CN107693491B - Pharmaceutical composition and preparation for children - Google Patents

Pharmaceutical composition and preparation for children Download PDF

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Publication number
CN107693491B
CN107693491B CN201710257005.6A CN201710257005A CN107693491B CN 107693491 B CN107693491 B CN 107693491B CN 201710257005 A CN201710257005 A CN 201710257005A CN 107693491 B CN107693491 B CN 107693491B
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cholesterol
nao
cyanomethylthio
methyltetrazol
thiomethyl
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CN107693491A (en
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朱旭伟
李秋荣
黄嘉玲
应鹏
黄奕睿
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Hainan guangshengyu Pharmaceutical Co.,Ltd.
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Guangdong Jincheng Jinsu Pharmacy Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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

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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
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Abstract

The invention discloses a medicine for children C15H16N7NaO5S3Pharmaceutical compositions and formulations. The raw materials include hydrogenated soybean lecithin and cholesterol as film-forming substances, and C15H16N7NaO5S3The raw material also comprises D-glucopyranosamide as a film forming substance stabilizer.

Description

Pharmaceutical composition and preparation for children
Technical Field
The invention belongs to the field of medicine; relates to a15H16N7NaO5S3Pharmaceutical entity composition, in particular a novel pediatric C15H16N7NaO5S3Pharmaceutical compositions and formulations.
Background
C15H16N7NaO5S3The chemical name is: (6R,7S) -7- [ [2- (cyanomethylthio) acetyl ] methyl]Amino group]-7-methoxy-3- [ (1-methyltetrazol-5-yl) thiomethyl]-8-oxo-5-thia-1-azabicyclo [4.2.0]Oct-2-ene-2-formic acid sodium salt, molecule 493.5, belongs to β -lactam cephalosporin, which is a semi-synthetic antimicrobial drug for parenteral application, introduced into the clinic in Japan, and a large number of animals and clinical studies are also carried out in the United states and other countries15H16N7NaO5S3Raw material and injection C15H16N7NaO5S3Both have been collected in the second part of the chinese pharmacopoeias 2010 edition and 2015 edition. The product is white to yellowish powder or crystalline powder, and is easily soluble in water.
C15H16N7NaO5S3Is the second generation cephalosporin with wide gram negative, positive and anaerobic bacteria resisting effect. It is composed ofThe product has strong antibacterial effect on staphylococcus and other gram-positive bacteria, has good effect on escherichia coli, pneumonia bacillus and proteus mirabilis, has drug resistance on pseudomonas and acinetobacter, is stable to β -lactamase (including penicillin and cephalosporin resistant enzyme), is used for intravenous injection of 1g to healthy people, has a blood concentration of 188 micrograms/ml in 10 minutes, has a1 hour intravenous injection period of 76 micrograms/ml after 1g is finished, has a 6 hour blood concentration of 1.9 micrograms/ml and a 2.7 micrograms/ml t1/2 about 1 hour, has a high concentration in bile, is hardly metabolized in vivo, has 85 to 90 percent of prototype drugs discharged from urine within 6 hours, and has a very high urine concentration.
C15H16N7NaO5S3The challenge presented by pharmaceutical entity compositions lies in C15H16N7NaO5S3Sensitive to environmental factors, easy to generate chemical reaction under the action of light and heat, and generate related substances, cefmetazole polymer and other impurities after being placed for a long time. These impurities are those resulting in C15H16N7NaO5S3The pharmaceutical entity composition causes allergens with immediate-type allergic reactions, which adversely affect the safety of the pharmaceutical use, especially in pediatric applications.
Chinese patent application CN201010100852.X discloses a C15H16N7NaO5S3，C15H16N7NaO5S3Purifying the compound through acid-base reaction, macroporous resin and activated carbon adsorption; however, C15H16N7NaO5S3The total yield is reduced, and simultaneously, after the cefmetazole is absorbed by the macroporous resin, a large amount of solvent is used for elution, the post-treatment is complex, and the production is greatly increasedCost of
Chinese patent application CN20151028029.2 discloses a C for children15H16N7NaO5S3Powder for injection. The pharmaceutical composition has improved C content by freezing15H16N7NaO5S3The solubility of the organic impurities in the extractant reduces the impurity content. However, the above pharmaceutical entity compositions still do not solve C15H16N7NaO5S3Impurities generated by environmental factors after long-term storage and standing.
On the other hand, in recent years, many fat-soluble or water-soluble drugs have been made into novel pharmaceutical entity compositions by various means, including rate-controlled release, directional controlled release, time-controlled release, and symptomatically regulated personalized drug delivery systems. Among them, liposomes are one of the most widely studied novel dosage forms. Practice proves that the liposome has obvious effect on improving the environmental sensitivity of various medicaments. However, with most liposome preparation methods, the encapsulation efficiency of water-soluble drug liposomes is significantly lower than that of fat-soluble drugs. The oil-water distribution coefficient of the water-soluble medicine is greatly influenced by environmental factors, so that the encapsulation is difficult to control; meanwhile, in the encapsulating process, the water-soluble medicine is simultaneously distributed in the internal and external water phases of the liposome, and the volume of the external water phase is usually larger than that of the internal water phase, so that the ideal encapsulating rate is difficult to achieve after the liposome is formed. In addition, the liposome of the water-soluble drug is encapsulated and then reconstituted in the external aqueous phase and the internal aqueous and oil phases, thereby causing the water-soluble drug to leak.
Chinese patent application CN201110026258.5 discloses a C15H16N7NaO5S3A freeze-dried liposome preparation is prepared from cefoxitin sodium, stabilizer, excipient and liposome carrier through mixing, ultrasonic treating, metering volume, sterilizing, packing and freeze drying to obtain C15H16N7NaO5S3A liposome lyophilized preparation. However, the liposomes use sodium chloride as a stabilizer, resulting in a high sodium content. In addition, the method adopts a thin film hydration methodThis results in a low encapsulation efficiency and a high tendency to leak.
Thus, as a water-soluble drug, C15H16N7NaO5S3The challenge of making liposomes is still how to increase their encapsulation efficiency, reduce their leakage rate, and at the same time better control the particle size distribution. In addition, the prepared liposome can solve C15H16N7NaO5S3The problems of impurities after prolonged storage and exposure to environmental factors and the possibility of using them as pediatric pharmaceutical entity compositions are unknown. No discovery of C15H16N7NaO5S3The literature reports the preparation of liposomes.
Disclosure of Invention
One of the objectives of the present invention is to overcome the disadvantages of the prior art and to provide a novel pediatric C with high encapsulation efficiency, low leakage rate, and small and uniform particle size distribution15H16N7NaO5S3A pharmaceutical entity composition.
Another object of the present invention is to provide a process for preparing the above-mentioned compound C15H16N7NaO5S3Methods of pharmaceutical entity compositions. The preparation method is simple and easy to implement and has good repeatability.
In order to achieve the above objects, in one aspect, the present invention provides a novel pediatric C15H16N7NaO5S3Pharmaceutical composition of matter consisting essentially of hydrogenated soy lecithin and cholesterol as film forming material, and C15H16N7NaO5S3Characterized in that the raw material also comprises D-glucopyranosamide as a film forming substance stabilizer,
Figure BSA0000143502260000021
wherein, the group R is C8-C22 fatty acid residue.
C according to the invention15H16N7NaO5S3The fatty acids include, but are not limited to, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, isopalmitic acid, stearic acid, isostearic acid, behenic acid, cocoic acid, oleic acid, linoleic acid, advantageously the fatty acids are linear, saturated C8-C22 fatty acids, preferably the fatty acids are selected from linear, saturated C8-C18 fatty acids, more preferably the fatty acids are selected from linear, saturated C7-C16 fatty acids, and, most preferably, the fatty acids are selected from linear, saturated C8-C14 fatty acids.
In a preferred embodiment, the fatty acid is selected from N-heptanoic acid, i.e., the D-glucopyranosamide is selected from N- (β -D-glucopyranose) octanoamide, CAS number 134403-86-4, molecular weight 329, purity greater than 98%, available from Calbose chemical technology, Inc. (Suzhou.) in another preferred embodiment, the fatty acid is selected from N-decanoic acid, i.e., the D-glucopyranosamide is selected from N- (β -D-glucopyranose) decanoamide, molecular weight 329, purity greater than 98%.
In addition to the commercially available route, other D-glucopyranosamides of the invention can be synthesized using methods well known to those skilled in the art. In some specific embodiments, the present invention utilizes the synthetic method described in U.S. patent application publication No. US2006/0160248A 1: firstly, reacting D-glucopyranose with excessive ammonium bicarbonate to obtain aminated D-glucopyranose; then reacting with the required fatty acid to obtain a crude product; the crude product was purified by silica gel column to obtain the final product. The purity of the final product is more than 98% after multiple purifications.
C according to the invention15H16N7NaO5S3A pharmaceutical entity composition, said D-glucopyranosamide being present in a molar ratio to the total amount of hydrogenated soy lecithin and cholesterol of (3).0-9.0: 100. Preferably, the molar ratio of the D-glucopyranosamide to the total amount of hydrogenated soy lecithin and cholesterol is (4.0-8.0) to 100; more preferably, the molar ratio of the D-glucopyranosamide to the total amount of hydrogenated soy lecithin and cholesterol is (4.5-7.5) to 100; and, most preferably, the molar ratio of the D-glucopyranosamide to the total amount of hydrogenated soy lecithin and cholesterol is (5.0-7.0): 100.
In a preferred embodiment, the molar ratio of the D-glucopyranosamide to the total amount of hydrogenated soy lecithin and cholesterol is 5.8: 100. That is, the number of moles of D-glucopyranosamide per 100 moles of the total amount of hydrogenated soybean lecithin and cholesterol was 5.8.
C according to the invention15H16N7NaO5S3The pharmaceutical composition of the solid substance is hydrogenated soybean lecithin with chemical name of 1-palmitoyl-2-stearoyl lecithin, short for HSPC, CAS number of 92128-87-5, molecular weight of 784 and purity of 99 percent, and is purchased from Shanghai Eviret pharmaceutical science and technology Limited. The HSPC has high phase transition temperature, and the human body tolerance is better than that of soybean lecithin; however, HSPC molecules are rigid and difficult to form stable lipid bilayer membranes alone. In the liposome of the present invention, cholesterol is added as a membrane-forming lipid together with HSPC, so that the fluidity of a lipid bilayer membrane can be adjusted. Cholesterol CAS number 57-88-5, molecular weight 387, purity 99%, available from Selleck, China.
C according to the invention15H16N7NaO5S3Pharmaceutical entity compositions, the molar ratio of hydrogenated soy lecithin to cholesterol being well known to the person skilled in the art. Advantageously, the molar ratio of hydrogenated soy lecithin to cholesterol is from 5: 1 to 1: 1. Preferably, the molar ratio of hydrogenated soy lecithin to cholesterol is from 4: 1 to 1: 1. More preferably, the molar ratio of hydrogenated soy lecithin to cholesterol is from 3:1 to 1: 1. And, most preferably, the molar ratio of hydrogenated soy lecithin to cholesterol is from 2: 1 to 1: 1.
In a preferred embodiment, the molar ratio of hydrogenated soy lecithin to cholesterol is 1.3: 1. That is, the mass ratio of the hydrogenated soybean lecithin to cholesterol was 2.67: 1.
C according to the invention15H16N7NaO5S3Pharmaceutical entity composition, said C15H16N7NaO5S3The mol ratio of the hydrogenated soybean lecithin to the total amount of the cholesterol is (2.0-6.0) to 100. Preferably, said C15H16N7NaO5S3The mol ratio of the hydrogenated soybean lecithin to the total amount of the cholesterol is (2.5-5.5) to 100; more preferably, C is15H16N7NaO5S3The mol ratio of the hydrogenated soybean lecithin to the total amount of the cholesterol is (3.0-5.0) to 100; and, most preferably, said C15H16N7NaO5S3The mol ratio of the hydrogenated soybean lecithin to the total amount of the cholesterol is (3.5-4.5) to 100.
In a preferred embodiment, said C15H16N7NaO5S3The molar ratio to the total amount of hydrogenated soybean lecithin and cholesterol was 4.1: 100. That is, C is based on the total amount of hydrogenated soybean lecithin and cholesterol per 100 moles15H16N7NaO5S3The number of moles of (a) is 4.1.
In another aspect, the invention also provides a method for preparing C15H16N7NaO5S3A method of pharmaceutical entity composition, said method comprising the steps of:
i) weighing hydrogenated soybean lecithin and cholesterol as film forming substances and D-glucopyranosamide as a film forming substance stabilizer, and dissolving the mixture with an organic solvent;
ii) adding thereto a catalyst comprising C15H16N7NaO5S3The mixed system becomes a homogeneous system by ultrasonic treatment;
iii) evaporating under reduced pressure to remove the organic solvent until gel is formed, adding a hydration medium to carry out hydration reaction, and then continuing to evaporate under reduced pressure for 5-30 minutes;
iv) standing after ultrasonication to obtain the above C15H16N7NaO5S3A pharmaceutical entity composition.
According to the method of the present invention, the organic solvent is selected from ether, chloroform, ethanol, methanol or a mixture thereof. Preferably, the organic solvent is selected from diethyl ether, chloroform, ethanol or a mixture thereof; more preferably, the organic solvent is selected from diethyl ether, chloroform or a mixture thereof; and, most preferably, the organic solvent is selected from diethyl ether or a mixture of diethyl ether and chloroform.
In a preferred embodiment, the organic solvent is selected from a 3:1 mixture of diethyl ether/chloroform.
According to the method of the invention, the volume ratio of the organic solvent to the total amount of the hydration medium is 2: 1 to 12: 1. Preferably, the volume ratio of the organic solvent to the total amount of the hydration medium is 2: 1 to 10: 1; more preferably, the volume ratio of the organic solvent to the total amount of the hydration medium is from 3:1 to 8: 1; and most preferably the volume ratio of the organic solvent to the total amount of hydration medium is from 3:1 to 6: 1.
In a preferred embodiment, the volume ratio of the organic solvent to the total amount of hydration medium is 5: 1.
According to the method of the invention, the hydration medium is selected from acidic buffers with a pH value of 4.5-7.0. Preferably, the hydration medium is selected from an acidic buffer having a pH value of 5.0-7.0; more preferably, the hydration medium is selected from an acidic buffer having a pH value of 5.5-7.0; and most preferably, the hydration medium is selected from an acidic buffer having a pH of 5.5-6.5.
In a preferred embodiment, the hydration medium is selected from PBS buffer at pH 6.0.
According to the method, the hydration reaction conditions are as follows: the temperature is 20-50 ℃, and the hydration time is 1-5 h. Preferably, the hydration reaction conditions are: the temperature is 20-40 ℃, and the hydration time is 1.5-4.5 h; more preferably, the hydration reaction conditions are: the temperature is 20-35 ℃, and the hydration time is 2-4 h; and, most preferably, the hydration reaction conditions are: the temperature is 20-30 ℃, and the hydration time is 2-3 h.
In a preferred embodiment, the hydration reaction conditions are: the temperature is 25 ℃, and the hydration time is 2 h.
According to the method of the invention, the standing conditions are as follows: the temperature is 4-30 ℃ and the time is 1-24 h. Preferably, the standing conditions are: the temperature is 4-20 ℃, and the time is 1-8 h; more preferably, the resting conditions are: the temperature is 4-15 ℃, and the time is 1-6 h; and, most preferably, the resting conditions are: the temperature is 4-10 ℃ and the time is 1-4 h.
In a preferred embodiment, the resting conditions are: the temperature was 4 ℃ and the time was 2 h.
In yet another aspect, the present invention also provides a composition comprising C as described above15H16N7NaO5S3A preparation of the pharmaceutical entity composition, which is a sterile powder injection preparation.
The inventors found that when a specific content of D-glucopyranosamide is added as a stabilizer to hydrogenated soybean lecithin and cholesterol as a film-forming substance, not only C is significantly increased15H16N7NaO5S3The encapsulation rate of the medicine is reduced, and the leakage rate after long-time placement is reduced.
Without wishing to be bound by any theory, the D-glucopyranosamides used according to the invention have amphiphilic surface-active properties themselves. The molecular structure comprises a lipophilic hydrophobic long chain which can be inserted into the inner oil phase of the liposome; also comprises hydrophilic glucose group extending to the inner water phase of the liposome; simultaneously, amide groups in molecules react with C under the weak acidic condition15H16N7NaO5S3In addition, the preparation method adopted by the invention is combined, the particle size distribution of the prepared medicine suspension is small and uniform, and the content of impurities generated after the medicine suspension is stored for a long time and placed under the action of environmental factors is still in an allowable rangeInside the enclosure.
Compared with the prior art, the invention has the following beneficial technical effects:
i) c of the invention15H16N7NaO5S3The medicinal entity composition has high encapsulation efficiency and low leakage rate, and simultaneously has small and uniform particle size distribution, and can meet the industrial requirements to a large extent.
ii) C of the invention15H16N7NaO5S3The content of related substances generated after the medicinal entity composition is subjected to the action of environmental factors after being stored and placed for a long time is still within an allowable range; therefore, the compound is hopeful to become a novel pediatric C15H16N7NaO5S3A pharmaceutical entity composition.
iii) the preparation method is simple and easy to implement, has good repeatability, and does not need other auxiliary materials; the equipment cost is low and no pollution is caused; can generate huge social benefit and economic benefit, and is suitable for being widely popularized and used.
Detailed Description
Example 1:
3.2g of hydrogenated soybean lecithin and 1.2g of cholesterol as film-forming substances and 0.155g of N- (β -D-glucopyranosyl) octanamide as a stabilizer for the film-forming substances were weighed, the above mixture was dissolved in 100mL of a mixture of diethyl ether/chloroform in a ratio of 3:1, and a solution containing 0.145g of C was added thereto15H16N7NaO5S315mL of PBS buffer solution with the pH value of 6.0, and performing ultrasonic treatment to enable the mixed system to become a homogeneous system; evaporating under reduced pressure to remove organic solvent until gel is formed, adding 5mL PBS buffer solution with pH value of 6.0 for hydration reaction at 25 deg.C for 2 h; then continuing to evaporate under reduced pressure for 15 minutes; standing at 4 deg.C for 2 hr after ultrasonic treatment to obtain the product C15H16N7NaO5S3A pharmaceutical entity composition.
Example 2:
3.2g of hydrogenated soybean lecithin and 1.2g of cholesterol were weighed as film-forming substances, and N- (β -D-glucopyranose) capramide 0.167g, and the mixture is dissolved by 100mL of a mixture of ether/chloroform 3: 1; adding into a reactor containing 0.145gC15H16N7NaO5S315mL of PBS buffer solution with the pH value of 6.0, and performing ultrasonic treatment to enable the mixed system to become a homogeneous system; evaporating under reduced pressure to remove organic solvent until gel is formed, adding 5mL PBS buffer solution with pH value of 6.0 for hydration reaction at 25 deg.C for 2 h; then continuing to evaporate under reduced pressure for 15 minutes; standing at 4 deg.C for 2 hr after ultrasonic treatment to obtain the product C15H16N7NaO5S3A pharmaceutical entity composition.
Example 3:
3.2g of hydrogenated soybean lecithin and 1.2g of cholesterol as film-forming substances and 0.144g of N- (β -D-glucopyranose) decanamide as a stabilizer for the film-forming substances were weighed, the above mixture was dissolved with 100mL of a mixture of diethyl ether/chloroform in a ratio of 3:1, and a solution containing 0.145g of C was added thereto15H16N7NaO5S3The mixed system becomes a homogeneous system by ultrasonic treatment with PBS buffer solution with the pH value of 8 mL6.0; evaporating under reduced pressure to remove organic solvent until gel is formed, adding 7mL of PBS buffer solution with pH value of 6.0 for hydration reaction at 25 deg.C for 2 h; then continuing to evaporate under reduced pressure for 15 minutes; standing at 4 deg.C for 2 hr after ultrasonic treatment to obtain the product C15H16N7NaO5S3A pharmaceutical entity composition.
Example 4:
3.2g of hydrogenated soybean lecithin and 1.2g of cholesterol as film-forming substances and 0.201g of N- (β -D-glucopyranose) decanamide as a stabilizer for the film-forming substances were weighed, the above mixture was dissolved with 100mL of a mixture of diethyl ether/chloroform in a ratio of 3:1, and a solution containing 0.145g of C was added thereto15H16N7NaO5S311mL of PBS buffer solution with the pH value of 6.0, and performing ultrasonic treatment to enable the mixed system to become a homogeneous system; evaporating under reduced pressure to remove organic solvent until gel is formed, adding 4mL PBS buffer solution with pH value of 6.0 for hydration reaction at 25 deg.C for 2 h; then continuing to reduce the pressureEvaporating for 15 minutes; standing at 4 deg.C for 2 hr after ultrasonic treatment to obtain the product C15H16N7NaO5S3A pharmaceutical entity composition.
Example 5:
3.2g of hydrogenated soybean lecithin and 1.2g of cholesterol as film-forming substances and 0.151g of N- (β -D-glucopyranosyl) myristamide as a stabilizer for the film-forming substances were weighed, the above mixture was dissolved in 100mL of a mixture of diethyl ether/chloroform in a ratio of 3:1, and a solution containing 0.145g of C was added thereto15H16N7NaO5S315mL of PBS buffer solution with the pH value of 6.0, and performing ultrasonic treatment to enable the mixed system to become a homogeneous system; evaporating under reduced pressure to remove organic solvent until gel is formed, adding 5mL PBS buffer solution with pH value of 6.0 for hydration reaction at 25 deg.C for 2 h; then continuing to evaporate under reduced pressure for 15 minutes; standing at 4 deg.C for 2 hr after ultrasonic treatment to obtain the product C15H16N7NaO5S3A pharmaceutical entity composition.
Comparative example 1:
the same procedure as in example 2 was repeated except that N- (β -D-glucopyranose) capramide was not added as a stabilizer for the film-forming substance.
Comparative example 2:
the same procedure as in example 2 was repeated except that N- (β -D-glucopyranose) capramide in example 2 was changed from 0.167g to 0.28 g.
Comparative example 3:
the procedure is as in example 2 except that the N- (β -D-glucopyranose) decanoamide from example 2 is replaced with 0.175g of dodecyl glucoside (CAS No. 110615-47-9, molecular weight 348, purity 99%, available from Scheka chemical technology Co., Ltd. of Yangzhou).
Application examples 1 to 5 and application comparative examples 1 to 3
Examples 1 to 5 and comparative examples 1 to 3 were subjected to the following tests.
Encapsulation efficiency test the liposomal pharmaceutical entity compositions of examples 1-5 and comparative examples 1-3 and the blank liposomes were diluted to reasonable fold, respectively, using Sephadex-G50 Sephadex column (1.2cm × 22cm), loading 0.5 mL; gradient elution conditions: eluting with 6.0 pH PBS solution at 2.0 mL/min-1The encapsulation efficiency was calculated according to the following formula, encapsulation efficiency (total amount of drug-free drug weight)/total amount of drug × 100%.
Leakage rate test by measuring the encapsulation rate on day 0 and the encapsulation rate on day n at 4 ℃ stored, the leakage rate was calculated according to the following formula (encapsulation rate on day 0-encapsulation rate on day n)/encapsulation rate on day 0 of × 100%.
And (3) particle size testing: the method is carried out by adopting a laser particle size analyzer.
The liposome pharmaceutical entity compositions of examples 1-5 and comparative examples 1-3 were taken, added with appropriate amount of solvent to demulsify, and then diluted to appropriate times, and the content of related substances was determined according to the test method of the second part of the Chinese pharmacopoeia 2015, page 280-282.
The results of the relevant tests are shown in tables 1 and 2 below:
TABLE 1 Performance index at day 0
Figure BSA0000143502260000061
TABLE 2 Performance index at day 10
Figure BSA0000143502260000071
As can be seen from Table 1, in comparative examples 1 and 3, in which N- (β -D-glucopyranose) decanamide was not added and dodecyl glucoside was added, respectively, the encapsulation efficiency of examples 1 to 5 of the present invention was significantly higher than that of the two in terms of encapsulation efficiency, and D-glucopyranosamide used in the present invention had amphiphilic surface active properties and amide groups in the molecule to react with C15H16N7NaO5S3Produces synergistic effect and greatly improves the penetration phenomenon of the medicine. As can be seen from the combination of the average particle diameters, the D-glucopyranosamide used in the present invention is organically bonded in the same direction as the film-forming substanceTogether, the average particle size is slightly increased, and the permeability of the oil phase outside the double-layer film is improved, so that the encapsulation efficiency is improved. However, if too much D-glucopyranosamide is added, the liposome becomes unstable in the external oil phase and the encapsulation efficiency is remarkably lowered as seen in comparative example 2. In addition, the particle size distribution of the drug substance composition of the present invention is relatively uniform, mainly located between 100 and 250 nm. In addition, the content of related substances meets the national standard.
As can be seen from Table 2, the encapsulation efficiency of the pharmaceutical entity compositions of each of the examples and comparative examples showed a different decrease after 10 days of storage at 4 ℃; however, the leakage rates of the pharmaceutical entity compositions of examples 1-6 of the present invention were all less than 15% compared to those of comparative examples 1-3, while the decrease rates of comparative examples 1-3 were much smaller. Meanwhile, the average particle size and the content of related substances of the pharmaceutical entity composition of each example of the present invention are increased to a smaller extent than those of comparative examples 1 to 3.
The inventors believe that this is because the D-glucopyranosamide used in the present invention has amphiphilic surface active properties and a specific amide group, and is compatible with the film-forming substance and C15H16N7NaO5S3Produces synergistic effect and greatly improves the permeation phenomenon of the medicine, thereby obtaining unexpected effect.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention shall fall within the protection scope of the present invention.

Claims (3)

1. A pharmaceutical composition of (6R,7S) -7- [ [2- (cyanomethylthio) acetyl ] amino ] -7-methoxy-3- [ (1-methyltetrazol-5-yl) thiomethyl ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid sodium salt for children, which comprises hydrogenated soybean lecithin and cholesterol as film-forming substances, and (6R,7S) -7- [ [2- (cyanomethylthio) acetyl ] amino ] -7-methoxy-3- [ (1-methyltetrazol-5-yl) thiomethyl ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid sodium salt, characterized in that the raw materials also comprise D-glucopyranosamide as a film forming substance stabilizer,
Figure FDA0002400986810000011
wherein the group R is a linear saturated C8-C14 fatty acid residue;
the molar ratio of the D-glucopyranosamide to the total amount of the hydrogenated soybean lecithin and the cholesterol is (3.0-9.0) to 100;
the molar ratio of the hydrogenated soybean lecithin to the cholesterol is 5: 1 to 1: 1;
the molar ratio of the (6R,7S) -7- [ [2- (cyanomethylthio) acetyl ] amino ] -7-methoxy-3- [ (1-methyltetrazol-5-yl) thiomethyl ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid sodium salt to the total amount of hydrogenated soy lecithin and cholesterol is (2.0-6.0): 100;
the pharmaceutical entity composition is prepared by a process comprising the steps of:
i) weighing hydrogenated soybean lecithin and cholesterol as film forming substances and D-glucopyranosamide as a film forming substance stabilizer, and dissolving the mixture with an organic solvent;
ii) adding thereto an aqueous medium comprising the sodium salt of (6R,7S) -7- [ [2- (cyanomethylthio) acetyl ] amino ] -7-methoxy-3- [ (1-methyltetrazol-5-yl) thiomethyl ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, and sonicating to bring the mixed system to a homogeneous system;
iii) evaporating under reduced pressure to remove the organic solvent until gel is formed, adding a hydration medium to carry out hydration reaction, and then continuing to evaporate under reduced pressure for 5-30 minutes;
iv) standing after ultrasonic treatment to obtain the pharmaceutical entity composition of the sodium salt of the (6R,7S) -7- [ [2- (cyanomethylthio) acetyl ] amino ] -7-methoxy-3- [ (1-methyltetrazol-5-yl) thiomethyl ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid;
the organic solvent is selected from a mixture of diethyl ether/chloroform 3: 1;
the volume ratio of the organic solvent to the total amount of the hydration medium is 3:1 to 6: 1;
the hydration medium is selected from an acidic buffer solution with the pH value of 5.5-6.5.
2. The pharmaceutical entity composition of sodium (6R,7S) -7- [ [2- (cyanomethylthio) acetyl ] amino ] -7-methoxy-3- [ (1-methyltetrazol-5-yl) thiomethyl ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate of claim 1 wherein said fatty acid is selected from n-decanoic acid.
3. A formulation comprising a pharmaceutical entity composition of the sodium salt of (6R,7S) -7- [ [2- (cyanomethylthio) acetyl ] amino ] -7-methoxy-3- [ (1-methyltetrazol-5-yl) thiomethyl ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid as claimed in claim 1 or 2, wherein said formulation is in the form of a sterile powder injection.
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