CN105853473B - oxiracetam pharmaceutical composition and preparation method thereof - Google Patents
oxiracetam pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN105853473B CN105853473B CN201610196278.XA CN201610196278A CN105853473B CN 105853473 B CN105853473 B CN 105853473B CN 201610196278 A CN201610196278 A CN 201610196278A CN 105853473 B CN105853473 B CN 105853473B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
Abstract
the invention belongs to the technical field of medicines, and particularly relates to an oxiracetam pharmaceutical composition, wherein the pharmaceutical composition is an injection for injection, and comprises the following components: 200mg/mL of oxiracetam, 1.0-3.0 mg/mL of water-soluble ginkgo leaf extract, 0.5-2.0 mg/mL of citric acid, an osmotic pressure regulator (such as sodium chloride and glucose) and a pH regulator, wherein the pH value of the pharmaceutical composition is 4.5-5.0. The invention also provides a preparation method of the oxiracetam pharmaceutical composition injection, which comprises the steps of dissolving the raw material medicines, decoloring by using active carbon, adjusting the pH value, sterilizing and the like. The oxiracetam and the water-soluble ginkgo leaf extract in the pharmaceutical composition obtained according to the formula and the preparation method have a synergistic effect, so that the capability of oxiracetam in repairing cerebral nerve cells is enhanced, the effects of improving the memory and the thinking ability of patients are improved, and the oxiracetam and the water-soluble ginkgo leaf extract have good stability.
Description
Technical Field
The invention relates to the technical field of medicines, and in particular relates to an oxiracetam medicine composition and a preparation method thereof.
Background
Oxiracetam is a pyrrolidone derivative with the chemical name of 4-hydroxy-2-oxopyrrolidine-N-acetamide and the molecular name of C6H10N2O3The structural formula is as follows:
was successfully developed in 1974 by stecker bichrom, italy and marketed in 1987. The medicine has various formulations on the market, wherein the injection administration mode is intravenous drip dissolved in normal saline or other diluent, 4g is taken each time, and the dosage can be increased and decreased as required. The treatment course for the neurological deficit is 2 weeks, and the treatment course for the memory and intelligence disorder is 3 weeks.
Oxiracetam is a derivative of piracetam, and the main action mechanism of oxiracetam comprises the following aspects: 1. promoting synthesis of phosphatidylcholine and phosphatidylethanolamine, increasing ATP/ADP ratio in brain, and increasing synthesis of protein and nucleic acid in brain; 2. enhancing brain plasticity change, strengthening synapse formability, and improving memory and learning function of senile dementia and dysmnesia patients; 3. reducing cerebrovascular resistance, inhibiting platelet aggregation, improving microcirculation and increasing brain tissue blood flow; 4. promoting the neurotoxicity of excitatory amino acid of damaged nerve cell. It is suitable for treating brain injury and its induced nerve function deficiency, memory and intelligence disorder, especially senile dementia, and can be used for treating brain diseases such as neurosis and encephalitis in convalescent period.
The molecular conformation of oxiracetam has two conditions that hydroxyl and carbonyl are positioned on the same side and the different side of a pyrrole ring, but oxiracetam diseases with different spatial conformations cannot be separated in the prior art, so when the hydroxyl and the carbonyl of oxiracetam are positioned on the same side of the pyrrole ring at the same time, intramolecular hydrogen bonds are easily formed, the solubility of oxiracetam in water for injection is reduced, and the condition that white crystal powder is separated out from injection is caused particularly under the influence of storage time and environmental temperature.
In addition, during the actual production process, oxiracetam needs to be dissolved by contacting a metal container and heating to 40-60 ℃, and needs to be sterilized at high temperature, so trace metal ions can be detected in the finished injection, and the content of related substances in the injection is increased along with long-term storage due to the action of oxidizing hydroxyl groups of the metal ions, and particularly during the storage in extremely high-temperature weather, the influence of the oxidization on the stability of the product is not negligible.
the Chinese patent application No. 201410135403.7 discloses a pharmaceutical composition containing 4-hydroxy-2-oxo-1-pyrrolidine acetamide, which comprises oxiracetam and borneol components, and has synergistic effect in treating nervous motor dysfunction and impaired memory dysfunction caused by vascular dementia and senile dementia. However, borneol is cold in nature, and borneol and 2-borneol contained in borneol have certain irritation, so that the aged patients may have adverse reactions such as allergy and the like after the borneol is prepared into injection.
The Chinese patent with the application number of 201210176595.7 discloses a stable S-oxiracetam injection preparation and a preparation method thereof, and the stable S-oxiracetam injection preparation is a composition which is prepared by taking S-oxiracetam or salt thereof as a medicinal active component and pharmaceutically acceptable auxiliary materials and can be used for injection. The medicine composition uses the disodium calcium ethylenediamine tetraacetate as a complexing agent to remove metal ions possibly existing in the injection, but the disodium calcium ethylenediamine tetraacetate cannot chelate calcium ions and still has influence on the stability of the medicine.
The invention discloses a Chinese patent with application number of 200910131292.1, which discloses an injection taking levo-oxiracetam as an active ingredient, and the invention takes levo-oxiracetam or salt or purified hydrate thereof as a medicinal active ingredient and a pharmaceutically acceptable auxiliary material to prepare a composition for injection. The antioxidant used in the pharmaceutical composition is sodium bisulfite, and sulfite can be generated after the sodium bisulfite is oxidized to cause harm to human bodies.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide an oxiracetam medicinal composition with better stability and more excellent medicinal effect.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
the oxiracetam pharmaceutical composition is an injection solution, and comprises the following components:
oxiracetam 200mg/mL
1.0-3.0 mg/mL of water-soluble ginkgo extract
0.5-2.0 mg/mL of citric acid
preferably, the composition of the injection water injection comprises:
Oxiracetam 200mg/mL
1.5-3.0 mg/mL of water-soluble ginkgo extract
1.0-2.0 mg/mL of citric acid
The folium Ginkgo extract (EGb761) has antioxidant activity, cardiovascular activity, antiinflammatory activity and antitumor activity, is a common traditional Chinese medicine for treating cardiovascular disease and cerebrovascular disease at present, and has effective components mainly including semen Ginkgo flavone and semen Ginkgo diterpene lactone compounds, wherein the semen Ginkgo flavone glycoside mainly includes quercetin, kaempferol, and isorhamnetin. The diterpene lactone components of semen Ginkgo mainly include bilobalide A, B, C, J, M and bilobalide.
The invention unexpectedly discovers that after a certain amount of water-soluble ginkgo biloba extract and citric acid are added into a formula, the ginkgo biloba extract and the citric acid generate a synergistic effect on oxidation resistance, and trace metal elements remained in an oxiracetam drug composition injection due to process problems can be eliminated due to the chelating capacity of the citric acid to metal ions. Meanwhile, animal experiments prove that the water-soluble ginkgo leaf extract enhances the effects of oxiracetam in treating dysmnesia and improving learning ability.
the pharmaceutical composition is characterized by further comprising an osmotic pressure regulator, wherein the osmotic pressure regulator is one of sodium chloride and glucose.
The pharmaceutical composition is characterized by further comprising an osmotic pressure regulator, preferably one of sodium chloride and glucose.
The pharmaceutical composition is characterized in that when the osmotic pressure regulator is sodium chloride, the concentration is 5-20 mg/mL, preferably 5-10 mg/mL; the concentration of the osmotic pressure regulator is 40-60 mg/mL when the osmotic pressure regulator is glucose.
The total ginkgo flavone glycosides in the water-soluble ginkgo extract are more than or equal to 24 percent, and the total ginkgo terpene lactones are more than or equal to 6 percent.
The pharmaceutical composition also comprises a pH regulator, wherein the pH regulator is sodium citrate, and the pH value of the injection water injection is controlled to be 4.5-5.0 by adding a proper amount of the pH regulator, and the preferable pH value range is 4.5-4.8. After considering the influence of phosphate buffer solution, sodium hydroxide, hydrochloric acid and other traditional buffering agents on the long-term stability of oxiracetam, sodium citrate capable of forming a buffering pair with citric acid is selected, and the selected buffering agent can enable the citric acid to better play a role of a metal ion chelating agent.
The concentration of metal ions in the pharmaceutical composition is less than 1ppm, and the trace concentration of metal ions in the process is strictly controlled because the trace metal ions can oxidize oxiracetam.
The invention also provides a preparation method of the oxiracetam pharmaceutical composition, which comprises the following steps:
(1) Under the protection of nitrogen, heating the water for injection to 40-60 ℃, wherein the residual oxygen in the liquid is lower than 2 ppm;
(2) Under the protection of nitrogen, adding water-soluble ginkgo extract and citric acid into water for injection to be fully dissolved;
(3) under the protection of nitrogen, slowly adding the water-soluble ginkgo leaf extract and the aqueous solution for injection of citric acid in the step (2) into the aqueous solution for injection in the step (1), adding oxiracetam bulk drug, and fully stirring until the oxiracetam bulk drug is completely dissolved;
(4) Adding 0.1-0.3 wt% of needle activated carbon into the completely dissolved solution in the step (3), uniformly stirring, standing for 20 minutes for decolorization, and filtering with a microporous filter membrane to remove carbon;
(5) cooling the temperature of the filtered solution obtained in the step (4) to 25 ℃, adjusting the pH value to 4.5-5.0 by using sodium citrate, and supplementing the injection water to the full amount;
(6) filtering the solution in the step (5) by using a microporous filter membrane;
(7) filling nitrogen, filling into ampoule bottle, and hot pressing for sterilization.
In the preparation method, the injection water in the step (1) is also added with an osmotic pressure regulator before being heated, and the osmotic pressure regulator is one of sodium chloride or glucose.
The pH value in the step (5) is 4.5-4.8.
the hot-pressing sterilization temperature in the step (7) is 121 ℃, the sterilization time is 15-30 minutes, preferably 15 minutes, and in order to prevent the influence of high temperature on the stability of the pharmaceutical composition, the sterilization time is not too long under the condition of ensuring the sterilization effect.
compared with the prior art, the oxiracetam pharmaceutical composition injection disclosed by the invention has better stability and better drug effect.
Detailed Description
The following are specific embodiments of the present invention, which are intended to further illustrate the invention and not to limit it.
Firstly, a prescription screening experiment is carried out on the oxiracetam pharmaceutical composition, the oxiracetam (200mg/mL) with the same content, an osmotic pressure regulator (sodium chloride), water-soluble ginkgo leaf extract (EGb761) with different concentrations and citric acid are selected to form a prescription, and the pharmaceutical composition with the same components is used for measuring the appearance of a solution, visible foreign matters, related substances or metal ion content under different pH conditions to determine the optimal range of the components, the preparation method is carried out according to the invention, and the test results are shown in tables 1 to 3:
TABLE 1 concentration test results of water-soluble ginkgo biloba extract (EGb761) screened by prescription
| EGb761(mg/mL) | Citric acid (mg/mL) | appearance of solution | Related substance (%) |
| 0.2 | 1.0 | clear, colorless and transparent | 0.057 |
| 0.4 | 1.0 | clear, colorless and transparent | 0.049 |
| 0.6 | 1.0 | Clear, colorless and transparent | 0.036 |
| 0.8 | 1.0 | Clear, colorless and transparent | 0.031 |
| 1.0 | 1.0 | Clear, colorless and transparent | 0.020 |
| 1.4 | 1.0 | Clear, colorless and transparent | 0.020 |
| 1.8 | 1.0 | clear, colorless and transparent | 0.019 |
| 2.2 | 1.0 | Clear, colorless and transparent | 0.019 |
| 2.6 | 1.0 | Clear, colorless and transparent | 0.018 |
| 3.0 | 1.0 | Clear, colorless and transparent | 0.018 |
| 3.2 | 1.0 | Clear, colorless and transparent | 0.020 |
| 3.4 | 1.0 | Clear, transparent and light brown | 0.022 |
| 3.6 | 1.0 | clear, transparent and light brown | 0.022 |
| 3.8 | 1.0 | Clear, transparent, reddish brown | 0.024 |
| 4.0 | 1.0 | clear, transparent, reddish brown | 0.025 |
As can be seen from Table 1, when the concentration of the water-soluble ginkgo leaf extract is in the range of 0.2-0.8 mg/mL, the content of the related substances is relatively high, and the related substances do not meet the requirement of the quality standard, when the concentration of the water-soluble ginkgo leaf extract is in the range of 1.0-3.0 mg/mL, the degree of the decrease of the related substances is not obvious, and then the related substances are close to 3.2mg/mL, the detection content is improved, and the color of the solution is changed from colorless to light brown red, and the quality standard is not met, so that 1.0-3.0 mg/mL is selected as the.
TABLE 2 recipe screening citric acid concentration test results
| EGb761(mg/mL) | Citric acid (mg/mL) | Visible foreign body | metal ion (ppm) |
| 1.5 | 0.1 | no visible foreign matter | 1.32 |
| 1.5 | 0.2 | no visible foreign matter | 1.19 |
| 1.5 | 0.4 | no visible foreign matter | 1.02 |
| 1.5 | 0.5 | No visible foreign matter | 0.91 |
| 1.5 | 0.8 | No visible foreign matter | 0.82 |
| 1.5 | 1.0 | No visible foreign matter | 0.74 |
| 1.5 | 1.2 | No visible foreign matter | 0.68 |
| 1.5 | 1.5 | No visible foreign matter | 0.62 |
| 1.5 | 1.8 | No visible foreign matter | 0.56 |
| 1.5 | 2.0 | no visible foreign matter | 0.51 |
| 1.5 | 2.2 | With insoluble particles | 0.45 |
| 1.5 | 2.5 | with insoluble particles | 0.41 |
| 1.5 | 3.0 | With insoluble particles | 0.37 |
as can be seen from Table 2, when the concentration of citric acid is within the range of 0.1-0.4 mg/mL, the detection content of related substances is high, and the detection content does not meet the requirement of the quality standard, and when the concentration of citric acid is within the range of 2.2-3.0 mg/mL, the content of related substances is still reduced, but a small amount of insoluble particles appear in the solution, and the detection content does not meet the requirement of the quality standard, so that 0.5-2.0 mg/mL is selected as the preferable concentration range of citric acid.
Table 3 recipe screening pH value test results (wherein the concentration of water-soluble ginkgo leaf extract is 1.5mg/mL, the concentration of citric acid is 1.0mg/mL)
As can be seen from Table 3, the content of the related substances is higher but the related substances tend to decrease when the pH value is within the range of 3.5 to 4.5, the content of the related substances is lower but the related substances tend to increase when the pH value is within the range of 5.2 to 5.9, and the solution has insoluble particles when the pH value is increased to 5.9, which does not meet the requirement of quality standard, so the pH range of 4.5 to 5.0, which has the lowest content of the related substances and a smooth trend, is selected as the preferable concentration range.
In summary, the concentration range of the water-soluble ginkgo biloba extract selected in the embodiment is 1.0-3.0 mg/mL, the concentration range of the citric acid selected is 0.5-2.0 mg/mL, and the selected pH value range is 4.5-5.0.
Example 1
Prescription:
the preparation process comprises the following steps:
(1) Under the condition of nitrogen protection, dissolving the prescription amount of sodium chloride in 70-80% of the prescription amount of injection water, heating to 40-60 ℃, wherein the residual oxygen amount in the liquid is lower than 2 ppm;
(2) Under the condition of nitrogen protection, taking water-soluble ginkgo extract and citric acid with the prescription amount, and adding water for injection to fully dissolve;
(3) Slowly adding the mixed solution in the step (2) into the mixed solution in the step (1) under the protection of nitrogen, simultaneously adding oxiracetam bulk drug, and fully stirring until the oxiracetam bulk drug is completely dissolved;
(4) adding 0.1 wt% of needle activated carbon into the mixed solution in the step (3), uniformly stirring, standing for 20 minutes for decolorization, and filtering with a microporous filter membrane to remove carbon;
(5) Cooling the filtered solution obtained in the step (4) to 25 ℃, adjusting the pH value to 4.5 by using sodium citrate, and supplementing the injection water to the full amount;
(6) Filtering the solution in the step (5) by using a 0.22 mu m microporous filter membrane;
(7) Filling nitrogen, filling into ampoule bottle, and sterilizing at 121 deg.C for 30 min.
Example 2
Prescription:
The preparation process comprises the following steps:
(1) under the condition of nitrogen protection, dissolving the prescription amount of sodium chloride in 70-80% of prescription amount of injection water, heating to 60 ℃, wherein the residual oxygen in the liquid is lower than 2 ppm;
(2) Under the condition of nitrogen protection, taking water-soluble ginkgo extract and citric acid with the prescription amount, and adding water for injection to fully dissolve;
(3) slowly adding the mixed solution in the step (2) into the mixed solution in the step (1) under the protection of nitrogen, simultaneously adding oxiracetam bulk drug, and fully stirring until the oxiracetam bulk drug is completely dissolved;
(4) Adding 0.3 wt% of needle activated carbon into the mixed solution in the step (3), uniformly stirring, standing for 20 minutes for decolorization, and filtering with a microporous filter membrane to remove carbon;
(5) Cooling the filtered solution obtained in the step (4) to 25 ℃, adjusting the pH value to 5.0 by using sodium citrate, and supplementing the injection water to the full amount;
(6) filtering the solution in the step (5) by using a 0.22 mu m microporous filter membrane;
(7) filling nitrogen, filling into ampoule bottle, and sterilizing at 121 deg.C for 20 min.
Example 3
Prescription:
The preparation process comprises the following steps:
(1) Under the condition of nitrogen protection, dissolving the prescription amount of sodium chloride in 70-80% of prescription amount of injection water, heating to 50 ℃, wherein the residual oxygen in the liquid is lower than 2 ppm;
(2) Under the condition of nitrogen protection, taking water-soluble ginkgo extract and citric acid with the prescription amount, and adding water for injection to fully dissolve;
(3) Slowly adding the mixed solution in the step (2) into the mixed solution in the step (1) under the protection of nitrogen, simultaneously adding oxiracetam bulk drug, and fully stirring until the oxiracetam bulk drug is completely dissolved;
(4) Adding 0.2 wt% of needle activated carbon into the mixed solution in the step (3), uniformly stirring, standing for 20 minutes for decolorization, and filtering with a microporous filter membrane to remove carbon;
(5) Cooling the filtered solution obtained in the step (4) to 25 ℃, adjusting the pH value to 4.8 by using sodium citrate, and supplementing the injection water to the full amount;
(6) Filtering the solution in the step (5) by using a 0.22 mu m microporous filter membrane;
(7) Filling nitrogen, filling into ampoule bottle, and sterilizing at 121 deg.C for 15 min.
Example 4
Prescription:
The preparation process comprises the following steps:
(1) Under the condition of nitrogen protection, dissolving the prescribed amount of glucose in 70-80% of the prescribed amount of injection water, heating to 40 ℃, wherein the residual oxygen in the liquid is lower than 2 ppm;
(2) Under the condition of nitrogen protection, taking water-soluble ginkgo extract and citric acid with the prescription amount, and adding water for injection to fully dissolve;
(3) slowly adding the mixed solution in the step (2) into the mixed solution in the step (1) under the protection of nitrogen, simultaneously adding oxiracetam bulk drug, and fully stirring until the oxiracetam bulk drug is completely dissolved;
(4) Adding 0.2 wt% of needle activated carbon into the mixed solution in the step (3), uniformly stirring, standing for 20 minutes for decolorization, and filtering with a microporous filter membrane to remove carbon;
(5) Cooling the filtered solution obtained in the step (4) to 25 ℃, adjusting the pH value to 4.8 by using sodium citrate, and supplementing the injection water to the full amount;
(6) Filtering the solution in the step (5) by using a 0.22 mu m microporous filter membrane;
(7) filling nitrogen, filling into ampoule bottle, and sterilizing at 121 deg.C for 20 min.
example 5
Prescription:
The preparation process comprises the following steps:
(1) under the condition of nitrogen protection, dissolving the prescribed amount of glucose in 70-80% of the prescribed amount of injection water, heating to 50 ℃, wherein the residual oxygen in the liquid is lower than 2 ppm;
(2) under the condition of nitrogen protection, taking water-soluble ginkgo extract and citric acid with the prescription amount, and adding water for injection to fully dissolve;
(3) Slowly adding the mixed solution in the step (2) into the mixed solution in the step (1) under the protection of nitrogen, simultaneously adding oxiracetam bulk drug, and fully stirring until the oxiracetam bulk drug is completely dissolved;
(4) adding 0.1 wt% of needle activated carbon into the mixed solution in the step (3), uniformly stirring, standing for 20 minutes for decolorization, and filtering with a microporous filter membrane to remove carbon;
(5) Cooling the filtered solution obtained in the step (4) to 25 ℃, adjusting the pH value to 4.5 by using sodium citrate, and supplementing the injection water to the full amount;
(6) Filtering the solution in the step (5) by using a 0.22 mu m microporous filter membrane;
(7) filling nitrogen, filling into ampoule bottle, and sterilizing at 121 deg.C for 15 min.
Example 6
prescription:
The preparation process comprises the following steps:
(1) Under the condition of nitrogen protection, dissolving the prescribed amount of glucose in 70-80% of the prescribed amount of injection water, heating to 60 ℃, wherein the residual oxygen in the liquid is lower than 2 ppm;
(2) Under the condition of nitrogen protection, taking water-soluble ginkgo extract and citric acid with the prescription amount, and adding water for injection to fully dissolve;
(3) slowly adding the mixed solution in the step (2) into the mixed solution in the step (1) under the protection of nitrogen, simultaneously adding oxiracetam bulk drug, and fully stirring until the oxiracetam bulk drug is completely dissolved;
(4) adding 0.3 wt% of needle activated carbon into the mixed solution in the step (3), uniformly stirring, standing for 20 minutes for decolorization, and filtering with a microporous filter membrane to remove carbon;
(5) Cooling the filtered solution obtained in the step (4) to 25 ℃, adjusting the pH value to 5.0 by using sodium citrate, and supplementing the injection water to the full amount;
(6) filtering the solution in the step (5) by using a 0.22 mu m microporous filter membrane;
(7) Filling nitrogen, sealing in ampoule bottle, and sterilizing at 121 deg.C for 30min to obtain final product
Comparative example 1
prescription:
The preparation process comprises the following steps:
(1) Under the condition of nitrogen protection, dissolving the prescription amount of sodium chloride in 70-80% of prescription amount of injection water, heating to 50 ℃, wherein the residual oxygen in the liquid is lower than 2 ppm;
(2) Under the condition of nitrogen protection, taking a prescribed amount of water-soluble ginkgo extract, and adding water for injection to fully dissolve the water-soluble ginkgo extract;
(3) Slowly adding the mixed solution in the step (2) into the mixed solution in the step (1) under the protection of nitrogen, simultaneously adding oxiracetam bulk drug, and fully stirring until the oxiracetam bulk drug is completely dissolved;
(4) Adding 0.2 wt% of needle activated carbon into the mixed solution in the step (3), uniformly stirring, standing for 20 minutes for decolorization, and filtering with a microporous filter membrane to remove carbon;
(5) Cooling the filtered solution obtained in the step (4) to 25 ℃, adjusting the pH value to 4.8 by using sodium citrate, and supplementing the injection water to the full amount;
(6) filtering the solution in the step (5) by using a 0.22 mu m microporous filter membrane;
(7) filling nitrogen, filling into ampoule bottle, and sterilizing at 121 deg.C for 15 min.
Comparative example 2
Prescription:
The preparation process comprises the following steps:
(1) Under the condition of nitrogen protection, dissolving the prescription amount of sodium chloride in 70-80% of prescription amount of injection water, heating to 50 ℃, wherein the residual oxygen in the liquid is lower than 2 ppm;
(2) under the condition of nitrogen protection, citric acid with the prescription amount is additionally taken and is added with water for injection to be fully dissolved;
(3) slowly adding the mixed solution in the step (2) into the mixed solution in the step (1) under the protection of nitrogen, simultaneously adding oxiracetam bulk drug, and fully stirring until the oxiracetam bulk drug is completely dissolved;
(4) Adding 0.2 wt% of needle activated carbon into the mixed solution in the step (3), uniformly stirring, standing for 20 minutes for decolorization, and filtering with a microporous filter membrane to remove carbon;
(5) cooling the filtered solution obtained in the step (4) to 25 ℃, adjusting the pH value to 4.8 by using sodium citrate, and supplementing the injection water to the full amount;
(6) filtering the solution in the step (5) by using a 0.22 mu m microporous filter membrane;
(7) Filling nitrogen, filling into ampoule bottle, and sterilizing at 121 deg.C for 15 min.
Comparative example 3
is selected from a commercial product oxiracetam injection (manufacturer: Harbin Tri drug industry Co., Ltd., trade name: Origan, dosage form 1g:5 mL).
test example 1 high temperature light influence factor test
the oxiracetam drug composition injection prepared in the embodiments 1, 2, 4 and 5 and the comparative examples 1 to 3 of the invention is subjected to high temperature (60 ℃ plus or minus 2 ℃) and illumination (4500Lx plus or minus 500Lx) influence factor tests for 10 continuous days respectively, and samples are taken on the 5 th day and the 10 th day to detect the contents of related substances and oxiracetam, and the obtained test results are shown in Table 4.
TABLE 4 test results of high temperature and light influence factors
as can be seen from Table 4, the content of substances related to the above comparative examples and examples is analyzed, and the content of substances related to the comparative examples and examples is found that the addition of water-soluble ginkgo leaf extract alone or citric acid alone in the formula of the comparative commercially available product can reduce the content of substances related to the comparative examples, but the content of substances related to the comparative examples and examples is lower due to the effect of the formula of adding water-soluble ginkgo leaf extract and citric acid together. Meanwhile, as can be seen from table 4, compared with the commercially available products, the content of oxiracetam can be stabilized by adding the water-soluble ginkgo leaf extract alone or the citric acid alone in the formula, but the content of oxiracetam is stabilized and higher than that of the comparative example added alone under the action of the formula of adding the water-soluble ginkgo leaf extract and the citric acid together in the examples. In combination with the above contents, the stability of the high-temperature resistant light irradiation of the embodiment of the invention is superior to that of the comparative example, which shows that the temperature resistance and the light resistance stability of the oxiracetam pharmaceutical composition are enhanced by the synergy of the water-soluble ginkgo leaf extract and the citric acid.
test example 2 accelerated test
The oxiracetam pharmaceutical composition injection prepared in the embodiments 3 and 6 and the comparative examples 1 to 3 of the invention is respectively subjected to an accelerated test, stored for 6 months at the constant temperature and humidity of 40 +/-2 ℃ and the relative humidity of 75 +/-5%, sampled and detected in 0, 1, 3 and 6 months, and the obtained test result is shown in table 5.
TABLE 5 accelerated test results
as can be seen from table 5, after the formula of examples 3 and 6 is subjected to the accelerated test for 6 months, the solution appearance and the items of visible foreign matters both meet the pharmacopeia standards, the related substances are increased, but the oxiracetam content is decreased slowly within the acceptable range of the quality standard; compared with examples 3 and 6, the formula of the comparative example 1 and the formula of the comparative example 2 with the water-soluble ginkgo leaf extract added separately have the advantages that the effect is stronger than that of the comparative example 3 with the solution appearance changed in 3 months and the visible foreign matters changed, the visible foreign matter items of the comparative examples 1 and 2 do not meet the pharmacopoeia requirements in 6 months, the content of related substances is increased more, and the oxiracetam has larger reduction amplitude. In conclusion, the water-soluble ginkgo leaf extract and the citric acid synergistically enhance the accelerated stability of the oxiracetam pharmaceutical composition, and the effect of the oxiracetam pharmaceutical composition is superior to that of a prescription using the water-soluble ginkgo leaf extract or the citric acid alone and is far better than that of similar drugs sold in the market.
test example 3 Effect on memory and learning ability of anisodine-induced dementia mouse
1 materials of the experiment
1.1 test drugs: the oxiracetam medicaments obtained in the embodiments 1, 3 and 5 and the comparative examples 1 to 3.
1.2 animal materials: the weight of the SPF-level mouse is 18-22 g, and 80 mice are half male and half female.
1.3 device: a channel type water maze (4 blind end) and a dark and bright box by a dark method.
2 Experimental method steps
2.1 grouping and administration
80 mice are divided into 8 groups according to the random distribution principle, namely a blank control group, a model group, an example 1 group, an example 3 group, an example 5 group, a comparative example 1 group, a comparative example 2 group and a comparative example 3 group, wherein each group comprises 10 mice. The blank control group and the model group were administered with physiological saline daily, and the drug groups were administered with the oxiracetam pharmaceutical compositions obtained by the methods of examples 2, 4, 6 and comparative examples 1 to 31 time daily for 14 consecutive days.
2.2 training and modeling
And (2) performing channel type water maze training and dark avoidance method electric shock tests on the mice of each group from the 1 st day of administration, continuously performing 3 times a day for 7 days, training for leaving the maze for no more than 20 seconds, performing route selection error for no more than 2 times to obtain qualified training, performing intraperitoneal injection of anisodine (5.0mg/kg) for memory impairment molding of the mice of each group 1 hour after administration except for a blank control group, performing channel type water maze and dark avoidance tests 30 minutes after injection, and determining that the molding is successful if the training result is unqualified. The capacity test was performed after the 14 th day molding.
2.3 memory and learning ability test recording method
Dark avoidance: the dark room in the light and dark box is communicated with 36V alternating current, the face of the mouse is placed in the light room, and the timer is started at the same time. The animal passes through the opening and enters the darkroom to receive electric shock, the timing is stopped, and the mouse is taken out. The latency to enter the dark room and the number of shocks received within 5 minutes, i.e. the number of errors, were recorded.
channel type water maze: the mouse head was placed into the water maze towards the wall and recording was started. The time to complete their journey (latency) and the number of times to swim into the dead end (number of errors) were recorded, e.g. 2 minutes beyond 2 minutes.
3 data analysis and conclusions
3.1 Experimental results and analysis by the dodging method
The latency of the mice into the dark room and the number of shocks received within 5 minutes were recorded and the results are shown in table 6: TABLE 6 Experimental results of the dark method ()
| Group of | Incubation period(s) | Number of errors (/5min) |
| Blank control group | 269.7±12.4 | 1.2±0.9 |
| model set | 69.2±15.6* | 7.3±2.6* |
| EXAMPLE 1 group | 131.5±38.3** | 3.2±1.8** |
| EXAMPLE 3 group | 152.2±52.3** | 2.4±0.8** |
| EXAMPLE 5 group | 136.4±41.5** | 3.4±1.2** |
| Comparative example 1 group | 105.9±29.4*** | 3.9±1.4*** |
| Comparative example 2 group | 93.7±24.8*** | 5.8±1.9*** |
| Comparative example 3 group | 85.1±28.6*** | 6.3±2.8*** |
P < 0.01 compared to the blank control; comparison with model groups: p < 0.01, P < 0.05.
as can be seen from Table 6, the latency of the anisodine dementia model mice in the light room can be prolonged and the number of electric shocks to the dark room can be reduced in the examples 1, 3, 5 (P < 0.01) and the comparative examples 1 to 3 (P < 0.05) compared with the model group. The group 3 of comparative examples, which did not contain water-soluble ginkgo biloba extract and citric acid, could improve the memory learning ability of the modeled mice, but the effect was inferior to the group 1 of comparative examples, which added water-soluble ginkgo biloba extract and the group 2 of comparative examples, which added citric acid, while the groups 1, 3, 5 of examples, which added water-soluble ginkgo biloba extract and citric acid, had more significant improvement than the groups 1, 2 of comparative examples. Therefore, the composition of the water-soluble ginkgo leaf extract, the citric acid and the oxiracetam can generate a synergistic effect, and the effect of the composition is far greater than that of a single component.
3.2 channel Water maze test results and analysis
The time to complete swimming (latency) and number of swimming into the dead end (number of errors) were recorded for the mice and the results are shown in table 7:
TABLE 7 results of channel Water maze experiment: ()
| Group of | latency(s) | number of errors |
| blank control group | 18.2±1.5 | 1.1±0.6 |
| Model set | 2min* | 6.2±2.7* |
| EXAMPLE 1 group | 31.7±6.3** | 2.4±1.8** |
| EXAMPLE 3 group | 28.6±5.7** | 2.1±1.5** |
| EXAMPLE 5 group | 33.9±5.9** | 2.8±1.4** |
| Comparative example 1 group | 59.0±11.6*** | 4.6±2.1*** |
| Comparative example 2 group | 64.4±15.4*** | 4.2±1.6*** |
| Comparative example 3 group | 72.1±13.0*** | 5.3±2.2*** |
P < 0.01 compared to the blank control; comparison with model groups: p < 0.01, P < 0.05.
As can be seen from Table 7, the groups of examples 1, 3 and 5 (P < 0.01) and the groups of comparative examples 1 to 3 (P < 0.05) all reduced the latency in the water maze and the number of times they entered the blind end in the anisodine-induced dementia model mice as compared with the model group. The group of comparative example 3 containing no water-soluble ginkgo leaf extract and citric acid was able to improve the cognitive learning ability of the dysmnesia mice, but the effect was inferior to that of the group of comparative example 1 containing a water-soluble ginkgo leaf extract component and the group of comparative example 2 containing a citric acid component, while the groups of examples 1, 3 and 5 containing a water-soluble ginkgo leaf extract and a citric acid component at the same time had more significant effects than the groups of comparative examples 1 and 2. Therefore, the composition of the water-soluble ginkgo leaf extract, the citric acid and the oxiracetam can generate a synergistic effect, and the effect of the composition is far greater than that of a single component.
the above tests were also performed on oxiracetam pharmaceutical compositions prepared according to other embodiments of the present invention, which gave similar results.
the present invention has been described in detail in order to enable those skilled in the art to understand the invention and to practice it, and it is not intended to limit the scope of the invention, and all equivalent changes and modifications made according to the spirit of the present invention should be covered by the present invention.
Claims (14)
1. The oxiracetam pharmaceutical composition is characterized by being an injection solution, and comprising the following components:
oxiracetam 200mg/mL
1.0-3.0 mg/mL of water-soluble ginkgo extract
0.5-2.0 mg/mL of citric acid;
the concentration of metal ions in the pharmaceutical composition is less than 1 ppm.
2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is an injection solution, and comprises:
oxiracetam 200mg/mL
1.5-3.0 mg/mL of water-soluble ginkgo extract
0.5-1.0 mg/mL of citric acid;
The concentration of metal ions in the pharmaceutical composition is less than 1 ppm.
3. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition further comprises an osmotic pressure regulator.
4. the pharmaceutical composition of claim 3, wherein the tonicity modifier is one of sodium chloride or dextrose.
5. the pharmaceutical composition according to claim 3, wherein the concentration of the osmotic pressure regulator is 5-20 mg/mL when sodium chloride is used as the osmotic pressure regulator; the concentration of the osmotic pressure regulator is 40-60 mg/mL when the osmotic pressure regulator is glucose.
6. The pharmaceutical composition according to claim 5, wherein the concentration of the osmotic pressure regulator is 5-10 mg/mL when the osmotic pressure regulator is sodium chloride.
7. The pharmaceutical composition of claim 1 or 2, wherein the water-soluble ginkgo extract contains at least 24% of ginkgo total flavonoid glycosides and at least 6% of ginkgo total terpene lactones.
8. The pharmaceutical composition of claim 7, further comprising a pH regulator, wherein the pH regulator is sodium citrate, and the pH value of the water for injection is controlled to be 4.5-5.0 by adding a proper amount of the pH regulator.
9. The pharmaceutical composition of claim 8, further comprising a pH regulator, wherein the pH regulator is sodium citrate, and the pH value of the water injection for injection is controlled to be 4.5-4.8 by adding a proper amount of the pH regulator.
10. a process for the preparation of a pharmaceutical composition according to claim 1 or 2, comprising the steps of:
(1) Under the protection of nitrogen, heating the water for injection to 40-60 ℃, wherein the residual oxygen in the liquid is lower than 2 ppm;
(2) Under the protection of nitrogen, adding water-soluble ginkgo extract and citric acid into water for injection to be fully dissolved;
(3) Slowly adding the water-soluble ginkgo leaf extract and the aqueous solution for injection of citric acid in the step (2) into the aqueous solution for injection in the step (1) under the protection of nitrogen, adding oxiracetam bulk drug, and fully stirring until the oxiracetam bulk drug is completely dissolved;
(4) Adding 0.1-0.3 wt% of needle activated carbon into the completely dissolved solution in the step (3), uniformly stirring, standing for 20 minutes for decolorization, and filtering with a microporous filter membrane to remove carbon;
(5) Cooling the temperature of the filtered solution obtained in the step (4) to 25 ℃, adjusting the pH value to 4.5-5.0 by using sodium citrate, and supplementing the injection water to the full amount;
(6) Filtering the solution in the step (5) by using a microporous filter membrane;
(7) filling nitrogen, filling into ampoule bottle, and hot pressing for sterilization.
11. the method according to claim 10, wherein the water for injection in step (1) is further added with an osmotic pressure regulator before heating, and the osmotic pressure regulator is one of sodium chloride or glucose.
12. The method according to claim 10, wherein the pH in the step (5) is 4.5 to 4.8.
13. The preparation method according to claim 10, wherein the autoclaving temperature in the step (7) is 121 ℃ and the sterilization time is 15 to 30 minutes.
14. the method of claim 13, wherein the sterilization time in step (7) is 15 minutes.
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| CN1663600A (en) * | 2005-02-04 | 2005-09-07 | 北京阜康仁生物制药科技有限公司 | Compound preparation composed of ginkgo leaf extracts and medicines promoting cerebral metabolism and its application |
| CN101035541A (en) * | 2004-08-30 | 2007-09-12 | 柳署弘 | Neuroprotective effect of solubilized UDCA in focal ischemic model |
| CN102512378A (en) * | 2011-12-09 | 2012-06-27 | 天津市汉康医药生物技术有限公司 | Stable and safe oxiracetam pharmaceutical composition for injection |
| CN103880857A (en) * | 2014-04-14 | 2014-06-25 | 石药银湖制药有限公司 | Ginkgo leaf lactone, extraction and preparation method for same, and pharmaceutical preparation containing same |
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| CN101035541A (en) * | 2004-08-30 | 2007-09-12 | 柳署弘 | Neuroprotective effect of solubilized UDCA in focal ischemic model |
| CN1663600A (en) * | 2005-02-04 | 2005-09-07 | 北京阜康仁生物制药科技有限公司 | Compound preparation composed of ginkgo leaf extracts and medicines promoting cerebral metabolism and its application |
| CN102512378A (en) * | 2011-12-09 | 2012-06-27 | 天津市汉康医药生物技术有限公司 | Stable and safe oxiracetam pharmaceutical composition for injection |
| CN103880857A (en) * | 2014-04-14 | 2014-06-25 | 石药银湖制药有限公司 | Ginkgo leaf lactone, extraction and preparation method for same, and pharmaceutical preparation containing same |
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