CN107737112B - Letrozole tablet and preparation method thereof - Google Patents
Letrozole tablet and preparation method thereof Download PDFInfo
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
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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
- A61K9/2054—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
- A61K9/2095—Tabletting processes
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to letrozole tablets and a preparation method thereof. The letrozole tablet comprises letrozole and silicified microcrystalline cellulose, wherein the content of the silicified microcrystalline cellulose accounts for 20-60% of the total weight of the tablet. The particle diameter D of letrozole(v,0.9)Particle size D of 60 μm or less, preferably letrozole(v,0.9)A particle size D of not more than 40 μm, more preferably letrozole(v,0.9)Less than or equal to 8 mu m. The silicified microcrystalline cellulose used in the invention enables the letrozole to be uniformly dispersed in the mixed powder, has good fluidity, can be directly tableted, simplifies the process, saves time and has low labor intensity; after the raw material medicines are crushed, the particle size is obviously reduced, the dissolution speed of the prepared letrozole tablet is obviously improved by controlling the content of the disintegrating agent, more than 85 percent can be achieved in 15min, and the letrozole tablet is a very quick dissolution tablet.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a letrozole tablet and a preparation method thereof, and more particularly relates to a letrozole tablet capable of being dissolved out very quickly and a preparation method thereof.
Background
Letrozole is a third-generation aromatase inhibitor and is a non-steroidal drug. The structural formula is as follows:
letrozole competes with an endogenous substrate for an active site of aromatase by combining with an iron atom in heme, so that the activity of the enzyme is reversibly inhibited, the level of plasma estrogen is effectively reduced, and the stimulation to hormone-sensitive tumors is removed. It is especially suitable for postmenopausal breast cancer patients.
Patent CN104146974A discloses a letrozole-containing composition and a preparation method thereof, wherein a letrozole solid dispersion is prepared by adopting a hot-melt extrusion technology, so that the technical defects of poor water solubility and the like of letrozole are solved, but the letrozole solid dispersion has the advantages of large and complicated process difficulty, high cost and unsuitability for industrial production; CN104586804A discloses a preparation method of letrozole tablets with good stability, wherein ethanol is used as a solvent to prepare letrozole particles, and the use of an organic solvent ethanol has certain requirements on explosion resistance of workshops and equipment, so that the letrozole particles are dangerous; CN103356495A discloses a letrozole tablet and its preparation method, which is characterized by adding surfactant as solubilizer to increase dissolution rate, but the addition of surfactant increases the risk of cytotoxicity and hemolysis.
CN101099724A discloses micronized letrozole and its composition, which is prepared into a preparation with suitable dissolution rate by processing the micronized letrozole into particles with a size of 10-100 microns and combining with a carrier. The letrozole tablet prepared by the method has the dissolution rate of 74.5 at 15min, and the letrozole capsule has the dissolution rate of 79.7 at 15 min.
And the letrozole is BCS I, belongs to a high-solubility and high-permeability medicament, and whether the dissolution can reach 85% in 15min or not is considered. The tablets and capsules obtained with the micronized letrozole described above clearly do not meet this requirement.
The prior art also provides a process for producing letrozole tablets by micronization processing of raw material medicines and direct tabletting of powder, so as to solve the problem of slow dissolution of letrozole. The auxiliary materials adopted in the process comprise microcrystalline cellulose and micro silica gel. However, the micropowder silica gel is not firmly adsorbed on the surface of the powder, so that a demixing phenomenon is easily caused in the material transfer and tabletting processes, and because the letrozole is micronized, the particle size and the density of the letrozole are far smaller than those of other auxiliary materials, the letrozole is more easily floated and adhered to preparation equipment after demixing, the material is lost, the dust pollution is caused, the satisfactory content uniformity cannot be obtained, and the industrial scale-up production is not facilitated.
The present invention has been made in view of this situation.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a letrozole tablet and a preparation method thereof.
In order to solve the technical problems, the invention adopts the following technical scheme:
letrozole tablet, wherein: the letrozole tablet comprises letrozole and silicified microcrystalline cellulose, wherein the content of the silicified microcrystalline cellulose accounts for 20-60% of the total weight of the tablet.
The direct powder tabletting process has high requirement on tabletting material, and the supplementary material has high flowability, excellent compressibility and high lubricating performance. The common type of microcrystalline cellulose cannot meet all requirements of a direct powder tabletting process due to the reasons of low bulk density, high lubrication sensitivity, poor fluidity, easiness in influence of water content on compressibility and the like. Although the prior art proposes a method for producing letrozole tablets by micronization of raw materials and direct powder compression using excipients comprising microcrystalline cellulose and aerosil. However, the superfine silica powder is not firmly adsorbed on the surface of the powder, so that a demixing phenomenon is easily caused in the material transfer and tabletting processes, and the letrozole is micronized to have particle size and density far smaller than those of other auxiliary materials, so that letrozole is more easily floated and adhered to preparation equipment after demixing, the material is lost, dust pollution is caused, satisfactory content uniformity cannot be obtained, and industrial scale-up production is not facilitated.
The letrozole tablet provided by the invention comprises letrozole and silicified microcrystalline cellulose, wherein the content of the silicified microcrystalline cellulose accounts for 20-60% of the total weight of the tablet.
Silicified microcrystalline cellulose (SMCC) is obtained by blending microcrystalline cellulose and colloidal silicon dioxide (98: 2) in water and spray drying, and has a lower angle of repose, a lower hawson ratio and more favourable flow and filling parameters than a physical mixture of homologous ordinary microcrystalline cellulose and aerosil. In addition, SMCC has the ability to disperse evenly low doses of drug. However, from the deformation mechanism, microcrystalline cellulose is a plastically deformed material, which is deformed by an external force, and cannot be restored to its original shape when the applied external force is removed or disappears. The auxiliary materials for shaping deformation, such as microcrystalline cellulose, starch, pregelatinized starch and the like, have good compressibility, but the shaping deformation can also bring some problems to the prescription, for example, the auxiliary materials are sensitive to a lubricant, and a continuous lubricating film formed by the lubricant on the surface of the materials for shaping deformation can influence the binding force between particles, thereby influencing the hardness of the tablets. While SMCC converts part of particles into brittle fracture after siliconization treatment, lubricated particles can be fractured into irregular shapes under the action of external force, and some regions which are not lubricated are exposed, so that the binding force between the particles is enhanced. Thus, one skilled in the art would expect that aerosil would have an adverse effect in silicified microcrystalline cellulose when used in letrozole tablets, i.e., reduced crushing strength and increased friability as is the case with the usual use of lubricants.
The SMCC has a good effect which is not surprising when used for preparing letrozole tablets, so that letrozole is uniformly dispersed in mixed powder, the flowability is good, the letrozole powder can be directly tableted, and finally prepared tablets have high dissolution rate and small dissolution difference under different pH conditions. More surprisingly, the crushing strength of the letrozole tablets is improved, the fragility is reduced, the letrozole tablets can be tabletted at a higher speed, and the production efficiency is greatly improved.
The particle diameter D of letrozole(v,0.9)Particle size D of 60 μm or less, preferably letrozole(v,0.9)A particle size D of not more than 40 μm, more preferably letrozole(v,0.9)≤8μm。
The inventor finds that after the particle size of the active ingredient is controlled, under different contents of the disintegrant, the dissolution difference of the tablet is large although the disintegration time is controlled to be the same, and the addition amount of the disintegrant greatly influences the quality of the tablet. The inventors have found that at a specific SMCC and disintegrant content, tablets with moderate hardness, complete dissolution and rapid speed can be obtained. Accordingly, the particle size of letrozole in the further limitation of the present invention is preferably D(v,0.9)Less than or equal to 40 mu m, more preferably D(v,0.9)≤8μm。
The letrozole tablet also comprises a disintegrant, and the content of the disintegrant accounts for 2-8 percent of the total weight of the tablet, preferably 4-8 percent, and more preferably 6 percent.
The letrozole tablet also comprises a filler, a binder and a lubricant.
The letrozole tablet comprises the following components in percentage by weight:
preferably:
the filler is one or more selected from lactose monohydrate, calcium hydrogen phosphate or mannitol, and preferably lactose monohydrate; the disintegrant is selected from croscarmellose sodium and/or sodium carboxymethyl starch, preferably sodium carboxymethyl starch; the adhesive is selected from povidone and/or pre-crosslinked starch; the lubricant is selected from magnesium stearate and/or talcum powder, preferably magnesium stearate.
The letrozole tablet comprises the following components in percentage by weight:
the letrozole tablets are prepared by a powder direct compression method.
The letrozole tablets contain a pharmaceutically acceptable coating material.
The invention also provides a preparation method of the letrozole tablets, wherein the preparation method comprises the following steps: the preparation method comprises the following steps:
1) sieving the crude drug of the trozole, silicified microcrystalline cellulose, disintegrant, filler and adhesive respectively, weighing according to the amount, placing in a mixer, and mixing;
2) adding lubricant, mixing, and tabletting to obtain plain tablets;
3) or further coating the tablet in a coating machine.
After adopting the technical scheme, compared with the prior art, the invention has the following beneficial effects:
(1) the SMCC used in the invention enables letrozole to be uniformly dispersed in mixed powder, has good fluidity and higher content and content uniformity, can directly tablet powder, simplifies the process, saves time and has low labor intensity;
(2) after the raw material medicines are crushed, the particle size is obviously reduced, the dissolution speed of the prepared letrozole tablet is obviously improved by controlling the content of the disintegrating agent, more than 85 percent can be achieved in 15min, and the letrozole tablet is a very quick dissolution tablet;
(3) the tablet prepared by the method provided by the invention has low friability, and can be prepared into tablets at a higher speed, so that the production efficiency is greatly improved.
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 will be clearly and completely described below with reference to the embodiments of the present invention, and the following embodiments are used for illustrating the present invention and are not intended to limit the scope of the present invention.
Example 1 letrozole tablets
Prescription:
the preparation method comprises the following steps:
(1) respectively sieving the trozole bulk drug, SMCC, lactose monohydrate, sodium carboxymethyl starch and pregelatinized starch with a 80-mesh sieve, weighing according to the amount, placing in a mixer, and mixing for 30 min;
(2) adding magnesium stearate, mixing for 15min, and tabletting;
(3) and (3) putting the letrozole tablets on a high-efficiency coating machine, and controlling the coating weight increment to be 2-6% to obtain the letrozole tablets.
Example 2 letrozole tablets
Prescription:
the preparation method comprises the following steps: the same as in example 1.
Example 3 letrozole tablets
Prescription:
the preparation method comprises the following steps: the same as in example 1.
Example 4 letrozole tablets
Prescription:
the preparation method comprises the following steps: the same as in example 1.
Example 5 letrozole tablets
Prescription:
the preparation method comprises the following steps:
(1) respectively sieving the trozole bulk drug, SMCC, calcium hydrogen phosphate, croscarmellose sodium and povidone by a 80-mesh sieve, weighing according to the amount, placing into a mixer, and mixing for 30 min;
(2) adding magnesium stearate, mixing for 15min, and tabletting.
Example 6 letrozole tablets
Prescription:
the preparation method comprises the following steps:
(1) respectively sieving the trozole bulk drug, SMCC, mannitol, croscarmellose sodium and povidone by a 80-mesh sieve, weighing according to the amount, placing in a mixer, and mixing for 30 min;
(2) adding magnesium stearate, mixing for 15min, and tabletting.
Test example 1: letrozole different particle size dissolution rate comparison experiment:
letrozole used in formulation 1 has a particle size of D(v,0.9)About 150 μm, and letrozole having a particle size D for formulation 2(v,0.9)About 60 μm, and letrozole used in formulation 3 having a particle size of D(v,0.9)About 8 μm.
The preparation method comprises the following steps:
(1) respectively sieving the raw materials of the letrozole, SMCC, lactose monohydrate, sodium carboxymethyl starch and pre-crosslinked starch with a 80-mesh sieve, weighing according to the amount, placing in a mixer, and mixing for 30 min;
(2) adding magnesium stearate, mixing for 15min, and tabletting;
(3) putting the plain tablets on a high-efficiency coating machine, and controlling the coating weight increase to be 2-6%;
(4) and (3) detecting the dissolution of the coated tablets in different media.
Table 1: dissolution results of formula 1
And (4) analyzing results: the dissolution results in table 1 show that, because letrozole has low water solubility, the dissolution rate is poor and the dissolution is incomplete when the particle size of the raw material drug is too large.
Table 2: recipe 2 and recipe 3 dissolution results
And (4) analyzing results: comparing the results in tables 1 and 2, it is found that the particle size of letrozole is controlled to D(v,0.9)Within the range of less than or equal to 60 mu m, the letrozole tablets can be dissolved out for 15min to reach more than 85 percent, the dissolution difference is small under different pH conditions, and the dissolution difference among different batches is small.
Test example 2: comparative test of different SMCC contents of letrozole tablets
Recipe 4 uses a premix of adjuvant SMCC and recipe 5 uses a physical mixture of homologous microcrystalline cellulose and colloidal silicon dioxide. The preparation method is the same as in test example 1. The particle size of letrozole in prescription 4 and prescription 5 is controlled within the range of less than or equal to 60 μm.
The angle of repose of the mixed powder, the hawson ratio of the mixed powder, the mixing uniformity and the like of the formulations 4 and 5 were examined below under the same test conditions, and the examination results are shown in tables 3, 4, 5, 6 and 7. Wherein upper 1, upper 2, upper 3 and middle 1, middle 2, middle 3 and lower 1, lower 2, lower 3 in table 6 refer to sampling 3 times each of the upper, middle and lower layers of the powder, respectively.
Table 3: comparison of repose angles of mixture powders of recipe 4 and recipe 5
| Prescription 4 | Prescription 5 | |
| Angle of repose (n is 3) | 33.4°±0.9° | 36.3°±1.3° |
Table 4: prescription 4 and prescription 5 mixed powder haxon ratio comparison results
| Prescription 4 | Prescription 5 | |
| Bulk Density (g/cm)3) | 0.306±0.001 | 0.339±0.003 |
| Tap density (g/cm)3) | 0.417±0.001 | 0.482±0.001 |
| Hawson ratio | 1.363±0.007 | 1.422±0.015 |
Table 5: comparison of recipe 4 and recipe 5 Mixed powder Chuanbei equation parameters
| Prescription 4 | Prescription 5 | |
| Flow index (a) | 0.2830 | 0.3141 |
| Compression index (b) | 0.0317 | 0.0302 |
Table 6: the mixed powder of prescription 4 and prescription 5 has uniform letrozole content
| Upper 1 | Upper 2 | Upper 3 | In 1 | In 2 | Middle 3 | Lower 1 | Lower 2 | Lower 3 | Bottom | Mean value | RSD％ | |
| Prescription 4 | 101.23 | 100.71 | 99.48 | 99.53 | 100.29 | 98.5 | 99.17 | 98.76 | 100.45 | 99.76 | 99.79 | 0.88 |
| Prescription 5 | 97.62 | 96.29 | 97.36 | 95.42 | 93.31 | 93.94 | 92.16 | 93.33 | 94.21 | 92.55 | 94.62 | 2.06 |
Table 7: letrozole content uniformity during compression of formula 4 and formula 5
| 1 | 2 | 3 | 4 | 5 | Mean value | RSD％ | |
| Prescription 4 | 101.26 | 100.31 | 101.11 | 99.86 | 99.69 | 100.45 | 0.71 |
| Prescription 5 | 101.54 | 98.53 | 99.76 | 94.44 | 93.91 | 96.44 | 3.59 |
From the comparison of the parameters, formula 4 using SMCC was found to be more powder flowable and compactible than formula 5. In the aspect of uniformity, the SMCC round particles prepared by spray drying have the advantages that part of the superfine silica gel powder is distributed on the surfaces of the particles, and the other part of the superfine silica gel powder is filled in the particles, so that friction and reduced flowability caused by excessive surface of glidant particles are avoided, and the letrozole content in the mixed powder and the tablet of the formula 4 is more uniform; and formula 5 using the mixed powder has the problems that due to the fact that the superfine silica powder is not firmly adsorbed on the surface of the powder, the demixing phenomenon is easily caused in the material transfer and tabletting processes, and due to the fact that the particle size and the density of the letrozole are far smaller than those of other auxiliary materials after micronization, letrozole is more prone to float and adhere to preparation equipment after demixing, materials are lost, dust pollution is caused, satisfactory content uniformity cannot be obtained, and industrial scale-up production is not facilitated.
Test example 3: content contrast test of different disintegrants of letrozole tablet
Lactose monohydrate is used as a filling agent, and small change has little influence on the tablets, so that the ingredients of the auxiliary materials in the prescription 6 to 8 are the same, the change amount of the disintegrating agent is supplemented by the lactose monohydrate of the filling agent correspondingly, the preparation process is the same as that of the experimental example 1, and the disintegration time of the tablets is controlled to be the same.
Table 8: dissolution results of formulas 6-8 in dissolution medium of pH68
| Serial number | 5min | 10min | 15min | 30min | 45min | 60min |
| Prescription 6 | 54.86 | 68.55 | 80.29 | 86.03 | 89.95 | 93.03 |
| Prescription 7 | 63.82 | 78.14 | 88.13 | 89.63 | 91.42 | 95.35 |
| Prescription 8 | 65.09 | 79.87 | 89.06 | 90.28 | 92.76 | 94.68 |
And (4) analyzing results: from the data in table 8, the dissolution rate becomes faster with increasing disintegrant in the tablet. However, the disintegrant is too little to be dissolved out quickly, the disintegrant is too much, the tablet is easy to absorb moisture, and the dissolution rate is easy to change when the tablet is placed, so that the in vivo absorption of the medicine is influenced. Through research, the inventor finds that when the disintegrant is in the range of 2% -8% in the tablet, the tablet can be dissolved out more quickly, and the product is stable under accelerated conditions.
Test example 4: comparative tests of different compositions of letrozole
Prescription 9-12 letrozole particle size controlled at D(v,0.9)The preparation process was the same as in test example 1, except that the particle size was not more than 60 μm and the other components were controlled within the range of the present invention.
Table 9: dissolution results of formula 9-12 in dissolution medium of pH6.8
| Serial number | 5min | 10min | 15min | 30min | 45min | 60min |
| Prescription 9 | 65.23 | 75.02 | 88.22 | 90.48 | 92.05 | 94.01 |
| Prescription 10 | 65.21 | 77.73 | 90.46 | 91.47 | 93.31 | 95.90 |
| Prescription 11 | 67.62 | 78.68 | 87.18 | 90.90 | 91.77 | 93.41 |
| Prescription 12 | 66.32 | 77.48 | 87.31 | 88.17 | 90.29 | 91.32 |
And (4) analyzing results: from the data in Table 9, it can be seen that when the particle size of letrozole is controlled to D(v,0.9)The range of less than or equal to 60 mu m and other compositions controlled in the range of the invention can ensure that the tablets have faster dissolution and smaller batch-to-batch difference.
Test example 5
The following test examples were conducted to examine the crushing strength and the crushing property of the tablets containing silicified microcrystalline cellulose and the tablets containing ordinary microcrystalline cellulose, which were prepared at different tabletting speeds as shown in Table 10.
The method comprises the following steps:
test products: letrozole tablets prepared in examples 1 to 6 were taken and labeled as test article 1 to test article 6, respectively;
comparison products: the silicified microcrystalline cellulose in the embodiments 1 to 6 is replaced by microcrystalline cellulose and aerosol, the sum of the total amount of the microcrystalline cellulose and the aerosol is equal to the amount of the silicified microcrystalline cellulose in each embodiment, wherein the mass ratio of the microcrystalline cellulose to the aerosol is 98: 2, the types, the amounts and the preparation methods of other auxiliary materials are respectively the same as the examples. The prepared letrozole tablets are respectively marked as reference 1-reference 6.
TABLE 10 compressive Strength and friability examination
Indicates inability to be tabletted
From the above test results, it can be seen that tablets containing ordinary microcrystalline cellulose cannot be tabletted with a tabletting speed higher than 80000 tablets/hour under otherwise identical conditions, because the tablets have broken.
The invention has been described with reference to the preferred embodiments described above. It should be understood that the foregoing description and examples are only illustrative of the present invention. Numerous alternatives and modifications can be devised by those skilled in the art without departing from the spirit and scope of the present invention, which should be construed as within the scope of the invention.
Claims (5)
1. Letrozole tablets characterized in that: the letrozole tablet comprises the following components in percentage by weight:
the particle diameter D of letrozole(v,0.9)≤60μm。
2. Letrozole tablet according to claim 1, wherein the letrozole has a particle size D(v,0.9)≤8μm。
3. Letrozole tablet according to claim 1, wherein: the letrozole tablets are prepared by a powder direct compression method.
4. Letrozole tablet according to claim 1, wherein: the letrozole tablets contain a pharmaceutically acceptable coating material.
5. A process for the preparation of letrozole tablets according to any of claims 1 to 4, characterized in that: the preparation method comprises the following steps:
1) sieving the crude drug of trozole, silicified microcrystalline cellulose, sodium carboxymethyl starch, lactose monohydrate and pregelatinized starch respectively, weighing according to the amount, placing in a mixer, and mixing;
2) adding magnesium stearate, mixing, and tabletting to obtain plain tablets;
3) or further coating the tablet in a coating machine.
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| CN111012752B (en) * | 2019-12-31 | 2020-09-01 | 瀚晖制药有限公司 | Letrozole tablet and preparation method thereof |
| CN111297819A (en) * | 2020-04-21 | 2020-06-19 | 北京鑫开元医药科技有限公司 | Letrozole tablet and preparation method thereof |
| CN112535674B (en) * | 2020-12-25 | 2022-09-27 | 北京悦康科创医药科技股份有限公司 | Letrozole tablet and preparation method thereof |
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| CN115444830A (en) * | 2022-08-25 | 2022-12-09 | 海南锦瑞制药有限公司 | Preparation method of letrozole tablets |
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| CN102688206A (en) * | 2012-05-29 | 2012-09-26 | 石药集团中奇制药技术（石家庄）有限公司 | Pitavastatin calcium tablet and preparation method thereof |
| CN103356495A (en) * | 2013-05-03 | 2013-10-23 | 海南林恒制药有限公司 | Letrozole tablet and preparation method thereof |
| CN103933004A (en) * | 2014-03-27 | 2014-07-23 | 哈药集团制药总厂 | Letrozole troche and preparation method of letrozole troche |
| CN104586804A (en) * | 2015-02-13 | 2015-05-06 | 孟红琳 | Preparation method for letrozole tablets with good stability |
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| CN107737112A (en) | 2018-02-27 |
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