CN105456223B - Mesalazine sustained release pellet and preparation method thereof and Mesalazine spansule - Google Patents
Mesalazine sustained release pellet and preparation method thereof and Mesalazine spansule Download PDFInfo
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- CN105456223B CN105456223B CN201510945644.2A CN201510945644A CN105456223B CN 105456223 B CN105456223 B CN 105456223B CN 201510945644 A CN201510945644 A CN 201510945644A CN 105456223 B CN105456223 B CN 105456223B
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
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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
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/606—Salicylic acid; Derivatives thereof having amino groups
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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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
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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Abstract
The present invention provides a kind of Mesalazine sustained release pellets and preparation method thereof and Mesalazine spansule, this method comprises: 5-aminosalicylic acid, microcrystalline cellulose and adhesive are mixed, through extrusion spheronization technique, obtain pellet core；Using the material including ethyl cellulose, the bundled slow-releasing coatings in the pellet core；Enteric coat layer is wrapped up on sustained-release coating layer using enteric material and processing aid, obtains Mesalazine sustained release pellet；The enteric material is methacrylic acid and ethyl acrylate copolymer.The present invention is combined using pH dependent form with two kinds of release Mechanisms of time-dependent, and ideal drug release profiles are reached, and improves the accuracy of drug release position.Mesalazine spansule provided by the invention includes the Mesalazine sustained release pellet, can be in gastrointestinal tract preferably slow releasing pharmaceutical, conducive to the treatment of ulcerative colitis and Crohn disease.
Description
Technical field
The present invention relates to Mesalazine technical field of medicine more particularly to a kind of Mesalazine sustained release pellet and its systems
Preparation Method and Mesalazine capsule.
Background technique
Inflammatory bowel disease (IBD) is a kind of chronic and easy to recur inflammatory bowel disease, can be divided into exedens knot in the narrow sense
Enteritis (UC) and Crohn disease (CD).Ulcerative colitis is a kind of common non specific chronic inflammatory disease, is fallen ill in colon
Mucous membrane, symptom are mainly abdominal pain, diarrhea, and concurrent colon cancer risk is high, and the course of disease 20 years cancer hair rates are up to 5%~10%.The disease
Pathogenesis it is unknown, one of modern difficult treatment is classified as by the World Health Organization.Crohn disease is also known as segmental enteritis
Or granulomatous enteritis, the disease can occur at any position of entire gastrointestinal tract, be most commonly in small intestine and terminal ileum.At present
The disease there is no basic cure method, and with multiple complications, need operative treatment, Postoperative recurrent rate is high.It is either exedens
Colitis or Crohn disease can betide any age level, but be more common in 20~40 years old, also be found in children and old
Year.Disease incidence of both diseases in developed country and city is higher than rural area, and its disease incidence is also constantly increasing.In addition, this
Two kinds of diseases are possible to occur with the same person simultaneously；And the diseased region of the patient with inflammatory bowel disease can expand
It dissipates or spreads.Therefore, the major issue that IBD has become modern medicine how is effectively treated.
Currently, mainly being treated using drugs such as Mesalazines to IBD patient.Mesalazine (or mesalazine), again
Name 5-aminosalicylic acid (can be abbreviated as 5-ASA), is the conventional medicament salicylazosulfapyridine for treating inflammatory bowel disease
(SASP) effective component.Because Mesalazine has many advantages, such as that curative effect is high, adverse reaction is few compared with SASP, clinic is had become
The first-line drug of upper treatment Mild and moderate ulcerative colitis and the active drug for the treatment of Crohn disease.Inflammation of the Mesalazine to intestinal wall
Disease has significant inhibiting effect, and the generation of main secretion and leukotriene and free radical by inhibiting prostaglandin reaches anti-
Inflammation effect；Mesalazine is to interact to reach inhibiting effect with the mucous membrane of diseased region, and this is local action, is not
General action will not enter blood circulation.Clinical therapeutics think that inflammatory bowel disease can not eradicate, and need to treat or tie up repeatedly
Treatment is held, Mesalazine preparation has become indispensable types of drugs in IBD clinical treatment.External clinical research shows
It selects the minosalicylates, drugs such as Mesalazine to carry out IBD treatment to maintain, recurrence rate can be made to reduce to 25%.
According to present Research, the type of 5-aminosalicylic acid preparation mainly includes Mesalazine enteric-coated tablet, Mesalazine intestines
Molten granule and Mesalazine controlled release capsule etc..The disease that these presently commercially available preparations are directed to all be ulcerative colitis and
Two kinds of Crohn disease, and it is increasingly directed to ulcerative colitis, it is mostly colon location preparation.But most for site of pathological change
It is common in the Crohn disease of small intestine and terminal ileum, the drug release effect of existing Mesalazine preparation is to be improved.
Summary of the invention
In view of this, the application provides a kind of Mesalazine sustained release pellet and preparation method thereof and Mesalazine is sustained glue
Capsule, Mesalazine spansule provided by the invention can in gastrointestinal tract preferably slow releasing pharmaceutical, be conducive to ulcerative colitis and gram
The treatment of sieve grace disease.
The present invention provides a kind of Mesalazine sustained release pellet, comprising:
Pellet core, the pellet core include 5-aminosalicylic acid, microcrystalline cellulose and adhesive；
The sustained-release coating layer being wrapped in the pellet core, the sustained-release coating layer is by the material including ethyl cellulose
It is made；
The enteric coat layer being wrapped on the sustained-release coating layer, the enteric coat layer include that enteric material and processing help
Agent, the enteric material are methacrylic acid and ethyl acrylate copolymer.
Preferably, described adhesive is selected from one of hydroxypropyl methylcellulose, povidone and starch or a variety of.
Preferably, based on mass fraction, the pellet core include 55%~85% 5-aminosalicylic acid, 15%~
45% microcrystalline cellulose and 3%~10% adhesive.
Preferably, the sustained-release coating layer is made of Aquacoat.
Preferably, the sustained-release coating layer makes pellet core weight gain 1%~10%.
Preferably, the processing aid includes one of antiplastering aid and plasticizer or a variety of.
Preferably, the antiplastering aid is talcum powder；The plasticizer is triethyl citrate.
Preferably, the enteric coat layer makes Mesalazine sustained release pellet weight gain 8%~20%.
The present invention provides a kind of preparation method of Mesalazine sustained release pellet, comprising the following steps:
5-aminosalicylic acid, microcrystalline cellulose and adhesive are mixed, through extrusion spheronization technique, obtain pellet core；
Using the material including ethyl cellulose, the bundled slow-releasing coatings in the pellet core；
Enteric coat layer is wrapped up on sustained-release coating layer using enteric material and processing aid, it is micro- to obtain Mesalazine sustained release
Ball；The enteric material is methacrylic acid and ethyl acrylate copolymer.
It include described above the present invention also provides a kind of Mesalazine spansule, in the Mesalazine spansule
Mesalazine sustained release pellet.
Compared with prior art, Mesalazine sustained release pellet provided by the invention successively includes pellet core, sustained release coating
Layer and enteric coat layer；Wherein, the pellet core includes 5-aminosalicylic acid, microcrystalline cellulose and adhesive；The sustained release
Coatings are by including that the material of ethyl cellulose is made；The enteric coat layer includes methacrylic acid and ethyl acrylate copolymers
Object and processing aid.In the present invention, the pellet core prescription is simple, and drugloading rate is high；The pellet core bundled slow-releasing
Coatings can make it slowly release the drug at enteron aisle position, reach small intestine 3h drug release 50% or so, colon drug delivery 50% or so, favorably
In the treatment of ulcerative colitis and Crohn disease.Also, the present invention wraps up enteric coat layer, can reduce 5-ASA in stomach
It discharges (release rate < 2%), reduces stimulation of the drug to stomach.The present invention utilizes pH dependent form and two kinds of time-dependent drug releases
Mechanism joint, reaches ideal drug release profiles, improves the accuracy of drug release position.
Mesalazine spansule provided by the invention includes the Mesalazine sustained release pellet, can gastrointestinal tract preferably
Slow releasing pharmaceutical, conducive to the treatment of ulcerative colitis and Crohn disease.
Detailed description of the invention
Fig. 1 is the drug release profiles figure of 2 gained Mesalazine spansule of embodiment；
Fig. 2 is the drug release profiles figure of Mesalazine spansule obtained by Examples 1 to 3；
Fig. 3 is the photo in filler screening comparison procedure according to 1 gained pellet of prescription；
Fig. 4 is the photo in filler screening comparison procedure according to 2 gained pellet of prescription；
Fig. 5 is the photo in filler screening comparison procedure according to 3 gained pellet of prescription；
Fig. 6 is the photo in filler screening comparison procedure according to 4 gained pellet of prescription；
Fig. 7 is the photo in filler screening comparison procedure according to 5 gained pellet of prescription；
Fig. 8 is the photo using drug matrices capsule core made from 6%HPMC E15；
Fig. 9 is the drug release profiles comparison of the present invention gained preparation and Pentasa in pH6.8PBS；
Figure 10 is the drug release profiles comparison of the present invention gained preparation and Pentasa in HCl-6.8PBS；
Figure 11 is the drug release profiles figure of different sustained release coatings weight gain；
Figure 12 is the drug release profiles figure that sustained release coating adds pore-foaming agent.
Specific embodiment
The following is a clear and complete description of the technical scheme in the embodiments of the invention, it is clear that described embodiment
Only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, the common skill in this field
Art personnel every other embodiment obtained without making creative work belongs to the model that the present invention protects
It encloses.
The present invention provides a kind of Mesalazine sustained release pellets, comprising:
Pellet core, the pellet core include 5-aminosalicylic acid, microcrystalline cellulose and adhesive；
The sustained-release coating layer being wrapped in the pellet core, the sustained-release coating layer is by the material including ethyl cellulose
It is made；
The enteric coat layer being wrapped on the sustained-release coating layer, the enteric coat layer include that enteric material and processing help
Agent, the enteric material are methacrylic acid and ethyl acrylate copolymer.
Mesalazine sustained release pellet provided by the invention includes pellet core, and bundled slow-releasing clothing, enteric coating thereon, in stomach
Enteron aisle can reach ideal drug release profiles, and the position that releases the drug is more acurrate.
Mesalazine sustained release pellet provided by the invention includes pellet core comprising 5-aminosalicylic acid, microcrystalline cellulose
Element and adhesive.In the present invention, the partial size of the pellet core is preferably 20~30 mesh；I.e. partial size be preferably 0.6mm~
0.9mm belongs to pellet preparations.Compared with other drugs dosage form, pellet is a kind of novel polynary drug delivery system, is had many excellent
It selects: 1) not being influenced by the food conveying rhythm and pace of moving things, individual difference is small；2) good fluidity can be widely distributed in gastrointestinal tract after taking,
Local irritation is small；3) will not due to individual pillers are in the fault or defect in preparation to the drug release behavior of whole preparation generate compared with
It is big to influence；4) pellet of several different release Mechanisms can be filled in a capsule or is pressed into tablet, to reach ideal effect.
Pellet core of the present invention mainly includes 5-aminosalicylic acid, microcrystalline cellulose and adhesive, the drug vegetable pill
Prescription it is simple, drugloading rate is high.Wherein, the 5-aminosalicylic acid is main active；The microcrystalline cellulose is filling
Agent；Described adhesive preferably is selected from one of hydroxypropyl methylcellulose (HPMC), povidone (PVP) and starch or a variety of, more preferably
For hydroxypropyl methylcellulose or povidone.The present invention is not particularly limited the source of the filler and adhesive, and use is commercially available
Product, if filler can be microcrystalline cellulose 101, microcrystalline cellulose 301, microcrystalline cellulose 302, it is preferred to use crystallite is fine
Tie up 301 (MCC 301) of element；Adhesive can be PVP k30, HPMC E15, HPMC E6.
Auxiliary material in pellet core of the present invention may also include one of diluent and wetting agent etc. or a variety of, but excellent
Auxiliary material is selected to contain only microcrystalline cellulose and adhesive, it is more simple and easy, effect is good.
In an embodiment of the present invention, based on mass fraction, the pellet core includes 55%~85% 5- amino water
Poplar acid, 15%~45% microcrystalline cellulose and 3%~10% adhesive.The pellet core preferably includes 60%~80%
5-aminosalicylic acid, more preferably include 65%~75% 5-aminosalicylic acid.The pellet core preferably includes 20%~
40% microcrystalline cellulose more preferably includes 25%~35% microcrystalline cellulose.In a specific embodiment of the present invention, U.S. is husky
The mass ratio for drawing the Qin, microcrystalline cellulose and adhesive can be 250:100:21,250:100:11,250:109:14.
Mesalazine sustained release pellet provided by the invention includes sustained-release coating layer, is wrapped in above-mentioned pellet core.At this
In invention, the sustained-release coating layer is preferably made of Aquacoat by including that the material of ethyl cellulose is made.
The sustained-release coating layer main function is to discharge sustained drug slowly, specifically plays rate of release, the release of control drug
Time and the effect for discharging position.In the present invention, the pellet core bundled slow-releasing coatings, can make it at enteron aisle position
Slowly drug release.Bundled slow-releasing coatings of the present invention are to utilize drug more constant in the transhipment time of small intestine, in 3h or so
Reach small intestine 3h drug release 50% or so, colon drug delivery 50% or so is conducive to the treatment of ulcerative colitis and Crohn disease.
Also, because the pH value of small intestine initial position, closer to 5.5, the present invention is just more advantageous in this way is sustained by control
The weight gain of coatings controls it in enteral drug release.The present invention can be slow to adjust by spraying the coating solution of different quality
The thickness of coatings is released, generally 1%~10% coating weight gain is horizontal；I.e. in general, the sustained-release coating layer can make to contain
Pill core weight gain 1%~10%, preferably weight gain 2%~6%.The present invention does not have the source of the material including ethyl cellulose
Have it is specifically limited, can use commercially available Aquacoat, such as Sulisi product.
In some embodiments of the invention, can not add pore-foaming agent in sustained release coating, be coated preferred weight gain 3%~
4%；In other embodiments of the invention, sustained release coating can add pore-foaming agent, if additive amount is 2%~3%；It is coated excellent
Choosing weight gain 4%~9%.Addition pore-foaming agent of the embodiment of the present invention does not add pore-foaming agent, can be reached by adjusting clothing film thickness
To good drug release profiles.The pore-foaming agent is using commonly used in the art, such as HPMC, PVP, PEG.
Mesalazine sustained release pellet provided by the invention includes enteric coat layer, is wrapped on sustained-release coating layer.At this
In invention, the enteric coat layer includes enteric material and processing aid；The enteric material is methacrylic acid and acrylic acid
Methacrylate copolymers are preferably made of methacrylic acid and ethyl acrylate copolymer aqueous dispersion etc..The present invention is to the enteric
The source of material is not particularly limited, and can use the commercially available aqueous dispersion containing enteric material, as Utech L30D-55 is produced
Product.
In one embodiment of the invention, the enteric material can use L100-55 product, be Utech
The Spray dried products of L30D-55, when use, needs oneself to be configured to reuse after aqueous dispersion, or uses organic solvent
It is prepared.The preferred L30D-55 aqueous dispersion of the present invention can be reduced to the greatest extent or be avoided using organic molten as enteric-coating material
Agent, it is safe and environment-friendly, it is easier.
The present invention can regulate and control the thickness of enteric coat layer, and generally 8%~20% coating weight gain is horizontal；It is i.e. general next
It says, the enteric coat layer can make Mesalazine sustained release pellet weight gain 8%~20%, preferably weight gain 10%~15%.
Enteric coat layer of the present invention mainly uses pH dependent form macromolecule enteric material, makes pharmaceutical preparation in stomach
It does not dissolve in liquid, and can quickly be dissolved under conditions of higher pH (> 5.5)；It so mainly can be to avoid main ingredient in gastric juice
Release in advance, reduce stimulation of the main ingredient to stomach, reduce toxic side effect, improve drug in the concentration of diseased region.Packet of the present invention
Enteric coat layer is wrapped up in, 5-ASA can be reduced in the release (release rate < 2%) of stomach, reduce its stimulation to stomach.
In addition to enteric material, enteric coat layer of the present invention includes processing aid.In an embodiment of the present invention, described
Processing aid includes one of antiplastering aid and plasticizer or a variety of.Wherein, the antiplastering aid is in preparation coating process
Prevent the substance to stick together in packet medicated pellet, such as talcum powder.The plasticizer refers to that improve coating membrane soft
A kind of compound of toughness, usually can be used triethyl citrate.In one embodiment of the invention, the enteric coat layer
It is made by the material for including methacrylic acid and ethyl acrylate copolymer, talcum powder and triethyl citrate.The present invention is implemented
When example preparation enteric coat layer, the mass ratio of aqueous dispersion, antitack agent and plasticizer containing enteric material be preferably (100~
160): (15~25): (3~5), concretely 157:23.5:4.7,114:17:3.4,103:15.5:3.1.In addition, of the invention
The materials such as solvent can be also added when preparing enteric coat layer in embodiment.
In the present invention, the partial size of the Mesalazine sustained release pellet is generally 0.6mm~1.5mm.Beauty of the present invention
Salad Qin sustained release pellet distribution area in enteron aisle is wide, is more suitable for quality inflammatory bowel disease compared to tablet.Since pellet is in enteron aisle
Inflammation part should have enough drug concentrations, and should discharge drug as quickly as possible, play having for anti-inflammatory effect to reach 5-ASA
Concentration is imitated, bundled slow-releasing clothing layer of the present invention can make it slowly release the drug.Inflammatory bowel disease patient needs long-term administration or prevention multiple
Hair, therefore 5-ASA few as far as possible should occur in blood, to reduce toxic side effect, and present invention package enteric coating layer can reach this
Purpose.In conclusion Mesalazine sustained release pellet provided by the invention is pH, the sustained release of time-dependent joint release Mechanisms is micro-
Ball, can preferably control its drug release, reach more preferably clinical therapeutic efficacy to Crohn disease.
Correspondingly, the present invention provides a kind of preparation methods of Mesalazine sustained release pellet, comprising: by 5- aminosalicyclic
Acid, microcrystalline cellulose and adhesive mixing, through extrusion spheronization technique, obtain pellet core；
Using the material including ethyl cellulose, the bundled slow-releasing coatings in the pellet core；
Enteric coat layer is wrapped up on sustained-release coating layer using enteric material and processing aid, it is micro- to obtain Mesalazine sustained release
Ball；The enteric material is methacrylic acid and ethyl acrylate copolymer.
The embodiment of the present invention uses extrusion spheronization technique, by 5-aminosalicylic acid and including microcrystalline cellulose, adhesive
Auxiliary material adds water, and pellet core is made after dry.
Wherein, the content of the microcrystalline cellulose and adhesive is as it was noted above, details are not described herein.Due to Mesalazine
It is the drug of big specification, and the amount that patient eats every time is bigger, prepares the higher preparation of drugloading rate as much as possible preferably.This hair
The properties such as bright stickiness, the mouldability for considering bulk pharmaceutical chemicals are bad, to be such as prepared into the sustained release pellet of skeleton combination film control, Shi Bixu
Many auxiliary materials are added, virtually just need to reduce drugloading rate in this way.If also, technological parameter slight difference, drug release will be made
At larger impact.When preparing the sustained release pellet of skeleton combination film control, if the slow-release material viscosity of use is higher, additional amount is just
The problem of seldom, thus facing dispersed homogeneous degree；And if additional amount is more, squeeze out item will too long, too consolidation, lead
Cause can not be round as a ball.According to the lower slow-release material of viscosity, then additional amount will increase many, and virtually drugloading rate just drops in this way
It is low, it will lead to that amount of fill is larger, to increase the difficulty that patient takes drugs.The present invention is using extrusion spheronization technology preparation element
Ball, and it is designed as film control pellet；The prescription of pellet core is simple, and drugloading rate is high, takes convenient for patient.
Adhesive and water are preferably mixed and made into binder aqueous solution by the embodiment of the present invention, then by the 5- amino of recipe quantity
Salicylic acid and microcrystalline cellulose are prepared into softwood with binder aqueous solution, then are placed in extrusion spheronization machine and prepare pellet.The present invention
The process for being prepared into binder aqueous solution is not particularly limited；The mass concentration of described adhesive aqueous solution can for 8%~
15%.The process that the present invention is prepared into softwood and prepares pellet is technological means well known to those skilled in the art, according to
Conventional technique.In an embodiment of the present invention, the process conditions of extrusion spheronization include: to squeeze out revolving speed for 25rpm, round as a ball
Revolving speed is 900rpm, and the round as a ball time is 3min~5min.In embodiments of the present invention, pellet obtained can be done in 40 DEG C of baking ovens
Dry, preferably 20~30 mesh of screening are to get coating pellet core.
After obtaining pellet core, the embodiment of the present invention can be placed it in fluidized bed, using the packet including ethyl cellulose
Clothing liquid is coated, and forms the sustained-release coating layer being wrapped in pellet core.In addition, the present invention can also be existed using other methods
Bundled slow-releasing coatings in the pellet core.
In the present invention, the coating is process well known to those skilled in the art.In an embodiment of the present invention, will contain
Pill core is placed in fluidized bed, is blown into hot-air, starts to be coated when capsule core temperature is 40~42 DEG C.In a tool of the invention
In body embodiment, the fluid supply rotate speed of coating is 4rpm~6rpm；Atomizing pressure can be 0.5MPa；Blower frequency can be 25Hz.
In coating process, coating solution need to be sealed and be stirred continuously.The coating solution includes ethyl cellulose；It can be by reviving
Liz Jia Shui, dispersion are made.The present invention can adjust the thickness of sustained-release coating layer by spraying the coating solution of different quality, and one
As for 1%~10% coating weight gain it is horizontal.
After coating solution has sprayed, the embodiment of the present invention can continue to fluidize 5min~10min, then preferably in 45 DEG C of dryings
30min.After drying, dry pellet is preferably carried out 20~30 meshes point by the embodiment of the present invention, obtains being enclosed with sustained release coating
The pellet of layer.
In pellet core after bundled slow-releasing coatings, the embodiment of the present invention is using enteric material and processing aid slow
It releases and wraps up enteric coat layer in coatings, obtain Mesalazine sustained release pellet.
In the present invention, the enteric coat layer includes enteric material and processing aid.The enteric material and processing help
The content of agent is as it was noted above, if the enteric material is methacrylic acid and ethyl acrylate copolymer.The embodiment of the present invention
Enteric material can be added to the materials such as water, such as homogenized according to conventional technique, stir and be configured to enteric coating liquid, in fluidized bed
It is coated；Enteric coat layer can also be wrapped up using other methods.
In the present invention, the coating is process commonly used in the art.The embodiment of the present invention will wrap sustained release coating
Pellet be placed in fluidized bed, be blown into hot-air, when pellet temperature be 30~33 DEG C when start to be coated.In a tool of the invention
In body embodiment, the fluid supply rotate speed of coating is 3rpm~4rpm；Atomizing pressure can be 0.4MPa；Blower frequency can be 20Hz.
In coating process, coating solution need to be stirred continuously, and prevent coating solution from settling.The present invention can be by spraying not homogeneity
The coating solution of amount regulates and controls the thickness of enteric coat layer, and generally 8%~20% coating weight gain is horizontal.To coating solution sprayed with
Afterwards, the embodiment of the present invention can continue to fluidize 5min~10min, then preferably in 45 DEG C of dry 30min.After drying, the present invention is real
It applies example and dry pellet is preferably subjected to 20~30 meshes point to get Mesalazine sustained release pellet.
Capsule can be made in Mesalazine sustained release pellet provided by the invention, other preparations can also be made.The present invention
A kind of Mesalazine spansule is additionally provided, includes that Mesalazine described above is sustained in the Mesalazine spansule
Pellet.
Conventionally, the embodiment of the present invention is encapsulated to get Mesalazine sustained release by Mesalazine sustained release pellet
Capsule.Capsule in the Mesalazine spansule is capsule type commonly used in the art；In embodiments of the present invention, 1000
The content of Mesalazine is 250g in grain Mesalazine spansule.
After obtaining Mesalazine spansule, the present invention carries out dissolution test to it.In order to investigate this product (Mesalazine
Spansule) drug release situation in human gastrointestinal tract, transformation pH medium measurement release is carried out using simulation human gastrointestinal tract.
Drug release determination uses first method of dissolution method (two the first method of annex XC Rotating shakers of " Chinese Pharmacopoeia " version in 2010)
Device, respectively using 900mL 0.1mol/L HCl and pH6.8 phosphate buffer as dissolution medium, revolving speed 100rpm, temperature
It is 37 DEG C, the 2h in 0.1mol/L HCl, changes with pH6.8 phosphate buffer to finally terminating, each conversion medium is in 5min
Interior completion.It samples at certain time intervals respectively, while supplementing equivalent equality of temperature medium and being taken with 0.45 μm of filtering with microporous membrane
Appropriate subsequent filtrate, according to UV-VIS spectrophotometry (two annex IV A of " Chinese Pharmacopoeia " version in 2010) after diluting,
Trap is measured at suitable wavelength, calculates release.
The present invention compared the 2h in 0.1mol/L HCl, change with pH6.8 phosphate buffer to finally terminate and
2h in 0.1mol/L HCl is changed and is carried out 3h with pH6.8 phosphate buffer, is finally changed with pH7.5 phosphate buffer to last
Terminate influence of the both methods to drug release, find after being changed to pH7.5 phosphate buffer, drug release can be slightly fast several
Percentage point, but generally drug release situation is similar.Also, Drug Releasing Test of the invention the result shows that, the Mesalazine sustained release
For capsule in small intestine 3h drug release 50% or so, colon drug delivery 50% or so is conducive to the treatment of ulcerative colitis and Crohn disease.
For a further understanding of the application, below with reference to embodiment to Mesalazine sustained release pellet provided by the present application and its
Preparation method and Mesalazine spansule are specifically described.
Embodiment 1
Pellet core prescription (1000):
Adhesive preparation: weighing the pure water of 119g and the PVP k30 of 21g, will under conditions of 500rpm is stirred continuously
21g PVP k30 is added in 119g pure water, stirs the PVP k30 aqueous solution that 20min is 15% to get concentration.
Capsule core preparation: it is uniformly mixed after taking the Mesalazine of recipe quantity to be sieved respectively with microcrystalline cellulose, with obtained
15% PVP k30 aqueous solution is that adhesive prepares softwood, and softwood is placed in extrusion spheronization machine and prepares pellet, squeezes out revolving speed and is
25rpm, round as a ball revolving speed are 900rpm, and the round as a ball time is 3min；Pellet in dry in 40 DEG C of baking ovens, sieve 20~30 mesh to get
Capsule core is used in coating.
Slow release layer coating fluid prescription:
Sulisi (Shanghai Colorcon Coating Technology Co., Ltd) 150g
Pure water 100g
Sustained release coating liquid is prepared: weighing Sulisi aqueous dispersion 150g, under conditions of 80rpm is stirred continuously, slowly
100g pure water is added, it is fully dispersed, obtain sustained release coating liquid.
Art for coating: capsule core obtained being placed in fluidized bed, hot-air is blown into, and starts to wrap when capsule core temperature is 41 DEG C
Clothing, fluid supply rotate speed 4rpm, atomizing pressure 0.5MPa, blower frequency are 25Hz.In coating process, coating solution need to be sealed
And it is stirred continuously.After coating solution has sprayed, continue to fluidize 5min, then 45 DEG C of dry 30min.It, will be dry micro- after drying
Ball carries out 20~30 meshes point, obtains the pellet for being enclosed with sustained-release coating layer.
Enteric layer coating fluid prescription:
Enteric coating liquid is prepared:
A, talcum powder 23.5g, triethyl citrate 4.7g and pure water 100g are weighed, 10min is homogenized using homogenization machine, obtains
Mixed liquor A；
B, Utech L30D-55157g is weighed, under conditions of 400rpm is stirred continuously, 91g pure water is slowly added, stirs
5min is mixed, mixed liquid B is obtained；
C, the mixed liquor A homogenized is added in mixed liquid B, stirs 30min；By 60 mesh mistakes of obtained suspension
Filter, obtains enteric coating liquid.
Art for coating: the pellet for having wrapped sustained release coating being placed in fluidized bed, hot-air is blown into, and is to capsule core temperature
Start to be coated at 32 DEG C, fluid supply rotate speed 4rpm, atomizing pressure 0.4MPa, blower frequency is 20Hz.In coating process, packet
Clothing liquid need to be stirred continuously, and prevent coating solution from settling.After coating solution has sprayed, continue to fluidize 5min, then 45 DEG C of dryings
30min.After drying, dry pellet is subjected to 20~30 meshes point.Encapsulated (the Zhejiang of Mesalazine sustained release pellet that will be obtained
Sky dragon capsule and pill Co., Ltd, model 0# (coffee is yellow) gelatin hollow capsule) to get Mesalazine spansule.
Embodiment 2
Pellet core prescription (1000):
Adhesive preparation: weighing the pure water of 127g and the HPMC E15 of 11g, will under conditions of 500rpm is stirred continuously
11g HPMC E15 is added in 127g pure water, stirs 20min, and placement overnight is water-soluble to get the HPMC E15 that concentration is 8%
Liquid.
Capsule core preparation: it is uniformly mixed after taking the Mesalazine of recipe quantity to be sieved respectively with microcrystalline cellulose, with obtained 8%
HPMC E15 aqueous solution be adhesive prepare softwood, softwood is placed in extrusion spheronization machine and prepares pellet；Squeezing out revolving speed is
25rpm, round as a ball revolving speed are 900rpm, and the round as a ball time is 3min.Pellet in dry in 40 DEG C of baking ovens, sieve 20~30 mesh to get
Capsule core is used in coating.
Slow release layer coating fluid prescription:
Sulisi (with embodiment 45g1)
Pure water 30g
Sustained release coating liquid is prepared: being weighed Sulisi aqueous dispersion 45g, under conditions of 80rpm is stirred continuously, is slowly added
Enter 30g pure water, it is fully dispersed, obtain sustained release coating liquid.
Art for coating: capsule core obtained being placed in fluidized bed, hot-air is blown into, and starts to wrap when capsule core temperature is 41 DEG C
Clothing, fluid supply rotate speed 4rpm, atomizing pressure 0.5MPa, blower frequency are 25Hz.In coating process, coating solution need to be sealed
And it is stirred continuously.After coating solution has sprayed, continue to fluidize 5min, then 45 DEG C of dry 30min.It, will be dry micro- after drying
Ball carries out 20~30 meshes point, obtains the pellet for being enclosed with sustained-release coating layer.
Enteric layer coating fluid prescription:
Enteric coating liquid is prepared:
A, talcum powder 17g, triethyl citrate 3.4g and pure water 89g are weighed, homogenizes 10min using homogenization machine, obtains
One mixed liquor；
B, Utech L30D-55 114g is weighed, under conditions of 400rpm is stirred continuously, 50g pure water is slowly added,
5min is stirred, the second mixed liquor is obtained；
C, the first mixed liquor homogenized is added in the second mixed liquor, stirs 30min；By obtained suspension with 60
Mesh screen obtains enteric coating liquid.
Art for coating: the pellet for having wrapped sustained release coating being placed in fluidized bed, hot-air is blown into, and is to capsule core temperature
Start to be coated at 32 DEG C, fluid supply rotate speed 4rpm, atomizing pressure 0.4MPa, blower frequency is 20Hz.In coating process, packet
Clothing liquid need to be stirred continuously, and prevent coating solution from settling.After coating solution has sprayed, continue to fluidize 5min, then 45 DEG C of dryings
30min.After drying, dry pellet is subjected to 20~30 meshes point.Obtained Mesalazine sustained release pellet is encapsulated (with real
Apply example 1) to get Mesalazine spansule.
Embodiment 3
Pellet core prescription (1000):
Adhesive preparation: weighing the pure water of 126g and the HPMC E6 of 14g, will under conditions of 500rpm is stirred continuously
14g HPMC E15 is added in 126g pure water, stirs 20min, and placement overnight is water-soluble to get the HPMC E6 that concentration is 10%
Liquid.
Capsule core preparation: it is uniformly mixed after taking the Mesalazine of recipe quantity to be sieved respectively with microcrystalline cellulose, with obtained 6%
HPMC E15 aqueous solution be adhesive prepare softwood, softwood is placed in extrusion spheronization machine and prepares pellet；Squeezing out revolving speed is
25rpm, round as a ball revolving speed are 900rpm, and the round as a ball time is 3min.Pellet in dry in 40 DEG C of baking ovens, sieve 20~30 mesh to get
Capsule core is used in coating.
Slow release layer coating fluid prescription:
Sulisi (with embodiment 1) 60g
Pure water 40g
Sustained release coating liquid is prepared: being weighed Sulisi aqueous dispersion 60g, under conditions of 80rpm is stirred continuously, is slowly added
Enter 40g pure water, it is fully dispersed, obtain sustained release coating liquid.
Art for coating: capsule core obtained being placed in fluidized bed, hot-air is blown into, and starts to wrap when capsule core temperature is 41 DEG C
Clothing, fluid supply rotate speed 4rpm, atomizing pressure 0.5MPa, blower frequency are 25Hz.In coating process, coating solution need to be sealed
And it is stirred continuously.After coating solution has sprayed, continue to fluidize 5min, then 45 DEG C of dry 30min.It, will be dry micro- after drying
Ball carries out 20~30 meshes point, obtains the pellet for being enclosed with sustained-release coating layer.
Enteric layer coating fluid prescription:
Enteric coating liquid is prepared:
A, talcum powder 15.5g, triethyl citrate 3.1g and pure water 77g are weighed, 10min is homogenized using homogenization machine, obtains
Processing aid solution；
B, Utech L30D-55 103g is weighed, under conditions of 400rpm is stirred continuously, 50g pure water is slowly added,
5min is stirred, enteric material solution is obtained；
C, the processing aid solution homogenized is added in enteric material solution, stirs 30min.The suspension that will be obtained
With 60 mesh screens, enteric coating liquid is obtained.
Art for coating: the pellet for having wrapped sustained release coating being placed in fluidized bed, hot-air is blown into, and is to capsule core temperature
Start to be coated at 32 DEG C, fluid supply rotate speed 4rpm, atomizing pressure 0.4MPa, blower frequency is 20Hz.In coating process, packet
Clothing liquid need to be stirred continuously, and prevent coating solution from settling.After coating solution has sprayed, continue to fluidize 5min, then 45 DEG C of dryings
30min.After drying, dry pellet is subjected to 20~30 meshes point.Obtained Mesalazine spansule is encapsulated (with real
Apply example 1) to get Mesalazine spansule.
Embodiment 4
Drug release rate test method as described above, simulation medium situation include: the 2h in 0.1mol/L HCl,
It changes with pH6.8 phosphate buffer to (hereinafter referred to as linear transformation medium method) and the 2h in 0.1mol/L HCl is finally terminated, changes
3h is carried out with pH6.8 phosphate buffer, is finally changed with pH7.5 phosphate buffer to finally terminating (hereinafter referred to as quadratic transformation
Medium method).Mesalazine spansule made from embodiment 2 is compared into Drug Releasing Test using both methods, is as a result joined
See that Fig. 1, Fig. 1 are the drug release profiles figure of 2 gained Mesalazine spansule of embodiment.
It will be seen from figure 1 that the medicine realeasing rate in pH7.5 phosphate buffer is slightly higher than after 5h replaces medium
PH6.8 phosphate buffer, but be not much different.
Drug release rate test method as described above, according to linear transformation medium method, by embodiment 1 and embodiment
Mesalazine spansule made from 3 carries out Drug Releasing Test.As a result referring to fig. 2, Fig. 2 is that Mesalazine obtained by Examples 1 to 3 is slow
Release the drug release profiles figure of capsule.1 corresponding embodiment 1 of example in Fig. 2, and so on.
Comparative example 1
For pellet core prescription (1000) referring to table 1, table 1 is that filler screens the prescription compared.
1 filler of table screens the prescription compared
According to the method for embodiment 1, coating capsule core is prepared；And it is the drugloading rate from pellet, roundness, yield, crisp
Four indexs of broken degree are evaluated.
Roundness is to investigate one of the important indicator of pellet, reflects the quality of pellet balling-up, directly affects coating solution
Deposition on pellet surface is sprawled, and then influences the coating quality and drug release feature of film control pellet.
Measuring method: the plane critical angle of pellet is measured, i.e., is set a certain amount of pellet on one plate, plate side is lifted
It rises, before measurement pellet starts rolling, clinoplain and horizontal plane are formed by angle.This angle is smaller, and pellet roundness is higher.
The height of friability directly affects coating process.The high pellet of friability has a large amount of micro- in coating process
Ball is broken, causes coating uneven, influences to release the drug.
Measuring method: weighing appropriate pellet and be placed in fluidized bed, and condition when according to coating is fluidized, and fluidizes 15min,
After fluidisation, broken pellet is weeded out, is weighed to remaining pellet, pellet loss amount and investment pellet amount ratio are as crisp
The lower broken degree, friability the better.
Yield is higher, and supplementary material wastes also fewer, and cost is lower, and efficiency can also increase accordingly.Calculation method:
The ratio for sieving the weight and inventory that obtain required pellet is yield.
Drugloading rate, roundness, yield, friability evaluation result referring to table 2, table 2 is that filler screens the pellet compared
Quality results.Pellet pattern result is successively in filler screening comparison procedure according to prescription 1 referring to Fig. 3~Fig. 7, Fig. 3~Fig. 7
The photo of~5 gained pellets.
2 filler of table screens the pellet quality results compared
| Drugloading rate | Roundness | Friability | Yield | |
| Prescription 1 | 67.4% | 17.2° | 0.63% | 94% |
| Prescription 2 | 67.6% | 16.8° | 0.51% | 97% |
| Prescription 3 | 62.9% | 28.3° | 4.53% | 78% |
| Prescription 4 | 62.9% | 31.7° | 3.48% | 73% |
| Prescription 5 | 63.1% | 36.4° | 4.17% | 68% |
In general from drugloading rate, roundness, friability, yield, it is best when filler is microcrystalline cellulose；Due to U.S. husky
Drawing the Qin is the drug of big specification, from the aspect of its drugloading rate, with microcrystalline cellulose (MCC) for filler, keeps U.S. of the invention husky
Draw Qin's spansule that there is better effect.From the point of view of microcrystalline cellulose model, MCC 301 is better than 302.
Comparative example 2
Directly addition slow-release material prepares sustained release pellet (skeleton capsule core).
It is respectively bone with additive amount 3%HPMC K100LV, 6%HPMC K100LV, 3%HPMC E15,6%HPMC E15
Frame material, preparation sustained release capsule core.
Wherein, 6%HPMC K100LV due to stickiness it is larger, squeeze out item it is very long, can not disconnect；
6%HPMC E15 can be squeezed out smoothly, but can not be round as a ball, eventually become corynebacterium, as shown in figure 8, Fig. 8 is to adopt
The photo of drug matrices capsule core made from 6%HPMC E15.
3%HPMC K100LV and 3%HPMC E15 can smooth extrusion spheronization, but release the drug it is too fast, do not reach requirement.
Comparative example 3
Preparation made from embodiment 3 and commercially available Pentasa are subjected to drug release profiles comparison, as a result referring to Fig. 9 and Figure 10, figure
9 for the present invention gained preparation and Pentasa in pH6.8PBS drug release profiles comparison, Figure 10 be the present invention gained preparation with
Drug release profiles comparison of the Pentasa in HCl-6.8PBS.
From as can be seen that in pH6.8PBS, the two drug release profiles are similar on curve, but simulation human gastrointestinal tract into
When row transformation pH medium measurement release, this preparation is substantially better than Pentasa, and 2h medicine realeasing rate is up to 66% to Pentasa under one's belt,
And the 2h drug release only 1% or so under one's belt of this preparation, substantially reduce the stimulation to stomach.
Embodiment 5
Using pellet core made from embodiment 3 as coating capsule core；
Pore-foaming agent is not added, it is 15% that Sulisi aqueous dispersion, which is directly diluted to solid content,.It increases weight and carries out to coating membrane
It investigates, weight gain is respectively 2.81%, 3.45%, 4.02%, 4.89%.Wherein 3.45% weight gain is the most suitable, can be with
Reach drug release to require, drug release profiles are shown in that Figure 11, Figure 11 are the drug release profiles figure of different sustained release coatings weight gain.
Embodiment 6
Using pellet core made from embodiment 3 as coating capsule core；
When due to not adding pore-foaming agent, coating weight gain range is smaller, therefore, investigates and adds different amounts of pore-foaming agent HPMC
Coating weight gain when E6.In Sulisi aqueous dispersion, it is respectively 2%, 3% that pore-foaming agent, which adds quality,.Wherein additive amount is 2%
When, coating weight gain 4.8% is the most suitable；When additive amount is 3%, coating weight gain 8.1% is the most suitable, can achieve requirement.It releases
Medicine curve is shown in that Figure 12, Figure 12 are the drug release profiles figure that sustained release coating adds pore-foaming agent.
As seen from the above embodiment, Mesalazine spansule provided by the invention can small intestine 3h release the drug 50% or so,
Colon drug delivery 50% or so.In the present invention, the pellet core prescription is simple, and drugloading rate is high；The pellet core package is slow
Coatings are released, it can be made slowly to release the drug at enteron aisle position, are conducive to the treatment of Crohn disease.Also, the present invention wraps up enteric packet
Clothing layer can reduce 5-ASA in the release (release rate < 2%) of stomach, reduce stimulation of the drug to stomach.The present invention using pH according to
Rely type to combine with two kinds of release Mechanisms of time-dependent, reach ideal drug release profiles, improves the accuracy of drug release position.This
Invention provide Mesalazine spansule include the Mesalazine sustained release pellet, can in gastrointestinal tract preferably slow releasing pharmaceutical,
Conducive to the treatment of ulcerative colitis and Crohn disease.
Claims (8)
1. a kind of Mesalazine sustained release pellet, has a structure that
Pellet core, the pellet core pass through extrusion spheronization technology system by 5-aminosalicylic acid, microcrystalline cellulose and adhesive
?；
The sustained-release coating layer being wrapped in the pellet core, the sustained-release coating layer is by the material system including ethyl cellulose
At；
The enteric coat layer being wrapped on the sustained-release coating layer, the enteric coat layer include enteric material and processing aid,
The enteric material is methacrylic acid and ethyl acrylate copolymer；
Described adhesive is selected from one of hydroxypropyl methylcellulose, povidone and starch or a variety of；Based on mass fraction, described to contain
The mass ratio of 5-aminosalicylic acid, microcrystalline cellulose and adhesive is 250:100:21,250:100:11 or 250 in pill core:
109:14；The partial size of the pellet core is 20~30 mesh.
2. Mesalazine sustained release pellet according to claim 1, which is characterized in that the sustained-release coating layer is by ethyl cellulose
Plain aqueous dispersion is made.
3. Mesalazine sustained release pellet according to claim 1, which is characterized in that the sustained-release coating layer makes pellet core
Weight gain 1%~10%.
4. Mesalazine sustained release pellet according to claim 1, which is characterized in that the processing aid include antiplastering aid and
One of plasticizer is a variety of.
5. Mesalazine sustained release pellet according to claim 4, which is characterized in that the antiplastering aid is talcum powder；It is described
Plasticizer is triethyl citrate.
6. Mesalazine sustained release pellet according to claim 1, which is characterized in that the enteric coat layer makes Mesalazine
Sustained release pellet weight gain 8%~20%.
7. the preparation method of Mesalazine sustained release pellet described in a kind of claim 1, comprising the following steps:
5-aminosalicylic acid, microcrystalline cellulose and adhesive are mixed, through extrusion spheronization technique, obtain pellet core；
Using the material including ethyl cellulose, the bundled slow-releasing coatings in the pellet core；
Enteric coat layer is wrapped up on sustained-release coating layer using enteric material and processing aid, obtains Mesalazine sustained release pellet；
The enteric material is methacrylic acid and ethyl acrylate copolymer.
8. a kind of Mesalazine spansule, which is characterized in that include claim 1~6 in the Mesalazine spansule
Any one of described in Mesalazine sustained release pellet or preparation method as claimed in claim 7 made from Mesalazine sustained release it is micro-
Ball.
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| CN105902500B (en) * | 2016-04-27 | 2019-11-29 | 上海理工大学 | A kind of mesalazine enteric positioning controlled-release preparation and preparation method thereof |
| CN112587506A (en) * | 2020-12-09 | 2021-04-02 | 南京森博医药研发有限公司 | Method for preparing mesalazine enteric sustained-release capsule |
| CN112494461A (en) * | 2020-12-31 | 2021-03-16 | 南京森博医药研发有限公司 | Mesalazine enteric sustained-release pharmaceutical composition and preparation method thereof |
| CN115245501A (en) * | 2021-08-26 | 2022-10-28 | 海南合瑞制药股份有限公司 | Mesalazine enteric sustained-release pellet with pulse release function and preparation method thereof |
| CN116650444B (en) * | 2023-07-31 | 2023-10-31 | 国药集团川抗制药有限公司 | Tacrolimus slow-release drug and preparation method thereof |
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