CN113116840B - Preparation method of hydroxychloroquine sulfate tablet - Google Patents

Abstract

The invention discloses a preparation method of hydroxychloroquine sulfate tablets. The method creatively participates the raw material medicine, the lubricant and other pharmaceutically acceptable auxiliary materials into wet granulation, then presses the granules into tablets and coats, overcomes the process difficulty caused by over-strong hygroscopicity of the raw material medicine, improves the soft material state of the wet granulation, ensures that the prepared soft material has uniform size, and is beneficial to mass production. In addition, the preparation process has the advantages of small difference in tablet batches, high stability, good in-vitro dissolution rate, good process reproducibility and the like, and has good commercial value.

Description

Preparation method of hydroxychloroquine sulfate tablet

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a hydroxychloroquine sulfate tablet and a preparation method thereof.

Background

Hydroxychloroquine sulfate tablets (HCQ) were developed by Sonofirantatt, and were approved for marketing in the United states in 1976 under the tradename of PLAQUENIL. The early hydroxychloroquine sulfate, an antimalarial drug, is composed of two aromatic rings and belongs to the class of 4-aminoquinolines, wherein one ethyl group in chloroquine is replaced by one hydroxyethyl group. In the 50 s of the 20 th century, along with the application of antimalarial drugs in the treatment of Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA), the curative effect of hydroxychloroquine sulfate in the treatment of rheumatic diseases is positive. Due to the unique action mechanism and better safety, hydroxychloroquine sulfate is widely applied in the field of clinical rheumatism, and after 90 years in the 20 th century, hydroxychloroquine sulfate is selected for more than 90% of clinical rheumatism treatment, so that hydroxychloroquine sulfate is a basic medicine for treating rheumatoid arthritis and lupus erythematosus at present.

The hydroxychloroquine sulfate raw material medicine is white or white-like crystalline powder, the flowability of the raw material medicine is extremely poor, and the ratio of the raw material medicine in the original grinding prescription is huge, so that the mixed powder direct-pressing or dry granulation process is not suitable for being adopted in the granulation process. The raw materials of the product are easily dissolved in water and have strong hygroscopicity. The experimental data show that the weight gain is up to 10% when the material is placed in a high-humidity environment with the humidity of 75% for 24 hours. Due to the high hygroscopicity of the hydroxychloroquine sulfate bulk drug, the hydroxychloroquine sulfate tablet is easy to agglomerate and form balls in the wet granulation process, the soft material granulation state is very uneven, the prepared granules are extremely uneven in size, and the dissolution curve difference in the tablet batch is large. Meanwhile, the finished tablet is very easy to cause moisture to influence the internal quality of the medicine, thereby not only bringing great difficulty to the industrial production and storage of the tablet, but also bringing great risk to the medication of patients. Therefore, in the process of developing the product, the problem of strong hygroscopicity of the raw materials needs to be solved, and the problems of non-uniform particle size of the granulated particles and large difference of dissolution curves in tablet batches are solved.

In the prior patent CN 102920674A in China, wet granulation pretreatment is carried out on a raw material drug by absolute ethyl alcohol, the hygroscopicity of the treated raw material drug is reduced, but the flowability of the granulated raw material drug is poor and is not enough to participate in subsequent processes, secondary wet granulation with auxiliary materials is also needed, the production efficiency is greatly reduced, and meanwhile, residual solvent is introduced into a finished product by adding the ethyl alcohol, so that the detection and control cost is increased. CN 102525969A proposes adding buffer solution to carry out wet granulation, the dissolution rate and stability of the preparation are obviously improved, but the problems of different sizes of wet granulation granules and large difference between batches and in batches of the product are still not solved. CN 102349877A mainly proposes two dosage forms of capsule and dispersible tablet based on the traditional tablet, and the main processing mode is as follows: mixing the medicine and the powder uniformly, micronizing the uniformly mixed material to ensure that the particle size is below 200 meshes, and directly tabletting or encapsulating. In fact, the raw material of the product accounts for more than 50%, and the raw and auxiliary materials subjected to micronization cannot be directly tabletted or encapsulated, so that the final industrial production is influenced.

The drug dissolution curve is an effective means for evaluating the quality of the preparation, and can reflect the bioavailability, the batch-to-batch difference and the like of the product to a certain extent. The test result of the dissolution curve of the hydroxychloroquine sulfate tablet imitation drugs on the market at present shows that the Relative Standard Deviation (RSD) in batches and among batches is large.

In patent CN 102525969A, CN 102920674 a and the prior art, there is almost no situation of lubricant addition and wet granulation, and this patent particularly provides a method for preparing granules by lubricant internal humidification, which is used to overcome the process difficulty caused by strong hygroscopicity of hydroxychloroquine sulfate bulk drug, and simultaneously reduce the inter-batch and intra-batch differences of dissolution curves, and improve the stability of the dissolution curve of hydroxychloroquine sulfate.

Aiming at the existing defects, the invention provides a preparation method of hydroxychloroquine sulfate tablets with a lubricant participating in wet granulation. The hydroxychloroquine sulfate tablet disclosed by the invention has the advantages of good dissolution rate, low hygroscopicity, uniform wet granulation granules, good process reproducibility, stable quality, easiness in scale-up production and the like.

Disclosure of Invention

The invention aims to provide a preparation method of hydroxychloroquine sulfate tablets, which has the advantages of good dissolution rate, low hygroscopicity of the tablets, uniform and stable granules prepared by wet granulation, good process reproducibility and small corrosion to equipment.

The invention provides a preparation method of hydroxychloroquine sulfate-containing tablets, which is characterized in that the technical difficulty caused by strong hygroscopicity of hydroxychloroquine sulfate bulk drugs is overcome by jointly participating the bulk drugs, lubricants and other pharmaceutically acceptable auxiliary materials in wet granulation, the soft material state of the wet granulation is improved, the mass production is facilitated, and finally the granules are pressed into tablets and coated. The preparation process has the advantages of high stability, good in-vitro dissolution rate, small RSD among dissolved tablets, uniform wet granulation granules, good process reproducibility and the like.

In some specific embodiments, the method for preparing hydroxychloroquine sulfate tablets provided by the invention is characterized in that a lubricant such as one of magnesium stearate, talcum powder or sodium fumarate stearate is added in the wet granulation process, and in some preferred embodiments, the lubricant is selected from magnesium stearate.

In some specific embodiments, the preparation method of the hydroxychloroquine sulfate tablet provided by the invention is characterized in that the particle size D90 of the main drug hydroxychloroquine sulfate bulk drug is between 80 μm and 160 μm.

In some embodiments, the present invention provides a method for preparing hydroxychloroquine sulfate tablet, which comprises: the selected filler is one or a combination of more of corn starch, microcrystalline cellulose and lactose; preferably, the filler combination adopts lactose and corn starch, and the dosage ratio of the lactose to the corn starch is 0.5-2.0.

In some specific embodiments, the preparation method of the hydroxychloroquine sulfate tablet provided by the invention is characterized in that: the adhesive is selected from one or more of corn starch slurry, polyvidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose; preferably, the adhesive is corn starch slurry.

More specifically, the preparation method of the hydroxychloroquine sulfate tablet provided by the invention comprises the following steps:

(1) placing corn starch for preparing slurry into a slurry preparation container, wetting with a small amount of cold water, quickly pouring boiling water, stirring uniformly, standing and cooling to room temperature;

(2) premixing: pouring hydroxychloroquine sulfate, the internal lubricant and other auxiliary materials into a wet granulator, and uniformly mixing;

(3) and (3) wet granulation: adding the corn starch slurry into a granulator for granulation, drying the soft material by using a fluidized bed, stopping drying when the drying weight loss of the granules is below 2.0%, and then granulating the dried granules by using a granulator;

(4) mixing the granules prepared in the step (3) with an additional lubricant for 3min, and tabletting;

(5) and (4) preparing the tablets prepared in the step (4) into coated tablets by using a gastric-soluble coating material.

Detailed Description

EXAMPLE 1 Hydroxychloroquine sulfate 200mg specification

The preparation method of the 200mg hydroxychloroquine sulfate tablet comprises the following steps:

(1) placing corn starch for preparing slurry into a slurry preparation container, wetting with a small amount of cold water, quickly pouring boiling water, stirring uniformly, standing and cooling to room temperature;

(2) premixing: pouring the raw material medicines, the lubricant and other auxiliary materials into a wet granulator, and uniformly mixing;

(3) and (3) wet granulation: adding the corn starch slurry into a granulator for granulation, drying the soft material by using a fluidized bed, stopping drying when the drying weight loss of the granules is below 2.0%, and then granulating the dried granules by using a granulator;

(4) mixing the granules prepared in the step (3) with an additional lubricant for 3min, and tabletting;

(5) and (4) preparing the tablets prepared in the step (4) into coated tablets by using a gastric-soluble coating material.

Hydroxychloroquine sulfate tablets were prepared according to the formulation ratios of tables 1-1, as described above, with formulation 4 being distinguished from the other three formulations primarily in that the lubricant does not participate in wet granulation. The tablets were placed under high humidity (25 ℃ C./75% RH) for 7 days, and the dissolution curves and hygroscopicity of the 4 formulations were measured.

TABLE 1-1

The lubricant in the formula 4 does not participate in wet granulation, the soft material is easy to aggregate into a dough shape in the preparation process of the soft material, and materials of a stirring paddle and a cutter of the wet granulator are obviously adhered after the granulation is finished. The lubricant is uniform in the preparation process of the prescription 1-3 participating in wet granulation, the phenomena of wet particle aggregation and cutter adhesion are not found in the granulation process, and the granulation state is obviously improved. The lubricant is participated in the granulation, which can obviously improve the properties of the soft material and is beneficial to mass production.

Examination of dissolution curves: placing the self-made tablets of the formula 1-4 and the commercially available tablets under a high humidity (25 ℃/75% RH) condition for 7 days, and measuring a dissolution curve; dissolution profile results tables 1-2:

TABLE 1-2 dissolution curve (% at pH1.0-75 rpm)

The lubricant is participated in wet granulation according to the prescription 1-3, the stability of the dissolution curve is obviously better than that of the lubricant not participated in wet granulation prescription 4, the dissolution of the lubricant in 0 day is close to that of the commercially available reference preparation, the lubricant has a larger influence on the inherent quality of the hydroxychloroquine sulfate tablet, the improvement of the stability of the dissolution curve of the hydroxychloroquine sulfate tablet is facilitated, and the lubricant is preferably magnesium stearate.

Examination of moisture-inducing weight gain: the bulk drugs and the prescription 1-4 are tabletted by self, a commercially available reference preparation is placed for 24 hours at the temperature of 25 ℃/75% to determine the moisture-wicking weight gain, and the moisture-wicking weight gain results are shown in the following table 1-3:

tables 1-3 moisture-wicking weight gain results

Item	Raw material medicine	Prescription 1	Prescription 2	Prescription 3	Prescription 4	Reference commercially available
							0 day weight (g)	3.000	3.030	3.000	3.010	3.010	3.010
Weight (g) after 24h	3.600	3.060	3.078	3.100	3.280	3.203
							Wet induced weight gain (%)	20.00	0.99	2.60	3.00	8.97	6.41

From the moisture-attracting weight-increasing result, the moisture-attracting property of the raw material drug is extremely strong (the moisture-attracting weight is increased by 10%), and the moisture-attracting property of the tablet prepared by adding the lubricant is obviously reduced. In the experimental process, the formula 4 and a commercially available reference have obvious moisture absorption phenomenon, and water stains obviously adhere to the surface of the tablet after the tablet is placed for 24 hours at the temperature of 25 ℃/75% RH; but the appearance of the prescription 1-3 is not changed, and the hardness of the tablet is basically unchanged. Compared with the bulk drug, the prescription 4 and the reference preparation sold in the market, the lubricant participating in wet granulation can effectively reduce the hygroscopicity of the tablet and prevent the tablet from absorbing moisture and softening in the process of placing, wherein the prescription of selecting the lubricant from magnesium stearate has the best effect.

Example 2 Hydroxychloroquine sulfate 200mg specification (bulk drug with different particle size)

The hydroxychloroquine sulfate tablets are prepared by adopting the raw material medicines with different particle sizes according to the formula proportion in the table 2-1 and the preparation steps in the example 1, the self-made samples are respectively placed under the high humidity (25 ℃/75% RH) condition for 7 days, and the dissolution curve results of the medicines are measured as the following table 2-2:

TABLE 2-1

Determination of dissolution curve: the prepared hydroxychloroquine sulfate tablet is placed under high humidity condition, and the dissolution curves of 0 day and 7 days are respectively measured under the dissolution condition of pH1.0/75rpm, and the measured results are shown in the following table 2-2:

TABLE 2-2PH1.0-75rpm dissolution curves (% units)

When the particle size of the raw material medicine D90 is controlled to be 80-160 μm, the dissolution rate of the prepared tablet is fastest, and when the particle size of the raw material medicine D90 is below 80 μm or above 200 μm, the dissolution rate is obviously reduced.

EXAMPLE 3 Hydroxychloroquine sulfate 200mg specification (different Filler compositions)

According to the recipe information of table 3-1 and the preparation procedure of example 1, hydroxychloroquine sulfate tablets were prepared in different combinations of fillers in the recipe:

TABLE 3-1 prescription information

Determination of dissolution curve: the hydroxychloroquine sulfate tablets prepared according to the formulas 8 to 10 are subjected to dissolution curve measurement under the condition of PH1.0-75rpm, and the measured data are shown in the following table 3-2:

TABLE 3-2PH1.0-75rpm dissolution curves (% units)

The results show that the combination of bulking agent with corn starch and lactose dissolves most rapidly and closely to the commercial raw mill, and that RSD is smaller than the commercial raw mill.

EXAMPLE 4 Hydroxychloroquine sulfate tablets of 200mg size (different ratio of lactose to starch)

Granules were prepared according to the recipe 4-1 and the preparation steps (1) to (3) of example 1. The prepared granules are tested for hygroscopicity according to the guiding principle of hygroscopicity test of medicines of No. 4 9103 in the pharmacopoeia of the people's republic of China 2020 edition, and the prescription information and the measurement results of hygroscopicity and weight gain are shown in the following tables 4-1 and 4-2:

TABLE 4-1 prescription information

TABLE 4-2 determination of moisture-wicking weight gain

Item	Prescription 1	Prescription 9	Prescription 11	Prescription 12
					0 day weight (g)	3.030	3.015	3.022	3.031
Weight (g) after 24h	3.060	3.077	3.143	3.219
					Moisture wicking weight gain (%)	0.99	2.06	4.00	6.20

The result shows that when the ratio of lactose to corn starch in the formula is 0.5-2.0, the hygroscopicity of the granules is low; when the ratio is 3.0, the hygroscopicity of the particles is drastically increased.

Meanwhile, when the lactose: when the ratio of the corn starch is 3.0, the phenomenon that particles are formed into balls and adhered to a cutter can occur in the preparation process, and the feasibility of the wet granulation process can be influenced by the excessively high lactose ratio.

EXAMPLE 5 Hydroxychloroquine sulfate tablets of 200mg size (different binders)

Hydroxychloroquine sulfate tablets were prepared in accordance with the prescription information of Table 5-1 and the preparation procedure of example 1; the tablets obtained by the above preparation were left to stand at a high humidity (25 ℃ C./75% RH) for 7 days, and the dissolution curves of the tablets were measured at a pH of 1.0 to 75rpm for 0 day and 7 days, and the results are shown in tables 5 to 2:

TABLE 5-1 prescription information

TABLE 5-2PH1.0-75rpm dissolution curves

The results show that: when the adhesive is corn starch slurry, the dissolution curve of the self-made tablet is more stable than that of other formulas and the original research, and the dissolution after the self-made tablet is placed for 7 days under high humidity is obviously faster than that of the original research.

From the above examples 1 to 5, we show that we successfully prepare hydroxychloroquine sulfate tablets with stable granulation process, low hygroscopicity and good dissolution curve stability by using the lubricant in wet granulation.

The above-mentioned embodiments are merely exemplary embodiments for fully illustrating the present invention, and the scope of the present invention is not limited to the above-mentioned embodiments, but defined by the contents of the claims. All matters disclosed in the specification including the abstract and all methods and steps disclosed herein may be combined in any combination, except combinations where the features and/or steps are mutually exclusive. Each feature disclosed in this specification, including the abstract, can be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features. Those skilled in the art should also realize that such equivalent substitutions and alterations can be made without departing from the spirit and scope of the present invention. Such modifications are also intended to be within the scope of the present invention. Each reference cited in this application is incorporated herein in its entirety.

Claims (4)

1. A preparation method of hydroxychloroquine sulfate tablets, which is characterized in that a) raw material medicines, a lubricant and other pharmaceutically acceptable auxiliary materials are jointly subjected to wet granulation; b) compressing the final granules into tablets and coating; the particle size D90 of the hydroxychloroquine sulfate bulk drug is 80-160 μm; the other pharmaceutically acceptable auxiliary materials comprise a filler, a bonding agent and a disintegrating agent; the filler is the combination of lactose and corn starch, and the lactose: the weight ratio of the corn starch is between 0.5 and 2.0; the adhesive is corn starch slurry.

2. The method for preparing hydroxychloroquine sulfate tablets of claim 1, wherein said lubricant is selected from one or more of magnesium stearate, talc, and sodium fumarate stearate.

3. The method for preparing hydroxychloroquine sulfate tablets as claimed in claim 2, wherein said lubricant is magnesium stearate.

4. The preparation method of hydroxychloroquine sulfate tablet as claimed in any one of claims 1 to 3, which comprises the following specific steps:

(1) placing corn starch for preparing slurry in a slurry preparation container, wetting with a small amount of cold water, quickly pouring boiling water, stirring uniformly, standing and cooling to room temperature;

(2) premixing: pouring the hydroxychloroquine sulfate raw material medicine, the internally added part of the lubricant and other auxiliary materials into a wet granulator, and uniformly mixing;

(3) and (3) wet granulation: adding the corn starch slurry into a granulator for granulation, drying the soft material by using a fluidized bed, stopping drying when the drying weight loss of the granules is below 2.0%, and then granulating the dried granules by using a granulator;

(4) mixing the granules prepared in the step (3) with an additional lubricant for 3min, and tabletting;

(5) and (4) preparing the tablets prepared in the step (4) into coated tablets by using a gastric-soluble coating material.