CN105342997A - Metoclopramide hydrochloride injection and preparation method thereof - Google Patents
Metoclopramide hydrochloride injection and preparation method thereof Download PDFInfo
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- CN105342997A CN105342997A CN201510841773.7A CN201510841773A CN105342997A CN 105342997 A CN105342997 A CN 105342997A CN 201510841773 A CN201510841773 A CN 201510841773A CN 105342997 A CN105342997 A CN 105342997A
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- metoclopramide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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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
- A61K47/02—Inorganic compounds
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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
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Abstract
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a metoclopramide hydrochloride injection and a preparation method thereof. The metoclopramide hydrochloride injection comprises metoclopramide, cosolvent, pH regulator and antioxidant. The metoclopramide hydrochloride injection is characterized in that a ratio of metoclopramide, cosolvent, pH regulator and antioxidant is 1:0.6-2:0.3-1:0.1-0.3. The metoclopramide hydrochloride injection is reasonable in prescription, simple in process and high in stability and has the advantages of safety, stability and quality controllability.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of metoclopramide dihydrochloride for injection and preparation method thereof.
Background technology
Metoclopramide (metoclopramide) is a kind of potent central Bendectin, and metoclopramide is dopamine D 2 receptor antagonists, also has 5-HT4 receptor agonism effect simultaneously, has slight inhibitory action to 5-HT3 receptor.Dopamine receptor in oblongata chemoreceptor trigger zone (CTZ) can be acted on and improve the threshold value of CTZ, there is powerful central antiemetic effect.This medicine acts predominantly on upper digestive tract, promotes the motion of stomach and top intestinal segment; Improve the sphincteral tension force of quiescent condition gastrointestinal tract, increase the tension force of lower esophageal sphincter and the amplitude of contraction, lower esophageal pressure is increased, retardance stomach-esophageal reflux, strengthen harmonization of the stomach esophageal peristalsis, and strengthen ability is cleaned up to esophageal contents, promote the emptying of stomach; Promote the lax of pylorus, duodenum and top jejunum, form gastric antrum, orthofunction between body of stomach and upper small intestine.These effects also can strengthen the antiemetic effect of this medicine.Play powerful central town and tell effect.
Go on the market abroad the earliest metoclopramide be injection by (1979), Yuan Yan producer: BAXTER, specification; 5mg/ml (2,10,30ml).Within 1980, to be gone on the market tablet in the U.S. by ANIPHARMS, specification: 5,10mg.Crinos in 1999 to have gone on the market Metoclopramide nasal spray in Italy, specification: 10,20mg/ spray (2,4ml).Injection is mainly used in the postoperative nausea and vomiting, the diabetic gastroparesis that cause with chemotherapy.Oral formulations is mainly used in disease such as treatment gastroesophageal reflux, diabetic gastroparesis etc.Metoclopramide injection and oral formulations have gone on the market for many years, and antiemetic effect has obtained the affirmative of multinomial clinical trial.Injection advantage: local tolerance is good, when reaching same therapeutic goal, pharmaceutical dosage is little.Tablet shortcoming: onset is slow.Nasal spray shortcoming: effectively spray is secondary less, residual many, and waste is large, increases the financial burden of patient.In the metoclopramide dihydrochloride for injection medicinal liquid injection sold in the market, metal ion content is higher, medicinal liquid sulfite hydrogen sodium content poor stability, thus affects liquid medicine stability, is unfavorable for safe medication.
Summary of the invention
The object of this invention is to provide a kind of metoclopramide dihydrochloride for injection and preparation method thereof, this injection formula is reasonable, and technique is simple, good stability.
In order to realize above object, the invention provides a kind of metoclopramide dihydrochloride for injection and preparation method thereof, comprising metoclopramide, cosolvent, pH adjusting agent, antioxidant; It is characterized in that metoclopramide: cosolvent: pH adjusting agent: antioxidant=1:0.6 ~ 2:0.3 ~ 1:0.1 ~ 0.3.
Wherein, described cosolvent is selected from phosphoric acid, hydrochloric acid, citric acid, tartaric acid, acetic acid, maleic acid, is preferably hydrochloric acid.
Described pH adjusting agent is selected from sodium hydroxide, sodium carbonate, sodium acetate, sodium bicarbonate, sodium citrate, phosphate buffer, acetate buffer and citrate buffer, is preferably sodium acetate.
Described antioxidant is selected from sodium sulfite, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, is preferably sodium sulfite.
The preparation method step of described metoclopramide dihydrochloride for injection:
(1) prepare: with beaker, the cosolvent of the metoclopramide recipe quantity diluted is dissolved for subsequent use.With beaker, the appropriate water for injection of antioxidant is dissolved for subsequent use; With beaker, the appropriate water for injection of pH adjusting agent is dissolved for subsequent use.In preparing tank, add the water for injection that Process Planning is quantitative, first the metoclopramide reserve liquid dissolved is joined in preparing tank, then the antioxidant stock solution of having dissolved is joined in preparing tank; Finally use 10%pH regulator solution adjust pH, mend and inject water to prescribed volume;
(2) embedding: liquid medicine filling is in ampoule;
(3) sterilizing: adopt water-bath sterilizer sterilizing.
Wherein, with 10%pH regulator solution adjust pH to 3.8 ~ 4.2.
Inventor finds under study for action, and cosolvent hydrochloric acid can promote the dissolving of metoclopramide, but is not enough to metoclopramide is dissolved when the consumption of hydrochloric acid is lower or hydrochloric acid concentration is in the formulation lower; When the consumption of hydrochloric acid is higher or hydrochloric acid concentration is in the formulation higher, too low pH can corrosion tank, and introduce metal ion, metal ion can play catalyst action, promotes antioxidant sodium sulfite degraded in medicinal liquid, thus affects the stability of medicinal liquid.And need to use more pH adjusting agent such as sodium acetate.Be unfavorable for the carrying out of preparation process, be particularly unfavorable for suitability for industrialized production.Therefore, the consumption of cosolvent is the key determining prescription stability.
Beneficial effect of the present invention is: carry out the control to charging sequence in strict control and preparation process to cosolvent in prescription, make to obtain metoclopramide inj medicinal liquid by this prescription and preparation technology and there is good stability, investigate result by acceleration, long-time stability and show that quality of liquid medicine is stablized controlled.
Detailed description of the invention
Be described in detail embodiment of the present invention below in conjunction with embodiment, the following example only for illustration of the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment, the condition of conveniently conditioned disjunction manufacturer suggestion is carried out.Agents useful for same or the unreceipted production firm person of instrument, being can by the conventional products of commercial acquisition.
embodiment 1
Prescription: metoclopramide: 0.77kg
Hydrochloric acid: 410ml(is equivalent to 0.49kg)
Sodium acetate: 0.30kg
Sodium sulfite: 0.10kg
Preparation technology:
(1) prepare: with beaker, the mass fraction 36.5% hydrochloric acid 410ml of the metoclopramide 0.77kg recipe quantity diluted is dissolved for subsequent use.With beaker, the appropriate water for injection of sodium sulfite 0.10kg is dissolved for subsequent use.With beaker, the appropriate water for injection of sodium acetate 0.30kg is dissolved for subsequent use.In preparing tank, add the water for injection of the quantitative 40L of Process Planning, open nitrogen valve, open and stir; In preparing tank, add the water for injection of the quantitative 40L of Process Planning, open nitrogen valve, open and stir; First the reserve liquid of the metoclopramide dissolved in hydrochloric acid solution is joined in preparing tank, then the stock solution of the sodium sulfite dissolved is joined in preparing tank; Finally join adjust pH to 4.0 in preparing tank by 10% sodium acetate solution of having dissolved, mend and inject water to prescribed volume 100L.Open and stir, stir 15 minutes.Medicinal liquid is through grade one filter (titanium rod, 3 μm), secondary filter (polyether sulfone, 0.45 μm), ultimate filter (polyether sulfone, 0.2 μm) circulating reflux 15 minutes;
(2) embedding: liquid medicine filling is in middle borosilicate glass ampoule.Adopt the embedding integration apparatus of automatic nitrogen-charging function in pouring process, ensure that the remaining oxygen of the rear product of sealing is below 2%;
(3) sterilizing: middle borosilicate glass ampoule dress product adopts water-bath sterilizer, 115 DEG C of sterilizings 30 minutes.
embodiment 2
Prescription: metoclopramide: 0.77kg
Citric acid: 1.58kg
Sodium bicarbonate: 0.40kg
Sodium sulfite: 0.12kg
Preparation technology:
(1) prepare: with beaker, the citric acid 1.58kg of the metoclopramide 0.77kg recipe quantity dissolved is dissolved for subsequent use.With beaker, the appropriate water for injection of sodium sulfite 0.12kg is dissolved for subsequent use.With beaker, the appropriate water for injection of sodium bicarbonate 0.40kg is dissolved for subsequent use.In preparing tank, add the water for injection of the quantitative 40L of Process Planning, open nitrogen valve, open and stir; First the reserve liquid of the metoclopramide dissolved in citric acid solution is joined in preparing tank, then the stock solution of the sodium sulfite dissolved is joined in preparing tank; Finally join adjust pH to 4.2 in preparing tank with the sodium bicarbonate solution dissolved, mend and inject water to prescribed volume 100L.Open and stir, stir 15 minutes.Medicinal liquid is through grade one filter (titanium rod, 3 μm), secondary filter (polyether sulfone, 0.45 μm), ultimate filter (polyether sulfone, 0.2 μm) circulating reflux 15 minutes.
(2) embedding: liquid medicine filling is in middle borosilicate glass ampoule.Adopt the embedding integration apparatus of automatic nitrogen-charging function in pouring process, ensure that the remaining oxygen of the rear product of sealing is below 2%;
(3) sterilizing: middle borosilicate glass ampoule dress product adopts water-bath sterilizer, 115 DEG C of sterilizings 30 minutes.
embodiment 3
prescription:metoclopramide: 0.77kg
Tartaric acid: 1.50kg
Sodium-acetate buffer: 400ml(is equivalent to 0.75kg)
Sodium pyrosulfite 0.18kg
Preparation technology:
(1) prepare: with beaker, the tartaric acid 1.50kg of the metoclopramide 0.77kg recipe quantity diluted is dissolved for subsequent use.With beaker, the appropriate water for injection of sodium pyrosulfite 0.18kg is dissolved for subsequent use.With beaker by the appropriate water for injection diluted for use of sodium-acetate buffer 400ml.In preparing tank, add the water for injection of the quantitative 40L of Process Planning, open nitrogen valve, open and stir; First the reserve liquid of the metoclopramide dissolved in tartaric acid solution is joined in preparing tank, then the stock solution of the sodium pyrosulfite dissolved is joined in preparing tank; Finally join adjust pH to 3.8 in preparing tank by the sodium acetate solution of having dissolved, mend and inject water to prescribed volume 100L.Open and stir, stir 15 minutes.Medicinal liquid is through grade one filter (titanium rod, 3 μm), secondary filter (polyether sulfone, 0.45 μm), ultimate filter (polyether sulfone, 0.2 μm) circulating reflux 15 minutes;
(2) embedding: liquid medicine filling is in middle borosilicate glass ampoule.Adopt the embedding integration apparatus of automatic nitrogen-charging function in pouring process, ensure that the remaining oxygen of the rear product of sealing is below 2%;
(3) sterilizing: middle borosilicate glass ampoule dress product adopts water-bath sterilizer, 115 DEG C of sterilizings 30 minutes.
experimental example 4: metal ion content contrasts
By after optimized production process, before optimized production process and common commercialized product metoclopramide dihydrochloride for injection get respectively in 1ml to 10ml volumetric flask, add mass fraction 2% dust technology standardize solution.Medicinal liquid is introduced ICP mass spectrum spectrometer, measure metal ion content in medicinal liquid, result is as following table:
Experimental result shows: can obviously reduce metal ion content in medicinal liquid after optimized production process.
experimental example 5: sodium sulfite stable content Comparative result
By after optimized production process, before optimized production process and common commercialized product metoclopramide dihydrochloride for injection carry out accelerated test, long-term stable experiment, sampling and measuring medicinal liquid sulfite hydrogen sodium content, result of the test is as following table: accelerated test (40 DEG C ± 2 DEG C constant incubators)
Long-term stable experiment (30 DEG C ± 2 DEG C constant incubators)
Result of the test shows: can improve medicinal liquid sulfite hydrogen stable sodium after optimized production process, ensure that quality of liquid medicine is stablized controlled.
Claims (9)
1. a metoclopramide dihydrochloride for injection, comprises metoclopramide, cosolvent, pH adjusting agent, antioxidant; It is characterized in that metoclopramide: cosolvent: pH adjusting agent: antioxidant=1:0.6 ~ 2:0.3 ~ 1:0.1 ~ 0.3.
2. metoclopramide dihydrochloride for injection according to claim 1, is characterized in that described cosolvent is selected from the one in phosphoric acid, hydrochloric acid, citric acid, tartaric acid, acetic acid, maleic acid.
3. metoclopramide dihydrochloride for injection according to claim 1 and 2, is characterized in that described cosolvent is preferably hydrochloric acid.
4. metoclopramide dihydrochloride for injection according to claim 1, is characterized in that described pH adjusting agent is selected from the one in sodium hydroxide, sodium carbonate, sodium acetate, sodium bicarbonate, sodium citrate, phosphate buffer, acetate buffer and citrate buffer.
5. the metoclopramide dihydrochloride for injection according to claim 1 or 4, is characterized in that described pH adjusting agent is preferably sodium acetate.
6. metoclopramide dihydrochloride for injection according to claim 1, is characterized in that described antioxidant is selected from the one in sodium sulfite, sodium pyrosulfite, sodium sulfite, sodium thiosulfate.
7. the metoclopramide dihydrochloride for injection according to claim 1 or 6, is characterized in that described antioxidant is preferably sodium sulfite.
8. metoclopramide dihydrochloride for injection according to claim 1, is characterized in that preparation method comprises the steps:
(1) prepare: with beaker, the cosolvent of the metoclopramide recipe quantity diluted is dissolved for subsequent use;
With beaker, the appropriate water for injection of antioxidant is dissolved for subsequent use; With beaker, the appropriate water for injection of pH adjusting agent is dissolved for subsequent use;
In preparing tank, add the water for injection that Process Planning is quantitative, first the metoclopramide reserve liquid dissolved is joined in preparing tank, then the antioxidant stock solution of having dissolved is joined in preparing tank; Finally use 10%pH regulator solution adjust pH, mend and inject water to prescribed volume;
(2) embedding: liquid medicine filling is in ampoule;
(3) sterilizing: adopt water-bath sterilizer sterilizing.
9. the metoclopramide dihydrochloride for injection according to claim 1 or 8, is characterized in that in preparation process with 10%pH regulator solution adjust pH to 3.8 ~ 4.2.
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| CN201510841773.7A CN105342997B (en) | 2015-11-28 | 2015-11-28 | A kind of metoclopramide dihydrochloride for injection and preparation method thereof |
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| CN201510841773.7A CN105342997B (en) | 2015-11-28 | 2015-11-28 | A kind of metoclopramide dihydrochloride for injection and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108392623A (en) * | 2018-01-25 | 2018-08-14 | 苏州科技城医院 | A kind of agonist drug composition of steroid non-depolarizing muscular relaxant |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5081153A (en) * | 1984-05-17 | 1992-01-14 | Beecham Group P.L.C. | Sterile parenteral composition |
| FR2720935A1 (en) * | 1994-06-08 | 1995-12-15 | Synthelabo | Powder for injection, for treatment of migraine |
| CN104606155A (en) * | 2014-12-25 | 2015-05-13 | 海南卫康制药(潜山)有限公司 | Metoclopramide composition freeze-dried tablet and preparation method thereof |
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2015
- 2015-11-28 CN CN201510841773.7A patent/CN105342997B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5081153A (en) * | 1984-05-17 | 1992-01-14 | Beecham Group P.L.C. | Sterile parenteral composition |
| FR2720935A1 (en) * | 1994-06-08 | 1995-12-15 | Synthelabo | Powder for injection, for treatment of migraine |
| CN104606155A (en) * | 2014-12-25 | 2015-05-13 | 海南卫康制药(潜山)有限公司 | Metoclopramide composition freeze-dried tablet and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108392623A (en) * | 2018-01-25 | 2018-08-14 | 苏州科技城医院 | A kind of agonist drug composition of steroid non-depolarizing muscular relaxant |
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Denomination of invention: Metoclopramide hydrochloride injection and preparation method thereof Effective date of registration: 20211208 Granted publication date: 20181016 Pledgee: Qi commercial bank Limited by Share Ltd. Linzi branch Pledgor: SHANDONG QIDU PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980014351 |