CN110638770B - Tadalafil tablet preparation method and tablet prepared by same - Google Patents

Abstract

The invention provides a preparation method of tadalafil tablets. According to the method, the tadalafil raw material and part of the hydrophilic diluent are mixed for micronization, so that the micronized composition powder does not agglomerate, the good fluidity is kept, and the subsequent processing is facilitated, so that the time is saved, the time consumed by the whole process of tablet preparation is shortened, and the method is particularly suitable for industrial large-scale production. Tadalafil tablets prepared by the micronized composition have better dissolution rate which is basically consistent with the dissolution rate of the original ground tablets; the combination of the formula and the process ensures that the prepared tadalafil tablet has the advantages of small change of total impurities and single impurity content.

Description

Tadalafil tablet preparation method and tablet prepared by same

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a tadalafil tablet preparation method and a tadalafil tablet prepared by the method.

Background

Tadalafil (Tadalafil) is a reversible, selective PDE5 inhibitor developed by the leisan corporation for the treatment of male Erectile Dysfunction (ED) and is approved by the FDA for marketing at 11/23/11/2003 and is chemically (6R-12aR) -6- (1, 3-benzodioxol-5-yl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazino [1',2' -1,6] -pyrido [3,4-b ] indole-1, 4-dione, having the structure:

tadalafil is considered to be a solid which is substantially insoluble in water and only slightly soluble in certain organic solvents such as methanol, ethanol and acetone, compounds with low water solubility have low dissolution rate and low bioavailability, and BCS is classified as class II or class IV, which is an poorly soluble drug.

US6841167 discloses that tadalafil has a solubility of 2ug/ml in water at 25 c, so it has a lower dissolution rate and a lower bioavailability. US patent US6821975, which is a product registered in "Orange Book" by the FDA and relates to "free drug particulate form" of tadalafil, specifically "wherein at least 90% of the particles have a particle size of less than about 40 microns", preferably at least 90% of the particles have a particle size of less than 10 microns.

International patent application WO 01/08686 discloses a pharmaceutical formulation containing tadalafil in the "free drug" form in admixture with a diluent, a lubricant, a hydrophilic binder and a disintegrant.

The CN104188912B patent discloses a preparation method of tadalafil solid dispersion, which comprises tadalafil and carrier material (one or two of polyvinylpyrrolidone K30(PVP K30) and poloxamer), ultrasonically dissolving the tadalafil and the carrier material in absolute ethyl alcohol, carrying out reduced pressure rotary evaporation on the absolute ethyl alcohol, carrying out vacuum drying, crushing and sieving, and then preparing the dried dispersion, the filler, the disintegrant and the lubricant into tablets.

The research focus of the technicians in the field is to improve the dissolution rate of tadalafil in the tablets and thus improve the drug effect. It is common to pulverize tadalafil as much as possible to make it exist in small-sized particles in tablets to enhance dissolution, for example, in CN107303284A, a process of mixing tadalafil with a surfactant and then micronizing is disclosed, which discloses that the dissolution and bioavailability of tadalafil tablets obtained by this process are improved and the process of preparing tablets is shortened. However, in the process of crushing tadalafil, as the particle size becomes smaller, the surface energy such as electric charge, moisture, van der waals force and the like carried by the particles becomes larger, and the fluidity is rapidly deteriorated, so that the agglomeration phenomenon occurs and the feeding is not smooth, which is particularly obvious in large-scale industrial production, and even though CN107303284A uses tadalafil to be premixed with a surfactant, the problem cannot be overcome.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides a preparation method of tadalafil tablets. The preparation method can greatly reduce the occurrence of agglomeration after micronization, and is particularly suitable for industrial large-scale production.

The above object of the present invention is achieved by the following scheme:

the preparation method of the tadalafil tablet comprises the steps of micronization, auxiliary material pretreatment, premixing, granulation, granule finishing, drying, total mixing and tabletting, wherein the micronization comprises the steps of mixing a tadalafil raw material and part of hydrophilic diluent, sieving, and carrying out air flow crushing treatment to obtain a micronized composition containing tadalafil;

the mass ratio of the tadalafil raw material to part of the hydrophilic diluent is 1: 1-1: 5.

Diluents are common aids in the preparation of tablets and are usually added during the granulation step. The inventor finds that the agglomeration phenomenon of the tadalafil raw material after micronization can be remarkably improved by mixing a proper amount of hydrophilic diluent with the tadalafil raw material through a large number of experimental summary analysis, so that particles with finer particle sizes can be obtained in the micronization process and subsequent excellent application can be guaranteed.

Preferably, the mass ratio of the tadalafil raw material to part of the hydrophilic diluent is 1: 1-1: 3.

Preferably, the partially hydrophilic diluent is preferably lactose and/or microcrystalline cellulose.

Preferably, the conditions of the jet milling process are: the feeding pressure is 0.4-0.8 MPa, and the crushing pressure is 0.2-0.6 MPa. Under such conditions, the particle size according to the invention can be achieved more easily.

Preferably, the number of the jet milling processes is 1.

The tadalafil raw material used generally has a particle size distribution of: d10 is 6-10 um, D50 is 35-45 um, and D90 is 80-100 um.

Generally, the micronized treated particles have reached a sufficiently small size, and preferably, in the present invention, the size of the microparticles in the micronized composition containing tadalafil is preferably D90 ≦ 10um, D50 ≦ 4um, D10 ≦ 2 um.

Preferably, the sieving is 60 mesh sieving.

Preferably, the auxiliary material pretreatment is to dissolve the adhesive, add the surfactant, and stir until the solution is clear, so as to obtain a mixed solution.

More specifically, the adjuvant pretreatment may be performed as follows: adding the adhesive into hot purified water, stirring to dissolve, then adding the surfactant, stirring uniformly, then adding the normal-temperature purified water, and stirring until the adhesive is dissolved clearly.

Preferably, the binder is hydroxypropyl cellulose and the surfactant is sodium lauryl sulfate.

Preferably, the pre-mixing is to uniformly mix the remaining amount of the hydrophilic diluent, the micronized composition containing tadalafil, the low-substituted hydroxypropyl cellulose, and the croscarmellose sodium to obtain a pre-mixture.

Preferably, the pre-mixing is performed in a granulator. The premixing condition is preferably that the mixture is mixed for 3-6 min at the stirring speed of 2-5 rps.

Preferably, the granulation is performed by spraying the pretreated auxiliary materials (i.e., the mixed solvent) into the mixture obtained by the pre-mixing, and performing wet granulation.

Preferably, when the pretreated auxiliary material is added, the stirring rotating speed is controlled to be 2-5 rps, and the rotating speed of the cutter is controlled to be 8-12 rps.

The soft mass formed by wet granulation is subjected to sieving and size stabilization, and preferably to size stabilization by a sieve having a diameter of 1.0 mm.

The drying of the granulated particles is preferably carried out in a fluidized bed. The drying condition is preferably that the air inlet temperature is 50-70 ℃, and the drying is carried out for 80-100 m³Drying until LOD is less than or equal to 3.0%.

After obtaining the dried granulation, the granulation is then combined with a lubricant in preparation for tableting.

The lubricant may be magnesium stearate.

Preferably, the tabletting weight is calculated according to the content of the particles in the tabletting process, and the hardness is controlled to be 40-90N.

Preferably, the method further comprises a coating step after tabletting, and the weight increasing quality of the coating is controlled to be 2-5%.

Preferably, the number of the tablets prepared by the preparation method is 0.1-100 ten thousand per time. Preferably, the number of the tablets prepared by the preparation method is 10-50 ten thousand per time.

Based on the preparation method, the invention provides a preferable tadalafil tablet which comprises the following components in percentage by weight:

the balance of diluent;

the total amount of diluents in the tadalafil tablet is 80.62% of the total weight of the tadalafil tablet.

Diluents in the tadalafil tablets include two original forms, one being a micropowder composition formed with tadalafil and the other being diluents added as conventional adjuvants during the process of preparing the tablets.

Most preferably, the binder is hydroxypropyl cellulose, the surfactant is sodium lauryl sulfate, and the lubricant is magnesium stearate.

The tadalafil tablet prepared by the preparation method has the advantages of being better than that of the tadalafil tabletGood solubility, and its solubility performance is comparable to that of reference

Substantially identical.

Compared with the prior art, the invention has the following beneficial effects:

the invention reduces the agglomeration phenomenon of the micronized tadalafil by changing the prior process, so that the obtained micronized composition containing tadalafil has good fluidity. The micronized tadalafil has good fluidity and is convenient to process, so that the time is saved, the time consumption of the whole process of tablet preparation is shortened, and the method is particularly suitable for industrial large-scale production.

Based on the new process, the invention also provides a better tadalafil tablet formula, the tadalafil tablet prepared by the formula has better dissolution rate, and the combination of the formula and the process ensures that the tadalafil tablet prepared by the method has the advantages of small change of total impurities and single impurity content.

Drawings

FIG. 1: example 1 appearance of micronized composition;

FIG. 2: example 2 appearance of micronized composition;

FIG. 3: example 3 appearance of micronized composition;

FIG. 4: example 4 appearance of micronized composition;

FIG. 5: comparative example 1 appearance of micronized composition;

FIG. 6: comparative example 2 appearance of micronized composition;

FIG. 7: comparative example 3 appearance of micronized composition;

FIG. 8: example 1 particle size distribution profile of micronized composition;

FIG. 9: example 2 particle size distribution profile of micronized composition;

FIG. 10: example 3 particle size distribution profile of micronized composition;

FIG. 11: example 4 particle size distribution profile of micronized composition;

FIG. 12: example 5 particle size distribution profile of micronized composition;

FIG. 13: example 6 particle size distribution profile of micronized composition;

FIG. 14: comparative example 1 particle size distribution profile of micronized composition;

FIG. 15: comparative example 2 particle size distribution profile of micronized composition;

FIG. 16: comparative example 3 particle size distribution profile of micronized composition.

Detailed Description

The following examples are presented to further illustrate the present invention and should not be construed as limiting the invention. It is within the scope of the present invention to make simple modifications or alterations to the methods, procedures or conditions of the present invention without departing from the spirit and substance of the invention; unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art.

In the examples, the agglomeration of the micronized composition containing tadalafil after the micronization process was checked by visual inspection.

The dissolution rate of the tadalafil tablet is detected according to the following method:

taking the product, according to a dissolution determination method (second method of appendix XC of second part of 2010 edition of Chinese pharmacopoeia), taking 1000ml of 0.5% sodium dodecyl sulfate solution as a dissolution medium, and operating according to the method at a rotating speed of 50 revolutions per minute; filtering 5ml of the solution at 10 minutes and 30 minutes, and taking the subsequent filtrate as a test solution; and precisely transferring 3ml of the reference substance solution under the content measurement item, putting the reference substance solution into a 50ml measuring flask, diluting the reference substance solution to a scale with a dissolution medium, and shaking up to obtain the reference substance solution. According to high performance liquid chromatography (appendix V D of the second part of the 2010 edition of Chinese pharmacopoeia), octyl silane bonded silica gel is used as a filling agent; methanol-water (50:50) is used as a mobile phase, the detection wavelength is 225nm, and the column temperature is 40 ℃. Precisely measuring 50 μ l of the reference solution, injecting into a liquid chromatograph, and recording chromatogram with tailing factor not greater than 1.5. Precisely measuring 50 μ l of the test solution and the reference solution, injecting into a liquid chromatograph, recording chromatogram, and calculating the elution amount of each tablet by peak area according to an external standard method. The amount of elution at 10 minutes and 30 minutes should correspond to not less than 40% and not less than 80% of the indicated amounts, respectively, and should meet the specification.

Example 1

1000 tadalafil tablets were prepared according to the prescription of table 1.

TABLE 1(1000 single-chip dosage and ingredient ratio, each ingredient unit is gram)

Composition (I)	Dosage (g)	Percentage of component (%)
			Tadalafil	20	5.37
Lactose	180	48.37
			Microcrystalline cellulose	120	32.25
Low-substituted hydroxypropyl cellulose	10	2.69
			Hydroxypropyl cellulose	10	2.69
Croscarmellose sodium	15	4.03
			Sodium dodecyl sulfate	1.5	0.40
Magnesium stearate	3.6	0.97
			Gastric-soluble film coating premix	12	3.22

The preparation process comprises the following steps:

micronization:

mixing tadalafil and lactose according to the mass ratio of 1:3, sieving with a 60-mesh sieve, carrying out air flow crushing for 1 time to form a micronized composition containing tadalafil, observing the appearance of the micronized composition containing tadalafil obtained after crushing, and recording the agglomeration condition. The conditions of jet milling are as follows: the feeding pressure is 0.4MPa, the crushing pressure is 0.2MPa, and a Malvern particle size detector is adopted to detect the micronized composition containing tadalafil.

Auxiliary material pretreatment:

adding hydroxypropyl cellulose into hot purified water, stirring uniformly, adding sodium dodecyl sulfate, stirring uniformly, adding purified water at normal temperature, and stirring until the solution is clear to obtain a mixed solution for later use.

Premixing, granulating, finishing and drying:

adding the micronized tadalafil composition, microcrystalline cellulose, the rest lactose, low-substituted hydroxypropyl cellulose and croscarmellose sodium into a wet mixing granulator, stirring at a rotating speed of 3rps, mixing for 5min, and mixing uniformly. Spray-adding the above hydroxypropyl celluloseMixing with sodium dodecyl sulfate solution, stirring at 3rps and 10rps, making soft material, controlling air pressure at 0.3MPa, and stirring for 3 min. Sieving the soft material, grading with sieve with diameter of 1.0mm, drying the wet granules, controlling inlet air temperature at 60 deg.C and 100m³Drying until LOD is less than or equal to 3.0%.

Total mixing and tabletting:

sieving the dried granules with 24 mesh sieve, adding the granules and magnesium stearate into a mixer, rotating at 10rpm, and mixing for 8 min. And (4) calculating the weight of tablets to be pressed according to the content of the granules, and tabletting to obtain plain tablets, wherein the hardness of the tablets is 70N.

Coating:

coating the plain tablets, wherein the weight of the coating is increased by 2-5%.

Example 2

The formulation is the same as example 1 except that in the micronization process, tadalafil and lactose are mixed according to the mass ratio of 1:1, sieved by a 60-mesh sieve, and subjected to air flow pulverization for 1 time to form the micronized composition containing tadalafil, and the appearance of the micronized composition containing tadalafil obtained after pulverization is observed and the agglomeration condition is recorded. The conditions of jet milling are as follows: the feeding pressure is 0.6MPa, the crushing pressure is 0.4MPa, and a Malvern particle size detector is adopted to detect the mixture of tadalafil and soluble lactose.

Example 3

The formulation is the same as example 1 except that in the micronization process, tadalafil and lactose are mixed according to the mass ratio of 1:5, sieved by a 60-mesh sieve, and subjected to air flow pulverization for 1 time to form the micronized composition containing tadalafil, and the appearance of the micronized composition containing tadalafil obtained after pulverization is observed and the agglomeration condition is recorded. The conditions of jet milling are as follows: the feeding pressure is 0.6MPa, the crushing pressure is 0.4MPa, and a Malvern particle size detector is adopted to detect the mixture of tadalafil and soluble lactose.

Example 4

The formula is the same as that of example 1, except that in the micronization process, tadalafil and microcrystalline cellulose are mixed according to the mass ratio of 1:3 and sieved by a 60-mesh sieve, and are subjected to jet milling for 1 time to form the micronized composition containing tadalafil, the appearance of the micronized composition containing tadalafil obtained after milling is observed, and the agglomeration condition is recorded. The conditions of jet milling are as follows: the feeding pressure is 0.4MPa, the crushing pressure is 0.2MPa, and a Malvern particle size detector is adopted to detect the mixture of tadalafil and soluble lactose.

Example 5

The formulation was the same as in example 1 except that in the micronization process, a mixture of tadalafil, lactose and microcrystalline cellulose was mixed at a mass ratio of 1:3 and sieved through a 60 mesh sieve, wherein the lactose and microcrystalline cellulose were mixed at a mass ratio of 1:2, and subjected to jet milling for 1 time to form a micronized composition containing tadalafil, and the appearance of the micronized composition containing tadalafil obtained after milling was observed and the agglomeration was recorded.

The conditions of jet milling are as follows: the feeding pressure is 0.4MPa, the crushing pressure is 0.2MPa, and a Malvern particle size detector is adopted to detect the mixture of tadalafil and soluble lactose.

Example 6

20 ten thousand tadalafil tablets were prepared according to the recipe in Table 2, and the preparation method steps and parameters were the same as in example 1.

TABLE 2(20 ten thousand tablets in kg of each ingredient)

Composition (I)	Dosage (Kg)	Percentage of component (%)
			Tadalafil	4	5.37
Lactose	36	48.37
			Microcrystalline cellulose	24	32.25
Low-substituted hydroxypropyl cellulose	2	2.69
			Hydroxypropyl cellulose	2	2.69
Croscarmellose sodium	3	4.03
			Sodium dodecyl sulfate	0.3	0.40
Magnesium stearate	0.72	0.97
			Gastric-soluble film coating premix	2.4	3.22

Comparative example 1

The formula is the same as that of example 1, except that no lactose is added in the micronization process of the tadalafil raw material, the tadalafil raw material is directly sieved by a 60-mesh sieve and is subjected to air flow pulverization for 1 time. The conditions of jet milling are as follows: the feeding pressure is 0.4MPa, the crushing pressure is 0.2MPa, and a Malvern particle size detector is adopted to detect the micronized tadalafil. The other steps are the same.

The observation shows that the flowability of the micronized tadalafil is poor, and the micronized tadalafil has a clustering phenomenon, so that the problem of unsmooth feeding is caused.

Comparative example 2

The preparation process is the same, except that starch is used for replacing lactose in the formula, the starch is also used for replacing the lactose in the micronization process, the tadalafil and the starch are mixed according to the mass ratio of 1:3 and pass through a 60-mesh sieve, the tadalafil micronized composition is formed after the tadalafil micronized composition is subjected to jet milling for 1 time, the appearance of the tadalafil-containing micronized composition obtained after the milling is observed, and the agglomeration condition is recorded. And detecting the mixture of tadalafil and starch by using a Malvern particle size detector. The rest of the procedure was the same as in example 1.

Comparative example 3

The formulation was the same as that of example 1, except that in the micronization process, in reference to CN107303284A, tadalafil and total sodium lauryl sulfate were mixed and sieved through a 60-mesh sieve, and subjected to jet milling 1 time to form a micronized composition of tadalafil, and the appearance of the micronized composition containing tadalafil obtained after milling was observed and the agglomeration was recorded. The conditions of jet milling are as follows: the feeding pressure is 0.4MPa, the crushing pressure is 0.2MPa, and a Malvern particle size detector is adopted to detect the mixture of tadalafil and sodium dodecyl sulfate. The rest of the procedure was the same as in example 1.

Comparative example 4

The formulation is the same as that of example 1, except that the adjuvant pretreatment step is carried out by simply preparing sodium lauryl sulfate into a solution, adding hydroxypropyl cellulose and other components into the system during the total mixing process, and the rest steps are the same as those of example 1.

The particle size and agglomeration of the micronized compositions containing tadalafil of examples 1, 2,3, 4, 5, 6 and comparative examples 1-3 are shown in table 3.

TABLE 3 examples 1-6 and comparative examples 1-3

The particle size distribution of the tadalafil raw material medicine is as follows: d10 ═ 6.69 micrometers, D50 ═ 39.3 micrometers, and D90 ═ 86.0 micrometers.

In order to eliminate the problems of flowability and agglomeration caused by larger particles in comparative examples 1-3, the micronized composition containing tadalafil in comparative examples 1-3 was subjected to secondary air flow pulverization, and the particle size and agglomeration phenomenon of the micronized composition containing tadalafil are shown in table 4.

TABLE 4

From the above it can be seen that: the tadalafil and the lactose or the microcrystalline cellulose or the mixture of the lactose and the microcrystalline cellulose are micronized together, the particle size of the obtained micronized composition is smaller and reaches D90 being less than or equal to 10um, D50 being less than or equal to 4um and D10 being less than or equal to 2um, and after the micronization, the particles have no agglomeration phenomenon and good fluidity. The particles obtained by adding lactose (comparative example 1), replacing lactose with other fillers (starch) (comparative example 2), replacing lactose with surfactant (comparative example 3) and performing secondary crushing are similar to the particles obtained by the examples in size, but agglomeration phenomenon obviously occurs after micronization; the particles of comparative examples 2 and 3 were different from those of D90 and D50, and also agglomerated; as is apparent from fig. 5 to 7, the particles are agglomerated into small groups, unlike the fine particles of fig. 1 to 4), and the flowability is poor, which affects the processing. The particle size distribution diagrams of examples 1 to 6 and comparative examples 1 to 3 are shown in FIGS. 8 to 13.

The dissolution rates and impurity contents of the prepared tadalafil tablets are shown in tables 5 and 6.

TABLE 5 examples, control and comparative examples cumulative dissolution

As can be seen from the above, the dissolution traces of examples 1 to 6 are similar to those of the comparative example (the original tablet), the 30-minute cumulative dissolution reaches 95 or more, the dissolution rates of comparative examples 1 to 4 at different time points are all close to 10 points lower than those of the comparative example, and the dissolution is not consistent with that of the comparative example (the original tablet).

TABLE 6 data on the measurement of substances and contents

As can be seen from tables 5 and 6, the tadalafil tablets prepared in the examples have the advantages of total impurities of less than 0.05%, single impurity content of less than 0.05% and good dissolution rate.

Claims (5)

1. The preparation method of the tadalafil tablet comprises the steps of micronization, auxiliary material pretreatment, premixing, granulation, size stabilization, drying, total mixing and tabletting, and is characterized in that the micronization step is completed by mixing a tadalafil raw material and part of hydrophilic diluent, sieving, and carrying out airflow pulverization treatment to obtain a micronized composition containing tadalafil;

the mass ratio of the tadalafil raw material to part of the hydrophilic diluent is 1: 1-1: 5;

the part of hydrophilic diluent is lactose and/or microcrystalline cellulose;

the auxiliary material pretreatment is to dissolve the adhesive, add the surfactant and stir until the adhesive is dissolved to obtain a mixed solution;

the pre-mixing is to uniformly mix the rest amount of hydrophilic diluent, the micronized composition containing tadalafil, the low-substituted hydroxypropyl cellulose and the croscarmellose sodium to obtain a pre-mixture;

the granulation is to spray and add the pretreated auxiliary materials into the mixture obtained by premixing and carry out wet granulation;

in the micronized composition containing tadalafil, the particle size of the particles is D90-10 um, D50-4 um and D10-2 um;

the adhesive is hydroxypropyl cellulose, and the surfactant is sodium dodecyl sulfate.

2. The preparation method of tadalafil tablets according to claim 1, wherein the mass ratio of the tadalafil raw material to the part of the hydrophilic diluent is 1:1 to 1: 3.

3. The method for preparing tadalafil tablets according to claim 1, wherein the conditions of the jet milling treatment are: the feeding pressure is 0.4-0.8 MPa, and the crushing pressure is 0.2-0.6 MPa.

4. The preparation method of tadalafil tablets according to claim 1, wherein the stirring speed is controlled to be 2 to 5rps and the cutter speed is controlled to be 8 to 12rps when the pretreated auxiliary material is added.

5. Tadalafil tablets prepared by the preparation method according to any one of claims 1 to 4, which are characterized by comprising the following components in percentage by weight:

the balance of diluent;

the total amount of diluents in the tadalafil tablet is 80.62% of the total weight of the tadalafil tablet.

Images