CN108096207B - Preparation method of lotafloxacin enteric-coated tablets - Google Patents
Preparation method of lotafloxacin enteric-coated tablets Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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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
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A61K9/2022—Organic macromolecular compounds
- A61K9/2063—Proteins, e.g. gelatin
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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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
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Abstract
The invention discloses a lotafloxacin enteric-coated tablet and a preparation method thereof, wherein the preparation method comprises the following steps: 1) sieving 70-91% of filler, 0.3-2% of lubricant, 4-8% of adhesive, 1-5% of disintegrating agent and 0.5-2% of surfactant respectively; mixing the filler and the adhesive to obtain a mixture; 2) adding purified water into a surfactant to prepare a surfactant aqueous solution with the concentration of 1-5%, and adding 0.5% of lotafloxacin into the aqueous solution for ultrasonic dissolution to obtain a mixed solution; 3) atomizing and spraying the mixed solution obtained in the step 2) into the mixture obtained in the step 1), granulating the sprayed mixture, and drying to obtain granules, wherein the percentages are mass percentages of the components in the raw materials; 4) granulating the granules obtained in the step 3), adding a lubricant, uniformly mixing, and tabletting to obtain plain tablets; 5) and (3) coating the plain tablets for the second time to obtain the enteric-coated tablets. The preparation technology has the advantages of uniform particle content, stable quality, small loss, simple process and effective cost saving.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a preparation method of a lotafloxacin enteric-coated tablet.
Background
The main causes of hypertension include genetic factors, mental and environmental factors, age factors, lifestyle factors, influence of drugs and influence of other diseases. Approximately 60% of patients with hypertension have a family history, and therefore, polygenic inheritance is generally considered. Hypertensive patients may have an increased risk of developing heart failure, stroke, and renal failure if they do not receive timely and effective treatment.
The pathogenesis of hypertension is generally thought to be due to sodium salt retention. However, the mechanism of the method is found to be far more complicated than the original idea through recent researches. Many studies suggest that only plasma endogenous ouabain levels are correlated with human blood pressure and blood pressure in many animal models of hypertension, although other cardiotonic hormones, such as digoxin and the like, are also present in human and animal plasma and tissues. Na (Na)+/K+ATPase can form a complex with non-receptor kinase Src and has a signaling function, endogenous ouabain levels are increased, and mutant adducin can increase Na+/K+Sodium potassium Pump Activity of ATPase to intracellular Na+Increase the retention of water and sodium in the body. The Na/Ca exchanger (NCX) works synergistically with the alpha 2 sodium pump to make intracellular Ca2+And increase the contractility of blood vessels, thereby increasing blood pressure. Endogenous ouabain can activate the signal transmission of Na +/K + -ATPaseSrc compound, and further influence the pathways of EGFR, ERK1/2 and the like, thereby controlling the growth and proliferation of cells, the synthesis of protein and glycogen, apoptosis and the like. Activation of this pathway is thought to be a mechanism by which ouabain induces hypertension-related organ hypertrophy and is also thought to be involved in the development of hypertension. Endogenous ouabain level increase and mutant adducin can coexist in individuals with hypertension, and the endogenous ouabain level increase and the mutant adducin can play a role in synergistically increasing the pressure.
Rotafloxacin is a novel ouabain antagonist which can not only normalize the sodium potassium pump activity induced by endogenous ouabain and/or mutant adducin, but also inhibit the increase in ouabain levels and Na induced by mutant adducin+/K+-ATPaseSrc complex signaling pathway activation. The specific mechanism is as follows: it is reacted with Na+/K+-ATPase binding, thereby blocking mutant adducin and endogenous ouabain and Na+/K+Interaction between-ATPase with Na+/K+Normalization of ATPase Activity, maintenance of Src activation and Na+/K+ATPase is phosphorylated, but does not cause diuretic effects and does not increase sodium excretion. The medicine is specifically applied to the gene expression protein of a patient containing a specific geneCan effectively reduce the blood pressure of patients, and has more obvious effect of reducing blood pressure than common blood pressure reducing medicines. And (4) no phase approximation implementation scheme.
Disclosure of Invention
Rotafloxacin is a new drug, and has no products on the market at home and abroad. The development of the antagonist has special research significance for treating essential hypertension, and the antagonist can antagonize endogenous ouabain and/or mutant adducin aiming at a new hypertension pathogenesis so as to effectively reduce the blood pressure of a patient. The problem of content uniformity is easy to exist due to the small size of the lotafloxacin, and the main drug of the lotafloxacin has low solubility in water, so that the preparation has technical difficulty and is difficult to reproduce in large-scale production. The preparation technology has the advantages of uniform particle content, stable quality, small loss, simple process, high efficiency, effective cost saving, and capability of solving the problem of content uniformity of the main drug in the preparation. The production quality is stable and controllable, and the commercial production feasibility is high. A preparation method of lotafloxacin enteric-coated tablets comprises the following steps:
1) sieving 70-91% of filler, 0.3-2% of lubricant, 4-8% of adhesive, 1-5% of disintegrating agent and 0.5-2% of surfactant respectively; mixing the filler and the adhesive to obtain a mixture;
2) adding purified water into the surfactant in the step 1) to prepare a surfactant aqueous solution with the concentration of 1% -5%, and adding 0.5% of lottaff to the surfactant aqueous solution for ultrasonic dissolution to obtain a mixed solution;
3) atomizing and spraying the mixed solution obtained in the step 2) into the mixture obtained in the step 1), granulating the sprayed mixture, and drying to obtain granules, wherein the percentages are mass percentages of the components in the raw materials;
4) granulating the granules obtained in the step 3), adding a lubricant, uniformly mixing, and tabletting to obtain plain tablets;
5) and (3) coating the plain tablets for the second time to obtain the enteric-coated tablets.
Preferably, the filler in step 1) comprises one or more of microcrystalline cellulose, lactose, pregelatinized starch, corn starch, dextrin, compressible starch, sugar powder, anhydrous calcium hydrogen phosphate or mannitol.
Preferably, the lubricant in step 1) comprises one or more of magnesium stearate, calcium stearate, talcum powder, superfine silica powder, hydrogenated vegetable oil, stearic acid, glyceryl behenate, silicon dioxide or sodium stearyl fumarate.
Preferably, the binder in step 1) comprises one of starch slurry, cellulose derivative, povidone, polyvinylpyrrolidone, gelatin, polyethylene glycol, sucrose, polyvinyl alcohol, liquid glucose, maltitol, poloxamer or sodium alginate.
Further preferably, the disintegrant in step 1) comprises one of crospovidone, croscarmellose sodium, starch or low-substituted hydroxypropyl cellulose.
Further optimizing, adding modes of the disintegrating agent in the step 1) are divided into three types: first, the disintegrant is added in its entirety to the mixture in step 1); second, in step 4), the disintegrant is added all together with the lubricant; in a third way, the disintegrant is divided in two parts in any ratio, one of which is added in the mixture of step 1) and the remaining part is added in step 4) together with the lubricant.
Further optimizing, the surfactant in the step 1) is one of sodium dodecyl sulfate, tween 80 and stearic acid.
Further optimizing, the drying in the step 3) is hot air drying, and the conditions are that the inlet air temperature is 60-70 ℃ and the material temperature is 26-30 ℃.
Further optimizing, and sieving the granules with a 30-50-mesh sieve in the step 4).
Further optimizing, coating in the step 5) is to use gastric-soluble film coating premix to carry out primer coating, and the weight is increased by 2-5%; then, enteric coating is carried out on the premix by using an enteric film coating agent, and the weight is increased by 8 to 15 percent, thus obtaining the finished product.
The invention has the beneficial effects that:
the wet granulation is adopted, the preparation link is complex, and the requirement of uniform content is difficult to meet. The method of mixing and direct pressing is simple, but the requirement of uniform content is still difficult to meet. The preparation method is fluidized bed spray granulation, has simple and efficient granulation process, and can meet the requirements of low specification and uniform content. In the process, materials are placed in a fluidized bed for mixing, raw materials are added in a spraying mode, and the fluidized bed is used for drying after granulation is finished. The materials do not need to be mixed separately and then granulated, and the materials do not need to be taken out and dried after the granulation is finished. The process is simple and the loss is reduced. And the materials are mixed in a fluidized bed in a boiling mode, so that the materials are more uniform. The granulation particles are uniform, and the drying efficiency is high. The parameters are controllable, and the process reproducibility is good.
Detailed Description
The 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.
Example 1
(1) Prescription composition
| Prescription | Proportion in the prescription (%) | The effects in the prescription |
| Rotaff sine | 0.5 | Active ingredient |
| Pregelatinized starch | 55.0 | Filler |
| Dextrin | 15.0 | Filler |
| Gelatin | 8.0 | Adhesive agent |
| Low-substituted hydroxypropyl cellulose | 5.0 | Disintegrating agent |
| Stearic acid | 2.0 | Surface active agent |
| Talcum powder | 2 | Lubricant agent |
| Purified water | 40 | Solvent(s) |
| Gastric-soluble film coating premix | 3％ | Subcoat layer |
| Enteric film coating premix | 10％ | Enteric layer |
(2) Preparation process
1) Sieving: and respectively sieving the various auxiliary materials with a 60-mesh sieve for later use.
2) Weighing: the pregelatinized starch, the dextrin and the gelatin are weighed according to the prescription and mixed for standby.
3) Dissolving: an aqueous stearic acid solution having a concentration of 1% was prepared in an appropriate container, and then, lottafloxacin was added to the aqueous stearic acid solution and dissolved with stirring.
4) Fluid bed granulation: transferring the weighed materials to a fluidized bed to prepare granules, mixing and preheating for about 15min, and spraying the API-stearic acid aqueous solution into the mixed materials in an atomization mode to granulate. After spraying of the aqueous API-stearic acid solution, the vessel is rinsed with appropriate purified water to reduce principal drug loss. If desired, an additional amount of purified water can be added and spraying continued to complete the granulation. After the granulation is finished, the granules are taken out after being dried properly. The air inlet temperature is controlled to be 60 ℃, the material temperature is controlled to be 26 ℃, and the atomization pressure is controlled to be 0.6 bar.
5) Straightening: and sieving the dried granules with a 40-mesh sieve for size stabilization.
6) Total mixing: adding the full amount of the low-substituted hydroxypropyl cellulose and the full amount of the talcum powder according to the total amount of the granules after finishing the granules, and uniformly mixing.
7) Tabletting: and (4) measuring the content of the particles before tabletting, calculating the weight of the tablets, and transferring the material to a tabletting machine for tabletting.
8) Coating: preparing a gastric-soluble film coating premix according to a preparation method, and putting plain tablets into a coating pan for undercoating, wherein the weight is increased by 2%; the enteric film coating premix is prepared according to a preparation method, and the subcoating tablets with 2 percent of weight gain are placed in a coating pan for enteric coating, and the weight gain is 10 percent, thus obtaining the finished product.
Example 2
(1) Prescription composition
| Prescription | Proportion in the prescription (%) | The effects in the prescription |
| Rotaff sine | 0.50 | Active ingredient |
| Lactose | 91.0 | Filler |
| Sodium alginate | 4.0 | Adhesive agent |
| Croscarmellose sodium | 1.0 | Disintegrating agent |
| Tween 80 | 0.5 | Surface active agent |
| Calcium stearate | 0.3 | Lubricant agent |
| Purified water | 40 | Solvent(s) |
| Gastric-soluble film coating premix | 5％ | Subcoat layer |
| Enteric film coating premix | 15％ | Enteric layer |
(2) Preparation process
1) Sieving: and respectively sieving the various auxiliary materials with a 100-mesh sieve for later use.
2) Weighing: weighing lactose, sodium alginate and croscarmellose sodium according to the prescription amount for later use.
3) Dissolving: the aqueous solution of tween 80 was prepared at a concentration of 5% in an appropriate container, and then, Rotaff's base was added to the aqueous solution of tween 80 and dissolved by sonication.
4) Fluid bed granulation: transferring the weighed materials to a fluidized bed to prepare granules, mixing and preheating for about 15min, and spraying the API-Tween 80 aqueous solution into the mixed materials in an atomization mode to granulate. After spraying the aqueous solution of API-Tween 80, rinsing the container with appropriate purified water to reduce the loss of the main drug. If desired, an additional amount of purified water can be added and spraying continued to complete the granulation. After the granulation is finished, the granules are taken out after being dried properly. The air inlet temperature is controlled to be 70 ℃, the material temperature is controlled to be 30 ℃, and the atomization pressure is controlled to be 1.0 bar.
5) Straightening: sieving the dried granules with a 50-mesh sieve for size stabilization.
6) Total mixing: adding the full amount of calcium stearate according to the prescription amount according to the total amount of the granules after finishing the granules, and uniformly mixing.
7) Tabletting: and (4) measuring the content of the particles before tabletting, calculating the weight of the tablets, and transferring the material to a tabletting machine for tabletting.
8) Coating: preparing a gastric-soluble film coating premix according to a preparation method, and putting plain tablets into a coating pan for undercoating, wherein the weight is increased by 5%; the enteric film coating premix is prepared according to a preparation method, and the bottom coating tablet with 3 percent weight gain is placed in a coating pan for enteric coating, and the weight gain is 15 percent, thus obtaining the finished product.
Example 3
(1) Prescription composition
| Prescription | Proportion in the prescription (%) | The effects in the prescription |
| Rotaff sine | 0.500 | Active ingredient |
| Mannitol | 79.00 | Filler |
| Microcrystalline cellulose | 10.0 | Filler |
| Hydroxypropyl cellulose | 5.0 | Adhesive agent |
| Crospovidone | 3.0 | Disintegrating agent |
| Sodium dodecyl sulfate | 1.0 | Surface active agent |
| Magnesium stearate | 1.5 | Lubricant agent |
| Purified water | 40 | Solvent(s) |
| Gastric-soluble film coating premix | 3％ | Subcoat layer |
| Enteric film coating premix | 10％ | Enteric layer |
(2) Preparation process
1) Sieving: and respectively sieving the auxiliary materials with a 80-mesh sieve for later use.
2) Weighing: weighing mannitol, microcrystalline cellulose, hydroxypropyl cellulose and crospovidone (half amount of the prescription) according to the prescription for later use.
3) Dissolving: the concentration of the sodium dodecyl sulfate aqueous solution is prepared to be 2% by using a proper container, and the lottaff is added into the sodium dodecyl sulfate aqueous solution for ultrasonic dissolution.
4) Fluid bed granulation: transferring the weighed materials to a fluidized bed to prepare particles, mixing and preheating for about 15min, and spraying the API-SDS aqueous solution into the mixed materials in an atomizing mode to granulate. After spraying of the aqueous API-SDS solution, the vessel was rinsed with appropriate purified water to reduce principal drug loss. If desired, an additional amount of purified water can be added and spraying continued to complete the granulation. After the granulation is finished, the granules are taken out after being dried properly. The air inlet temperature is controlled to be 65 ℃, the material temperature is controlled to be 28 ℃, and the atomization pressure is controlled to be 0.8 bar.
5) Straightening: and sieving the dried granules with a 30-mesh sieve for size stabilization.
6) Total mixing: adding the rest half of the crospovidone in the amount of the prescription and the total amount of magnesium stearate according to the total amount of granules after finishing granules, and uniformly mixing.
7) Tabletting: and (4) measuring the content of the particles before tabletting, calculating the weight of the tablets, and transferring the material to a tabletting machine for tabletting.
8) Coating: preparing a gastric-soluble film coating premix according to a preparation method, and putting plain tablets into a coating pan for undercoating, wherein the weight is increased by 3%; the enteric film coating premix is prepared according to a preparation method, and the bottom coating tablet with 3 percent weight gain is placed in a coating pan for enteric coating, and the weight gain is 8 percent, thus obtaining the finished product.
Example 4
(1) Prescription composition
| Prescription | Proportion in the prescription (%) | The effects in the prescription |
| Rotaff sine | 0.500 | Active ingredient |
| Mannitol | 87.0 | Filler |
| Starch slurry | 6.0 | Adhesive agent |
| Starch | 4.0 | Disintegrating agent |
| Sodium dodecyl sulfate | 1.5 | Surface active agent |
| Silica gel micropowder | 1.0 | Lubricant agent |
| Purified water | 40 | Solvent(s) |
| Gastric-soluble film coating premix | 3.5％ | Subcoat layer |
| Enteric film coating premix | 12％ | Enteric layer |
(2) Preparation process
1) Sieving: and respectively sieving the auxiliary materials with a 80-mesh sieve for later use.
2) Weighing: weighing mannitol, starch slurry and starch (two thirds of the amount of the prescription) according to the prescription amount for later use.
3) Dissolving: preparing the concentration of the sodium dodecyl sulfate aqueous solution to be 3% by using a proper container, and adding the Rotaff base into the sodium dodecyl sulfate aqueous solution for ultrasonic dissolution.
4) Fluid bed granulation: transferring the weighed materials to a fluidized bed to prepare particles, mixing and preheating for about 15min, and spraying the API-SDS aqueous solution into the mixed materials in an atomizing mode to granulate. After spraying of the aqueous API-SDS solution, the vessel was rinsed with appropriate purified water to reduce principal drug loss. If desired, an additional amount of purified water can be added and spraying continued to complete the granulation. After the granulation is finished, the granules are taken out after being dried properly. The air inlet temperature is controlled to be 68 ℃, the material temperature is controlled to be 25 ℃, and the atomization pressure is controlled to be 0.7 bar.
5) Straightening: and sieving the dried granules with a 35-mesh sieve for size stabilization.
6) Total mixing: adding one third of the rest of the starch and the whole amount of the superfine silica gel powder according to the total amount of the granules after the whole granules are granulated, and uniformly mixing.
7) Tabletting: and (4) measuring the content of the particles before tabletting, calculating the weight of the tablets, and transferring the material to a tabletting machine for tabletting.
8) Coating: preparing a gastric-soluble film coating premix according to a preparation method, and putting plain tablets into a coating pan for undercoating, wherein the weight is increased by 3%; the enteric film coating premix is prepared according to a preparation method, and the bottom coating tablet with 3 percent weight gain is placed in a coating pan for enteric coating, and the weight gain is 8 percent, thus obtaining the finished product.
Comparative example 1
Compared with example 1, the difference is that in the step 5), the dried particles are sieved by a 100-mesh sieve, and other sequences and conditions are not changed.
Comparative example 2
Compared with the example 2, the difference is that the granulating in the step 4) does not adopt an atomizing spraying mode, and other sequences and conditions are not changed.
Comparing the accelerated tests of comparative examples 1-3 and comparative examples 1-2:
by comparing the above sample tests, all indexes of the samples prepared in examples 1 to 3 all meet the quality standard regulations. The stability in comparative examples 1 to 2 was poor.
Claims (5)
1. A preparation method of lotafloxacin enteric-coated tablets comprises the following steps:
1) sieving 70-91% of filler, 0.3-2% of lubricant, 4-8% of adhesive, 1-5% of disintegrating agent and 0.5-2% of surfactant respectively; mixing the filler and the adhesive to obtain a mixture;
2) adding purified water into the surfactant in the step 1) to prepare a surfactant aqueous solution with the concentration of 1% -5%, and adding 0.5% of lotafloxacin into the aqueous solution for dissolving to obtain a mixed solution;
3) atomizing and spraying the mixed solution obtained in the step 2) into the mixture obtained in the step 1), granulating the sprayed mixture, and drying to obtain granules, wherein the percentages are mass percentages of the components in the raw materials;
4) granulating the granules obtained in the step 3), adding a lubricant, uniformly mixing, and tabletting to obtain plain tablets;
5) coating the plain tablets for the second time to obtain the enteric-coated tablets;
wherein, the filling agent in the step 1) comprises one or more of microcrystalline cellulose, lactose, pregelatinized starch, corn starch, dextrin, compressible starch, powdered sugar, anhydrous calcium hydrogen phosphate or mannitol;
the lubricant in the step 1) comprises one or more of magnesium stearate, calcium stearate, talcum powder, superfine silica powder, hydrogenated vegetable oil, stearic acid, glyceryl behenate, silicon dioxide or sodium stearate fumarate;
the adhesive in the step 1) comprises one of starch slurry, cellulose derivatives, polyvidone, polyvinylpyrrolidone, gelatin, polyethylene glycol, sucrose, polyvinyl alcohol, liquid glucose, maltitol, poloxamer or sodium alginate;
the disintegrant in the step 1) comprises one of crospovidone, croscarmellose sodium, starch or low-substituted hydroxypropyl cellulose;
the surfactant in the step 1) is one of sodium dodecyl sulfate, tween 80 and stearic acid.
2. The method for preparing lottavudine enteric coated tablets according to claim 1, wherein the addition modes of the disintegrant in step 1) are divided into three types: first, the disintegrant is added in its entirety to the mixture in step 1); second, in step 4), the disintegrant is added all together with the lubricant; in a third way, the disintegrant is divided in two parts in any ratio, one of which is added in the mixture of step 1) and the remaining part is added in step 4) together with the lubricant.
3. The preparation method of lotaflavin enteric-coated tablets as claimed in claim 1, wherein the drying in step 3) is hot air drying, and the conditions are that the air inlet temperature is 60-70 ℃ and the material temperature is 26-30 ℃.
4. The method for producing lottavudine enteric coated tablets according to claim 1, wherein the size reduction in step 4) is performed by sieving with a 30-50 mesh sieve.
5. The method for preparing lotafloxacin enteric-coated tablets according to claim 1, wherein the secondary coating in step 5) is performed by coating the premix with a gastric-soluble film coating agent, and then the weight is increased by 2-5%; then, enteric coating is carried out on the premix by using an enteric film coating agent, and the weight is increased by 8 to 15 percent, thus obtaining the finished product.
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