CN111789827A - Etomicin sulfate aerosol inhalation preparation and preparation method thereof - Google Patents
Etomicin sulfate aerosol inhalation preparation and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutics, and particularly relates to an etimicin sulfate solution preparation for inhalation and a preparation method thereof. The invention provides an etimicin sulfate solution preparation for inhalation, which comprises the following components: etimicin sulfate or hydrate thereof, osmotic pressure regulator, metal complexing agent, pH regulator and solvent. The etimicin sulfate inhalation solution changes the administration route of the existing product, and provides a novel safe and effective etimicin sulfate administration preparation and administration mode, thereby avoiding various inconveniences caused by intravenous drip; can directly reach target organs for respiratory tract infection including acute bronchitis, acute attack of chronic bronchitis and the like, and has the advantages of quick response and small dosage.
Description
Technical Field
The invention belongs to the field of pharmaceutics, and particularly relates to an etimicin sulfate solution preparation for inhalation and a preparation method thereof.
Background
Etimicin (Etimicin), alias E-402, and antibiotic 89-07, are semi-synthetic water-soluble antibiotics, belonging to aminoglycosides. The etimicin has an action mechanism of inhibiting the normal protein synthesis of sensitive bacteria, is a broad-spectrum antibiotic, is mainly used for treating respiratory tract infection, digestive tract infection, genitourinary system infection, skin infection, soft tissue infection, bone infection, joint infection, abdominal cavity infection, wound infection and the like caused by gram-negative bacteria such as escherichia coli, klebsiella, proteus, enterobacter, citrobacter, serratia, haemophilus influenzae, salmonella, shigella, neisseria and the like, and is also suitable for septicemia.
Etimicin has been developed and marketed as injection and freeze-dried preparation, both forms of the product are administered by intravenous drip when in use, systemic or local infection is easy to generate due to improper treatment, the drug is excessive or drip too fast, adverse reaction is easy to generate, even the life is endangered, and continuous excessive infusion easily causes heavy circulation load or electrolyte imbalance. For example, chinese patent CN1209320A discloses a medicinal spray, which comprises antibiotic selected from etimicin, solvent selected from distilled water, adjuvant selected from glycerol, ethylene glycol, ethanol, dimethyl sulfoxide and span-85, antioxidant selected from anhydrous sodium sulfite and sodium pyrosulfate, flavoring agent selected from borneol and peppermint oil. However, when the spray is used, the particle size of the liquid medicine sprayed by the sprayer hardly meets the requirement of inhalation medication, the sprayed liquid medicine is basically adsorbed on the oral mucosa, the target site administration cannot be realized, and excessive auxiliary materials such as antioxidant and the like are added in the spray, so that the spray has adverse effects on human bodies.
In summary, the etimicin preparations disclosed in the prior art have various defects, and thus the safe and effective administration requirements of the market cannot be met, so that the development of a new etimicin dosage form meeting the market requirements is urgently needed.
Disclosure of Invention
In order to solve the technical problems, the invention provides a safe and effective etimicin sulfate solution preparation for inhalation, a preparation method and application thereof. The etimicin sulfate inhalation solution changes the administration route of the existing product, thereby avoiding various inconveniences caused by intravenous drip or injection, directly reaching target organs for respiratory tract infection including acute bronchitis, acute attack of chronic bronchitis and other symptoms, and having the advantages of quick response, small dosage and good drug effect.
The invention provides an etimicin sulfate solution preparation for inhalation, which is realized by the following technical scheme:
an etimicin sulfate solution formulation for inhalation comprising: etimicin sulfate or hydrate thereof, osmotic pressure regulator, metal complexing agent, pH regulator and solvent. The formula has the characteristics that the product quality is stable, the stability can be ensured without adding auxiliary materials such as preservatives, antioxidants and the like, key quality attributes such as product properties, pH values, colors, impurities and the like can be maintained in a controllable range, the safety is high, and the side reaction is less.
The etimicin sulfate aerosol inhalation solution preparation comprises 20-120mg of etimicin sulfate or hydrate thereof, more preferably 50-100mg of etimicin sulfate or hydrate thereof, calculated as free etimicin in single dose.
When the content of etimicin sulfate or the hydrate thereof in a single dose is in the range, the exposure (AUC0-24) of rats in vivo is equivalent to that of a reference preparation, and no statistical difference exists; and can inhibit the normal protein synthesis of sensitive bacteria, and can be well used for treating diseases such as acute bronchitis, acute attack of chronic bronchitis, community lung infection and the like.
The etimicin sulfate solution preparation for atomization and inhalation comprises an osmotic pressure regulator, wherein the osmotic pressure regulator is selected from one or a combination of two or more of inorganic salt osmotic pressure regulators and saccharide osmotic pressure regulators, the inorganic salt osmotic pressure regulators are selected from sodium chloride, magnesium chloride and the like, and the more preferable inorganic salt osmotic pressure regulator is sodium chloride; the sugar-type osmotic pressure regulator is selected from glucose, fructose, mannitol, etc., and more preferably glucose. The osmotic pressure regulator has good regulating capacity on the osmotic pressure of the solution, and the osmotic pressure regulator can be used alone or in a mixture of more than two, and preferably, the osmotic pressure regulator is inorganic salt.
In the etimicin sulfate solution preparation for atomization and inhalation, the dosage of the inorganic salt osmotic pressure regulator in a single dosage of the preparation is preferably 1-10mg/ml, preferably 5-9mg/ml, and more preferably 8-9 mg/ml. By controlling the dosage of the osmotic pressure regulator within the range, the osmotic pressure of the etimicin sulfate solution preparation for aerosol inhalation can reach isotonic, thereby reducing the irritation to mucosa during use and being beneficial to the product to exert the drug effect.
The etimicin sulfate solution preparation for atomization and inhalation comprises a metal complexing agent, wherein the metal complexing agent can be selected from edetic acid, edetate and the like, the edetate can be selected from edetate disodium, edetate calcium sodium and the like, and the metal complexing agent can be used singly or by mixing more than two of the metal complexing agents. The metal complexing agent is preferably edetate, and more preferably disodium edetate. The metal ion complexing agent is added into the preparation, so that the influence of metal ions introduced in the liquid preparation process on the quality of liquid medicine can be avoided, and the stability of the etimicin sulfate aerosol inhalation solution preparation is obviously improved.
In the etimicin sulfate solution preparation for atomization and inhalation, the dosage of the metal complexing agent in a single dosage of the preparation is preferably 0.1-5mg, and more preferably 0.5-2 mg. By controlling the dosage of the metal complexing agent within the range, the drug effect of the etimicin sulfate solution preparation for atomization and inhalation can be promoted, the stability of the etimicin sulfate is improved, various detection indexes are not obviously changed even the etimicin sulfate solution preparation is placed for a long time, and the qualified product quality in the validity period is ensured.
The etimicin sulfate solution preparation for atomization and inhalation comprises a pH regulator, wherein the pH regulator is selected from sodium bicarbonate, sodium hydroxide, disodium hydrogen phosphate, sodium citrate, dipotassium hydrogen phosphate, sodium carbonate, sodium dihydrogen phosphate, hydrochloric acid, sulfuric acid, lactic acid, malic acid, acetic acid, phosphoric acid, citric acid and the like. These pH adjusters may be used alone, or may also be used in combination of a plurality. Among these, hydrochloric acid, sodium hydrogen carbonate, sodium hydroxide, disodium hydrogen phosphate, sodium citrate, or dipotassium hydrogen phosphate is more preferable, and hydrochloric acid or sodium hydroxide is particularly preferable.
The etimicin sulfate solution preparation for atomization and inhalation has a pH value of 4.0-6.5, preferably 4.5-6.0, and more preferably 5.2-5.8 in a single dose. By controlling the pH of the etimicin sulfate solution for aerosol inhalation within the above range, the stability of etimicin sulfate can be increased. If the pH is less than 4.0 or if the pH exceeds 6.5, the degradation of etimicin sulfate tends to be accelerated.
In the above inhalation solution preparation, as a preferred embodiment, the solvent is selected from purified water, water for injection or sterile water for injection.
The etimicin sulfate solution preparation for atomization and inhalation is packaged by single dose medicines. A single dose refers to a dose of the pharmaceutically active ingredient used in a single inhalation. In the present invention, the single dose may be 1 to 5mL (e.g., 1mL, 2mL, 3mL, 4mL, 5mL), preferably 2 to 5mL, more preferably 5 mL. When the solution preparation is single dose, the use process is convenient, dilution and preparation are not needed, the microbial pollution and waste in the use process can be greatly reduced, and the dosage of single administration is adopted, so that the defects that multiple doses of large package solution cause repeated measurement and repeated dilution preparation are easy to breed microbes are overcome.
The second object of the present invention is to provide a method for preparing etimicin sulfate solution formulation for inhalation, comprising the steps of:
(1) adding 50-80% of solvent into the liquid preparation device, controlling the water temperature at 25 + -10 deg.C, introducing nitrogen gas until the dissolved oxygen is less than 1mg/L, and continuing until the sample preparation is finished;
(2) weighing a metal complexing agent and an osmotic pressure regulator, slowly adding the metal complexing agent and the osmotic pressure regulator into the water for injection, and stirring until the metal complexing agent and the osmotic pressure regulator are completely dissolved;
(3) slowly adding etimicin sulfate or its hydrate, and stirring until it is completely dissolved;
(4) adding a pH regulator to regulate the pH value;
(5) adding the solvent to full amount, and stirring to mix uniformly;
(6) filtering, and packaging in ampoule.
In the above preparation method, the solvent is selected from purified water, water for injection or sterile water for injection.
In the above production method, the pH of the solution is adjusted to 4.0 to 6.5, preferably 4.5 to 6.0, more preferably 5.2 to 5.8 in the step (4).
In the preparation method, the filtration in the step (6) is primary filtration by using a 0.45 mu m filter membrane, and fine filtration by using a 0.22 mu m filter membrane, which are aseptic filtration.
The etimicin sulfate solution preparation for inhalation has the effect of resisting infection, so the invention also aims to provide the application of the etimicin sulfate solution preparation for inhalation in preparing the medicines for treating infectious diseases, including but not limited to acute and chronic bronchitis.
Compared with the prior art, the invention has the following technical effects:
1. the etimicin sulfate inhalation solution provides a novel safe and effective etimicin sulfate administration preparation and administration mode for infants, children and patients with active dyspnea without self-inhalation capability, thereby making up for various defects caused by administration routes such as intravenous drip, aerosol and the like.
2. The etimicin sulfate inhalation solution preparation provided by the invention does not contain a preservative, an antioxidant and a buffering agent, can achieve good stability by adding a certain proportion of a complexing agent and a pH value regulator, and has reliable quality and high safety.
3. The preparation method adopts a sterilization filtration process, and improves the stability of the sample while ensuring the sterility level of the product. Simple process, good reproducibility, good product stability and easy large-scale industrial production.
Detailed Description
The preparation process and the materials used in the preparation or the dosage of the materials used in the preparation in the following examples of the pharmaceutical preparation are not limited to the words, and all methods containing the pharmaceutical preparation provided by the present invention are within the protection scope of the present invention.
The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
EXAMPLE 1 Etomicin sulfate Aerosol inhalation solution 200 arms
Etimicin sulfate 4.0g (as C)21H43N5O7Calculated) proper amount of sodium chloride
Adjusting pH to 4.5 with sodium hydroxide to 0.02g disodium edetate
The volume of the water for injection is up to 1000ml
The process comprises the following steps:
adding 50% water for injection into a container, introducing nitrogen gas until dissolved oxygen is less than 1mg/L (continuously until the sample preparation is finished), adding edetate disodium, sodium chloride and etimicin sulfate, stirring for dissolving, adjusting pH of the solution to 4.5 with sodium hydroxide, metering volume with water for injection, fine filtering, packaging into ampoules, introducing nitrogen gas for protection, and sealing by melting.
EXAMPLE 2 Etomicin sulfate Aerosol inhalation solution 200 arms
Etomicin sulfate 10.0g (as C)21H43N5O7Calculated) proper amount of sodium chloride
Adjusting pH to 5.2 with sodium hydroxide to 0.1g disodium edetate
The volume of the water for injection is up to 1000ml
The process comprises the following steps:
adding 70% of water for injection into a container, introducing nitrogen until dissolved oxygen is less than 1mg/L (continuously until the sample preparation is finished), adding edetate disodium, sodium chloride and etimicin sulfate, stirring for dissolving, adjusting pH of the solution to 5.2 with sodium hydroxide, metering volume with water for injection, fine-filtering, packaging in an ampoule under nitrogen protection, and sealing by melting.
EXAMPLE 3 Etomicin sulfate Aerosol inhalation solution 200 arms
Etimicin sulfate 20.0g (as C)21H43N5O7Calculated) proper amount of sodium chloride
Adjusting pH to 6.0 with sodium hydroxide to obtain 0.4g disodium edetate
The volume of the water for injection is up to 1000ml
The process comprises the following steps:
adding 70% of water for injection into a container, introducing nitrogen until dissolved oxygen is less than 1mg/L (continuously until the sample preparation is finished), adding edetate disodium, sodium chloride and etimicin sulfate, stirring for dissolving, adjusting pH of the solution to 6.0 with sodium hydroxide, metering volume with water for injection, fine-filtering, packaging in an ampoule under nitrogen protection, and sealing by melting.
EXAMPLE 4 Etomicin sulfate Aerosol inhalation solution 200 arms
Etomicin sulfate 24.0g (as C)21H43N5O7Calculated) proper amount of sodium chloride
Adjusting pH to 5.8 with sodium hydroxide to obtain 1.0g disodium edetate
The volume of the water for injection is up to 1000ml
The process comprises the following steps:
adding 80% water for injection into a container, introducing nitrogen gas until dissolved oxygen is less than 1mg/L (continuously until the sample preparation is finished), adding edetate disodium, sodium chloride and etimicin sulfate, stirring for dissolving, adjusting pH of the solution to 5.8 with sodium hydroxide, metering volume with water for injection, fine filtering, packaging into ampoule, introducing nitrogen gas for protection, and sealing by melting.
EXAMPLE 5 Etomicin sulfate Aerosol inhalation solution 200 arms
Etomicin sulfate 10.0g (as C)21H43N5O7Calculated) proper amount of sodium chloride
Adjusting pH to 4.5 with sodium hydroxide to obtain 0.2g disodium edetate
The volume of the water for injection is up to 1000ml
The process comprises the following steps:
adding 70% of water for injection into a container, introducing nitrogen until dissolved oxygen is less than 1mg/L (continuously until the sample preparation is finished), adding edetate disodium, sodium chloride and etimicin sulfate, stirring for dissolving, adjusting pH of the solution to 4.5 with sodium hydroxide, metering volume with water for injection, fine-filtering, packaging in an ampoule under nitrogen protection, and sealing by melting.
EXAMPLE 6 Etomicin sulfate Aerosol inhalation solution 200 arms
Etimicin sulfate 15.0g (as C)21H43N5O7Calculated) proper amount of sodium chloride
Adjusting pH to 5.5 with sodium hydroxide to obtain 0.4g disodium edetate
The volume of the water for injection is up to 1000ml
The process comprises the following steps:
adding 80% water for injection into a container, introducing nitrogen until dissolved oxygen is less than 1mg/L (continuously until the sample preparation is finished), adding edetate disodium, sodium chloride and etimicin sulfate, stirring for dissolving, adjusting pH of the solution to 5.5 with sodium hydroxide, metering volume with water for injection, fine-filtering, packaging in ampoule, and sealing by melting.
EXAMPLE 7 Etomicin sulfate Aerosol inhalation solution 200 arms
Etimicin sulfate 20.0g (as C)21H43N5O7Calculated) proper amount of sodium chloride
Adjusting pH to 6.0 with sodium hydroxide to obtain 0.5g disodium edetate
The volume of the water for injection is up to 1000ml
The process comprises the following steps:
adding 70% water for injection into a container, introducing nitrogen until dissolved oxygen is less than 1mg/L (continuously until the sample preparation is finished), adding edetate disodium, sodium chloride and etimicin sulfate, stirring for dissolving, adjusting pH of the solution to 6.0 with sodium bicarbonate, metering volume with water for injection, fine filtering, packaging in ampoule, and sealing by melting.
Example 8 Etomicin sulfate spray 200
Etimicin sulfate 20.0g (as C)21H43N5O7Meter) anhydrous sodium sulfite 12g
Glycerol 400g borneol 2g
Adding water for injection to 1000ml
Dissolving etimicin sulfate, water for injection, anhydrous sodium sulfite, glycerol and borneol, mixing uniformly, subpackaging in a proper container (5 ml), and packaging a micro sprayer head, wherein the operation is carried out in a bacterium-avoiding environment.
Test example 1: the samples were prepared by the recipe process based on example 2, the amount of the complexing agent was adjusted, and the stability of the formulation when disodium edetate was used as the complexing agent was examined, and the results are shown in table 1.
TABLE 1 Long-term test results of complexing agent screening of the present invention
And (4) conclusion: when the dosage of the edetate disodium is 0.1-5.0mg, the product stability is obviously improved, wherein when the dosage of the edetate disodium is 0.5-2.0mg, related substances and contents of a sample are more stable, and when the dosage of the edetate disodium is more than 2.0mg, the sample stability is not obviously improved.
Test example 2: samples were prepared by the recipe process based on example 3 and the stability of the formulations was examined using hydrochloric acid and/or sodium hydroxide as pH adjusting agent, and the results are shown in tables 2 and 3.
Table 2 long term test assay results for pH screening of the invention 1
TABLE 3 Long term test results of pH screening of the present invention 2
And (4) conclusion: the stability of the formulation is within an acceptable range when the pH of the solution is within the range of 4.0-6.5, with more stability regarding the substances and amounts present when the pH is within the range of 4.5-6.0. On the basis of further optimizing the pH value, the key quality attributes such as product properties, the pH value, related substances, content and the like are obviously improved in the long-term storage process when the pH value is within the range of 5.2-5.8.
Test example 3: the preparation quality of the sterile filtration process and the conventional sterilization process is examined by taking the example 2, the example 3 and the example 4 as the basic prescription, and the comparison result is shown in the table 4.
TABLE 4 results of the sterilization mode examination test of the present invention
And (4) conclusion: compared with the sterilizing filtration process, the related substances of the sterilizing process are obviously increased, so the sterilizing filtration process which is more stable to the product is selected.
Test example 4: test for anti-inflammatory Effect
SD rats, female and male, after quarantine and adaptive feeding, are randomly divided into 6 groups according to body weight, and each group comprises 8 rats, namely a normal control group G1, a model control group G2, an etimicin sulfate atomization inhalation group G3-G5 and an etimicin sulfate atomization inhalation group G6. After adaptive feeding grouping, the G1 group is administrated with 0.9% sodium chloride injection for 80 min; the rats in groups G2-G6 were administered 2mg/ml LPS solution and 80min after administration by nebulization and inhalation, immediately after administration of the test article. Wherein the normal control group and the model control group are perfused with the same amount of normal saline, the etimicin sulfate aerosol inhalation group G3-G5 is administered to the etimicin sulfate inhalation solution prepared in examples 5-7 by aerosol, and the etimicin sulfate spray group is administered to the etimicin sulfate spray prepared in example 8 by spray, 1 time a day for 3 days, and a LPS rat pneumonia model is established. The rats in each group were euthanized by 16h of the last dose, and the material was obtained and the bronchoalveolar lavage leukocytes of the rats were classified and determined as shown in table 5.
TABLE 5 test results of anti-inflammatory effects of the drugs of the present invention
| Group of | White blood cell count (wbc) |
| Blank control group (G1) | 1.05±0.39 |
| Model control group (G2) | 41.01±11.27* |
| Etimicin sulfate aerosol inhalation group 1(G3) | 25.57±7.31*&& |
| Etimicin sulfate aerosol inhalation group 2(G4) | 22.16±13.76* |
| Etimicin sulfate aerosol inhalation group 3(G5) | 25.03±11.6*&& |
| Etimicin sulfate spray set (G6) | 31.14±8.93*& |
"" comparison with blank control (G1) p < 0.05
"&" compared to model control (G2) p < 0.05; "& &" compared with model control group p < 0.01
The results show that compared with the etimicin sulfate spray, the etimicin sulfate atomized inhalation solution has more remarkable treatment effect on acute pneumonia.
Claims (10)
1. An etimicin sulfate solution formulation for inhalation comprising: etimicin sulfate or hydrate thereof, osmotic pressure regulator, metal complexing agent, pH regulator and solvent.
2. The solution formulation according to claim 1, wherein the formulation comprises 20-120mg etimicin sulfate or its hydrate, preferably 50-100mg etimicin sulfate or its hydrate, in a single dose, based on free etimicin.
3. The solution preparation according to claim 1, wherein the osmotic pressure regulator is selected from one, two or more combinations of inorganic salt type osmotic pressure regulators, and sugar type osmotic pressure regulators, and the inorganic salt type osmotic pressure regulators are preferably sodium chloride or magnesium chloride, and more preferably sodium chloride; the saccharide osmotic pressure regulator is preferably glucose, fructose or mannitol, more preferably glucose.
4. The solution preparation of claim 1, wherein the amount of the inorganic salt-based tonicity modifier is 1-10mg/ml, preferably 5-9mg/ml, and more preferably 8-9mg/ml in a single dose of the preparation.
5. The solution preparation according to claim 1, wherein the metal complexing agent is selected from edetic acid, edetate and the like, edetate is selected from edetate disodium and edetate calcium sodium, and the metal complexing agent is used alone or in combination of two or more thereof; the metal complexing agent is preferably edetate, and more preferably disodium edetate.
6. The solution formulation according to claim 1, characterized in that the amount of metal complexing agent is 0.1-5mg, preferably 0.5-2mg, in a single dose of the formulation.
7. The solution formulation according to claim 1, wherein the formulation has a pH value of 4.0-6.5, preferably 4.5-6.0, more preferably 5.2-5.8; the pH regulator is selected from one or more of sodium bicarbonate, sodium hydroxide, disodium hydrogen phosphate, sodium citrate, dipotassium hydrogen phosphate, sodium carbonate, sodium dihydrogen phosphate, hydrochloric acid, sulfuric acid, lactic acid, malic acid, acetic acid, phosphoric acid or citric acid, preferably one or more of hydrochloric acid, sodium bicarbonate, sodium hydroxide, disodium hydrogen phosphate, sodium citrate or dipotassium hydrogen phosphate, and more preferably hydrochloric acid or sodium hydroxide.
8. The solution formulation of claim 1, wherein the solvent is selected from purified water, water for injection, or sterile water for injection.
9. A method of preparing a solution formulation according to any one of claims 1 to 8, comprising the steps of:
(1) adding 50-80% of solvent based on water into the liquid preparation device, controlling water temperature at 25 + -10 deg.C, introducing nitrogen gas until dissolved oxygen is less than 1mg/L, and continuing until sample preparation is finished;
(2) weighing a metal complexing agent and an osmotic pressure regulator, slowly adding the metal complexing agent and the osmotic pressure regulator into the water for injection, and stirring until the metal complexing agent and the osmotic pressure regulator are completely dissolved;
(3) slowly adding etimicin sulfate or its hydrate, and stirring until it is completely dissolved;
(4) adding a pH regulator to regulate the pH value;
(5) adding the solvent to full amount, and stirring to mix uniformly;
(6) filtering, and filling into ampoule;
preferably, the filtration in the step (6) is a primary filtration with a 0.45 μm filter membrane, and a secondary filtration with a 0.22 μm filter membrane, which are both aseptic filtration.
10. Use of a solution formulation according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment of infectious diseases including, but not limited to, acute and chronic bronchitis.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910257063 | 2019-04-01 | ||
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| CN111789827A true CN111789827A (en) | 2020-10-20 |
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