CN101697973B

CN101697973B - Cefathiamidine preparation for injection and preparation method thereof

Info

Publication number: CN101697973B
Application number: CN2009102724651A
Authority: CN
Inventors: 吴秋萍
Original assignee: Individual
Current assignee: Individual
Priority date: 2009-10-20
Filing date: 2009-10-20
Publication date: 2011-07-20
Anticipated expiration: 2029-10-20
Also published as: CN101697973A

Abstract

The invention discloses a cefathiamidine preparation for injection, comprising cefathiamidine containing active ingredients and stable cosolvent L-arginine. The invention has the preferred scheme that gram molecular ratio of cefathiamidine containing active ingredients to L-arginine is 1:0.1-2.0. L-arginine is adopted to replace anhydrous sodium carbonate or sulphur-containing amino acid to serve as cefathiamidine stabilizing agent and cosolvent and achieves the effects that cefathiamidine has high solubility, better clarity and color and stable chemical property. The invention also discloses a preparation method of the cefathiamidine preparation for injection.

Description

A kind of cefathiamidine preparation for injection and preparation method thereof

Technical field

The present invention relates to a kind of cefathiamidine novel formulation of injectable administration, particularly relate to the cefathiamidine preparation for injection that contains new stable cosolvent, the invention still further relates to the preparation method of this cefathiamidine preparation for injection.

Background technology

Cefathiamidine is the cephalo-type semisynthetic antibiotics of China Baiyunshan Pharmaceutics Stock-sharing Co., Ltd., Guangzhou City research and development, has good antibacterial effect, in listing in 1994, be used for the caused respiratory system of sensitive organism, liver and gall, face, urinary tract infection and endocarditis, septicemia.

Baiyunshan Pharmaceutics Stock-sharing Co., Ltd., Guangzhou City etc. have tens patents of cefathiamidine.The lyophilized formulations of patent 03129662.9 wherein, adjuvant is support, antioxidant (vitamin c, carbon dioxide, nitrogen).Patent 03146824.1 is lyophilizing crude drug or powder pin, and lyophilized formulations does not add any adjuvant.Patent 200410035759.X solves is dissolvent residual problem in the lyophilizing raw material.Patent 200410102451.2 is to add L-cysteine, sodium sulfite, vitamin c or sodium thiosulfate antioxidant in injection cefathiamidine powder pin, and what sulphite brought body is not the good curing effect.Patent 200810001191.8 has been reported the freeze-dried powder of cefathiamidine, does not add any adjuvant, and prescription is theoretical good.And more widely used prescription is the aseptic subpackaged cefathiamidine preparation that does not add any adjuvant.

Above-mentioned patent, the cefathiamidine preparation of known technology and bibliographical information be in various degree existence deficiency all, brings potential risk for the clinical practice of this product.We know that cephalo-type antibiotics all has chemically active free amino and/or free carboxy, is unstable factor.Chemical change can take place and produce other chemical compounds in the cefathiamidine preparation placement for a long time that does not add any adjuvant, may produce comparatively serious adverse clinically.The antioxidant that adds carbon dioxide, nitrogen, L-cysteine, sodium sulfite or sodium thiosulfate then can bring body unpredictable injury, and the non-body endogenous material of vitamin c should not be used without exception.

Summary of the invention

The purpose of this invention is to provide a kind of shortcoming that overcomes the poor stability of existing cefathiamidine preparation for injection existence, and a kind of cefathiamidine preparation for injection is provided, make novel formulation can reach the regulation of state-promulgated pharmacopoeia easily.

Another object of the present invention provides the preparation method of this cefathiamidine preparation for injection.

The present invention adopts body endogenous essential amino acid L-arginine as stabilizing agent, is beneficial to the chemically stable of cefathiamidine, and help solubilization.

The objective of the invention is to reach by following measure: a kind of cefathiamidine preparation for injection is characterized in that it comprises and contains active component cefathiamidine and stable cosolvent L-arginine.

In technique scheme, described active component cefathiamidine and the arginic mole ratio of L-are 1: 0.1-2.0.

In technique scheme, described active component cefathiamidine and the arginic mole ratio of L-are 1: 0.5.

The preparation method of cefathiamidine preparation for injection is characterized in that the cefathiamidine aseptic powder of described mistake 60 mesh sieves and the L-arginine after aseptic process mix evenly; Mixed-powder is sub-packed in the cillin bottle behind the sterilization, jumps a queue immediately and seal with aluminium-plastic cap.

The inventor adopts the stable cosolvent of L-arginine as cefathiamidine, has accomplished to make cefathiamidine dissolubility height, and clarity and color and luster all meet the injecting drug use of National Drug Administration forces standard.

The inventor is mixed in proportion aseptic cefathiamidine and stable cosolvent L-arginine and carries out dissolubility and stability test: 1 gram (pure) cefathiamidine and L-arginine are 1: 0.1 to 1: 2.0 by mole ratio, preferable mole ratio is to mix at 1: 0.5, uses water for injection 2-5 milliliter just can make cefathiamidine mix powder and dissolves fully.

Adopting mole ratio is under 1: 0.5 the L-arginine proportioning, after 1 gram (pure) cefathiamidine adds 10 milliliters of water for injection dissolvings, pH value further with the 250 milliliters of dilutions of normal saline of this solution, dissolves pH value decline 0.20-0.30 simultaneously between 7.00-9.00; Or with 250 milliliters of dilutions of 5% glucose injection, the also corresponding decline 0.20-0.30 of pH value.The related substance amount minimum of cefathiamidine.

Cefathiamidine preparation of the present invention shows that advantage is as follows owing to adopt the L-arginine to make cosolvent:

1) during L-arginine used as stabilizers, cefathiamidine preparation equal conditions is placed catabolite still less down;

When 2) the L-arginine was made cosolvent, the cefathiamidine preparation was easier to dissolving, only needed slight vibrations that cefathiamidine is dissolved fully;

3) because the L-arginine itself is the aminoacid of needed by human, adopt the L-arginine as stable cosolvent, both can play and well must stablize the hydrotropy effect, can play aminoacid as the effect in the clinical nutrition supporting treatment simultaneously.

The specific embodiment

Describe performance of the present invention in detail below in conjunction with embodiment, but they do not constitute the qualification to the present invention's protection, simultaneously by illustrating that advantage of the present invention will become clear more and understanding easily.

Embodiment 1 (stability test of injection cefathiamidine)

The inventor is mixed in proportion cefathiamidine and L-arginine and carries out solubility test: 1 gram (pure) cefathiamidine and L-arginine were by mole ratio 1: 0.1 to 1: 2.0, mix, placed 6 months for 40 ± 2 ℃, preferable mole ratio is the related substance amount minimum of cefathiamidine in 1: 0.5 the mixed powder.

The stability of table 1 cefathiamidine

L-arginine (g/1g cefathiamidine)	Appearance character	Clarity	Related substance (%)
				0	White powder	Up to specification	1.96
0.1	White powder	Up to specification	1.53
				0.2	White powder	Up to specification	1.24
0.5	White powder	Up to specification	0.84
				1.0	White powder	Up to specification	0.89
1.8	White powder	Up to specification	0.92
				2.0	White powder	Up to specification	0.95

2.3

White powder

Up to specification

0.97

Embodiment 2 (dissolubility test of injection cefathiamidine)

The inventor is mixed in proportion cefathiamidine and L-arginine and carries out solubility test: 1 gram (pure) cefathiamidine and L-arginine were by mole ratio 1: 0.1 to 1: 2.0, preferable mole ratio is to mix at 1: 0.3, uses 2～5 milliliters of waters for injection can make cefathiamidine mix powder and dissolves fully.

The dissolubility test of table 2 cefathiamidine

L-arginine (g/1g cefathiamidine)	Appearance character	Dissolve water (ml) fully
			0	White powder	6.7
0.1	White powder	4.8
			0.2	White powder	3.1
0.5	White powder	2.0
			1.0	White powder	2.5
1.8	White powder	3.8
			2.0	White powder	4.6
2.3	White powder	5.9

Embodiment 3 (injection cefathiamidine preparation method)

1, the prescription of injection cefathiamidine

Cefathiamidine (pure) 1.00g

L-arginine 0.50g

2, the preparation of injection cefathiamidine

Cefathiamidine aseptic powder and the L-arginine aseptic powder of crossing 60 mesh sieves are taken by weighing the back mix homogeneously by formula ratio; Middle product are sub-packed in mixed-powder in the cillin bottle after aseptic process after the assay was approved, and the cillin bottle after the packing is jumped a queue immediately and sealed with aluminium-plastic cap.

Test example 4 (injection cefathiamidine and the test of L-arginine room temperature stability)

Cefathiamidine 10g and L-arginine 5g mix, and in 25 ℃ of placements, investigate its stability.Through investigating one-year age, this preparation stabilization.

The compatibility test of table 3 cefathiamidine 10g and L-arginine 5g

Standing time (moon)	Appearance character	Related substance
			0	White powder	0.76

2	White powder	0.78
			4	White powder	0.78
8	White powder	0.81
			1.2	White powder	0.82

Test example 5 (the injection cefathiamidine is dissolved in room temperature stability test in the water for injection)

[cefathiamidine 1g (pure) adds L-arginine 0.5g one solution that water for injection 10ml makes of drawing and preserves down in room temperature (25 ℃) the injection cefathiamidine, investigates its steadiness.Result of the test shows, solution at room temperature, and is stable in 5 hours.

Table 4 injection cefathiamidine is dissolved in room temperature stability test in the water for injection

Standing time (hour)	Appearance character	Related substance
			0	Clear liquid	0.76
1	Clear liquid	0.78
			2	Clear liquid	0.81
3	Clear liquid	0.88
			4	Clear liquid	0.95
5	Clear liquid	0.97
			6	Clear liquid	1.12

Test example 6 (the injection cefathiamidine carries out stability test in 0.9% sodium chloride injection)

During this product clinical practice, need to dissolve with water for injection, further reuse 0.9% sodium chloride injection 250ml dilutes laggard row vein intramuscular injection, so investigated the injection cefathiamidine after the L-arginine is done under the stable cosolvent situation to dilute with 0.9% sodium chloride injection, in 25 ℃ stable case.The result shows that its 0.9% sodium chloride injection dilution was stablized in 4.5 hours, for clinical use provides foundation.

Table 5 injection cefathiamidine is the room temperature stability test in 250ml 0.9% sodium chloride injection

Standing time (hour)	Appearance character	Related substance
			0	Clear liquid	0.78
0.5	Clear liquid	0.79
			1	Clear liquid	0.82

1.5	Clear liquid	0.86
			2	Clear liquid	0.89
2.5	Clear liquid	0.92
			3	Clear liquid	0.93
3.5	Clear liquid	0.95
			4	Clear liquid	0.97
4.5	Clear liquid	0.99
			5	Clear liquid	1.07

Test example 7 (the injection cefathiamidine is stability test in 5% glucose solution)

During this product clinical practice, with after the water for injection dissolving, also available 5% glucose solution 250ml dilution is carried out quiet, does under the cosolvent situation after 5% glucose solution dilutes, in 25 ℃ stable case at the L-arginine so investigated the injection cefathiamidine.The result shows: in 5% glucose diluent, solution-stabilized in 4.5 hours.

Table 6 injection cefathiamidine is the room temperature stability test in 250ml 5% glucose injection

Standing time (hour)	Appearance character	Related substance
			0	Clear liquid	0.75
0.5	Clear liquid	0.75
			1	Clear liquid	0.77
1.5	Clear liquid	0.79
			2	Clear liquid	0.81
2.5	Clear liquid	0.85
			3	Clear liquid	0.89
3.5	Clear liquid	0.91
			4	Clear liquid	0.95
4.5	Clear liquid	0.97
			5	Clear liquid	1.04

Need to prove: to those of ordinary skill in the art, can also make some changes or distortion to the present invention under the prerequisite that does not change the principle of the invention, this belongs to protection scope of the present invention equally.

Claims

1. cefathiamidine preparation for injection is characterized in that it comprises and contains active component cefathiamidine and stable cosolvent L-arginine; Described active component cefathiamidine and the arginic mole ratio of L-are 1: 0.5.

2. as the preparation method of the described cefathiamidine preparation for injection of above-mentioned claim, it is characterized in that the cefathiamidine aseptic powder of described mistake 60 mesh sieves and the L-arginine after aseptic process mix evenly; Mixed-powder is sub-packed in the cillin bottle behind the sterilization, jumps a queue immediately and seal with aluminium-plastic cap.