CN109045034B - Moxifloxacin hydrochloride pharmaceutical composition and preparation method and application thereof - Google Patents
Moxifloxacin hydrochloride pharmaceutical composition and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the technical field of medicines, and provides a moxifloxacin hydrochloride pharmaceutical composition, and a preparation method and application thereof. The moxifloxacin hydrochloride pharmaceutical composition comprises, by weight, 40-50 parts of moxifloxacin hydrochloride, 4-5 parts of pregelatinized starch, 10-15 parts of microcrystalline cellulose, 3-4 parts of croscarmellose sodium and 0.3-1 part of magnesium stearate; the preparation method comprises mixing moxifloxacin hydrochloride, pregelatinized starch, microcrystalline cellulose and croscarmellose sodium uniformly, adding water for granulating, adding magnesium stearate, mixing uniformly, and making into capsule or tablet. In the embodiment, the contents of the components are limited, so that the medicine can be slowly released in vivo, and the direct stimulation of moxifloxacin hydrochloride to gastrointestinal tracts is reduced, so that the side effects, particularly the occurrence of serious gastrointestinal tract reactions, of the moxifloxacin hydrochloride are reduced, the medication compliance and safety of patients are improved, the patients are more tolerant, and the long-term treatment is facilitated.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a moxifloxacin hydrochloride pharmaceutical composition and a preparation method and application thereof.
Background
Moxifloxacin hydrochloride is an 8-methoxy fluoroquinolone antibacterial drug with a broad spectrum and antibacterial activity, but the excessive dose of moxifloxacin hydrochloride can cause diarrhea of individual patients. When diarrhea occurs more than 5 times a day or bloody diarrhea occurs, the dosage of the drug must be reduced or the drug must be stopped immediately and treated promptly. Generally, after the medicine is stopped, the treatment is difficult to smoothly carry out, thereby affecting the treatment effect.
The main reason for diarrhea in patients receiving chemical drugs is due to direct inhibition or destruction of intestinal mucosal cells by the drugs, and is also related to many other factors such as secondary infection of intestinal tract, emotional stress, etc. Persistent and severe diarrhea can cause renal insufficiency, electrolyte disturbance, cardiovascular insufficiency, increase the incidence of infection complications, and the appearance of chemical-related sepsis or even life-threatening conditions. In addition to this, the quality of life of the patient is severely affected.
Disclosure of Invention
The invention aims to provide a moxifloxacin hydrochloride pharmaceutical composition which can effectively improve the side reaction of the digestive tract caused by moxifloxacin hydrochloride.
The invention also aims to provide a preparation method of the moxifloxacin hydrochloride medicinal composition, the method is simple, and the prepared medicine can effectively improve the side reaction of the digestive tract caused by moxifloxacin hydrochloride.
The invention also aims to provide the application of the moxifloxacin hydrochloride medicinal composition in preparing a medicament for relieving side effects of diarrhea caused by moxifloxacin hydrochloride.
In order to achieve at least one of the above objects, the following technical solutions are adopted in the embodiments of the present invention:
the moxifloxacin hydrochloride pharmaceutical composition comprises, by weight, 40-50 parts of moxifloxacin hydrochloride, 4-5 parts of pregelatinized starch, 10-15 parts of microcrystalline cellulose, 3-4 parts of croscarmellose sodium and 0.3-1 part of magnesium stearate; preferably, the components comprise, by weight, 42-48 parts of moxifloxacin hydrochloride, 4.2-4.8 parts of pregelatinized starch, 11-14 parts of microcrystalline cellulose, 3-3.8 parts of croscarmellose sodium and 0.4-0.9 part of magnesium stearate; preferably, the components comprise, by weight, 42-45 parts of moxifloxacin hydrochloride, 4.3-4.7 parts of pregelatinized starch, 12-13.5 parts of microcrystalline cellulose, 3-3.5 parts of croscarmellose sodium and 0.5-0.8 part of magnesium stearate.
The moxifloxacin hydrochloride pharmaceutical composition comprises, by weight, 43-44 parts of moxifloxacin hydrochloride, 80-400 parts of corn peptide, 4.4-4.6 parts of pregelatinized starch, 12.5-13.5 parts of microcrystalline cellulose, 3.2-3.5 parts of croscarmellose sodium, 0.6-0.8 part of magnesium stearate and 2-2.5 parts of a coating agent.
A process for preparing the moxifloxacin hydrochloride medicine composition includes such steps as mixing moxifloxacin hydrochloride, pregelatinized starch, microcrystalline cellulose and croscarmellose sodium, adding water, granulating, adding magnesium stearate, mixing and making capsules or tablets.
Application of moxifloxacin hydrochloride pharmaceutical composition or moxifloxacin hydrochloride pharmaceutical composition prepared by the preparation method of moxifloxacin hydrochloride pharmaceutical composition in preparation of drugs for relieving side effects of diarrhea caused by moxifloxacin hydrochloride.
The beneficial effects of the embodiment of the invention include:
in the embodiment, the contents of moxifloxacin hydrochloride, pregelatinized starch, microcrystalline cellulose, croscarmellose sodium and magnesium stearate are limited, so that the medicine can be slowly released in vivo, the direct stimulation of moxifloxacin hydrochloride to gastrointestinal tracts is reduced, the side effects, particularly the occurrence of severe gastrointestinal tract reactions, of the moxifloxacin hydrochloride are reduced, the effective blood concentration is maintained, the compliance and the safety of the medicine for patients are improved, the patients are more tolerant, and the long-term treatment is facilitated. The moxifloxacin hydrochloride pharmaceutical composition can promote gastrointestinal motility and promote digestion and absorption of food, can effectively improve side effects of digestive tracts caused by moxifloxacin hydrochloride, improves the chemical compliance of patients, and has good effects on nausea, diarrhea and inappetence.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The moxifloxacin hydrochloride pharmaceutical composition, the preparation method and the application thereof in the embodiment of the invention are specifically described below.
The moxifloxacin hydrochloride is a dark red film coated tablet, and is an 8-methoxy fluoroquinolone antibacterial drug with broad spectrum and antibacterial activity. Moxifloxacin is indicated for upper and lower respiratory tract infections. Its main side effects on digestive system include nausea, diarrhea, vomiting, dyspepsia, and abnormal liver function test.
The inventor researches and discovers that normal people defecate 1-2 times per day or 1 time every 2-3 days, and the nature of excrement is normal. The diarrhea patients not only have increased stool frequency, but also have changed properties, and have loose stools, watery stools and even bloody diarrhea.
The diarrhea is judged according to the principle that the water content of the collected feces is not less than 70 percent and the feces are not deformed. Diarrhea can be classified as grade 5 depending on severity. Grade 1, stool frequency increased <4 times/day, and excretion amount slightly increased; 2, the stool number is increased for 4-6 times per day, the discharged matter is moderately increased, and the daily life is not influenced; grade 3, stool frequency is increased by more than 7 times per day, incontinence needs 24 hours of intravenous fluid infusion, hospitalization is needed, and the amount of discharged substances is severely increased, so that daily life is influenced; grade 4: life threatening (e.g., hemodynamic failure); and 5, death.
There are two main pathologies of chemical drugs causing diarrhea: one is due to gastrointestinal motility; secondly, chemical drugs cause damage to the intestinal mucosa.
The mechanism of diarrhea is as follows: firstly, intestinal mucosa damage and water absorption disorder; ② the peristalsis of the intestine is strengthened, so that the contents in the intestine can be discharged quickly; ③ intestinal mucosa secretes intestinal juice and is hyperfunction.
The small intestine has the functions of peristalsis, secretion of digestive enzymes, electrolytes, water, digestion and absorption and the like. The colon receives the contents of the small intestine, absorbs water and electrolyte and stores excrement, and the excrement is crawled for 2-4 times every day to push the excrement to advance. Adults have about 9L of fluid entering the small intestine per day, of which 2L is from food and about 7L is from saliva, gastric juice, pancreatic juice, bile and small intestinal juice. Depending on the food contents, these fluids may be hypertonic, isotonic or hypotonic, but become isotonic by the time of arrival in the ileum, to facilitate absorption. A3000-5000 ml of liquid absorbed by jejunum, 2000-4000 ml of ileum and 1000-2000 ml of colon are generally taken every day. About 200g of excrement is discharged every day, and the internal water content is 75 percent. The small intestine is arranged in the abdominal cavity in a wrinkle shape, and a plurality of villi and microvilli are formed on the surface of the intestinal mucosa, so that the area of the intestinal mucosa is large, and is about 200 ten thousand cm when measured by the microvilli2Therefore, a large amount of liquid can be absorbed every day. The microvilli contains sucrase and maltase, and can specifically digest sucrose and maltose in intestinal contents. The division and proliferation speed of intestinal mucosa cells is fast, and 2 to 5 million epithelial cells are estimated to be renewed and shed every minute under normal conditions.
Because the cell division and proliferation speed of the intestinal mucosa is fast, the intestinal mucosa is easy to be directly inhibited or destroyed by cytotoxic drugs, the atrophy of the intestinal mucosa is caused, the intestinal villi is shortened or stripped, the absorption area of the small intestine is reduced, and the integrity of the mucosa is destroyed, so that the digestive disorder, the digestion of cane sugar and maltose are insufficient, and the fermentation is carried out in the intestinal canal, thereby causing intestinal flatulence and intestinal spasm; absorbing obstacles; and thirdly, secretion is increased, and undigested sucrose and maltose increase the osmotic pressure of intestinal contents, so that a large amount of extracellular interstitial fluid permeates into the intestinal cavity.
The main reason for diarrhea in patients receiving chemical drugs is due to direct inhibition or destruction of intestinal mucosal cells by the drugs, and is also related to many other factors such as secondary infection of intestinal tract, emotional stress, etc.
In view of this, the embodiment of the invention provides a moxifloxacin hydrochloride pharmaceutical composition, which comprises, by weight, 40-50 parts of moxifloxacin hydrochloride, 4-5 parts of pregelatinized starch, 10-15 parts of microcrystalline cellulose, 3-4 parts of croscarmellose sodium and 0.3-1 part of magnesium stearate.
Wherein, moxifloxacin hydrochloride is used as a main drug, and pregelatinized starch, microcrystalline cellulose and croscarmellose sodium are used as a diluent and a disintegrating agent in the embodiment, which can increase the weight of the drug and facilitate the forming of the drug so as to prepare capsules or tablets, and meanwhile, the disintegrating ability is strong. It is to be understood that diluents include, but are not limited to, pregelatinized starch and microcrystalline cellulose as claimed in the present example, for example, in other embodiments of the invention, diluents may also include one or more of dibasic calcium phosphate, sorbitol, dibasic calcium phosphate, starch, mannitol, and lactose. In this example, the pregelatinized starch had good fluidity, compressibility, self-lubricity, and dry adhesion, and had a good disintegrating effect. Meanwhile, the microcrystalline cellulose also has good compressibility, and the croscarmellose sodium is used as a disintegrating agent, plays a role in disintegrating by virtue of capillary and swelling, and has good compressibility and strong disintegrating force. Pregelatinized starch, microcrystalline cellulose and croscarmellose sodium are used as diluent and disintegrant, and can improve compressibility and disintegration ability of the medicine. Meanwhile, the pregelatinized starch and the microcrystalline cellulose can be used as sustained release agents, so that the medicament can be slowly released in vivo, the effective blood concentration is maintained, and the compliance and the safety of the medicament administration of a patient are improved. Wherein, the croscarmellose sodium swells in water, and the disintegration time and the release effect of the croscarmellose sodium do not change with time.
Magnesium stearate is used as a lubricant and is matched with pregelatinized starch for use, so that the lubricity of the medicament is improved, the friction between the tablet and the die hole can be effectively avoided, and the quality of the medicament is ensured. It is to be understood that lubricants include, but are not limited to, magnesium stearate as protected in the present examples, for example, in other embodiments of the present invention, lubricants may also include one or more of micronized silica gel and talc.
The research of the inventor finds that the components preferably comprise 42-48 parts of moxifloxacin hydrochloride, 4.2-4.8 parts of pregelatinized starch, 11-14 parts of microcrystalline cellulose, 3-3.8 parts of croscarmellose sodium and 0.4-0.9 part of magnesium stearate in parts by weight; preferably, the components comprise, by weight, 42-45 parts of moxifloxacin hydrochloride, 4.3-4.7 parts of pregelatinized starch, 12-13.5 parts of microcrystalline cellulose, 3-3.5 parts of croscarmellose sodium and 0.5-0.8 part of magnesium stearate.
The contents of the components are further limited, so that the medicine can be slowly released in vivo, the direct stimulation of moxifloxacin hydrochloride to gastrointestinal tracts is reduced, the side effects, particularly the occurrence of serious gastrointestinal tract reaction, are reduced, the effective blood concentration is maintained, the medication compliance and safety of patients are improved, the patients are more tolerant, and the long-term treatment is facilitated.
In other embodiments of the invention, the components comprise 50-500 parts by weight of corn peptide; preferably, the corn peptide is 100-450 parts; preferably, the corn peptide is 200-400 parts.
The corn peptide is a small molecular polypeptide substance obtained by performing directional enzyme digestion and a specific small peptide separation technology on protein extracted from corn. The corn peptide amino acid has high glutamine content, wherein the glutamine is amino acid forming protein and is a nitrogen source for synthesizing nucleic acid, is closely related to tissue growth and repair, and although the glutamine is non-essential amino acid, the corn peptide amino acid can improve the immunity of the organism, maintain the normal structure and function of intestinal mucosa and improve the capability of the organism adapting to external harmful stimulation. As found in the research of the inventor, the main reason for diarrhea of the patient who receives the chemical drugs is caused by direct inhibition or damage of the drugs to intestinal mucosa cells, in this embodiment, the corn peptide is added as one of the main drugs, so that inhibition and damage of moxifloxacin hydrochloride to gastrointestinal mucosa can be slowed down, the immunity of the organism can be improved, and the gastrointestinal mucosa can maintain a normal structure.
In the embodiment, the moxifloxacin hydrochloride and the corn peptide are matched for use, the corn peptide can inhibit gastrointestinal absorption, enhance metabolism and reduce direct stimulation of moxifloxacin hydrochloride to gastrointestinal tracts, so that side effects, particularly serious gastrointestinal tract reactions, of the moxifloxacin hydrochloride are reduced, effective blood concentration is maintained, the compliance and safety of medication of patients are improved, the patients are more tolerant, and long-term treatment is facilitated.
In addition, the amount of the corn peptide used in the embodiment is large, and the corn peptide is 50 to 500 parts; preferably, the corn peptide is 100-450 parts; preferably, the corn peptide is 200-400 parts. The weight of the corn peptide is about 1-10 times of that of moxifloxacin hydrochloride, which is beneficial to drug forming, and the dosage of diluent or filler can be reduced, so that the disintegration brought by the diluent is reduced, the drug is slowly released, and the blood concentration is effectively maintained.
Further, the moxifloxacin hydrochloride pharmaceutical composition provided by the embodiment can be in various dosage forms, such as capsules or tablets. When the moxifloxacin hydrochloride pharmaceutical composition is a tablet, the components comprise 2-5 parts of a coating agent, preferably 2-3 parts by weight; preferably, the coating agent is a gastric-soluble film-coated premix.
The coating agent in the embodiment is a gastric-soluble film coating premix, and the moxifloxacin hydrochloride pharmaceutical composition is disintegrated in the stomach, but due to the effect of the corn peptide, the absorption of the stomach to the moxifloxacin hydrochloride pharmaceutical composition is inhibited, the damage of the moxifloxacin hydrochloride to the gastrointestinal mucosa is slowed down, the moxifloxacin hydrochloride is disintegrated in advance, the blood concentration in the blood is high, and the blood concentration is favorably maintained.
In other embodiments of the present invention, a moxifloxacin hydrochloride pharmaceutical composition is provided, wherein the components comprise, by weight, 43-44 parts of moxifloxacin hydrochloride, 80-400 parts of corn peptide, 4.4-4.6 parts of pregelatinized starch, 12.5-13.5 parts of microcrystalline cellulose, 3.2-3.5 parts of croscarmellose sodium, 0.6-0.8 part of magnesium stearate, and 2-2.5 parts of a coating agent.
In a second aspect, the embodiment of the present invention further provides a preparation method of a moxifloxacin hydrochloride pharmaceutical composition, which includes the following steps:
s1, uniformly mixing moxifloxacin hydrochloride, pregelatinized starch, microcrystalline cellulose and croscarmellose sodium, and adding water for granulation.
The method specifically comprises the following steps: firstly, crushing moxifloxacin hydrochloride to 80-100 meshes, then placing moxifloxacin hydrochloride, microcrystalline cellulose, pregelatinized starch and croscarmellose sodium into a wet granulator, mixing for 5-6 minutes, adding a proper amount of purified water (the amount of the purified water is 1.5-3 times of the weight of the microcrystalline cellulose), and granulating for 1-2 minutes. Wet granulating with a rocking granulator, wherein the mesh number of the screen is 12-14 meshes. And (3) placing the wet granules in a high-efficiency boiling dryer, preheating for 10min at the air inlet temperature of 60-70 ℃, drying at room temperature, and controlling the moisture of the granules to be 1.5-6.5%. And (4) granulating the dried granules in a swing granulator, wherein the mesh number of a screen is 16-18 meshes. And (5) finishing the granules and storing the granules in a transfer barrel for later use.
When the components also comprise 700 portions of 100-700 portions of corn peptide; the corn peptide and moxifloxacin hydrochloride are added after being mixed in advance. Premixing is beneficial to shortening subsequent mixing time, and the coating effect between the corn peptide and the moxifloxacin hydrochloride can be improved.
S2, adding magnesium stearate, mixing, and making into capsule or tablet.
Adding magnesium stearate accounting for 0.8-0.9% of the weight of the premixed granules, putting the premixed granules into a mixer, and mixing for 5-6 minutes. Then making into capsule or tablet.
When the tablet is prepared, the filling amount, the tablet thickness and the tablet press speed are adjusted, the tablet hardness is controlled to be 70-90N, the tablet weight is converted into the standard tablet weight according to the content of the intermediate particles, and the tablet weight difference is +/-4.5%.
S3, preparation of a coating agent: adding a proper amount of purified water into a liquid preparation barrel, starting a stirring paddle to stir to enable the liquid surface to form a vortex, scattering gastric-soluble film coating powder on the liquid surface of the vortex at a constant speed, and continuously stirring for more than 1 hour, wherein the dosage of the coating powder is 0.5-2.0% of the weight of the tablet, and the concentration of the coating agent is 8-10%. Adjusting air inlet and outlet quantity, controlling the air outlet temperature to be 50-60 ℃, enabling the negative pressure in the pan to be 2-5 pa, adding the plain tablets into a coating pan, taking out the pan at 2 revolutions per minute after the temperature of the plain tablets is preheated to 34-40 ℃ and the optimal distance between a spray gun and a tablet surface is 26-30 cm, and adjusting the gun head of the spray gun to the position 1/3 on the inclined surface of the tablet layer to start spraying liquid. In the coating process, the spraying air pressure and the spraying angle of the spray gun are adjusted to be consistent as much as possible, and the rotating speed of the peristaltic pump is properly adjusted, so that an ideal atomizing state required by the process can be achieved. After the film coating liquid is sprayed, cooling the film coated tablet by using air exhaust, and packaging by using aluminum plastic.
In this example, after wet granulation, wet granulation and drying were performed, and dry granulation was performed, and the mesh sizes of the wet granulation and the dry granulation were controlled to 12 to 14 mesh and 16 to 18 mesh, respectively, so that the uniformity of the finally obtained granules was better.
On the other hand, the embodiment of the invention also provides application of the moxifloxacin hydrochloride pharmaceutical composition in preparation of a medicine for relieving side effects of diarrhea caused by moxifloxacin hydrochloride.
The moxifloxacin hydrochloride pharmaceutical composition, the preparation method and the application thereof are further illustrated by the following examples.
Example 1
The embodiment provides a moxifloxacin hydrochloride pharmaceutical composition, and the preparation method comprises the following steps:
s1, preparing materials: 40g of moxifloxacin hydrochloride, 4g of pregelatinized starch, 10g of microcrystalline cellulose, 3g of croscarmellose sodium and 0.4g of magnesium stearate;
s2, granulating: crushing moxifloxacin hydrochloride to 80 meshes; then the moxifloxacin hydrochloride, the pregelatinized starch, the microcrystalline cellulose and the croscarmellose sodium are placed in a wet granulator, mixed for 5 minutes, added with 15ml of purified water and granulated for 2 minutes. Wet granulating with a rocking granulator, wherein the mesh number of the screen is 12. Placing the wet granules in a high-efficiency boiling dryer, preheating the dryer by using wind with the temperature of 70 ℃ for 10min, and then drying at room temperature. The moisture of the particles is controlled to be 1.5-6.5%. And (4) granulating the dried granules in a swing granulator, wherein the mesh number of a screen is 16. And (5) finishing the granules and storing the granules in a transfer barrel for later use. And then adding magnesium stearate, uniformly mixing to obtain a mixture required by the filled capsule, filling the mixture required by the filled capsule into a hollow capsule according to the filling amount, and controlling the filling amount difference to prepare the capsule preparation of the moxifloxacin hydrochloride pharmaceutical composition.
Example 2
The embodiment provides a moxifloxacin hydrochloride pharmaceutical composition, and the preparation method comprises the following steps:
s1, preparing materials: 96g of moxifloxacin hydrochloride, 9.6g of pregelatinized starch, 28g of microcrystalline cellulose, 7g of croscarmellose sodium, 1.8g of magnesium stearate and 4g of gastric-soluble film coating premix.
S2, granulating: crushing moxifloxacin hydrochloride to 100 meshes; then the moxifloxacin hydrochloride, the pregelatinized starch, the microcrystalline cellulose and the croscarmellose sodium are placed in a wet granulator, mixed for 6 minutes, and 20ml of purified water is added to granulate for 1 minute. Wet granulating with a rocking granulator, wherein the mesh number of the screen is 14. Placing the wet granules in a high-efficiency boiling dryer, preheating the dryer by using air with the temperature of 60 ℃ for 15min, and then drying at room temperature. The moisture of the particles is controlled to be 1.5-6.5%. And (4) granulating the dried granules in a swing granulator, wherein the mesh number of a screen is 18. And (5) finishing the granules and storing the granules in a transfer barrel for later use. Adding magnesium stearate, mixing, and making into capsule or tablet.
S3, coating: adding appropriate amount of purified water into the liquid preparation barrel, starting stirring slurry to stir to form vortex on the liquid surface, scattering gastric-soluble film coating powder on the vortex liquid surface at constant speed, and continuously stirring for more than 1 hour, wherein the coating powder accounts for 0.5% of the weight of the tablet, and the coating agent concentration is 10%. Adjusting air inlet and outlet quantity, controlling the air outlet temperature to be 50 ℃, enabling the negative pressure in the pan to be 5pa, adding the plain film into the coating pan, taking out the pan at 2 revolutions per minute after the temperature of the plain film is preheated to 50 ℃ and the optimal distance between the spray gun and the film surface is 26cm, and adjusting the gun head of the spray gun to the upper part 1/3 of the inclined surface of the film layer to start spraying liquid. In the coating process, the spraying air pressure and the spraying angle of the spray gun are adjusted to be consistent as much as possible, and the rotating speed of the peristaltic pump is properly adjusted, so that an ideal atomizing state required by the process can be achieved. After the film coating liquid is sprayed, cooling the film coated tablets by using air exhaust, and packaging the film coated tablets by aluminum plastic to obtain the tablets of the moxifloxacin hydrochloride pharmaceutical composition.
Example 3
The embodiment provides a moxifloxacin hydrochloride pharmaceutical composition, and the preparation method comprises the following steps:
s1, preparing materials: 50g of moxifloxacin hydrochloride, 80g of corn peptide, 5g of pregelatinized starch, 15g of microcrystalline cellulose, 3g of croscarmellose sodium, 0.4g of magnesium stearate and 3g of gastric-soluble film coating premix;
s2, granulating: crushing moxifloxacin hydrochloride to 100 meshes; then the moxifloxacin hydrochloride, the corn peptide, the pregelatinized starch, the microcrystalline cellulose and the croscarmellose sodium are placed in a wet granulator, mixed for 5 minutes, added with 45ml of purified water and granulated for 1 minute. Wet granulating with a rocking granulator, wherein the mesh number of the screen is 14. Placing the wet granules in a high-efficiency boiling dryer, preheating the dryer by using air with the temperature of 65 ℃ for 10min, and then drying at room temperature. The moisture of the particles is controlled to be 1.5-6.5%. And (4) granulating the dried granules in a swing granulator, wherein the mesh number of a screen is 18. And (5) finishing the granules and storing the granules in a transfer barrel for later use. Then adding magnesium stearate, mixing uniformly and preparing into plain tablets.
S3, coating: adding appropriate amount of purified water into the liquid preparation barrel, starting stirring slurry to stir to form vortex on the liquid surface, scattering gastric-soluble film coating powder on the vortex liquid surface at constant speed, and continuously stirring for more than 1 hr, wherein the coating powder accounts for 1.0% of the weight of the tablet, and the coating agent concentration is 12%. Adjusting air inlet and outlet quantity, controlling the air outlet temperature to be 45 ℃, enabling the negative pressure in the pan to be 3pa, adding the plain film into the coating pan, taking the plain film out at 2 revolutions per minute when the temperature of the plain film is preheated to 65 ℃ and the optimal distance between the spray gun and the film surface is 28cm, and adjusting the gun head of the spray gun to the upper part 1/3 of the inclined surface of the film layer to start spraying liquid. In the coating process, the spraying air pressure and the spraying angle of the spray gun are adjusted to be consistent as much as possible, and the rotating speed of the peristaltic pump is properly adjusted, so that an ideal atomizing state required by the process can be achieved. After the film coating liquid is sprayed, cooling the film coated tablets by using air exhaust, and packaging the film coated tablets by aluminum plastic to obtain the tablets of the moxifloxacin hydrochloride pharmaceutical composition.
Examples 4 to 7
Examples 4-7 provide pharmaceutical compositions of moxifloxacin hydrochloride that are prepared in substantially the same manner as in example 1, except that the components are different.
In example 4, 420g of moxifloxacin hydrochloride, 500g of corn peptide, 42g of pregelatinized starch, 110g of microcrystalline cellulose, 32g of croscarmellose sodium, 4g of magnesium stearate and 30g of gastric-soluble film coating premix;
in example 5, the components of the moxifloxacin hydrochloride pharmaceutical composition comprise 436.4g of moxifloxacin hydrochloride, 4000g of corn peptide, 45.6g of pregelatinized starch, 130.2g of microcrystalline cellulose, 32.6 g of croscarmellose sodium, 6.5g of magnesium stearate and 20g of gastric-soluble film coating premix;
in example 6, the components of the moxifloxacin hydrochloride pharmaceutical composition comprise 43g of moxifloxacin hydrochloride, 300g of corn peptide, 4.4g of pregelatinized starch, 12.5g of microcrystalline cellulose, 3.3g of croscarmellose sodium, 0.7g of magnesium stearate and 2g of gastric-soluble film-coated premix;
in example 7, the components of the moxifloxacin hydrochloride pharmaceutical composition comprise 44g of moxifloxacin hydrochloride, 380g of corn peptide, 4.5g of pregelatinized starch, 13.5g of microcrystalline cellulose, 3.5g of croscarmellose sodium, 0.8g of magnesium stearate and 2.5g of gastric-soluble film coating premix;
first, animal experiment
The following is a combination of animal experiments to evaluate the effects of the pharmaceutical compositions provided in examples 1 to 7, test examples 1 to 3, and comparative examples 1 to 3 of the present invention in improving the gastrointestinal response caused by moxifloxacin hydrochloride.
1. Composition of matter
Test examples 1 to 3: the content of the corn peptide in example 3 was changed from 80g to 100g, 300g and 500g, and the rest was the same as in example 3.
Comparative examples 1 to 3: the corn peptides of test examples 1-3 were replaced with starch at constant levels.
2. Effect of the composition of the invention on diarrhea in domestic Pigeon
130 domestic pigeons with the weight of 200-300 g are selected, the male pigeons and the female pigeons are half of each other, the domestic pigeons are randomly divided into 13 groups, and each group comprises 10 pigeons. After 24 hours of fasting without water prohibition before the experiment, the domestic pigeons are administered with the compositions for intragastric administration (examples 1-7, experimental examples 1-3 and comparative examples 1-3), the content of moxifloxacin hydrochloride is 50 mg/pigeon, the diarrhea frequency and the number of the domestic pigeons within 12 hours after administration are recorded, and the experimental results are compared among groups, which is shown in table 1:
TABLE 1 diarrhea in domestic pigeon
| Number of animals | Diarrhea in several cases | Frequency of diarrhea | Mean number of diarrhea | |
| Example 1 | 10 | 6 | 23 | 3.83 |
| Example 2 | 10 | 6 | 22 | 3.66 |
| Example 3 | 10 | 5 | 18 | 3.6 |
| Example 4 | 10 | 3 | 11 | 3.6 |
| Example 5 | 10 | 2 | 3 | 1.5 |
| Example 6 | 10 | 3 | 7 | 2.33 |
| Example 7 | 10 | 3 | 6 | 2 |
| Test example 1 | 10 | 5 | 18 | 3.60 |
| Test example 2 | 10 | 3 | 9 | 3.00 |
| Test example 3 | 10 | 2 | 3 | 1.50 |
| Comparative example 1 | 10 | 9 | 55 | 6.11 |
| Comparative example 2 | 10 | 7 | 32 | 4.57 |
| Comparative example 3 | 10 | 6 | 23 | 3.83 |
As can be seen from the results in Table 1, the diarrhea counts and the average diarrhea frequency of the pigeons of examples 1 to 7 and test examples 1 to 3 were significantly lower than those of the pigeons of comparative examples 1 to 3. From the test examples 1-3, it can be seen that when the ratio of the moxifloxacin hydrochloride to the corn peptide is 1:2-10, the side effect of the digestive tract caused by moxifloxacin hydrochloride can be effectively improved, the improvement effect is better and more obvious along with the increase of the dosage of the corn peptide, and the number of diarrhea and the diarrhea frequency are also obviously reduced.
Through the animal tests, the pharmaceutical composition provided by the invention can promote gastrointestinal motility and promote food digestion and absorption, can effectively improve the side effect of the digestive tract caused by moxifloxacin hydrochloride, improves the drug compliance of patients, and has good effects on nausea, diarrhea and inappetence.
Secondly, selection of granulation process
Comparative example 4: the wet finishing step in example 3 was omitted; comparative example 5: the dry finishing step in example 3 was omitted. The degree of deviation from the indicated amounts of the product obtained according to the different granulation processes was calculated with a limit within + -15% and a uniformity according to the regulations. See table 2 for experimental results.
TABLE 2 Effect of different granulation processes on product uniformity
| Examples of the invention | Preparation process | Product uniformity |
| Example 3 | Wet granulation, drying and dry granulation | +6％ |
| Comparative example 4 | Wet granulation, drying and dry granulation | +11％ |
| Comparative example 5 | Wet granulation, wet granulation and drying | +9％ |
As can be seen from table 2, after wet granulation, wet granulation and drying, and dry granulation, the finally obtained granules showed the lowest deviation from the labeled amount and better uniformity.
In conclusion, in the embodiment, the contents of moxifloxacin hydrochloride, pregelatinized starch, microcrystalline cellulose and magnesium stearate are limited, so that the medicine can be slowly released in vivo, the direct stimulation of moxifloxacin hydrochloride to gastrointestinal tracts is reduced, the side effects, particularly the occurrence of severe gastrointestinal tract reactions, of the moxifloxacin hydrochloride are reduced, the effective blood concentration is maintained, the compliance and the safety of the medicine for patients are improved, the patients are more tolerant, and the long-term treatment is facilitated. Particularly, the corn peptide is added as one of the main medicines, so that the inhibition and the damage of moxifloxacin hydrochloride to gastrointestinal mucosa can be slowed down, the immunity of the organism is improved, and the gastrointestinal mucosa can maintain a normal structure. The pharmaceutical composition can promote gastrointestinal motility and promote food digestion and absorption, has the effect of preventing vomiting, can effectively improve the side effect of the digestive tract caused by moxifloxacin hydrochloride, improves the compliance of patients with chemical medicines, and has good effects on nausea, diarrhea and inappetence.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and various modifications and changes will occur to those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (14)
1. The moxifloxacin hydrochloride pharmaceutical composition is characterized by comprising, by weight, 40-50 parts of moxifloxacin hydrochloride, 4-5 parts of pregelatinized starch, 10-15 parts of microcrystalline cellulose, 3-4 parts of croscarmellose sodium, 50-500 parts of corn peptide and 0.3-1 part of magnesium stearate.
2. The moxifloxacin hydrochloride pharmaceutical composition according to claim 1, wherein the components comprise, by weight, 42-48 parts of moxifloxacin hydrochloride, 4.2-4.8 parts of pregelatinized starch, 11-14 parts of microcrystalline cellulose, 3-3.8 parts of croscarmellose sodium, 100 parts of corn peptide, 450 parts of sodium stearate and 0.4-0.9 part of magnesium stearate.
3. The moxifloxacin hydrochloride pharmaceutical composition according to claim 1, wherein the components comprise, by weight, 42-45 parts of moxifloxacin hydrochloride, 4.3-4.7 parts of pregelatinized starch, 12-13.5 parts of microcrystalline cellulose, 3-3.5 parts of croscarmellose sodium, 200-400 parts of corn peptide and 0.5-0.8 part of magnesium stearate.
4. The moxifloxacin hydrochloride pharmaceutical composition according to claim 1, wherein the moxifloxacin hydrochloride pharmaceutical composition is a capsule or a tablet.
5. The moxifloxacin hydrochloride pharmaceutical composition according to claim 4, wherein the moxifloxacin hydrochloride pharmaceutical composition is a tablet, and the components comprise 2-5 parts by weight of a coating agent.
6. The moxifloxacin hydrochloride pharmaceutical composition according to claim 5, wherein the components comprise 2-3 parts by weight of a coating agent.
7. The moxifloxacin hydrochloride pharmaceutical composition according to claim 6, wherein the coating agent is a gastric-soluble film coating premix.
8. The moxifloxacin hydrochloride pharmaceutical composition according to claim 1, wherein the components comprise 43-44 parts by weight of moxifloxacin hydrochloride, 400 parts by weight of corn peptide, 4.4-4.6 parts by weight of pregelatinized starch, 12.5-13.5 parts by weight of microcrystalline cellulose, 3.2-3.5 parts by weight of croscarmellose sodium and 0.6-0.8 part by weight of magnesium stearate, and the components further comprise 2-2.5 parts by weight of coating agent.
9. The preparation method of the moxifloxacin hydrochloride pharmaceutical composition according to claim 1, characterized in that the preparation method comprises the steps of uniformly mixing the moxifloxacin hydrochloride, the pregelatinized starch, the microcrystalline cellulose and the croscarmellose sodium, adding water for granulation, then adding the magnesium stearate, uniformly mixing and preparing into capsules or tablets, wherein the components further comprise 50-500 parts by weight of corn peptide; the corn peptide and the moxifloxacin hydrochloride are added after being mixed in advance.
10. The method for preparing moxifloxacin hydrochloride pharmaceutical composition according to claim 9, wherein before adding the moxifloxacin hydrochloride, the moxifloxacin hydrochloride is firstly pulverized to 80-100 meshes.
11. The method for preparing moxifloxacin hydrochloride pharmaceutical composition according to claim 9, wherein the granulation comprises wet granulation, sieving with a 12-14 mesh sieve, drying until the moisture content of the granules is 1.5% -6.5%, dry granulation of the dried granules, and sieving with a 16-18 mesh sieve.
12. The method for preparing moxifloxacin hydrochloride pharmaceutical composition according to claim 11, wherein before the granules are placed in a dryer for drying, the dryer is preheated for 10-15min by wind with the temperature of 60-70 ℃, and then is dried at room temperature.
13. The preparation method of moxifloxacin hydrochloride pharmaceutical composition according to claim 10, wherein the components comprise 2-5 parts by weight of coating agent, coating powder is prepared into the coating agent with the concentration of 8-10%, plain tablets are preheated to 50-60 ℃, then the coating agent is sprayed on the surfaces of the plain tablets, and the tablets are cooled after the spraying is finished.
14. Use of the moxifloxacin hydrochloride pharmaceutical composition according to any one of claims 1 to 8 or the moxifloxacin hydrochloride pharmaceutical composition prepared by the preparation method of the moxifloxacin hydrochloride according to any one of claims 9 to 13 in the preparation of a medicament for reducing side effects of diarrhea caused by moxifloxacin hydrochloride.
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| CN103768063A (en) * | 2012-10-19 | 2014-05-07 | 深圳信立泰药业股份有限公司 | Moxifloxacin hydrochloride pharmaceutical composition and preparation method thereof |
| CN105030717A (en) * | 2015-08-21 | 2015-11-11 | 哈尔滨珍宝制药有限公司 | Moxifloxacin hydrochloride film-coated tablet and preparation method thereof |
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| WO2005020998A1 (en) * | 2003-09-03 | 2005-03-10 | Ranbaxy Laboratories Limited | Pharmaceutical compositions of moxifloxacin and processes for their preparation |
| CN103768063A (en) * | 2012-10-19 | 2014-05-07 | 深圳信立泰药业股份有限公司 | Moxifloxacin hydrochloride pharmaceutical composition and preparation method thereof |
| CN105030717A (en) * | 2015-08-21 | 2015-11-11 | 哈尔滨珍宝制药有限公司 | Moxifloxacin hydrochloride film-coated tablet and preparation method thereof |
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