CN1317314A - Kelamycin injection and its preparing process - Google Patents

Abstract

A Kelamycin injection, a macrolide antibiotic, contains kelamycin as active components, cosolvent, chelating agent, plasma developer, stabilizer, antioxidizing agent, solutino osmotic pressure regulator and pH regulator, and features that the micro-molecular kelamycin is wrapped by macro-molecular polyvinyl pyrrolidone and poloxamer to generate "molecular capsules". Its advantages include no irritation, high solubility and stability.

Description

Kelamycin injection and preparation method

The present invention relates to antibiotic medicine preparation and preparation method, especially relate to macrolide antibiotics injection and preparation method thereof.

Clarithromycin is new 14-membered ring macrolides antibiotic, and clarithromycin is by combining the synthetic antibacterial action that produces of Profilin matter with 50S subunit on the 70S nucleoprotein of antibacterial.Except that the solid preparation dosage form is arranged, also develop multiple dosage forms such as injection both at home and abroad, adopt the number of ways administration more can bring into play the drug action of clarithromycin.

The clarithromycin of external injection has lyophilized preparation and two kinds of dosage forms of emulsifying agent a few days ago: (1) injection clarithromycin lyophilized preparation; At first with clarithromycin and sour salify, through lyophilization, dried frozen aquatic products, before the use again dissolved dilution in 250ml aseptic normal saline or 5% G/W, intravenous drip, this lyophilized preparation complicated process of preparation is used inconvenient; There is 60% above case to produce phlebitis after this lyophilized preparation intravenous drip of external report approximately; Domestic pharmaceutical factory develops the lyophilized preparation of producing, and phlebitis also takes place during intravenous drip, and phlebitis is brought hard to bear misery to patient.(2) clarithromycin vein emulsion; This vein emulsion has overcome the shortcoming of lyophilized preparation, and patient produces phlebitic problem when having solved intravenous drip substantially, but the lecithin materials that this Emulsion adopts costs an arm and a leg making Emulsion cost height.

The objective of the invention is to research and develop out a kind of prescription and preparation method of new preparation Kelamycin injection, patient does not produce phlebitis during this injection intravenous drip, alleviates patient's the painful production cost that can reduce injection simultaneously of medical treatment.

The objective of the invention is to be achieved through the following technical solutions.

We adopt the polyvinylpyrrolidone (plasma substitute) (molecular weight 5000-70000) of nonirritant macromolecule, and poloxamer (molecular weight 7000-10000) comprises the clathrate that micromolecular clarithromycin (molecular weight 747.96) forms " molecular capsule ".Clarithromycin is a macrolide antibiotics, has fat-soluble characteristics, is insoluble in water, and its dissolubility is about 1: 1000, and the difficulty for preparing this injection is very big; As pH value injection instability on the low side, 40 ℃ the time, clarithromycin just separates out as the higher then injection of pH value behind the clarithromycin salify; We are by screening, prescriptions such as a large amount of cosolvents, stabilizing agent, chelating agen, antioxidant, pH regulator agent, osmotic pressure regulators, finally develop qualified clarithromycin transfusion, through 120 ℃ of sterilizations 30 minutes, the each side index all meets the requirements, pH5.5-7.0, osmotic pressure is at 280-310mosm normal range.

The invention provides the effective way that solves an above difficult problem, through pharmacology aspect Kelamycin injection toxicity test, pharmacodynamics test, hemolytic test, local excitation test, tests such as Kelamycin injection systemic allergy test, pyrogen all meet the requirements.

The in-vitro antibacterial test of Kelamycin injection shows: clarithromycin in-vitro antibacterial spectrum is similar with other macrolide antibiotics such as erythromycin, and gram-positive bacterium is had strong bacteriostasis.MIC to staphylococcus aureus ₅₀Be 0.06mg/L; To micrococcus scarlatinae, streptococcus pneumoniae, enterococcal MIC ₅₀, MIC ₉₀Be respectively 0.03,0.06mg/L; 0.015,0.5mg/L; 0.06,16mg/L; Stronger 2 times than erythromycin.MIC to bloodthirsty hemophilus influenza ₅₀Be 2mg/L, to the MIC of bacteroides fragilis ₅₀Be 0.5mg/L.In vivo test shows that Kelamycin injection is stronger 6.3 times and 10.2 times than erythromycin to the interior curative effect that mice staphylococcus aureus, micrococcus scarlatinae infect, ED ₅₀Be respectively 10.3mg/kg and 5.4mg/kg.

Kelamycin injection is lower to the acute toxicity of mice, and the Kelamycin injection of intravenous injection Cmax there is no animal dead.LD ₅₀Greater than 127mg/kg.

Haemolysis, the irritation test of Kelamycin injection show that rabbit auricular vein every day is injected the Kelamycin injection 5ml that concentration is 5mg/ml, continuous three times, and no obvious stimulation reaction; The Kelamycin injection 2ml of quadriceps femoris injection 5mg/ml does not also have the obvious stimulation reaction, shows that the local excitation test of this medicine is up to specification.Every Kelamycin injection 0.5ml that intramuscular injection concentration is 5mg/ml next day of Cavia porcellus, totally 3 times.Respectively at attacking in the 14th day and the 21st day after the injection first, symptoms of allergic does not all appear in the result, shows that this medicine hypersensitive test is qualified.

Kelamycin injection has the following advantages:

(1) this injection preparation technology is easy, and cost of material is low;

(2) dosage is little so toxic and side effects is little, nonirritant problem during use;

(3) can directly enter tissue or blood vessel, absorb soon, effect is rapid, human bioavailability 100%;

(4) no anaphylaxis need not to do the human body hypersensitive test, and can race against time in time gives emergency treatment to a patient.

The present invention is described in further detail below in conjunction with embodiment:

The preparation of embodiment Kelamycin injection

1, the prescription of Kelamycin injection

Clarithromycin 0.1-1.0g

1,2-propylene glycol 3-50ml

Polyvinylpyrrolidone 1-15g

Calcium disodium chelate salt 0.02-0.5g

Sodium pyrosulfite 0.01-0.2g

Poloxamer 3-5.5g

Nicotiamide 1.0-15g

L-cysteine hydrochloride 0.01-0.5g

Hydrochloric acid is an amount of

Sodium chloride is an amount of

Sodium hydroxide is an amount of

Distilled water is to 100ml

2, the preparation process of Kelamycin injection

Recipe quantity clarithromycin, 1,2-propylene glycol, polyvinylpyrrolidone, poloxamer and L-cysteine hydrochloride mixing, add an amount of distilled water, stir extremely dissolving of dripping hydrochloric acid down, add sodium pyrosulfite and nicotiamide, after waiting to dissolve, add sodium chloride and regulate osmotic pressure (being about 280-310mosm) in right amount, adding distil water is to 100ml (regulating pH value with sodium hydroxide is 5.5-7.0), added the proper amount of active carbon agitating heating 15 minutes, filtered while hot, 120 ℃ of autoclavings of subsequent filtrate 30 minutes are promptly.

Test example 1 Kelamycin injection heat stabilization test

40 ℃ of heat stabilization tests of Kelamycin injection (transfusion)

Lot number	Time (my god)	Color (yellow reference colour level pipe)	Clarity	PH value	Assay
							(u/ml) tires	Labelled amount (%)
					????990301	????0			≤ No. 2	Qualified	6.55	????5080	????100.0
????1	No. 2	Qualified	6.50	????4917			????96.8
						????3		No. 2	Qualified	6.42	????4828	????95.0
????5	No. 2	Qualified	6.39	????5047			????99.4
						????10		No. 2	Qualified	6.36	????4895	????96.4

60 ℃ of heat stabilization tests of Kelamycin injection (transfusion)

Lot number	Time (my god)	Color (yellow reference colour level pipe)	Clarity	PH value	Assay
							(u/ml) tires	Labelled amount (%)
					????990301	????0			≤ No. 2	Qualified	6.55	????5080	????100.0
????1	No. 2	Qualified	6.40	????5063			????99.7
						????3		No. 2	Qualified	6.24	????4928	????97.0
????5	No. 2	Qualified	6.20	????4869			????95.8
						????10		No. 3	Qualified	6.01	????4765	????93.8

80 ℃ of heat stabilization tests of Kelamycin injection (transfusion)

Lot number	Time (my god)	Color (yellow reference colour level pipe)	Clarity	PH value	Assay
							(u/ml) tires	Labelled amount (%)
					????990301	????0			≤ No. 2	Qualified	6.55	????5080	????100.0
????1	No. 2	Qualified	6.25	????4811			????94.7
						????3		No. 5	Qualified	5.85	????3981	????78.4
????5	No. 7	Qualified	5.59	????3094			????60.9
						????10		No. 9	Qualified	5.26	????2209	????43.5

The test of test example 2 Kelamycin injection light durabilities

Lot number	Time (my god)	Color (yellow reference colour level pipe)	Clarity	PH value	Assay
							(u/ml) tires	Labelled amount (%)
					????99030	????0			≤ No. 2	Qualified	6.55	????5080	????100.0
????1	≤ No. 2	Qualified	6.49	????4996			????98.3
								No. 2	Qualified	6.40	????4811	????94.7
????5	No. 2	Qualified	6.38	????4919			????96.8
						????10		No. 2	Qualified	6.34	????5027	????99.0

Test example 3 Kelamycin injection accelerated tests

40 ℃ of 75%RH accelerated tests of Kelamycin injection (transfusion)

Lot number	Time (moon)	Color (yellow reference colour level pipe)	Clarity	PH value	Assay
							(u/ml) tires	Labelled amount (%)
					????990301	????0			≤ No. 2	Qualified	6.55	????5080	????100.0
????1	No. 2	Qualified	6.32	????5056			????99.5
						????2		〉=No. 2	Qualified	6.17	????4942	????97.3
????3	No. 3	Qualified	6.05	????4813			????94.7
						????990302		????0	≤ No. 2	Qualified	6.95	????5038	????100.0
????1	No. 2	Qualified	6.68	????5028	????99.8
							????2	〉=No. 2	Qualified	6.47	????4986	????99.0
????3	No. 3	Qualified	6.34	????4830	????95.9
							????990303	????0	≤ No. 2	Qualified	6.20	????5101	????100.0
????1	No. 2	Qualified	6.00	????5068	????99.4
						????2		No. 3	Qualified	5.86	????4986	????97.7
????3	No. 4	Qualified	5.76	????4718	????92.5

Test example 4 Kelamycin injection long term tests

25 ℃ of 58%RH long term tests of Kelamycin injection (transfusion)

Lot number	Time (moon)	Color (yellow reference colour level pipe)	Clarity	PH value	Assay
							(u/ml) tires	Labelled amount (%)
					990301	????0			≤ No. 2	Qualified	6.55	????5080	????100.0
????3	≤ No. 2	Qualified	6.42	????5085			????100.1
						????6		No. 2	Qualified	6.28	????4964	????97.7
????9	≤ No. 2	Qualified	6.18	????4944			????97.3
						?990302		????0	≤ No. 2	Qualified	6.95	????5038	????100.0
	≤ No. 2	Qualified	6.80	????4985	????98.9
							????6	No. 2	Qualified	6.64	????5000	????99.2
????9	No. 2	Qualified	6.51	????5023	????99.7
							?990303	????0	≤ No. 2	Qualified	6.20	????5101	????100.0
????3	≤ No. 2	Qualified	6.08	????5080	????99.6
						????6		No. 2	Qualified	5.95	????4985	????97.7
????9	No. 2	Qualified	5.86	????5000	????98.0

Test example 5 local excitations test

1, test material

(1) animal: rabbit, the male and female dual-purpose, 2.0-2.5kg is available from Sichuan laboratory animal administration commission test site.The quality certification number: the real moving pipe 99-14 in river.

(2) experimental animal: test under this with hemolytic.

2, experimental technique

(1) tame rabbit ear edge vascular stimulation test

According to " Chinese medicine development guideline (tentative; in April, 1993) ", get 3 of healthy rabbits, inject the Kelamycin injection 5.0ml that concentration is 5mg/ml in the edge vein of picking up the ears with sterile working's method every day, opposite side is injected the isometric(al) normal saline, continuous three times, rabbit is put to death in 24 hours after having annotated medicinal liquid, dissect animal blood vessels and do the pathology section, observation has or not significant stimulation reactions such as metaplasia or necrosis.

(2) rabbit quadriceps femoris irritant test

Get 3 of healthy rabbits, sentence the Kelamycin injection 2ml that sterile working's method implantation concentration is 5mg/ml in the side quadriceps femoris of every rabbit, the opposite side corresponding site is used with method and is injected the 2ml sterile saline in contrast.In having injected medicinal liquid sacrificed by exsanguination rabbit after 48 hours, dissect the back and take out quadriceps femoris, vertically cut, observe the irritant reaction of injection site muscle, by general " injection irritant reaction standards of grading " judged result.

3, experimental result:

(1) tame rabbit ear edge vascular stimulation test

Rabbit auricular vein every day is injected the Kelamycin injection 5ml of 5mg/ml, and continuous three times, injection site blood vessel perusal there is no obvious hyperemia or the existing edge of edema, also significant stimulation reaction such as inorganization degeneration or necrosis of pathology section examination after 24 hours.

(2) rabbit quadriceps femoris irritant test

Rabbit quadriceps femoris injection concentration is behind the Kelamycin injection 2ml of 5mg/ml 48 hours, does not see the obvious stimulation reaction, and the reaction score value is 0.Show that injection 5mg/ml Kelamycin injection does not have the obvious stimulation effect to the rabbit quadriceps femoris.

Claims (8)

1, a kind of Kelamycin injection contains active component clarithromycin and cosolvent, chelating agen, blood plasma expansion agent, stabilizing agent and antioxidant, solution osmotic pressure regulator, pH regulator agent.

2, Kelamycin injection as claimed in claim 1, its cosolvent can be Macrogol 200, Liquid Macrogol, PEG400, tween 80,1,2-propylene glycol, glycerol, polyvinylpyrrolidone; Be preferably 1, the 2-propylene glycol.

3, Kelamycin injection as claimed in claim 1, its chelating agen (chelating agent) can be disodium EDTA, calcium disodium chelate salt, polyvinylpyrrolidone; Disodium EDTA has the effect of cosolvent and antioxidant synergist, the effect that polyvinylpyrrolidone has cosolvent, dispersant simultaneously simultaneously.

4, Kelamycin injection as claimed in claim 1, its stabilizing agent and solubilizing agent can be L-cysteine hydrochloride, poloxamer, nicotiamide.

5, Kelamycin injection as claimed in claim 1, its antioxidant can be sodium sulfite, sodium sulfite, ascorbic acid, thiourea, sodium pyrosulfite, L-cysteine hydrochloride, is preferably sodium pyrosulfite, L-cysteine hydrochloride.

6, Kelamycin injection as claimed in claim 1, its pH regulator agent can be ascorbic acid, succinic acid, phosphate buffer, L-cysteine hydrochloride, pH4-5 acetate buffer, citric acid, hydrochloric acid, succinic acid, maleic acid, lactic acid, sodium hydroxide.Be preferably hydrochloric acid and sodium hydroxide.

7, a kind of preparation method of Kelamycin injection, with active component clarithromycin 0.1-1.0g and 1,2-propylene glycol 3-50ml, polyvinylpyrrolidone 1-15g, calcium disodium chelate salt 0.02-0.5g, poloxamer 3-5.5g, L-cysteine hydrochloride 0.01-0.5g stirs extremely dissolving of dripping hydrochloric acid down, add sodium pyrosulfite 0.01-0.2g, after nicotiamide 1.0-15g waits to dissolve, add sodium chloride and regulate osmotic pressure (being about 280-310mosm) in right amount, adding distil water is to 100ml, regulate pH value in right amount with sodium hydroxide, added the proper amount of active carbon agitating heating 15 minutes, filtered while hot, 120 ℃ of autoclavings of subsequent filtrate 30 minutes are promptly; The Kelamycin injection of making (transfusion) is yellowish clear liquid.

8, the preparation method of Kelamycin injection as claimed in claim 5, its pH value is adjusted between the 5.5-7.0.