CN106727381B - Orally disintegrating tablet of dexlansoprazole sodium and preparation method thereof - Google Patents
Orally disintegrating tablet of dexlansoprazole sodium and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a dexlansoprazole sodium orally disintegrating tablet and a preparation method thereof, the dexlansoprazole sodium orally disintegrating tablet is prepared from a new crystal form A of dexlansoprazole sodium, sodium bicarbonate, an enteric fast-release pellet A, an enteric slow-release pellet B, a premixed auxiliary material compound and other pharmaceutically acceptable auxiliary material tabletting, wherein the new crystal form A of the dexlansoprazole sodium has characteristic diffraction peaks at diffraction angles 2 theta of 5.9, 7.6, 12.2, 12.7, 16.6, 18.4, 20.5, 25.8, 26.8 and 31.4 degrees; the enteric fast-release pellet A and the enteric slow-release pellet B are both prepared by taking a novel crystal form A of dexlansoprazole sodium as a raw material medicine through a hot-melt extrusion process, and are coated with enteric coatings degraded under different pH conditions, and the premix adjuvant compound is also prepared by carrying out a hot-melt extrusion process on an adjuvant suitable for orally disintegrating tablets. The orally disintegrating tablet of the invention releases a small amount of drug in the stomach, reducing the disadvantages of irritation to the stomach and instability in gastric acid. The subsequent micro-pills are mainly dissolved and released in the intestinal tract, so that the drug effect is prolonged. The orally disintegrating tablet has the advantages of good taste, rapid disintegration, fast dissolution, convenient taking, improved patient compliance and the like, and is advanced in preparation process, simple, safe and pollution-free in operation and suitable for industrial mass production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an orally disintegrating tablet of dexlansoprazole sodium and a preparation method thereof.
Background
Dexlansoprazole (Dexlansoprazole, R- (+) -Lansoprazole), the chemical name of which is (R) - (+) -2- ([ 3-methyl-4- (2,2, 2-trifluoroethoxy) pyridin-2-yl ] methylsulfinyl) -1H-benzimidazole, the structural formula of which is shown as follows,
dexlansoprazole is a new esophagitis treatment drug developed by martian pharmaceutical company of japan, and is approved by the FDA in the united states for marketing in 1 month and 30 days in 2009. The medicine is a single enantiomer of a proton pump inhibitor lansoprazole, is used for treating heartburn and erosive esophagitis with different degrees related to non-erosive gastroesophageal reflux disease, and has higher bioavailability and fewer side effects than lansoprazole.
The dexlansoprazole belongs to prazole PPIs antiulcer drugs, a chemical structure of sulfinyl benzimidazole exists in the structure of the dexlansoprazole, the physicochemical property is extremely unstable, and the dexlansoprazole is easily influenced by various factors such as light, heavy metal ions, oxidability and reducing components, particularly, the chemical structure of the dexlansoprazole can be destructively changed under an acidic condition, and the phenomena of color change and polymerization occur, so that the dexlansoprazole is unstable in a slightly acidic diluent, after the dexlansoprazole is prepared into an oral preparation, a drug disintegration and release process is needed after drug absorption, and the dexlansoprazole is destroyed and decomposed due to gastric acid in stomach, so that the drug effect taking speed and bioavailability are reduced, and how to enable the dexlansoprazole capsule not to be destroyed in the gastric acid and even to play the drug effect is realized. In addition, how to ensure the controlled release in the intestinal environment is one of the key technical points.
The existing preparation technology for avoiding the release of the active ingredient in gastric acid mostly adopts a mode of coating an enteric coating layer on an outer layer, namely a dexlansoprazole sustained-release capsule (trade name Dexilant) for Wutian pharmacy, wherein each capsule contains two pellets 1 and 2 with different enteric coatings. To avoid release of the active ingredient in gastric acid and to control the release twice in the intestine, DEXILANT uses three different enteric coating materials, ewing L30D-55, ewing L100, ewing S100, which clearly increase the cost. In addition, ethanol is used as a coating solution solvent, the production safety is additionally reduced, production workshops and equipment need to be provided with explosion-proof devices, the modern green environmental protection requirements are not met, and quality problems such as over-standard ethanol solvent and the like are easily caused.
Although the stability of the dexlansoprazole is improved after the dexlansoprazole is prepared into a sodium salt, the dexlansoprazole is insoluble in water, is easy to degrade in gastric acid, is slowly absorbed when being prepared into tablets or capsules, has relatively low bioavailability and low stability, and the main dosage forms of the current lansoprazole products comprise lansoprazole tablets and enteric capsules, but the dosage forms are not suitable for children, the old and patients with dysphagia, so that the development of a new dosage form of lansoprazole sodium suitable for the patients is important and has very strong practicability.
The hot melt extrusion technology (HME), also known as melt extrusion technology, is characterized by that it uses single/double screw extruder to make the material undergo the three stages of solid conveying, melting and melt conveying, and under the action of strong shearing force of kneading device and screw element the formed product with high mixing dispersion can be obtained. The hot melting extrusion process can realize unit operations of mixing, granulating, forming products and the like on one device, and has the characteristics of less working procedures, low energy consumption, low cost, high yield, continuity, closed production and the like. The technology has breakthrough advantages in improving the dissolution rate of insoluble drugs, preparing sustained-release preparations and local administration preparations, becomes a new hotspot in a drug delivery system of a preparation technology, and particularly has high cost in that the preparation process is easy to realize industrial scale-up production. In the prior art, the application of the dexlansoprazole sodium in a hot-melt extrusion process is not reported, and a new crystal form of the dexlansoprazole sodium suitable for the hot-melt extrusion process is not screened out.
Disclosure of Invention
Aiming at the defects of the prior art, such as poor stability, sensitivity to temperature and humidity, great operation difficulty, high production cost and low preparation product stability when being applied to a preparation process, particularly defects that the preparation product is not suitable for a hot-melt extrusion process, such as obvious drug degradation in the hot-melt process, the invention provides a novel crystal form A of a dexlansoprazole sodium dimethylacetamide solvate and a preparation method thereof.
The invention also aims to provide application of the novel crystal form A of the dexlansoprazole sodium in preparing medicines for treating gastric ulcer, duodenal ulcer and reflux esophagitis and eradicating helicobacter pylori.
Meanwhile, aiming at the novel crystal form A of the dexlansoprazole sodium, the inventor also aims to provide a dried dexlansoprazole sodium orally disintegrating tablet which has good compliance and stable quality, can exert drug effect on the stomach and intestinal tract at proper time and has higher bioavailability so as to be convenient for children, old people and dysphagia patients to use.
In order to achieve the technical object of the orally disintegrating tablet, the present invention adopts the following technical means.
The invention provides an orally disintegrating tablet of dexlansoprazole sodium, which comprises a novel crystal form A of the dexlansoprazole sodium, sodium bicarbonate, an enteric fast-release pellet A, an enteric slow-release pellet B, a premix adjuvant compound and other pharmaceutically acceptable adjuvant tablets; wherein the chemical structure of the novel crystal form A of the dexlansoprazole sodium is a dimethylacetamide solvate of the dexlansoprazole sodium, the structural formula is shown as follows,
the enteric fast-release pellet A is prepared by taking a new crystal form A of dexlansoprazole sodium as a raw material medicine, preparing a fast-release pellet core A by adopting a hot-melt extrusion process, and coating an enteric coating A, wherein the enteric coating A is decomposed under the condition that the pH value is more than or equal to 5.5;
the enteric sustained-release pellet B is prepared by taking a new crystal form A of the dexlansoprazole sodium as a raw material medicine, preparing a sustained-release pellet core B by adopting a hot-melt extrusion process, and coating an enteric coating B, wherein the enteric coating B is decomposed under the condition that the pH value is more than or equal to 6.8;
the compound of the premixed auxiliary materials comprises a filling agent, an adhesive, a disintegrating agent, a lubricant, a flavoring agent and a hot melt auxiliary agent,
preferably, the powder X-ray diffraction pattern of the novel crystal form A of the dexlansoprazole sodium has characteristic diffraction peaks at diffraction angles 2 theta of 5.9, 7.6, 12.2, 12.7, 16.6, 18.4, 20.5, 25.8, 26.8 and 31.4 degrees, wherein the error range of the 2 theta value is +/-0.2, and the pattern is shown in the attached figure 1 of the specification; and the DSC spectrum has an endothermic characteristic peak at 132.4 +/-1 ℃ and an exothermic characteristic peak at 204.6 +/-1 ℃, and is shown in the attached figure 2 of the specification.
Preferably, the wave number of the Fourier transform infrared spectrum of the novel crystal form A of the dexlansoprazole sodium is 3383 +/-2, 3134 +/-2, 3072 +/-2, 2975 +/-2, 1646 +/-2, 1583 +/-2, 1475 +/-2, 1441 +/-2, 1316 +/-2, 1265 +/-2, 1198 +/-2, 1168 +/-2, 1111 +/-2, 1036 +/-2, 972 +/-2, 915 +/-2, 857 +/-2, 745 +/-2 and 662 +/-2 cm-1The characteristic absorption peak is shown in figure 3 in the specification; and the thermogravimetric analysis TG spectrum of the novel crystal form A of the dexlansoprazole sodium is shown in the attached figure 4 of the specification.
The orally disintegrating tablet of the invention is characterized in that the components are as follows in parts by mass,
novel crystal form A of dexlansoprazole sodium: 1 part;
sodium bicarbonate: 4-6 parts;
enteric quick-release pellet A: 35-40 parts of a solvent;
enteric sustained-release pellets B: 85-100 parts of a binder;
premixing auxiliary material compound: 200-250 parts of a binder;
and, the free dexlansoprazole sodium: dexlansoprazole sodium in the enteric immediate-release pellet A: the weight ratio of the dexlansoprazole sodium in the enteric sustained-release pellet B is 1: 3.8-4.2: 9.8-10.2, preferably 1: 4: 10; in the premix auxiliary material compound, the filler is selected from one or more of glucose, lactose, xylitol, sucrose, mannitol, sorbitol, pregelatinized starch, microcrystalline cellulose, sucrose and starch; the adhesive is one or more selected from polyvidone, hydroxypropyl methylcellulose, sodium carboxymethylcellulose water, and hydroxypropyl cellulose; the disintegrating agent is selected from one or more of low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, sodium carboxymethyl cellulose and calcium carboxymethyl cellulose; the lubricant is selected from one or more of magnesium stearate, calcium stearate, talcum powder and superfine silica gel powder; the correctant is selected from one or more of herba Menthae essence, glycyrrhizin, maltitol, fructus Musae essence, fructus Ananadis Comosi essence, fructus Citri Junoris essence, fructus Citri Limoniae essence, fructus Myrtilli essence, aspartame, stevioside, and acesulfame potassium; the hot melt adjuvant is one or more selected from glyceryl behenate and polyethylene glycol.
The premix auxiliary material compound comprises the following components in parts by weight:
the content of the filler is 75-85%, and the preferable content is microcrystalline cellulose: xylitol: the weight ratio of lactose is 1: 1: 1;
the content of the adhesive is 2-9%, and povidone K30 is preferred;
the content of the disintegrant is 3-6%, and the preferred content is croscarmellose sodium;
the content of the lubricant is 1-3%, and magnesium stearate is preferred;
the content of the flavoring agent is 2-4%, and the preferred content is mint essence: the weight ratio of aspartame is 1: 1;
the content of the hot-melt auxiliary agent is 5-10%, and PEG6000 is preferred;
the sum of the weight percentages of the components is 100 percent.
The preparation method of the premix auxiliary material compound comprises the following steps: uniformly mixing the filler, the adhesive, the disintegrating agent, the lubricant, the flavoring agent and the hot-melt auxiliary agent, adding the mixture into a hot-melt extruder, setting the temperature of the hot-melt extrusion to be 180-280 ℃, preparing granules, grinding and crushing the granules, and sieving the granules by a 80-100-mesh pharmacopeia sieve to obtain the premix auxiliary material compound for later use.
The prescription and the mass portion of the quick-release pill core A of the invention are as follows,
dexlansoprazole sodium form a: 10-20 parts;
magnesium carbonate: 10-20 parts;
water-soluble carrier: 40-80 parts of water-soluble carrier, wherein the water-soluble carrier comprises povidone, polyacrylic resin and cellulose, and is selected from one or more of Plasdone K29, Plasdone K32, Kollidon VA64, Plasdone S630, Eudragit E100, Eudragit EPO, Klucel EF, Klucel ELF, poloxamer 188, PEG4000 and PEG 6000;
plasticizer: 2-10 parts of one or more of sorbitol, mannitol, xylitol, glyceryl monostearate and glyceryl behenate;
a stabilizer: 10-20 parts of one or more selected from polysorbate 80, Soluplus, polyethylene glycol laurate Gelucire44/14 and polyoxyethylene 40 hydrogenated castor oil KolliphorRH 40;
anti-aging agent: 2-5 parts of one or more selected from tromethamine, glycerol and propyl gallate;
disintegrating agent: 0.2-1 part of one or more selected from croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch.
The formula and the parts by mass of the sustained-release pill core B are as follows,
dexlansoprazole sodium form a: 10-20 parts;
magnesium carbonate: 10-20 parts;
enteric carrier: 40-80 parts of one or more selected from cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate HPMCP, hydroxypropyl methylcellulose acetate succinate HPMCAS, hydroxypropyl methylcellulose acetate maleate, carboxymethyl ethyl cellulose, Ewing L100-55, Ewing S100, Ewing RL100 and Ewing RS 100;
plasticizer: 2-10 parts of one or more of sorbitol, mannitol, xylitol, glyceryl monostearate and glyceryl behenate;
a stabilizer: 10-20 parts of one or more selected from polysorbate 80, Soluplus, polyethylene glycol laurate Gelucire44/14 and polyoxyethylene 40 hydrogenated castor oil KolliphorRH 40;
anti-aging agent: 2-5 parts of one or more selected from tromethamine, glycerol and propyl gallate;
release modifier: 0-1 part of one or more of sodium dodecyl sulfate, sodium taurocholate, xanthan gum and carbomer.
Preferably, the coating prescription and the mass portion of the enteric immediate-release pellet A are as follows,
jack preferably 93F 19255: 20 parts of (1);
arginine: 11-12 parts;
talc powder: 5 parts of a mixture;
triethyl citrate: 3 parts of a mixture;
water: proper amount;
the weight of the coating is increased by 10-20%;
the coating prescription and the mass portion of the enteric sustained-release pellet B are as follows,
jack preferably 93F 19255: 20 parts of (1);
arginine: 3-4 parts;
talc powder: 5 parts of a mixture;
polyethylene glycol 4000: 4 parts of a mixture;
water: proper amount;
the weight of the coating is increased by 10-20%.
The present invention also provides a process for the preparation of the dry suspension according to claims 1-8, comprising the steps of:
1) preparing an enteric quick-release pellet A: the novel crystal form A of the dexlansoprazole, a water-soluble carrier, a plasticizer, a stabilizer, an anti-aging agent and a disintegrant are mixedUniformly adding the mixture into a feeding hopper of a double-screw extruder, setting the feeding speed to be 2kg/h, the rotating speed to be 200rpm, setting the melt extrusion temperature to be 80-120 ℃, starting to collect the material after extruding for 10min, and cutting the material into pellets with the diameter of 0.3-0.8 mm by a cutter at the tail end for later use; uniformly mixing all components in the enteric coating solution A, and coating by using a fluidized bed coating machine under the conditions that the inlet temperature is 45 ℃, the spraying rate of the coating solution is 3.8 g/min, and the spraying pressure is 1.0 kg/cm2Drying to obtain enteric fast-release pellet A;
2) preparing an enteric sustained-release pellet B: the novel crystal form A of the dexlansoprazole sodium, an enteric carrier, a plasticizer, a stabilizer, an anti-aging agent and a release regulator are uniformly mixed and then added into a feeding hopper of a double-screw extruder, the feeding speed is set to be 2kg/h, the rotating speed is set to be 200rpm, the melt extrusion temperature is set to be 80-120 ℃, after 10min of extrusion, the material starts to be collected and is cut into pellets with the diameter of 0.3-0.8 mm by a cutter at the tail end for later use; uniformly mixing all components in the enteric coating solution B, and coating by using a fluidized bed coating machine under the conditions that the inlet temperature is 45 ℃, the spraying rate of the coating solution is 3.8 g/min, and the spraying pressure is 1.0 kg/cm2Drying to obtain enteric sustained-release pellet B;
3) uniformly mixing the novel crystal form A of the dexlansoprazole sodium, sodium bicarbonate, the enteric fast-release pellet A, the enteric slow-release pellet B and the premix auxiliary material compound, and directly tabletting powder to obtain the dexlansoprazole sodium orally disintegrating tablet.
Through the intensive research of the inventor, in the orally disintegrating tablet, the new crystal form A of the dexlansoprazole sodium subjected to micronization always maintains the crystal form structure characteristics, and characteristic diffraction peaks always exist in a powder X-ray diffraction pattern at diffraction angles 2 theta of 5.9, 7.6, 12.2, 12.7, 16.6, 18.4, 20.5, 25.8, 26.8 and 31.4 degrees, wherein the error range of the 2 theta value is +/-0.2. The main medicine components contained in the quick-release pellets A and the sustained-release pellets B are prepared by adopting the novel crystal form A of the dexlansoprazole sodium as a raw material medicine, and after a hot-melt extrusion process, the final state can be an amorphous state, a microcrystalline state or a mixture of the amorphous state and the microcrystalline state, and can be related to the melt extrusion temperature and other technical indexes.
The invention achieves the following beneficial technical effects:
(1) no bacteriostatic agent or preservative is added, so that the medication safety is improved; high physical and chemical stability, stable quality, convenient storage, transportation and carrying, simple preparation method, easy operation and suitability for industrial production and application.
(2) The novel crystal form A of the dexlansoprazole sodium provided by the invention has the advantages that the content of oxidized impurities is obviously reduced, the impurity change is very small along with the prolonging of the storage time, the mobility is excellent, the dissolution rate is obviously improved, and the orally disintegrating tablet of the dexlansoprazole sodium prepared by utilizing the novel crystal form A has good stability and low impurity content.
(3) Because dexlansoprazole is easily degraded in gastric acid, most of the currently marketed lansoprazole preparations in China are enteric-coated preparations, and the medicines are protected from being degraded by the gastric acid in an enteric-coated mode, but the recovery of the medicines and the initial inhibition effect on the gastric acid are delayed. The orally disintegrating tablet prepared by the scheme of the invention can release dexlansoprazole in gastric acid, firstly, sodium bicarbonate is utilized to quickly neutralize partial gastric acid, so that the pH value in the stomach is increased to a proper range and is maintained for a period of time to protect omeprazole from being degraded by the gastric acid, and the omeprazole can quickly and directly achieve the effect of inhibiting gastric acid secretion. The sodium bicarbonate can improve the pH value of the gastric environment and maintain for a certain time, so that the acid-unstable dexlansoprazole can be quickly absorbed and taken effect before being damaged by gastric acid, gastric acid secretion is inhibited, the dexlansoprazole is uniformly dispersed in the stomach, the action area in the stomach is enlarged, the absorption of the medicament in the stomach is increased, the bioavailability is improved, the symptoms of excessive gastric acid secretion, stomach pain and the like are quickly relieved, the cure satisfaction of patients is improved, and an ideal curative effect is achieved.
(4) The premix auxiliary material compound is prepared by adopting a hot-melt extrusion process and is specially used for premix auxiliary materials of orally disintegrating tablets. The use of the premixing auxiliary materials can make the direct powder tabletting more convenient and smooth, and avoid the degradation of the wetting solvent to the medicine in the wet granulation process.
(5) The quick-release pellet A and the slow-release pellet B both contain magnesium carbonate instead of sodium bicarbonate in the formula, and repeated experiments show that the use of the magnesium carbonate maintains the alkaline environment of the main drug in the solid dispersion, the physical and chemical properties of the main drug are stable, and meanwhile, the direct coating of enteric coatings released at different pH values on the surface of the solid dispersion becomes possible, so that an isolating layer is avoided, and the operation process is simplified. The invention contains two different types of enteric-coated pellets with the positioning and releasing functions and free dexlansoprazole sodium salt. When the medicine enters the stomach, the free dextratoprazole sodium is matched with the treatment effect of the sodium bicarbonate, so that the absorption of the medicine in the stomach is firstly increased, and the symptoms such as gastric acid secretion, stomachache and the like are quickly relieved. The enteric fast-release pellet A starts to remove the coating layer at the near end of the small intestine, and the medicament is quickly released through the water-soluble solid dispersion to take the treatment effect of the stomach, so that the medicament effect is continuously provided at a controlled speed. The enteric sustained-release pellet B starts to remove the coating layer at the far end of the small intestine, and slowly releases the medicament through the enteric solid dispersion, so that the steady and continuous blood concentration can be maintained, the treatment effect is ensured, and the frequent administration is avoided.
(6) The enteric-coated pellet contains two enteric-coated pellets of different types, and adopts three enteric-coated materials compared with a commercial product DEXILANT, the enteric-coated layers in the enteric-coated pellet adopt respectively the elekang Yake Yi 93F19255, arginine of different amounts is added in the process of preparing the Yake Yi aqueous solution, carboxyl groups of different mole numbers in a polymer are neutralized, and the enteric-coated material is controlled to be dissolved under different pH values, so that the double controlled-release effect of two times of patterns is realized, the production cost is reduced, and the production process is simplified. Because the invention adopts aqueous solution coating, the production safety is greatly improved, the pollution to the environment is reduced, and the problem of ethanol residue is effectively avoided.
(7) The orally disintegrating tablet of the invention has the advantages of uniform distribution in gastrointestinal tract, difficult burst release, good stability, convenient dose division, good absorption, quick effect, good bioavailability, good taste, improved patient compliance, simple preparation method and suitability for industrial production and application, and is taken after being mixed with water.
(8) The pellet cores of the two pellets are finished by adopting a hot-melting extrusion technology, the technology is advanced, the process is simple, no organic solvent is used, the safety and no pollution are realized, no dead angle is generated during mixing, the dispersion effect is good, the medicine loss is less, various unit operations are integrated, the space is saved, the cost is reduced, and the method is suitable for industrial mass production.
Drawings
Figure 1 is a powder X-ray diffraction PXRD pattern for new crystalline form a of dexlansoprazole sodium dimethylacetamide solvate.
Figure 2 is a DSC profile of new form a of dexlansoprazole sodium dimethylacetamide solvate.
Figure 3 is an infrared spectrum of novel crystalline form a of dexlansoprazole sodium dimethylacetamide solvate.
Fig. 4 is a TG pattern of novel crystalline form a of dexlansoprazole sodium dimethylacetamide solvate.
Detailed Description
The foregoing and other objects of the present invention will be attained by the following detailed description of the embodiments, but it should not be construed that the scope of the subject matter of the present invention is limited to the embodiments. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Example 1 preparation of novel crystalline form A of dexlansoprazole sodium dimethylacetamide according to the present invention
The invention provides a novel crystal form A of dexlansoprazole sodium dimethylacetamide solvate, wherein each mole of the novel crystal form A comprises 1 mole of dimethylacetamide solvent molecules, and the structural formula is as follows:
the novel crystal form A of the dexlansoprazole sodium has a powder X-ray diffraction pattern which has characteristic diffraction peaks at diffraction angles 2 theta of 5.9, 7.6, 12.2, 12.7, 16.6, 18.4, 20.5, 25.8, 26.8 and 31.4 degrees, wherein the error range of the 2 theta value is +/-0.2, and the pattern is shown in the attached figure 1 of the specification.
The novel crystal form A of the dexlansoprazole sodium has a DSC spectrum with an endothermic characteristic peak at 132.4 +/-1 ℃ and an exothermic characteristic peak at 204.6 +/-1 ℃; and the map is shown in the attached figure 2 in the specification.
The wave number of the novel crystal form A of the dexlansoprazole sodium is 3383 +/-2, 3134 +/-2, 3072 +/-2, 2975 +/-2, 1646 +/-2, 1583 +/-2, 1475 +/-2, 1441 +/-2, 1316 +/-2, 1265 +/-2, 1198 +/-2, 1168 +/-2, 1111 +/-2, 1036 +/-2, 972 +/-2, 915 +/-2, 857 +/-2, 745 +/-2 and 662 +/-2 cm-1Has characteristic absorption peaks, and the spectrum is shown in figure 3 in the specification; and the thermogravimetric analysis TG spectrum of the novel crystal form A of the dexlansoprazole sodium is shown in the attached figure 4 of the specification.
The preparation method comprises the following steps: adding 50g of dexlansoprazole sodium into a mixed solvent of 200mL of dimethylacetamide and 100mL of purified water, adding 0.1g of copovidone S630 and 0.1g of propyl gallate, stirring and dissolving at 35-40 ℃, under the condition of applying ultrasonic action, slowly dripping 900mL of methyl tert-butyl ether into the solution, cooling to 0-5 ℃ under the condition of maintaining the cooling rate at 0.3-1 ℃/min, continuously stirring for 1-3 h, carrying out suction filtration and drying on the formed suspension, drying at 35-45 ℃ and the vacuum degree of 0-0.1 MPa, and obtaining about 57g of a new crystal form A of dexlansoprazole sodium dimethylacetamide solvate with the yield of 93%.
The novel crystal form A of the dexlansoprazole sodium dimethylacetamide solvate has the main particle size of about 90 mu m, so that the crystal has moderate particle size and good fluidity, is not easy to aggregate and degrade, and is convenient to operate in the preparation process.
Example 2 preparation of comparative form 1
The preparation is carried out with reference to PCT patent WO2012095859A1, page 15, Example 5. Dissolving 25g of dexlansoprazole in 250mL of absolute ethanol, adding 32.5g of sodium isooctanoate, stirring for reaction for 30min, removing the solvent under reduced pressure, adding 250mL of n-heptane into the residue, stirring for 3h at room temperature, filtering, and drying to obtain about 18.5g of comparative crystal form 1.
Example 3 preparation of comparative form 2
The preparation is carried out with reference to PCT patent WO2012095859A1, specification page 16, Example 8.
Dissolving 10g of dextrangeprazole in 100mL of absolute ethanol and 5mL of water, cooling to-5 ℃, adding 2.2g of sodium hydroxide, stirring at-5 ℃ for 30min, adding 80mL of n-heptane into the reaction solution, continuing stirring for 30min, collecting solids, and drying to obtain about 6g of a comparative crystal form 2.
Example 4 stability evaluation of New form A of Dexlansoprazole sodium dimethylacetamide solvate
The prepared comparative crystal form 1 and comparative crystal form 2 and the novel crystal form A of the dexlansoprazole sodium of the invention are used for carrying out influence factor tests and accelerated stability tests, and the test method is shown in the stability test guiding principle of the traditional Chinese medicine and the pharmaceutical preparation in the appendix of Chinese pharmacopoeia.
(I) influence factor test:
1) high-temperature test: taking the comparative crystal form 1 and the comparative crystal form 2, placing the crystal forms and the novel crystal form A of the dexlansoprazole sodium at the temperature of 60 ℃ for 10 days, sampling at the 5 th day and the 10 th day, and comparing each index with a sample at the 0 th day, wherein the test results are as follows.
2) High humidity test: the original comparative crystal form 1 and the comparative crystal form 2 are taken, and are placed for 10 days at RH75% with the new crystal form A of the dexlansoprazole sodium, samples are taken at the 5 th day and the 10 th day, and each index is measured to be compared with the sample at the 0 th day, and the test results are as follows.
3) Strong light irradiation test: taking the comparative crystal form 1 and the comparative crystal form 2, placing the crystal form and the novel crystal form A of the dexlansoprazole sodium under the condition that the illumination is (4500 +/-500) lx for 10 days, sampling on the 5 th day and the 10 th day, and comparing each index with the sample on the 0 th day, wherein the test results are as follows.
(II) accelerated stability test:
and carrying out an accelerated stability test for 6 months on the comparative crystal form 1 and the comparative crystal form 2 and the novel crystal form A of the dexlansoprazole sodium in a constant temperature and humidity box. The test conditions were: 40 ℃/75% Relative Humidity (RH), sampled at 0, 1, 2, 3, 6 months respectively, and tested for purity and impurities (hplc), with the results shown in the table below.
From the above, the stability of the novel crystal form a of dexlansoprazole sodium is stronger than that of the comparative crystal form 1 and crystal form 2 in the prior art. Particularly under the conditions of high temperature, high humidity and illumination, the stability of the novel crystal form A of the dexlansoprazole sodium is obviously improved.
Example5 moisture absorption test
And (3) placing the comparative crystal form 1 and the comparative crystal form 2 and the novel crystal form A of the dexlansoprazole sodium in a dynamic vapor adsorption instrument, and recording the weight when the mass change is less than 0.01g within 3 hours at the temperature of below 40 ℃.
Example 6 suitability of different crystalline forms for application in Hot melt extrusion Process
The inventor weighs a comparative crystal form 1 (related substances are 0.11%), a comparative crystal form 2 (related substances are 0.12%) and a new crystal form A (related substances are 0.10%) in equal weight, selects a water-soluble carrier material PEG6000 and an enteric carrier material hydroxypropyl methylcellulose acetate succinate HPMCAS as representatives, takes glyceryl behenate as a plasticizer, and prepares solid dispersion particles by hot-melt extrusion according to the following formula in parts by weight: 1 part of raw material medicine, 10 parts of carrier material and 2 parts of glyceryl behenate. The results are as follows.
EXAMPLE 7 preparation of immediate Release pellet A
The prescription is as follows:
novel crystal form A of dexlansoprazole sodium: 8g of the total weight of the mixture;
magnesium carbonate: 10g of a mixture;
Plasdone S630：24g；
Klucel EF：8g；
glyceryl behenate: 4g of the total weight of the mixture;
Soluplus：8g；
tromethamine: 3g of the total weight of the mixture;
cross-linked povidone: 0.8 g;
the prescription of the enteric coating liquid A is as follows:
jack preferably 93F 19255: 20 parts of (1);
arginine: 11-12 parts;
talc powder: 5 parts of a mixture;
triethyl citrate: 3 parts of a mixture;
water: proper amount;
the weight of the coating is increased by 10 percent;
the pellet is prepared as follows:
uniformly mixing dexlansoprazole new crystal form A, magnesium carbonate, Plasdone S630, Klucel EF, glyceryl behenate, Soluplus, tromethamine and crospovidone, adding the mixture into a feeding hopper of a double-screw extruder, setting the feeding speed to be 2kg/h, the rotating speed to be 200rpm, setting the melt extrusion temperature to be 80-90 ℃, starting to collect materials after extruding for 10min, and cutting the materials into pellets with the diameter of 0.5-0.7 mm by a cutter at the tail end for later use; uniformly mixing all components in the enteric coating solution A, and coating by using a fluidized bed coating machine under the conditions that the inlet temperature is 45 ℃, the spraying rate of the coating solution is 3.8 g/min, and the spraying pressure is 1.0 kg/cm2And drying to obtain the enteric fast-release pellet A.
Example8 preparation of sustained Release pellet B
Novel crystal form A of dexlansoprazole sodium: 20g of the total weight of the mixture;
magnesium carbonate: 25g of the total weight of the mixture;
HPMCAS：60g；
yuteqi RS 100: 20g of the total weight of the mixture;
glyceryl behenate: 5g of the total weight of the mixture;
lauric acid polyglycol ester Gelucire 44/14: 15g of the total weight of the mixture;
propyl gallate: 5g of the total weight of the mixture;
carbomer: 1g of a compound;
the formulation of the enteric coating B is as follows,
jack preferably 93F 19255: 20 parts of (1);
arginine: 3-4 parts;
talc powder: 5 parts of a mixture;
polyethylene glycol 4000: 4 parts of a mixture;
water: proper amount;
the weight of the coating is increased by 15 percent;
the pellet is prepared as follows:
uniformly mixing dexlansoprazole sodium novel crystal form A, magnesium carbonate, HPMCAS, Ewing RS100, glyceryl behenate, polyethylene glycol laurate glyceride Gelucire44/14, propyl gallate and carbomer, adding the mixture into a feeding hopper of a double-screw extruder, setting the feeding speed to be 2kg/h, the rotating speed to be 200rpm, setting the melt extrusion temperature to be 85-95 ℃, starting to collect materials after extruding for 10min, and cutting the materials into pellets with the diameter of 0.5-0.7 mm by a cutter at the tail end for later use; uniformly mixing all components in the enteric coating solution B, and coating by using a fluidized bed coating machine under the conditions that the inlet temperature is 45 ℃, the spraying rate of the coating solution is 3.8 g/min, and the spraying pressure is 1.0 kg/cm2And drying to obtain the enteric sustained-release pellet B.
EXAMPLE 9 preparation of immediate Release pellet A
The prescription of the pill core A is as follows,
novel crystal form A of dexlansoprazole sodium: 8g of the total weight of the mixture;
magnesium carbonate: 11g of a reaction solution;
Kollidon VA64：25g；
PEG6000：9g；
glyceryl behenate: 5g of the total weight of the mixture;
polysorbate 80: 8g of the total weight of the mixture;
tromethamine: 3g of the total weight of the mixture;
croscarmellose sodium: 0.5 g;
the prescription of the enteric coating liquid A is as follows:
jack preferably 93F 19255: 20 parts of (1);
arginine: 11-12 parts;
talc powder: 5 parts of a mixture;
triethyl citrate: 3 parts of a mixture;
water: proper amount;
the weight of the coating is increased by 10 percent;
the pellet is prepared as follows:
uniformly mixing dexlansoprazole new crystal form A, magnesium carbonate, Kollidon VA64, Klucel EF, PEG6000, glyceryl behenate, tromethamine and croscarmellose sodium, adding the mixture into a feeding hopper of a double-screw extruder, setting the feeding speed to be 2kg/h, the rotating speed to be 200rpm, setting the melt extrusion temperature to be 80-90 ℃, starting to collect materials after extruding for 10min, and cutting the materials into pellets with the diameter of 0.5-0.7 mm by a cutter at the tail end for later use; uniformly mixing all components in the enteric coating solution A, and coating by using a fluidized bed coating machine under the conditions that the inlet temperature is 45 ℃, the spraying rate of the coating solution is 3.8 g/min, and the spraying pressure is 1.0 kg/cm2And drying to obtain the enteric fast-release pellet A.
Example 10 preparation of sustained Release pellet B
Novel crystal form A of dexlansoprazole sodium: 20g of the total weight of the mixture;
magnesium carbonate: 30g of the total weight of the mixture;
HPMCP：65g；
yuteqi S100: 25g of the total weight of the mixture;
glyceryl monostearate: 5g of the total weight of the mixture;
glycerol: 6g of a mixture;
sodium taurocholate: 1.5 g;
the formulation of the enteric coating B is as follows,
jack preferably 93F 19255: 20 parts of (1);
arginine: 3-4 parts;
talc powder: 5 parts of a mixture;
polyethylene glycol 4000: 4 parts of a mixture;
water: proper amount;
the weight of the coating is increased by 15 percent;
the pellet is prepared as follows:
the novel crystal form A of the dexlansoprazole sodium, magnesium carbonate, HPMCP, Ewing S100, glyceryl monostearate, polyoxyethylene 40 hydrogenated castor oil KolliphorRH40, glycerol and sodium taurocholate are evenly mixed and then added into a feeding hopper of a double-screw extruder, the feeding speed is set to be 2kg/h, the rotating speed is set to be 200rpm,setting the melt extrusion temperature to be 85-95 ℃, starting to collect materials after extruding for 10min, and cutting the materials into pellets with the diameter of 0.5-0.7 mm by a cutter at the tail end for later use; uniformly mixing all components in the enteric coating solution B, and coating by using a fluidized bed coating machine under the conditions that the inlet temperature is 45 ℃, the spraying rate of the coating solution is 3.8 g/min, and the spraying pressure is 1.0 kg/cm2And drying to obtain the enteric sustained-release pellet B.
EXAMPLE 11 preparation of premix adjuvant Compound
Uniformly mixing 560g of microcrystalline cellulose, 560g of xylitol, 560g of lactose, 60g of povidone K30, 80g of croscarmellose sodium, 40g of magnesium stearate, 40g of mint essence, 40g of aspartame and 6000140g, adding the mixture into a hot-melt extruder, setting the melt extrusion temperature to be 180-240 ℃, preparing granules, grinding and crushing the granules, and sieving the granules by using a 80-100-mesh pharmacopoeia sieve to obtain the premixed auxiliary material compound for later use.
Example 12 preparation of orally disintegrating tablets of the invention, calculated as 1000 tablets, with a specification of 30mg
Novel crystal form A of dexlansoprazole sodium: 2g of the total weight of the mixture;
sodium bicarbonate: 8g of the total weight of the mixture;
enteric quick-release pellet A: 70-75 g, prepared according to the prescription and process of the gastric-soluble quick-release pellet A obtained in the example 7;
enteric sustained-release pellets B: 170-175 g, prepared according to the prescription and process of the enteric sustained-release pellet B obtained in the embodiment 8;
premixing auxiliary material compound: 400g, prepared according to the recipe procedure for premix adjuvant compound of example 11;
the preparation method comprises the following steps:
the enteric fast-release pellets A are prepared according to example 7, the enteric slow-release pellets B are prepared according to example8, and the premix and adjuvant compound is prepared according to example 11, which is not described in detail herein.
Uniformly mixing the novel crystal form A of the dexlansoprazole sodium, sodium bicarbonate, the enteric fast-release pellet A, the enteric slow-release pellet B and the premix auxiliary material compound, and directly tabletting powder to obtain the dexlansoprazole sodium orally disintegrating tablet.
Example 13 preparation of orally disintegrating tablets of the invention, calculated as 1000 tablets, with a specification of 30mg
Novel crystal form A of dexlansoprazole sodium: 2g of the total weight of the mixture;
sodium bicarbonate: 10g of a mixture;
gastric soluble quick release pellet a: 70-75 g, prepared according to the prescription and process of the gastric-soluble quick-release pellet A obtained in the example 7;
enteric sustained-release pellets B: 170-175 g, prepared according to the prescription and process of the enteric sustained-release pellet B obtained in the embodiment 8;
premixing auxiliary material compound: 400g, prepared according to the recipe for premix adjuvant composition of example 11
The preparation method comprises the following steps:
the enteric fast-release pellets A are prepared according to example 7, the enteric slow-release pellets B are prepared according to example8, and the premix and adjuvant compound is prepared according to example 11, which is not described in detail herein.
Uniformly mixing the novel crystal form A of the dexlansoprazole sodium, sodium bicarbonate, the enteric fast-release pellet A, the enteric slow-release pellet B and the premix auxiliary material compound, and directly tabletting powder to obtain the dexlansoprazole sodium orally disintegrating tablet.
Example 14 preparation of orally disintegrating tablets of the invention, calculated as 1000 tablets, with a specification of 30mg
Novel crystal form A of dexlansoprazole sodium: 2g of the total weight of the mixture;
sodium bicarbonate: 8g of the total weight of the mixture;
gastric soluble quick release pellet a: 72-78 g, prepared according to the prescription and process of the gastric-soluble quick-release pellet A obtained in example 9;
enteric sustained-release pellets B: 192-198 g, prepared according to the prescription and process of the enteric sustained-release pellet B obtained in the example 10;
premixing auxiliary material compound: 400g, prepared according to the recipe procedure for premix adjuvant compound of example 11;
the preparation method comprises the following steps:
the enteric fast-release pellets A are prepared according to example 9, the enteric slow-release pellets B are prepared according to example 10, and the premix and adjuvant compound is prepared according to example 11, which is not described in detail herein.
Uniformly mixing the novel crystal form A of the dexlansoprazole sodium, sodium bicarbonate, the enteric fast-release pellet A, the enteric slow-release pellet B and the premix auxiliary material compound, and directly tabletting powder to obtain the dexlansoprazole sodium orally disintegrating tablet.
EXAMPLE 15 preparation of control orally disintegrating tablets
The novel crystal form A of the dexlansoprazole sodium is used for preparing the enteric orally disintegrating tablet by referring to the method in example 1 in Chinese patent CN 102805737A. The operation is as follows: preparing acrylic resin into capsule material solution by using ethanol, adding soybean oil and nano main drug, stirring for 0.5h, slowly adding the solution into 5 times of the volume of aqueous solution containing 0.1% poloxamer while stirring, stirring for 1h, filtering by using a microporous filter membrane, standing for layering, drying precipitates to prepare an enteric nano capsule, and mixing and tabletting the nano capsule with the cross-linked povidone, the magnesium stearate and the citric acid according to the prescription amount to obtain the enteric nano capsule.
Example 16 stability data for orally disintegrating tablets of the invention
From the stability data, the samples of examples 12-14 were accelerated for 6 months, the isomers were slightly increased, the other indexes were not significantly changed, and the indexes were not significantly changed for 12 months, while the control example was accelerated for 6 months, the substances were significantly increased, and the substances were also increased for 12 months. The stability of the embodiment of the invention is improved and optimized.
Example 17 Release test of pellets prepared by three different Processes in pH6.8-7.0 Environment
1) Pellet preparation
The inventor tries to weigh the same weight parts of the novel crystal form A of the dexlansoprazole sodium and the magnesium carbonate, and prepares three kinds of pellets respectively by adopting different processes, wherein the size of the pellets is controlled to be 550-600 um. The preparation method of the sustained-release pellet core A in the embodiment 7 is that the preparation method of the sustained-release pellet core B in the embodiment 8 is that the most commonly used preparation method in the prior art is adopted, namely main drugs, magnesium carbonate, cane sugar and low-substituted hydroxypropyl cellulose are uniformly mixed to obtain solid dusting powder, hydroxypropyl methyl cellulose is dispersed in water to obtain 3% adhesive solution, a blank microcrystalline cellulose pellet core (28-32 meshes) is filled into a centrifugal coating granulator and is sprayed, the obtained pellet particles are dried in an oven at 40 ℃ for 12 hours, and the obtained pellet-carrying agent is coated with an Opadry coating solution to form an isolation layer. The three kinds of pellets are coated with the same enteric coating film. The principle is to examine the dissolution rate of the pellets obtained by different preparation methods, and other factors are kept consistent as much as possible.
2) Dissolution determination
According to the dissolution method of Chinese pharmacopoeia, 900mL of phosphate buffer solution with the pH value of 6.8 is taken as a dissolution medium, the temperature is 37 ℃, the rotating speed is 75 revolutions per minute, the medicine amount in each sample to be tested is 30mg, and the samples are respectively taken at various time points by adopting an ultraviolet spectrophotometry to measure the dissolution, and the results are shown in the following table.
Example 18 pharmacokinetics of dexlansoprazole sodium enteric capsules in rats
The test method comprises the following steps: 12 SD rats with body weight of about 200 + -10 g and male sex are divided into two groups at random, and the two groups are respectively compared with orally disintegrating tablet groups (example 15), wherein the orally disintegrating tablet groups are prepared by taking example 12 as an example and have the specification of 30 mg. The administration dosage of the dexlansoprazole is 6mg per kilogram, samples are taken at 1h, 2h, 4h, 6h, 7h, 8h, 10h and 24h after administration, detection is carried out by an HPLC method, data are recorded, and pharmacokinetic parameters are calculated.
And (3) test results: after rats orally take the control orally disintegrating tablets and the self-made orally disintegrating tablets respectively, the relevant pharmacokinetic parameters are shown in the following table.
Under the condition of the same specification, compared with a control group, the orally disintegrating tablet has the advantages of similar peak reaching time, increased AUC area, improved peak concentration and slow elimination rate, which shows that the orally disintegrating tablet has longer action time, higher bioavailability and more obvious clinical advantages.
Claims (6)
1. An orally disintegrating tablet of dexlansoprazole sodium is characterized by comprising a novel crystal form A of the dexlansoprazole sodium, sodium bicarbonate, an enteric fast-release pellet A, an enteric slow-release pellet B, a premix adjuvant compound and other pharmaceutically acceptable adjuvant tabletting; wherein the chemical structure of the novel crystal form A of the dexlansoprazole sodium is a dimethylacetamide solvate of the dexlansoprazole sodium, and the structural formula is shown as follows;
the enteric fast-release pellet A is prepared by taking a new crystal form A of dexlansoprazole sodium as a raw material medicine, preparing the fast-release pellet A by adopting a hot-melt extrusion process, and coating an enteric coating A, wherein the enteric coating A is decomposed under the condition that the pH value is more than or equal to 5.5;
the enteric sustained-release pellet B is prepared by taking a new crystal form A of the dexlansoprazole sodium as a raw material medicine, preparing the sustained-release pellet B by adopting a hot-melt extrusion process, and coating an enteric coating B, wherein the enteric coating B is decomposed under the condition that the pH value is more than or equal to 6.8;
the premix auxiliary material compound comprises a filler, an adhesive, a disintegrating agent, a lubricant, a flavoring agent and a hot melt auxiliary agent;
the powder X-ray diffraction pattern of the novel crystal form A of the dexlansoprazole sodium has characteristic diffraction peaks at diffraction angles 2 theta of 5.9, 7.6, 12.2, 12.7, 16.6, 18.4, 20.5, 25.8, 26.8 and 31.4 degrees, wherein the error range of the 2 theta value is +/-0.2, and the pattern is shown in the attached figure 1 of the specification; and the DSC spectrum has an endothermic characteristic peak at 132.4 +/-1 ℃ and an exothermic characteristic peak at 204.6 +/-1 ℃, and the spectrum is shown as the attached figure 2 of the specification;
the mass parts of the components are as follows,
novel crystal form A of dexlansoprazole sodium: 1 part;
sodium bicarbonate: 4-6 parts;
enteric quick-release pellet A: 35-40 parts of a solvent;
enteric sustained-release pellets B: 85-100 parts of a binder;
premixing auxiliary material compound: 200-250 parts of a binder;
and, the free dexlansoprazole sodium: dexlansoprazole sodium in the enteric immediate-release pellet A: the weight ratio of the dexlansoprazole sodium in the enteric sustained-release pellet B is 1: 3.8-4.2: 9.8-10.2;
the prescription and the mass portion of the enteric quick-release pellet A are as follows,
dexlansoprazole sodium form a: 10-20 parts;
magnesium carbonate: 10-20 parts;
water-soluble carrier: 40-80 parts of water-soluble carrier, wherein the water-soluble carrier is one or more selected from Plasdone S630, Klucel EF, KollidonVA64 and PEG 6000;
plasticizer: 2-10 parts of glyceryl behenate;
a stabilizer: 10-20 parts of one or more of polysorbate 80 and Soluplus;
anti-aging agent: 2-5 parts of tromethamine;
disintegrating agent: 0.2-1 part of one or more selected from croscarmellose sodium and crospovidone;
the prescription and the mass portion of the enteric sustained-release pellet B are as follows:
dexlansoprazole sodium form a: 10-20 parts;
magnesium carbonate: 10-20 parts;
enteric carrier: 40-80 parts of one or more selected from cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methyl cellulose HPMCP phthalate, hydroxypropyl methyl cellulose acetate succinate HPMCAS, Ewing S100 and Ewing RS 100;
plasticizer: 2-10 parts of one or more selected from glyceryl monostearate and glyceryl behenate;
a stabilizer: 10-20 parts of one or more selected from lauric acid polyethylene glycol glyceride Gelucire44/14 and polyoxyethylene 40 hydrogenated castor oil KolliphorRH 40;
anti-aging agent: 2-5 parts of one or more selected from glycerol and propyl gallate;
release modifier: 0-1 part of one or more selected from sodium taurocholate and carbomer;
the premix auxiliary material compound comprises the following components in parts by weight:
the content of the filler is 75-85%, and the filler is microcrystalline cellulose: xylitol: the weight ratio of lactose is 1: 1: 1;
the content of the adhesive is 2-9%, and the adhesive is povidone K30;
the content of the disintegrating agent is 3-6% and the disintegrating agent is croscarmellose sodium;
the lubricant accounts for 1-3% and is magnesium stearate;
the content of the flavoring agent is 2-4%, and the flavoring agent is mint essence: the weight ratio of aspartame is 1: 1;
the content of the hot-melt auxiliary agent is 5-10% and PEG6000 is used;
the sum of the weight percentages of the components is 100 percent.
2. The orally disintegrating tablet of claim 1, wherein the novel form a of dexlansoprazole sodium has a fourier transform infrared spectrum at wave numbers of 3383 ± 2, 3134 ± 2, 3072 ± 2, 2975 ± 2, 1646 ± 2, 1583 ± 2, 1475 ± 2, 1441 ± 2, 1316 ± 2, 1265 ± 2, 1198 ± 2, 1168 ± 2, 1111 ± 2, 1036 ± 2, 972 ± 2, 915 ± 2, 857 ± 2, 745 ± 2, 662 ± 2 cm-1The characteristic absorption peak is shown in figure 3 in the specification; and the thermogravimetric analysis TG spectrum of the novel crystal form A of the dexlansoprazole sodium is shown in the attached figure 4 of the specification.
3. The orally disintegrating tablet of claim 1, wherein the free dexlansoprazole sodium: dexlansoprazole sodium in the enteric immediate-release pellet A: the weight ratio of the dexlansoprazole sodium in the enteric sustained-release pellet B is 1: 4: 10.
4. the orally disintegrating tablet of claim 1, wherein the premix excipient composition is prepared by the following method: uniformly mixing the filler, the adhesive, the disintegrating agent, the lubricant, the flavoring agent and the hot-melt auxiliary agent, adding the mixture into a hot-melt extruder, setting the temperature of the hot-melt extrusion to be 180-280 ℃, preparing granules, grinding and crushing the granules, and sieving the granules by a 80-100-mesh pharmacopeia sieve to obtain the premixed auxiliary material compound for later use.
5. The orally disintegrating tablet according to claim 1, wherein the enteric immediate release pellet A has a coating formulation and the following parts by mass,
jack preferably 93F 19255: 20 parts of (1);
arginine: 11-12 parts;
talc powder: 5 parts of a mixture;
triethyl citrate: 3 parts of a mixture;
water: proper amount;
the weight of the coating is increased by 10-20%;
the coating prescription and the mass portion of the enteric sustained-release pellet B are as follows,
jack preferably 93F 19255: 20 parts of (1);
arginine: 3-4 parts;
talc powder: 5 parts of a mixture;
polyethylene glycol 4000: 4 parts of a mixture;
water: proper amount;
the weight of the coating is increased by 10-20%.
6. A process for the preparation of orally disintegrating tablets according to any of claims 1 to 5, comprising the steps of:
1) preparing an enteric quick-release pellet A: the novel crystal form A of the dexlansoprazole, a water-soluble carrier, a plasticizer, a stabilizer, an anti-aging agent, a disintegrating agent and magnesium carbonate are uniformly mixed and then added into a feeding hopper of a double-screw extruder, the feeding speed is set to be 2kg/h, the rotating speed is 200rpm, the melt extrusion temperature is set to be 80-120 ℃, after 10min of extrusion, the materials are collected and cut into pellets with the diameter of 0.3-0.8 mm by a cutter at the tail end for later use; uniformly mixing all components in the enteric coating solution A, and coating by using a fluidized bed coating machine under the conditions that the inlet temperature is 45 ℃, the spraying rate of the coating solution is 3.8 g/min, and the spraying pressure is 1.0 kg/cm2Drying to obtain enteric fast-release pellet A;
2) preparing an enteric sustained-release pellet B: the novel crystal form A of the dexlansoprazole sodium, an enteric carrier, a plasticizer, a stabilizer, an anti-aging agent, a release regulator and magnesium carbonate are uniformly mixed and then added into a feeding hopper of a double-screw extruder, the feeding speed is set to be 2kg/h, the rotating speed is 200rpm, the melt extrusion temperature is set to be 80-120 ℃, after 10min of extrusion, the materials are collected and cut into pellets with the diameter of 0.3-0.8 mm by a cutter at the tail end for later use; uniformly mixing all components in the enteric coating solution B, and coating by using a fluidized bed coating machine under the conditions that the inlet temperature is 45 ℃, the spraying rate of the coating solution is 3.8 g/min, and the spraying pressure is 1.0 kg/cm2Drying to obtain enteric sustained-release pellet B;
3) uniformly mixing the novel crystal form A of the dexlansoprazole sodium, sodium bicarbonate, the enteric fast-release pellet A, the enteric slow-release pellet B and the premix auxiliary material compound, and directly tabletting powder to obtain the dexlansoprazole sodium orally disintegrating tablet.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611241494.8A CN106727381B (en) | 2016-12-29 | 2016-12-29 | Orally disintegrating tablet of dexlansoprazole sodium and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201611241494.8A CN106727381B (en) | 2016-12-29 | 2016-12-29 | Orally disintegrating tablet of dexlansoprazole sodium and preparation method thereof |
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| CN101137371A (en) * | 2005-01-14 | 2008-03-05 | 克卡制药新梅斯托股份公司 | Process for preparing lansoprazole |
| CN101977909A (en) * | 2008-03-18 | 2011-02-16 | 雷迪博士实验室有限公司 | Dexlansoprazole process and polymorphs |
| CN102641285A (en) * | 2012-03-12 | 2012-08-22 | 南京海纳医药科技有限公司 | Compound omeprazole capsule and preparation method thereof |
| CN102793706A (en) * | 2012-08-14 | 2012-11-28 | 浙江华海药业股份有限公司 | Preparation method of tolvaptan solid dispersion |
| CN103788068A (en) * | 2014-02-26 | 2014-05-14 | 南京海融医药科技有限公司 | High-melting point chiral benzimidazole compound sodium salt as well as preparation method and application thereof |
| CN104940169A (en) * | 2015-06-26 | 2015-09-30 | 山东省药学科学院 | Dexlansoprazole sustained release capsule and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012095859A1 (en) * | 2011-01-12 | 2012-07-19 | Hetero Research Foundation | Polymorphs of dexlansoprazole salts |
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| CN101137371A (en) * | 2005-01-14 | 2008-03-05 | 克卡制药新梅斯托股份公司 | Process for preparing lansoprazole |
| CN101977909A (en) * | 2008-03-18 | 2011-02-16 | 雷迪博士实验室有限公司 | Dexlansoprazole process and polymorphs |
| CN102641285A (en) * | 2012-03-12 | 2012-08-22 | 南京海纳医药科技有限公司 | Compound omeprazole capsule and preparation method thereof |
| CN102793706A (en) * | 2012-08-14 | 2012-11-28 | 浙江华海药业股份有限公司 | Preparation method of tolvaptan solid dispersion |
| CN103788068A (en) * | 2014-02-26 | 2014-05-14 | 南京海融医药科技有限公司 | High-melting point chiral benzimidazole compound sodium salt as well as preparation method and application thereof |
| CN104940169A (en) * | 2015-06-26 | 2015-09-30 | 山东省药学科学院 | Dexlansoprazole sustained release capsule and preparation method thereof |
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Address after: 210061 122, Hua Kang Road, hi tech Development Zone, Nanjing, Jiangsu. Applicant after: NANJING HAIRONG PHARMACEUTICAL CO., LTD. Applicant after: Chengdu Dikang pharmaceutical Limited by Share Ltd Address before: 210061 122, Hua Kang Road, hi tech Development Zone, Nanjing, Jiangsu. Applicant before: NANJING HAIRONG PHARMACEUTICAL CO., LTD. Applicant before: Chengdu Dikang Pharmaceutical Co., Ltd. |
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Application publication date: 20170531 Assignee: Chongqing Dikang Changjiang Pharmaceutical Co.,Ltd. Assignor: NANJING HAIRONG PHARMACEUTICAL Co.,Ltd.|Chengdu Di Kang medicine companies LLC Contract record no.: X2021510000035 Denomination of invention: The invention relates to an orally disintegrating tablet of right lansoprazole sodium and a preparation method thereof Granted publication date: 20200707 License type: Common License Record date: 20210916 |