CN116832006A - Dexlansoprazole sustained-release pellet - Google Patents

Dexlansoprazole sustained-release pellet Download PDF

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CN116832006A
CN116832006A CN202310615258.1A CN202310615258A CN116832006A CN 116832006 A CN116832006 A CN 116832006A CN 202310615258 A CN202310615258 A CN 202310615258A CN 116832006 A CN116832006 A CN 116832006A
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layer
dexlansoprazole
release
enteric
sustained
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李洪程
刘彬
杨会顺
张雯
赵英霞
王宁宁
王福洲
魏悃
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SHOUGUANG FUKANG PHARMACEUTICAL CO Ltd
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SHOUGUANG FUKANG PHARMACEUTICAL CO Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—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
    • A61K9/5005—Wall or coating material
    • A61K9/501—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—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
    • A61K9/5073—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

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Abstract

The application discloses a dexlansoprazole sustained-release pellet which sequentially comprises a pellet core, a drug layer I, an isolation layer I, an enteric layer I, an isolation layer II, a drug layer II, an isolation layer III and an enteric layer II from inside to outside, wherein the drug layer I, the isolation layer I and the enteric layer I form a sustained-release layer, and the drug layer II, the isolation layer III and the enteric layer II form a quick-release layer. The application combines the sustained-release pellets and the quick-release pellets into a whole, thereby avoiding the technical problem of uneven mixing of the two pellets; the slow release layer is arranged inside, the quick release layer is arranged outside, a drug release mechanism and a release position similar to those of the original ground drug are achieved, and release can be carried out at different parts of the small intestine; meanwhile, compared with the original grinding medicine, the dexlansoprazole sustained-release pellet disclosed by the application has better capsule content, dissolution and acid resistance data than the original grinding medicine.

Description

Dexlansoprazole sustained-release pellet
Technical Field
The application relates to the field of sustained-release pharmaceutical preparations, in particular to a sustained-release pellet of dexlansoprazole.
Background
Dexlansoprazole belongs to a PPIs antiulcer drug of the omeprazole, can inhibit H+/K+ -ATP with high efficiency and high speed, achieves the effect of inhibiting gastric acid secretion, and is the 2 nd proton pump inhibitor after omeprazole. The dexlansoprazole is a dextrorotatory body of lansoprazole, the chemical structure of sulfinyl benzimidazole exists in the structure, the stability is easily influenced by various factors such as light, heavy metal ions, oxidizing and reducing components, and the like, and the stability is unstable to damp and heat. Especially under acidic conditions, the chemical structure of dexlansoprazole may undergo destructive changes, and discoloration and polymerization occur, so that dexlansoprazole is unstable in a slightly acidic diluent. After the preparation is prepared into an oral preparation, the medicine is required to be absorbed through a medicine disintegration and release process, but the dexlansoprazole is destroyed and decomposed due to gastric acid in the stomach, so that the acting speed and bioavailability of the medicine are reduced.
In order to prolong the acting time and reduce the frequency and dosage of taking medicines, the enteric preparation is generally prepared, and a typical composition adopts two pellets, namely quick release pellets and slow release pellets, for example, dexrazoxane enteric capsule dexrazoxane, which is a dexrazoxane controlled release capsule (Japanese Wuta-tsu corporation) approved by the United states FDA in 2009 and marketed, is a proton pump inhibitor with twice release characteristics for the first time worldwide, and each capsule contains two pellets, namely an enteric quick release pellet A and an enteric slow release pellet B, which can be released twice in sequence at different parts of the small intestine and can permanently inhibit gastric acid secretion. The prior technical improvement mainly comprises improvement of two micropill compositions of quick release and slow release, and improvement of slow release effect, for example, CN107648231A discloses a dexlansoprazole drug preparation comprising an enteric quick release micropill and an enteric delay micropill, wherein a delay layer of the enteric delay micropill adopts hydroxypropyl methylcellulose phthalate (HPMCP) and methacrylic acid copolymer S100 to be mixed according to a specific proportion, so that the effects of good acid control effect, stable drug release and long maintenance time are achieved.
However, the enteric materials of the two pellets are different, so that the surface roughness of the pellets is different, and the situation of uneven mixing of the two pellets during capsule filling can occur, so that the dosage uniformity of a finished product is influenced, and the exertion of the drug effect is influenced. In order to avoid the mixing problem of the two pellets, CN103961329A discloses a novel enteric preparation of a dexlansoprazole multilayer coating system, which comprises a drug layer I, an isolation layer III-1, an enteric coating layer IV-1, an isolation layer III-2, a drug layer II, an isolation layer III-3 and an enteric coating layer IV-2 from inside to outside. However, the enteric coating layer IV-2 of this patent comprises acrylic resins S100, L100, wherein S100 releases drug when the pH reaches about 7.0 and L100 releases drug when the pH reaches about 6.0, and the mixture releases drug when the pH reaches about 6.75, i.e., at the distal end of the small intestine. Has low bioavailability and short acting time, and can not achieve the same or similar drug release mechanism and drug effect of the original ground drug.
The medicine release mechanism which is the same or similar to the original medicine is achieved, the mixing problem of the two pellets is solved, and the similar or higher medicine effect is the technical problem which is not solved yet for the dexlansoprazole medicine preparation.
Disclosure of Invention
In order to solve the technical problems, the first aspect of the application provides a quick-release micropill and a slow-release micropill, namely a two-in-one dexlansoprazole sustained-release micropill, wherein the quick-release micropill is prepared on the basis of the sustained-release micropill, so that the problem of uneven mixing is avoided. The technical scheme adopted is as follows:
the dexlansoprazole sustained-release pellet sequentially comprises a pellet core, a drug layer I, an isolation layer I, an enteric layer I, an isolation layer II, a drug layer II, an isolation layer III and an enteric layer II from inside to outside (the structural schematic diagram is shown in figure 1); the medicine layer I and the medicine layer II comprise dexlansoprazole and pharmaceutic adjuvants; the enteric layer I comprises 3% -10% of methacrylic acid copolymer A type S100,8% -30% of methacrylic acid copolymer B type L100,1% -3% of plasticizer and 1-10% of anti-adhesion agent, and the enteric layer II comprises 5% -15% of methacrylic acid copolymer dispersion L30D-55, methacrylic acid copolymer dispersion 100-55 or hydroxypropyl methylcellulose phthalate, 0.5% -1.5% of plasticizer, 0.5% -1.5% of solubilizer and 1-5% of anti-adhesion agent; the percentage refers to the mass percentage of the component in the pellet.
Wherein the medicine layer I, the isolation layer I and the enteric layer I form a slow release layer, the medicine layer II, the isolation layer III and the enteric layer II form a quick release layer, and the slow release layer is isolated from the quick release layer through the isolation layer II; the slow release layer and the quick release layer realize slow release or quick release effect mainly through the composition of the enteric layer. Methacrylic acid copolymer type A S100, commercially available as Uttky S100, is a 1:1 copolymer of methacrylic acid and methyl methacrylate; the product name of the methacrylic acid copolymer B type L100 is Eudragit L100, and the methacrylic acid copolymer B type L100 is a copolymer of methacrylic acid and methyl methacrylate in a ratio of 1:2; methacrylic acid copolymer dispersions 100-55, commercially available under the trade name Uttky 100-55, are 1:1 copolymers of methacrylic acid and ethyl acrylate; the methacrylic acid copolymer dispersion L30D-55, which was designated by the trade name Uttky L30D-55, was an aqueous dispersion of a copolymer of methacrylic acid and ethyl acrylate in a ratio of 1:1 and had a solids content of 30%.
Preferably, the plasticizer in the enteric layer I or the enteric layer II is selected from one or more of triethyl citrate, polyethylene glycol, dibutyl phthalate and propylene glycol; more preferably, the plasticizer is triethyl citrate.
Preferably, the anti-adhesion agent in the enteric layer I or the enteric layer II is selected from one or two of talcum powder and glyceryl monostearate; more preferably, the anti-sticking agent is talc.
Preferably, the solubilizer in the enteric layer II is selected from one or two of Tween 80 and poloxamer; more preferably, the solubilizing agent is tween 80. The dexlansoprazole drug substance is slightly soluble in water, and tween 80 is a solubilizer, so that the release in vivo can be increased, and the bioavailability of the drug is increased.
In a preferred embodiment, the enteric layer I comprises 3% -10% methacrylic acid copolymer type a S100,8% -30% methacrylic acid copolymer type B L100,1% -3% triethyl citrate and 1-10% talc; the percentage refers to the mass percentage of the component in the pellet.
In a preferred embodiment, the enteric layer II comprises 5% to 15% methacrylic acid copolymer dispersion L30D-55,0.5% to 1.5% triethyl citrate, 0.5% to 1.5% tween 80 and 1% to 5% talc; the percentage refers to the mass percentage of the component in the pellet.
In a preferred embodiment, the drug layer I comprises 10% -20% dexlansoprazole and the drug layer II comprises 3% -10% dexlansoprazole, by which is meant the mass percentage of the component in the pellet.
In one or more embodiments, the pharmaceutical excipients in drug layer I or drug layer II include binders, alkalizers, and disintegrants.
Preferably, the binder is selected from one or more of povidone K30, povidone K90, starch, sodium carboxymethylcellulose, hypromellose, hyprolose, dextrin, sucrose; more preferably, the binder is povidone K30. Preferably, the alkalizing agent is one or more of heavy magnesium carbonate, magnesium hydroxide, sodium hydroxide and ammonia water; more preferably, the alkalizing agent is magnesium carbonate. Preferably, the disintegrating agent is one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch and croscarmellose sodium; more preferably, the disintegrant is low substituted hydroxypropyl cellulose.
In a preferred embodiment, the drug layer I comprises 10% -20% dexlansoprazole, 5% -10% binder, 2% -7% alkalizing agent and 2% -5% disintegrating agent; more preferably, the medicine layer I comprises 10% -20% of dexlansoprazole, 5% -10% of povidone K30,2% -7% of heavy magnesium carbonate and 2% -5% of low-substituted hydroxypropyl cellulose, wherein the percentages refer to the mass percentage of the components in the pellets.
In a preferred embodiment, the drug layer II comprises 3% -10% dexlansoprazole, 2% -8% binder, 1% -5% alkalizing agent and 1% -3% disintegrating agent; more preferably, the medicine layer I comprises 3% -10% of dexlansoprazole, 2% -8% of povidone K30,1% -5% of heavy magnesium carbonate and 1% -3% of low-substituted hydroxypropyl cellulose, wherein the percentages refer to the mass percentage of the components in the pellets.
In one or more embodiments, the barrier layer I or III comprises a barrier polymer, an anti-adhesion agent, and titanium dioxide, and the barrier layer II comprises a barrier polymer; preferably, the isolating polymer is hypromellose, and the anti-adhesion agent is one or more of talcum powder, glyceryl monostearate and titanium dioxide.
In a preferred embodiment, the barrier layer I comprises 2% to 6% hypromellose, 1% to 5% talc and 1.5% to 3% titanium dioxide; the isolation layer II comprises 2% -6% of hydroxypropyl methylcellulose; the isolation layer III comprises 1% -10% of hypromellose, 0.1% -5% of talcum powder and 0.1% -5% of titanium dioxide; the percentage refers to the mass percentage of the component in the pellet.
In one or more embodiments, the pellet core is a sucrose pellet core; preferably, the dosage of the pill core accounts for 5-15% of the mass of the pellet; more preferably, the pellet core has a diameter of 250-350 μm.
In a preferred embodiment, the composition of the dexlansoprazole sustained-release pellets of the present application is shown in table 1.
TABLE 1 composition of dexlansoprazole sustained-release pellets
In order to achieve the same or similar drug release mechanism of the original ground drug (the original ground drug release curve, as shown in fig. 2, is derived from the FDA drug specification), the dexlansoprazole sustained-release pellet is mainly improved by the following aspects: (1) The quick release layer of the slow release pellet is arranged on the outer side and the slow release layer is arranged on the inner side, in the process of releasing the medicine, the quick release layer is firstly released to reach the effective treatment concentration of the medicine, then the slow release layer releases the medicine, and the double controlled release of the medicine is respectively released at the proximal end and the distal end of the small intestine and is the same as the release mechanism and the release position of the original medicine, so that the action time of the medicine is prolonged; (2) Because the quick release and the slow release of the slow release pill are in sequence and the speed is slightly slower than that of the two micropills, the disintegrating agent is also added in the medicine layer I and the medicine layer II of the slow release pill, the solubilizer is also added in the enteric layer II, and the proportion of each layer and the composition ratio of each layer are adjusted, so that the effect basically consistent with that of the original ground medicine is achieved.
The second aspect of the application provides a preparation method of the dexlansoprazole sustained-release pellet, which comprises the following steps: on the basis of the sucrose pill core, the coating of a medicine layer I, an isolation layer I, an enteric layer I, an isolation layer II, a medicine layer II, an isolation layer III and an enteric layer II is sequentially carried out.
Preferably, the method comprises:
1. preparation of a sustained release layer
1.1 preparation of drug layer I
1.1.1 adhesive formulation: weighing the adhesive, the disintegrating agent and the purified water according to the prescription amount, and dissolving the adhesive in the purified water until the adhesive is clear and transparent for standby;
1.1.2 preparation of liquid medicine: weighing the dexlansoprazole raw material medicine according to the prescription amount, and dissolving the dexlansoprazole raw material medicine in an adhesive; adding an alkalizing agent, and stirring for later use.
1.1.3 fluidized bed dosing: the method comprises the steps of (1) putting a blank pill core with a prescription amount into a fluidized bed material chamber, setting parameters such as air inlet temperature, air inlet quantity, spray gun atomization pressure and the like, coating liquid medicine to the blank pill core, and drying after coating is finished to obtain a medicine layer base pill;
1.2 preparation of isolation layer I
1.2.1 preparation of barrier layer solution: respectively weighing each auxiliary material of the isolation layer I according to the prescription amount, dispersing the isolation polymer into purified water, fully stirring, adding an anti-sticking agent (talcum powder and titanium dioxide), and uniformly stirring for later use;
1.2.2 isolation layer fluid bed coating: the prepared drug layer base pill is put into a fluidized bed material chamber, parameters such as air inlet temperature, air inlet quantity, spray gun atomization pressure and the like are set, an isolation layer is coated on the drug layer pill, and the drug layer pill is dried after coating is finished, so that sustained-release isolation layer micropill is obtained;
1.3 preparation of sustained-Release enteric layer I
1.3.1 preparation of enteric coating liquid: respectively weighing the auxiliary materials of the enteric layer I with the prescription amount, adding the plasticizer into 95% ethanol, stirring and dissolving, adding the methacrylic acid copolymer A type S100 and the methacrylic acid copolymer B type L100, adding the anti-adhesion agent, and stirring for later use.
1.3.2 enteric layer fluidized bed coating: the prepared sustained release isolation layer pellets are put into a fluidized bed material chamber, parameters such as air inlet temperature, air inlet quantity, spray gun atomization pressure and the like are set, enteric coating layer coating liquid is coated on the sustained release isolation layer pellets, and the sustained release pellets are obtained after coating is finished;
2. isolation layer II
2.1 preparation of coating liquid: weighing auxiliary materials with a prescription amount, adding the isolating polymer into purified water, stirring and dissolving for later use;
2.2 barrier coating: putting the slow-release pellets into a fluidized bed, setting parameters such as air inlet temperature, air inlet quantity, spray gun atomization pressure and the like, and drying after coating is finished to obtain isolation layer pellets;
3. preparation of immediate release layer
3.1 the operation method of the drug layer II and the isolation layer III is consistent with that of the slow release layer.
3.2 preparation of enteric layer II
3.2.1 preparation of coating liquid: weighing the auxiliary materials of the enteric layer II according to the prescription, adding the plasticizer into purified water, stirring and dissolving, adding the methacrylic acid copolymer dispersion L30D-55, the methacrylic acid copolymer dispersion 100-55 or the hydroxypropyl methylcellulose phthalate, stirring and dispersing, adding the solubilizer and the anti-adhesion agent, and stirring for standby.
3.2.2 enteric coating
And (3) putting the prepared isolation layer pellets into a fluidized bed material chamber, setting parameters such as air inlet temperature, air inlet quantity, spray gun atomization pressure and the like, coating enteric coating layer coating liquid on the isolation layer pellets, and drying after coating is finished to obtain the dexlansoprazole sustained-release pellets.
Further preferably, the method comprises:
1. preparation of a sustained release layer
1.1 preparation of drug layer I
1.1.1 adhesive formulation: weighing povidone K30, low-substituted hydroxypropyl cellulose and purified water according to the prescription amount, and dissolving the adhesive in the purified water until the adhesive is clear and transparent for later use;
1.1.2 preparation of liquid medicine: weighing the dexlansoprazole raw material medicine according to the prescription amount, and dissolving the dexlansoprazole raw material medicine in an adhesive; adding an alkalizing agent, and stirring for later use.
1.1.3 fluidized bed dosing: the blank pill core with the prescription amount is put into a fluidized bed material chamber, the air inlet temperature is set to be 40-70 ℃ and the air inlet quantity is set to be 350-1000m 3 And/h, spraying the liquid medicine to the blank pill core at a spraying speed of 10-30% at an atomization pressure of 1.5-3.0bar by a spray gun, and drying for at least 30 minutes after the coating is finished to obtain a medicine layer base pill;
1.1.4 sieving
Putting the dried drug layer base pills into a sieving machine, collecting micro pills with the particle size of below 35 meshes and above 60 meshes, and performing the next operation;
1.2 preparation of isolation layer I
1.2.1 preparation of barrier layer solution: respectively weighing each auxiliary material of the isolation layer I according to the prescription amount, dispersing hydroxypropyl methylcellulose into purified water, fully stirring, adding talcum powder and titanium dioxide, and uniformly stirring for later use;
1.2.2 isolation layer fluid bed coating: the prepared drug layer base pill is put into a fluidized bed material chamber, the air inlet temperature is set to be 40-70 ℃ and the air inlet quantity is set to be 350-1200m 3 And/h, spraying the drug into the drug pellets at a spray gun atomization pressure of 1.5-4.0bar and a spray speed of 10-30%, coating the drug pellets with an isolation layer, and drying after coating to obtain sustained release isolation layer pellets;
1.3 preparation of sustained-Release enteric layer I
1.3.1 preparation of enteric coating liquid: respectively weighing the auxiliary materials of the enteric layer I with the prescription dosage, adding the triethyl citrate into 95% ethanol, stirring and dissolving, adding the methacrylic acid copolymer A type S100 and the methacrylic acid copolymer B type L100, adding talcum powder, and stirring for later use.
1.3.2 enteric layer fluidized bed coating: the prepared sustained release isolation layer pellets are put into a fluidized bed material chamber,setting air inlet temperature at 25-45deg.C and air inlet volume at 500-1500m 3 And/h, spraying the enteric coating layer coating liquid to the sustained release isolation layer pellets at the spray gun atomization pressure of 1.5-4bar and the spray speed of 10-30%, and drying after coating is finished to obtain the sustained release pellets;
1.3.3 sieving
And (3) putting the dried pellets into a sieving machine, collecting pellets with the size of below 30 meshes and more than 50 meshes, and performing the next operation.
2. Isolation layer II
2.1 preparation of coating liquid: weighing auxiliary materials with a prescription amount, adding hypromellose into purified water, stirring and dissolving for later use;
2.2 barrier coating: putting the sustained-release pellets into a fluidized bed, setting the air inlet temperature at 40-70deg.C and the air inlet volume at 350-1200m 3 And/h, spray gun atomization pressure is 1.5-4.0bar, spray speed is 10-30%, and after coating is completed, the pellets of the isolation layer are obtained;
3. preparation of immediate release layer
3.1 preparation of drug layer II
3.1.1 preparation method of adhesive and coating liquid, coating parameters are consistent with the drug layer I of the slow-release layer;
3.1.2 sieving
And (3) putting the dried pellets into a sieving machine, collecting pellets with the size of more than 50 meshes below 25 meshes, and carrying out the next operation.
3.2 preparation of isolation layer III
3.2.1 coating liquid preparation method and coating parameters are consistent with the isolation layer I of the slow release layer.
3.2.2 sieving
And (3) putting the dried pellets into a sieving machine, collecting pellets with the size of below 25 meshes and 45 meshes, and performing the next operation.
3.3 preparation of enteric layer II
3.3.1 preparation of coating liquid
Weighing the auxiliary materials of the enteric layer according to the prescription, adding triethyl citrate into purified water, stirring and dissolving, adding the methacrylic acid copolymer dispersion, stirring and dispersing, adding tween 80 and talcum powder, and stirring for standby.
3.3.2 enteric coating
The coating parameters are consistent with those of the enteric coating layer I of the slow release layer.
3.3.3 sieving
And (3) putting the dried pellets into a sieving machine, and collecting pellets with the size of below 18 meshes and the size of above 40 meshes to obtain the dexlansoprazole sustained-release pellets.
In a third aspect of the application, a dexlansoprazole enteric-coated capsule is provided, comprising the dexlansoprazole sustained-release pellet of the application.
Preferably, the preparation method of the dexlansoprazole enteric capsule comprises the following steps: weighing talcum powder according to the weight of the pellets, setting mixing time and mixing rotating speed, and carrying out total mixing by using a hopper mixer; and calculating filling quantity according to the content of the pellets, setting parameters such as filling speed and the like, and filling the capsule to obtain the dexlansoprazole enteric capsule. More preferably, the mixing time is 10min, the mixing speed is 7rpm, and the filling speed is 3.6 ten thousand/hour.
Compared with the prior art, the application has the beneficial effects that at least:
1. the application combines the sustained-release pellets and the quick-release pellets into a whole, thereby avoiding the technical problem of uneven mixing of the two pellets.
2. The slow release layer is arranged inside, the quick release layer is arranged outside, the quick release layer comprises two coating materials, and then the disintegrating agent is added into the medicine layer, the dosage proportion is adjusted, and the like, so that a medicine release mechanism and a release position similar to those of the original medicine are achieved, the medicine can be released at different parts of the small intestine, the local medicine concentration is prevented from being too high, the accumulation of the medicine in the body can be reduced, and the medicine effect is stably and durably exerted.
3. According to the application, the medicine layer is added, the alkalizing agent is added, and an alkaline microenvironment is formed in the medicine release process, so that the stability of the active ingredients is enhanced; the components of the medicine layer I, the medicine layer II and the isolation layer I and the isolation layer III are basically consistent, the types of auxiliary materials are reduced, and the stability of the medicine is improved.
4. Compared with the original grinding medicine, the content, the dissolution rate and the acid resistance data of the application are superior to those of the original grinding medicine, and the impurity is less than that of the reference preparation, thus having certain advantages in the aspect of stability.
Drawings
FIG. 1 is a schematic diagram of a multilayer structure of a dexlansoprazole sustained-release pellet;
FIG. 2 is a graph of dexlansoprazole plasma concentration versus time following oral administration of the original drug substance DEXILANT;
FIG. 3 is the in vitro dissolution data results of the dexlansoprazole sustained release pellet capsule of example 1 with the original drug substance and the comparative example.
Detailed Description
In order to make the objects, technical solutions and advantageous effects of the present application more apparent, the present application will be described in further detail with reference to the accompanying drawings and specific embodiments. Examples of which are illustrated in the accompanying drawings. It should be understood that the specific examples described in the following embodiments of the present application are intended to be illustrative of the specific embodiments of the present application and are not to be construed as limiting the application.
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein. In the description of the present application, unless otherwise indicated, the meaning of "a", "an", "a plurality" and the like are two or more.
Example 1 preparation of dexlansoprazole sustained-release pellets and capsules a composition of dexlansoprazole sustained-release pellets is shown in table 2:
table 2 composition of dexlansoprazole sustained-release pellets of example 1
The preparation method of the dexlansoprazole sustained-release pellet and the capsule comprises the following steps: 1. preparation of a sustained release layer
1.1 preparation of drug layer I
1.1.1 adhesive formulation: weighing povidone K30, low-substituted hydroxypropyl cellulose and purified water according to the prescription amount, and dissolving the adhesive in the purified water until the adhesive is clear and transparent for later use;
1.1.2 preparation of liquid medicine: weighing the dexlansoprazole raw material medicine according to the prescription amount, and dissolving the dexlansoprazole raw material medicine in an adhesive; adding an alkalizing agent, and stirring for later use.
1.1.3 fluidized bed dosing: the blank pill core with the prescription amount is put into a fluidized bed material chamber, the air inlet temperature is set to be 40-70 ℃ and the air inlet quantity is set to be 350-1000m 3 And/h, spraying the liquid medicine to the blank pill core at a spraying speed of 10-30% at an atomization pressure of 1.5-3.0bar by a spray gun, and drying for at least 30 minutes after the coating is finished to obtain a medicine layer base pill;
1.1.4 sieving
Putting the dried drug layer base pills into a sieving machine, collecting micro pills with the particle size of below 35 meshes and above 60 meshes, and performing the next operation;
1.2 preparation of isolation layer I
1.2.1 preparation of barrier layer solution: respectively weighing each auxiliary material of the isolation layer I according to the prescription amount, dispersing hydroxypropyl methylcellulose into purified water, fully stirring, adding talcum powder and titanium dioxide, and uniformly stirring for later use;
1.2.2 isolation layer fluid bed coating: the prepared drug layer base pill is put into a fluidized bed material chamber, the air inlet temperature is set to be 40-70 ℃ and the air inlet quantity is set to be 350-1200m 3 And/h, spraying the drug into the drug pellets at a spray gun atomization pressure of 1.5-4.0bar and a spray speed of 10-30%, coating the drug pellets with an isolation layer, and drying after coating to obtain sustained release isolation layer pellets;
1.3 preparation of sustained-Release enteric layer I
1.3.1 preparation of enteric coating liquid: respectively weighing the auxiliary materials of the enteric layer I with the prescription dosage, adding the triethyl citrate into 95% ethanol, stirring and dissolving, adding the methacrylic acid copolymer A type S100 and the methacrylic acid copolymer B type L100, adding talcum powder, and stirring for later use.
1.3.2 enteric layer fluidized bed coating: the prepared sustained release isolation layer pellets are put into a fluidized bed material chamber, the air inlet temperature is set to be 25-45 ℃ and the air inlet quantity is set to be 500-1500m 3 /h, spray gun atomizationCoating enteric coating layer coating liquid to the sustained release isolation layer pellets at a pressure of 1.5-4bar and a spraying speed of 10-30%, and drying after coating is completed to obtain the sustained release pellets;
1.3.3 sieving
And (3) putting the dried pellets into a sieving machine, collecting pellets with the size of below 30 meshes and more than 50 meshes, and performing the next operation.
2. Isolation layer II
2.1 preparation of coating liquid: weighing auxiliary materials with a prescription amount, adding hypromellose into purified water, stirring and dissolving for later use;
2.2 barrier coating: putting the sustained-release pellets into a fluidized bed, setting the air inlet temperature at 40-70deg.C and the air inlet volume at 350-1200m 3 And/h, spray gun atomization pressure is 1.5-4.0bar, spray speed is 10-30%, and the isolation layer pellets are obtained after coating is finished and drying is carried out.
3. Preparation of immediate release layer
3.1 preparation of drug layer II
3.1.1 preparation method of adhesive and coating liquid, coating parameters are consistent with the drug layer I of the slow-release layer;
3.1.2 sieving
And (3) putting the dried pellets into a sieving machine, collecting pellets with the size of more than 50 meshes below 25 meshes, and carrying out the next operation.
3.2 preparation of isolation layer III
3.2.1 coating liquid preparation method and coating parameters are consistent with the isolation layer I of the slow release layer.
3.2.2 sieving
And (3) putting the dried pellets into a sieving machine, collecting pellets with the size of below 25 meshes and 45 meshes, and performing the next operation.
3.3 preparation of enteric layer II
3.3.1 preparation of coating liquid
Weighing the auxiliary materials of the enteric layer according to the prescription, adding triethyl citrate into purified water, stirring and dissolving, adding the methacrylic acid copolymer dispersion, stirring and dispersing, adding tween 80 and talcum powder, and stirring for standby.
3.3.2 enteric coating
The coating parameters are consistent with those of the enteric coating layer I of the slow release layer.
3.3.3 sieving
And (3) putting the dried pellets into a sieving machine, and collecting pellets with the size of below 18 meshes and the size of above 40 meshes to obtain the dexlansoprazole sustained-release pellets.
4. General mixing
The talcum powder is weighed according to the weight of the pellets, the mixing time is set to be 10 minutes, the rotating speed is 7rpm, and a hopper mixer is used for total mixing.
5. Capsule filling
And calculating the weight of the central tablet according to the content of the pellets, setting the filling speed to be 3.6 ten thousand/hour, and filling capsules.
EXAMPLE 2 preparation of dexlansoprazole sustained-release pellets and capsules
The compositions of the dexlansoprazole sustained-release pellets are shown in table 3, and the preparation methods of the dexlansoprazole sustained-release pellets and capsules are the same as those of example 1.
TABLE 3 composition of dexlansoprazole sustained-release pellets of example 2
Test example 3 dissolution and stability of dexlansoprazole sustained-release pellets
In vitro dissolution data:
the dexlansoprazole sustained-release pellet capsules of example 1 were tested for in vitro dissolution data using the dissolution method recommended in the U.S. FDA dissolution method database, using basket method, 100rpm, first acid-resistant for 120 minutes under 500ml of 0.1n hydrochloric acid, then transferred to ph7.0 phosphate buffer, 900ml, and sampled at different time points at the same rotational speed. The results of in vitro dissolution data are shown in FIG. 3, comparing the capsule prepared in example 1 of the original drug DEXILANT (abbreviated as original drug) with the capsule prepared in example 1 of CN103961329A (abbreviated as comparative example).
The results show that the comparative example has larger in-vitro dissolution behavior and the original grinding medicine, and the in-vivo bioequivalence is reasonably deduced to be poor; the dexlansoprazole enteric-coated capsule prepared by the technical scheme has a more similar in-vitro dissolution curve as the original ground drug.
Stability test:
stability tests were performed on the dexlansoprazole sustained release pellet capsules of example 1.
The method for detecting the content of the original grinding medicine comprises the following steps: taking 20 pieces of content of the product, precisely weighing, mixing, grinding, precisely weighing a proper amount of fine powder, namely about 10mg containing dexlansoprazole, placing into a 100ml measuring flask, adding solvent and carrying out ultrasonic treatment to dissolve and dilute the pellets to a scale, filtering with a 0.45 mu m microporous filter membrane, taking the continuous filtrate as a sample solution, precisely weighing 10 mu l, injecting into a liquid chromatograph, and recording a chromatogram; and precisely weighing a proper amount of dexlansoprazole reference substance, dissolving in a solvent, quantitatively diluting to obtain a solution containing about 0.1mg of dexlansoprazole reference substance per 1ml, and measuring by the same method. Calculated by the external standard method and peak area, the content is 90.0 to 110.0 percent of the marked amount
The dissolution rate detection method comprises the following steps: according to the release degree measuring method of the 2020 edition of Chinese pharmacopoeia, 500ml of 0.1mol/L hydrochloric acid solution is used as a release medium by adopting a basket method and 100rpm, acid is resisted for 120 minutes, then the solution is transferred to a phosphate buffer solution with pH of 7.0, 900ml, the rotating speed is kept unchanged, and the release amounts of 20 minutes, 50 minutes and 105 minutes in the buffer solution are respectively more than 15 percent, less than 35 percent and more than 80 percent of the marked amount, and all the release amounts are in accordance with the regulations.
Related substances: taking the content of the product, grinding, precisely weighing a proper amount, namely 30mg of dexlansoprazole, placing in a measuring flask with 10ml, diluting to a scale, centrifuging, taking a supernatant with a 0.45 mu m filter membrane for filtering, precisely measuring 2ml of the subsequent filtrate, placing in a measuring flask with 10ml, diluting to the scale, and shaking uniformly to obtain a sample solution; taking proper amounts of the dexlansoprazole reference substance and the lansoprazole sulfide reference substance, adding methanol for dissolving and quantitatively diluting to prepare mixed solution containing about 30 mug of each of the dexlansoprazole and the lansoprazole sulfide reference substance in 1ml, taking 1ml, placing the mixed solution into a 50ml measuring flask, adding solvent for dilution to a scale, wherein the single impurity is less than 0.15%, and the total impurity is less than 1.0%.
The results of measuring the content, dissolution rate, acid resistance and related substances of example 1 and the original grinding powder at 0 month, 3 months and 6 months of acceleration by setting acceleration conditions (40 ℃ + -2 ℃/75% RH+ -5% RH) are shown in Table 4. The results show that the product prepared in the embodiment 1 of the application is placed for 6 months, the content, the dissolution and the acid resistance data are all superior to those of the original grinding medicine, the impurities are less than those of the original grinding medicine, and the product has certain advantages in the aspect of stability.
Table 4 stability test results
Content uniformity:
the content uniformity of the dexlansoprazole sustained-release pellet capsule and the original ground drug of the example 1 is tested, 1 capsule is taken, the content is poured into a 200ml measuring flask, the solvent under the content measuring item is added for ultrasonic dissolution and dilution of the pellets to scale, centrifugation is carried out, the supernatant is filtered by a microporous filter membrane with the size of 0.45 mu m, the subsequent filtrate is taken as a sample solution, and the content measurement is carried out by using an HPLC method, so that the requirements of pharmacopoeia are met. The test results are shown in table 5, and the results show that the dexlansoprazole sustained-release pellet capsule provided by the application has better content uniformity.
TABLE 5 content uniformity comparison
Content of Example 1 Original grinding medicine
Average content (%) 100.2 99.3
Content uniformity (A+2.2S) 2.5 5.6
Finally, the above embodiments are only for illustrating the technical solution of the present application, and do not limit the present application. Within the scope of the technical idea of the application, a number of simple variants of the technical solution of the application are possible, including combinations of the individual technical features in any other suitable way, which simple variants and combinations should likewise be regarded as being disclosed by the application, all falling within the scope of protection of the application.

Claims (10)

1. The dexlansoprazole sustained-release pellet is characterized by comprising a pellet core, a drug layer I, an isolation layer I, an enteric layer I, an isolation layer II, a drug layer II, an isolation layer III and an enteric layer II from inside to outside in sequence; the medicine layer I and the medicine layer II comprise dexlansoprazole and pharmaceutic adjuvants; the enteric layer I comprises 3% -10% of methacrylic acid copolymer A type S100,8% -30% of methacrylic acid copolymer B type L100,1% -3% of plasticizer and 1-10% of anti-adhesion agent, and the enteric layer II comprises 5% -15% of methacrylic acid copolymer dispersion L30D-55, methacrylic acid copolymer dispersion 100-55 or hydroxypropyl methylcellulose phthalate, 0.5% -1.5% of plasticizer, 0.5% -1.5% of solubilizer and 1-5% of anti-adhesion agent; the percentage refers to the mass percentage of the component in the pellet.
2. The dexlansoprazole sustained-release pellet as claimed in claim 1, wherein the plasticizer in the enteric layer I or the enteric layer II is selected from one or more of triethyl citrate, polyethylene glycol, dibutyl phthalate and propylene glycol; more preferably, the plasticizer is triethyl citrate;
the anti-adhesion agent in the enteric layer I or the enteric layer II is selected from one or two of talcum powder and glyceryl monostearate; more preferably, the anti-sticking agent is talc;
the solubilizer in the enteric layer II is one or two selected from Tween 80 and poloxamer; more preferably, the solubilizing agent is tween 80.
3. A dexlansoprazole sustained-release pellet as defined in claim 2, wherein the enteric layer I comprises 3% -10% methacrylic acid copolymer type a S100,8% -30% methacrylic acid copolymer type B L100,1% -3% triethyl citrate and 1-10% talc;
the enteric layer II comprises 5% -15% of methacrylic acid copolymer dispersion L30D-55,0.5% -1.5% of triethyl citrate, 0.5% -1.5% of Tween 80 and 1-5% of talcum powder; the percentage refers to the mass percentage of the component in the pellet.
4. The dexlansoprazole sustained-release pellet as claimed in claim 1, wherein the drug layer I comprises 10% -20% of dexlansoprazole, the drug layer II comprises 3% -10% of dexlansoprazole, and the% means that the component accounts for the mass percentage of the pellet.
5. The dexlansoprazole sustained-release pellet as claimed in claim 4, wherein the pharmaceutical excipients in the drug layer I or the drug layer II comprise an adhesive, an alkalizing agent and a disintegrating agent;
preferably, the binder is selected from one or more of povidone K30, povidone K90, starch, sodium carboxymethylcellulose, hypromellose, hyprolose, dextrin, sucrose; more preferably, the binder is povidone K30;
preferably, the alkalizing agent is one or more of heavy magnesium carbonate, magnesium hydroxide, sodium hydroxide and ammonia water; more preferably, the alkalizing agent is magnesium carbonate;
preferably, the disintegrating agent is one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch and croscarmellose sodium; more preferably, the disintegrant is low substituted hydroxypropyl cellulose.
6. A dexlansoprazole sustained-release pellet as defined in claim 5, wherein the drug layer I comprises 10% -20% dexlansoprazole, 5% -10% binder, 2% -7% alkalizing agent, and 2% -5% disintegrating agent; more preferably, the drug layer I comprises 10% -20% of dexlansoprazole, 5% -10% of povidone K30,2% -7% of heavy magnesium carbonate and 2% -5% of low substituted hydroxypropylcellulose;
the medicine layer II comprises 3% -10% of dexlansoprazole, 2% -8% of adhesive, 1% -5% of alkalizing agent and 1% -3% of disintegrating agent; more preferably, the medicine layer I comprises 3% -10% of dexlansoprazole, 2% -8% of povidone K30,1% -5% of heavy magnesium carbonate and 1% -3% of low-substituted hydroxypropyl cellulose, wherein the percentages refer to the mass percentage of the components in the pellets.
7. A dexlansoprazole sustained-release pellet as claimed in claim 1, wherein the isolation layer I or III comprises an isolation polymer, an anti-sticking agent and titanium dioxide, and the isolation layer II comprises an isolation polymer;
preferably, the isolating polymer is hypromellose, and the anti-adhesion agent is one or more of talcum powder, glyceryl monostearate and titanium dioxide;
more preferably, the isolating layer I comprises 2% -6% of hypromellose, 1% -5% of talcum powder and 1.5-3% of titanium dioxide; the isolation layer II comprises 2% -6% of hydroxypropyl methylcellulose; the isolation layer III comprises 1% -10% of hypromellose, 0.1% -5% of talcum powder and 0.1% -5% of titanium dioxide; the percentage refers to the mass percentage of the component in the pellet.
8. The dexlansoprazole sustained-release pellet as defined in claim 1, wherein the pellet core is a sucrose pellet core; preferably, the dosage of the pill core accounts for 5-15% of the mass of the pellet; more preferably, the pellet core has a diameter of 250-350 μm.
9. A process for the preparation of a sustained release pellet of dexlansoprazole as claimed in any one of claims 1 to 8, wherein the process comprises: on the basis of the sucrose pill core, the coating of a medicine layer I, an isolation layer I, an enteric layer I, an isolation layer II, a medicine layer II, an isolation layer III and an enteric layer II is sequentially carried out.
10. A dexlansoprazole enteric capsule, characterized in that the capsule comprises a dexlansoprazole sustained-release pellet as defined in any one of claims 1-8; preferably, the preparation method of the capsule comprises the following steps: weighing talcum powder according to the weight of the pellets, setting mixing time and mixing rotating speed, and carrying out total mixing by using a hopper mixer; and calculating filling quantity according to the content of the pellets, setting parameters such as filling speed and the like, and filling the capsule to obtain the dexlansoprazole enteric capsule.
CN202310615258.1A 2023-05-29 2023-05-29 Dexlansoprazole sustained-release pellet Pending CN116832006A (en)

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