphur
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CN107019700A (en
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周白水
段学民
应鹏
傅苗青
朱旭伟
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Guangdong Jincheng Pharmaceutical Co Ltd
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Guangdong Jincheng Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a kind of children to use C16H16N3NaO7S2Pharmaceutical entities composition and preparation.Raw material includes the hydrogenated soy phosphatidyl choline and cholesterol and C as film forming matter16H16N3NaO7S2, the raw material further includes the D glucopyranose amides as film forming matter stabilizer.

Description

A kind of pediatric pharmaceuticals compositions and preparation
Technical field
The invention belongs to drug fields；It is related to a kind of C16H16N3NaO7S2Pharmaceutical entities composition, it is especially a kind of novel Children use C16H16N3NaO7S2Pharmaceutical entities composition and preparation.
Background technology
C16H16N3NaO7S2Chemical name is：3- carbamyl yloxymethyl -7- methoxyl group -8- oxos -7- (2- thiophene second Amide groups) bicyclic (4.2.0) oct-2-ene -2- formic acid sodium salts of the miscellaneous nitrogen of -5- sulphur -1-, molecular weight 449.4 belongs to cephamycin-type antibiosis Element. C16H16N3NaO7S2Mechanism of action is similar to second generation cephalosporin, therefore custom is included in second generation cephalosporin class. C16H16N3NaO7S2Raw material and injection C16H16N3NaO7S2It has recorded in Chinese Pharmacopoeia versions in 2010 and version second in 2015 Portion.This product is white or off-white powder, soluble easily in water.
C16H16N3NaO7S2With broad spectrum antibiotic activity.C16H16N3NaO7S2It is weak to the anti-microbial property of gram-positive bacteria, it is right Gram-negative bacteria effect is strong.To Escherichia coli, Klebsiella, haemophilus influenzae, gonococcus, proteus mirabilis, Yin Diindyl positive proteus etc. has antibacterial action.Also there is good effect to anaerobic bacteria.Such as peptococcus, peptostreptococcus, fusiform Bacillus, bacteroid (including bacteroides fragilis).Most bacterial strains of Pseudomonas aeruginosa, enterococcus and bacillus cloacae are unwise to this product Sense.Eliminate t1/2For 0.7~1h, about 85% drug with prototype in 6h by homaluria.Clinical practice is in sensitive Gram-negative The site infections such as lower respiratory tract, urogenital system, abdominal cavity, bone and joint, skin and soft tissue caused by the anaerobic bacteria of bacterium, Available for septicemia.This product has antagonism with most cephalosporins, and compatible use can cause antibacterial action to weaken.
C16H16N3NaO7S2The existing challenge of pharmaceutical entities composition is C16H16N3NaO7S2It is more quick to environmental factor Sense generates the impurity such as related substance after placing for a long time.These impurity are to lead to C16H16N3NaO7S2Pharmaceutical entities composition draws The anaphylactogen of type Ⅰ hypersensitivity reaction is sent out, the safety so as to use drug generates harmful effect, especially in pediatric drugs Problem is particularly acute.
Chinese patent application CN201510280540.4 discloses a kind of children and uses C16H16N3NaO7S2Powder ampoule agent for injection. The pharmaceutical entities composition improves C by freezing means16H16N3NaO7S2Solubility of the middle organic impurities in extractant, So as to reduce impurity content.However, said medicine combination of entities object still cannot solve C16H16N3NaO7S2Long time stored With after placement by contaminant problem caused by environmental factor.
On the other hand, in recent years, newtype drug group of entities is made by various means in many fat-soluble or water soluble drug Close object, including speed controlled release, directionality controlled release, timeliness controlled release and with disease regulate and control Personalized Drug Administration system.Wherein, liposome It is one of most commonly used novel dosage forms of research.It was verified that environmental sensitivity effect of the liposome for improvement various kinds of drug Significantly.However, using most of method for preparing lipidosome, the envelop rate of water-soluble drug liposome is significantly lower than fat-soluble medicine Object.Because water soluble drug Determination of oil-water partition coefficient is very big by such environmental effects, it is difficult control to lead to encapsulating；Meanwhile it is encapsulating In the process, water soluble drug is distributed in the interior outer aqueous phase of liposome simultaneously, and the volume of outer aqueous phase is typically larger than inner aqueous phase, is formed Ideal envelop rate is extremely difficult to after liposome.In addition, water soluble drug it is liposomal encapsulated after, can in outer aqueous phase and interior water It re-matches in phase, oil phase, is leaked so as to cause water soluble drug.
Chinese patent application CN201010592642.7 discloses a kind of C16H16N3NaO7S2Lipidosome freeze-dried preparation and system Preparation Method, by by C16H16N3NaO7S2, stabilizer, excipient mixes with the blank membrane material of middle lecithin, cholesterol, surpasses Through constant volume, degerming, packing after sonication, it is freeze-dried, obtains C16H16N3NaO7S2Lipidosome freeze-dried preparation.It however, should The lipidosome freeze-dried preparation broad particle distribution that method obtains, while grain size is larger, also needs further to lead to when as injection Cross filtering with microporous membrane.Meanwhile the liposome uses sodium chloride to cause sodium content higher as stabilizer.In addition, this method is adopted With film hydration method, cause envelop rate not high, while easily generate leakage.
Therefore, as water soluble drug, by C16H16N3NaO7S2The challenge that liposome is made still is how to improve it Envelop rate reduces its slip, while preferably Control granularity is distributed.In addition, can made liposome solve C16H16N3NaO7S2Long time stored and generated contaminant problem and whether can after being acted on by environmental factor after placing It is also a unknown number as pediatric pharmaceuticals object combination of entities object.
Invention content
One of the object of the invention be overcome the deficiencies of the prior art and provide that a kind of envelop rate is higher, slip is relatively low and The smaller and uniform novel children of particle diameter distribution use C16H16N3NaO7S2Pharmaceutical entities composition.
The two of the object of the invention, which are to provide, a kind of prepares above-mentioned C16H16N3NaO7S2The method of pharmaceutical entities composition.The system Preparation Method is simple and practicable, reproducible.
To achieve the above object, on the one hand, the present invention provides a kind of novel children to use C16H16N3NaO7S2Pharmaceutical entities Composition, raw material include the hydrogenated soy phosphatidyl choline and cholesterol and C as film forming matter16H16N3NaO7S2, feature exists In, the raw material further includes the D- glucopyranose amides as film forming matter stabilizer,
Wherein, group R is C8-C22 fatty acid residues.
C according to the present invention16H16N3NaO7S2Pharmaceutical entities composition, the aliphatic acid are selected from straight chain or branched Unrighted acid；It can be single fat acid, or fatty acid mixed.Those skilled in the art could be aware that, D- pyrroles Glucopyranoside amide can include α types, β types or its mixture.The residue refers to all bases of the aliphatic acid in addition to COOH Group.Aliphatic acid example includes but not limited to, coconut oil, oleic acid, linoleic acid.Advantageously, the aliphatic acid is the unsaturation of straight chain C12-C22 aliphatic acid.Preferably, the aliphatic acid is selected from the unsaturated C14-C22 aliphatic acid of straight chain；It is highly preferred that the fat Fat acid is selected from the unsaturated C16-C22 aliphatic acid of straight chain；And most preferably, the aliphatic acid is selected from the unsaturation of straight chain C18-C22 aliphatic acid.
In one preferred embodiment, the aliphatic acid is selected from oleic acid, i.e., described D- glucopyranoses amide is selected from N- (β-D- glucopyranoses) oleamide, molecular weight 423, the compound can use side well-known to those skilled in the art Method synthesizes.For example, the synthetic method that U.S. Patent application document US2006/0160248 A1 are recorded：First by D- glucopyranoses Amidized D- glucopyranoses are obtained by the reaction with excessive ammonium hydrogen carbonate；Then crude product is obtained with required fatty acid response；Slightly Product crosses silica gel column purification and obtains final product.Final product is by repeatedly purity is more than 98% after purification.
C according to the present invention16H16N3NaO7S2Pharmaceutical entities composition, the D- glucopyranoses amide and hydrogenation The molar ratio of soybean lecithin and cholesterol total amount is (1.5-9.5): 100.Preferably, the D- glucopyranoses amide and hydrogen The molar ratio for changing soybean lecithin and cholesterol total amount is (2.5-8.5): 100；It is highly preferred that the D- glucopyranoses amide It is (3.5-7.5) with the molar ratio of hydrogenated soy phosphatidyl choline and cholesterol total amount: 100；And most preferably, the D- pyrans Glucose amide is (4.5-6.5) with the molar ratio of hydrogenated soy phosphatidyl choline and cholesterol total amount: 100.
In one preferred embodiment, the D- glucopyranoses amide and hydrogenated soy phosphatidyl choline and cholesterol are total The molar ratio of amount is 5.4: 100.That is, for based on every 100 moles of hydrogenated soy phosphatidyl choline and cholesterol total amount, D- The molal quantity of glucopyranose amide is 5.4.
C according to the present invention16H16N3NaO7S2Pharmaceutical entities composition, the entitled 1- palm fibres of hydrogenated soy phosphatidyl choline chemistry Palmitic acid acyl group -2- stearyl lecithin, abbreviation HSPC, No. CAS is 92128-87-5, molecular weight 784, and purity 99% is purchased from Shanghai Advanced viecle Technology Co., Ltd..HSPC phase transition temperatures are high, and human tolerance is more preferable than soybean lecithin；But HSPC Molecular rigidity is big, it is difficult to independently form stable bimolecular lipid membrane.In invented liposomes, cholesterol and HSPC are added Together as into membrane lipid, so as to adjust the mobility of bimolecular lipid membrane.Cholesterol CAS is 57-88-5, molecular weight It is 387, purity 99%, purchased from Selleck Chinese companies.
C according to the present invention16H16N3NaO7S2Pharmaceutical entities composition, the hydrogenated soy phosphatidyl choline and cholesterol Molar ratio be well known to those skilled in the art.Advantageously, the molar ratio of the hydrogenated soy phosphatidyl choline and cholesterol is 5: 1 To 1: 1.Preferably, the molar ratio of the hydrogenated soy phosphatidyl choline and cholesterol is 4: 1 to 1: 1.It is highly preferred that the hydrogenation The molar ratio of soybean lecithin and cholesterol is 3: 1 to 1: 1.And most preferably, the hydrogenated soy phosphatidyl choline and cholesterol Molar ratio be 2: 1 to 1: 1.
In one preferred embodiment, the molar ratio of the hydrogenated soy phosphatidyl choline and cholesterol is 1.6: 1.Also It is to say, the mass ratio of the hydrogenated soy phosphatidyl choline and cholesterol is 3.5: 1.0.
C according to the present invention16H16N3NaO7S2Pharmaceutical entities composition, the C16H16N3NaO7S2With hydrogenated soybean The molar ratio of lecithin and cholesterol total amount is (1.5-6.0): 100.Preferably, the C16H16N3NaO7S2With hydrogenated soybean ovum The molar ratio of phosphatide and cholesterol total amount is (2.0-5.0): 100；It is highly preferred that the C16H16N3NaO7S2With hydrogenated soybean ovum The molar ratio of phosphatide and cholesterol total amount is (2.5-4.5): 100；And most preferably, the C16H16N3NaO7S2With hydrogenation The molar ratio of soybean lecithin and cholesterol total amount is (3.0-4.0): 100.
In one preferred embodiment, the C16H16N3NaO7S2With hydrogenated soy phosphatidyl choline and cholesterol total amount Molar ratio is 3.4: 100.That is, for based on every 100 moles of hydrogenated soy phosphatidyl choline and cholesterol total amount, C16H16N3NaO7S2Molal quantity be 3.4.
On the other hand, the present invention also provides prepare above-mentioned C16H16N3NaO7S2The method of pharmaceutical entities composition, it is described Method includes the following steps：
I) D- as the hydrogenated soy phosphatidyl choline and cholesterol of film forming matter and as film forming matter stabilizer is weighed Glucopyranose amide dissolves said mixture with organic solvent；
Ii it) is added in thereto comprising C16H16N3NaO7S2Aqueous vehicles, ultrasound make mixed system become homogeneous system；
Iii it) is evaporated under reduced pressure and removes organic solvent until forming gel, add in aqueous vehicles and carry out hydration reaction, Ran Houji It is continuous to be evaporated under reduced pressure 5-30 minutes；
Iv it) is stood after ultrasound, obtains above-mentioned C16H16N3NaO7S2Pharmaceutical entities composition.
Method according to the present invention, the organic solvent are selected from ether, chloroform, ethyl alcohol, methanol or its mixture.It is excellent Selection of land, the organic solvent are selected from ether, chloroform, ethyl alcohol or its mixture；It is highly preferred that the organic solvent be selected from ether, Chloroform or its mixture；And most preferably, the organic solvent is selected from ether or the mixture of ether and chloroform.
In one preferred embodiment, the organic solvent is selected from ether.
The volume ratio of method according to the present invention, the organic solvent and aqueous vehicles total amount is 2: 1 to 12: 1.It is excellent The volume ratio of selection of land, the organic solvent and aqueous vehicles total amount is 2: 1 to 10: 1；It is highly preferred that the organic solvent and water The volume ratio for changing medium total amount is 3: 1 to 8: 1；And most preferably, the organic solvent and the volume ratio of aqueous vehicles total amount It is 3: 1 to 6: 1.
In one preferred embodiment, the volume ratio of the organic solvent and aqueous vehicles total amount is 3: 1.
Method according to the present invention, the aqueous vehicles are selected from the acidic buffer that pH value is 4.5-7.0.It is preferred that Ground, the aqueous vehicles are selected from the acidic buffer that pH value is 5.0-7.0；It is highly preferred that the aqueous vehicles are selected from pH value The acidic buffer of 5.5-7.0；And most preferably, the aqueous vehicles are selected from the acidic buffer that pH value is 5.5-6.5.
In one preferred embodiment, the aqueous vehicles are selected from the PBS buffer solution that pH value is 6.0.
Method according to the present invention, the hydration reaction condition are：Temperature is 20-50 DEG C, hydration time 1-5h. Preferably, the hydration reaction condition is：Temperature is 20-40 DEG C, hydration time 1.5-4.5h；It is highly preferred that the aquation Reaction condition is：Temperature is 20-35 DEG C, hydration time 2-4h；And most preferably, the hydration reaction condition is：Temperature It is 20-30 DEG C, hydration time 2-3h.
In one preferred embodiment, the hydration reaction condition is：Temperature is 25 DEG C, hydration time 2h.
Method according to the present invention, the static conditions are：Temperature is 4-30 DEG C, time 1-24h.Preferably, The static conditions are：Temperature is 4-20 DEG C, time 1-8h；It is highly preferred that the static conditions are：Temperature is 4-15 DEG C, Time is 1-6h；And most preferably, the static conditions are：Temperature is 4-10 DEG C, time 1-4h.
In one preferred embodiment, the static conditions are：Temperature is 4 DEG C, time 2h.
Another aspect, the present invention also provides include above-mentioned C16H16N3NaO7S2The preparation of pharmaceutical entities composition, it is described Preparation is aseptic powder injection preparation.
Inventor has found, as the D- that certain content is added in the hydrogenated soy phosphatidyl choline and cholesterol as film forming matter When glucopyranose amide is as stabilizer, C is not only significantly improved16H16N3NaO7S2The envelop rate of drug, reduces simultaneously Slip after placing for a long time.
Any theory is not intended to limited to, D- glucopyranoses amide itself used in the present invention is lived with parents surface Property property.Both include the hydrophobic long-chain of lipophilic in molecular structure, may be inserted into the interior oil phase of liposome；Further include hydrophilic Portugal Grape glycosyl is stretched in the inner aqueous phase of liposome；Simultaneously the amide group in molecule under mildly acidic conditions with C16H16N3NaO7S2 β-lactam structure segment generate synergistic effect, substantially improve the phenomenon of osmosis of drug, it is unexpected so as to achieve Effect.In addition, with reference to preparation method used in the present invention, the particle diameter distribution in prepared drug suspension is smaller and equal It is even；Generated impurity content is still within allowed band after being acted on after long time stored and placement by environmental factor.
Compared with prior art, the present invention has following advantageous effects：
I) C of the invention16H16N3NaO7S2Not only envelop rate is higher and slip is relatively low, while grain for pharmaceutical entities composition Diameter distribution is smaller and uniform, can largely meet industry demand.
Ii) C of the invention16H16N3NaO7S2Pharmaceutical entities composition is made after long time stored and placement by environmental factor With rear generated related content of material still within allowed band；Therefore a kind of novel children are promised to be to use C16H16N3NaO7S2Pharmaceutical entities composition.
Iii) preparation method of the present invention is simple and practicable, reproducible, while without other auxiliary materials；Equipment cost is low and without dirt Dye；It can have a tremendous social and economic benefits, popularity is suitble to use.
Specific embodiment
Embodiment 1：
It weighs as the hydrogenated soy phosphatidyl choline 3.5g and cholesterol 1.0g of film forming matter and stablizes as film forming matter N- (β-D- glucopyranoses) oleamide 0.163g of agent, by said mixture 90mL ether dissolutions；It adds in and includes thereto 0.110 gC16H16N3NaO7S220mL pH value be 6.0 PBS buffer solution, ultrasound make mixed system become homogeneous system；Subtract Evaporating organic solvent is pressed until forming gel, the PBS buffer solution that 10mL pH value is 6.0 is added in and carries out hydration reaction, temperature It is 25 DEG C, hydration time 2h；It then proceedes to be evaporated under reduced pressure 15 minutes；2h is stood under the conditions of being 4 DEG C in temperature after ultrasound, is obtained Above-mentioned C16H16N3NaO7S2Pharmaceutical entities composition.
Embodiment 2：
It weighs as the hydrogenated soy phosphatidyl choline 3.5g and cholesterol 1.0g of film forming matter and stablizes as film forming matter N- (β-D- glucopyranoses) oleamide 0.136g of agent, by said mixture 90mL ether dissolutions；It adds in and includes thereto 0.110 gC16H16N3NaO7S225mL pH value be 6.0 PBS buffer solution, ultrasound make mixed system become homogeneous system；Subtract Evaporating organic solvent is pressed until forming gel, the PBS buffer solution that 5mL pH value is 6.0 is added in and carries out hydration reaction, temperature It is 25 DEG C, hydration time 2h；It then proceedes to be evaporated under reduced pressure 15 minutes；1h is stood under the conditions of being 4 DEG C in temperature after ultrasound, is obtained Above-mentioned C16H16N3NaO7S2Pharmaceutical entities composition.
Embodiment 3：
It weighs as the hydrogenated soy phosphatidyl choline 3.5g and cholesterol 1.0g of film forming matter and stablizes as film forming matter N- (β-D- glucopyranoses) oleamide 0.196g of agent, by said mixture 90mL ether dissolutions；It adds in and includes thereto 0.110 gC16H16N3NaO7S215mL pH value be 6.0 PBS buffer solution, ultrasound make mixed system become homogeneous system；Subtract Evaporating organic solvent is pressed until forming gel, the PBS buffer solution that 15mL pH value is 6.0 is added in and carries out hydration reaction, temperature It is 25 DEG C, hydration time 3h；It then proceedes to be evaporated under reduced pressure 15 minutes；4h is stood under the conditions of being 4 DEG C in temperature after ultrasound, is obtained Above-mentioned C16H16N3NaO7S2Pharmaceutical entities composition.
Comparative example 1：
N- (β-D- glucopyranoses) oleamide as film forming matter stabilizer is added without, remaining condition is the same as embodiment 1.
Comparative example 2：
N- (β-D- glucopyranoses) oleamide of embodiment 1 is replaced with into 0.30g by 0.163g, remaining condition is the same as implementation Example 1.
Comparative example 3：
N- (β-D- glucopyranoses) oleamide of embodiment 1 is replaced with into 0.14g lauryl glucosyls (No. CAS For 110615-47-9, molecular weight 348, purity 99%, purchased from Yangzhou Shi Kai Chemical Industry Science Co., Ltd), remaining condition With embodiment 1.
Application Example 1-3 and application comparative example 1-3
Embodiment 1-3 and comparative example 1-3 is subjected to following test.
Envelop rate is tested：By the liposome medicament combination of entities object and blank liposome of embodiment 1-3 and comparative example 1-3 point It is not diluted to reasonable multiple；Using Sephadex-G50 sephadex columns (1.6cm × 25cm)；Applied sample amount 0.5mL；Gradient is washed De- condition：PH=6.5PBS solution elutes, elution speed 1.0mLmin-1；Detach free drug and liposome.HPLC side Method measures the concentration of free drug, so as to calculate packaging medicine and the respective weight of free drug.It calculates according to the following formula Envelop rate：Envelop rate=(drug total amount-free drug weight)/drug total amount × 100%.
Leakage rate is tested：By storing n-th day envelop rate under the conditions of the 0th day envelop rate of measurement and 4 DEG C, according to the following formula It calculates：Leakage rate=(- the n-th day envelop rate of the 0th day envelop rate)/the 0th day envelop rate × 100%.
Grain size is tested：It is carried out using laser particle size analyzer.
The liposome medicament combination of entities object of Example 1-3 and comparative example 1-3 adds in appropriate solvent demulsification, then dilute It releases to suitable multiple, related content of material is measured according to the test method of Chinese Pharmacopoeia second the 250-251 pages of version in 2015.
Shown in the following Tables 1 and 2 of dependence test result：
The 0th day property indices of table 1
The 10th day property indices of table 2
As it can be seen from table 1 comparative example 1 and 3 is to be added without N- (β-D- glucopyranoses) oleamides and addition ten respectively The situation of dialkyl group glucoside, from the point of view of envelop rate, the envelop rate of 1-3 of the embodiment of the present invention is significantly higher than both；This hair D- glucopyranoses amide has the amide group in parents' surface-active property and molecule used in bright, thus with C16H16N3NaO7S2Synergistic effect is generated, substantially improves the phenomenon of osmosis of drug.With reference to average grain diameter as can be seen that the present invention Used D- glucopyranoses amide, towards consistently organically combining, is omited with film forming matter so as to cause average grain diameter There is increase, while also improve the permeability of the outer oil phase of duplicature, and then improve envelop rate.But if add in excessive D- pyrroles Glucopyranoside amide, from comparative example 2 as can be seen that the outer oil phase of liposome is unstable instead, envelop rate can be remarkably decreased.This Outside, the particle diameter distribution in pharmaceutical entities composition of the present invention is more uniform, is predominantly located between 100-200nm.In addition, related object Matter content meets national standard.
From table 2 it can be seen that after being stored the 10th day under the conditions of 4 DEG C, each embodiment and the combination of comparative example pharmaceutical entities There is different degrees of decline in the envelop rate of object；However, compared with comparative example 1-3,1-3 pharmaceutical entities groups of the embodiment of the present invention The slip for closing object is respectively less than 15%, and comparative example 1-3 then declines by a big margin.Meanwhile for comparative example 1-3, this Average grain diameter and the related content of material increasing degree for inventing each embodiment pharmaceutical entities composition are smaller.
It has been recognised by the inventors that this is because D- glucopyranoses amide itself used in the present invention has parents' surface-active Property and specific amide group, at the same with film forming matter and C16H16N3NaO7S2Synergistic effect is generated, substantially improves medicine The phenomenon of osmosis of object, so as to achieve unexpected effect.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, that is made any repaiies Change, equivalent replacement, improvement etc., be all contained within protection scope of the present invention.

Claims (2)

1. a kind of children are with 3- carbamyls yloxymethyl -7- methoxyl group -8- oxos -7- (2- thiophenacetyls amido) -5- sulphur -1- The pharmaceutical entities composition of miscellaneous bicyclic (4.2.0) oct-2-ene -2- formic acid sodium salts of nitrogen, raw material include the hydrogenation as film forming matter Soybean lecithin and cholesterol and 3- carbamyl yloxymethyl -7- methoxyl group -8- oxos -7- (2- thiophenacetyls amido) - Bicyclic (4.2.0) oct-2-ene -2- formic acid sodium salts of the miscellaneous nitrogen of 5- sulphur -1-, which is characterized in that the raw material is further included as film forming matter The D- glucopyranose amides of matter stabilizer,
Wherein, group R is C8-C22 fatty acid residues；
The D- glucopyranoses amide is (1.5-9.5) with the molar ratio of hydrogenated soy phosphatidyl choline and cholesterol total amount: 100；
The molar ratio of the hydrogenated soy phosphatidyl choline and cholesterol is 5: 1 to 1: 1；
3- carbamyls yloxymethyl -7- methoxyl group -8- oxos -7- (2- thiophenacetyls the amido) -5- sulphur -1- is miscellaneous, and nitrogen is bicyclic (4.2.0) oct-2-ene -2- formic acid sodium salt is (1.5-6.0) with the molar ratio of hydrogenated soy phosphatidyl choline and cholesterol total amount: 100；
The pharmaceutical entities composition is prepared by following method, and the method includes the following steps：
I) hydrogenated soy phosphatidyl choline and cholesterol as film forming matter and the D- pyrans as film forming matter stabilizer are weighed Glucose amide dissolves said mixture with organic solvent；
Ii it) is added in thereto comprising 3- carbamyls yloxymethyl -7- methoxyl group -8- oxos -7- (2- thiophenacetyls amido) -5- The aqueous vehicles of bicyclic (4.2.0) oct-2-ene -2- formic acid sodium salts of the miscellaneous nitrogen of sulphur -1-, ultrasound make mixed system become homogeneous system；
Iii it) is evaporated under reduced pressure and removes organic solvent until forming gel, add in aqueous vehicles and carry out hydration reaction, then proceed to subtract Pressure evaporation 5-30 minutes；
Iv it) is stood after ultrasound, obtains above-mentioned 3- carbamyls yloxymethyl -7- methoxyl group -8- oxos -7- (2- thiophenacetyl amine Base) bicyclic (4.2.0) oct-2-ene -2- formic acid sodium salts of the miscellaneous nitrogen of -5- sulphur -1- pharmaceutical entities composition；
Wherein, the organic solvent is selected from ether；
The volume ratio of the organic solvent and aqueous vehicles total amount is 3: 1 to 6: 1；
The hydration reaction condition is：Temperature is 20-30 DEG C, hydration time 2-3h；
The static conditions are：Temperature is 4-10 DEG C, time 1-4h；
Wherein, the C8-C22 aliphatic acid is selected from oleic acid.
2. one kind includes 3- carbamyls yloxymethyl -7- methoxyl group -8- oxos -7- (2- thiophenacetyl amine described in claim 1 Base) bicyclic (4.2.0) oct-2-ene -2- formic acid sodium salts of the miscellaneous nitrogen of -5- sulphur -1- pharmaceutical entities composition preparation, feature exists In the preparation is aseptic powder injection preparation.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102716082A (en) * 2012-06-29 2012-10-10 海南灵康制药有限公司 Cefoxitin sodium liposome injection

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102716082A (en) * 2012-06-29 2012-10-10 海南灵康制药有限公司 Cefoxitin sodium liposome injection

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