CN112190564A - Compound pellet preparation and preparation method thereof - Google Patents
Compound pellet preparation and preparation method thereof Download PDFInfo
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- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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Abstract
The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a compound pellet preparation and a preparation method thereof. Wherein the compound pellet tablet comprises aspirin pellet and esomeprazole magnesium pellet; the aspirin micropill is obtained by directly coating aspirin recrystallization; the preparation method of the aspirin recrystallization comprises the following steps: (1) dissolving aspirin in acetone, controlling the temperature to be 50-60 ℃, and adding purified water; (2) controlling the temperature to be 50-60 ℃ at the stirring speed of 150-200 rpm, and stirring for 1-2 h; (3) cooling to 40-50 ℃ at a cooling speed of 5-10 ℃/h, and stirring for 2-3 h; (4) then cooling to 10-20 ℃ at a cooling speed of 5-10 ℃/h, and stirring for 4-5 h. The aspirin recrystallization of the invention can be directly coated without crushing and adding auxiliary materials, so that the release of the aspirin is more controllable and can be better matched with other active ingredients.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a compound pellet preparation and a preparation method thereof.
Background
Aspirin is widely applied, is a classic medicament in medical history and is the earliest anti-platelet aggregation medicament in clinical application. However, it often produces nausea, vomiting, epigastric discomfort or pain during use, and may damage the gastric and duodenal mucosa after long-term administration. The proton pump is also called gastric acid pump and can specifically pump H+Pumping into stomach cavity to form strong acid state in stomach. Proton pump inhibitors inactivate the proton pump and thereby inhibit centrally or peripherally mediated gastric acid secretion, and omeprazole is often administered clinically after aspirin.
The esomeprazole is an S-type isomer of omeprazole, and compared with other proton pump inhibitors, the esomeprazole has the lowest variation degree of AUC ratio in strong and weak metabolizers, and AUC is higher than that of racemate omeprazole, so that the esomeprazole has a stronger acid inhibition effect. The esomeprazole magnesium is magnesium salt hydrate of the esomeprazole, and the coordination effect of the aspirin and the esomeprazole magnesium can effectively reduce the occurrence of gastrointestinal adverse reactions when the aspirin is taken to prevent thrombus diseases.
At present, the two medicines are taken separately. However, the peak reaching time of the release concentration of the esomeprazole magnesium in vivo is different, so that the effect of the esomeprazole magnesium for inhibiting the side effect of aspirin is difficult to penetrate through the treatment period all the time. Although this situation can be improved to some extent by staggering the administration time, different manufacturers and manufacturing processes may affect the release pattern of the active ingredient, which makes it difficult to accurately determine how to ensure effective coordination of the two drugs in actual use. Based on the above situation, it is necessary to provide a new method to solve the above problems.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a compound pellet tablet, a compound pellet capsule and a compound suspension granule which can continuously and effectively reduce the probability of gastrointestinal adverse reactions caused by aspirin, simplify the medication scheme and improve the medication compliance of patients.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a compound pellet tablet comprises aspirin pellets and esomeprazole magnesium pellets;
wherein, the aspirin micropills are obtained by directly coating the recrystallized aspirin; the preparation method of the aspirin recrystallization comprises the following steps:
(1) dissolving aspirin in acetone, controlling the temperature to be 50-60 ℃, and adding purified water to obtain an aspirin clear solution, wherein the mass of the acetone is 5-10 times that of the aspirin, and the mass of the purified water is 5-10 times that of the aspirin;
(2) controlling the temperature of the obtained aspirin clear solution at 50-60 ℃ under the condition that the stirring speed is 150-200 rpm, and stirring for 1-2 hours;
(3) then cooling to 40-50 ℃ at a cooling speed of 5-10 ℃/h, and stirring for 2-3 h;
(4) then cooling to 10-20 ℃ at a cooling speed of 5-10 ℃/h, and stirring for 4-5 h.
As is known, aspirin raw material medicines currently supplied on the market are all crystalline powders, but the crystalline powders are not beneficial to use of preparations, and the prepared preparations have poor bioavailability in vivo and influence the drug effect. At present, most of production enterprises generally need to mix aspirin bulk drug and various auxiliary materials (such as filler, adhesive, glidant and the like) to prepare a pill core, and then carry out coating of a coating layer, otherwise, uniform coating is difficult to realize successfully, and the preparation requirement of the product cannot be met. And aspirin is extremely unstable to moist heat, and can produce degradation impurities, and the wet granulation process has adverse effects on the quality of products.
Therefore, a great deal of research shows that after the existing aspirin raw material is subjected to a specific recrystallization process, the crystal form, the uniformity and the granularity of aspirin fine crystals can be effectively controlled, so that the aspirin fine crystals can be directly coated without crushing or additionally adding auxiliary materials. And the release rate of the aspirin pellets prepared by the direct coating process is easier to design and control, and when the aspirin pellets and the esomeprazole magnesium pellets are prepared into the compound pellets together, the compound pellets can well generate a matching effect in the whole medicine taking period, so that the aspirin can well exert the curative effect, the side effect is avoided, and the compliance of patients is improved.
As a preferred crystallization process: the aspirin raw material medicine is dispersed in acetone, heated to a certain temperature under stirring to be dissolved, added with purified water at a certain temperature, stirred for a certain time at a certain stirring speed, cooled to a certain temperature at a certain cooling speed, stirred for a certain time, filtered or centrifuged, and dried to obtain aspirin fine crystals with the particle size range of 200-1000 mu m.
The preparation process comprises the following steps:
(1) dispersing aspirin raw material medicine into acetone, wherein the dosage of the acetone is 5-10 times (weight ratio) of the dosage of aspirin, heating to 50-60 ℃ under stirring to dissolve the aspirin, controlling the temperature to be 50-60 ℃, adding purified water, and the dosage of the purified water is 5-10 times (weight ratio) of the dosage of the aspirin to obtain an aspirin clear solution;
(2) adjusting the stirring speed to 150-200 rpm to obtain an aspirin clear solution, controlling the temperature to be 50-60 ℃, and stirring for 1-2 hours;
(3) then cooling to 40-50 ℃ at a cooling speed of 5-10 ℃/h, and stirring for 2-3 h;
(4) then cooling to 10-20 ℃ at a cooling speed of 5-10 ℃/h, and stirring for 4-5 h;
(5) filtering or centrifuging to obtain fine aspirin crystal wet product;
(6) drying the fine aspirin crystal wet product at 40-50 ℃ in vacuum until the drying weight loss is less than 0.3%;
(7) the obtained fine aspirin crystal raw material has a particle size range of 200-1000 μm, preferably 400-700 μm.
In the present invention, the particle size D90 of the aspirin recrystallization is 200-1000 μm, preferably 400-700 μm, so that the compressed tablet is less prone to cracking after enteric coating.
In the invention, the esomeprazole magnesium pellet comprises a blank pellet core, a drug-containing layer, an isolating layer and an enteric coating layer from inside to outside in sequence; the drug-containing layer comprises esomeprazole magnesium, an adhesive and a stabilizer;
preferably, the particle size D90 of the esomeprazole magnesium is 0.5-50 μm, more preferably 2-15 μm;
the adhesive is hydroxypropyl methylcellulose; the stabilizer is magnesium hydroxide and/or magnesium aluminum silicate, and more preferably magnesium aluminum silicate;
the mass ratio of the esomeprazole magnesium to the stabilizer is 1: (0.15-0.35).
When the esomeprazole magnesium pellet is prepared, the medicine-containing layer is specially designed, and the active ingredients are matched with the specific stabilizing agent and the adhesive, so that the active ingredients can be stably combined on the pellet core during preparation, and the efficacy of the esomeprazole magnesium can be stably exerted during in vivo release.
In the invention, the aspirin pellet comprises the following components in parts by weight:
and/or the esomeprazole magnesium pellet comprises the following components in parts by weight:
the enteric coating material is one or a mixture of more of shellac, acrylic resin, cellulose and derivatives thereof; the plasticizer is one or a mixture of polyethylene glycol, triacetin, triethyl citrate, tributyl citrate, phthalate and monoacetin; the antisticking agent is one or a mixture of more of talcum powder, magnesium stearate and glyceryl monostearate; the blank pellet core is one or a mixture of more of starch, sucrose, microcrystalline cellulose and mannitol; the coating material of the isolating layer is HPMC (Hydroxypropyl methylcellulose), HPC (Hydroxypropyl cellulose) or povidone.
In the invention, the compound pellet tablet also comprises a filler, a disintegrant and a lubricant; the filler is microcrystalline cellulose; the disintegrant is croscarmellose sodium; the lubricant is sodium stearyl fumarate.
In the invention, the mass ratio of the aspirin pellet to the esomeprazole magnesium pellet is 1: (0.5-2.5); the mass ratio of the aspirin micropills to the filler is 1: (1-5); the mass ratio of the filler, the disintegrant and the lubricant is (100-800): (5-50): (1-8);
preferably, the compound pellet tablet comprises the following components in parts by weight:
a great deal of attempts are made on auxiliary materials of the compound pellet tablet, and the finding that the auxiliary material combination mode can ensure that two different pellets have good compressibility, can not be pressed and broken during compression, and can meet certain hardness and disintegration requirements, so that the combination cooperation of two different active ingredients is successfully realized.
The invention also provides a method for preparing the compound pellet tablet, which is obtained by directly recrystallizing aspirin for coating when aspirin pellets are prepared.
As a specific embodiment, the preparation method specifically comprises:
(1) the preparation method of the aspirin pellet comprises the following specific steps:
providing a mixed coating solution containing an enteric coating material, a plasticizer and an anti-sticking agent;
recrystallizing the aspirin with the mixed coating solution and directly coating the aspirin;
(2) the preparation method of the esomeprazole magnesium pellet comprises the following specific steps:
providing a suspension comprising esomeprazole magnesium, a binding agent and a stabilizing agent;
coating the suspension on a blank pellet core to obtain a drug-containing pellet;
coating an isolation layer outside the drug-containing pellets, wherein the isolation layer contains an isolation layer coating material;
coating a coating layer outside the isolating layer, wherein the coating layer comprises an enteric coating material, a plasticizer and an anti-sticking agent;
(3) mixing the aspirin pellet and the esomeprazole magnesium pellet with the rest components, and tabletting.
As a preferred embodiment, the method for preparing the compound pellet tablet of the present invention specifically comprises the following steps:
(1) preparation of aspirin micropill
Screening aspirin with the particle size of 400-700 μm, coating with coating solution prepared from Eudragit L30D-55, triethyl citrate and pulvis Talci, and coating with fluidized bed.
(2) Preparation of esomeprazole magnesium pellet
Taking the sucrose pellet core as a blank pellet core. Preparing esomeprazole magnesium, magnesium aluminum silicate and hypromellose into suspension, spraying the suspension onto the blank pellet core in a fluidized bed by using a suspension medicine application method, and preparing into medicine-containing pellets. A5% hydroxypropyl cellulose water solution is adopted, and an isolating layer is coated outside an esomeprazole magnesium drug layer by utilizing a fluidized bed. And finally coating the pellets coated with the isolation layer by using a coating solution prepared from Eudragit L30D-55, triethyl citrate and glyceryl monostearate.
(3) And uniformly mixing the prepared aspirin pellets and esomeprazole magnesium pellets with the formulated microcrystalline cellulose, sodium stearyl fumarate and crospovidone, and tabletting to obtain the aspirin esomeprazole magnesium enteric-coated tablet (compound pellet tablet).
Wherein, the coating material of the isolating layer of the esomeprazole magnesium pellet can also be ethanol or ethanol water solution of hydroxypropyl methylcellulose, ethanol or ethanol water solution of hydroxypropyl cellulose, and ethanol or ethanol water solution of povidone.
The invention also provides a compound pellet capsule, which comprises aspirin pellets and esomeprazole magnesium pellets; the aspirin pellets and the esomeprazole magnesium pellets are as described above; the mass ratio of the aspirin pellet to the esomeprazole magnesium pellet is (3-6): (4-7).
The preparation method of the capsule comprises the following steps:
and filling the prepared aspirin pellets and the esomeprazole magnesium pellets into a gelatin hollow capsule to obtain the aspirin esomeprazole magnesium enteric capsule (compound pellet capsule).
The invention also provides compound pellet dry suspension granules, which comprise aspirin pellets and esomeprazole magnesium pellets; the aspirin pellets and the esomeprazole magnesium pellets are as described above; the mass ratio of the aspirin pellet to the esomeprazole magnesium pellet is (100-175): (100-210).
In the invention, the compound pellet dry suspension granule comprises the following components in parts by weight:
the sweetener for preparing the aspirin esomeprazole magnesium dry-mixed suspension granules can be one or a mixture of more of sucrose, xylitol, mannitol, sorbitol, sucralose, aspartame and acesulfame potassium; the suspending agent is one or more of xanthan gum, carrageenan, carboxymethylcellulose, sodium carboxymethylcellulose, and polyvidone.
The preferable specific preparation method is as follows: and adding xanthan gum, carboxymethyl cellulose, sucrose, citric acid and essence into the prepared aspirin pellets and the esomeprazole magnesium pellets, uniformly mixing, and subpackaging into aluminum bags to obtain the aspirin esomeprazole magnesium enteric dry-mixed suspension granules (compound pellet dry-mixed suspension granules).
The invention successfully prepares the two pellets into different compound preparation formulations, thereby meeting various use requirements.
The invention has the beneficial effects that:
1. compared with other proton pump inhibitors, the compound inhibitor provided by the invention contains the esomeprazole magnesium, and compared with other proton pump inhibitors, the compound inhibitor has the advantages that the variation degree of the ratio of AUC (Area under the curve during medicine) of the esomeprazole magnesium in strong and weak metabolins is lowest, the curative effect is more stable, the AUC is higher than that of racemic omeprazole, and the acid inhibition effect is stronger.
2. The aspirin and the esomeprazole magnesium are respectively prepared into the enteric pellets, so that the risk of stability problems caused by mutual contact of the aspirin and the esomeprazole magnesium when the aspirin and the esomeprazole magnesium are directly mixed and tableted and then coated with enteric coatings is avoided.
3. The aspirin and the esomeprazole magnesium are combined to prepare the compound preparation, so that the serious gastrointestinal side effect caused by long-term aspirin administration is avoided, the risk that a patient forgets to take the aspirin due to the fact that the aspirin and the esomeprazole magnesium are taken for a long time is avoided, meanwhile, the release time of each active component is reasonably matched with each other, the medication compliance of the patient is improved, and the curative effect of the medication can be indirectly guaranteed.
4. The aspirin obtained by the invention is recrystallized, fine in crystallization, uniform in particle, higher in product purity and higher in yield, can be directly coated, does not need to be subjected to pretreatment such as crushing and sieving, avoids adding auxiliary materials into the pill core, saves the cost, enables the release of the aspirin to be more controllable, and can be better matched with other active ingredients.
5. The compound pellet is prepared into tablets, capsules or dry suspensions, is convenient to take and good in patient compliance, and is more beneficial to transportation and storage.
Drawings
Figure 1 is a graph of salicylic acid when administered in Beagle canines (n-8);
figure 2 is a graph of esomeprazole magnesium when administered in Beagle dogs (n-8).
Detailed Description
Preferred embodiments of the present invention will be described in detail with reference to the following examples. It is to be understood that the following examples are given for illustrative purposes only and are not intended to limit the scope of the present invention. Various modifications and alterations of this invention will become apparent to those skilled in the art without departing from the spirit and scope of this invention.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The aspirin bulk drug used in the specific embodiment of the invention is purchased from Shandong Xinhua pharmaceutical Co., Ltd, with the batch number of 19505 and the particle size of D (0.9) ═ 80.5 μm; esomeprazole magnesium was purchased from Jiangsu Zhongbang pharmaceutical Co., Ltd, with a particle size D (0.9) ═ 7.5 μm, lot number D10045-20190601; hypromellose was purchased from JRS, lot No. 81005182622; microcrystalline cellulose was purchased from Huzhou experient pharmaceuticals, Inc., lot No. 20180303; croscarmellose sodium was purchased from pharmaceutic adjuvant, inc, of shanhe, anhui, lot No. 180904; sodium carboxymethylcellulose was purchased from nan er kang pharmaceutical products, inc, lake No. 180301; acrylic resin was purchased from Anhui mountain river pharmaceutic adjuvant, Inc., lot number 181201; polyethylene glycol was purchased from nan er kang pharmaceutical products, inc, lot No. 180605; hydroxypropylcellulose was purchased from Nippon Caoda corporation under lot number NHG-1111.
Example 1
This example provides a compound pellet tablet of the present invention.
The preparation method comprises the following steps:
(1) preparation of aspirin recrystallization
Dispersing 10kg of aspirin raw material medicine into 100kg of acetone, heating to 55 ℃ under stirring for dissolving, controlling the temperature to 55 ℃, adding 100kg of purified water, obtaining an aspirin clear solution, regulating the stirring speed to 150rpm, controlling the temperature to 55 ℃, stirring for 2h, then cooling to 40 ℃ at 5 ℃/h, stirring for 2h, then cooling to 10 ℃ at 5 ℃/h, stirring for 4h, centrifuging to obtain an aspirin recrystallization wet product, drying in vacuum at 40 ℃ until the drying weight loss is less than 0.3%, obtaining 9.2kg of aspirin recrystallization, wherein the yield is 92%, the purity is 99.81%, and the particle size D90 range is 400-700 mu m.
(2) Preparing aspirin enteric-coated pellets:
recrystallizing the aspirin prepared in the step (1), and coating a coating solution prepared from Eudragit L30D-55, triethyl citrate, talcum powder and water by using a fluidized bed.
(3) Preparing esomeprazole magnesium enteric-coated pellets:
taking the sucrose pellet core as a blank pellet core. Preparing esomeprazole magnesium, magnesium aluminum silicate and 6mg of hydroxypropyl methylcellulose into a suspension, and spraying the suspension on the blank pellet core in a fluidized bed by adopting a suspension medicine feeding method to prepare the medicine-containing pellet. Preparing the rest 10mg of hydroxypropyl methylcellulose into 6% of hydroxypropyl methylcellulose water solution, and coating an isolation layer on the esomeprazole magnesium drug layer by using a fluidized bed. And finally coating the pellets coated with the isolating layer by using a coating solution prepared from Eudragit L30D-55, triethyl citrate, glyceryl monostearate and water.
(4) Preparing a compound pellet tablet:
the tablet comprises the following components:
and uniformly mixing the prepared aspirin enteric-coated pellets and esomeprazole magnesium enteric-coated pellets with the formula amount of microcrystalline cellulose, sodium stearate fumarate and croscarmellose sodium, and tabletting to obtain the aspirin esomeprazole magnesium enteric-coated tablet.
Example 2
This example provides a compound pellet tablet of the present invention.
The preparation method comprises the following steps:
(1) preparation of aspirin recrystallization
Dispersing 10kg of aspirin raw material medicine into 50kg of acetone, heating to 56 ℃ under stirring for dissolving, controlling the temperature to 56 ℃, adding 50kg of purified water, obtaining an aspirin clear solution, regulating the stirring speed to 200rpm, controlling the temperature to 56 ℃, stirring for 2h, then cooling to 50 ℃ at 10 ℃/h, stirring for 2h, then cooling to 20 ℃ at 10 ℃/h, stirring for 4h, centrifuging to obtain an aspirin recrystallization wet product, drying in vacuum at 50 ℃ until the drying weight loss is less than 0.3%, obtaining 9.5kg of aspirin crystals, wherein the yield is 95%, the purity is 99.85%, and the particle size D90 range is 300-800 mu m.
(2) Preparing aspirin enteric-coated pellets:
recrystallizing the aspirin prepared in the step (1), and coating a coating solution prepared from Eudragit L30D-55, triethyl citrate, talcum powder and water by using a fluidized bed.
(3) Preparing esomeprazole magnesium enteric-coated pellets:
taking the sucrose pellet core as a blank pellet core. Preparing esomeprazole magnesium, magnesium aluminum silicate and 4mg of hydroxypropyl methylcellulose into a suspension, and spraying the suspension on the blank pellet core in a fluidized bed by adopting a suspension medicine feeding method to prepare the medicine-containing pellet. Preparing the rest 8mg of hydroxypropyl methylcellulose into 6% of hydroxypropyl methylcellulose water solution, and coating an isolation layer on the esomeprazole magnesium drug layer by using a fluidized bed. And finally coating the pellets coated with the isolating layer by using a coating solution prepared from Eudragit L30D-55, triethyl citrate, glyceryl monostearate and water.
(4) Preparing a compound pellet tablet:
the tablet comprises the following components:
and uniformly mixing the prepared aspirin enteric-coated pellets and esomeprazole magnesium enteric-coated pellets with the formula amount of microcrystalline cellulose, sodium stearate fumarate and croscarmellose sodium, and tabletting to obtain the aspirin esomeprazole magnesium enteric-coated tablet.
Example 3
This example provides a compound pellet capsule of the present invention.
The preparation method comprises the following steps:
(1) preparation of aspirin recrystallization
Dispersing 10kg of aspirin raw material medicine into 80kg of acetone, heating to 50 ℃ under stirring for dissolving, controlling the temperature to 50 ℃, adding 50kg of purified water to obtain an aspirin clear solution, regulating the stirring speed to 200rpm, controlling the temperature to 50 ℃, stirring for 2h, then cooling to 40 ℃ at 8 ℃/h, stirring for 2h, then cooling to 10 ℃ at 8 ℃/h, stirring for 4h, centrifuging to obtain an aspirin recrystallization wet product, drying in vacuum at 40 ℃ until the drying weight loss is less than 0.3%, obtaining 9.3kg of aspirin crystals, wherein the yield is 93%, the purity is 99.87%, and the particle size D90 range is 200-900 mu m.
(2) Preparing aspirin enteric-coated pellets:
recrystallizing the aspirin prepared in the step (1), and coating the coating liquid prepared from acrylic resin, polyethylene glycol, talcum powder and ethanol by adopting a fluidized bed.
(3) Preparing esomeprazole magnesium enteric-coated pellets:
taking the sucrose pellet core as a blank pellet core. Preparing esomeprazole magnesium, magnesium aluminum silicate and 6mg of hydroxypropyl cellulose into a suspension, spraying the suspension on the blank pellet core in a fluidized bed by adopting a suspension medicine feeding method, and preparing the medicine-containing pellet. Preparing the rest 10mg of hydroxypropyl cellulose into a 6% hydroxypropyl cellulose aqueous solution, and coating an isolation layer on the esomeprazole magnesium drug layer by using a fluidized bed. And finally coating the pellets coated with the isolating layer by using a coating solution prepared from Eudragit L30D-55, triethyl citrate, talcum powder and water.
(4) Preparing a compound pellet capsule:
the capsule comprises the following components:
aspirin enteric-coated pellet 195mg
Esomeprazole magnesium enteric-coated pellet 200mg
Gelatin hollow capsule
And filling the prepared aspirin enteric-coated pellets and the esomeprazole magnesium enteric-coated pellets into gelatin hollow capsules.
Example 4
This example provides a compound pellet capsule of the present invention.
The preparation method comprises the following steps:
(1) preparation of aspirin recrystallization
Dispersing 100kg of aspirin raw material medicine into 700kg of acetone, heating to 55 ℃ under stirring for dissolving, controlling the temperature to 55 ℃, adding 50kg of purified water to obtain an aspirin clear solution, regulating the stirring speed to 180rpm, controlling the temperature to 55 ℃, stirring for 2h, then cooling to 50 ℃ at 5 ℃/h, stirring for 2h, then cooling to 10 ℃ at 5 ℃/h, stirring for 5h, centrifuging to obtain an aspirin recrystallization wet product, drying in vacuum at 40 ℃ until the drying weight loss is less than 0.3%, obtaining 95kg of aspirin recrystallization, wherein the yield is 95%, the purity is 99.84%, and the particle size D90 range is 400-700 mu m.
(2) Preparing aspirin enteric-coated pellets:
recrystallizing the aspirin prepared in the step (1), and coating a coating solution prepared from hydroxypropyl methylcellulose acetate succinate, glycerol triacetate, magnesium stearate and water by adopting a fluidized bed.
(3) Preparing esomeprazole magnesium enteric-coated pellets:
taking the sucrose pellet core as a blank pellet core. Preparing esomeprazole magnesium, magnesium aluminum silicate and 6mg of hydroxypropyl methylcellulose into a suspension, and spraying the suspension on the blank pellet core in a fluidized bed by adopting a suspension medicine feeding method to prepare the medicine-containing pellet. Preparing the rest 10mg of hydroxypropyl methylcellulose into 6% of hydroxypropyl methylcellulose water solution, and coating an isolation layer on the esomeprazole magnesium drug layer by using a fluidized bed. Finally, coating the pellets coated with the isolation layer by using a coating solution prepared from hydroxypropyl methylcellulose acetate succinate, triethyl citrate, glyceryl monostearate and water.
(4) Preparing a compound pellet capsule:
the capsule comprises the following components:
aspirin enteric-coated pellet 175mg
Espressol omeprazole magnesium enteric-coated pellet 118.5mg
Gelatin hollow capsule
And filling the prepared aspirin enteric-coated pellets and the esomeprazole magnesium enteric-coated pellets into gelatin hollow capsules.
Example 5
This example provides a dry suspension granule of a compound pellet of the present invention.
The preparation method comprises the following steps:
(1) preparation of aspirin recrystallization
The preparation method is the same as example 1.
(2) Preparing aspirin enteric-coated pellets:
recrystallizing the aspirin prepared in the step (1), and coating a coating solution prepared from Eudragit L30D-55, triethyl citrate, talcum powder and water by using a fluidized bed.
(3) Preparing esomeprazole magnesium enteric-coated pellets:
taking the sucrose pellet core as a blank pellet core. Preparing esomeprazole magnesium, magnesium aluminum silicate and 6mg of hydroxypropyl methylcellulose into a suspension, and spraying the suspension on the blank pellet core in a fluidized bed by adopting a suspension medicine feeding method to prepare the medicine-containing pellet. Preparing the rest 10mg of hydroxypropyl methylcellulose into 6% of hydroxypropyl methylcellulose water solution, and coating an isolation layer on the esomeprazole magnesium drug layer by using a fluidized bed. And finally coating the pellets coated with the isolating layer by using a coating solution prepared from Eudragit L30D-55, triethyl citrate, glyceryl monostearate and water.
(4) Preparing compound pellet dry suspension particles:
the dry suspension granules comprise the following components:
and (3) uniformly mixing the prepared aspirin enteric-coated pellets and the esomeprazole magnesium enteric-coated pellets with the sucrose, the xanthan gum, the citric acid, the sodium carboxymethylcellulose and the apple essence according to the prescription amount, and subpackaging in aluminum bags to obtain the aspirin esomeprazole magnesium enteric-coated dry-mixed suspension granules.
Example 6
This example provides a dry suspension granule of a compound pellet of the present invention.
The preparation method comprises the following steps:
(1) preparation of aspirin recrystallization
The preparation method is the same as example 1.
(2) Preparing aspirin enteric-coated pellets:
recrystallizing the aspirin prepared in the step (1), and coating a coating solution prepared from acrylic resin, triethyl citrate, talcum powder and ethanol by adopting a fluidized bed.
(3) Preparing esomeprazole magnesium enteric-coated pellets:
taking the sucrose pellet core as a blank pellet core. Preparing esomeprazole magnesium, magnesium aluminum silicate and 4mg of hydroxypropyl methylcellulose into a suspension, and spraying the suspension on the blank pellet core in a fluidized bed by adopting a suspension medicine feeding method to prepare the medicine-containing pellet. Preparing the rest 8mg of hydroxypropyl methylcellulose into 6% of hydroxypropyl methylcellulose water solution, and coating an isolation layer on the esomeprazole magnesium drug layer by using a fluidized bed. And finally coating the pellets coated with the isolating layer by using a coating solution prepared from Eudragit L30D-55, triethyl citrate, glyceryl monostearate and water.
(4) Preparing compound pellet dry suspension particles:
the dry suspension granules comprise the following components:
and (3) uniformly mixing the prepared aspirin enteric-coated pellets and the esomeprazole magnesium enteric-coated pellets with the sucrose, the xanthan gum, the citric acid, the sodium carboxymethylcellulose and the apple essence according to the prescription amount, and subpackaging the mixture into aluminum bags to obtain the aspirin esomeprazole magnesium enteric-coated dry-mixed suspension granules.
Comparative example 1
The comparative example provides a compound pellet tablet. The preparation method is the same as that of example 1, except that the method for preparing the aspirin recrystallization in the step (1) is as follows:
dispersing 100kg of aspirin crystalline powder raw material medicine into 700kg of acetone, heating to 55 ℃ under stirring for dissolving, controlling the temperature to 55 ℃, adding 50kg of purified water to obtain an aspirin clear solution, regulating the stirring speed to 180rpm, controlling the temperature to 55 ℃, stirring for 2h, cooling to room temperature, centrifuging to obtain an aspirin recrystallization wet product, and performing vacuum drying at 40 ℃ until the loss on drying is less than 0.3%, so that 95kg of aspirin recrystallization is obtained, the yield is 95%, the purity is 99.84%, and the particle size D90 range is 20-100 mu m. Through tests, the crystals obtained by the comparative example cannot be directly coated, namely, the comparative example cannot crystallize aspirin particles meeting the requirement of direct coating.
Comparative example 2
The comparative example provides a compound pellet tablet. The preparation method is the same as that in the example 1, except that when the aspirin enteric-coated pellet is prepared, 100 parts of aspirin raw material drug (crystalline powder), 20 parts of sucrose powder, 20 parts of mannitol, 510 parts of hydroxypropyl methylcellulose E and 30 parts of purified water are added, and the mixture is subjected to wet granulation, extrusion and spheronization, and drying to prepare pellet core particles, and then the coating is carried out by adopting the method in the example 1.
Comparative example 3
The comparative example provides a compound pellet tablet. The preparation method is the same as that of example 1, except that the stabilizer is disodium hydrogen phosphate when preparing the esomeprazole magnesium pellet.
Comparative example 4
The comparative example provides a compound pellet tablet. The preparation method is the same as that in example 1, except that the filler of the compound pellet tablet is corn starch, the disintegrant is low-substituted hydroxypropyl cellulose, and the lubricant is sodium stearate fumarate.
Comparative example 5
The comparative example provides a compound pellet tablet. The preparation method is the same as that of the example 1, and the difference is that the filler of the compound pellet tablet is lactose, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate.
Experimental example 1 Release test
In this experimental example, the in vitro release profile of enteric aspirin, esomeprazole magnesium preparation prepared in examples 1 to 6 and comparative examples 2 to 5 was investigated, and the dissolution rate and the release rate were measured in the four parts of the 2015 edition of the "chinese pharmacopoeia" (general rule 0931 second method).
Dissolution conditions: taking 300ml of 0.1mol/L hydrochloric acid solution as a dissolution medium, rotating at 100rpm/min, carrying out sampling according to the method, detecting the dissolution rate in acid after 2 hours, adding 700ml of 0.086mol/L disodium hydrogen phosphate solution, and sampling and detecting the cumulative dissolution rate at 5, 10, 15, 30 and 45 minutes respectively.
The cumulative dissolution results of example 1 are shown in table 1.
TABLE 1
The cumulative dissolution results of example 2 are shown in table 2.
TABLE 2
The cumulative dissolution results of example 3 are shown in table 3.
TABLE 3
The cumulative dissolution results of example 4 are shown in table 4.
TABLE 4
The cumulative dissolution results of example 5 are shown in table 5.
TABLE 5
The cumulative dissolution results of example 6 are shown in table 6.
TABLE 6
The cumulative dissolution results of comparative example 2 are shown in table 7.
TABLE 7
The cumulative dissolution results of comparative example 3 are shown in table 8.
TABLE 8
The cumulative dissolution results of comparative example 4 are shown in table 9.
TABLE 9
The cumulative dissolution results of comparative example 5 are shown in table 10.
Experimental example 2 test of related substances
In this experimental example, aspirin free salicylic acid and esomeprazole magnesium related substances of aspirin enteric-coated esomeprazole magnesium preparations prepared in examples 1 to 6 and comparative examples 2 to 3 were studied, and the results were measured according to the related substance method under the item of the second aspirin enteric-coated tablet and the esomeprazole magnesium enteric-coated tablet in the version of "chinese pharmacopoeia" 2015.
Free aspirin salicylic acid: is used newly. Taking a proper amount of aspirin micropills (containing about 0.1g of aspirin), precisely weighing, putting into a 100ml measuring flask, adding 1% glacial acetic acid methanol solution, shaking to dissolve aspirin, diluting to scale, shaking uniformly, filtering, discarding at least 2ml of primary filtrate, and taking the subsequent filtrate as a test sample solution; taking a salicylic acid reference substance of about 15mg, accurately weighing, placing in a 50ml measuring flask, adding a methanol solution of 1% glacial acetic acid to dissolve and dilute to a scale, shaking uniformly, accurately weighing 5ml, placing in a 100ml measuring flask, diluting to a scale with a methanol solution of 1% glacial acetic acid, shaking uniformly, and taking as a reference substance solution. Octadecylsilane chemically bonded silica is used as a filling agent, and acetonitrile-tetrahydrofuran-glacial acetic acid-water (35:5:5:55) is used as a mobile phase; the detection wavelength was 303 nm. Precisely measuring 10 μ l of each of the test solution and the reference solution, respectively injecting into a liquid chromatograph, and recording chromatogram. If a chromatographic peak consistent with the retention time of the salicylic acid peak exists in the chromatogram of the test solution, calculating the salicylic acid content by the peak area according to an external standard method.
Testing related substances of esomeprazole magnesium: taking a proper amount of esomeprazole magnesium pellets (containing about 20mg of esomeprazole magnesium), precisely weighing, placing in a 100ml measuring flask, adding 10ml of methanol, shaking, adding 20ml of phosphate buffer solution (pH11.0) under the item (1) for identification, shaking, ultrasonically dissolving the esomeprazole magnesium, diluting with water to a scale, filtering, and taking a subsequent filtrate as a test sample solution. Measuring by high performance liquid chromatography (general rule 0512), using octadecylsilane chemically bonded silica as filler (Microspher Cl8, 4.6mm × 100mm, 3 μm or column with equivalent efficiency); water-phosphate buffer solution (pH7.6) (0.0052 mol of sodium dihydrogen phosphate and 0.0315mol of disodium hydrogen phosphate per 1000 ml) -acetonitrile (80:10:10) is used as mobile phase A; acetonitrile-phosphate buffer (pH7.6) -water (80:1:19) was used as mobile phase B, and the detection wavelength was 302 nm. Gradient elution was performed as in Table 11 below. Respectively taking a proper amount of omeprazole magnesium and an impurity I reference substance, adding a mobile phase A for dissolving and diluting to prepare a mixed solution containing 0.02mg of omeprazole magnesium in each 1ml, taking 20 mu l of mixed solution as a system applicability solution, injecting into a liquid chromatograph, wherein the retention time of an esomeprazole magnesium peak is 14-19 minutes, and the separation degree of the esomeprazole magnesium peak and the impurity I peak is more than 2.5.
TABLE 11
| Time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 100 | 0 |
| 10 | 80 | 20 |
| 30 | 0 | 100 |
| 31 | 100 | 0 |
| 45 | 100 | 0 |
And (3) injecting 20 mu l of the test solution into a liquid chromatograph, and recording the chromatogram for 30 minutes. If an impurity peak exists in a chromatogram of a sample solution, the content of the impurity I is not more than 0.5 percent, the content of other single impurities is not more than 0.2 percent, and the total amount of the impurities is not more than 2.0 percent according to the calculation of a peak area normalization method.
The test results are shown in Table 12.
TABLE 12
Experimental example 3 in vivo and in vitro correlation study
(1) Laboratory animal
An male Beagle dog with the weight of 10-15 kg is selected as an experimental animal to carry out in-vivo pharmacokinetics research on the esomeprazole magnesium aspirin enteric-coated tablet.
(2) Single dose dosing regimen
Single dose, randomized, non-blind, two-way crossover, fed and fasted control studies, 3d prior to the start of the experiment, experimental animals were placed in the laboratory setting to familiarize themselves with the experimental setting. Fasted study, experimental animals were fasted 12h before the start of the experiment, but had free access to water. 8 Beagle dogs were randomly divided into A, B groups of 4 dogs each. The dose administered was the enteric capsule of example 3/animal, two groups of animals were cross-dosed. Feeding study, the fed state was the consumption of a standard high fat meal 25 minutes prior to dosing.
Each group was treated with 2.0ml of venous blood taken from the canine hind limb saphenous vein before and at 0, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 12.0 and 24 hours after administration, placed in heparinized tubes, centrifuged at 3000rpm for 10min, plasma was isolated and stored at-20 ℃ for testing.
The dosage regimen for the different formulations of the enteric capsules is shown in table 13.
Watch 13
| Administration cycle | Test formulations | Control formulation |
| First cycle (fasting) | Group A | Group B |
| Second cycle (fasting) | Group B | Group A |
| First cycle (eating) | Group A | Group B |
| Second cycle (meal) | Group B | Group A |
Note:
1. test formulations: the enteric capsule of example 3;
2. control formulation: aspirin enteric-coated tablets (bai aspirin), dosage: 100 mg/time, 40 mg/time of esomeprazole magnesium enteric capsule (NEXIUM);
3. the interval between two experimental periods is 7 d;
(3) the results are shown in figure 1 for salicylic acid (n-8) and figure 2 for esomeprazole magnesium (n-8) in Beagle canines.
As can be seen from the figure: the peak reaching time of esomeprazole magnesium in the tested compound preparation is about 1.5h, the peak reaching time of aspirin is about 3.0h, the esomeprazole magnesium is released firstly, the gastrointestinal side effect of aspirin is favorably antagonized, meanwhile, the half-life period is short, the in vivo elimination is fast, the side effect caused by excessive inhibition of gastric acid secretion is avoided, the tested compound preparation and a contrast single preparation have similar in vivo drug time curves, the in vitro drug release is basically consistent with in vivo absorption, the formula of the compound capsule is reasonable, the preparation process is stable, and certain in vivo and in vitro correlation is realized.
Experimental example 4
In the experimental example, the weight difference, disintegration time, friability and hardness of the compound pellet tablets prepared in examples 1-2 and comparative examples 4-5 were tested.
The weight difference is checked according to the examination method of the weight difference under the 0101 tablet item in the general rules of 0100 preparations in the four parts of the 'Chinese pharmacopoeia' 2015, and the disintegration time limit is examined according to the examination method of the disintegration time limit of 0921 tablets in the four parts of the 'Chinese pharmacopoeia' 2015; the friability is checked according to the friability checking method of 0923 tablets in the four parts of 2015 of Chinese pharmacopoeia; the hardness was checked with a durometer. The test results are shown in Table 14.
TABLE 14
| Test items | Difference in weight | Disintegration time limit | Degree of friability | Hardness of |
| Example 1 | -3.1％～+3.5％ | 1～2min | 0.2％ | 15～20kg |
| Example 2 | -3.0％～+4.5％ | 1～2min | 0.2％ | 15～20kg |
| Comparative example 4 | -7.2％～+6.5％ | 5～8min | 1.6％ | 7～9kg |
| Comparative example 5 | -6.4％～+6.6％ | 4～7min | 1.2％ | 8～10kg |
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. The compound pellet tablet is characterized by comprising aspirin pellets and esomeprazole magnesium pellets;
wherein, the aspirin micropills are obtained by directly coating the recrystallized aspirin; the preparation method of the aspirin recrystallization comprises the following steps:
(1) dissolving aspirin in acetone, controlling the temperature to be 50-60 ℃, and adding purified water to obtain an aspirin clear solution, wherein the mass of the acetone is 5-10 times that of the aspirin, and the mass of the purified water is 5-10 times that of the aspirin;
(2) controlling the temperature of the obtained aspirin clear solution at 50-60 ℃ under the condition that the stirring speed is 150-200 rpm, and stirring for 1-2 hours;
(3) then cooling to 40-50 ℃ at a cooling speed of 5-10 ℃/h, and stirring for 2-3 h;
(4) then cooling to 10-20 ℃ at a cooling speed of 5-10 ℃/h, and stirring for 4-5 h.
2. The compound pellet tablet according to claim 1, wherein the particle size D90 of the aspirin recrystallization is 200-1000 μm, preferably 400-700 μm.
3. The compound pellet tablet of claim 1, wherein the esomeprazole magnesium pellet comprises a blank pellet core, a drug-containing layer, an isolating layer and an enteric coating layer from inside to outside in sequence; the drug-containing layer comprises esomeprazole magnesium, an adhesive and a stabilizer;
preferably, the particle size D90 of the esomeprazole magnesium is 0.5-50 μm, more preferably 2-15 μm;
the adhesive is hydroxypropyl methylcellulose; the stabilizer is magnesium hydroxide and/or magnesium aluminum silicate, and more preferably magnesium aluminum silicate;
the mass ratio of the esomeprazole magnesium to the stabilizer is 1: (0.15-0.35).
4. The compound pellet tablet of any one of claims 1 to 3, wherein the aspirin pellets comprise the following components in parts by weight:
and/or the esomeprazole magnesium pellet comprises the following components in parts by weight:
the enteric coating material is one or a mixture of more of shellac, acrylic resin, cellulose and derivatives thereof; the plasticizer is one or a mixture of polyethylene glycol, triacetin, triethyl citrate, tributyl citrate, phthalate and monoacetin; the antisticking agent is one or a mixture of more of talcum powder, magnesium stearate and glyceryl monostearate; the blank pellet core is one or a mixture of more of starch, sucrose, microcrystalline cellulose and mannitol; the coating material of the isolating layer is HPMC, HPC or povidone.
5. The compound pellet tablet of claim 1, further comprising a filler, a disintegrant, and a lubricant; the filler is microcrystalline cellulose; the disintegrant is croscarmellose sodium; the lubricant is sodium stearyl fumarate.
6. The compound pellet tablet of claim 5, wherein the mass ratio of the aspirin pellet to the esomeprazole magnesium pellet is 1: (0.5-2.5); the mass ratio of the aspirin micropills to the filler is 1: (1-5); the mass ratio of the filler, the disintegrant and the lubricant is (100-800): (5-50): (1-8);
preferably, the compound pellet tablet comprises the following components in parts by weight:
7. a method for preparing the compound pellet tablet of any one of claims 1 to 6, which is characterized in that aspirin is directly recrystallized and coated when aspirin pellets are prepared.
8. A compound pellet capsule is characterized in that the compound pellet capsule comprises aspirin pellets and esomeprazole magnesium pellets; the aspirin pellets and the esomeprazole magnesium pellets are as described in any one of claims 1-4; the mass ratio of the aspirin pellet to the esomeprazole magnesium pellet is (3-6): (4-7).
9. A compound pellet dry suspension granule is characterized in that the compound pellet dry suspension granule comprises an aspirin pellet and an esomeprazole magnesium pellet; the aspirin pellets and the esomeprazole magnesium pellets are as described in any one of claims 1-4; the mass ratio of the aspirin pellet to the esomeprazole magnesium pellet is (100-175): (100-210).
10. The compound pellet dry suspension granule of claim 9, comprising the following components in parts by weight:
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| CN103479653A (en) * | 2013-10-09 | 2014-01-01 | 山东大学 | Aspirin-esomeprazole compound enteric coated pellet preparation and preparation method |
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| CN103479653A (en) * | 2013-10-09 | 2014-01-01 | 山东大学 | Aspirin-esomeprazole compound enteric coated pellet preparation and preparation method |
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| MELITA HUREMOVIC ETAL.: "Crystallization and morphological characteristics of acetyl-salicylic acid(aspirin) synthesized from substrates of different source", 《JOURNAL OF CHEMICAL, BIOLOGICAL AND PHYSICAL SCIENCES》 * |
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| CN113350313B (en) * | 2021-06-23 | 2023-08-11 | 福建金山生物制药股份有限公司 | Esomeprazole magnesium sustained-release preparation and preparation method thereof |
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