CN105456223A - Mesalazine sustained-release pellets, preparation method thereof and mesalazine sustained-release capsule - Google Patents
Mesalazine sustained-release pellets, preparation method thereof and mesalazine sustained-release capsule Download PDFInfo
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- CN105456223A CN105456223A CN201510945644.2A CN201510945644A CN105456223A CN 105456223 A CN105456223 A CN 105456223A CN 201510945644 A CN201510945644 A CN 201510945644A CN 105456223 A CN105456223 A CN 105456223A
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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
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- 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 invention provides mesalazine sustained-release pellets, a preparation method thereof and a mesalazine sustained-release capsule. The preparation method comprises the steps that 5-aminosalicylic acid, microcrystalline cellulose and a binding agent are mixed, and cores with pills are obtained through an extrusion rolling technology; materials comprising ethyecellulose are adopted, and cores with the pills are coated with sustained-release coating layers; the sustained-release coating layers are coated with enteric coating layers by the adoption of enteric materials and a processing aid, and mesalazine sustained-release pellets are obtained; the enteric materials are methacrylic acid and ethyl acrylate copolymer. PH dependent form and time dependent form drug release mechanisms are combined to achieve an ideal drug release curve, and the drug release position accuracy is improved. The mesalazine sustained-release capsule comprises the mesalazine sustained-release pellets, can be better released in the gastrointestinal tract and is beneficial to treatment on ulcerative colitis and Crohn's disease.
Description
Technical field
The present invention relates to mesalazine technical field of medicine, particularly relate to a kind of mesalazine slow-release micro-pill and preparation method thereof and mesalazine capsule.
Background technology
Inflammatory bowel (IBD) is a kind of chronic and inflammatory bowel disease of easily recurrence, can be divided into ulcerative colitis (UC) and Crohn disease (CD) in the narrow sense.Ulcerative colitis is a kind of common non specific chronic inflammatory diseases, falls ill in colonic mucosa, and symptom is mainly stomachache, diarrhoea, and concurrent colon cancer danger is high, and the course of disease cancer of 20 years is sent out rate and reached 5% ~ 10%.The pathogenesis of this disease is failed to understand, is now classified as one of modern difficult treatment by World Health Organization (WHO).Crohn disease is also called segmental enteritis or granulomatous enteritis, and this disease all can occur at any position of whole gastrointestinal, is most commonly in small intestinal and terminal ileum.This disease there is no basic cure method at present, and with multiple complications, need operative treatment, Postoperative recurrent rate is high.No matter be ulcerative colitis or Crohn disease, any age level can be betided, but be more common in 20 ~ 40 years old, also be found in child and old age.The sickness rate of these two kinds of diseases in developed country and city is higher than rural area, and its sickness rate is also in continuous rising.In addition, these two kinds of diseases likely occur in it same person simultaneously; And diffusion can be there is or spreads in the diseased region suffering from the patient of inflammatory bowel.Therefore, how the major issue that IBD has become modern medicine is effectively treated.
At present, the main medicines such as mesalazine that use are treated IBD patient.Mesalazine (or mesalazine), has another name called 5-aminosalicylic acid (can be abbreviated as 5-ASA), is the effective ingredient of the conventional medicament sulfasalazine (SASP) being used for the treatment of inflammatory bowel.Because mesalazine has the advantages such as curative effect is high, untoward reaction is few compared with SASP, it has become the first-line drug of clinical treatment Mild and moderate ulcerative colitis and the active drug for the treatment of Crohn disease.The inflammation of mesalazine to intestinal wall has significant inhibitory action, reaches antiinflammatory action mainly through the suppression secretion of prostaglandin and the generation of leukotriene and free radical; Mesalazine interacts with the mucosa of diseased region thus reaches inhibitory action, and this is local action, is not general action, can not enter blood circulation.Clinical therapeutics thinks that inflammatory bowel cannot effect a radical cure, and need repeatedly treat or maintaining treatment, mesalazine preparation has become indispensable types of drugs in IBD clinical treatment.External clinical research shows, selects the minosalicylates, drugs such as mesalazine to carry out IBD treatment and maintains, relapse rate can be made to be reduced to 25%.
According to present Research, the kind of 5-aminosalicylic acid preparation mainly comprises Mesalazine enteric-coated tablet, mesalazine enteric coated granule and Mesalazine controlled release capsule etc.These commercially available at present preparations for disease be all ulcerative colitis and Crohn disease two kinds, and be more and more directed to ulcerative colitis, be mostly colon location preparation.But site of pathological change is most commonly in the Crohn disease of small intestinal and terminal ileum, the 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 slow-release micro-pill and preparation method thereof and mesalazine slow releasing capsule, and mesalazine slow releasing capsule provided by the invention at gastrointestinal tract slow releasing pharmaceutical better, can be beneficial to the treatment of ulcerative colitis and Crohn disease.
The invention provides a kind of mesalazine slow-release micro-pill, comprising:
Containing pill core, the described pill core that contains comprises 5-aminosalicylic acid, microcrystalline Cellulose and binding agent;
Be wrapped in described containing the sustained-release coating layer on pill core, described sustained-release coating layer is made up of the material comprising ethyl cellulose;
Be wrapped in the enteric coat layer on described sustained-release coating layer, described enteric coat layer comprises enteric material and processing aid, and described enteric material is methacrylic acid and ethyl acrylate copolymer.
Preferably, described binding agent is selected from one or more in hypromellose, polyvidone and starch.
Preferably, in mass fraction, described containing pill core comprise the 5-aminosalicylic acid of 55% ~ 85%, the microcrystalline Cellulose of 15% ~ 45% and 3% ~ 10% binding agent.
Preferably, described sustained-release coating layer is made up of Aquacoat.
Preferably, described sustained-release coating layer makes containing pill core weightening finish 1% ~ 10%.
Preferably, described processing aid comprises one or more in antiplastering aid and plasticizer.
Preferably, described antiplastering aid is Pulvis Talci; Described plasticizer is triethyl citrate.
Preferably, described enteric coat layer makes mesalazine slow-release micro-pill increase weight 8% ~ 20%.
The invention provides a kind of preparation method of mesalazine slow-release micro-pill, comprise the following steps:
5-aminosalicylic acid, microcrystalline Cellulose and binding agent are mixed, through extrusion spheronization technique, obtains containing pill core;
Adopt the material comprising ethyl cellulose, described containing bundled slow-releasing coatings on pill core;
Adopt enteric material and processing aid to wrap up enteric coat layer on sustained-release coating layer, obtain mesalazine slow-release micro-pill; Described enteric material is methacrylic acid and ethyl acrylate copolymer.
The present invention also provides a kind of mesalazine slow releasing capsule, and described mesalazine slow releasing capsule comprises mesalazine slow-release micro-pill mentioned above.
Compared with prior art, mesalazine slow-release micro-pill provided by the invention comprises containing pill core, sustained-release coating layer and enteric coat layer successively; Wherein, the described pill core that contains comprises 5-aminosalicylic acid, microcrystalline Cellulose and binding agent; Described sustained-release coating layer is made up of the material comprising ethyl cellulose; Described enteric coat layer comprises methacrylic acid and ethyl acrylate copolymer and processing aid.In the present invention, described simple containing pill core prescription, drug loading is high; Described containing pill core bundled slow-releasing coatings, it can be made in the slow release in intestinal position, reach small intestinal 3h release about 50%, colon drug delivery about 50%, be conducive to the treatment of ulcerative colitis and Crohn disease.Further, the present invention wraps up enteric coat layer, can reduce the release (release rate < 2%) of 5-ASA at stomach, reduces medicine to the stimulation of stomach.The present invention utilizes pH dependent form and time-dependent two kinds of release Mechanisms to combine, and reaches desirable drug release profiles, improves the accuracy of release position.
Mesalazine slow releasing capsule provided by the invention comprises described mesalazine slow-release micro-pill, at gastrointestinal tract slow releasing pharmaceutical better, can be beneficial to the treatment of ulcerative colitis and Crohn disease.
Accompanying drawing explanation
Fig. 1 is the drug release profiles figure of embodiment 2 gained mesalazine slow releasing capsule;
Fig. 2 is the drug release profiles figure of embodiment 1 ~ 3 gained mesalazine slow releasing capsule;
Fig. 3 is the photo according to prescription 1 gained micropill in filler screening comparison procedure;
Fig. 4 is the photo according to prescription 2 gained micropill in filler screening comparison procedure;
Fig. 5 is the photo according to prescription 3 gained micropill in filler screening comparison procedure;
Fig. 6 is the photo according to prescription 4 gained micropill in filler screening comparison procedure;
Fig. 7 is the photo according to prescription 5 gained micropill in filler screening comparison procedure;
Fig. 8 is the photo of the drug matrices ball core adopting 6%HPMCE15 to obtain;
Fig. 9 is that gained preparation of the present invention and the drug release profiles of Pentasa in pH6.8PBS contrast;
Figure 10 is that gained preparation of the present invention and the drug release profiles of Pentasa in HCl-6.8PBS contrast;
Figure 11 is the drug release profiles figure of different sustained release coating weightening finish;
Figure 12 is the drug release profiles figure that sustained release coating adds porogen.
Detailed description of the invention
Be clearly and completely described the technical scheme in the embodiment of the present invention below, obviously, described embodiment is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art, not making the every other embodiment obtained under creative work prerequisite, belong to the scope of protection of the invention.
The invention provides a kind of mesalazine slow-release micro-pill, comprising:
Containing pill core, the described pill core that contains comprises 5-aminosalicylic acid, microcrystalline Cellulose and binding agent;
Be wrapped in described containing the sustained-release coating layer on pill core, described sustained-release coating layer is made up of the material comprising ethyl cellulose;
Be wrapped in the enteric coat layer on described sustained-release coating layer, described enteric coat layer comprises enteric material and processing aid, and described enteric material is methacrylic acid and ethyl acrylate copolymer.
Mesalazine slow-release micro-pill provided by the invention comprises containing pill core, and bundled slow-releasing clothing, enteric coating on it, desirable drug release profiles can be reached at gastrointestinal tract, and release position is more accurate.
Mesalazine slow-release micro-pill provided by the invention comprises containing pill core, and it comprises 5-aminosalicylic acid, microcrystalline Cellulose and binding agent.In the present invention, the described particle diameter containing pill core is preferably 20 ~ 30 orders; Namely particle diameter is preferably 0.6mm ~ 0.9mm, belongs to pellet preparations.Compared with other drug dosage form, micropill is a kind of novel polynary drug-supplying system, has many advantages: the 1) impact of the unable to take food thing conveying rhythm and pace of moving things, and individual variation is little; 2) good fluidity, can extensively be distributed in gastrointestinal tract after taking, local irritation be little; 3) considerable influence can not be produced because of the error of indivedual piller in preparation or defect to the drug release behavior of overall preparation; 4) micropill of several different release Mechanisms can be filled in a capsules or be pressed into tablet, to reach ideal effect.
The pill core that contains of the present invention mainly comprises 5-aminosalicylic acid, microcrystalline Cellulose and binding agent, and the prescription of this medicine element ball is simple, and drug loading is high.Wherein, described 5-aminosalicylic acid is main active; Described microcrystalline Cellulose is filler; One or more preferably in hypromellose (HPMC), polyvidone (PVP) and starch of described binding agent, are more preferably hypromellose or polyvidone.The source of the present invention to described filler and binding agent is not particularly limited, and adopts commercially available prod, as filler can be MCC, microcrystalline Cellulose 301, microcrystalline Cellulose 302, preferably adopts microcrystalline Cellulose 301 (MCC301); Binding agent can be PVPk30, HPMCE15, HPMCE6.
Of the present invention containing the adjuvant in pill core also can comprise in diluent and wetting agent etc. one or more, but preferably adjuvant is only containing microcrystalline Cellulose and binding agent, more simple, effective.
In an embodiment of the present invention, in mass fraction, described containing pill core comprise the 5-aminosalicylic acid of 55% ~ 85%, the microcrystalline Cellulose of 15% ~ 45% and 3% ~ 10% binding agent.Described containing pill core preferably include 60% ~ 80% 5-aminosalicylic acid, more preferably comprise the 5-aminosalicylic acid of 65% ~ 75%.Described containing pill core preferably include 20% ~ 40% microcrystalline Cellulose, more preferably comprise the microcrystalline Cellulose of 25% ~ 35%.In a particular embodiment of the present invention, the mass ratio of mesalazine, microcrystalline Cellulose and binding agent can be 250:100:21,250:100:11,250:109:14.
Mesalazine slow-release micro-pill provided by the invention comprises sustained-release coating layer, is wrapped in above-mentioned containing on pill core.In the present invention, described sustained-release coating layer is made up of the material comprising ethyl cellulose, is preferably made up of Aquacoat.Described sustained-release coating layer Main Function is that sustained drug is discharged lentamente, specifically plays the rate of release of control medicine, release time and discharges the effect at position.In the present invention, described containing pill core bundled slow-releasing coatings, it can be made in the slow release in intestinal position.Bundled slow-releasing coatings of the present invention utilizes medicine comparatively constant in the transhipment time of small intestinal, at about 3h, can reach small intestinal 3h release about 50%, colon drug delivery about 50%, be conducive to the treatment of ulcerative colitis and Crohn disease.
Further, because the pH value of small intestinal initial position is closer to 5.5, the such the present invention just weightening finish be more conducive to by controlling sustained-release coating layer controls it in enteral release.The present invention can regulate the thickness of sustained-release coating layer by the coating solution spraying different quality, be generally the coating weight gain level of 1% ~ 10%; Namely in general, described sustained-release coating layer can make, containing pill core weightening finish 1% ~ 10%, preferably to increase weight 2% ~ 6%.The present invention is not particularly limited the described source comprising the material of ethyl cellulose, can adopt commercially available Aquacoat, as Sulisi product.
In some embodiments of the invention, can not add porogen in sustained release coating, coating preferably increases weight 3% ~ 4%; In other embodiments of the present invention, sustained release coating can add porogen, if addition is 2% ~ 3%; Coating preferably increases weight 4% ~ 9%.The embodiment of the present invention is added porogen or is not added porogen, all can reach good drug release profiles by regulating clothing film thickness.Described porogen adopts this area to commonly use, as HPMC, PVP, PEG etc.
Mesalazine slow-release micro-pill provided by the invention comprises enteric coat layer, and it is wrapped on sustained-release coating layer.In the present invention, described enteric coat layer comprises enteric material and processing aid; Described enteric material is methacrylic acid and ethyl acrylate copolymer, is preferably made up of methacrylic acid and ethyl acrylate copolymer aqueous dispersion etc.The source of the present invention to described enteric material is not particularly limited, and can adopt the commercially available aqueous dispersion containing enteric material, as especially strange L30D-55 product.
In one embodiment of the invention, described enteric material can adopt L100-55 product, and it is the Spray dried products of especially strange L30D-55, re-uses, or with an organic solvent prepare during use after needing oneself to be mixed with aqueous dispersion.The preferred L30D-55 aqueous dispersion of the present invention, as enteric-coating material, can reduce as far as possible or avoid with an organic solvent, safety, environmental protection, easier.
The present invention can regulate and control the thickness of enteric coat layer, is generally the coating weight gain level of 8% ~ 20%; Namely in general, described enteric coat layer can make mesalazine slow-release micro-pill increase weight 8% ~ 20%, preferably increases weight 10% ~ 15%.
Enteric coat layer of the present invention mainly uses pH dependent form macromolecule enteric material, and pharmaceutical preparation is not dissolved in gastric juice, and can rapid solution under the condition of higher pH (> 5.5); Mainly like this can avoid the release in advance of principal agent in gastric juice, reduce principal agent to the stimulation of stomach, reduce toxic and side effects, improve the concentration of medicine at diseased region.The present invention wraps up enteric coat layer, can reduce the release (release rate < 2%) of 5-ASA at stomach, reduces its stimulation to stomach.
Except enteric material, enteric coat layer of the present invention comprises processing aid.In an embodiment of the present invention, described processing aid comprises one or more in antiplastering aid and plasticizer.Wherein, described antiplastering aid is the class material preventing from preparation coating process sticking together when comprising medicine micropill, as Pulvis Talci etc.Described plasticizer refers to and can improve the flexible compounds of coating membrane, usually can adopt triethyl citrate.In one embodiment of the invention, described enteric coat layer is obtained by the material comprising methacrylic acid and ethyl acrylate copolymer, Pulvis Talci and triethyl citrate.When the embodiment of the present invention prepares enteric coat layer, mass ratio containing the aqueous dispersion of enteric material, antitack agent and plasticizer is preferably (100 ~ 160): (15 ~ 25): (3 ~ 5), specifically can be 157:23.5:4.7,114:17:3.4,103:15.5:3.1.In addition, also the materials such as solvent can be added when the embodiment of the present invention prepares enteric coat layer.
In the present invention, the particle diameter of described mesalazine slow-release micro-pill is generally 0.6mm ~ 1.5mm.Mesalazine slow-release micro-pill of the present invention distribution area in intestinal is wide, compares tablet and is more suitable for quality inflammatory bowel.Because micropill should have enough drug level at enteritis position, and should discharge medicine as quickly as possible, to reach the valid density that 5-ASA plays antiinflammatory action, bundled slow-releasing clothing layer of the present invention, can make its slow release.Inflammatory bowel client need long-term prescription or prevention of recurrence, therefore 5-ASA should occur in blood as far as possible less, and to reduce toxic and side effects, and the present invention wraps up enteric coating layer and can reach this object.In sum, mesalazine slow-release micro-pill provided by the invention is the slow-release micro-pill of pH, time-dependent associating release Mechanisms, can control its release better, reach more preferably clinical therapeutic efficacy to Crohn disease.
Correspondingly, the invention provides a kind of preparation method of mesalazine slow-release micro-pill, comprising: 5-aminosalicylic acid, microcrystalline Cellulose and binding agent are mixed, through extrusion spheronization technique, obtain containing pill core;
Adopt the material comprising ethyl cellulose, described containing bundled slow-releasing coatings on pill core;
Adopt enteric material and processing aid to wrap up enteric coat layer on sustained-release coating layer, obtain mesalazine slow-release micro-pill; Described enteric material is methacrylic acid and ethyl acrylate copolymer.
The embodiment of the present invention adopts extrusion spheronization technique, by 5-aminosalicylic acid and comprise microcrystalline Cellulose, the adjuvant of binding agent adds water, make containing pill core after drying.
Wherein, the content of described microcrystalline Cellulose and binding agent as mentioned before, does not repeat them here.Due to the medicine that mesalazine is large gauge, and the amount that patient eats at every turn is larger, will prepare the higher preparation of drug loading as much as possible as well.The present invention considers that the character such as stickiness, mouldability of crude drug is all bad, as being prepared into the slow-release micro-pill of skeleton binding film control, certainly will add a lot of adjuvant, so virtually just needs to reduce drug loading.Further, if technological parameter slightly difference, will affect greatly release.When preparing the slow-release micro-pill of skeleton binding film control, if the slow-release material viscosity of employing is higher, then addition will be little, so just faces the problem of dispersed homogeneous degree; And addition is more, extruding bar will oversize, too consolidation, and causing cannot be round as a ball.According to the lower slow-release material of viscosity, then addition can increase many, and drug loading just reduces so virtually, amount of fill can be caused comparatively large, thus increase the difficulty of patient's drug administration.The present invention adopts extrusion spheronization technology to prepare plain ball, and is designed to film control micropill; Prescription containing pill core is simple, and drug loading is high, is convenient to clothes for patients and uses.
Binding agent and water are preferably mixed and made into binder aqueous solution by the embodiment of the present invention, then the 5-aminosalicylic acid of recipe quantity and microcrystalline Cellulose binder aqueous solution are prepared into soft material, then are placed in extrusion spheronization machine and prepare micropill.The present invention is not particularly limited the operation being prepared into binder aqueous solution; The mass concentration of described binder aqueous solution can be 8% ~ 15%.The operation that the present invention is prepared into soft material and prepares micropill is technological means well known to those skilled in the art, technique conveniently.In an embodiment of the present invention, the process conditions of extrusion spheronization comprise: extruding rotating speed is 25rpm, and round as a ball rotating speed is 900rpm, and the round as a ball time is 3min ~ 5min.In embodiments of the present invention, obtained micropill at 40 DEG C of baking oven inner dryings, can preferably sieve 20 ~ 30 orders, obtains coating with containing pill core.
Obtain containing after pill core, the embodiment of the present invention can be placed in fluid bed, adopts the coating solution comprising ethyl cellulose to carry out coating, is formed and be wrapped in containing the sustained-release coating layer on pill core.In addition, the present invention also can adopt additive method described containing bundled slow-releasing coatings on pill core.
In the present invention, described coating is operation well known to those skilled in the art.In an embodiment of the present invention, will be placed in fluid bed containing pill core, be blown into hot-air, when ball core temperature is 40 ~ 42 DEG C, start coating.In one particular embodiment of the present invention, the feed flow rotating speed of coating is 4rpm ~ 6rpm; Atomizing pressure can be 0.5MPa; Blower fan frequency can be 25Hz.
In coating process, coating solution needs good seal and constantly stirs.Described coating solution comprises ethyl cellulose; Can be added water by Sulisi, disperse to make.The present invention can regulate the thickness of sustained-release coating layer by the coating solution spraying different quality, be generally the coating weight gain level of 1% ~ 10%.
After liquid to be coated has sprayed, the embodiment of the present invention can continue fluidisation 5min ~ 10min, then preferred at 45 DEG C of dry 30min.After drying, the micropill of drying is preferably carried out 20 ~ 30 mesh sieves and divides by the embodiment of the present invention, obtains the micropill being enclosed with sustained-release coating layer.
After containing bundled slow-releasing coatings on pill core, the embodiment of the present invention adopts enteric material and processing aid to wrap up enteric coat layer on sustained-release coating layer, obtains mesalazine slow-release micro-pill.
In the present invention, described enteric coat layer comprises enteric material and processing aid.The content of described enteric material and processing aid as mentioned before, as described in enteric material be methacrylic acid and ethyl acrylate copolymer.Enteric material such as can to add water at the material by the embodiment of the present invention, and technique conveniently such as homogenize, stirring etc. are mixed with enteric coating liquid, carry out coating in fluid bed; Also additive method can be adopted to wrap up enteric coat layer.
In the present invention, described coating is the operation that this area is commonly used.The micropill wrapping sustained release coating is placed in fluid bed by the embodiment of the present invention, is blown into hot-air, when micropill temperature is 30 ~ 33 DEG C, start coating.In one particular embodiment of the present invention, the feed flow rotating speed of coating is 3rpm ~ 4rpm; Atomizing pressure can be 0.4MPa; Blower fan frequency can be 20Hz.
In coating process, coating solution needs constantly to stir, and prevents coating solution sedimentation.The present invention can regulate and control the thickness of enteric coat layer by the coating solution spraying different quality, be generally the coating weight gain level of 8% ~ 20%.After liquid to be coated has sprayed, the embodiment of the present invention can continue fluidisation 5min ~ 10min, then preferred at 45 DEG C of dry 30min.After drying, the micropill of drying is preferably carried out 20 ~ 30 mesh sieves and divides by the embodiment of the present invention, obtains mesalazine slow-release micro-pill.
Mesalazine slow-release micro-pill provided by the invention can make capsule, also can make other preparations.Present invention also offers a kind of mesalazine slow releasing capsule, described mesalazine slow releasing capsule comprises mesalazine slow-release micro-pill mentioned above.
Conventionally, the embodiment of the present invention, by encapsulated for mesalazine slow-release micro-pill, obtains mesalazine slow releasing capsule.Capsule in described mesalazine slow releasing capsule is the capsule kind that this area is commonly used; In embodiments of the present invention, in 1000 mesalazine slow releasing capsule, the content of mesalazine is 250g.
After obtaining mesalazine slow releasing capsule, the present invention carries out dissolution test to it.In order to investigate this product (mesalazine slow releasing capsule) the release situation in human gastrointestinal tract, adopting simulation human gastrointestinal tract to carry out conversion pH medium and measuring release.Drug release determination adopts the first method device of dissolution method (" Chinese Pharmacopoeia " version in 2010 two annex XC first method Rotating shaker), respectively with 900mL0.1mol/LHCl and pH6.8 phosphate buffer for release medium, rotating speed is 100rpm, temperature is 37 DEG C, 2h in 0.1mol/LHCl, change with pH6.8 phosphate buffer to finally terminating, each conversion medium completes in 5min.Sample at certain time intervals respectively, supplement equivalent equality of temperature medium simultaneously, with the filtering with microporous membrane of 0.45 μm, get subsequent filtrate appropriate, according to ultraviolet visible spectrophotometry (" Chinese Pharmacopoeia " version in 2010 two annex IVA) after dilution, measure trap at suitable wavelength place, calculate release.
The present invention compared for 2h in 0.1mol/LHCl, change with pH6.8 phosphate buffer to finally terminating and 2h in 0.1mol/LHCl, change and carry out 3h with pH6.8 phosphate buffer, finally change with pH7.5 phosphate buffer to finally terminating these two kinds of methods to the impact of release, find after being replaced by pH7.5 phosphate buffer, release can a little soon several percentage points, but release situation is generally similar.Further, Drug Releasing Test result of the present invention shows, described mesalazine slow releasing capsule is in small intestinal 3h release about 50%, and colon drug delivery about 50%, is conducive to the treatment of ulcerative colitis and Crohn disease.
In order to understand the application further, below in conjunction with embodiment, mesalazine slow-release micro-pill that the application provides and preparation method thereof and mesalazine slow releasing capsule are described particularly.
Embodiment 1
Containing pill core prescription (1000):
Prepared by binding agent: weigh the pure water of 119g and the PVPk30 of 21g, under the condition that 500rpm constantly stirs, joined by 21gPVPk30 in 119g pure water, stirs 20min, obtains the PVPk30 aqueous solution that concentration is 15%.
Prepared by ball core: mix homogeneously after the mesalazine getting recipe quantity sieves respectively with microcrystalline Cellulose, PVPk30 aqueous solution with obtained 15% is that binding agent prepares soft material, soft material is placed in extrusion spheronization machine and prepares micropill, extruding rotating speed is 25rpm, round as a ball rotating speed is 900rpm, and the round as a ball time is 3min; Micropill is in 40 DEG C of baking oven inner dryings, and screening 20 ~ 30 orders, obtain coating ball core.
Slow release layer coating fluid prescription:
Sulisi (Shanghai Colorcon Coating Technology Co., Ltd) 150g
Pure water 100g
Sustained release coating liquid is prepared: take Sulisi aqueous dispersion 150g, under the condition that 80rpm constantly stirs, add 100g pure water slowly, fully disperse, obtain sustained release coating liquid.
Art for coating: be placed in fluid bed by obtained ball core, be blown into hot-air, starts coating when ball core temperature is 41 DEG C, and feed flow rotating speed is 4rpm, and atomizing pressure is 0.5MPa, and blower fan frequency is 25Hz.In coating process, coating solution needs good seal and constantly stirs.After liquid to be coated has sprayed, continue fluidisation 5min, then 45 DEG C of dry 30min.After drying, the micropill of drying is carried out 20 ~ 30 mesh sieves and divides, obtain the micropill being enclosed with sustained-release coating layer.
Enteric layer coating fluid prescription:
Enteric coating liquid is prepared:
A, take Pulvis Talci 23.5g, triethyl citrate 4.7g and pure water 100g, use homogenization machine homogenize 10min, obtain mixed liquor A;
B, take especially strange L30D-55157g, under the condition that 400rpm constantly stirs, add 91g pure water slowly, stir 5min, obtain mixed liquid B;
C, the mixed liquor A that homogenize is good is joined in mixed liquid B, stir 30min; By the suspension obtained 60 mesh screen, obtain enteric coating liquid.
Art for coating: be placed in fluid bed by the micropill wrapping sustained release coating, be blown into hot-air, starts coating when ball core temperature is 32 DEG C, and feed flow rotating speed is 4rpm, and atomizing pressure is 0.4MPa, and blower fan frequency is 20Hz.In coating process, coating solution needs constantly to stir, and prevents coating solution sedimentation.After liquid to be coated has sprayed, continue fluidisation 5min, then 45 DEG C of dry 30min.After drying, the micropill of drying is carried out 20 ~ 30 mesh sieves and divides.By encapsulated for the mesalazine slow-release micro-pill obtained (Zhejiang Gekko Swinhonis soft gelatin capsule company limited, model 0# (coffee is yellow) gelatin hollow capsule), obtain mesalazine slow releasing capsule.
Embodiment 2
Containing pill core prescription (1000):
Prepared by binding agent: weigh the pure water of 127g and the HPMCE15 of 11g, under the condition that 500rpm constantly stirs, joined by 11gHPMCE15 in 127g pure water, and stir 20min, placement overnight, obtains the HPMCE15 aqueous solution that concentration is 8%.
Prepared by ball core: mix homogeneously after the mesalazine getting recipe quantity sieves respectively with microcrystalline Cellulose, the HPMCE15 aqueous solution with obtained 8% is that binding agent prepares soft material, soft material is placed in extrusion spheronization machine and prepares micropill; Extruding rotating speed is 25rpm, and round as a ball rotating speed is 900rpm, and the round as a ball time is 3min.Micropill is in 40 DEG C of baking oven inner dryings, and screening 20 ~ 30 orders, obtain coating ball core.
Slow release layer coating fluid prescription:
Sulisi (with embodiment 45g1)
Pure water 30g
Sustained release coating liquid is prepared: take Sulisi aqueous dispersion 45g, under the condition that 80rpm constantly stirs, add 30g pure water slowly, fully disperse, obtain sustained release coating liquid.
Art for coating: be placed in fluid bed by obtained ball core, be blown into hot-air, starts coating when ball core temperature is 41 DEG C, and feed flow rotating speed is 4rpm, and atomizing pressure is 0.5MPa, and blower fan frequency is 25Hz.In coating process, coating solution needs good seal and constantly stirs.After liquid to be coated has sprayed, continue fluidisation 5min, then 45 DEG C of dry 30min.After drying, the micropill of drying is carried out 20 ~ 30 mesh sieves and divides, obtain the micropill being enclosed with sustained-release coating layer.
Enteric layer coating fluid prescription:
Enteric coating liquid is prepared:
A, take Pulvis Talci 17g, triethyl citrate 3.4g and pure water 89g, use homogenization machine homogenize 10min, obtain the first mixed liquor;
B, take especially strange L30D-55114g, under the condition that 400rpm constantly stirs, add 50g pure water slowly, stir 5min, obtain the second mixed liquor;
C, the first good for homogenize mixed liquor is joined in the second mixed liquor, stir 30min; By the suspension obtained 60 mesh screen, obtain enteric coating liquid.
Art for coating: be placed in fluid bed by the micropill wrapping sustained release coating, be blown into hot-air, starts coating when ball core temperature is 32 DEG C, and feed flow rotating speed is 4rpm, and atomizing pressure is 0.4MPa, and blower fan frequency is 20Hz.In coating process, coating solution needs constantly to stir, and prevents coating solution sedimentation.After liquid to be coated has sprayed, continue fluidisation 5min, then 45 DEG C of dry 30min.After drying, the micropill of drying is carried out 20 ~ 30 mesh sieves and divides.By encapsulated for the mesalazine slow-release micro-pill obtained (with embodiment 1), obtain mesalazine slow releasing capsule.
Embodiment 3
Containing pill core prescription (1000):
Prepared by binding agent: weigh the pure water of 126g and the HPMCE6 of 14g, under the condition that 500rpm constantly stirs, joined by 14gHPMCE15 in 126g pure water, and stir 20min, placement overnight, obtains the HPMCE6 aqueous solution that concentration is 10%.
Prepared by ball core: mix homogeneously after the mesalazine getting recipe quantity sieves respectively with microcrystalline Cellulose, the HPMCE15 aqueous solution with obtained 6% is that binding agent prepares soft material, soft material is placed in extrusion spheronization machine and prepares micropill; Extruding rotating speed is 25rpm, and round as a ball rotating speed is 900rpm, and the round as a ball time is 3min.Micropill is in 40 DEG C of baking oven inner dryings, and screening 20 ~ 30 orders, obtain coating ball core.
Slow release layer coating fluid prescription:
Sulisi (with embodiment 1) 60g
Pure water 40g
Sustained release coating liquid is prepared: take Sulisi aqueous dispersion 60g, under the condition that 80rpm constantly stirs, add 40g pure water slowly, fully disperse, obtain sustained release coating liquid.
Art for coating: be placed in fluid bed by obtained ball core, be blown into hot-air, starts coating when ball core temperature is 41 DEG C, and feed flow rotating speed is 4rpm, and atomizing pressure is 0.5MPa, and blower fan frequency is 25Hz.In coating process, coating solution needs good seal and constantly stirs.After liquid to be coated has sprayed, continue fluidisation 5min, then 45 DEG C of dry 30min.After drying, the micropill of drying is carried out 20 ~ 30 mesh sieves and divides, obtain the micropill being enclosed with sustained-release coating layer.
Enteric layer coating fluid prescription:
Enteric coating liquid is prepared:
A, take Pulvis Talci 15.5g, triethyl citrate 3.1g and pure water 77g, use homogenization machine homogenize 10min, obtain processing aid solution;
B, take especially strange L30D-55103g, under the condition that 400rpm constantly stirs, add 50g pure water slowly, stir 5min, obtain enteric material solution;
C, processing aid solution good for homogenize is joined in enteric material solution, stir 30min.By the suspension obtained 60 mesh screen, obtain enteric coating liquid.
Art for coating: be placed in fluid bed by the micropill wrapping sustained release coating, be blown into hot-air, starts coating when ball core temperature is 32 DEG C, and feed flow rotating speed is 4rpm, and atomizing pressure is 0.4MPa, and blower fan frequency is 20Hz.In coating process, coating solution needs constantly to stir, and prevents coating solution sedimentation.After liquid to be coated has sprayed, continue fluidisation 5min, then 45 DEG C of dry 30min.After drying, the micropill of drying is carried out 20 ~ 30 mesh sieves and divides.By encapsulated for the mesalazine slow releasing capsule obtained (with embodiment 1), obtain mesalazine slow releasing capsule.
Embodiment 4
According to drug release rate test method mentioned above, simulation medium situation comprises: 2h in 0.1mol/LHCl, change with pH6.8 phosphate buffer to finally terminating (hereinafter referred to as linear transformation medium method) and 2h in 0.1mol/LHCl, changing and carry out 3h with pH6.8 phosphate buffer, finally changing with pH7.5 phosphate buffer to finally terminating (hereinafter referred to as quadratic transformation medium method).Adopt these two kinds of methods to carry out contrast Drug Releasing Test mesalazine slow releasing capsule obtained for embodiment 2, result is the drug release profiles figure of embodiment 2 gained mesalazine slow releasing capsule see Fig. 1, Fig. 1.
As can be seen from Figure 1, after 5h changes medium, the medicine realeasing rate in pH7.5 phosphate buffer is slightly higher than pH6.8 phosphate buffer, but is more or less the same.
According to drug release rate test method mentioned above, according to linear transformation medium method, the mesalazine slow releasing capsule that embodiment 1 and embodiment 3 obtain is carried out Drug Releasing Test.Result is the drug release profiles figure of embodiment 1 ~ 3 gained mesalazine slow releasing capsule see Fig. 2, Fig. 2.The corresponding embodiment 1 of example 1 in Fig. 2, the like.
Comparative example 1
Containing pill core prescription (1000) see table 1, table 1 screens the prescription compared for filler.
Table 1 filler screens the prescription compared
According to the method for embodiment 1, prepare coating ball core; And evaluate from the drug loading of micropill, roundness, yield, friability four indexs.
Roundness is one of important indicator investigating micropill, reflects the quality of micropill balling-up, directly affects coating solution and sprawls in the deposition on micropill surface, and then affect coating quality and the drug release feature of film control micropill.
Assay method: the plane critical angle measuring micropill, puts on a flat board by a certain amount of micropill, is lifted dull and stereotyped side, before measurement micropill starts rolling, and the angle that clinoplain and horizontal plane are formed.This angle is less, and micropill roundness is higher.
The height of friability directly affects coating process.The micropill that friability is high, in coating process, has a large amount of micropills broken, causes coating uneven, affect release.
Assay method: take appropriate micropill and be placed in fluid bed, carry out fluidisation according to condition during coating, fluidisation 15min, after fluidisation terminates, sieve removes broken micropill, weighs to remaining micropill, micropill loss amount and input micropill amount ratio, be friability, friability is more low better.
Yield is higher, and it is also fewer that supplementary material is wasted, and cost is lower, and efficiency also can increase accordingly.Computational methods: the ratio sieving the weight and inventory obtaining required micropill is yield.
The evaluation result of drug loading, roundness, yield, friability is see table 2, and table 2 screens the micropill quality results compared for filler.Micropill pattern result is the photo according to prescription 1 ~ 5 gained micropill in filler screening comparison procedure see Fig. 3 ~ Fig. 7, Fig. 3 ~ Fig. 7 successively.
Table 2 filler screens the micropill quality results compared
| Drug loading | 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％ |
From drug loading, roundness, friability, yield in general, it is best when filler is microcrystalline Cellulose; Due to the medicine that mesalazine is large gauge, from the viewpoint of its drug loading, with microcrystalline Cellulose (MCC) for filler, mesalazine slow releasing capsule of the present invention is made to have better effect.From microcrystalline Cellulose model, MCC301 is better than 302.
Comparative example 2
Direct interpolation slow-release material prepares slow-release micro-pill (skeleton ball core).
Respectively with addition 3%HPMCK100LV, 6%HPMCK100LV, 3%HPMCE15,6%HPMCE15 are framework material, prepare slow release ball core.
Wherein, 6%HPMCK100LV is comparatively large due to stickiness, extrudes bar very long, cannot disconnect;
6%HPMCE15 can extrude smoothly, but cannot be round as a ball, finally becomes corynebacterium, and as shown in Figure 8, Fig. 8 is the photo of the drug matrices ball core adopting 6%HPMCE15 to obtain.
3%HPMCK100LV and 3%HPMCE15 can extrusion spheronization smoothly, but release is too fast, does not reach requirement.
Comparative example 3
Preparation obtained for embodiment 3 and commercially available Pentasa are carried out drug release profiles contrast, result is see Fig. 9 and Figure 10, Fig. 9 is that gained preparation of the present invention and the drug release profiles of Pentasa in pH6.8PBS contrast, and Figure 10 is that gained preparation of the present invention and the drug release profiles of Pentasa in HCl-6.8PBS contrast.
As can be seen from curve, in pH6.8PBS, both drug release profiles are similar, but when simulating human gastrointestinal tract and carrying out conversion pH medium mensuration release, this preparation is obviously better than Pentasa, 2h medicine realeasing rate is up to 66% under one's belt for Pentasa, and this preparation 2h release only about 1% under one's belt, substantially reduces the stimulation to stomach.
Embodiment 5
What obtain with embodiment 3 contains pill core for coating ball core;
Do not add porogen, directly Sulisi aqueous dispersion being diluted to solid content is 15%.Investigate coating membrane weightening finish, weightening finish is respectively 2.81%, 3.45%, 4.02%, 4.89%.Wherein 3.45% weightening finish is the most suitable, and can reach release requirement, drug release profiles is shown in Figure 11, and Figure 11 is the drug release profiles figure of different sustained release coating weightening finish.
Embodiment 6
What obtain with embodiment 3 contains pill core for coating ball core;
During owing to not adding porogen, coating weight gain scope is less, therefore, investigates coating weight gain when adding not commensurability porogen HPMCE6.In Sulisi aqueous dispersion, porogen adds quality and is respectively 2%, 3%.When wherein addition is 2%, coating weight gain 4.8% is the most suitable; When addition is 3%, coating weight gain 8.1% is the most suitable, can reach requirement.Drug release profiles is shown in Figure 12, and Figure 12 is the drug release profiles figure that sustained release coating adds porogen.
As seen from the above embodiment, mesalazine slow releasing capsule provided by the invention can in small intestinal 3h release about 50%, colon drug delivery about 50%.In the present invention, described simple containing pill core prescription, drug loading is high; Described containing pill core bundled slow-releasing coatings, it can be made in the slow release in intestinal position, be conducive to the treatment of Crohn disease.Further, the present invention wraps up enteric coat layer, can reduce the release (release rate < 2%) of 5-ASA at stomach, reduces medicine to the stimulation of stomach.The present invention utilizes pH dependent form and time-dependent two kinds of release Mechanisms to combine, and reaches desirable drug release profiles, improves the accuracy of release position.Mesalazine slow releasing capsule provided by the invention comprises described mesalazine slow-release micro-pill, at gastrointestinal tract slow releasing pharmaceutical better, can be beneficial to the treatment of ulcerative colitis and Crohn disease.
Claims (10)
1. a mesalazine slow-release micro-pill, comprising:
Containing pill core, the described pill core that contains comprises 5-aminosalicylic acid, microcrystalline Cellulose and binding agent;
Be wrapped in described containing the sustained-release coating layer on pill core, described sustained-release coating layer is made up of the material comprising ethyl cellulose;
Be wrapped in the enteric coat layer on described sustained-release coating layer, described enteric coat layer comprises enteric material and processing aid, and described enteric material is methacrylic acid and ethyl acrylate copolymer.
2. mesalazine slow-release micro-pill according to claim 1, is characterized in that, described binding agent be selected from hypromellose, polyvidone and starch one or more.
3. mesalazine slow-release micro-pill according to claim 1 and 2, is characterized in that, in mass fraction, described containing pill core comprise the 5-aminosalicylic acid of 55% ~ 85%, the microcrystalline Cellulose of 15% ~ 45% and 3% ~ 10% binding agent.
4. mesalazine slow-release micro-pill according to claim 1, is characterized in that, described sustained-release coating layer is made up of Aquacoat.
5. mesalazine slow-release micro-pill according to claim 1, is characterized in that, described sustained-release coating layer makes containing pill core weightening finish 1% ~ 10%.
6. mesalazine slow-release micro-pill according to claim 1, is characterized in that, described processing aid comprise in antiplastering aid and plasticizer one or more.
7. mesalazine slow-release micro-pill according to claim 6, is characterized in that, described antiplastering aid is Pulvis Talci; Described plasticizer is triethyl citrate.
8. mesalazine slow-release micro-pill according to claim 1, is characterized in that, described enteric coat layer makes mesalazine slow-release micro-pill increase weight 8% ~ 20%.
9. a preparation method for mesalazine slow-release micro-pill, comprises the following steps:
5-aminosalicylic acid, microcrystalline Cellulose and binding agent are mixed, through extrusion spheronization technique, obtains containing pill core;
Adopt the material comprising ethyl cellulose, described containing bundled slow-releasing coatings on pill core;
Adopt enteric material and processing aid to wrap up enteric coat layer on sustained-release coating layer, obtain mesalazine slow-release micro-pill; Described enteric material is methacrylic acid and ethyl acrylate copolymer.
10. a mesalazine slow releasing capsule, is characterized in that, described mesalazine slow releasing capsule comprises mesalazine slow-release micro-pill according to any one of claim 1 ~ 8 or the obtained mesalazine slow-release micro-pill of preparation method according to claim 9.
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