CN102743383A

CN102743383A - Stable moxifloxacin injection water-borne preparation

Info

Publication number: CN102743383A
Application number: CN2012101658052A
Authority: CN
Inventors: 杨可为; 刘文琴
Original assignee: NANJING HENGTONG MEDICAL DEVELOPMENT Co Ltd
Current assignee: NANJING HENGTONG MEDICAL DEVELOPMENT Co Ltd
Priority date: 2012-05-25
Filing date: 2012-05-25
Publication date: 2012-10-24

Abstract

The invention belongs to the field of medicine preparation, and relates to an injection water-borne preparation of an anti-infective medicine moxifloxacin or a hydrochloride salt thereof, a preparation method thereof, and an application thereof in production of medicines used for preventing and treating bacterial infections of human or animals. Under a low-temperature storage state, the water-borne preparation can maintain stable. Therefore, a defect of a requirement on being stored under a temperature above 15 DEG C of current preparations in markets is overcome.

Description

A kind of stable MOXIFLOXACIN water for injection preparation

Technical field

The invention belongs to field of pharmaceutical preparations, be specifically related to the water for injection preparation, method for preparing of anti-infectives MOXIFLOXACIN or its hydrochlorate and be used for the purposes of prophylactic treatment human or animal bacterial infection medicine in production.

Background technology

MOXIFLOXACIN (moxifloxacin) for Beyer Co., Ltd development the 4th generation fluoroquinolone antibiotics; Chemistry is by name: 1-cyclopropyl-7-{ (S; S)-2,8-diazonium-bicyclo-[4.3.0] nonanal-8-group }-6-fluoro-8-methoxy-1,4-dihydro-4-oxygen-3-quinoline carboxylic acid hydrochloride.Trade name: visit multiple pleasure.Clinically be used to treat acute sinus gland inflammation, the acute attack of chronic bronchitis, community acquired pneumonia, and uncomplicated skin infection and skin soft-tissue infection.Have broad spectrum antibiotic activity, especially the activity for gram positive bacteria, chlamydia, mycoplasma is superior to levofloxacin greatly.

The moxifloxacin hydrochloride of clinical use has the structure that is shown below:

Moxifloxacin oral absorbs good, and bioavailability is high, long half time, and tissue distribution is wide.Has taking convenience, the advantage that patient dependence is good aspect, the grade and moderate infection light at clinical treatment.But for the inpatient, severe infections and oral patient that can't administration still need develop injecting medicine-feeding form.Beyer Co., Ltd has developed the moxifloxacin hydrochloride sodium chloride injection and has supplied clinical use, has obtained great success.

The patent CN1246039 of Beyer Co., Ltd discloses a kind of Moxilfloxacin formulation containing common salt, contains the MOXIFLOXACIN hydrochlorate of 0.04-0.4% (weight/volume) and the sodium chloride of 0.4-0.9% (weight/volume).According to the disclosed preparation of this patent, preparation be the moxifloxacin hydrochloride sodium chloride infusion preparation of 400mg: 250ml, sodium chloride makes this infusion solution reach the acceptable osmotic pressure of physiology as the physiological osmotic pressure regulator.But because the adding of sodium chloride greatly reduces the dissolubility of moxifloxacin hydrochloride, so the large capacity transfusion agent that only can process 250ml, Cmax only can reach 0.4% (weight/volume).This injection has caused edema sexually transmitted disease (STD) people clinically, acute renal failure oliguria stage, chronic renal failure hypourocrinia and to diuretic reaction gastrointestinal disease patient, and the hypertensive patient, hypernatremia, the hypokalemia patient can't use.In addition, there is inconvenience in the large capacity transfusion agent with respect to small-volume injection in producing, preserve and transporting.The more important thing is; Because the dissolubility of moxifloxacin hydrochloride is very low in sodium chloride solution, has caused this large capacity transfusion agent will separate out crystal below 15 ℃, therefore must preserve more than 15 ℃; To the product storage, transit link has proposed higher requirement and inconvenience greatly.

Patent CN200910255714 discloses moxifloxacin aqueous solution type injection; The sodium salt, the water for injection that contain MOXIFLOXACIN and pharmaceutically acceptable salt thereof, faintly acid sodium salt or phosphoric acid; Wherein the content of MOXIFLOXACIN is 0.8-4% (g/m1), and the molar concentration of the sodium salt of faintly acid sodium salt or phosphoric acid is 0.0002-1mol/L.The professional of pharmaceutical field is well-known, must be prudent as the adding of excipient substance, should be in line with add less as far as possible, and the principle that does not preferably add reduces the adding of supplementary product kind and quantity, to greatest extent the minimizing compatibility, the safety issue that possibly caused by adjuvant.Through research, we think that the sodium salt of faintly acid sodium salt or phosphoric acid promptly belongs to the adjuvant scope that can not add, in fact; The disclosed Comparative Examples of this patent 1, prescription described in 2 are dissolved in water for injection with moxifloxacin hydrochloride, concentration 2%, and pH is respectively 4.09; 4.77,, have solid to separate out after the placement in 10 days in 60 ℃; Causing processing injection, is not to be because do not add the sodium salt of faintly acid sodium salt or phosphoric acid, but because is not adjusted to suitable pH value institute extremely.Obviously, this patent does not search out and is disclosed under the situation of the sodium salt adjuvant that does not add faintly acid sodium salt or phosphoric acid, and how in the pH scope, MOXIFLOXACIN or its hydrochlorate can be prepared into stable aqueous solution for injection.

Summary of the invention

Among the patent CN1246039 of Beyer Co., Ltd moxifloxacin hydrochloride is disclosed at 5 ℃; Dissolubility in the variable concentrations sodium-chloride water solution; Increase along with sodium chloride concentration; The moxifloxacin hydrochloride dissolubility descends rapidly, and in 0.9% sodium chloride solution that reaches physiological concentration, the dissolubility of moxifloxacin hydrochloride is merely 0.1% (W/V).

In the process of research, the discovery that we are surprised, the dissolubility of moxifloxacin hydrochloride in water is not to increase like the reduction of imagining with pH value, and on the contrary, along with the rising of pH value, the dissolubility of moxifloxacin hydrochloride in water significantly increases.Result of the test is as shown in the table:

Solubility table (25 ℃) in the water under the different pH value of table 1 moxifloxacin hydrochloride

Based on this discovery, foundation is provided for developing moxifloxacin hydrochloride injection stable under the high pH value.Stability of solution is the problem that needs emphasis to consider in the injection development process under the low temperature.When solution concentration during, in the low temperature put procedure, might separate out and form deposition near the dissolubility of chemical compound.Moxifloxacin hydrochloride is dissolved in the aqueous solution between the pH5-7, because the increase greatly of dissolubility has reduced the possibility of separating out at low temperatures.Through a large amount of experiments, we have developed and a kind ofly can keep down stable MOXIFLOXACIN water for injection preparations at 5 ℃.Preferably, at pH=5.6-7.0, moxifloxacin hydrochloride (in MOXIFLOXACIN) concentration is 2% injection, can be 5 ℃ of steady statues that keep more than 3 months.

The invention discloses a kind of stable MOXIFLOXACIN water for injection preparation; Said preparation is characterised in that by the MOXIFLOXACIN of 1.0%-3.0% (mass/volume) or its hydrochlorate (in MOXIFLOXACIN), water for injection, pH regulator agent to be formed, and wherein the pH value of obtained preparation is 5.6-7.0.Said preparation can exist with stable form, and an outstanding advantage of the present invention is can overcome existing MOXIFLOXACIN sodium chloride large capacity transfusion preparation must can get final product in preservation more than 0 ℃ equally like normal injection in the shortcoming of preserving more than 15 ℃.And the compatibility experimental result shows that this preparation is stablized with 5% glucose, 0.9% sodium chloride injection compatibility, when clinical use, has multiple choices, compares with existing MOXIFLOXACIN sodium chloride transfusion, has enlarged suitable patient's scope.

Further, the water for injection preparation of moxifloxacin hydrochloride of the present invention or its hydrochlorate, the concentration range of the MOXIFLOXACIN that is comprised or its hydrochlorate (in MOXIFLOXACIN) is: 1.0%-3.0% (mass/volume);

Further, employed pH regulator agent is one or both in hydrochloric acid, the sodium hydroxide;

Further, the pH value of obtained preparation is 5.6-7.0;

Further; The method for preparing of the water for injection preparation of moxifloxacin hydrochloride or its hydrochlorate is provided, has it is characterized in that: MOXIFLOXACIN or its hydrochlorate have been dissolved in the water for injection, regulate pH=5.6-7.0 with hydrochloric acid and/or sodium hydroxide; Filtering with microporous membrane; Embedding, 121 ℃ of sterilizations promptly get;

Further, relate to said preparation is used to prevent or treat the medicine of animal bacterial infection in production application.

The specific embodiment

Embodiment 1

Method for preparing: get moxifloxacin hydrochloride 437g (in MOXIFLOXACIN 400g) and drop in the 18L water for injection, be heated to 50 ℃, be cooled to room temperature, regulate pH=6.0-6.1 to all dissolvings; The needle-use activated carbon that adds 0.05% (W/V) stirs, and filtering decarbonization is respectively with 0.45; 0.22 the filtering with microporous membrane of μ m, intermediate detects, and qualified back embedding is in the 20ml ampoule; In 121 ℃ of flowing steams, the 15min sterilization promptly gets.

Embodiment 2

Method for preparing: get moxifloxacin hydrochloride 437g (in MOXIFLOXACIN 400g) and drop in the 18L water for injection, be heated to 50 ℃, be cooled to room temperature, regulate pH=5.6-5.7 to all dissolvings; The needle-use activated carbon that adds 0.05% (W/V) stirs, and filtering decarbonization is respectively with 0.45; 0.22 the filtering with microporous membrane of μ m, intermediate detects, and qualified back embedding is in the 10ml ampoule; In 121 ℃ of flowing steams, the 15min sterilization promptly gets.

Embodiment 3

Method for preparing: get moxifloxacin hydrochloride 437g (in MOXIFLOXACIN 400g) and drop in the 38L water for injection, be heated to 45 ℃, be cooled to room temperature, regulate pH=5.8-5.9 to all dissolvings; The needle-use activated carbon that adds 0.1% (W/V) stirs, and filtering decarbonization is respectively with 0.45; 0.22 the filtering with microporous membrane of μ m, intermediate detects, and qualified back embedding is in the 20ml ampoule; In 121 ℃ of flowing steams, the 15min sterilization promptly gets.

Embodiment 4

Method for preparing: get moxifloxacin hydrochloride 2185g (in MOXIFLOXACIN 2000g) and drop in the 95L water for injection, be heated to 50 ℃, be cooled to room temperature, regulate pH=6.5-6.6 to all dissolvings; The needle-use activated carbon that adds 0.05% (W/V) stirs, and filtering decarbonization is respectively with 0.45; 0.22 the filtering with microporous membrane of μ m, intermediate detects, and qualified back embedding is in the 20ml ampoule; In 121 ℃ of flowing steams, the 15min sterilization promptly gets.

Embodiment 5

Method for preparing: get moxifloxacin hydrochloride 437g (in MOXIFLOXACIN 400g) and drop in the 9L water for injection, be heated to 50 ℃, be cooled to room temperature, regulate pH=7.0-7.1 to all dissolvings; The needle-use activated carbon that adds 0.05% (W/V) stirs, and filtering decarbonization is respectively with 0.45; 0.22 the filtering with microporous membrane of μ m, intermediate detects, and qualified back embedding is in the 10ml ampoule; In 121 ℃ of flowing steams, the 15min sterilization promptly gets.

Embodiment 6

Method for preparing: get moxifloxacin hydrochloride 437g (in MOXIFLOXACIN 400g) and drop in the 18L water for injection, be heated to 50 ℃, be cooled to room temperature, regulate pH=6.8-6.9 to all dissolvings; The needle-use activated carbon that adds 0.05% (W/V) stirs, and filtering decarbonization is respectively with 0.45; 0.22 the filtering with microporous membrane of μ m, intermediate detects, and qualified back embedding is in the 20ml ampoule; In 121 ℃ of flowing steams, the 15min sterilization promptly gets.

Embodiment 7

The embodiment of the invention is placed under 5 ℃ of environment, placed 30 days, the result sees the following form.

5 ℃ of table 2 embodiment of the invention, 30 days placement results

Under 5 ℃, preserved 30 days, embodiment preparation outward appearance, pH value, significant change does not all take place in particulate matter and content, and it is stable that the illustrative embodiment preparation can keep under 5 ℃.

Embodiment 8

The embodiment of the invention is placed under 60 ℃ of environment, placed 30 days, the result sees the following form.

60 ℃ of table 3 embodiment of the invention, 30 days placement results

The result of accelerated test shows that the embodiment preparation was preserved 1 month under 60 ℃ of conditions, it is stable that each item index keeps.

Need to prove; The above is merely part embodiment of the present invention; And being not used in qualification scope of the present invention, all any modifications of within spirit of the present invention and principle, having done, the replacement that is equal to and improvement etc. all should be included within protection scope of the present invention.

Claims

1. the water for injection preparation of a stable MOXIFLOXACIN or its hydrochlorate; It is characterized in that being made up of the MOXIFLOXACIN of 1.0%-3.0% (mass/volume) or its hydrochlorate (in MOXIFLOXACIN), water for injection, pH regulator agent, wherein the pH value of obtained preparation is 5.6-7.0.

2. the water for injection preparation of MOXIFLOXACIN according to claim 1 or its hydrochlorate, comprise MOXIFLOXACIN or its hydrochlorate (in MOXIFLOXACIN) concentration range be: 1.0%-3.0% (mass/volume).

3. the water for injection preparation of MOXIFLOXACIN according to claim 1 or its hydrochlorate, wherein the pH regulator agent is one or both in hydrochloric acid, the sodium hydroxide.

4. the water for injection preparation of MOXIFLOXACIN according to claim 1 or its hydrochlorate, the pH value of obtained preparation are 5.6-7.0.

5. the method for the water for injection preparation of the preparation described MOXIFLOXACIN of claim 1 or its hydrochlorate is characterized in that: MOXIFLOXACIN or its hydrochlorate are dissolved in the water for injection, regulate pH=5.6-7.0 with hydrochloric acid and/or sodium hydroxide; Filtering with microporous membrane; Embedding, 121 ℃ of sterilizations promptly get.

6. the described preparation of claim 1 is used for preventing or treating the application of the medicine of human or animal's bacterial infection in production.