CN115969778A - Sulpiride injection for treating mental diseases and preparation method and application thereof - Google Patents
Sulpiride injection for treating mental diseases and preparation method and application thereof Download PDFInfo
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- CN115969778A CN115969778A CN202211522363.2A CN202211522363A CN115969778A CN 115969778 A CN115969778 A CN 115969778A CN 202211522363 A CN202211522363 A CN 202211522363A CN 115969778 A CN115969778 A CN 115969778A
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Abstract
The invention relates to sulpiride injection for treating mental diseases and a preparation method and application thereof. On one hand, the invention relates to sulpiride injection, which comprises sulpiride and water for injection, wherein each 100ml of the sulpiride injection comprises 1 to 10g of sulpiride, and also comprises 0.45 to 0.55g/100ml of sodium chloride and an acid-base regulator, and the dosage of the acid-base regulator is used for regulating the pH value of the injection to be within the range of 3 to 6. The method for preparing the sulpiride injection comprises the following steps: mixing water for injection with sulpiride and other adjuvants, dissolving, adjusting pH to target value, adding active carbon, filtering, packaging, sealing, and sterilizing. The sulpiride injection can be effectively used for the symptoms of autism, retraction and apathy of the schizophrenia simplex type, paranoid type, tension type and chronic schizophrenia.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a medicine for treating mental diseases, and particularly relates to a pharmaceutical composition for treating autism, retraction and apathy symptoms of schizophrenia simplex type, paranoid type, tension type and chronic schizophrenia.
Background
Sulpiride (Sulpiride), also known as antiemetic, has a molecular formula of C15H23N3O4S, a molecular weight of 341.42, and a chemical name of N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -2-methoxy-5- (aminosulfonyl) benzamide, and has a chemical structural formula of:
the sulpiride bulk drug is white or white-like crystalline powder and is odorless; slightly soluble in ethanol or acetone, slightly soluble in trichloromethyl and almost insoluble in water; it is very soluble in sodium hydroxide solution. The melting point of sulpiride is 177-180 ℃.
Sulpiride was synthesized by l.justin-Besancon in 1967, made in 1975, and was originally used for the treatment of peptic ulcers and emesis. Wilk and Stanley found that sulpiride increased the level of peripheral homovanillic acid (HVA) in both animals and humans, and presumably had an antipsychotic effect. Borenstein first published clinical studies on 320 patients of all types of mental disease in 1969 and found that the drug was effective in both schizophrenia and depressive states. And subsequently confirmed by some authors. Borenstein, also known as a "relationship modulating drug", is thought to ameliorate poor patient contact. Ceraud found that this drug was particularly effective in the catatonic group and was therefore referred to as a "disinhibition agent", and Collard emphasized its anti-autistic and mood-exciting effects and was therefore referred to as an "affective agent". It is classified as an "atypical antipsychotic" because of its chemical structure, which is different from other antipsychotics.
Sulpiride has been collected in the multi-national pharmacopoeias, for example, in the chinese pharmacopoeias (bulk drug, tablet 10 mg/tablet and 100 mg/tablet), the japanese pharmacopoeias (bulk drug, tablet, capsule), the british pharmacopoeias (bulk drug, tablet), the european pharmacopoeias (bulk drug), the korea (bulk drug), and the like. China also has sulpiride injection on the market, which comprises two concentration specifications: 50mg/2ml and 100mg/2ml.
The commercially available Sulpiride Injection (Sulpiride Injection) is a colorless clear liquid, and the clinical indications are the symptoms of autism, withdrawal and apathy for schizophrenia simplex, paranoid, catatonic and chronic schizophrenia; has certain curative effect on depression symptoms; other uses are to arrest vomiting. In the treatment of schizophrenia, intramuscular injections: one time is 100mg, and 2 times a day; during intravenous drip, 100-200mg of injection can be diluted into 250-500ml of glucose sodium chloride injection for slowly intravenous drip for patients with the mummification and the stropanthus, 1 time a day, the dosage can be gradually increased to 300-600mg a day, and the daily dosage is not more than 800mg; the dripping time is not less than 4 hours; the dosage of children over 6 years old is converted into adult dosage, and the dosage is increased slowly from small dosage.
Sulpiride belongs to benzamide antipsychotics, has the action characteristics of selectively blocking dopamine (DA 2) receptors of the mesolimbic system, having small influence on other transmitter receptors, having light anticholinergic effect, having no obvious sedative and antimanic effects, and also has the effects of strongly stopping vomit and inhibiting gastric secretion. Animal experiments show that sulpiride can enter cord blood circulation through placenta barrier. Sulpiride is mainly excreted through the kidney. Can be excreted from the breast milk.
CN103405400A (application number: 201310385440.9) discloses a levosulpiride injection and its preparation method, which uses biodegradable capsule-forming material to pulverize levosulpiride into nano-powder, and prepares the slow-release nano-capsule injection under the ultrasonic condition. The preparation method of the levosulpiride injection comprises the following steps: taking 19-21 parts of gelatin, 4-6 parts of polymethyl methacrylate and 9-11 parts of Arabic gum, adding 200 parts of water for injection, stirring for 30 minutes, standing for 12 hours, performing suction filtration by using a vertical melting glass sand funnel to obtain a colloidal solution, and placing the colloidal solution into an ultrasonic reactor; taking 50 parts of levosulpiride and 5 parts of D-tartaric acid, mixing for 30 minutes, crushing into nano mixed powder with the particle size of 150-200 nm by using a high-energy nanosphere mill, adding the nano mixed powder into a colloidal solution, selecting the ultrasonic frequency of 33kHz, reacting for 1 hour, adding 20% formaldehyde solution, continuing to react for 30 minutes, adding 600 parts of injection water, moving the mixture into a spray refrigerator, selecting the spray refrigeration temperature of-20 ℃ and the pressure of 25Pa, and spraying to obtain levosulpiride nanocapsules; adding 5 parts of sodium chloride and 1000 parts of water for injection, stirring for 10 minutes, adding glacial acetic acid to adjust the pH value to 5.5-6, adding 1 part of activated carbon, stirring for 30 minutes, filtering and decarbonizing by using a 0.45-micron microporous filter membrane, injecting the filtrate into an ampoule, sealing, and sterilizing by flowing steam at 121 ℃ for 30 minutes to obtain the levosulpiride injection. The method for preparing the injection is not suitable for the industrial production of the injection.
CN1836651A (application number: 200610026137.X, and minister) relates to a preparation method of levo sulpiride injection, which is characterized in that levo sulpiride is dissolved by injection water containing equimolar medicinal acid, and the specific preparation method is as follows: dissolving levo-sulpiride, adjusting pH, adding activated carbon for filtration, and finely filtering by using a microporous filter membrane, and subpackaging and sterilizing the obtained injection to prepare a water injection or preparing a powder injection by freeze drying, and is characterized in that the levo-sulpiride is dissolved in the injection water containing pharmaceutically acceptable acid, the pharmaceutically acceptable acid is hydrochloric acid or sulfuric acid or benzenesulfonic acid or citric acid, and the dosages of the pharmaceutically acceptable acid and the levo-sulpiride are equal in molar; adjusting the pH to 4.0-6.0.
However, those skilled in the art would still expect to employ superior methods for preparing sulpiride injection, and would expect to employ sulpiride injection prepared by such methods/methods to have one or more advantages.
Disclosure of Invention
It is an object of the present invention to provide a more elegant method for preparing sulpiride injection or to provide sulpiride injection having one or more aspects of its advantages using such a method/methods. It has been unexpectedly discovered that sulpiride injection solutions prepared using the methods and formulations of the present invention exhibit one or more advantages, and the present invention has been accomplished based on such discovery.
Therefore, the invention provides a sulpiride injection in a first aspect, which comprises sulpiride and water for injection.
The sulpiride injection according to the first aspect of the invention comprises 1 to 10g of sulpiride per 100ml.
The sulpiride injection according to the first aspect of the present invention comprises 2 to 5g of sulpiride per 100ml.
The sulpiride injection according to the first aspect of the present invention comprises 2.5 to 5g of sulpiride per 100ml.
The sulpiride injection according to the first aspect of the present invention, further comprises sodium chloride.
The sulpiride injection according to the first aspect of the invention comprises 0.45-0.55 g, e.g. 0.5g, of sodium chloride per 100ml.
The sulpiride injection according to the first aspect of the present invention, further comprises an acid-base modifier.
The sulpiride injection according to the first aspect of the invention, wherein the amount of the acid-base modifier is such as to adjust the pH of the injection to a value in the range of 3 to 6, such as in the range of 3.5 to 5, such as in the range of 3.5 to 4.5, such as in the range of 4 to 4.5.
The sulpiride injection according to the first aspect of the present invention further comprises propylene glycol.
The sulpiride injection according to the first aspect of the invention comprises 4 to 6g, for example 5g, of propylene glycol per 100ml.
The sulpiride injection according to the first aspect of the present invention, wherein the acid-base modifier comprises a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, or the like.
The sulpiride injection according to the first aspect of the present invention, to which 0.45 to 0.55g, for example, 0.5g of sodium hydroxide is added per 100ml.
The sulpiride injection according to the first aspect of the present invention, wherein the pH adjusting agent comprises an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc., such as sulfuric acid.
The sulpiride injection according to the first aspect of the present invention, wherein the pH adjusting agent comprises sulfuric acid in an amount to adjust the pH of the injection to within a range of 3 to 6, such as within a range of 3.5 to 5, such as within a range of 3.5 to 4.5, such as within a range of 4 to 4.5.
The sulpiride injection according to the first aspect of the present invention is prepared according to a method comprising the steps of:
(a) Mixing proper amount of water for injection with propylene glycol, adding sulpiride, slowly adding sodium hydroxide solution prepared by water for injection in advance under stirring, and stirring until the sodium hydroxide solution is completely dissolved;
(b) Adding a proper amount of water for injection, adding sodium chloride to dissolve the water and ensure that the temperature of the liquid medicine is raised to 45-50 ℃ and maintained at the temperature, and then slowly adding a sulfuric acid solution under stirring until the pH value of the liquid medicine reaches a target value;
(c) Adding activated carbon into the liquid medicine, stirring for removing carbon at proper time, cooling to room temperature, adding water for injection to nearly full dose, regulating the pH of the liquid medicine to a target value again by using a sulfuric acid solution, and supplementing water for injection to full dose;
(d) Filtering the medicinal liquid with microporous membrane, packaging into medicine bottle, sealing, and sterilizing.
The injection solution of sulpiride according to the first aspect of the present invention, wherein in step (a), sulpiride is added after mixing the prescribed amount of 25 to 35%, for example, 30% water for injection with propylene glycol.
The sulpiride injection according to the first aspect of the present invention, wherein in step (a), a sodium hydroxide solution (1M) previously prepared with water for injection is slowly added with stirring and stirred until completely dissolved.
The sulpiride injection according to the first aspect of the present invention, wherein in step (b), the injection water is supplemented to 55 to 65%, for example, 60% of the total volume of the prescription.
The sulpiride injection according to the first aspect of the present invention, wherein in step (b), the sulfuric acid solution (2M) is slowly added with stirring until the pH of the drug solution reaches a target value.
The sulpiride injection according to the first aspect of the present invention, wherein in step (c), 0.5% activated carbon is added to the liquid medicine, and the carbon is removed after stirring for 30 minutes.
The sulpiride injection according to the first aspect of the present invention, wherein in step (d), the drug solution is filtered with 0.45 μm and 0.22 μm microporous filter membrane for 2 times, separately filled into ampoule bottles, and sealed by melting.
The sulpiride injection according to the first aspect of the present invention, wherein in step (d), sterilization is performed at 121 ℃ for 15min.
Sulpiride injection according to the first aspect of the invention having a formulation as described in any one of examples 1 to 6.
Sulpiride injection according to the first aspect of the invention having the preparation method as described in any one of examples 1 to 6.
Sulpiride injection according to the first aspect of the invention having the formulation and the process as described in any one of examples 1 to 6.
Further, the second aspect of the present invention provides a method for preparing sulpiride injection, which comprises the following steps:
(a) Mixing a proper amount of water for injection with propylene glycol, adding sulpiride, slowly adding a sodium hydroxide solution prepared by water for injection in advance under stirring, and stirring until the sodium hydroxide solution is completely dissolved;
(b) Adding a proper amount of water for injection, adding sodium chloride to dissolve the mixture and heating the liquid medicine to 45-50 ℃ and maintaining the temperature, and then slowly adding a sulfuric acid solution while stirring until the pH value of the liquid medicine reaches a target value;
(c) Adding activated carbon into the liquid medicine, stirring for removing carbon at proper time, cooling to room temperature, adding water for injection to nearly full volume, regulating the pH value of the liquid medicine to a target value again by using a sulfuric acid solution, and adding water for injection to full volume;
(d) Filtering the medicinal liquid with microporous membrane, packaging into medicine bottle, sealing, and sterilizing.
The process according to the second aspect of the invention, wherein in step (a) sulpiride is added after mixing the prescribed amount of 25 to 35%, for example 30% water for injection, with propylene glycol.
The method according to the second aspect of the present invention, wherein in the step (a), a sodium hydroxide solution (1M) prepared in advance with water for injection is slowly added with stirring and stirred until completely dissolved.
The method according to the second aspect of the present invention, wherein in the step (b), the water for injection is supplemented to 55 to 65%, for example, 60% of the total volume of the prescription.
The method according to the second aspect of the present invention, wherein in the step (b), the sulfuric acid solution (2M) is slowly added with stirring until the pH of the drug solution reaches a target value.
The method according to the second aspect of the present invention, wherein in the step (c), 0.5% of activated carbon is added to the liquid medicine, and the liquid medicine is stirred for 30 minutes and then decarburized.
The method according to the second aspect of the present invention, wherein in step (d), the liquid medicine is filtered with 0.45 μm and 0.22 μm microporous filter membranes for 2 times, respectively, filled into ampoules, and sealed by fusing.
The method according to the second aspect of the present invention, wherein in step (d), sterilization is carried out at 121 ℃ for 15min.
A method according to the second aspect of the invention having a formulation as described in any one of examples 1 to 6.
The method according to the second aspect of the present invention, which has the production method described in any one of examples 1 to 6.
A method according to a second aspect of the invention having a formulation and a method of preparation as described in any one of examples 1 to 6.
The method according to the second aspect of the present invention, wherein the sulpiride injection comprises sulpiride and water for injection.
The method according to the second aspect of the present invention, wherein the sulpiride injection comprises 1-10 g of sulpiride per 100ml.
The method according to the second aspect of the present invention, wherein said sulpiride injection comprises 2-5 g of sulpiride per 100ml.
The method according to the second aspect of the invention, wherein the sulpiride injection comprises 2.5-5 g sulpiride per 100ml.
The method according to the second aspect of the present invention, wherein the sulpiride injection further comprises sodium chloride.
The method according to the second aspect of the present invention, wherein said sulpiride injection comprises 0.45-0.55 g, such as 0.5g, of sodium chloride per 100ml.
The method according to the second aspect of the present invention, wherein the sulpiride injection comprises an acid-base modifier.
The method according to the second aspect of the present invention, wherein the amount of the acid-base modifier in the sulpiride injection is such that the pH of the injection is adjusted within the range of 3 to 6, such as within the range of 3.5 to 5, such as within the range of 3.5 to 4.5, such as within the range of 4 to 4.5.
The method according to the second aspect of the present invention, wherein the sulpiride injection further comprises propylene glycol.
The method according to the second aspect of the present invention, wherein said sulpiride injection comprises 4 to 6g, such as 5g, of propylene glycol per 100ml.
The method according to the second aspect of the present invention, wherein the pH adjusting agent in the sulpiride injection comprises a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, etc.
The method according to the second aspect of the invention, wherein 0.45-0.55 g, such as 0.5g, of sodium hydroxide is added to each 100ml of the sulpiride injection.
The method according to the second aspect of the present invention, wherein the pH modifying agent in the sulpiride injection comprises an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc., such as sulfuric acid.
The method according to the second aspect of the present invention, wherein the pH adjusting agent in the sulpiride injection comprises sulfuric acid in an amount to adjust the pH of the injection to be in the range of 3 to 6, such as 3.5 to 5, such as 3.5 to 4.5, such as 4 to 4.5.
In a further aspect, the invention provides the use of sulpiride injection in preparing a medicament for treating autism, withdrawal and apathy symptoms of schizophrenia in simplex, paranoid, catatonic and chronic schizophrenia.
The use according to the third aspect of the invention, wherein the sulpiride injection comprises sulpiride and water for injection.
The use according to the third aspect of the invention, wherein the sulpiride injection comprises 1-10 g of sulpiride per 100ml.
The use according to the third aspect of the invention, wherein the sulpiride injection contains 2-5 g of sulpiride per 100ml.
The use according to the third aspect of the invention, wherein the sulpiride injection comprises 2.5-5 g of sulpiride per 100ml.
The use according to the third aspect of the invention, wherein the sulpiride injection further comprises sodium chloride.
The use according to the third aspect of the invention, wherein the sulpiride injection comprises 0.45-0.55 g, such as 0.5g, of sodium chloride per 100ml.
The use according to the third aspect of the invention, wherein the sulpiride injection further comprises an acid-base regulator.
The use according to the third aspect of the invention, wherein the amount of the pH modifier in the sulpiride injection is used for adjusting the pH value of the injection to be in the range of 3 to 6, such as 3.5 to 5, such as 3.5 to 4.5, such as 4 to 4.5.
The use according to the third aspect of the invention, wherein the sulpiride injection further comprises propylene glycol.
The use according to the third aspect of the invention, wherein the sulpiride injection comprises 4 to 6g, for example 5g, of propylene glycol per 100ml.
The use according to the third aspect of the invention, wherein the pH modifier in the sulpiride injection comprises a base such as sodium hydroxide, potassium hydroxide, sodium carbonate and the like.
The use according to the third aspect of the invention, wherein 0.45-0.55 g, such as 0.5g, of sodium hydroxide is added to each 100ml of the sulpiride injection.
The use according to the third aspect of the invention, wherein the pH modifier in the sulpiride injection comprises an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the like, such as sulfuric acid.
The use according to the third aspect of the invention, wherein the pH modifier in the sulpiride injection comprises sulfuric acid in an amount to adjust the pH of the injection to be in the range of 3 to 6, such as 3.5 to 5, such as 3.5 to 4.5, such as 4 to 4.5.
The use according to the third aspect of the invention, wherein the sulpiride injection is prepared according to the method comprising the following steps:
(a) Mixing a proper amount of water for injection with propylene glycol, adding sulpiride, slowly adding a sodium hydroxide solution prepared by water for injection in advance under stirring, and stirring until the sodium hydroxide solution is completely dissolved;
(b) Adding a proper amount of water for injection, adding sodium chloride to dissolve the mixture and heating the liquid medicine to 45-50 ℃ and maintaining the temperature, and then slowly adding a sulfuric acid solution while stirring until the pH value of the liquid medicine reaches a target value;
(c) Adding activated carbon into the liquid medicine, stirring for removing carbon at proper time, cooling to room temperature, adding water for injection to nearly full volume, regulating the pH value of the liquid medicine to a target value again by using a sulfuric acid solution, and adding water for injection to full volume;
(d) Filtering the medicinal liquid with microporous membrane, packaging into medicinal bottles, sealing, and sterilizing.
Use according to a third aspect of the invention, wherein in step (a) sulpiride is added after mixing a prescribed amount of 25 to 35%, for example 30% water for injection, with propylene glycol.
The use according to the third aspect of the present invention, wherein in the step (a), a sodium hydroxide solution (1M) prepared in advance with water for injection is slowly added with stirring and stirred until completely dissolved.
Use according to the third aspect of the invention, wherein in step (b) the water for injection is added to 55 to 65%, for example 60%, of the total volume of the prescription.
The use according to the third aspect of the present invention, wherein in the step (b), the sulfuric acid solution (2M) is slowly added with stirring until the pH of the drug solution reaches a target value.
The use according to the third aspect of the present invention, wherein in the step (c), 0.5% of activated carbon is added to the liquid medicine, and the liquid medicine is decarburized after stirring for 30 minutes.
The use according to the third aspect of the present invention, wherein in the step (d), the liquid medicine is filtered by 0.45 μm and 0.22 μm microporous filter membranes for 2 times, filled into ampoules and sealed by fusing.
Use according to the third aspect of the invention, wherein in step (d), the sterilization is carried out at 121 ℃ for 15min.
The use according to a third aspect of the invention, wherein said sulpiride injection has a formulation as described in any one of examples 1 to 6.
The use according to the third aspect of the invention, wherein the sulpiride injection has the preparation method as described in any one of embodiments 1 to 6.
The use according to a third aspect of the invention, wherein said sulpiride injection has the formulation and preparation as described in any one of examples 1 to 6.
In the above-described steps of the preparation method of the present invention, although the specific steps described therein are distinguished in some detail or in language specific to the steps described in the preparation examples of the following detailed description, those skilled in the art can fully summarize the above-described method steps in light of the detailed disclosure of the entire disclosure of the invention.
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict. The invention is further described below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
3236 Zxft 3236, 5262 Zxft 5262, et al, the current research and clinical application of sulpiride, sichuan mental health, 3763 Zxft 3763 (1): 58, have reviewed sulpiride in its pharmacological and clinical aspects, as summarized below. The sulpiride is a derivative of phthalide amine, the chemical name of which is N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -2-methoxy-5- (aminosulfonyl) benzamide, and the chemical structure of the sulpiride is similar to metoclopramide without the side chain of the typical antipsychotic drug, namely-C-NK < ". Pharmacokinetic studies have found that the oral absorption of sulpiride is slow, the peak concentration occurs 3-8 hours after administration, the half-life of plasma varies depending on the analytical method used, the open two-compartment model analysis is 5.3 hours, and the three-compartment model analysis is 11 hours. The apparent volume of distribution is 2.7 + -0.66L/kg, the bioavailability is low, the average is 27%, and the poor absorption can be related. At present, no correlation between blood concentration and dosage and clinical curative effect is found. Sulpiride has 150 times higher antiemetic effect than chlorpromazine and 5 times higher than metoclopramide. Small dose can inhibit the chemical sensitive area of the brain-extending and emetic-promoting, and large dose can directly inhibit the vomiting center. And can slow down the peristalsis of the gastrointestinal tract and increase the blood flow of gastric mucosa without influencing the secretion of gastric acid and pepsin. The gastrointestinal tract effects may be anticholinergic antagonism.
Sulpiride can enhance dopamine renewal, and has strong antipsychotic effect. The compound has antagonism on the emetic of dopamine agonist apomorphine, has the typical characteristics of strong tranquilizer such as increasing prolactin level and the like, but has the atypical characteristics, such as no inhibition on dopamine-excited adenylate cyclase, weak catalepsy, which is only 1/30 of chlorpromazine. The mechanism of the antipsychotic effect of sulpiride may be a selective D2 receptor antagonism of the agent. In addition, the drug may have different effects on DA receptors in different brain regions, such as higher affinity for D2 receptors in the limbic system and lower affinity for the striatum, which may explain its weak cataleptic effect. The small dose of sulpiride has the effect of inhibiting, and can improve mood.
Sulpiride has no sedative and antimanic effects, no hypnotic effect of barbiturates, no analgesic effect of morphine, below 8-10 mg/kg, and no inhibition of sympathetic and parasympathetic functions. Achoff was found in volunteer subjects, with no effect on psychomotor performance or alertness during treatment with sulpiride. Animal experiments also prove that the medicine has high safety and no teratogenic or carcinogenic phenomenon.
In the aspect of clinical application, the curative effect of sulpiride on schizophrenia is 65.4 percent as reported by West round Changchang and the like, and the average effective rate of the sulpiride is 77.88 percent by integrating a plurality of domestic documents for treating schizophrenia. For the target symptom, more authors think that the medicine has obvious curative effects on apathy, mutism, stupor, food refusal and emotional disturbance and negative words accompanied by schizophrenia. However, they are inferior to phenothiazines and butyrophenones in hallucinogenic delusions. For the type of disease, the tension type is the best, the paranoid type is the second, and the youth type is ineffective. It is known in literature that sulpiride has good curative effect on negative symptoms, but has activating effect on hallucinations, delusions and motor excitations of individual patients. Sulpiride has been reported to be less effective in treating thought disorder. The literature suggests that the medicine has earlier curative effect on apathy than chlorpromazine and has high curative effect. In 31 cases of intractable schizophrenia, the drug was tried out and the drug was expected to be effective even for patients who could not be cured for a long time. The reference shows that the sulpiride and the medicaments such as the chlorimuron tremula are subjected to a control study, and the medicaments are considered to have similar curative effects with other antipsychotic medicaments; sulpiride is considered to be superior to sulpiride in terms of affective disorder, contact failure, hypovolemia and the like.
In the aspect of curative effect on depression, sulpiride has better curative effect on mood disorders of various psychoses, for example, the curative effect of the drug on depression is 79.2% reported in West Yuanchang, which is similar to that (75%) reported in China. The double blind control research of the good results of the three and the like shows that the curative effects of sulpiride and imipramine have no significant difference, and the former is quick to change the concept of depression and suicide. The literature reports that the drug is used for treating psychosis and neurosis with excellent depression state, and as a result, the drug is considered to be most effective for adaptation symptoms to be 'sad'.
Other therapeutic action documents report that sulpiride is used for treating various psychoses, and the cure and significant efficiency accounts for 56.8 percent. There is a literature on the treatment of patients over 50 years old, and sulpiride is considered safe and effective for the treatment of senile mental disorders or mental disorders accompanied by organic diseases. Secondly, the drug is reported to be effective for peptic ulcer and ulcerative colitis, but there is also objection to this, but it at least contributes to the improvement of mood and digestive tract complaints since ulcerative diseases are regarded as psychosomatic diseases. In addition, a hospital in Shanghai tries sulpiride to treat vomit of cancer patients, and a better effect is obtained. In addition, the composition can also improve depression anxiety mood, self-injuring behavior of mental retardation, traumatic vertigo, alcohol toxicity delirium, and prevent migraine.
Generally speaking, sulpiride is an ideal antipsychotic drug, and is novel in that it has both neuroleptic and affective active agent effects, with slight side effects. Currently, sulpiride will have a wider application prospect as antipsychotics progress toward "atypical".
The sulpiride injection prepared by the formula and the preparation method of the invention has excellent effects in one or more aspects as described herein.
Detailed Description
The following examples are provided for the purpose of illustration only and are not intended to, nor should they be construed as limiting the invention in any way. Those skilled in the art will recognize that conventional variations and modifications can be made to the following embodiments without departing from the spirit or scope of the invention. The present invention generally and/or specifically describes the materials used in the tests, as well as the test methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. It will be apparent to those skilled in the art that the materials and methods of operation used in the present invention are well known in the art, unless otherwise specified. In the following preparation of the injection, the total amount of injection per batch is 10L, if not otherwise specified, but may be scaled up or down in describing the formulation and/or preparation process. In the present invention, when the injection is subjected to microfiltration membrane filtration, a Polyethersulfone (PES) microfiltration membrane is used.
Example 1: preparation of sulpiride injection
The formula is as follows:
5g of sulpiride,
5g of propylene glycol,
0.5g of sodium hydroxide,
0.5g of sodium chloride,
Sulfuric acid, regulating pH of medicine liquid to 4-4.5,
Water for injection, proper amount to 100ml.
The preparation method comprises the following steps:
(a) Mixing 30% of injection water and propylene glycol according to the prescription amount, adding sulpiride, slowly adding a sodium hydroxide solution (1M) prepared by the injection water in advance under stirring, and stirring until the sodium hydroxide solution is completely dissolved;
(b) Adding water for injection to 60% of the total volume of the prescription, adding sodium chloride to dissolve the water, heating the liquid medicine to 45-50 deg.C, maintaining the temperature, and slowly adding sulfuric acid solution (2M) under stirring until the pH value of the liquid medicine reaches a target value;
(c) Adding 0.5% of activated carbon into the liquid medicine, stirring for 30 minutes, removing the carbon, cooling to room temperature, adding water for injection to nearly full volume, adjusting the pH value of the liquid medicine to a target value again by using a sulfuric acid solution, and adding water for injection to full volume;
(d) Filtering the medicinal liquid with 0.45 μm and 0.22 μm microporous filter membrane respectively for 2 times, packaging into ampoule bottle, sealing, and sterilizing at 121 deg.C for 15min.
Example 2: preparation of sulpiride injection
The formula is as follows:
5g of sulpiride,
4g of propylene glycol,
0.55g of sodium hydroxide,
0.55g of sodium chloride,
Sulfuric acid, regulating pH of medicine liquid to 4-4.5,
Water for injection, proper amount to 100ml.
The preparation method comprises the following steps:
(a) Mixing 35% of injection water and propylene glycol according to the prescription amount, adding sulpiride, slowly adding a sodium hydroxide solution (1M) prepared by the injection water in advance under stirring, and stirring until the sodium hydroxide solution is completely dissolved;
(b) Adding water for injection to 60% of the total volume of the prescription, adding sodium chloride to dissolve the water, heating the liquid medicine to 45-50 deg.C, maintaining the temperature, and slowly adding sulfuric acid solution (2M) under stirring until the pH value of the liquid medicine reaches a target value;
(c) Adding 0.5% of activated carbon into the liquid medicine, stirring for 30 minutes, removing the carbon, cooling to room temperature, adding water for injection to nearly full volume, adjusting the pH value of the liquid medicine to a target value again by using a sulfuric acid solution, and adding water for injection to full volume;
(d) Filtering the medicinal liquid with 0.45 μm and 0.22 μm microporous filter membrane respectively for 2 times, packaging into ampoule bottle, sealing, and sterilizing at 121 deg.C for 15min.
Example 3: preparation of sulpiride injection
The formula is as follows:
5g of sulpiride,
6g of propylene glycol,
0.45g of sodium hydroxide,
0.45g of sodium chloride,
Sulfuric acid, regulating pH of medicine liquid to 4-4.5,
Water for injection, proper amount to 100ml.
The preparation method comprises the following steps:
(a) Mixing 25% of injection water and propylene glycol according to the prescription amount, adding sulpiride, slowly adding a sodium hydroxide solution (1M) prepared by the injection water in advance under stirring, and stirring until the sodium hydroxide solution is completely dissolved;
(b) Adding water for injection to 60% of the total volume of the prescription, adding sodium chloride to dissolve the water, heating the liquid medicine to 45-50 deg.C, maintaining the temperature, and slowly adding sulfuric acid solution (2M) under stirring until the pH value of the liquid medicine reaches a target value;
(c) Adding 0.5% of activated carbon into the liquid medicine, stirring for 30 minutes, removing the carbon, cooling to room temperature, adding water for injection to nearly full volume, adjusting the pH value of the liquid medicine to a target value again by using a sulfuric acid solution, and adding water for injection to full volume;
(d) Filtering the medicinal liquid with 0.45 μm and 0.22 μm microporous filter membrane respectively for 2 times, packaging into ampoule bottle, sealing, and sterilizing at 121 deg.C for 15min.
Example 4: preparation of sulpiride injection
The formula is as follows:
5g of sulpiride,
5g of propylene glycol,
0.5g of sodium hydroxide,
0.5g of sodium chloride,
Sulfuric acid, regulating pH of medicine liquid to 3.5-4.0,
Water for injection, proper amount to 100ml.
The preparation method comprises the following steps:
(a) Mixing 30% of injection water and propylene glycol according to the prescription amount, adding sulpiride, slowly adding a sodium hydroxide solution (1M) prepared by the injection water in advance under stirring, and stirring until the sodium hydroxide solution is completely dissolved;
(b) Adding water for injection to 65% of the total volume of the prescription, adding sodium chloride to dissolve the water, heating the liquid medicine to 45-50 deg.C, maintaining the temperature, and slowly adding sulfuric acid solution (2M) under stirring until the pH value of the liquid medicine reaches a target value;
(c) Adding 0.4% of activated carbon into the liquid medicine, stirring for 30 minutes, removing the carbon, cooling to room temperature, adding water for injection to nearly full volume, adjusting the pH value of the liquid medicine to a target value again by using a sulfuric acid solution, and adding water for injection to full volume;
(d) Filtering the medicinal liquid with 0.45 μm and 0.22 μm microporous filter membrane respectively for 2 times, packaging into ampoule bottle, sealing, and sterilizing at 121 deg.C for 15min.
Example 5: preparation of sulpiride injection
The formula is as follows:
5g of sulpiride,
5g of propylene glycol,
0.5g of sodium hydroxide,
0.8g of sodium chloride,
Sulfuric acid, regulating pH of medicine liquid to 4.5-5.0,
Water for injection, proper amount to 100ml.
The preparation method comprises the following steps:
(a) Mixing 30% of injection water and propylene glycol according to the prescription amount, adding sulpiride, slowly adding a sodium hydroxide solution (1M) prepared by the injection water in advance under stirring, and stirring until the sodium hydroxide solution is completely dissolved;
(b) Adding water for injection to 55% of the total volume of the prescription, adding sodium chloride to dissolve the water, heating the liquid medicine to 45-50 deg.C, maintaining the temperature, and slowly adding sulfuric acid solution (2M) under stirring until the pH value of the liquid medicine reaches a target value;
(c) Adding 0.6% of active carbon into the liquid medicine, stirring for 30 minutes, removing the carbon, cooling to room temperature, adding water for injection to nearly full dose, regulating the pH value of the liquid medicine to a target value again by using a sulfuric acid solution, and adding water for injection to full dose;
(d) Filtering the medicinal liquid with 0.45 μm and 0.22 μm microporous filter membrane respectively for 2 times, packaging into ampoule bottle, sealing, and sterilizing at 121 deg.C for 15min.
Example 6: preparation of sulpiride injection
The formula is as follows:
2.5g of sulpiride,
5g of propylene glycol,
0.3g of sodium hydroxide,
0.5g of sodium chloride,
Sulfuric acid, regulating pH of medicine liquid to 4-4.5,
Water for injection, proper amount to 100ml.
The preparation method comprises the following steps:
(a) Mixing 30% of injection water and propylene glycol according to the prescription amount, adding sulpiride, slowly adding a sodium hydroxide solution (1M) prepared by the injection water in advance under stirring, and stirring until the sodium hydroxide solution is completely dissolved;
(b) Adding water for injection to 60% of the total volume of the prescription, adding sodium chloride to dissolve the water, heating the liquid medicine to 45-50 deg.C, maintaining the temperature, and slowly adding sulfuric acid solution (2M) under stirring until the pH value of the liquid medicine reaches a target value;
(c) Adding 0.5% of active carbon into the liquid medicine, stirring for 30 minutes, removing the carbon, cooling to room temperature, adding water for injection to nearly full dose, regulating the pH value of the liquid medicine to a target value again by using a sulfuric acid solution, and adding water for injection to full dose;
(d) Filtering the medicinal liquid with 0.45 μm and 0.22 μm microporous filter membrane respectively for 2 times, packaging into ampoule bottle, sealing, and sterilizing at 121 deg.C for 15min.
Example 11: preparation of sulpiride injection
This example 11 refers to CN1836651a the formulation and preparation of formula 2 of example 1 to prepare sulpiride injection.
Prescription: 25g of sulpiride, 14g of sodium chloride, 73.2ml of 1M hydrochloric acid, 1g of activated carbon and 2000ml of water for injection.
The preparation method comprises the following steps: adding sulpiride, sodium chloride and 1M hydrochloric acid into 1500ml of water for injection, stirring to dissolve, adding water for injection to 2000ml, and adjusting the pH value to 5.0 by using 0.1M hydrochloric acid and 0.1M sodium hydroxide solution; adding active carbon, stirring and adsorbing for 15 minutes, and then removing carbon; filtering the medicinal liquid with 0.45 μm and 0.22 μm microporous filter membrane respectively for 2 times, packaging into ampoule bottle, sealing, and sterilizing at 121 deg.C for 15min.
Sulpiride has a solubility in slightly acidic and slightly basic conditions that is significantly better than the solubility in water, although slightly basic is more soluble than slightly acidic. In the embodiments 1 to 6 of the present invention, sulpiride is dissolved under a slightly alkaline condition, and then the solution is adjusted to weak acidity with pH =3 to 5 with an acid to prepare an injection. Several examples are provided below with slight variations from the recipes and processes of examples 1-6.
Example 12: preparation of sulpiride injection
This example was carried out with reference to example 1 herein, but without sodium hydroxide, the pH was adjusted directly with sulfuric acid to a slightly acidic pH = 4-4.5 and the drug was dissolved.
The formula is as follows: 5g of sulpiride, 5g of propylene glycol, 0.5g of sodium chloride, proper amount of sulfuric acid, proper amount of medicinal liquid pH = 4-4.5, and proper amount of water for injection to 100ml.
The preparation method comprises the following steps:
(a) Mixing 30% of injection water and propylene glycol according to the prescription amount, adding sulpiride, slowly adding a sulfuric acid solution (2M) under stirring until the pH value of the liquid medicine reaches a target value, and stirring until the liquid medicine is completely dissolved;
(b) Adding water for injection to 60% of the total volume of the prescription, adding sodium chloride to dissolve, heating the liquid medicine to 45-50 deg.C, maintaining the temperature, and checking the pH value of the liquid medicine to a target value with sulfuric acid solution (2M);
(c) Adding 0.5% of activated carbon into the liquid medicine, stirring for 30 minutes, removing the carbon, cooling to room temperature, adding water for injection to nearly full volume, adjusting the pH value of the liquid medicine to a target value again by using a sulfuric acid solution, and adding water for injection to full volume;
(d) Filtering the medicinal liquid with 0.45 μm and 0.22 μm microporous filter membrane respectively for 2 times, packaging into ampoule bottle, sealing, and sterilizing at 121 deg.C for 15min.
Example 13: preparation of sulpiride injection
This example was carried out in accordance with example 1 herein, but without the addition of propylene glycol.
The formula is as follows: 5g of sulpiride, 0.5g of sodium hydroxide, 0.5g of sodium chloride, proper amount of sulfuric acid, proper amount of medicinal liquid pH = 4-4.5, and proper amount of water for injection to 100ml.
The preparation method comprises the following steps:
(a) Mixing sulpiride with 30% of water for injection, slowly adding a sodium hydroxide solution (1M) prepared by water for injection in advance under stirring, and stirring until the sulpiride is completely dissolved;
(b) Adding water for injection to 60% of the total volume of the prescription, adding sodium chloride to dissolve the water, heating the liquid medicine to 45-50 deg.C, maintaining the temperature, and slowly adding sulfuric acid solution (2M) under stirring until the pH value of the liquid medicine reaches a target value;
(c) Adding 0.5% of activated carbon into the liquid medicine, stirring for 30 minutes, removing the carbon, cooling to room temperature, adding water for injection to nearly full volume, adjusting the pH value of the liquid medicine to a target value again by using a sulfuric acid solution, and adding water for injection to full volume;
(d) Filtering the medicinal liquid with 0.45 μm and 0.22 μm microporous filter membrane respectively for 2 times, packaging into ampoule bottle, sealing, and sterilizing at 121 deg.C for 15min.
Example 14: preparation of sulpiride injection
This example was conducted with reference to example 1 herein, but propylene glycol was added to the weakly acidic medicinal solution obtained at the latter stage.
The formula is as follows: 5g of sulpiride, 5g of propylene glycol, 0.5g of sodium hydroxide, 0.5g of sodium chloride, proper amount of sulfuric acid, proper amount of medicinal liquid pH = 4-4.5, and proper amount of water for injection to 100ml.
The preparation method comprises the following steps:
(a) Mixing sulpiride with 30 percent of injection water according to the prescription amount, slowly adding a sodium hydroxide solution (1M) prepared by the injection water in advance under stirring, and stirring until the sulpiride is completely dissolved;
(b) Adding water for injection to 60% of the total volume of the prescription, adding sodium chloride to dissolve the water, heating the liquid medicine to 45-50 deg.C, maintaining the temperature, and slowly adding sulfuric acid solution (2M) under stirring until the pH value of the liquid medicine reaches a target value;
(c) Adding propylene glycol into the liquid medicine, stirring uniformly, then adding 0.5% of activated carbon, stirring for 30 minutes, removing carbon, cooling to room temperature, adding water for injection to nearly full dose, adjusting the pH value of the liquid medicine to a target value again by using a sulfuric acid solution, and adding water for injection to full dose;
(d) Filtering the medicinal liquid with 0.45 μm and 0.22 μm microporous filter membrane respectively for 2 times, packaging into ampoule bottle, sealing, and sterilizing at 121 deg.C for 15min.
Test example 1: HPLC method for determining content and impurities
The sulpiride bulk drug carried in European pharmacopoeia EP10.0 edition is subjected to related substance examination by using an HPLC method, wherein clearly detectable impurities comprise an impurity D which is a benzoic acid part obtained after hydrolysis of a sulpiride amido bond, and the chemical names of the sulpiride and the impurity D are respectively as follows:
sulpiride: n- [ (1-ethyl-2-pyrrolidinyl) methyl ] -2-methoxy-5- (aminosulfonyl) benzamide,
impurity D: 2-methoxy-5-sulfamoylbenzoic acid.
Monitoring the content change of the impurity D in the injection is beneficial to the quality monitoring of the medicine. In addition, impurity B (2-methoxy-5-aminosulfonyl) benzoic acid methyl ester), impurity G (N- [ [ (2 RS) -1-ethylpyrrolidin-2-yl ] methyl ] -2-hydroxy-5-aminosulfonylbenzamide), and the like can also be monitored by the HPLC method. The reference substances of the impurity B, the impurity D, the impurity G and the sulpiride can be purchased from Sigma-Aldrich and can also be easily prepared by self, and the reference substances used in the invention are all made by self and have the purity of more than 99.6 percent.
This test example 1 provides the following HPLC method to determine the sulpiride content in the injection and can be used to detect the amount of impurity D and other possible impurities in the injection:
measuring according to the standard of high performance liquid chromatography 0512 of the general rule of four departments in 2020 edition of Chinese pharmacopoeia;
test solution: precisely measuring a proper amount of sulpiride injection, and diluting with a mobile phase to prepare a solution (1 mg/mL) containing 1mg of sulpiride in each 1 mL;
control solution: precisely measuring 1ml of the test solution, placing the test solution in a 100ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up (10 mu g/ml);
sulpiride control solution: precisely measuring 10.0mg of sulpiride reference substance, placing into a 10mL measuring flask, dissolving with mobile phase, diluting to scale, and shaking up (1 mg/mL);
solution of impurity D: accurately weighing 10.0mg of an impurity D reference substance, placing the reference substance in a 100ml measuring flask, dissolving and diluting the reference substance to a scale by using a mobile phase, shaking up, placing 1ml, 2.5ml, 5ml or 10ml in a 50ml measuring flask, diluting the reference substance to the scale by using the mobile phase, and shaking up (2 mu g/ml, 5 mu g/ml, 10 mu g/ml and 20 mu g/ml which are respectively equal to 0.2%, 0.5%, 1.0% and 20% of the concentration of the solution of the sulpiride test sample); other impurity solutions can be similarly prepared
Chromatographic conditions are as follows: octyl silane bonded silica gel was used as a filler (4.6 mm. Times.250mm, 5 μm); a potassium dihydrogen phosphate buffer (6.8 g of potassium dihydrogen phosphate, 2.8g of sodium octane sulfonate, 1000ml of water was added to dissolve, and pH was adjusted to 3.5 with phosphoric acid) -acetonitrile-methanol (75; the detection wavelength is 240nm; the column temperature was 35 ℃; flow rate was 1.5ml per minute; the sample injection volume is 10 mu l;
system applicability requirements: the number of theoretical plates of the reference solution is not less than 5000 according to the peak of sulpiride;
the determination method comprises the following steps: precisely measuring a test solution, a reference solution, a sulpiride reference solution, an impurity D solution or other impurity solutions, respectively injecting into a liquid chromatograph, and recording the chromatogram until the retention time of a main component peak is 3 times;
relative retention time: the retention time of sulpiride is about 13min, and the relative retention times of the impurity B, the impurity D and the impurity G are about 0.74, 0.22 and 1.96 respectively;
and (3) calculating:
content of sulpiride in the injection: calculating the content of sulpiride in the test solution according to the peak areas of the main components of the test solution and the sulpiride reference solution and the concentration of the reference solution,
content of impurity B, impurity D or impurity G in the injection: and calculating the content of the impurity in the injection according to the peak area of the corresponding impurity in the chromatogram of the test solution and the peak area and concentration of the reference solution of the impurity (equivalent concentration).
Particular attention must be paid to the fact that impurities B and G and other impurities in the injection solution change very little during long-term storage, while impurity D changes somewhat in some cases.
Test example 2: yield of active ingredient of injection
The concentration of the active ingredient in the injection solutions obtained in examples 1 to 6 and examples 11 to 14 was measured by the HPLC method of test example 1, and the quotient of the concentration divided by the theoretical charge concentration in the preparation process and multiplied by 100% was the active ingredient yield, which reflects the loss ratio of the active ingredient in the preparation process, and the loss was smaller as the yield was higher. The results were as follows:
the yields of active ingredients of the injections of examples 1 to 6 are in the range of 99.57 to 99.81% (i.e., loss of 0.19 to 0.43%), for example, the yield of active ingredients of the injection of example 1 is 99.68% (i.e., loss of 0.32%), the theoretical charge concentration of the injection of example 1 is 5.025g/100ml, and the measured concentration of the obtained injection is 5.009g/100ml;
the yield of the active ingredient of the injection of example 11 is 99.62% (i.e. 0.38% loss);
example 12 injection yield of active ingredient is 99.73% (i.e. loss 0.27%);
example 13 injection yield 95.14% active ingredient (i.e. loss 4.86%);
the yield of the active ingredient of the injection of example 14 is 95.57% (i.e. 4.43% loss).
After the activated carbon tests (suspending the activated carbon by a mobile phase, treating the activated carbon by ultrasonic waves for 30 minutes, centrifuging, filtering and testing again) of the filtered activated carbon of the examples 13 to 14, the active ingredients in the activated carbon are respectively 4.93 percent and 4.31 percent of the theoretical feeding amount, and the results are equivalent to the loss percent results; the amounts of active ingredients in the activated carbon of examples 1 to 6 and examples 11 to 12 were measured in the same manner, and were each within the range of 0.22 to 0.42% of the theoretical amount, for example, the amount of active ingredient in the activated carbon of example 1 was 0.30% of the theoretical amount.
From the above results, it can be seen that in examples 11 to 12, when the chemical solution was prepared as a weakly acidic chemical solution using an acid as it is and then subjected to the activated carbon treatment, the amount of the active material adsorbed in the activated carbon was small; in the process of firstly adding alkali to dissolve the liquid medicine and then adjusting the liquid medicine to be weakly acidic, only the propylene glycol activated carbon is added to absorb less when the alkali is dissolved in the embodiment 1-6; whereas when propylene glycol is not added or is added in the latter acidic state, significant loss of active ingredient is caused by carbon adsorption. That is, the loss of active ingredients adsorbed by activated carbon can be avoided by using propylene glycol when using a process of alkalinizing dissolution prior to acidification.
Test example 3: change of impurity D content of injection
The injection solutions obtained in examples 1 to 6 and examples 11 to 14 were left at a temperature of 40 ℃ for 6 months, and the content of impurity D in each injection solution was measured at 0 month and 6 months by the method of test example 1, and the increase (%) of impurity D at 6 months was calculated as follows for each injection solution:
as a result:
the 6-month impurity D growth rate of the injections of examples 1 to 6 and examples 13 to 14 was in the range of 38 to 53%, for example, the 6-month impurity D growth rate of the injection of example 1 was 44.5% (0.137% and 0.198% for the impurity D content at 0 month and 6 months, respectively);
the 6-month impurity D growth rates of the injections of example 11 and example 12 were 438.5% (0.156% and 0.840% for the impurity D contents in months 0 and 6), and 476.1% (0.134% and 0.772% for the impurity D contents in months 0 and 6), respectively. Example 11 of the present invention is an injection solution obtained by referring to the formulation and preparation method of formula 2 of example 1 of CN1836651a, which has a significant increase in impurity D, this data feature is not shown in the results of table 7 of CN1836651a, which may be due to various reasons, for example, the present invention is sulpiride and CN1836651a is levosulpiride, which may differ in the generation of impurity D; for another example, the HPLC method of the present invention can separate and measure the impurity D efficiently, while CN1836651a does not describe a method for measuring a relevant substance, for example, if CN1836651a uses thin layer chromatography, it may be difficult to quantitatively measure the impurity D, especially to examine its change, and if the HPLC chromatographic conditions are not ideal (it is possible to understand that this is completely possible under the technical conditions at the time of this document from the viewpoint of scientific development), it may be impossible to separate the impurity D from the main component and thus the impurity D and its change state cannot be obtained accurately; therefore, the result of the change of impurity D in example 11 of the present invention is not comparable to the data of CN 1836651A.
As can be seen from the above results, the injection solutions obtained by the processes of examples 1 to 6 and examples 13 to 14, in which the active drug was dissolved under weakly alkaline conditions and the drug solutions were adjusted to be weakly acidic, had a significantly low increase rate of the impurity D during long-term sample retention, while the injection solutions obtained by the processes in which the drug solutions were directly adjusted to be weakly acidic and the drug was dissolved had a significantly high increase rate of the impurity D during long-term sample retention.
As can be seen from the results of test examples 2 and 3 described above, the injection solutions obtained by the process of dissolving the active drug in the presence of propylene glycol under weakly alkaline conditions and then adjusting the solution to weak acidity according to examples 1 to 6 of the present invention have a significantly low rate of increase of impurity D during long-term sample retention and a small loss of active ingredient. This finding is not at all anticipated by the prior art.
Test example 4: properties of injection solution
Based on the results of the above test examples 2 to 3, it was revealed that the embodiments of examples 1 to 6 are excellent, and some properties of the injection solutions of examples 1 to 6 were measured as follows. The following month 0 and 6 data were determined for the injections of examples 1-6 after 0 and 6 months at a temperature of 40 ℃:
note: the clarity and color of the solution are checked according to methods of 0901, the four-part rule of 2020 edition of Chinese pharmacopoeia and 0902, the four-part rule of 2020 edition of Chinese pharmacopoeia;
the osmotic pressure molar concentration is checked according to the general rule 0632 of the four departments of the 2020 edition of Chinese pharmacopoeia;
the bacterial endotoxin is checked according to the general rule 1143 of the four ministry of China pharmacopoeia 2020 edition;
the substances and contents were examined by HPLC method in test example 1 of the present invention.
In additional experiments, the injection solutions of example 13 and example 14 were found to have a relatively significant change in pH after prolonged standing, as follows: the injections of examples 1 to 6 and examples 11 to 14 were left at 40 ℃ for 6 months, and the pH of each injection was measured at 0 month and 6 months, respectively, to obtain a pH difference by subtracting the pH at 0 month from the pH at 6 months, and the results were as follows: examples 1 to 6 had pH differences of = -0.2 to 0.3 for injections, = -0.09 pH units for injections, 0.16 pH units and-0.12 pH units for injections in example 11 and example 12, and 2.26 pH units and 2.53 pH units for injections in example 13 and example 14, respectively, as in the above tables, indicating that the pH stability of the injections in example 13 and example 14 is significantly worse than that of the other injections.
The present invention is illustrated in detail by the examples described above, but the present invention is not limited to the details described above, i.e., it is not intended that the present invention be implemented by relying on the details described above. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. Sulpiride injection comprises sulpiride and water for injection.
2. Sulpiride injection according to claim 1, comprising per 100ml sulpiride 1-10 g; for example, it contains 2 to 5g of sulpiride per 100ml; for example, it contains 2.5 to 5g of sulpiride per 100ml.
3. Sulpiride injection according to claim 1, further comprising sodium chloride; for example, it contains 0.45 to 0.55g, for example, 0.5g of sodium chloride per 100ml.
4. Sulpiride injection according to claim 1, further comprising an acid-base modifier; for example, the pH-adjusting agent may be used in an amount to adjust the pH of the injection solution to a range of 3 to 6, such as 3.5 to 5, such as 3.5 to 4.5, such as 4 to 4.5.
5. Sulpiride injection according to claim 1, further comprising propylene glycol; for example, 4 to 6g, such as 5g, of propylene glycol is included per 100ml; for example, the acid-base modifier includes bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, and the like; for example, 0.45 to 0.55g, for example, 0.5g of sodium hydroxide is added to 100ml of the solution.
6. Sulpiride injection according to claim 1, wherein the pH modifying agent comprises an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc., such as sulfuric acid; for example, the pH adjusting agent may comprise sulfuric acid in an amount to adjust the pH of the injection solution to a value in the range of 3 to 6, such as 3.5 to 5, such as 3.5 to 4.5, such as 4 to 4.5.
7. Sulpiride injection according to claim 1, prepared according to a process comprising the steps of:
(a) Mixing proper amount of water for injection with propylene glycol, adding sulpiride, slowly adding sodium hydroxide solution prepared by water for injection in advance under stirring, and stirring until the sodium hydroxide solution is completely dissolved;
(b) Adding a proper amount of water for injection, adding sodium chloride to dissolve the mixture and heating the liquid medicine to 45-50 ℃ and maintaining the temperature, and then slowly adding a sulfuric acid solution while stirring until the pH value of the liquid medicine reaches a target value;
(c) Adding activated carbon into the liquid medicine, stirring for removing carbon at proper time, cooling to room temperature, adding water for injection to nearly full dose, regulating the pH of the liquid medicine to a target value again by using a sulfuric acid solution, and supplementing water for injection to full dose;
(d) Filtering the medicinal liquid with microporous membrane, packaging into medicine bottle, sealing, and sterilizing.
8. Sulpiride injection according to claim 7, wherein:
in the step (a), the sulpiride is added after 25 to 35 percent of the prescription amount, such as 30 percent of water for injection, is mixed with the propylene glycol;
in the step (a), slowly adding a sodium hydroxide solution (1M) prepared by water for injection in advance under stirring, and stirring until the sodium hydroxide solution is completely dissolved;
in the step (b), adding the injection water to 55-65 percent, for example 60 percent of the total volume of the prescription;
in the step (b), slowly adding a sulfuric acid solution (2M) until the pH value of the liquid medicine reaches a target value under stirring;
in the step (c), 0.5 percent of activated carbon is added into the liquid medicine, and the liquid medicine is stirred for 30 minutes and then decarburized;
in the step (d), filtering the liquid medicine with 0.45 μm and 0.22 μm microporous filter membranes for 2 times, subpackaging into ampoule bottles, and sealing by fusing;
sterilizing at 121 ℃ for 15min in step (d);
having a formulation as described in any one of examples 1 to 6;
having the preparation process as described in any one of embodiments 1 to 6;
having the formulation and method of manufacture of any one of examples 1 to 6.
9. A process for the preparation of sulpiride injection according to any of claims 1 to 8, comprising the steps of:
(a) Mixing a proper amount of water for injection with propylene glycol, adding sulpiride, slowly adding a sodium hydroxide solution prepared by water for injection in advance under stirring, and stirring until the sodium hydroxide solution is completely dissolved;
(b) Adding a proper amount of water for injection, adding sodium chloride to dissolve the water and ensure that the temperature of the liquid medicine is raised to 45-50 ℃ and maintained at the temperature, and then slowly adding a sulfuric acid solution under stirring until the pH value of the liquid medicine reaches a target value;
(c) Adding activated carbon into the liquid medicine, stirring for removing carbon at proper time, cooling to room temperature, adding water for injection to nearly full volume, regulating the pH value of the liquid medicine to a target value again by using a sulfuric acid solution, and adding water for injection to full volume;
(d) Filtering the medicinal liquid with microporous membrane, packaging into medicine bottle, sealing, and sterilizing.
10. Use of the sulpiride injection according to any of claims 1-8 for the preparation of a medicament for the autistic, withdrawal and apathy symptoms of schizophrenia in the form of simplex, paranoid, catatonic and chronic schizophrenia.
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| CN117180189A (en) * | 2023-09-20 | 2023-12-08 | 海南卓泰制药有限公司 | Shubianli injection and preparation method and application thereof |
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| CN117180189A (en) * | 2023-09-20 | 2023-12-08 | 海南卓泰制药有限公司 | Shubianli injection and preparation method and application thereof |
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