CN110314234B - Rosuvastatin calcium resin complex and composition thereof - Google Patents

Rosuvastatin calcium resin complex and composition thereof Download PDF

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CN110314234B
CN110314234B CN201910212554.0A CN201910212554A CN110314234B CN 110314234 B CN110314234 B CN 110314234B CN 201910212554 A CN201910212554 A CN 201910212554A CN 110314234 B CN110314234 B CN 110314234B
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rosuvastatin calcium
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mannitol
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CN110314234A (en
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石添香
李雪
黄心
游劲松
黄芳芳
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Sunshine Lake Pharma Co Ltd
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Guangdong HEC Pharmaceutical
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Abstract

The invention provides a rosuvastatin calcium resin compound and a composition thereof, wherein the resin compound contains rosuvastatin calcium and anion exchange resin. The rosuvastatin calcium resin complex of the present invention can completely mask the bitter taste of rosuvastatin calcium. The composition prepared from the rosuvastatin calcium resin compound and pharmaceutically acceptable auxiliary materials has the advantages of high stability, good taste, high patient acceptability and the like.

Description

Rosuvastatin calcium resin complex and composition thereof
Technical Field
The invention relates to the field of medicines, in particular to a rosuvastatin calcium resin compound and a composition thereof.
Background
Rosuvastatin calcium is an HMG CoA reductase inhibitor which reduces cholesterol synthesis and also increases low density lipoprotein receptor synthesis by selectively inhibiting HMG-CoA reductase, a rate limiting enzyme in cholesterol synthesis in vivo, and as a result, reduces blood cholesterol and low density lipoprotein cholesterol levels in the liver, for the treatment of incipient hyperlipidemia, heterozygous dyslipidemia, hypertriglyceridemia, and the like. The rosuvastatin calcium dosage forms on the market at present are tablets, capsules and orally disintegrating tablets.
Hyperlipidemia is a chronic disease, and patients need to take the medicine for a long time, so that the taste of the medicine has great influence on the compliance of the patients to take the medicine. The elderly are the most frequent people with hyperlipidemia, and a common problem with their administration is dysphagia. In the rosuvastatin calcium preparation on the market at present, although tablets and capsules have no bad taste, the tablets and capsules need to be swallowed by whole tablets (granules), and the difficulty is high for patients with dysphagia; orally disintegrating tablet can be rapidly disintegrated in oral cavity, and is easy to swallow, but only Japanese salt wild drug product is marketedOD tables, which can taste a pronounced bitter taste, are relatively unacceptable to patients.
Therefore, developing a composition of rosuvastatin calcium that has good taste and no dysphagia to improve patient compliance is a key issue to be addressed by drug developers.
Disclosure of Invention
Summary of The Invention
In a first aspect of the present invention, there is provided a rosuvastatin calcium resin complex which can completely mask the bitter taste of rosuvastatin calcium.
The rosuvastatin calcium resin compound provided by the invention comprises the following components: rosuvastatin calcium and anion exchange resin.
In some embodiments, the anion exchange resin contained in the rosuvastatin calcium resin complex is selected from the group consisting of strong base anion resins, weak base anion resins, or mixtures thereof, such as commercially available anion resins having the DUOLITE AP series,IRA series.
In some implementations, the weight ratio of rosuvastatin calcium to anion exchange resin of the rosuvastatin calcium resin complex is 1:0.5-1:10. Within the proportion range, the compound can better or completely cover the bitter taste of rosuvastatin calcium, and has suitable economic cost.
In some embodiments, the weight ratio of rosuvastatin calcium to anion exchange resin of the rosuvastatin calcium resin complex is 1:1-1:7, and within this ratio range, the complex can better or completely mask the bitter taste of rosuvastatin calcium, and the economic cost is more suitable.
In some implementations, the weight ratio of rosuvastatin calcium to anion exchange resin of the rosuvastatin calcium resin complex is 1:2.5-1:5, and in the range of the ratio, the complex can better or completely mask the bitter taste effect of rosuvastatin calcium, and the economic cost is more suitable.
In some embodiments, the rosuvastatin calcium resin complex provided by the invention is composed of rosuvastatin calcium and anion exchange resin.
In a second aspect of the invention, a preparation method of a rosuvastatin calcium resin compound is provided, and the preparation method of the resin compound is simple and feasible and can be industrially produced.
The preparation method of the rosuvastatin calcium resin compound is characterized in that rosuvastatin calcium and anion exchange resin are dispersed in water to form suspension, and the suspension is stirred, filtered and dried to obtain the rosuvastatin calcium resin compound.
In some embodiments, the method for preparing the rosuvastatin calcium resin compound comprises dispersing rosuvastatin calcium in water at room temperature, adding ion exchange resin, stirring for 0.25-8 h, filtering, and drying to obtain rosuvastatin calcium resin compound.
In some embodiments, the method for preparing the rosuvastatin calcium resin compound comprises dispersing rosuvastatin calcium in water at room temperature, adding ion exchange resin, stirring for 2 hours, filtering, and drying to obtain the rosuvastatin calcium resin compound.
In a third aspect of the invention, a composition containing rosuvastatin calcium resin complex is provided, which has the advantages of rapid disintegration, high stability, good taste, high patient acceptability and the like.
In some embodiments, the composition comprising rosuvastatin calcium resin complex further comprises pharmaceutically acceptable excipients selected from fillers, disintegrants, flavoring agents, stabilizers, lubricants or mixtures thereof; wherein the filler and the medicine are stable in compatibility, so that the preparation process is easy to form, and the prepared composition is easy to disintegrate; the disintegrating agent breaks the composition into a plurality of fine particles from a whole block to realize disintegration, thereby facilitating the dissolution and absorption of the main drug in the composition; the addition of the flavoring agent enables the taste of the composition to be fragrant and sweet; the stabilizer ensures better stability of active ingredients in the composition, prolongs the shelf life of the composition, reduces the friction force among particles, improves the particle flow and is beneficial to uniform distribution of medicines.
In some embodiments, the weight ratio of rosuvastatin calcium to anion exchange resin in the composition of rosuvastatin calcium resin complex is 1:0.5-1:10 or 1:1-1:7 or 1:2.5-1:5. The composition prepared by adopting the proportion range can better or completely cover bad taste, and has good disintegration and release.
In some embodiments, the rosuvastatin calcium resin complex in the composition is 5-65% by weight based on the total weight of the composition, such that the volume of the composition is moderate for convenient administration to a patient.
In some embodiments, the filler is present in the composition in an amount of 5 to 70 weight percent, the disintegrant is present in an amount of no more than 30 weight percent, the flavoring agent is present in an amount of no more than 6 weight percent, the stabilizer is present in an amount of no more than 5 weight percent, and the lubricant is present in an amount of no more than 2 weight percent, based on the total weight of the composition. The composition prepared by the proportion range can completely cover bad taste, has good disintegration and release, has moderate volume and is convenient for patients to take.
In some embodiments, the filler in the composition is selected from microcrystalline cellulose, mannitol, sorbitol, lactose, pregelatinized starch, calcium sulfate, dibasic calcium phosphate, or a mixture thereof.
In some embodiments, the disintegrant in the composition is selected from magnesium aluminum silicate, dry starch, microcrystalline cellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, or a mixture thereof.
In some embodiments, the flavoring agent in the composition is selected from the group consisting of flavor, aspartame, acesulfame potassium, steviol glycosides, sucrose, sucralose, sodium saccharin, cyclamate, fructose, xylitol, or mixtures thereof.
In some embodiments, the stabilizer in the composition is selected from bicarbonate, carbonate, tribasic phosphate, citrate, or a mixture thereof.
In some embodiments, the lubricant in the composition is selected from talc, magnesium stearate, stearic acid, colloidal silicon dioxide, mineral oil, wax, sodium stearyl fumarate, glyceryl behenate, polyethylene glycol, hydrogenated vegetable oil, or mixtures thereof.
In some embodiments, the filler in the composition is selected from microcrystalline cellulose, mannitol, sorbitol, lactose, pregelatinized starch, calcium sulfate, dibasic calcium phosphate, or a mixture thereof; the disintegrating agent is selected from magnesium aluminum silicate, dry starch, microcrystalline cellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose or a mixture thereof; the flavoring agent is selected from essence, aspartame, acesulfame potassium, stevioside, sucrose, sucralose, saccharin sodium, sodium cyclamate, fructose, xylitol or mixture thereof; the stabilizer is selected from bicarbonate, carbonate, tribasic phosphate, citrate or a mixture thereof; the lubricant is selected from talcum powder, magnesium stearate, stearic acid, colloidal silicon dioxide, mineral oil, wax, sodium stearate fumarate, glyceryl behenate, polyethylene glycol, hydrogenated vegetable oil or a mixture thereof.
In some embodiments, the composition comprises 57.87% by weight rosuvastatin calcium resin complex, 21.63% by weight mannitol, 15.00% by weight low substituted hydroxypropyl cellulose, 2.00% by weight sucralose, 2.00% by weight sodium bicarbonate, 1.00% by weight magnesium stearate, and 0.50% by weight perfume, based on the total weight of the composition.
In some embodiments, the composition comprises 36.23 wt% rosuvastatin calcium resin complex, 20.27 wt% mannitol, 30.00 wt% microcrystalline cellulose, 8.00 wt% croscarmellose sodium, 2.00 wt% sucralose, 2.00 wt% sodium bicarbonate, 1.00 wt% magnesium stearate, and 0.50 wt% flavoring, based on the total weight of the composition.
In some embodiments, the composition comprises 27.59% by weight rosuvastatin calcium resin complex, 33.91% by weight mannitol, 22.00% by weight anhydrous dibasic calcium phosphate, 10.00% by weight sodium carboxymethyl starch, 5.00% by weight aspartame, 1.00% by weight magnesium stearate, and 0.50% by weight essence, based on the total weight of the composition.
In some embodiments, the composition comprises 16.22 wt.% rosuvastatin calcium resin complex, 38.28 wt.% mannitol, 15.00 wt.% microcrystalline cellulose, 15.00 wt.% aluminum magnesium silicate, 10.00 wt.% crospovidone, 2.00 wt.% aspartame, 2.00 wt.% sodium bicarbonate, 1.00 wt.% magnesium stearate, and 0.50 wt.% essence, based on the total weight of the composition.
In some embodiments, the composition comprises rosuvastatin calcium resin compound in an amount of 7.08 wt%, mannitol in an amount of 44.92 wt%, microcrystalline cellulose in an amount of 21.00 wt%, crospovidone in an amount of 20.00 wt%, sodium citrate in an amount of 1.00 wt%, sodium saccharin in an amount of 4.00 wt%, magnesium stearate in an amount of 1.00 wt%, and flavoring in an amount of 1.00 wt%, based on the total weight of the composition.
In some embodiments, the composition is obtained by direct compression of a powder. The powder direct tabletting process is adopted, the method is simple, and the prepared tablet disintegrates fast.
In some embodiments, the composition is an oral formulation that is capable of completely masking bad taste and releases well.
In some embodiments, the composition is an orally disintegrating tablet, granule, dry suspension, or suspension that is capable of completely masking the bad taste and releases well.
In a fourth aspect, the present invention provides the use of a composition of rosuvastatin calcium resin complex in the preparation of a medicament for the treatment of primary hypercholesterolemia or mixed dyslipidemia.
Definition of terms
The term "Smartseal 30D" refers to a copolymer dispersion of methyl methacrylate and diethylaminoethyl methacrylate.
The term "Uttky E" refers to aminoalkyl methacrylate copolymer E.
The term "room temperature" means a temperature of about 15 ℃ to 32 ℃ or about 20 ℃ to 30 ℃ or about 23 ℃ to 28 ℃ or about 25 ℃.
In the present invention, DEG C represents degrees Celsius, mg represents milligrams, mL represents milliliters, μL represents microliters, s represents seconds, min represents minutes, h represents hours, rpm represents revolutions per minute, nm represents nanometers, μm represents micrometers, and mm represents millimeters.
Drawings
FIG. 1 is a flow chart of detection of an electronic tongue.
Detailed Description
In order to better understand the technical solution of the present invention, the following non-limiting examples are further disclosed for further details of the present invention.
The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
In the examples below, the proportions are calculated as weight proportions.
EXAMPLE 1 preparation of resin composite
Table 1 preparation of rosuvastatin calcium-ion exchange resin complexes in different ratios
Sample of Medicine-resin ratio
Drug resin composite 1 1:10
Drug resin composite 2 1:7
Drug resin composite 3 1:5
Drug resin composite 4 1:2.5
Drug resin composite 5 1:1
Drug resin composite 6 1:0.5
The preparation method comprises the following steps: at room temperature, rosuvastatin calcium was dispersed in water, then ion exchange resins (resin type: duolite AP143 1096) were added according to different proportions according to Table 1, stirred for 2 hours, filtered, and dried at 45 ℃.
Example 2
Table 2 example 2 prescription information table
The preparation method comprises the following steps: mixing the medicinal resin compound 1 with sucralose, sodium bicarbonate, essence and low-substituted hydroxypropyl cellulose for 10min, adding mannitol, mixing for 10min, adding magnesium stearate, mixing for 5min, and tabletting.
Example 3
Table 3 example 3 prescription information table
Prescription composition Prescription proportion (%)
Drug resin composite 2 36.23
Mannitol (mannitol) 20.27
Microcrystalline cellulose 30.00
Croscarmellose sodium 8.00
Sucralose 2.00
Sodium bicarbonate 2.00
Magnesium stearate 1.00
Essence 0.50
Totals to 100.00
The preparation method comprises the following steps: mixing the drug resin compound 2 with sucralose, sodium bicarbonate, essence and croscarmellose sodium for 10min, adding microcrystalline cellulose, mixing for 10min, adding mannitol, mixing for 10min, adding magnesium stearate, mixing for 5min, and tabletting.
Example 4
Table 4 example 4 prescription information table
The preparation method comprises the following steps: mixing the drug resin compound 3 with aspartame, essence and sodium carboxymethyl starch for 10min, adding anhydrous calcium hydrophosphate for 10min, adding mannitol for 10min, adding magnesium stearate for 5min, and tabletting.
Example 5
Table 5 example 5 prescription information table
Prescription composition Prescription proportion (%)
Drug resin composite 4 16.22
Mannitol (mannitol) 38.28
Microcrystalline cellulose 15.00
Magnesium aluminum silicate 15.00
Crosslinked povidone 10.00
Aspartame 2.00
Sodium bicarbonate 2.00
Magnesium stearate 1.00
Essence 0.50
Totals to 100.00
The preparation method comprises the following steps: mixing the drug resin compound 4 with aspartame, sodium bicarbonate, essence and crospovidone for 10min, adding microcrystalline cellulose and aluminum magnesium silicate for 10min, adding mannitol for 10min, adding magnesium stearate for 5min, and tabletting.
Example 6
Table 6 example 6 prescription information table
The preparation method comprises the following steps: mixing the drug resin compound 5 with aspartame, sodium bicarbonate, essence and crospovidone for 10min, adding microcrystalline cellulose and aluminum magnesium silicate for 10min, adding mannitol for 10min, adding magnesium stearate for 5min, and tabletting.
Example 7
Table 7 example 7 prescription information table
Prescription composition Prescription proportion (%)
Drug resin composite 6 7.08
Mannitol (mannitol) 44.92
Microcrystalline cellulose 21.00
Crosslinked povidone 20.00
Sodium citrate 1.00
Saccharin sodium salt 4.00
Magnesium stearate 1.00
Essence 1.00
Totals to 100.00
The preparation method comprises the following steps: mixing the medicinal resin compound 6 with saccharin sodium, sodium citrate, essence and crosslinked povidone for 10min, adding microcrystalline cellulose, mixing for 10min, adding mannitol, mixing for 10min, adding magnesium stearate, mixing for 5min, and tabletting.
Example 8
Preparation of orally disintegrating tablets by spray-drying coating, the prescription information is shown in Table 8
Table 8 example 8 information table
The preparation method comprises the following steps: adding rosuvastatin calcium into Smartseal 30D suspension, stirring and dispersing; then spray drying the suspension to obtain spray-dried particles; mixing the spray-dried granules with sodium bicarbonate, sucralose and crospovidone for 10min, adding mannitol and mixing for 10min, adding magnesium stearate and mixing for 5min, and tabletting the total mixture to obtain the final product.
Example 9
Preparation of orally disintegrating tablets by coating micropill, the prescription information is shown in Table 9
Table 9 example 9 information table
Prescription composition Prescription proportion (%)
Microcrystalline cellulose pill core 12.15
Rosuvastatin calcium 3.25
Sodium bicarbonate 0.16
Talc powder 1.45
Povidone 0.70
Equiz E type 0.64
Talc powder 0.19
Sodium dodecyl sulfate 0.06
Mannitol (mannitol) 54.40
Microcrystalline cellulose 10.00
Crosslinked povidone 15.00
Aspartame 1.00
Magnesium stearate 1.00
Totals to 100.00
The preparation method comprises the following steps:
preparing a suspension of a medicine applying layer: and adding povidone, rosuvastatin calcium, sodium bicarbonate and talcum powder into isopropanol, and uniformly dispersing for later use.
Preparing a taste masking layer suspension: dissolving Eudragit E type in 50% ethanol solution, adding sodium dodecyl sulfate, dissolving, adding pulvis Talci, and dispersing uniformly.
Preparing a drug-containing pellet: adding blank microcrystalline cellulose pill core into fluidized bed, spraying suspension of upper drug layer, and drying.
Preparing taste-masking pellets: adding the drug-containing pellets into a fluidized bed by using a pellet coating process, spraying taste-masking layer suspension, and drying.
Mixing the prepared taste-masking micropill with other adjuvants, and tabletting.
Example 10
Preparation of orally disintegrating tablets by fluidized bed granule coating, the prescription information is shown in Table 10
Table 10 example 10 side information table
Prescription composition Prescription proportion (%)
Rosuvastatin calcium 2.60
Anhydrous calcium hydrogen phosphate 26.00
Povidone 0.46
Equiz E type 2.97
Sodium dodecyl sulfate 0.30
Stearic acid 0.44
Talc powder 1.48
Mannitol (mannitol) 30.75
Magnesium aluminum silicate 10.00
Sodium bicarbonate 2.00
Crosslinked povidone 20.00
Sucralose 2.00
Magnesium stearate 1.00
Totals to 100.00
The preparation method comprises the following steps:
preparing taste masking suspension: adding sodium dodecyl sulfate into purified water under stirring, adding stearic acid and Eudragit E, stirring, homogenizing for 30min, adding pulvis Talci, and homogenizing for 15 min.
Wet granulating rosuvastatin calcium and anhydrous calcium hydrophosphate and povidone with purified water, drying, granulating, and coating the granule after granulating with the taste masking suspension to obtain the taste masking granule. Mixing the taste-masking granule with other adjuvants, and tabletting.
Example 11
Orally disintegrating tablets are prepared by adding flavoring agents, and the prescription information is shown in Table 11
Table 11 example 11 prescription information table
The preparation method comprises the following steps: firstly, mixing rosuvastatin calcium with sucralose, micro-powder silica gel, magnesium oxide, mannitol and low-substituted hydroxypropyl cellulose for 5min, then adding microcrystalline cellulose for mixing for 10min, then adding anhydrous calcium hydrophosphate for mixing for 10min, and finally adding magnesium stearate for mixing for 5min. Tabletting the total mixture to obtain the final product.
Example 12
Preparation of orally disintegrating tablets by wet granulation, the prescription information is shown in Table 12
Table 12 example 12 side information table
The preparation method comprises the following steps: preparing wet granules of rosuvastatin calcium, mannitol and aluminum magnesium silicate with Smartseal 30D suspension, drying, granulating, mixing the obtained dry granules with sucralose, sodium bicarbonate and crospovidone for 10min, adding mannitol, mixing for 10min, adding magnesium stearate, mixing for 5min, and tabletting to obtain the final product.
1. Disintegration assay
The tablets of examples 2 to 12 and the commercially available rosuvastatin calcium orally disintegrating tablet (manufacturer: salt field pharmaceutical Co., ltd.) were measured by using a method of measuring disintegration in China pharmacopoeia of 2015 edition, and the measurement results are shown in Table 13:
table 13 table of relative distances between tablets, examples 2-12, commercially available rosuvastatin calcium orally disintegrating tablets and reference
The above-mentioned disintegrating results show that the resin composite of the present invention has a remarkable disintegrating advantage after tabletting, compared with other examples, and has an excellent disintegrating effect with an average disintegrating time limit of not more than 40s in the disintegrating basket.
Examples 2,5,7-12, commercially available rosuvastatin calcium orally disintegrating tablets were taste masked with 2 manufacturer's electronic tongues, respectively, and 10 volunteers were recruited for taste evaluation.
2. Electronic tongue taste masking detection 1
Experimental instrument: model number of taste analysis system of INSENT, japan: TS-5000Z; sensor AN0 (B-bitterless 2)
Reagents for experiments: reference solution (near odorless): 30mM KCl+0.3mM tartaric acid; negative electrode cleaning liquid: water + ethanol + HCl;
positive electrode cleaning liquid: KCl+water+ethanol+KOH
The sample treatment method comprises the following steps: 10 tablets of examples 2,5,7-12 were taken, and commercially available rosuvastatin calcium orally disintegrating tablets (manufacturer: salt field pharmaceutical Co., ltd.) were put into a beaker (37 ℃ C.) containing 160mL of warm water, respectively, stirred for 60 seconds by a magnetic stirrer, and then the samples were centrifuged at 3000rpm for 3 minutes, and the supernatant was taken and tested, and the measurement flow is shown in FIG. 1.
Measurement results:
TABLE 14 electronic tongue bitterness value test results
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When the taste value is greater than 0, a bitter taste is indicated, and the greater the number, the greater the bitter taste. When the taste value is 0 or less, no bitter taste is indicated.
From the table, the various tablets differed significantly in terms of basic bitter taste, with the bitter taste of the tablets of examples 2,5,7 being negative, it was seen that the three formulations were non-bitter, the tablets of examples 11-12, the commercially available rosuvastatin calcium orally disintegrating tablets were more bitter, followed by the tablets of examples 8-10.
The above results indicate that the compositions prepared using the resin composite have the best taste masking effect and can completely mask the bitter taste, while other examples cannot completely mask the bitter taste. The composition prepared by using the resin compound has better taste masking effect than the commercially available simvastatin calcium orally disintegrating tablets.
3. Electronic tongue taste masking detection 2
Experimental instrument: french Alpha MOS company electronic tongue, model: an Astree; the sensors include SRS, GPS, STS, UMS, SPS, SWS, BRS and 7 sensors.
The sample treatment method comprises the following steps: taking 3 tablets of examples 2,5 and 7-12, respectively dissolving commercially available rosuvastatin calcium orally disintegrating tablets (manufacturer: salt field pharmaceutical Co., ltd.) in 50mL distilled water, stirring for 1min, centrifuging at 3000rpm for 3min, taking supernatant, and placing in a special beaker (25 mL) for testing; reference solution: weighing 15mg of rosuvastatin calcium raw material medicine, dissolving in 50mL of distilled water, stirring for 1min, centrifuging at 3000rpm for 3min, taking supernatant, and placing in a beaker (25 mL) special for electronic tongue to be tested;
the treated samples were directly placed in beakers dedicated to electronic tongue for analysis, each sample was repeated 9 times during the experiment under the following conditions:
sample volume: 25mL; sample collection time: 120s; each analysis time: 180s;
measurement results:
table 15 examples 2,5,7-12, relative distance between commercially available rosuvastatin calcium orally disintegrating tablets and reference
Table 15 shows the relative distances between the commercially available rosuvastatin calcium orally disintegrating tablets of examples 2,5,7 to 12 and the reference (rosuvastatin calcium drug substance), and in the principal component analysis, the farther the distance between the examples and the reference, the better the taste of the tablet, and the closer the relative distance between the samples, the closer the taste of the sample.
The relative distance from the reference from the table above is from far to near: example 2 > example 5 > example 7 > example 9 > example 10 > example 8 > example 12 > example 11 > commercially available rosuvastatin calcium orally disintegrating tablets. That is, the reference product had the greatest bitter taste, and example 2 was furthest from the reference product with the least bitter taste. The results indicate that the taste masking effect of the formulations prepared using the resin composite is superior to other techniques.
Summary of electronic tongue taste masking detection:
from the analysis of the above 2 groups of electronic tongue data, it is known that the composition prepared by using the resin composition has the best taste masking effect, and can better or completely mask the bitter taste, namely, has excellent taste masking effect when the weight ratio of rosuvastatin calcium to anion exchange resin is 1:0.5-1:10.
4. Volunteer taste evaluation
Sample testing method: volunteers rinsed 2 times with 30mL of purified water, then placed the example sample on the tongue, moistened with saliva and lightly pressed with tongue for 60s, and performed a single time (30 s) of head-raising motion during which the bitter taste feeling areas of the tongue root and tongue side were allowed to feel the bitter taste of the drug. After 60s, the mixture was discharged, rinsed 5 times until no bitter taste was observed in the oral cavity, and after 30min, another example was measured.
Evaluation criteria: the volunteers scored for bitterness based on taste results on the following criteria, with each example score taking the average of the scores of 10 volunteers.
Table 16 taste evaluation criteria
Table 17 results of evaluation of mouth taste of volunteers
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The results show that examples 2-7 were both bitter and aftertaste after rinsing, with the values being greater, i.e. the bitter was least pronounced, the taste masking effect was better than the other examples, and the taste results matched the electronic tongue data.
5. Dissolution detection
The drug is released in the mouth, contacts with the taste buds, and causes the person to feel bitter. Therefore, the dissolution rate of the medicine, particularly the dissolution rate after the tablet is disintegrated, directly affects the taste. The dissolution rate of the tablets of examples 2 to 12 and the commercially available rosuvastatin calcium orally disintegrating tablet (manufacturer: salt wild pharmaceutical Co., ltd.) was measured for 1min by the following method in the present invention, and the dissolution rate was compared.
Dissolution detection instrument and detection method
HPLC instrument model: agilent 1260;
chromatographic conditions: the detection wavelength is UV 290nm; the chromatographic column adopts Kromasil C18,4.6mm×100mm,5 μm; the flow rate is 1.0mL/min; the column temperature is 30 ℃; the sample injection amount is 10 mu L; the run time was 3min.
The tablets of examples 2-12, commercially available rosuvastatin calcium orally disintegrating tablets, were each put into 50mL volumetric flasks, added to 10mL of purified water, and shaken for 1min using a shaking flask apparatus. The dispersed tablet powder solution was collected, filtered through a filter (PES, 0.45 μm,) Filtering, removing the primary filtrate, taking the subsequent filtrate to prepare a sample solution, and performing HPLC test.
Table 18 determination of dissolution results for tablets, commercially available rosuvastatin calcium orally disintegrating tablets of examples 2-12
The dissolution results show that the tablets of examples 2-6 of the present invention do not have a dissolution of more than 6% after shaking in 10mL of purified water for 60s, and the tablets of example 7 have a slightly higher dissolution of 26.9% but significantly lower dissolution than the other examples. The drug is less released in the purified water, and the drug is less contacted with taste buds in the oral cavity, so the taste masking effect is better.
In addition, 1 tablet of the tablet of example 5 and commercially available rosuvastatin calcium orally disintegrating tablet of the present invention was respectively put into 900mL of 0.1N hydrochloric acid medium, and dissolution test was performed using a DISTSK 6300 dissolution apparatus using USPI (i.e., basket method described in United states pharmacopoeia) at 100 rpm. At the time points of 5, 10, 15, 20, 30, and 60min, 2mL of the sample was taken at any position 10mm from the inner wall of the release cup at the middle part of the liquid, and the sample was filtered with a filter membrane (polyethersulfone, 0.45μm，Totem) was filtered to remove 2mL of the primary filtrate, and the subsequent filtrate was taken and subjected to HPLC test for each of the two filtrates. 3 parts were measured in parallel.
HPLC instrument model: agilent 1260;
chromatographic conditions: the detection wavelength is UV 240nm; the chromatographic column adopts Kromasil C18,4.6mm×100mm,5 μm; the flow rate is 1.0mL/min; the column temperature is 30 ℃; the sample injection amount is 20 mu L; the run time was 3min.
Table 19 determination of the dissolution results of the tablets, commercially available rosuvastatin calcium orally disintegrating tablets of example 5
The dissolution result of the hydrochloric acid medium shows that the release amount of the tablet in the embodiment of the invention in hydrochloric acid for 15min is more than 85%, and the tablet is consistent with the release behavior of the commercially available rosuvastatin calcium orally disintegrating tablet and shows quick dissolution. The tablet provided by the embodiment of the invention can mask taste in the oral cavity and does not influence normal release of the tablet in gastric juice, so that the applicability of a patient is improved, and the exertion of the drug effect is not influenced.
6. Stability quality assessment
The tablets of example 5 of the present invention were subjected to double aluminum blister packaging, and the substances related to 6 months long and 6 months acceleration were examined, and the results are shown in table 20:
table 20 stability results
As shown by the stability test results, the orally disintegrating tablet prepared in the embodiment 5 of the invention has no increase of substances related to long-term 6 months and acceleration 6 months, and has stable quality.
From the above 6 results, it is clear that the oral preparation obtained by the technique of the present invention can completely mask the bitter taste, and has obvious advantages compared with the commercial reference preparation. Meanwhile, the oral preparation obtained by the technology has excellent disintegration property and excellent stability, and meets the requirement of the preparation. The technology of the invention can improve the administration taste of patients, increase the administration compliance and has important significance for improving the life quality of the patients.
While the methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and combinations of the methods and applications described herein can be made and applied within the spirit and scope of the invention. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present invention.

Claims (8)

1. A composition, characterized in that the composition consists of a rosuvastatin calcium resin compound and pharmaceutically acceptable excipients, wherein the rosuvastatin calcium resin compound is: the rosuvastatin calcium and anion exchange resin are of a DUOLITE (TM) AP series, the model of the DUOLITE (TM) AP series is Duolite AP143 1096, and the weight ratio of the rosuvastatin calcium to the anion exchange resin is 1:0.5-1:10; the pharmaceutically acceptable auxiliary materials are selected from filling agents, disintegrating agents, flavoring agents, stabilizing agents, lubricating agents or mixtures thereof; the preparation method of the rosuvastatin calcium resin compound comprises the following steps: dispersing rosuvastatin calcium and anion exchange resin in water to form suspension, stirring, filtering and drying to obtain rosuvastatin calcium resin compound; the filler is selected from microcrystalline cellulose, mannitol, calcium hydrophosphate or a mixture thereof, the disintegrating agent is selected from aluminum magnesium silicate, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose or a mixture thereof, the flavoring agent is selected from essence, sucralose and saccharin sodium or a mixture thereof, the stabilizer is selected from bicarbonate, citrate or a mixture thereof, and the lubricant is magnesium stearate; based on the total weight of the composition,
the rosuvastatin calcium resin compound is 5 to 65 weight percent,
the filler is 5-70 wt%,
the disintegrant is not more than 30% by weight,
the flavouring agent is not more than 6% by weight,
the stabilizer is not more than 5 wt%,
the lubricant is not more than 2% by weight.
2. The composition of claim 1, wherein the weight ratio of rosuvastatin calcium to the anion exchange resin is 1:2.5 to 1:5.
3. The composition of claim 1, wherein the composition comprises, based on the total weight of the composition,
the rosuvastatin calcium resin complex content was 57.87% by weight,
the mannitol content was 21.63 wt%,
the low-substituted hydroxypropylcellulose content was 15.00% by weight,
the sucralose content was 2.00 wt%,
the sodium bicarbonate content was 2.00 wt%,
the magnesium stearate content was 1.00 wt%,
the perfume content was 0.50 wt%.
4. The composition of claim 1, wherein the composition comprises, based on the total weight of the composition,
the rosuvastatin calcium resin complex content was 36.23% by weight,
mannitol content was 20.27 wt%,
the microcrystalline cellulose content was 30.00 wt%,
the croscarmellose sodium content was 8.00 wt%,
the sucralose content was 2.00 wt%,
the sodium bicarbonate content was 2.00 wt%,
the magnesium stearate content was 1.00 wt%,
the perfume content was 0.50 wt%.
5. The composition of claim 1, wherein the composition comprises, based on the total weight of the composition,
the rosuvastatin calcium resin complex content was 27.59% by weight,
mannitol content was 33.91 wt%,
the anhydrous dibasic calcium phosphate content was 22.00 wt%,
the sodium carboxymethyl starch content was 10.00% by weight,
the magnesium stearate content was 1.00 wt%,
the perfume content was 0.50 wt%.
6. The composition of claim 1, wherein the composition comprises, based on the total weight of the composition,
the rosuvastatin calcium resin complex content was 16.22% by weight,
the mannitol content was 38.28 wt%,
the microcrystalline cellulose content was 15.00 wt%,
the magnesium aluminum silicate content was 15.00 wt%,
the crospovidone content was 10.00% by weight,
the sodium bicarbonate content was 2.00 wt%,
the magnesium stearate content was 1.00 wt%,
the perfume content was 0.50 wt%.
7. The composition of claim 1, wherein the composition comprises, based on the total weight of the composition,
the rosuvastatin calcium resin complex content was 7.08% by weight,
the mannitol content was 44.92 wt%,
the microcrystalline cellulose content was 21.00 wt%,
the crospovidone content was 20.00% by weight,
the sodium citrate content was 1.00 wt%,
the saccharin sodium content was 4.00 wt%,
the magnesium stearate content was 1.00 wt%,
the perfume content was 1.00 wt%.
8. A composition according to any one of claims 1 to 3, wherein the composition is an oral formulation which is an orally disintegrating tablet, granule, dry suspension or suspension.
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