CN1557317A - Enoxacin Glyconate little volume injection and its preparation method - Google Patents

Abstract

The present invention relates to new Enoxacin gluconate preparation, and is especially small dosage Enoxacin gluconate injection and its preparation process. The injection consists of Enoxacin gluconate as active component pharmacologically acceptable carrier component. The injection of the present invention has stability superior to that of great dosage Enoxacin gluconate injection, and the active component may be also prepared into powder for injection and eye drop.

Description

Enoxacin Gluconate small-volume injection and preparation method

Technical field

The present invention relates to the novel formulation of antibacterials Enoxacin Gluconate, particularly Enoxacin Gluconate small-volume injection and preparation method.

Background technology

Enoxacin Gluconate (English name: Enoxacin Gluconate; Chemical name: 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridines-3-carboxylic acid-maltonic acid salt-hydrate) be the salt compounds of carbostyril family antibacterial drugs enoxacin, the bulk capacity injection of Enoxacin Gluconate has been used for clinical, obtained excellent curative, but be subjected to the influence of its manner of packing because of the Enoxacin Gluconate bulk capacity injection, the direct ingress of air of its solution, easily oxidation, stability is good inadequately, and small-volume injection well addresses the above problem, and has improved stability of drug.

In addition, there only have the Enoxacin Gluconate injection to be used at present on the market to be clinical, limited the clinical scope of application, according to the pharmacological effect characteristics of Enoxacin Gluconate, can also develop multiple dosage form, select for the clinician as small-volume injection, injectable powder, eye drop etc.

Summary of the invention

The small-volume injection that the purpose of this invention is to provide a kind of Enoxacin Gluconate because small-volume injection adopts ampoule filling on technology, fills the mode of nitrogen sealing by fusing, has avoided oxygen directly to contact with medicinal liquid, has improved stability of drug.

The invention provides a kind of Enoxacin Gluconate small-volume injection, this injection is become to be grouped into the medicine acceptable carrier by the active component Enoxacin Gluconate, its Chinese medicine acceptable carrier is one of in water and/or glucide, alcohol, sugared acid anhydride, the sodium chloride, concrete available glucose, lactose, mannitol, sorbitol, gelatin hydrolysate, low molecular dextran etc.

The content of glucose in aqueous solution is 1%～10% (w/v) in the described injection, contains glucose 1～10g in just every 100ml aqueous solution.

The content of sodium chloride in aqueous solution is 0.5%～1.5% (w/v) in the described injection, sodium chloride-containing 0.5～1.5g in just every 100ml aqueous solution.

The single dose specification of described Enoxacin Gluconate small-volume injection is 50mg～400mg, and the single dose loading amount is 0.5ml～20ml.

Injection of the present invention prepares in order to the below method, carry out according to the following steps: accurately take by weighing Enoxacin Gluconate by recipe quantity, glucose or sodium chloride, add in 50～60 ℃ of waters for injection, be mixed with 10% solution (w/v), the active carbon that adds solution amount 0.1% boiled 15 minutes, treat cold after, the filtering active carbon, add water to nearly full dose, regulate pH to 4.0～5.5, add water to ormal weight with hydrochloric acid or sodium hydroxide, Enoxacin Gluconate content should be 93.0%～107.0% of labelled amount, use the 0.45um filtering with microporous membrane, fill charges into nitrogen in ampoule bottle, sealing by fusing, 115 ℃ of pressure sterilizings got final product in 35 minutes.

The present invention also provides injectable powder, the eye drop of active component Enoxacin Gluconate and the preparation of medicine acceptable carrier.

The using method of injection of the present invention: medicinal liquid (0.2g:2ml) is diluted the lucifuge intravenous drip with 250ml～500ml glucose injection.The 0.2g that is grown up one time, 2 times on the one, patient with severe symptoms's maximal dose once is no more than 0.6g, disease journey 7～10 days.

Injection of the present invention has good stability, determined curative effect, characteristics such as easy to use.Effective effect of the present invention can illustrate by experiment and the adnexa " tests such as the anaphylaxis of Enoxacin Gluconate injection systemic administration, hemolytic, blood vessel irritation " of embodiment.

The specific embodiment

Embodiment 1

Enoxacin Gluconate 167.5g

Water for injection 2000ml

Make 1000 of injections altogether

The preparation of preparation technology and medicinal liquid:

The water for injection that in ingredients pot, adds 50～60 ℃ of 1000ml, the Enoxacin Gluconate that adds recipe quantity then stirs, and complete molten back adds the 10g needle-use activated carbon, heated and boiled 15 minutes, filter, filtrate adds water to full dose after transferring pH to 4.0～5.5 with the hydrochloric acid of 0.1N, survey content and should be 93.0%～107.0% of labelled amount, after qualified, with 0.45 μ m filtering with microporous membrane, filtrate is handed over the embedding group;

Embedding: fill is cleaned with water for injection with ampoule, oven dry, and medicinal liquid enters the injection embedding machine, irritates in ampoule, feeds nitrogen then, seals.

Sterilization: sterilization is carried out in the sterilization cabinet, 115 ℃ of sterilising temps, and sterilization time 35 minutes, then by lamp inspection, full inspection makes qualified products.

Enoxacin Gluconate small-volume injection (2ml:0.2g) and the comparative test of Enoxacin Gluconate bulk capacity injection stability.

Test specimen:

The Enoxacin Gluconate high-capacity injection	Specification	100ml：0.2g
			Lot number	031201
	Manufacturer	Wuhan Yuanda Pharmaceutical Group Co., Ltd.
			The Enoxacin Gluconate injection with small volume	Specification	2ml：0.2g
Lot number	031201
		Trial-production producer		Wuhan Yuanda Pharmaceutical Group Co., Ltd.

Detection method: the detection of related substance

Related substance is measured according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).

The system suitability test: with octadecylsilane chemically bonded silica is filler; It is mobile phase that methanol-2.1% citric acid soln-acetonitrile (5: 15: 1) drips triethylamine adjust pH 3.0, and the detection wavelength is 270nm, and number of theoretical plate calculates by enoxacin should be not less than 3000.

Algoscopy: get this product 2ml, put in the 100ml measuring bottle, thin up shakes up to scale, and it is an amount of to get this solution again, adds mobile phase and makes the anhydrous enoxacin solution that contains 50ug among every 1ml, as need testing solution.Measure in right amount, add mobile phase and make the anhydrous enoxacin solution that every 1ml contains 0.75ug, solution in contrast.Get contrast solution 20ul, inject chromatograph of liquid, regulate detection sensitivity, the peak height that makes the main constituent chromatographic peak is 5～10% of a full scale, gets above-mentioned two kinds of each 20ul of solution again, injects chromatograph of liquid respectively, the record chromatogram is to 2 times of main constituent peak retention time, in the chromatogram of need testing solution if any impurity peaks, measure each impurity peak area and, must not be greater than the peak area (1.5%) at contrast solution main constituent peak.

Test method: will detect before the test specimen sterilization and after the sterilization, then operation as follows:

60 ℃ of heat runs

Sample is put into constant temperature water bath, 60 ℃ of heating in water bath, respectively at the 5th, 10,15 take out sample, full inspection.

Under 60 ℃ of heating conditions, bulk capacity injection and small-volume injection stability relatively see Table 1

Test item		Bulk capacity injection				Small-volume injection
											Before the sterilization	The sterilization back (my god)				Before the sterilization	The sterilization back (my god)
		???0???????????5??????????10??????????15					??0	??5	??10	??15
											Outward appearance	Qualified	Qualified	Qualified	Qualified	Qualified	Qualified	Qualified	Qualified	Qualified	Qualified
Clarity	Qualified	Qualified	Qualified	Qualified	Qualified	Qualified	Qualified	Qualified	Qualified	Qualified
											Content	??99.8	??99.6	??99.3	??99.0	??98.4	??99.7	??99.3	??99.8	??99.6	??99.0
Related substance	??0.10	??0.27	??0.35	??0.45	??0.58	??0.11	??0.13	??0.17	??0.15	??0.20

Conclusion: 60 ℃ were heated 15 days, the related substance of bulk capacity injection is apparently higher than small-volume injection, every data show is under heating condition, and the catabolite of bulk capacity injection is higher than small-volume injection, illustrates that the stability of small-volume injection is better than bulk capacity injection.

Adnexa:

Tests such as the anaphylaxis of Enoxacin Gluconate injection systemic administration, hemolytic, blood vessel irritation

Enoxacin Gluconate injection anaphylaxis test

[summary] Cavia porcellus intravenous injection Enoxacin Gluconate injection is not observed animal and is coughed, rolls up, erects anaphylaxis phenomenons such as hair, dyspnea.Show that the Enoxacin Gluconate injection does not have sensitization to animal subject.

One, test objective

Observe the Enoxacin Gluconate injection and have or not sensitization through the whole body administration.

Two, test material

1, animal subject: the adult healthy albino guinea-pig, male and female are partly individual, body weight 200～250g.Tongji Medical College, Huazhong Science and Technology Univ.'s animal center provides, the quality certification number: the moving word 19-025 of doctor.Issuing unit: Hubei Province medical experiment animal Ethics Committee.

2, medicine

Tried thing: Enoxacin Gluconate injection, lot number: 020801.Specification: 0.1g/2ml.Group Plc provides by the Wuhan pharmacy, and facing with preceding the dilution by clinical working concentration is that 0.2% Enoxacin Gluconate injection is standby.

Solvent: 5% glucose injection, company of Wuhan Bin Hu Double-Crane Pharmaceutical Co., Ltd produces, lot number: 020530307.The contrast medicine: ovalbumin, available from Rehabilitation's skill Development Co., Ltd in the Wuhan.Facing with preceding becomes 5% ovalbumin standby with distilled water diluting.

Three, test method

1, sensitization contact: get 24 of Cavia porcelluss, be divided into 3 groups at random, be respectively the solvent matched group, be subjected to reagent thing group and positive controls.Every group of 8 animals.Each treated animal is 5% glucose injection, 0.2% Enoxacin Gluconate injection and 5% ovalbumin of capacity (0.5ml) such as lumbar injection respectively, the next day once, continuous three times.

2, provocative test: each treated animal is divided into 2 batches, and first after the sensitization administration first time 14 days, second batch was carried out the excitability injection in 21 days respectively after the sensitization administration first time.The solvent matched group is subjected to reagent thing group and positive controls to inject 5% glucose injection, 0.2% Enoxacin Gluconate injection and 5% ovalbumin 1ml through external jugular vein respectively.Observe and the record administration after in 15,30,60 and 120 minutes animal have or not cough, roll up, anaphylaxis phenomenons such as perpendicular mao, dyspnea even death.Cavia porcellus anaphylaxis grade scale sees Table 1.

Table 1 Cavia porcellus anaphylaxis grading

The order of reaction	Reaction
		????0	There is not obviously reflection
????1	Have only and slightly grab nose, tremble or erect hair
		????2	Have several times to cough, have and slightly grab nose, tremble or erect hair
????3	Repeatedly or continuously cough, twitch with dyspnea or spasm
		????4	Spasm, tic, gatism, death

Four, result of the test

Behind Cavia porcellus abdominal cavity sensitizing injection 5% glucose injection, 0.2% Enoxacin Gluconate injection and 5% ovalbumin sensitization, the animal ordinary circumstance is good, diet, urinate and the feces situation normal.Animal is in two batches respectively at exciting in 14 days and 21 days after the sensitization administration first time.The solvent matched group and be subjected to that reagent thing treated animal excites after the administration that animal has or not cough in 15,30,60 and 120 minutes, rolls up, anaphylaxis phenomenons such as perpendicular hair, dyspnea even death, so evaluation reflection degree is 0 grade.The positive controls Cavia porcellus excite for twice all occur that spasm is twitched, panted after the administration immediately, phenomenons and dead in 5 minutes after exciting administration such as dyspnea and cyanosis, anaphylaxis is 4 grades.See Table 2

Table 2 Enoxacin Gluconate injection causes Cavia porcellus anaphylaxis and degree thereof

Grouping	Medicine	Time (branch)	Cavia porcellus anaphylaxis grading
											Excited in 14 days				Excited in 21 days
			??1*	??2	??3	??4	??5	??6	??7	??8
											The solvent matched group	5% glucose injection	????15	??0	??0	??0	??0	??0	??0	??0	??0
????30	??0	??0	??0	??0	??0	??0	??0	??0
									????60	??0			??0	??0	??0	??0	??0	??0	??0
????120	??0	??0	??0	??0	??0	??0	??0	??0
									Organized by examination	0.2% Enoxacin Gluconate injection			????15	??0	??0	??0	??0	??0	??0	??0	??0
????30	??0	??0	??0	??0	??0	??0	??0	??0
											????60	??0	??0	??0	??0	??0	??0	??0	??0
????120	??0	??0	??0	??0	??0	??0	??0	??0
											Positive controls	5% ovalbumin	????15	??4	??4	??4	??4	??4	??4	??4	??4
????30	??-	??-	??-	??-	??-	??-	??-	??-
									????60	??-			??-	??-	??-	??-	??-	??-	??-
????120	??-	??-	??-	??-	??-	??-	??-	??-

^*: number of animals

Five, conclusion (of pressure testing):

This test shows: the Enoxacin Gluconate injection does not have allergenic effect to Cavia porcellus.

Embodiment 2:

Enoxacin Gluconate 167.5g

Glucose 100g

Water for injection 2000ml

Make 1000 altogether

Preparation method is except that adjuvant is pressed the recipe quantity adding, and other are with embodiment 1.

Embodiment 3:

Enoxacin Gluconate 167.5g

Sodium chloride 18g

Water for injection 2000ml

Make 1000 altogether

Preparation method is except that adjuvant is pressed the recipe quantity adding, and other are with embodiment 2.

Embodiment 4:

Enoxacin Gluconate 167.5g

Mannitol 20g

Make 1000 altogether

The water for injection that adds 50～60 ℃ of 1000ml in ingredients pot adds the Enoxacin Gluconate of recipe quantity then, and mannitol stirs, and is molten entirely, adds the 10g needle-use activated carbon then, and heated and boiled 15 minutes is filtered the nearly full dose of filtrate moisturizing.Regulate pH to 4.0-5.5, measure intermediate content, the 0.22um fine straining, be sub-packed in the 10ml cillin bottle-45 ℃ of pre-freezes 6 hours, evacuation by every bottle of 2ml, when vacuum＜10Pa, be warming up to-10 ℃ gradually, (control vacuum＜10Pa) about 30 hours is warming up to 35 ℃ gradually and kept 2-3 hour to keep distillation, when products temperature and flaggy temperature approaching, during vacuum＜5Pa, finish lyophilizing, the tamponade packing.

Embodiment 5:

Enoxacin Gluconate 167.5g

Dextran-20 g

Make 1000 altogether

Preparation method is except that adjuvant is pressed the recipe quantity adding, and other are with embodiment 4.

Embodiment 6:

Enoxacin Gluconate 167.5g

Mannitol 20g

Make 1000 altogether

Preparation method is except that adjuvant is pressed the recipe quantity adding, and other are with embodiment 4.

Claims (9)

1, the small-volume injection of Enoxacin Gluconate is characterized in that: this injection consist of Enoxacin Gluconate and medicine acceptable carrier.

2, injection according to claim 1 is characterized in that: its Chinese medicine acceptable carrier is one of in water and/or glucide, alcohol, sugared acid anhydride, the sodium chloride.

3, injection according to claim 2 is characterized in that: described medicine acceptable carrier is glucose, lactose, mannitol, sorbitol, gelatin hydrolysate or low molecular dextran.

4, injection according to claim 2 is characterized in that: the content of glucose in aqueous solution is 1%～10% (w/v) in the described injection, contains glucose 1～10g in just every 100ml aqueous solution.

5, injection according to claim 2 is characterized in that: the content of sodium chloride in aqueous solution is 0.5%～1.5% (w/v) in the described injection, sodium chloride-containing 0.5 in just every 100ml aqueous solution～l.5g.

6, injection according to claim 1 is characterized in that: the single dose specification of described Enoxacin Gluconate small-volume injection is 50mg～400mg.

7, injection according to claim 1 is characterized in that: the single dose loading amount is 0.5ml～20ml.

8, according to the preparation method of the described injection of claim 1, it is characterized in that: carry out according to the following steps: accurately take by weighing Enoxacin Gluconate by recipe quantity, glucose or sodium chloride, add in 50～60 ℃ of waters for injection, be mixed with 10% solution (w/v), the active carbon that adds solution amount 0.1% boiled 15 minutes, treat cold after, the filtering active carbon; Add water to nearly full dose, regulate pH to 4.0～5.5, add water to ormal weight with hydrochloric acid or sodium hydroxide, Enoxacin Gluconate content should be 93.0%～107.0% of labelled amount, and filtering with microporous membrane is sub-packed in the ampoule bottle, charge into nitrogen, sealing by fusing, 115 ℃ of pressure sterilizings got final product in 35 minutes.

9, injection according to claim 1 is characterized in that: described Enoxacin Gluconate also can be prepared into powder ampoule agent for injection or eye drop.