CN110664744B - Doxycycline hydrochloride solution and preparation method thereof - Google Patents
Doxycycline hydrochloride solution and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/65—Tetracyclines
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a doxycycline hydrochloride solution and a preparation method thereof. The preparation raw materials of the doxycycline hydrochloride solution comprise: doxycycline hydrochloride calculated by doxycycline, urea, an antioxidant, edetate disodium, an organic solvent and water. The doxycycline hydrochloride solution prepared by the method has stable property, does not darken in long-term storage, has less impurities, and can be stored for a long time. And secondly, the preparation method of the doxycycline hydrochloride solution is simple, the price of the preparation raw materials is low, and the doxycycline hydrochloride solution is suitable for large-scale popularization and application.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a doxycycline hydrochloride solution as well as a preparation method and application thereof.
Background
Doxycycline hydrochloride (Doxycycline Hyclate) is also called Doxycycline hydrochloride or Doxycycline hydrochloride, is a tetracycline broad-spectrum antibiotic, and has broad-spectrum antibacterial effect. Sensitive bacteria of doxycycline hydrochloride include gram-positive bacteria such as streptococcus, pneumococcus, anthrax bacillus, staphylococcus partially, tetanus bacillus, corynebacterium, and gram-negative bacteria such as escherichia coli, salmonella, pasteurella, brucella and haemophilus, klebsiella and meliloti bacillus. Besides, doxycycline hydrochloride has a certain inhibiting effect on mycoplasma (such as mycoplasma hyopneumoniae), rickettsia, spirochete and the like.
At present, doxycycline hydrochloride tablets, soluble powder, powder (for aquatic products), granules, injection, uterus injection and the like are clinically available. However, tablets and injections are inconvenient to administer, and the procedures for mass administration are troublesome, and therefore, are generally used less frequently. Soluble powder and particles are put into water in a solid form, are slow to dissolve and are easy to deposit at the bottom, and glucose and the like contained in the soluble powder and the particles can cause the problem of water eutrophication, so that bacteria in drinking water pipelines are bred. Therefore, it is very important to develop an oral solution dosage form which is convenient to use.
Doxycycline hydrochloride is stable when existing in a solid form, and is unstable due to various degradation reactions such as oxidation, hydrolysis, isomerization and the like in a solution, so that the application of doxycycline hydrochloride in the aspect of preparing a liquid preparation is limited. At present, doxycycline hydrochloride is usually complexed with metal ions to form a complex so as to improve the stability of doxycycline hydrochloride, but the oxidation and discoloration of the medicament can be accelerated when the metal ions and doxycycline are complexed. Therefore, the doxycycline hydrochloride injection prepared by the method has very dark color after being placed for a long time, the colored impurities are increased, and the oxidation products are increased quickly.
The applicant of the invention finds that the stability of doxycycline hydrochloride in a solution can be obviously improved by adding urea into the doxycycline hydrochloride solution under the condition of not adopting magnesium ions, and the color of the doxycycline hydrochloride solution prepared by adopting the method can not be obviously changed after the doxycycline hydrochloride solution is placed for a long time.
Disclosure of Invention
The invention aims to provide a doxycycline hydrochloride solution with a stable state, and the invention also aims to provide a preparation method and application of the doxycycline hydrochloride.
In order to achieve the above object, the present invention provides a doxycycline hydrochloride solution, which is prepared from the following raw materials: doxycycline hydrochloride calculated by doxycycline, urea, an antioxidant, edetate disodium, an organic solvent and water.
Preferably, the raw materials for preparing the hydrochloric acid cycline solution per 100ml comprise:
preferably, the preparation raw materials of each 100ml of the doxycycline hydrochloride solution comprise:
preferably, the antioxidant is selected from one or more of sodium sulfite, sodium bisulfite, sodium metabisulfite, vitamin C and butyl hydroxy anisol.
Preferably, the organic solvent is selected from one or more of polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, 1, 2-propylene glycol, glycerol, and dimethylacetamide.
In addition, the invention provides a preparation method of the doxycycline hydrochloride solution, and the preparation method of each 100ml of the doxycycline hydrochloride solution comprises the following steps:
(1) dissolving antioxidant and edetate disodium in 1-5g of water, adding organic solvent, mixing, and stirring to obtain mixed solution;
(2) and adding doxycycline hydrochloride and urea into the mixed solution, mixing, stirring, heating at a controlled temperature, cooling to room temperature, adding water to make up to 100ml, filtering, subpackaging, filling nitrogen during packaging, and filling and sealing to obtain the doxycycline hydrochloride solution.
Preferably, the temperature of the temperature-controlled heating is 20-60 ℃, and the time of the temperature-controlled heating is 0.5-2 h.
Preferably, the temperature of the temperature-controlled heating is 30-50 ℃, and the time of the temperature-controlled heating is 1-1.5 h.
In addition, the invention provides the use of said doxycycline hyclate solution for the treatment of infections caused by gram-positive cocci and gram-negative bacilli.
The invention has the beneficial effects that:
compared with the prior art, the doxycycline hydrochloride solution provided by the invention has the advantages that the property is stable, the color cannot be darkened in long-term storage, and impurities are less, so that the doxycycline hydrochloride solution can be stored for a long time.
And secondly, the preparation method of the doxycycline hydrochloride solution is simple, the price of the preparation raw materials is low, and the doxycycline hydrochloride solution is suitable for large-scale popularization and application.
Detailed Description
In order to clearly illustrate the technical features of the present solution, the present solution is explained below by way of specific embodiments.
Example 1
The preparation raw materials of 100mL doxycycline hydrochloride solution by mass comprise the following components:
the preparation steps of the doxycycline hydrochloride solution are as follows:
(1) dissolving 0.1g of antioxidant sodium bisulfite and 0.05g of edetate disodium in 1g of water, and adding into 70g of glycerol to obtain a mixed solution;
(2) adding doxycycline hydrochloride and 10g of urea in 5g of doxycycline hydrochloride into the mixed solution obtained in the step 1, mixing, stirring, heating and dissolving, controlling the temperature at 20 ℃ and the mixing time at 2 hours, then cooling to room temperature, adding water to supplement 100ml, filtering, subpackaging, filling nitrogen gas during packaging, and filling nitrogen gas to encapsulate to obtain doxycycline hydrochloride solution 1.
Example 2
The preparation raw materials of 100mL doxycycline hydrochloride solution by mass comprise the following components:
the preparation steps of the doxycycline hydrochloride solution are as follows:
(1) dissolving 0.05g of antioxidant vitamin C and 0.1g of edetate disodium in 5g of water, and adding the mixture into 40g of polyethylene glycol 400 to prepare a mixed solution;
(2) adding doxycycline hydrochloride and 20g of urea in the amount of 10g of doxycycline into the mixed solution obtained in the step 1, mixing, stirring, heating and dissolving, controlling the temperature at 30 ℃ and the mixing time at 1.5 hours, cooling to room temperature, adding water to make up to 100ml, filtering, subpackaging, filling nitrogen during packaging, and obtaining doxycycline hydrochloride solution 2.
Example 3
The preparation raw materials of 100mL doxycycline hydrochloride solution by mass comprise the following components:
the preparation method of the doxycycline hydrochloride solution comprises the following steps:
(1) dissolving 0.05g of antioxidant sodium sulfite and 0.02g of edetate disodium in 2g of water, and adding the mixture into 30g of 1, 2-propylene glycol to prepare a mixed solution;
(2) adding doxycycline hydrochloride and 20g of urea in 15g of doxycycline hydrochloride into the mixed solution obtained in the step 1, mixing, stirring, heating and dissolving, controlling the temperature at 50 ℃ and the mixing time at 1 hour, then cooling to room temperature, adding water to make up to 100ml, filtering, subpackaging, filling nitrogen gas during packaging, and filling nitrogen gas into the bottles to obtain a doxycycline hydrochloride solution 3.
Example 4
The preparation raw materials of 100mL doxycycline hydrochloride solution by mass comprise the following components:
the preparation method of the doxycycline hydrochloride solution comprises the following steps:
(1) dissolving 0.05g of antioxidant butylated hydroxyanisole and 0.05g of edetate disodium in 3g of water, and adding the obtained solution into 60g of glycerol to obtain a mixed solution;
(2) adding doxycycline hydrochloride and 15g of urea in the amount of 10g of doxycycline into the mixed solution obtained in the step 1, mixing, stirring, heating and dissolving, controlling the temperature at 60 ℃ and the mixing time at 0.5 hour, cooling to room temperature, adding water to make up to 100ml, filtering, subpackaging, filling nitrogen during packaging, and obtaining doxycycline hydrochloride solution 4.
Example 5
The preparation raw materials of 100mL doxycycline hydrochloride solution by mass comprise the following components:
the preparation method of the doxycycline hydrochloride solution comprises the following steps:
(1) dissolving 0.05g of antioxidant sodium bisulfite and 0.05g of edetate disodium in 1g of water, and adding into 50g of dimethylacetamide to prepare a mixed solution;
(2) adding doxycycline hydrochloride and 20g of urea in the amount of 20g of doxycycline hydrochloride into the mixed solution obtained in the step 1, mixing, stirring, heating and dissolving, controlling the temperature at 60 ℃ and the mixing time at 0.5 hour, cooling to room temperature, adding water to make up to 100ml, filtering, subpackaging, filling nitrogen during packaging, and obtaining doxycycline hydrochloride solution 5.
Example 6
The preparation raw materials of 100mL doxycycline hydrochloride solution by mass comprise the following components:
the preparation method of the doxycycline hydrochloride solution comprises the following steps:
(1) dissolving 0.05g of antioxidant sodium metabisulfite and 0.03g of edetate disodium in 2g of water, and adding the obtained solution into 40g of polyethylene glycol 200 to prepare a mixed solution;
(2) adding doxycycline hydrochloride and 15g of urea in 5g of doxycycline hydrochloride into the mixed solution obtained in the step 1, mixing, stirring, heating and dissolving, controlling the temperature at 30 ℃ and the mixing time at 2 hours, cooling to room temperature, adding water to make up to 100ml, filtering, subpackaging, filling nitrogen gas during packaging, and filling nitrogen gas into the bottles to obtain a doxycycline hydrochloride solution 6.
Example 7
The preparation raw materials of 100mL doxycycline hydrochloride solution by mass comprise the following components:
the preparation method of the doxycycline hydrochloride solution comprises the following steps:
(1) dissolving 0.05g of antioxidant vitamin C and 0.1g of edetate disodium in 4g of water, and adding the dissolved solution into 40g of polyethylene glycol 600 to prepare a mixed solution;
(2) adding doxycycline hydrochloride and 20g of urea in an amount of 5g of doxycycline hydrochloride into the mixed solution obtained in the step 1, mixing, stirring, heating and dissolving, controlling the temperature at 35 ℃ and the mixing time at 1 hour for 20 minutes, cooling to room temperature, adding water to make up to 100ml, filtering, subpackaging, filling nitrogen during packaging, and obtaining the doxycycline hydrochloride solution 7.
Control group
The doxycycline hydrochloride solution is prepared by adopting the prior art for preparing doxycycline hydrochloride injection and taking magnesium ions as a doxycycline hydrochloride stabilizing agent.
The preparation raw materials of 100mL doxycycline hydrochloride solution by mass comprise the following components:
the preparation method of the doxycycline hydrochloride solution comprises the following steps:
(1) dissolving 0.5g of sodium bisulfite, 0.05g of edetate disodium and 1g of povidone K30 with 10g of water to obtain an aqueous solution, and mixing the aqueous solution with 80% by weight and 50g of polyethylene glycol 200 to obtain a mixed solution;
(2) adding doxycycline hydrochloride in 15g of doxycycline and 9g of MgCl to the mixed solution in the step 12·6H2O, mixing, stirring, heating and dissolving, controlling the temperature at 50 ℃, stirring for 30 minutes, adjusting the pH to 4.0 by using a pH regulator hydrochloric acid/ethanolamine, and then cooling to room temperature to obtain a brown yellow solution;
(3) and (3) continuously adding all the water solution remained in the step (1) into the brown yellow solution obtained in the step (2) under the heat preservation environment of 50 ℃, then adjusting the pH to 4.0 by using a pH regulator hydrochloric acid/ethanolamine, adding water to supplement the total amount to 100ml, filtering, subpackaging, and filling nitrogen to protect and package to obtain a doxycycline hydrochloride comparison solution.
The doxycycline hydrochloride solution of the present invention and the prior art doxycycline hydrochloride solution are compared by specific experiments as follows
Experimental mode
The doxycycline hydrochloride solution 2 in the embodiment and a doxycycline hydrochloride solution in a control group are taken to carry out an accelerated test, the experimental conditions are that the temperature is 40 +/-2 ℃, the humidity is 75% +/-5 ℃, the color of the doxycycline hydrochloride solution is checked by the absorbance of impurities, the absorbance of the impurities can quantitatively represent the color of the solution, and the degradation condition of the main component is determined by preparing the solution with the same concentration by adopting a method for determining related substances of a doxycycline hydrochloride raw material. The method for detecting the absorbance of the impurities comprises the following steps: precisely measuring appropriate amount of the product, adding methanol solution (1 → 100) of hydrochloric acid solution (9 → 100), dissolving, quantitatively diluting to obtain solution containing doxycycline 10mg per 1ml, and measuring at 490mn wavelength by ultraviolet-visible spectrophotometry (see pharmacopoeia of Chinese beasts).
The test results are shown in table 1:
as can be seen from Table 1, in the aspect of the color of the solution, the determination by an absorbance method shows that the color of the doxycycline hydrochloride solution prepared by the method is basically unchanged, the absorbance of the impurity is basically not increased, the absorbance of the impurity of the doxycycline hydrochloride control solution prepared by the prior art is obviously increased, the colored impurity is increased, and the color is darkened, and the increase degree of related substances (total impurities) of the doxycycline hydrochloride prepared by the method is smaller than that of the doxycycline hydrochloride control solution prepared by the prior art. Therefore, the doxycycline hydrochloride solution prepared by the method is more stable.
Claims (8)
1. The doxycycline hydrochloride solution is characterized in that the preparation raw materials of each 100ml of the doxycycline hydrochloride solution comprise:
2. the doxycycline hydrochloride solution of claim 1, wherein the starting material for preparing each 100ml of the doxycycline hydrochloride solution comprises:
3. doxycycline hydrochloride solution according to claim 1, wherein the antioxidant is selected from one or more of sodium sulfite, sodium bisulfite, sodium metabisulfite, vitamin C, butylated hydroxyanisole.
4. Doxycycline hydrochloride solution according to claim 1, wherein the organic solvent is selected from one or more of polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, 1, 2-propylene glycol, glycerol, dimethylacetamide.
5. Doxycycline hydrochloride solution according to claim 1, prepared per 100ml by a process comprising the steps of:
(1) dissolving antioxidant and edetic acid with 1-5g of water, adding organic solvent, mixing, and making into mixed solution;
(2) and adding doxycycline hydrochloride and urea into the mixed solution, mixing, stirring, heating at a controlled temperature, cooling to room temperature, adding water to make up to 100ml, filtering, subpackaging, filling nitrogen during packaging, and filling and sealing to obtain the doxycycline hydrochloride solution.
6. The preparation method according to claim 5, wherein the temperature of the temperature-controlled heating is 20-60 ℃, and the time of the temperature-controlled heating is 0.5-2 h.
7. The preparation method according to claim 6, wherein the temperature of the temperature-controlled heating is 30-50 ℃, and the time of the temperature-controlled heating is 1-1.5 h.
8. Doxycycline hydrochloride solution according to claim 1, for use directly in the treatment of infections caused by gram-positive cocci and negative bacilli.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE723144A (en) * | 1968-10-30 | 1969-04-01 | ||
| CN104274474A (en) * | 2014-09-12 | 2015-01-14 | 安徽天安动物药业有限公司 | Doxycycline hydrochloride injection and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE723144A (en) * | 1968-10-30 | 1969-04-01 | ||
| CN104274474A (en) * | 2014-09-12 | 2015-01-14 | 安徽天安动物药业有限公司 | Doxycycline hydrochloride injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 高效液相色谱法检测四环素母液中尿素含量;靳艳仿等;《科技专论》;20141231;第306页 * |
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