CN102755286A - Gentamycin sulfate injection containing buffer agent - Google Patents

Abstract

The invention discloses gentamycin sulfate injection containing a buffer agent. Each milliliter of injection consists of 18 to 45 milligrams of gentamycin sulfate, an antioxidant, a pH buffer agent and the balance of injection water, wherein the antioxidant is one of sodium sulfite, sodium bisulfite or sodium pyrosulfite. The injection is characterized in that the pH value of the pH buffer agent is 5.5 to 6.0.

Description

A kind of gentamicin injection liquid that contains buffer agent

Technical field

The present invention relates to a kind of injection gentamycin sulfate medicine and preparation method thereof.

Background technology

Gentamycin sulfate is a kind of widely used aminoglycoside antibiotics.Existing gentamicin injection liquid, adjuvant is water for injection and sodium sulfite or sodium pyrosulfite, can adopt intramuscular injection or dilution posterior vein to instil.

The related substance of gentamicin injection liquid is not made stipulations in 2005 editions Chinese Pharmacopoeias, but in 2010 editions Chinese Pharmacopoeias, stipulated that the gentamycin sulfate related substance should be less than 5% standard.One Chinese patent application 200910074602.0 discloses a kind of gentamicin injection liquid and preparation method thereof; Adjuvant is p-Hydroxybenzoate, sodium sulfite; And EDTA-2Na, and adopt sodium carbonate liquor that injection pH is transferred to 5.5-6.0, but disclosed injection sterilizing methods is a filtration sterilization in this application; We are according to existing technology of the technology of this application and prescription; When adopting high temperature sterilization to produce gentamicin injection liquid, it is higher to find that the product that makes gets related substance, and related substance increases more after carrying out high temperature sterilize; And related substance is also very fast with increasing memory time, can't in whole effect duration, satisfy the regulation of 2010 editions Chinese Pharmacopoeias.

Chinese in addition document " separation of the main component of gentamycin and structural research " (Zheng's first-class of restricting, antibiotic, 1980,5 (1); 5-11) point out; Carbon dioxide can form carbamate with the free alkali of gentamycin; Thereby become the source of impurity, regulate pH, thereby sodium carbonate also can be produced a certain amount of carbon dioxide when being weakly acidic gentamycin sulfate reaction and generates impurity therefore and add sodium carbonate in the prior art; Reduce the gentamycin sulfate its related substances, improve its stability and become the current technical problem underlying that will solve.

Summary of the invention

We find that unexpectedly select specific adjuvant for use, the gentamycin sulfate that makes has been realized better stable content property unexpectedly through research

The invention provides a kind of gentamicin injection liquid; Every milliliter of injection is by the gentamycin sulfate of 18-45mg; Antioxidant, the water for injection of pH buffer agent and surplus is formed, and described antioxidant is selected from sodium sulfite; A kind of in sodium sulfite or the sodium pyrosulfite is characterized in that said pH buffer agent is selected from the buffer agent that pH value is 5.5-6.0.

The addition of said antioxidant is counted 0.01-0.04mol/L with the concentration of sulfite ion, is preferably 0.02-0.03mol/L.When selecting the antioxidant that contains sodium pyrosulfite for use, every 1mol sodium pyrosulfite is amounted to 2mol sulfite ion, and when selecting the antioxidant that contains sodium sulfite for use, every 1mol sodium sulfite is amounted to 1mol sulfite ion.

Described pH buffer agent is selected from a kind of in PB, acetic acid-acetate buffer, the citrate buffer agent.

Salt particular certain cancers in the buffer agent.

Described gentamicin injection liquid is characterized in that preferred sodium pyrosulfite of described antioxidant or sodium sulfite,

Described PB is counted 0.1-0.2mol/L with phosphoric acid concentration, and described phosphoric acid concentration is meant and comprises H ₃PO ₄, H ₂PO ₄ ^-, HPO ₄ ^2-Concentration summation in said gentamicin injection liquid;

Described acetate buffer is counted 0.1-0.3mol/L with acetate concentration, and described acetate concentration is meant and comprises CH ₃COOH, CH ₃COO is the concentration summation in said gentamicin injection liquid;

Described citrate buffer agent; Count 0.05-0.1mol/L with citric acid concentration, described citric acid concentration is meant and comprises

concentration summation in said gentamicin injection liquid;

Described gentamicin injection liquid is characterized in that by following method preparation:

1) get recipe quantity 50-90% water for injection, add antioxidant and be stirred to dissolving fully, subsequent use;

2) gentamycin sulfate is added to 1) in the stock solution that makes, be stirred to dissolving fully, add the pH buffer agent, fully dissolving

3) to 2) add weight ratio percentage ratio 0.1-0.3% medicinal charcoal in the stock solution that makes, stir;

4) filter;

5) fine straining, embedding;

6) high temperature sterilize promptly gets.

Preferably when preparation and embedding, adopt inert gas shielding, said noble gas is selected from one or more in nitrogen or the carbon dioxide.

Said high temperature sterilize preferably adopts water-bath or steam sterilization.Sterilising temp is selected from 100～115 ℃.

Said percent weight in volume is the ratio of adding active carbon weight with the prescription volume of the injection of being prepared.

We find unexpectedly; With adopt sodium carbonate and compare with adjuvant prior art such as antibacterial; Stable content property when the present invention provides the injection storage after the heat stability of injection when carrying out high temperature sterilize adopted and the sterilization is better, can satisfy the requirement of Chinese Pharmacopoeia 2010 editions.The gentamicin injection liquid that obtains is behind the process high-temperature sterilizing process; Not only its related substances does not increase basically, when storing experiment, has shown better stability yet, replaces carbonate to regulate pH through adopting the pH buffer agent; And do not add antibacterial and other adjuvants; Influence stable content property thereby avoided when carrying out high temperature sterilize, forming unstable compound, thereby the stable content property that obtains knowing clearly is better, meets the gentamicin injection liquid of 2010 editions standards of Chinese Pharmacopoeia.

The specific embodiment

Prescription described in the present embodiment is the inventory in 1000 bottles of injection, and per ten thousand units of gentamycin sulfate are in 10mg.High temperature sterilize among the embodiment adopts the high-temperature steam sterilization process of 105 ℃ of 25min without exception.

All embodiment

PB adopts Na ₂HPO ₄And NaH ₂PO ₄, two kinds of raw materials are mixed with the solution for standby of 0.25mol/L respectively, get an amount of NaH during preparation earlier ₂PO ₄Solution adds Na again ₂HPO ₄Be adjusted to required pH value.

Citrate buffer agent adopts citric acid and trisodium citrate, and two kinds of raw materials are mixed with the solution for standby of 0.15mol/L respectively, gets an amount of citric acid three sodium solution during preparation earlier, adds citric acid solution again and is adjusted to required pH value.

Acetate buffer adopts acetic acid and sodium acetate, and two kinds of raw materials are prepared respectively becomes the molten subsequent use of 0.4mol/L, gets an amount of SAS during preparation earlier, adds acetic acid again and is adjusted to required pH value.

Different Example formulations tables (principal agent is represented gentamycin sulfate, water for injection milliliter numerical table show add to a milliliter number)

What " C " represented this embodiment interpolation under the buffer concentration item is citrate buffer agent, and what " P " represented this embodiment interpolation is PB, and what " A " represented this embodiment interpolation is acetate buffer

Embodiment 1

Preparation technology

1) the pH buffer agent of preparation recipe quantity, the sodium sulfite and the sodium sulfite that add recipe quantity are stirred to dissolving fully, supply water for injection to 90% recipe quantity volume, and be subsequent use;

2) gentamycin sulfate with recipe quantity adds to 1) in the stock solution that makes, be stirred to dissolving fully, to 2) adding the 1g medicinal charcoal in the stock solution that makes, placed 10 minutes the back that stirs;

3) filter, supply water for injection to recipe quantity;

4) fine straining to visible foreign matters qualified after, embedding;

5) high temperature sterilize promptly gets.

Embodiment 2

Preparation technology

1) the pH buffer agent of preparation recipe quantity, the sodium sulfite that adds recipe quantity is stirred to dissolving fully, supplies water for injection to 90% recipe quantity volume, and is subsequent use;

2) gentamycin sulfate with recipe quantity adds to 1) in the stock solution that makes, subsequent use;

3) to 2) add the 3g medicinal charcoal in the stock solution that makes, placed 10 minutes the back that stirs;

4) filter, supply water for injection to recipe quantity;

5) fine straining to visible foreign matters qualified after, embedding;

6) high temperature sterilize promptly gets.

Embodiment 3-15 preparation technology is with embodiment 2, and wherein embodiment 4,7-10,12-15 are with sodium sulfite replacement becoming sodium pyrosulfite;

Embodiment 16 preparation technologies are with embodiment 1

The reference examples formula table, other prescriptions are identical with the embodiment of corresponding numbering, do not add the pH buffer agent, adopt sodium carbonate as the pH regulator agent, are adjusted to the same pH value of reference numeral embodiment, calculate recipe quantity according to 1000 bottles amount equally

Reference examples 1

Preparation technology

1) gets recipe quantity 70% water for injection; The sodium sulfite that adds recipe quantity is stirred to dissolving fully with sodium sulfite, with recipe quantity methyl parahydroxybenzoate/dissolve with the water for injection of propyl p-hydroxybenzoate with 80 ℃, adds above-mentioned medicinal liquid; Add the EDTA-2Na dissolving again, subsequent use;

2) gentamycin sulfate with recipe quantity adds to 1) in the stock solution that makes, be stirred to dissolving fully, recipe quantity sodium carbonate and sodium bicarbonate are modulated into 10% solution respectively regulate and add the adjusting pH value, subsequent use;

3) to 2) add the 1g medicinal charcoal in the stock solution that makes, placed 10 minutes the back that stirs;

4) filter, supply water for injection to recipe quantity;

5) fine straining to visible foreign matters qualified after, embedding;

6) high temperature sterilize promptly gets.

Reference examples 2

Preparation technology

1) gets recipe quantity 80% water for injection; The sodium sulfite that adds recipe quantity is stirred to dissolving fully, with recipe quantity methyl parahydroxybenzoate/dissolve with the water for injection of propyl p-hydroxybenzoate with 80 ℃, adds above-mentioned medicinal liquid; Add the EDTA-2Na dissolving again, subsequent use;

2) gentamycin sulfate with recipe quantity adds to 1) in the stock solution that makes, be stirred to dissolving fully, the recipe quantity sodium carbonate is modulated into 10% solution regulates to add and regulate pH value, subsequent use;

3) to 2) add the 2g medicinal charcoal in the stock solution that makes, placed 10 minutes the back that stirs;

4) filter, supply water for injection to recipe quantity;

5) fine straining to visible foreign matters qualified after, embedding;

6) high temperature sterilize promptly gets.

Reference examples 13-20

Reference examples 3-15 preparation technology is with reference examples 2, and wherein reference examples 4,7-10,12-15 are with sodium sulfite replacement becoming sodium pyrosulfite

Reference examples 16 preparation technologies are with reference examples 1

According to the prescription of reference examples 10, buffer changed into add sodium hydroxide and regulate pH value, add fashionablely, adopt 10% sodium hydroxide solution, reference examples 17-18 transfers to 5.5,6.0 with gained injection pH successively.

Reference examples and embodiment respectively organize whole process using nitrogen protection in the preparation.

The stability comparative example

Annotate: what adopt in all embodiment and the reference examples all is same gentamycin sulfate crude drug, its crude drug before carrying out preparation, and its related substances is 2.86%

Stability test adopts according to the method among 2010 editions appendix XIXC of Chinese Pharmacopoeia, carries out accelerated stability test, and preserving environment is 40 ℃ ± 2 ℃, stores under the condition of relative humidity 75% ± 5%.Detecting storage front and back injection related substance according to Chinese Pharmacopoeia 2010 editions changes; Wherein embodiment 1-16 is respectively experimental group 1-16; Reference examples 1-16 is respectively experimental group 17-32; Reference examples 17-18 is respectively experimental group 33-34, and wherein experimental group 17-32 is after storing 3 months, and experimental group 33-34 its related substances after storing 2 months has all surpassed 5% standard.

Carrying out stability experiment through the gentamicin injection liquid that embodiment and reference examples are made can find out; Only adopt sodium sulfite, sodium pyrosulfite or sodium sulfite as antioxidant; Phosphate, acetate or citrate buffer agent sodium is as the pH regulator agent, and do not add other embodiment 1-16 like the adjuvant of antibacterial, and the injection stability that it obtains will obviously be better than all reference examples; Storage stability is higher; In the reference examples 1-16 that adopts one Chinese patent application 200910074602.0 disclosed prescriptions, other adjuvants that added when adopting conventional high temperature sterilize, not only do not play the effect that increases stability; Significantly improving has appearred in its related substances after handling through high temperature sterilize on the contrary; And when experiment proceeds to 3 months, just surpassed 5% standard, and adopted the experimental group 33,34 of sodium hydroxide, pH regulator to 5.5 or 6.0 o'clock as the pH regulator agent; The injection stable content property that obtains is all relatively poor, when experiment proceeds to 2 months, has also surpassed 5% standard.Explain that gentamicin injection liquid provided by the invention compares with prescription of the prior art, storage stability is strong, is applicable to high-temperature sterilizing process.

And the gentamicin injection liquid that present embodiment provides, not only related substance does not have increase basically behind high temperature sterilize, and in 6 months stability experiments, it is stable that content also remains, and can meet the regulation of 2010 editions relevant its related substances of Chinese Pharmacopoeia.

Claims (10)

1. gentamicin injection liquid; Every milliliter of injection is by the gentamycin sulfate of 18-45mg; Antioxidant, the water for injection of pH buffer agent and surplus is formed, and described antioxidant is selected from sodium sulfite; A kind of in sodium sulfite or the sodium pyrosulfite is characterized in that said pH buffer agent is selected from the buffer agent that pH value is 5.5-6.0.

2. gentamicin injection liquid as claimed in claim 1 is characterized in that the addition of said antioxidant is counted 0.01-0.04mol/L with the concentration of sulfite ion.

3. gentamicin injection liquid as claimed in claim 1 is characterized in that preferred sodium pyrosulfite of described antioxidant or sodium sulfite.

4. like the arbitrary described gentamicin injection liquid of claim 1-4, it is characterized in that described pH buffer agent is selected from a kind of in PB, acetic acid-acetate buffer, the citrate buffer agent.

5. gentamicin injection liquid as claimed in claim 5, the salt particular certain cancers in its characteristic buffer agent.

6. like the said gentamicin injection liquid of claim 5; It is characterized in that described PB, count 0.1-0.2mol/L with phosphoric acid concentration, described phosphoric acid concentration is meant and comprises H3PO4; H2PO4-, HPO42-is the concentration summation in said gentamicin injection liquid.

7. like the said gentamicin injection liquid of claim 5; It is characterized in that described acetate buffer; Count 0.1-0.3mol/L with acetate concentration, described acetate concentration is meant and comprises CH3COOH that CH3COO-is the concentration summation in said gentamicin injection liquid.

8. like the said gentamicin injection liquid of claim 5; It is characterized in that described citrate buffer agent; Count 0.05-0.1mol/L with citric acid concentration, described citric acid concentration is meant and comprises

concentration summation in said gentamicin injection liquid.

9. like the arbitrary described gentamicin injection liquid of claim 1-9, it is characterized in that described gentamicin injection liquid, it is characterized in that by following method preparation:

1) get recipe quantity 50-90% water for injection, add antioxidant and be stirred to dissolving fully, subsequent use;

2) gentamycin sulfate is added to 1) in the stock solution that makes, be stirred to dissolving fully, add the pH buffering, fully dissolving

3) to 2) add weight ratio percentage ratio 0.1-0.3% medicinal charcoal in the stock solution that makes, stir;

4) filter;

5) fine straining, embedding;

6) high temperature sterilize promptly gets.

10. gentamicin injection liquid as claimed in claim 10 is characterized in that when preparation and embedding, adopting inert gas shielding.