CN105796531A - (R)-Lansoprazole time-selection pulse controlled-release pellet preparation and preparation method thereof - Google Patents
(R)-Lansoprazole time-selection pulse controlled-release pellet preparation and preparation method thereof Download PDFInfo
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- CN105796531A CN105796531A CN201610234639.5A CN201610234639A CN105796531A CN 105796531 A CN105796531 A CN 105796531A CN 201610234639 A CN201610234639 A CN 201610234639A CN 105796531 A CN105796531 A CN 105796531A
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- 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
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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
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- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- 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
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- 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
Abstract
The invention discloses an (R)-Lansoprazole time-selection pulse controlled-release pellet preparation and a preparation method thereof.The basic structure of the preparation comprises a blank pellet core, a medicine layer, a swelling layer and an enteric controlled release layer from inside to outside.The swelling layer contains swelling materials and a binding agent, and the enteric controlled release layer contains enteric materials and sustained-release materials.Compared with routine technologies, the release rate of the pellets, prepared through the preparation method, in a 0.1 mol/L hydrochloric acid solution is smaller than 10% of labeled amount within two hours of tolerance, certain time lag is presented at the upper end of the small intestine, and then quick pulse controlled-release is conducted.Adopted adjuvant is easy to get, the production technology is simple and controllable, and the preparation is suitable for industrial production.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to the composition of pulsatile release pellets preparation when a kind of Dexlansoprazole is selected and the preparation method of said preparation.
Background technology
Proton pump inhibitor (PPIs) plays a role by hindering the secretion of parietal cell H+, K+-ATP enzyme level gastric acid, it is current maximally effective gastric acid secretion inhibitor and anti-ulcer medicament, is widely used in peptic ulcer, eradicates the treatment of the acid-related diseases such as helicobacter pylori (HP), Zollinger-Ellison Syndrome, gastroesophageal reflux disease and upper gastrointestinal hemorrhage.Proton pump inhibitor is benzimidazoles derivative, parietal cell film can be quickly passed through, accumulate in highly acid secretory tubyle, it is converted into sulfenamide compounds, sulfydryl covalent bond with H+, K+-ATP enzyme, form disulfide bond, make proton pump inactivate, thus suppressing maincenter or the gastric acid secretion of periphery mediation.Proton pump inhibitor poor stability, and to humidity, temperature and photo-labile, especially that acid is unstable, when being configured to aqueous solution or suspension, extremely unstable.In order to solve its stability problem, the patent disclosure such as CN103356489A, CN103340829B method that adopts enteric technology parcel enteric coating, it is to avoid directly contact with acid, it is simultaneously introduced micronized alkaline stabiliser, improve local pH scope, it is ensured that alkaline environment, strengthen the stability of preparation.
Omeprazole was in Initial Public Offering in 1988, and existing 8 PPI launch so far, wherein first generation proton pump inhibitor includes omeprazole, lansoprazole, pantoprazole, and second filial generation proton pump inhibitor includes rabeprazole, esomeprazole.But, clinical research shows, first generation proton pump inhibitor comes with some shortcomings and limitation, and its pharmacokinetics and pharmacodynamics have obvious individual variation, has stronger interaction with other medicines.Additionally, its 24h Acidinhibitor is had significant impact by the difference of first generation proton pump inhibitor administration time, and acid suppression effect is not lasting, and onset is slow, and clinical efficacy is big by the impact of time and food.In most of cases, first generation PPI is the maximum Acidinhibitor of competence exertion after multiple dosing only.Acid suppresses unstability, the limitation such as need the activation of concentration and enzyme, half-life short that plays a role have impact on the application of clinic, and cure rate and remission rate are all unstable.And the PPI of a new generation overcomes some above-mentioned defect to a certain extent, second filial generation PPI has significant advantage when treating gastroesophageal reflux disease (GERD) and other acid-related disease, and acid suppression is effective, and more thoroughly, the persistent period is long.But, it is still limited by the fat-soluble of food and the impact of empty stomach, full abdomen.
Dexlansoprazole is the dextroisomer of lansoprazole; it it is the antiulcer drug of a new generation; for the benzimidizole derivatives replaced; chemical name is: (+)-2-[(R)-[[3-methyl-4-(2; 2,2-trifluoro ethoxies)-2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole.Dexlansoprazole is soluble in dimethylformamide, methanol, dichloromethane, ethanol and ethyl acetate；It is dissolved in acetonitrile；It is slightly soluble in ether；Atomic it is dissolved in water；Almost insoluble in hexane.Dissolubility changes along with the change of pH, atomic molten at pH7-9, and the slightly soluble when pH11 is readily soluble when pH13, and in water, dissolubility is 0.16mg/ml, belongs to low dissolving, the BCSII class medicine of Thief zone type.Dexlansoprazole is very easily degraded in acid condition, and under neutrality and alkaline environment, stability is greatly improved.Having the effect of gastric acid secretion inhibiting, effect is better than other drug (omeprazole, pantoprazole, rabeprazole), can significantly inhibit ulcer and occur.
The preparation method that CN104721151A discloses a kind of segmented intestine targeted multiple coatings micropill with multicomponent synchronous release function, it includes medicine carrying capsule core, internal layer coating, intermediate layer coating, outer layer coating, after it can postpone a period of time in vivo, discharge medicine in colon site, but said preparation onset is slower.The preparation method that CN103961329A discloses the multiple coatings system enteric coated preparation of a kind of Dexlansoprazole, said preparation is made up of two-layer medicine layer, three layers sealing coat, two-layer enteric layer.But add solubilizing agent in its medicine accommodation layer, surfactant carrys out regulating drug release, and prescription is more complicated, and does not add alkaline stabiliser in medicine accommodation layer, can bring the stability problem of this type of medicine.Additionally, this multiple coatings preparation is complex in technique, there is certain difficulty in industrialized production.
Summary of the invention
The key technology of the present invention is in that said preparation does not discharge medicine after oral immediately, but maintains certain lag time, and then medicine realizes rapidly again fast-pulse release from micropill, and in 2h, completely, blood drug level is pulsed peak value in release.Said preparation has the double characteristic of time delay and pulse, in 2h time lag, burst size lower than 10%, time delayed 2h during release amount be the 90% of content of dispersion, can discharge at intestinal far-end specific part, control medicine absorb preferably, extend drug exposure.
The pulsatile release pellets when Dexlansoprazole of the present invention is selected, compared with common enteric coated micropill, not only has acidproof effect, and said preparation also has certain slow release effect in intestinal environment；Compared with common slow-release micro-pill, said preparation, after time lag, quickly realizes pulse release, reaches certain blood drug level and rapid-onset.Its release Mechanisms depends on film controlled release medicine, and slow-release material, as film forming matrix, plays time-lag action；Enteric material has pH dependency, can be acidproof, can dissolve again under specific pH, and as water soluble pore formers, the disintegrating agent in collaborative swell layer expands to burst enteric controlled-release film after absorbing water and realizes pulse release.Therefore, the thickness of swell layer, the ratio of enteric material and slow-release material in enteric controlled-release layer, the thickness of controlled release layer becomes the key factor affecting time lag length and pulse release speed.
Technical scheme is as follows:
The invention provides the composition of pulsatile release pellets preparation when a kind of Dexlansoprazole is selected and preparation method.Structure from the inside to the outside respectively celphere, medicine layer, swell layer, enteric controlled-release layer.When drug release process is more than certain pH, in controlled release layer, enteric material dissolves, form small duct, moisture and is contacted to micropill internal penetration with swell layer by the duct in outer layer clothing film, when the expansive force of swell layer exceedes the tensile strength of outer layer clothing film, clothing film just starts to break, and dissolution medium penetrates into thus triggering drug release.Control gains, swell layer and enteric controlled-release layer can be come by change outer layer clothing film thickness and collectively form pulse release layer.
The enteric pulsatile release pellets of the present invention, celphere is one or more in sucrose capsule core, microcrystalline Cellulose capsule core or starch capsule core, and capsule core particle diameter is selected from one or more in 300-500 μm, 510-700 μm, 710-810 μm.Celphere particle diameter is the key factor affecting micropill release.Capsule core particle diameter is little, then specific surface area is big, and the surface area contacted with medium is relatively big, and more hydrone penetrates into inside micropill, promotes the release of capsule core medicine.
The enteric pulsatile release pellets of the present invention, medicine layer is made up of principal agent, stabilizer, binding agent, disintegrating agent, and described stabilizer is one or more in magnesium carbonate, calcium carbonate, sodium hydroxide, disodium hydrogen phosphate, magnesium oxide；Described binding agent is one or more in hydroxypropyl cellulose, hypromellose, polyvidone；Described disintegrating agent is one or more in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium；Medicine layer accounts for the 43%-65% of whole micropill weight, and wherein Dexlansoprazole accounts for the 15%-65% of medicine layer, and stabilizer accounts for the 15%-50% of medicine layer, and disintegrating agent accounts for the 10%-40% of medicine layer, and binding agent accounts for the 2%-30% of medicine layer.It is necessary for adding alkaline stabiliser in medicine layer, and owing to drawing azole drug that acid is unstable, stability is better in the basic conditions, adds alkaline stabiliser and can make local pH > 7, is conducive to maintaining its stability.The ratio of Dexlansoprazole and stabilizer is 1: 0.2-1: 2, it is preferable that 1: 0.5-1: 2.
The enteric pulsatile release pellets of the present invention, in medicine layer, adds disintegrating agent and can promote the release of micropill, with swell layer synergism.When medicine layer does not add or adds less disintegrating agent, its imbibition poor effect, make medicine can not discharge by fast-pulse in the later stage.The ratio of Dexlansoprazole and disintegrating agent is 1: 0.2-1: 1, it is preferable that 1: 0.4-1: 0.8.
The enteric pulsatile release pellets of the present invention, swell layer is made up of binding agent, swollen material, and described binding agent is one or more in hydroxypropyl cellulose, hypromellose, polyvidone；Described swollen material is one or more in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium；Swell layer accounts for the 3%-10% of whole micropill weight.Disintegrating agent have to have stronger water absorption and swelling performance, and swelling rate is moderate, swelling causes that time lag extends too slowly, and Swelling Capacity is weak causes that clothing film rupture is incomplete, it is difficult to present pulse release.
The enteric pulsatile release pellets of the present invention, enteric controlled-release layer is made up of enteric material, slow-release material, plasticizer, antitackiness agent, and described enteric material is one or more in cellulose acetate-phthalate, especially strange L30D-55, especially strange L100, especially strange S100, hydroxypropyl methyl cellulose phthalate, polyvinyl alcohol phthalate ester, cellulose acetate benzenetricarboxylic acid ester, Eudragit E uS100, EuL100；Described slow-release material is one or more in ethyl cellulose, cellulose acetate, especially strange RL, especially strange RS, especially strange NE30D, HP-55, Hydroxypropyl Methyl Cellulose Phthalate；Described plasticizer is one or more in adjacent stupid dicarboxylate, dibutyl sebacate, Polyethylene Glycol, triethyl citrate；Described antitackiness agent is one or more in Pulvis Talci, glyceryl monostearate, magnesium stearate, titanium dioxide；Enteric controlled-release layer accounts for the 5%-20% of whole micropill weight.
The dissolving of enteric material is affected by pH, and pH is more high, dissolves more fast, and different enteric materials can regulate time lag to a certain extent.The kind of slow-release material and the thickness of enteric controlled-release layer all can affect sustained release performance, thus affecting time lag.The ratio of slow-release material preferred, ethyl, enteric material and slow-release material is the key factor affecting time lag with pulse release speed, and enteric material ratio is too high, then extended release coatings film is formed imperfect, and slow release effect is poor, does not reach good time lag effect；Enteric material ratio is too low, then extended release coatings film is compact and complete, but porogen consumption is few, and slow-releasing is too strong, and later stage release slowly, does not reach the effect of pulse release.The ratio of slow-release material Yu enteric material has been screened by the present invention, investigates its impact on vitro release.
When the Dexlansoprazole of the present invention is selected, the preparation of pulsatile release pellets preparation comprises the steps:
Medicine layer: after Dexlansoprazole, stabilizer, disintegrating agent fully being mixed, is dispersed in 3%～5% binder solution, forms suspension of adding medicine to uniformly, adopts the mode of spray at the bottom of fluid bed, is coated to by suspension in blank sucrose capsule core and forms medicine layer.Control temperature of charge and be 40-45 DEG C.
Swell layer: be dispersed in binder solution by swollen material, forms swell layer coating solution, adopts the mode of spray at the bottom of fluid bed to be coated to by coating suspensions on medicine layer and form swell layer.Control temperature of charge and be 36-40 DEG C.
Enteric controlled-release layer: after enteric material, slow-release material, plasticizer, antiplastering aid dispersion are formed homogenous suspension, adopts the mode of spray at the bottom of fluid bed to be coated to by coating suspensions in swell layer and form enteric controlled-release layer.Control temperature of charge and be 26-32 DEG C.
On this basis, define technical scheme, the Dexlansoprazole enteric pulsatile release pellets preparation of the present invention, active component is Dexlansoprazole, coating medicine layer, swell layer on celphere, enteric controlled-release layer, wherein swell layer and enteric controlled-release layer realize the pulse release of medicine jointly.
Pulsatile release pellets preparation when selecting of present invention design is compared with current existing common enteric coated preparation, slow releasing preparation, multiple coatings preparation, and advantage is in that:
(1) on dosage form designs, compared with common enteric coated preparation, it will not discharge medicine immediately after taking, but delayed release when certain；Compared with slow releasing preparation, it takes the later stage is not slow releasing medicine, but discharges rapidly with impulse form and reach effective blood drug concentration；Compared with multiple coatings preparation, its technique is relatively simple, and process controllability is good, can guarantee that the stability of preparation.In controlled release layer, compared to individually adopting enteric material coating control gains, slow-release material is used in combination and plays slow releasing function, coating of pellets thickness can be substantially reduced, reduce process costs.
(2) on formulation characteristic, when Dexlansoprazole prepared by the present invention is selected, pulsatile release pellets preparation belongs to multiple-unit dosage form, is composed of multiple units, and the drug release behavior of preparation will not be impacted by the deficiency of indivedual pillers and defect.
(3) when Dexlansoprazole prepared by the present invention is selected, pulsatile release pellets preparation can reach specific time lag, and pulsatile effect is obvious, and release is complete, technique favorable reproducibility.Adjuvant used is easy to get, and easily realizes industrialized production.
Accompanying drawing explanation
Fig. 1 is the In-vitro release curves of embodiment 4-6
Fig. 2 is the In-vitro release curves of embodiment 7
Fig. 3 is the In-vitro release curves of embodiment 8
Fig. 4 is the In-vitro release curves of embodiment 9-13
Fig. 5 makes the In-vitro release curves of pulsatile release pellets and common enteric coated capsule when Dexlansoprazole is selected by oneself
Fig. 6 is that Oral Administration in Rats makes the average drug-time curve of pulsatile release pellets and common enteric coated capsule when Dexlansoprazole is selected by oneself
Specific embodiment mode
Embodiment 1-3 investigates the stabilizing agent dosage impact on there being related substance in medicine accommodation layer
Embodiment 1
Medicine layer prescription:
Process for preparation:
Hydroxypropyl cellulose is dissolved in 30% alcoholic solution；Adding magnesium carbonate and low-substituted hydroxypropyl cellulose, dispersed with stirring is uniform；Finally Dexlansoprazole is added in above-mentioned suspension, continuously stirred be uniformly dispersed.
Embodiment 2
Medicine layer prescription:
Process for preparation is with embodiment 1.
Embodiment 3
Medicine layer prescription:
Process for preparation is with embodiment 1.
The medicine accommodation layer suspension of embodiment 1-3 is continuously stirred at room temperature, in 4,8,12,24,36,72h takes out appropriate mensuration related substance, and contrasts the color change in placement process, result is as follows:
Along with stabilizing agent dosage increases, total assorted reduction, the stability of Dexlansoprazole improves.
Embodiment 4-6 investigates the disintegrating agent consumption impact on release in medicine accommodation layer
Embodiment 4
Medicine layer prescription:
Preparation technology:
Hydroxypropyl cellulose is dissolved in 30% alcoholic solution；Adding magnesium carbonate and low-substituted hydroxypropyl cellulose, dispersed with stirring is uniform；
Finally Dexlansoprazole is added in above-mentioned suspension, be uniformly dispersed standby.Adopt spray mode at the bottom of fluid bed to add medicine to, control temperature of charge and be 40-45 DEG C, after medicine-feeding, in 50 DEG C of dry 30min.
Swell layer prescription:
Preparation technology:
Recipe quantity hydroxypropyl methyl cellulose and low-substituted hydroxypropyl cellulose are added in 600g hot water, after stirring, adds Pulvis Talci, continuously stirred uniformly standby.Adopt spray mode at the bottom of fluid bed to carry out swell layer coating, control temperature of charge and be 36-40 DEG C, increase weight respectively to 5%, 15%, 35%, after coating terminates, in 50 DEG C of dry 30min.
Enteric controlled-release layer prescription:
Preparation technology:
By dispersed to triethyl citrate and Pulvis Talci to 95% alcoholic solution of 1/3 recipe quantity, prepare dispersion liquid (1)；Weigh especially strange L100, each recipe quantity of ethyl cellulose, be dissolved in residue alcoholic solution, stir, prepare dispersion liquid (2)；(1) is slowly added in (2), stirring while adding.Adopting spray mode at the bottom of fluid bed to be coated with enteric controlled-release layer, control temperature of charge and be 26-32 DEG C, enteric layer increases weight to 10%, in 40 DEG C of dry 30min after coating.
The drug release determination method of embodiment 4-14:
Become a full member standard with reference to the new drug of lansoprazole intestine dissolving capsule, adopt drug release determination method the first subtraction unit, select basket method 100rpm, after preparation tolerate 2 hours in 0.1mol/L hydrochloric acid solution, be transferred in pH7.0 phosphate buffer, continue to discharge.After hydrochloric acid medium tolerates 2 hours, sampling time point is 10min, 20min, 60min, 120min, 180min, 240min.Each point in time sampling 10mL filters with 0.45 μm of filter membrane, and supplements the medium that equivalent is identical in time, takes subsequent filtrate by ultraviolet spectrophotometry, measures the absorbance of Dexlansoprazole, calculate Accumulation dissolution.
Embodiment 5
Medicine layer prescription:
Preparation technology is with embodiment 4.
Swell layer: formulation and technology keeps consistent with the swell layer of embodiment 4.
Enteric controlled-release layer: formulation and technology keeps consistent with the enteric controlled-release layer of embodiment 4.
Embodiment 6
Medicine layer prescription:
Preparation technology is with embodiment 4.
Swell layer: formulation and technology keeps consistent with the swell layer of embodiment 4.
Enteric controlled-release layer: formulation and technology keeps consistent with the enteric controlled-release layer of embodiment 4.
The different micropills prepared by embodiment 4-6 carry out vitro release mensuration.Tolerating 2 hours in 0.1mol/L hydrochloric acid, enteric coating film complete appearance, the release in acid of all micropills is respectively less than the 10% of labelled amount.Preparation release profiles in pH7.0 phosphate buffer is shown in Fig. 1.
Embodiment 7
The celphere of different-grain diameter affects the release in vitro behavior of micropill, and selecting celphere particle diameter is 300-500 μm, 510-700 μm, 710-810 μm, and other parts keep consistent with embodiment 1, investigate the particle diameter impact on micropill vitro release.
Different micropills embodiment 7 prepared carry out vitro release mensuration.Tolerating 2 hours in 0.1mol/L hydrochloric acid, enteric coating film complete appearance, the release in acid of all micropills is respectively less than the 10% of labelled amount.Preparation release profiles in pH7.0 phosphate buffer is shown in Fig. 2.
Embodiment 8 investigates the swell layer difference weightening finish impact on release
Embodiment 8
Medicine layer prescription:
Preparation technology:
Hydroxypropyl cellulose is dissolved in 30% alcoholic solution；Adding magnesium carbonate and low-substituted hydroxypropyl cellulose, dispersed with stirring is uniform；Finally Dexlansoprazole is added in above-mentioned suspension, be uniformly dispersed standby.Adopt spray mode at the bottom of fluid bed to add medicine to, control temperature of charge and be 40-45 DEG C, after medicine-feeding, in 50 DEG C of dry 30min.
Swell layer prescription:
Preparation technology:
Recipe quantity hydroxypropyl methyl cellulose and low-substituted hydroxypropyl cellulose are added in 600g hot water, after stirring, adds Pulvis Talci, continuously stirred standby.Adopt spray mode at the bottom of fluid bed to carry out swell layer coating, control temperature of charge and be 36-40 DEG C, increase weight respectively to 5%, 15%, 35%, after coating terminates, in 50 DEG C of dry 30min.
Enteric controlled-release layer prescription:
Preparation technology:
By dispersed to triethyl citrate and Pulvis Talci to 1/3 recipe quantity 95% alcoholic solution, prepare dispersion liquid (1)；Weigh especially strange L100, each recipe quantity of ethyl cellulose, be dissolved in remaining alcoholic solution, prepare dispersion liquid (2), stir；Dispersion liquid (1) is slowly added in (2), stirring while adding.The micropill of above-mentioned three kinds of different swell layer weightening finish being carried out enteric controlled-release layer coating, controls temperature of charge and be 26-32 DEG C, weightening finish is to about 10%, in 40 DEG C of dry 30min after coating.Different micropills embodiment 8 prepared carry out vitro release mensuration.Tolerating 2 hours in 0.1mol/L hydrochloric acid, enteric coating film complete appearance, the release in acid of all micropills is respectively less than the 10% of labelled amount.Release profiles in pH7.0 phosphate buffer is shown in Fig. 3.
Embodiment 9-13 investigates ethyl cellulose and the especially strange different proportion impact on release in enteric controlled-release layer
Embodiment 9
Medicine layer prescription:
Preparation technology:
Hydroxypropyl cellulose is dissolved in 30% alcoholic solution；Adding magnesium carbonate and low-substituted hydroxypropyl cellulose, dispersed with stirring is uniform；Finally Dexlansoprazole is added in above-mentioned suspension, be uniformly dispersed standby.Adopt spray mode at the bottom of fluid bed to add medicine to, control temperature of charge and be 40-45 DEG C, add medicine to complete in 50 DEG C of dry 30min.
Swell layer prescription:
Preparation technology:
Recipe quantity hydroxypropyl methyl cellulose and low-substituted hydroxypropyl cellulose are added in 600g hot water, after stirring, adds Pulvis Talci, continuously stirred uniformly standby.Adopt spray mode at the bottom of fluid bed to be coated with swell layer, control temperature of charge and be 36-40 DEG C, after coating terminates, in 50 DEG C of dry 30min.
Enteric controlled-release layer prescription:
Preparation technology:
By dispersed to triethyl citrate and Pulvis Talci to 95% alcoholic solution of 1/3 recipe quantity, prepare dispersion liquid (1)；Weigh especially strange L100, each recipe quantity of ethyl cellulose, be dissolved in residue alcoholic solution, prepare dispersion liquid (2), stir；(1) is slowly added in (2), stirring while adding.Adopting spray mode at the bottom of fluid bed to be coated with enteric controlled-release layer, control temperature of charge and be 26-32 DEG C, enteric layer increases weight to 10%, after coating, in 40 DEG C of dry 30min.
Embodiment 10
Medicine layer: formulation and technology is with the medicine layer of embodiment 9.
Swell layer: formulation and technology is with the swell layer of embodiment 9.
Enteric controlled-release layer prescription:
Preparation technology:
By dispersed to triethyl citrate and Pulvis Talci to 95% alcoholic solution of 1/3 recipe quantity, prepare dispersion liquid (1)；Weigh especially strange S100, each recipe quantity of ethyl cellulose, be dissolved in residue alcoholic solution, prepare dispersion liquid (2), stir；(1) is slowly added in (2), stirring while adding.Adopting spray mode at the bottom of fluid bed to be coated with enteric controlled-release layer, control temperature of charge and be 26-32 DEG C, enteric layer increases weight to 10%, after coating, in 40 DEG C of dry 30min.
Embodiment 11
Medicine layer: formulation and technology is with the medicine layer of embodiment 9.
Swell layer: formulation and technology is with the swell layer of embodiment 9.
Enteric controlled-release layer prescription:
Preparation technology:
By dispersed to triethyl citrate and Pulvis Talci to 95% alcoholic solution of 1/3 recipe quantity, prepare dispersion liquid (1)；Weigh especially strange S100, each recipe quantity of ethyl cellulose, be dissolved in residue alcoholic solution, prepare dispersion liquid (2), stir；(1) is slowly added in (2), stirring while adding.Adopting spray mode at the bottom of fluid bed to be coated with enteric controlled-release layer, control temperature of charge and be 26-32 DEG C, enteric layer increases weight to 10%, after coating, in 40 DEG C of dry 30min.
Embodiment 12
Medicine layer: formulation and technology is with the medicine layer of embodiment 9.
Swell layer: formulation and technology is with the swell layer of embodiment 9.
Enteric controlled-release layer prescription:
Preparation technology:
By dispersed to triethyl citrate and Pulvis Talci to 95% alcoholic solution of 1/3 recipe quantity, prepare dispersion liquid (1)；Weigh especially strange L100, especially strange S100, each recipe quantity of ethyl cellulose, be dissolved in residue alcoholic solution, prepare dispersion liquid (2), stir；(1) is slowly added in (2), stirring while adding.Adopting spray mode at the bottom of fluid bed to be coated with enteric controlled-release layer, control temperature of charge and be 26-32 DEG C, enteric layer increases weight to 10%, after coating, in 40 DEG C of dry 30min.
Embodiment 13
Medicine layer: formulation and technology is with the medicine layer of embodiment 9.
Swell layer: formulation and technology is with the swell layer of embodiment 9.
Enteric controlled-release layer prescription:
Preparation technology:
By dispersed to triethyl citrate and Pulvis Talci to 95% alcoholic solution of 1/3 recipe quantity, prepare dispersion liquid (1)；Weigh especially strange L100, especially strange S100, each recipe quantity of ethyl cellulose, be dissolved in residue alcoholic solution, prepare dispersion liquid (2), stir；(1) is slowly added in (2), stirring while adding.Adopting spray mode at the bottom of fluid bed to be coated with enteric controlled-release layer, control temperature of charge and be 26-32 DEG C, enteric layer increases weight to 10%, after coating, in 40 DEG C of dry 30min.
The different micropills prepared by embodiment 9-13 carry out vitro release mensuration.Tolerating 2 hours in 0.1mol/L hydrochloric acid, enteric coating film complete appearance, the release in acid of all micropills is respectively less than the 10% of labelled amount.Preparation release profiles in pH7.0 phosphate buffer is shown in Fig. 4.
When self-control is selected, when Internal pharmacokinetics is studied by pulsatile release pellets with common enteric coated micropill vitro release:
In order to compare the vitro release difference of pulsatile release pellets and common enteric coated micropill when self-control is selected, according to drug release determination method, pulsatile release pellets (embodiment 11) and common enteric coated micropill (Takepron when self-control Dexlansoprazole is selected, Tianjin Wu Tian medicine company limited, 100A) carry out vitro release investigation.Tolerating 2 hours in 0.1mol/L hydrochloric acid, enteric coating film complete appearance, the release in acid of all micropills is respectively less than the 10% of labelled amount.Preparation release profiles in pH7.0 phosphate buffer is shown in Fig. 5.
In order to compare pulsatile release pellets and common enteric coated micropill difference in vivo when self-control is selected, pulsatile release pellets (embodiment 11) and common enteric coated micropill (Takepron when self-control Dexlansoprazole is selected, Tianjin Wu Tian medicine company limited, 100A) pharmacokinetics in rat body studied.Adopt the test of binary cycle dual crossing, 6 rat oral gavages are administered, pulsatile release pellets when selecting of same dose and common enteric coated micropill was given on an empty stomach respectively at early morning on the same day, in 0.5,1,1.5,2,2.5,3,4,5,6,8,10,12,24h extracting vein blood 0.4ml respectively, adopt high performance liquid chromatography, measuring the concentration of Dexlansoprazole in blood plasma, internal drug-time curve is shown in Fig. 6.
Result shows that the principal agent pharmacokinetic parameters making pulsatile release pellets and common enteric coated micropill when selecting by oneself is: Tmax is 3h and 0.5h, Cmax respectively 0.67 μ g/ml and 0.51 μ g/ml respectively, both AUC no significant differences.When self-control is selected, pulsatile release pellets is 123% relative to the relative bioavailability of common enteric coated micropill, therefore pulsatile release pellets and common enteric coated micropill bioequivalence when self-control is selected, and pulsatile release pellets has significantly administration time lag and pulse release feature when selecting, reach the requirement of dosage form invention design.
Claims (9)
1. when a Dexlansoprazole is selected, pulsatile release pellets preparation is multiple coatings preparation, preparation includes celphere, medicine layer, swell layer and enteric controlled-release layer from the inside to the outside, it is characterized in that: in enteric controlled-release layer, slow-release material plays time-lag action, enteric material has pH dependency, can be acidproof, can dissolve again as porogen under certain pH, the disintegrating agent in collaborative swell layer expands to burst enteric controlled-release film after absorbing water and realizes pulse release.
2. pulsatile release pellets preparation when Dexlansoprazole according to claim 1 is selected, it is characterized in that one or more that celphere is selected from sucrose capsule core, microcrystalline Cellulose capsule core or starch capsule core, micropill particle diameter is selected from one or more in 300-500 μm, 510-700 μm, 710-810 μm；Medicine layer is made up of principal agent, stabilizer, binding agent, disintegrating agent, and described stabilizer is one or more in magnesium carbonate, calcium carbonate, sodium hydroxide, disodium hydrogen phosphate, magnesium oxide；Described binding agent is one or more in hydroxypropyl cellulose, hypromellose, polyvidone；Described disintegrating agent is one or more in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium；Medicine layer accounts for the 43%-65% of whole micropill weight, and wherein Dexlansoprazole accounts for the 15%-65% of medicine layer, and stabilizer accounts for the 15%-50% of medicine layer, and disintegrating agent accounts for the 10%-40% of medicine layer, and binding agent accounts for the 2%-30% of medicine layer.
3. pulsatile release pellets preparation when Dexlansoprazole according to claim 1 is selected, it is characterised in that swell layer is made up of binding agent, swollen material, described binding agent is one or more in hydroxypropyl cellulose, hypromellose, polyvidone；Described swollen material is one or more in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium；Swell layer accounts for the 3%-10% of whole micropill weight.
4. pulsatile release pellets preparation when Dexlansoprazole according to claim 1 is selected, it is characterized in that enteric controlled-release layer is made up of enteric material, slow-release material, plasticizer, antitackiness agent, described enteric material is one or more in cellulose acetate-phthalate, especially strange L30D-55, especially strange L100, especially strange S100, hydroxypropyl methyl cellulose phthalate, polyvinyl alcohol phthalate ester, cellulose acetate benzenetricarboxylic acid ester, Eudragit E uS100, EuL100；Described slow-release material is one or more in ethyl cellulose, acetate fiber rope, especially strange RL, especially strange RS, especially strange NE30D, HP-55, Hydroxypropyl Methyl Cellulose Phthalate；Described plasticizer is one or more in adjacent stupid dicarboxylate, dibutyl sebacate, Polyethylene Glycol, triethyl citrate；Described antitackiness agent is one or more in Pulvis Talci, glyceryl monostearate, magnesium stearate, titanium dioxide；Enteric controlled-release layer accounts for the 5%-20% of whole micropill weight.
5. pulsatile release pellets preparation when Dexlansoprazole according to claim 1 is selected, is characterised by medicine layer, and the ratio of Dexlansoprazole and stabilizer is 1: 0.2-1: 2, it is preferable that 1: 0.5-1: 2.
6. pulsatile release pellets preparation when Dexlansoprazole according to claim 1 is selected, is characterised by medicine layer, and the ratio of Dexlansoprazole and disintegrating agent is 1: 0.2-1: 1, it is preferable that 1: 0.4-1: 0.8.
7. pulsatile release pellets preparation when Dexlansoprazole according to claim 3 is selected, is characterised by that swell layer accounts for the 3%-10% of whole micropill weight, it is preferable that 5%-10%.
8. pulsatile release pellets preparation when Dexlansoprazole according to claim 4 is selected, it is 0.2: 1-2: 1 that enteric material preferably is selected from the ratio of one or more acrylate polymers, acrylate polymer and slow-release material, it is preferable that 0.4: 1-1.8: 1.
9. the preparation method of pulsatile release pellets preparation when Dexlansoprazole according to claim 1 is selected, including: adopt spray mode at the bottom of fluid bed to be coated with said medicine layer, swell layer, enteric controlled-release layer successively on celphere.
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| CN113350350A (en) * | 2020-03-07 | 2021-09-07 | 齐鲁制药有限公司 | Preparation method of pharmaceutical composition containing pexaparib hydrochloride |
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| CN103705481A (en) * | 2013-11-15 | 2014-04-09 | 中国药科大学 | Naproxen colon-specific drug-release micro pill and preparation method thereof |
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| CN1284868A (en) * | 1997-12-22 | 2001-02-21 | 阿斯特拉曾尼卡有限公司 | Oral pharmaceutical pulsed release dosage form |
| EP1681052A1 (en) * | 2005-01-18 | 2006-07-19 | Dr. Reddy's Laboratories Ltd. | Solid pharmaceutical dosage forms for reducing the bioavailability food effect |
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| CN113350350A (en) * | 2020-03-07 | 2021-09-07 | 齐鲁制药有限公司 | Preparation method of pharmaceutical composition containing pexaparib hydrochloride |
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