CN107868009B - Metoprolol tartrate crystal, pharmaceutical composition containing metoprolol tartrate crystal and preparation method of pharmaceutical composition - Google Patents
Metoprolol tartrate crystal, pharmaceutical composition containing metoprolol tartrate crystal and preparation method of pharmaceutical composition Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
- C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/255—Tartaric acid
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a metoprolol tartrate crystal, a pharmaceutical composition containing the metoprolol tartrate crystal and a preparation method of the metoprolol tartrate crystal, wherein the metoprolol tartrate crystal has the following chemical structural formula:
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a metoprolol tartrate crystal, a pharmaceutical composition containing the metoprolol tartrate crystal and a preparation method of the metoprolol tartrate crystal.
Background
Metoprolol tartrate is a cardioselective β -receptor blocker without endogenous sympathomimetic activity, and can inhibit excessive release of catecholamine in the circulatory system, raise the receptors of cardiac muscle cells, restore the sensitivity of the receptors, inhibit an overactivated renin-angiotensin-aldosterone system, dilate peripheral blood vessels, reduce water and sodium retention, reduce the load before and after the heart, simultaneously play a role in preventing hypertrophy of the cardiac muscle cells and resisting utilization of oxidants, improve myocardial energy metabolism, effectively inhibit sympathetic nerve excitation after administration, reduce the excessively fast heart rate, fully fill the diastolic phase of the heart chambers, improve the active diastolic function, reduce energy demand and increase myocardial efficiency, and enhance parasympathetic activity, thereby preventing fatal arrhythmia including ventricular arrhythmia and ventricular fibrillation.
The tablet is a common preparation form in oral preparations, the quality of the tablet is related to factors such as raw materials, auxiliary materials, prescription composition, particle size, particle hardness, process conditions and the like, and the dissolution rate serving as an important index of quality control is also influenced by the factors. The dissolution rate refers to the rate and degree of dissolution of a drug from a solid preparation such as a tablet, a capsule, a granule and the like under a specified condition, and is an in vitro test method for simulating disintegration and dissolution of an oral solid preparation in the gastrointestinal tract.
① drying the solid drug, so it needs to be dried, so it needs to observe whether there is crystal transformation in the drying temperature range, drying makes many false crystal lose crystal water or solvent molecule, but usually, the dissolution rate and dissolution rate of anhydrous substance are larger than those of water substance, so it has different drug effect, ② cooling drug may generate crystal transformation in the cooling process, and its transformation type varies with different cooling temperature, ③ crystallization and recrystallization processes, so it has different drug effect and chemical properties.
Chinese patent with application number CN201410306235.3 discloses a pharmaceutical composition containing metoprolol tartrate and a preparation method thereof. The pharmaceutical composition comprises the following components: the metoprolol tartrate accounts for 40-50 percent of the weight, the microcrystalline cellulose accounts for 30-40 percent of the weight, the hydroxypropyl methylcellulose accounts for 5-13 percent of the weight, the povidone K30 ethanol solution accounts for 2-5 percent of the weight, the silicon dioxide accounts for 2-4 percent of the weight, and the magnesium stearate accounts for 2-4 percent of the weight. The dosage of the magnesium stearate in the pharmaceutical composition is larger, and the large dosage of the magnesium stearate is a hydrophobic auxiliary material, which can influence the dissolution rate of the tablet.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a metoprolol tartrate novel crystal, a pharmaceutical composition containing the metoprolol tartrate novel crystal and a preparation method of the metoprolol tartrate novel crystal.
In order to realize the purpose, the invention adopts the following technical scheme:
the chemical structural formula of the metoprolol tartrate crystal is as follows:
characteristic peaks of an X-ray powder diffraction pattern obtained by using Cu-K α ray measurement are shown at 10.65 degrees, 12.98 degrees, 14.28 degrees, 15.03 degrees, 15.89 degrees, 16.93 degrees, 18.13 degrees, 19.45 degrees, 20.43 degrees, 20.87 degrees, 21.66 degrees, 22.39 degrees, 23.20 degrees, 23.62 degrees and 24.06 degrees of 2 theta.
The metoprolol tartrate crystal has high bioavailability, and a pharmaceutical composition prepared by using the obtained crystal as a main drug has better drug effect.
The preparation method of the metoprolol tartrate crystal comprises the following steps:
(1) dissolving the crude product of the metolachlor tartrate in a mixed solvent of methanol and propanol, and stirring for dissolving;
(2) and (3) putting the solution obtained in the step (1) into a drying oven, and evaporating until crystals are separated out to obtain the metoprolol tartrate crystal.
The propanol used in the present invention is 1-propanol.
In the step (1), the dosage of the methanol and the propanol is 10-12 times of the weight of the crude metolachlor tartrate, the dosage is volume, the weight is mass, namely the volume is multiple of the weight, and the unit is L/kg or mL/g, and the volume ratio of the methanol to the propanol is 3-5: 1.
The temperature of the oven in the step (2) is 75-80 ℃, and the crystallization time is 2-10 hours.
The invention also provides a pharmaceutical composition containing the metoprolol tartrate crystal, which comprises the following components in percentage by weight:
preferably, the formula comprises the following components in percentage by weight:
in the pharmaceutical composition of the present invention, starch is used as a filler, and mainly serves to fill the weight or volume of the tablet, so as to facilitate the formulation formation and the dose division, thereby facilitating the tabletting.
The low-substituted hydroxypropyl cellulose is an excellent disintegrant and adhesive, has stronger hydrophilicity, expansibility and hygroscopicity, and also has larger surface area and porosity, so that the compressed tablet has neat and beautiful appearance, large hardness, rapid disintegration and high dissolution rate.
Sodium carboxymethyl starch is an excellent disintegrant and exerts its disintegrating action together with low-substituted hydroxypropyl cellulose.
Silicon dioxide is an excellent flow promoter, can greatly improve the flowability of granules, improve the bulk density, increase the hardness of the prepared tablet, shorten the disintegration time limit and further improve the dissolution speed of the medicine.
Magnesium stearate is used as a lubricant to reduce friction between granules and between the material and the die holes, increase the flowability of the material, and prevent the adhesion of the material to the punch and die under pressurized conditions. However, magnesium stearate is a hydrophobic auxiliary material, the dissolution rate of the tablet can be influenced when the dosage is large, and in order to meet the requirement of the fluidity of the tablet, the magnesium stearate is selected to be used together with a certain amount of silicon dioxide.
The hydroxypropyl methylcellulose is used as a binder, so that the contact angle of the medicament can be reduced, the medicament is easy to wet, the secondary disintegration of the tablet can be effectively improved, the dissolution rate is remarkably improved, and the dissolution rate of the finally obtained medicament is greatly improved through the synergistic effect of the hydroxypropyl methylcellulose and the low-substituted hydroxypropyl cellulose.
The invention determines the main and auxiliary materials and the dosage thereof through a series of tests, the hardness and friability, content uniformity, stability test and other aspects of the tablet obtained by the formula all meet the requirements of Chinese pharmacopoeia 2010 edition, and the dissolution rate is better. The dissolution rate is used as an important index for quality control, and the drug effect condition is also reflected, and the drug effect is superior when the dissolution rate is good.
The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps:
(1) weighing hydroxypropyl methylcellulose, uniformly dispersing with ethanol, adding purified water, stirring until the liquid is uniform and transparent, and cooling to obtain binder;
(2) weighing metoprolol tartrate, starch, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch according to the proportion of the formula, and uniformly mixing to obtain mixed powder;
(3) adding a binder into the mixed powder in the step (2) to obtain a soft material, then preparing the soft material into granules, and then drying, sieving and grading to obtain dry granules;
(4) weighing silicon dioxide and magnesium stearate according to the proportion of the prescription, adding the silicon dioxide and magnesium stearate and sodium carboxymethyl starch into the dry granules in the step (3), and uniformly mixing to obtain a mixture;
(5) and (4) tabletting the mixture obtained in the step (4), packaging by aluminum plastic, and warehousing a finished product after the product is qualified by detection.
The mixing sequence in the step (2) is the sequence of tartaric acid metoprolol → starch → sodium carboxymethyl starch → low-substituted hydroxypropyl cellulose, and the mixing mode is an equivalent increasing method. The mixing sequence of the main material and the auxiliary material has certain influence on the fluidity of the obtained mixed powder, and the fluidity is particularly important for the tabletting process and influences the quality of tablets. According to the invention, the influence of different mixing orders on the fluidity of the mixed powder is examined, so that the mixing order of the main material and the auxiliary material is determined, the mixed powder obtained by the order has good fluidity, and the tablet quality is higher. Because the proportions of the components in the prescription are very different and are not easy to mix uniformly, in order to ensure the uniformity of the granules and the uniform distribution of the drug content of the tablets, the components are mixed by an equivalent incremental method.
The amount of the sodium carboxymethyl starch used in the step (2) is 2/3 prescription amount; the amount of the sodium carboxymethyl starch in the step (4) is 1/3 prescription amount. The sodium carboxymethyl starch is used as a main disintegrating agent, and in order to better play a role, the addition mode of the sodium carboxymethyl starch is determined through a series of screening tests.
The soft material and the granules in the step (3) are prepared by a wet granulator, and the drying mode is boiling drying.
The particle size, uniformity, and flowability of the granules affect the hardness, weight variation, and content uniformity of the tablets. The smaller the particle size of the granules is, the greater the hardness of the extruded tablet is, and the granules with good uniformity and fluidity can ensure small weight difference, uniform distribution of drug content and good second disintegration of the granules, thereby improving the dissolution performance of the drug. The granules prepared by the wet granulator are uniform in size, round in appearance and good in fluidity, and can be dried to obtain fine granules similar to spheres, and tablets prepared from the granules are smooth and fine in surfaces and relatively uniform in drug dissolution. The invention has more components in the prescription, better adaptability of boiling drying to various materials and less particle damage.
The tablet prepared by the invention has the specification of 25 mg.
Compared with the prior art, the pharmaceutical composition containing the new crystal of metoprolol tartrate has the following beneficial effects:
1. the crystal obtained by the invention has high bioavailability, so that the medicinal composition prepared by the crystal as a main medicament has better medicinal effect.
2. The auxiliary materials adopted by the invention enable the tablet to have neat appearance, and simultaneously improve the dissolution rate of the tablet, thereby improving the drug effect of the pharmaceutical composition.
3. The preparation method adopted by the invention improves the uniformity of the tablet, improves the dissolution performance of the tablet and greatly improves the quality of the tablet.
Drawings
FIG. 1 is a dissolution curve of a pharmaceutical composition obtained by different sodium carboxymethyl starch addition modes;
fig. 2 is a dissolution rate graph of the obtained pharmaceutical composition of the invention in a dissolution medium with a pH of 1.2;
fig. 3 is a graph of the dissolution rate of the pharmaceutical composition obtained by the present invention in a dissolution medium with pH 4.0;
fig. 4 is a graph of the dissolution rate of the pharmaceutical composition obtained by the present invention in a dissolution medium with pH 6.8;
FIG. 5 is a graph showing the dissolution rate of the pharmaceutical composition of the present invention in an aqueous dissolution medium;
FIG. 6 is a graph showing dissolution profiles of commercially available products in dissolution media at pH 6.8;
FIG. 7 is a graph showing the dissolution rate of a commercial product in an aqueous dissolution medium;
FIG. 8 is an X-ray powder diffraction pattern of metoprolol tartrate crystals obtained by the present invention measured by Cu-K α radiation.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments are clearly and completely described below, and the following embodiments are used for illustrating the present invention and are not used for limiting the scope of the present invention.
Crystal production example 1
(1) Dissolving 1.0kg of metoprolol tartrate crude product in a mixed solvent of 8.0L of methanol and 2.0L of propanol, and stirring for dissolving;
(2) and (3) putting the solution obtained in the step (1) into a 75 ℃ oven for evaporation crystallization for 2 hours to obtain the metoprolol tartrate crystal.
The characteristic peaks of an X-ray powder diffraction pattern obtained by measuring the crystal by using Cu-K α rays are shown at the positions of 10.65 degrees, 12.98 degrees, 14.28 degrees, 15.03 degrees, 15.89 degrees, 16.93 degrees, 18.13 degrees, 19.45 degrees, 20.43 degrees, 20.87 degrees, 21.66 degrees, 22.39 degrees, 23.20 degrees, 23.62 degrees and 24.06 degrees of 2 theta.
The following are crystal preparation examples 2-5, the operation steps are the same as crystal preparation example 1, and the specific process parameters are shown in Table 1.
TABLE 1 Crystal production examples 2 to 5
The X-ray powder diffraction pattern of the metoprolol tartrate crystals prepared in the crystallization examples 2-5 by using Cu-K α ray measurement is similar to that of the crystallization example 1.
Example 1
Prescription:
the preparation process comprises the following steps:
(1) weighing hydroxypropyl methylcellulose, uniformly dispersing with ethanol, adding purified water, stirring until the liquid is uniform and transparent, and cooling to obtain binder;
(2) weighing metoprolol tartrate, starch, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch according to the proportion of the prescription, and uniformly mixing the metoprolol tartrate, the starch, the low-substituted hydroxypropyl cellulose and the sodium carboxymethyl starch → the order of the metoprolol tartrate → the starch → 2/3 according to the prescription amount by adopting an equivalent incremental method to obtain mixed powder;
(3) adding an adhesive into the mixed powder in the step (2), obtaining a soft material by a wet granulator, then preparing the soft material into granules, and then carrying out fluidized drying and sieving and granulating to obtain dry granules;
(4) weighing silicon dioxide and magnesium stearate according to the prescription proportion, adding the silicon dioxide and magnesium stearate and 1/3 prescription sodium carboxymethyl starch into the dry granules in the step (3), and uniformly mixing to obtain a mixture;
(5) and (4) tabletting the mixture obtained in the step (4), packaging by aluminum plastic, and warehousing a finished product after the product is qualified by detection.
Example 2
Prescription:
the preparation process comprises the following steps:
(1) weighing hydroxypropyl methylcellulose, uniformly dispersing with ethanol, adding purified water, stirring until the liquid is uniform and transparent, and cooling to obtain binder;
(2) weighing metoprolol tartrate, starch, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch according to the proportion of the prescription, and uniformly mixing the metoprolol tartrate, the starch, the low-substituted hydroxypropyl cellulose and the sodium carboxymethyl starch → the order of the metoprolol tartrate → the starch → 2/3 according to the prescription amount by adopting an equivalent incremental method to obtain mixed powder;
(3) adding an adhesive into the mixed powder in the step (2), obtaining a soft material by a wet granulator, then preparing the soft material into granules, and then carrying out fluidized drying and sieving and granulating to obtain dry granules;
(4) weighing silicon dioxide and magnesium stearate according to the prescription proportion, adding the silicon dioxide and magnesium stearate and 1/3 prescription sodium carboxymethyl starch into the dry granules in the step (3), and uniformly mixing to obtain a mixture;
(5) and (4) tabletting the mixture obtained in the step (4), packaging by aluminum plastic, and warehousing a finished product after the product is qualified by detection.
Example 3
Prescription:
the preparation process comprises the following steps:
(1) weighing hydroxypropyl methylcellulose, uniformly dispersing with ethanol, adding purified water, stirring until the liquid is uniform and transparent, and cooling to obtain binder;
(2) weighing metoprolol tartrate, starch, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch according to the proportion of the prescription, and uniformly mixing the metoprolol tartrate, the starch, the low-substituted hydroxypropyl cellulose and the sodium carboxymethyl starch → the order of the metoprolol tartrate → the starch → 2/3 according to the prescription amount by adopting an equivalent incremental method to obtain mixed powder;
(3) adding an adhesive into the mixed powder in the step (2), obtaining a soft material by a wet granulator, then preparing the soft material into granules, and then carrying out fluidized drying and sieving and granulating to obtain dry granules;
(4) weighing silicon dioxide and magnesium stearate according to the prescription proportion, adding the silicon dioxide and magnesium stearate and 1/3 prescription sodium carboxymethyl starch into the dry granules in the step (3), and uniformly mixing to obtain a mixture;
(5) and (4) tabletting the mixture obtained in the step (4), packaging by aluminum plastic, and warehousing a finished product after the product is qualified by detection.
The following are examples 4 to 12, the operation steps are the same as those of example 1, and the specific process parameters are shown in Table 2.
TABLE 2 examples 4 to 12
Comparative example 1
The amount of the sodium carboxymethyl starch used in the step (2) is a prescription amount, the sodium carboxymethyl starch is not added in the step (4), and other conditions are the same as those in the example 1.
Comparative example 2
The amount of the sodium carboxymethyl starch used in the step (2) is 1/2 prescription amount, the amount of the sodium carboxymethyl starch used in the step (4) is 1/2 prescription amount, and other conditions are the same as those in the example 1.
Comparative example 3
The amount of the sodium carboxymethyl starch used in the step (2) is 1/3 prescription amount, the amount of the sodium carboxymethyl starch used in the step (4) is 2/3 prescription amount, and other conditions are the same as those in the example 1.
Comparative example 4
No sodium carboxymethyl starch is added in the step (2), the dosage of the sodium carboxymethyl starch in the step (4) is the amount of the prescription, and other conditions are the same as those in the example 1.
Comparative example 5
The metoprolol tartrate crystals in the formulation were replaced with the commercially available metoprolol tartrate starting material (manufacturer: Wuhan Galaxy Co., Ltd.) under the same conditions as in example 3.
Test example 1 selection of sodium carboxymethyl starch addition mode
1. This test examined the dissolution of the pharmaceutical compositions obtained with different sodium carboxymethyl starch additions under otherwise identical conditions (as in example 1), and the results are shown in FIG. 1.
As can be seen from figure 1, the effect is better when sodium carboxymethyl starch is used as a main disintegrating agent and the addition mode is selected from the internal addition and the external addition, wherein the internal addition is 2/3 prescription amount, and the external addition is 1/3 prescription amount, so that the effect is best.
Test example 2 dissolution test
The results of examining the dissolution rates of the pharmaceutical composition obtained in the embodiment of the present invention in different dissolution media are shown in fig. 2 to 5.
As can be seen from FIGS. 2 to 5, the pharmaceutical composition obtained in the embodiment of the present invention has good dissolution rate in each dissolution medium.
Two dissolution media were arbitrarily selected, and the dissolution rates of a commercial product "betalenk" (manufacturer: Aslicon pharmaceutical Co., Ltd.) were examined in parallel for 3 samples, and the results were compared with the dissolution rates of the pharmaceutical compositions obtained in the examples of the present invention, and shown in FIGS. 6 and 7.
As can be seen from fig. 6 and 7, the dissolution rate of the pharmaceutical composition obtained in the example of the present invention is superior to that of the commercially available product "betalake".
Test example 3 animal experiments
1. Experimental animal and medicine
Animals: 30 healthy male rats with body mass (240 +/-20) g are randomly divided into a sham operation group, a sepsis group, a treatment I group, a treatment II group and a treatment III group, wherein a sepsis model is established by adopting a cecal ligation and perforation method, and the sham operation group only opens the abdomen and explores the cecal without cecal ligation and perforation.
Medicine preparation: the pharmaceutical composition obtained in example 3 and comparative example 5 of the present invention was a commercial product "betamethake".
2. Experimental procedure
2h after sepsis, 2mg/kg of the medicine is respectively injected into the abdominal cavity, and the same amount of physiological saline is injected into the sham operation group and the sepsis group. The animals in each group are respectively anesthetized by 10% chloral hydrate 300mg/kg intraperitoneal injection after 3h of operation, and are killed after blood collection through abdominal aorta, and the drug intervention effect is observed. All experimental groups ensured that the rat fluid infusion amount was 5 mL/(kg. h). Fixing the skin of a conventional sterile operation area of each group of animals under the drug anesthesia state, quickly opening an abdominal cavity, separating and exposing an abdominal aorta, collecting 4-5 mL of abdominal aorta blood under direct vision, performing anticoagulation, centrifuging at 3000r/min for 10min, sucking the upper layer serum by using a suction pipe, placing the upper layer serum in an EP (EP) tube, storing at-20 ℃, measuring the serum cTnI by adopting an enzyme-linked immunosorbent assay, quickly opening a chest cavity after blood collection, taking out a heart, flushing the heart by using precooled normal saline, sucking dry by using filter paper, leaving left ventricular myocardial tissue and dividing into 2 parts, and placing a near-heart tip into liquid nitrogen for freezing and storing to prepare the SOD and MDA levels of the myocardial tissue to be detected of tissue homogenate.
3. Statistical treatment
Statistical analysis is performed by using statistical software, and the data are measured by mean + -standard deviation
It is shown that P < 0.05 is statistically significant.
4. Conclusion of the results
Treatment group i: the pharmaceutical composition prepared in example 3 of the present invention;
treatment group ii: the pharmaceutical composition of comparative example 5 of the present invention;
treatment group III: the commercial product "betamethake".
TABLE 1 comparison of the test indexes of the respective groups
Compared with the group of the pseudo-operation,aP<0.01, compared with the sepsis group,abP<0.05
as can be seen from Table 1, the pharmaceutical composition and the commercial product 'betaxolol' prepared in the embodiment 3 and the comparative example 5 of the invention have a protective effect on the myocardium of a sepsis rat, can relieve apoptosis of the myocardium cells of the myocardium of the sepsis rat, relieve myocardial damage, reduce MDA level of the myocardium tissue of the sepsis rat and raise SOD level of the myocardium tissue, in each treatment group, the pharmaceutical composition prepared in the embodiment 3 of the invention has the most excellent drug effect, while the pharmaceutical composition prepared in the comparative example 5 has better drug effect than the commercial product 'betaxolol', so that the crystal form and the auxiliary materials of the invention play an important role in the aspect of drug effect, and the metoprolol tartrate pharmaceutical composition with excellent drug effect is prepared by the synergistic effect of the two products.
Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. The metoprolol tartrate crystal is characterized in that the chemical structural formula of the metoprolol tartrate crystal is as follows:
characteristic peaks of an X-ray powder diffraction pattern obtained by using Cu-K α ray measurement are shown at 10.65 degrees, 12.98 degrees, 14.28 degrees, 15.03 degrees, 15.89 degrees, 16.93 degrees, 18.13 degrees, 19.45 degrees, 20.43 degrees, 20.87 degrees, 21.66 degrees, 22.39 degrees, 23.20 degrees, 23.62 degrees and 24.06 degrees of 2 theta.
2. The method for preparing the metoprolol tartrate crystal according to claim 1, which is characterized by comprising the following steps:
(1) dissolving the metoprolol tartrate crude product in a mixed solvent of methanol and propanol, and stirring for dissolving;
(2) and (3) putting the solution obtained in the step (1) into an oven to evaporate until crystals are separated out, and obtaining the metoprolol tartrate crystal.
3. The method for preparing metoprolol tartrate crystals, according to claim 2, wherein the amount of the methanol and the propanol in step (1) is 10 to 12 times of the weight of the crude metoprolol tartrate product, wherein the amount is volume, the weight is mass, that is, the volume is multiple of the weight, and the unit is L/kg or mL/g, and the volume ratio of the methanol and the propanol is 3 to 5: 1.
4. The method for preparing metoprolol tartrate crystals according to claim 2, wherein the temperature of the oven in the step (2) is 75-80 ℃, and the crystallization time is 2-10 hours.
5. A pharmaceutical composition comprising the metoprolol tartrate crystal of claim 1, wherein the metoprolol tartrate crystal is formulated as follows in weight percent:
6. the pharmaceutical composition according to claim 5, wherein the formulation is as follows, in weight percent:
7. a process for preparing a pharmaceutical composition according to claim 5 or 6, comprising the steps of:
(1) weighing hydroxypropyl methylcellulose, uniformly dispersing with ethanol, adding purified water, stirring until the liquid is uniform and transparent, and cooling to obtain binder;
(2) weighing metoprolol tartrate, starch, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch according to the proportion of the formula, and uniformly mixing to obtain mixed powder;
(3) adding a binder into the mixed powder in the step (2) to obtain a soft material, then preparing the soft material into granules, and then drying, sieving and grading to obtain dry granules;
(4) weighing silicon dioxide and magnesium stearate according to the proportion of the prescription, adding the silicon dioxide and magnesium stearate and sodium carboxymethyl starch into the dry granules in the step (3), and uniformly mixing to obtain a mixture;
(5) and (4) tabletting the mixture obtained in the step (4), packaging by aluminum plastic, and warehousing a finished product after the product is qualified by detection.
8. The method according to claim 7, wherein the mixing in step (2) is performed in an order of metoprolol tartrate → starch → sodium carboxymethyl starch → low-substituted hydroxypropyl cellulose, and the mixing is performed in an equal increment manner.
9. The method of claim 7, wherein the amount of sodium carboxymethyl starch used in step (2) is 2/3 and the amount of sodium carboxymethyl starch used in step (4) is 1/3.
10. The method according to claim 7, wherein the soft material and granules in step (3) are prepared by a wet granulator, and the drying method is boiling drying.
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