CN100571694C - Mesalazine colon positioning release pellet preparations and preparation method thereof - Google Patents
Mesalazine colon positioning release pellet preparations and preparation method thereof Download PDFInfo
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- CN100571694C CN100571694C CNB2004100204556A CN200410020455A CN100571694C CN 100571694 C CN100571694 C CN 100571694C CN B2004100204556 A CNB2004100204556 A CN B2004100204556A CN 200410020455 A CN200410020455 A CN 200410020455A CN 100571694 C CN100571694 C CN 100571694C
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- mesalazine
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Abstract
The invention discloses a kind of mesalazine colon positioning release pellet preparations and preparation method thereof, it has to absorb on gastrointestinal tract lacks, and keeps the characteristics of the effective drug level of pathological changes intestinal segment.It is to be effective pharmacology composition in conjunction with the site-specific drug delivery mini-pill of excipient and diluent preparation with mesalazine.Wherein the percentage by weight of mesalazine, excipient, diluent composition is as follows: mesalazine 300-600 weight portion, excipient 100-300 weight portion, diluent 50-200 weight portion.Excipient is a microcrystalline Cellulose, and diluent is starch, dextrin etc.To sieve mix homogeneously behind medicine and excipient, the diluent pulverize separately.The system soft material is extruded wet micropill and is got the ball core, hands over ball core coating, with hot-air dry promptly.The present invention has therapeutical effect preferably to colitis, and the economic level situation of suitable China.
Description
Technical field:
The present invention relates to medical technical field, it is mesalazine colon positioning release pellet preparations and preparation method thereof in definite saying.
Background technology:
(colon-specific drug delivery system CDDS) is a kind of novel medicine-releasing system that grew up in the last few years in the oral colon-specific drug release system.CDDS utilizes one or more controlled-release technologies to make not release in the upper gastrointestinal zone after the preparation oral administration, and when preparation arrives colon, discharge medicine rapidly, make the therapeutical effect of medicine performance part or whole body, the safety that has improved preparation has simultaneously reduced toxic and side effects.At present, existing a large amount of document proves, CDDS has compared its unique advantages: a. and has passed through at colon positioning release with other medicine-releasing system, make medicine directly act on diseased region, improve local drug concentration, alleviate owing to medicine absorbs the side effect cause in upper gi tract, reaching the purpose for the treatment of colon local disease effectively, as ulcerative colitis, segmental colitis (Crohn ' s disease), colon cancer, constipation etc.B. colon positioning release has guaranteed that medicine do not degraded by gastrointestinal enzyme and destroy in upper gi tract, can make macromole class medicines such as polypeptide, protein realize oral administration, and medicine is longer relatively in the transhipment time of colon, metabolic enzyme in the colon is also less relatively, thereby has improved this class bioavailability of medicament.C. colon positioning release is combined with chronopharmacology, to some disease that influenced by temporal rhythm, as asthma, morning deadlock etc. better therapeutic effect is also arranged.
Micropill is a kind of novel polynary drug-supplying system, particle diameter commonly used is generally 0.5-1.5mm, compares many advantages with conventional formulation (as tablet): be subjected to physiological effect less (as gastric emptying, small intestinal transhipment etc.), be easy to control to improve bioavailability of medicament, drug release behavior more greatly at the area of gastrointestinal tract surface distributed, bioavailability among individuals difference is little.
Mesalazine has another name called 5-aminosalicylic acid (5-Aminosalicylic Acid is abbreviated as 5-ASA), effective ingredient for sulfasalazine (Sulfasalazine is abbreviated as SASP), this local action medicine is substituting that SASP becomes that treatment is light, the active drug of the active ulcerative colitis of moderate and Crohn disease (crohn), the mucous membrane of rectum of mesalazine inflammation-inhibiting intestinal diseases discharges leukotriene, stop macrophage to enter the inflammation district, reduce the local inflammation cellular infiltration, suppress prostaglandin E in the mucous membrane of colon
2, leukotriene B
4And 5-hydroxyl 12 carbon tetraenoic acids synthetic and discharge and bring into play antiinflammatory action with this, its effect is partial, is promptly contacting with big intestinal mucosa and is playing a role during complexation, rather than playing a role after entering blood circulation.Mesalazine is oral can the absorption rapidly by the harmonization of the stomach small intestinal directly, can not have the q.s medicine to arrive a colon and an antiinflammatory action like this, sucks intravital medicine simultaneously and easily produces nephrotoxicity.Therefore, the Mesalazine oral preparation must design especially, to reduce in upper gastrointestinal absorption, make it navigate to terminal ileum or colon release medicine, could keep the effective drug level of pathological changes intestinal segment, mesalazine seldom has absorption after arriving colon, mainly excrete with feces, seldom produces untoward reaction.Seminar thinks that this medicine has promotional value widely under China's applied economics level, and market prospect is very good.The formulation products of at present domestic relevant this medicine is few, and prior dosage form can not be fit to needs clinically far away, and this medicine is developed as the needs that the colon positioning release pellet preparations meets the medical market.
Summary of the invention:
The purpose of this invention is to provide a kind of mesalazine colon positioning release pellet preparations and preparation method thereof.It is the site-specific drug delivery mini-pill of effective pharmacology composition in conjunction with excipient and diluent preparation with mesalazine.
The percentage by weight that mesalazine, excipient, diluent are formed is as follows:
Mesalazine 300-600 weight portion
Excipient 100-300 weight portion
Diluent 50-200 weight portion
The specification of mesalazine is per unit 300,400,500,600mg.
It also can be made up of following component:
Mesalazine 380-420 weight portion
Excipient 80-200 weight portion
Diluent 30-150 weight portion
Excipient is a microcrystalline Cellulose.
Diluent consist of starch, dextrin, lactose, microcrystalline Cellulose etc.
Wherein also can add binding agent and ethanol, binding agent is the mixed solution of polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, methylcellulose, water, water or alcohol.
The weight proportion of each component is:
Mesalazine 400 weight portions
Excipient 100 weight portions
25% ethanol is an amount of
To sieve behind medicine and excipient, the diluent pulverize separately, mix homogeneously, with 25% ethanol is binding agent system soft material, put and extrude the wet micropill of system in the spheronizator, wet 30 ± 5 ℃ of dryings of micropill, the screening micropill promptly gets coating ball core, carries out coating with fluid unit or centrifugal coating machine or conventional dose coating pan etc. by continuous or short spray method, the coating solution flow velocity is 0.5-1.0mL/min, and atomizing pressure is 0.8-1.2kg/cm
2, inlet temperature 30-35 ℃, reach weightening finish 30-35% to the thickness of ball core outer coatings film, continue to be blown into hot-air dry 15min, then with coated micropill in drying baker 40 ℃ down dry 24h get product.
Mesalazine colon positioning release pellet preparations, filmogen is a methacrylic resin, plasticizer is PEG1500, PEG4000, PEG6000, phthalic acid ester, glyceride, succinate, benzoate, adipate ester, tartrate, citrate etc., antiplastering aid is pharmaceutically useful adjuvant, comprise magnesium stearate, Pulvis Talci, glyceryl monostearate, the coating solvent is water, 95% ethanol, acetone, isopropyl alcohol and their mixture.
Advantage of the present invention is: the absorption on gastrointestinal tract is few, make it navigate to terminal ileum or colon release medicine, kept the effective drug level of pathological changes intestinal segment, mesalazine seldom has absorption after arriving colon, mainly excrete with feces, seldom produce untoward reaction, be fit to the market demand under China's applied economics level.
Description of drawings:
Fig. 1 is the release result of the test figure that each section pH of coated micropill Gl tract changes among the embodiment 2.
Fig. 2 is the release conditions of coated micropill in different pH release medium figure as a result among the embodiment 2.
Among the figure-◆-pH1.2 HCl solution-■-pH6.0 phosphate buffer
The pH6.8 of-▲-phosphate buffer-zero-pH7.2 phosphate buffer
-◇-pH7.5 phosphate buffer
The specific embodiment:
The following examples are in order to further specifying the present invention, but should understand that the present invention is not limited to this.
Embodiment 1
Ball core prescription:
Mesalazine 400g
Microcrystalline Cellulose 120g
Starch 80g
25% ethanol is an amount of
Ball core preparation: will sieve behind the medicine and the microcrystalline Cellulose of recipe quantity, the starch pulverize separately, mix homogeneously is a binding agent system soft material with 25% ethanol, and soft material is put the system of extruding in the spheronizator micropill that wets, and 30 ± 5 ℃ of dryings of micropill that wet are sieved, and promptly get coating ball core.
Coating fluid prescription:
Polyethylene Glycol (PEG) 6000 4.0g
Pulvis Talci 10.0g
Isopropyl acetone 726g
Art for coating: the ball core is placed in the fluid bed, be blown into hot-air, when treating that ball core temperature is 30 ℃ of left and right sides, carry out coating, the coating solution flow velocity is 0.6mL/min, and pressure is 1.0kg/cm
2, temperature is about 35 ℃ in the fluid bed, reaches weightening finish 30-35% to the thickness of ball core outer coatings film, continues to be blown into hot-air dry 15min, then with coated micropill in drying baker 40 ℃ down dry 24h get product.
Embodiment 2:
Ball core prescription:
Mesalazine 400g
Microcrystalline Cellulose 140g
Lactose 60g
25% ethanol is an amount of
Ball core preparation: with embodiment 1.
Coating fluid prescription:
S100 75.0g
Triethyl citrate 10.0g
Pulvis Talci 25.0g
Sodium hydroxide solution (1mol/L) 32.0g
Water 633g
L100 is for gathering (methacrylic acid, methyl methacrylate) 1: 1, and Rohm Tech produces
Art for coating: with embodiment 1.
Embodiment 3:
Ball core prescription:
Mesalazine 400g
Microcrystalline Cellulose 140g
Lactose 60g
Polyvinylpyrrolidone is an amount of
Ball core preparation: with embodiment 1.
Coating fluid prescription:
FS30D 200.0g
Triethyl citrate 3.0g
Pulvis Talci 18.0g
Water 79.0g
Art for coating: with embodiment 1.
Embodiment 4:
Coated micropill to embodiment 2 carries out the release test that each section pH of Gl tract changes.
Pressing 2000 editions dissolution methods of Chinese Pharmacopoeia (appendix XC first method) measures.Rotating speed is 100rpm, 900mL dissolution medium, 37 ± 0.5 ℃ of temperature.0-2 hour dissolution medium is pH1.2 HCl solution, and dissolution medium was replaced by pH 6.0 phosphate buffers in 3 hours, dissolution medium was changed to the phosphate buffer of pH 7.2 in 4-8 hour again, the results are shown in accompanying drawing 1.
By accompanying drawing 1 as can be known the coated micropill of embodiment 2 in the pH1.2 dissolution medium in 2 hours the release amount be no more than 1%, the release amount is no more than 5% in 1 hour in pH 6.0 dissolution mediums, and in pH 7.2 dissolution mediums in 5 hours the release amount greater than 95%, because the dissolution medium of pH1.2 is mimic is pH value in the stomach, the dissolution medium of pH6.0 is mimic to be pH value in the duodenum, the dissolution medium of pH7.2 is mimic to be pH value in small intestine distal end and the colon, can show that therefore coated micropill realized the purpose of colon positioning release.
Embodiment 5:
Coated micropill release situation in different pH release medium to embodiment 2 is investigated.
Pressing 2000 editions dissolution methods of Chinese Pharmacopoeia (appendix XC first method) measures.Rotating speed is 100rpm, 900mL dissolution medium, 37 ± 0.5 ℃ of temperature.Release medium is respectively pH1.2 HCl solution and pH6.0,6.8,7.2,7.5 phosphate buffer, the results are shown in accompanying drawing 2.
By accompanying drawing 2 coated micropill of embodiment 2 as can be known, its release situation is influenced significantly by the pH value of release medium, and along with pH value changes to 7.5 from 1.2, the rate of release of medicine significantly increases.There are some researches show that the gastrointestinal pH value presents the rule of graded, the pH value of terminal ileum and colon is higher than other zones of gastrointestinal tract, so coated micropill can reach the effect of colon positioning release.
Claims (3)
1, mesalazine colon positioning release pellet preparations is characterized in that: its prescription consists of:
Ball core prescription:
Mesalazine 400g
Microcrystalline Cellulose 120g
Starch 80g
25% ethanol is an amount of
Coating fluid prescription:
Polyethylene glycol 6000 4.0g
Pulvis Talci 10.0g
Isopropyl acetone 726g
Preparation by the following method:
To sieve behind the mesalazine of recipe quantity and microcrystalline Cellulose, the starch pulverize separately, mix homogeneously is a binding agent system soft material with 25% ethanol, soft material is put extruded the wet micropill of system in the spheronizator, and wet 30 ± 5 ℃ of dryings of micropill, screening promptly gets coating ball core; The ball core is placed in the fluid bed, be blown into hot-air, when treating that ball core temperature is 30 ℃ of left and right sides, carry out coating, the coating solution flow velocity is 0.6mL/min, and pressure is 1.0kg/cm
2, temperature is about 35 ℃ in the fluid bed, reaches weightening finish 30-35% to the thickness of ball core outer coatings film, continues to be blown into hot-air dry 15min, then with coated micropill in drying baker 40 ℃ down dry 24h get product.
2, mesalazine colon positioning release pellet preparations is characterized in that: its prescription consists of:
Ball core prescription:
Mesalazine 400g
Microcrystalline Cellulose 140g
Lactose 60g
25% ethanol is an amount of
Coating fluid prescription:
Triethyl citrate 10.0g
Pulvis Talci 25.0g
The sodium hydroxide solution 32.0g of 1mol/L
Water 633g
Preparation by the following method:
To sieve behind the mesalazine of recipe quantity and microcrystalline Cellulose, the lactose pulverize separately, mix homogeneously is a binding agent system soft material with 25% ethanol, soft material is put extruded the wet micropill of system in the spheronizator, and wet 30 ± 5 ℃ of dryings of micropill, screening promptly gets coating ball core; The ball core is placed in the fluid bed, be blown into hot-air, when treating that ball core temperature is 30 ℃ of left and right sides, carry out coating, the coating solution flow velocity is 0.6mL/min, and pressure is 1.0kg/cm
2, temperature is about 35 ℃ in the fluid bed, reaches weightening finish 30-35% to the thickness of ball core outer coatings film, continues to be blown into hot-air dry 15min, then with coated micropill in drying baker 40 ℃ down dry 24h get product.
3, mesalazine colon positioning release pellet preparations is characterized in that: its prescription consists of:
Ball core prescription:
Mesalazine 400g
Microcrystalline Cellulose 140g
Lactose 60g
Polyvinylpyrrolidone is an amount of
Coating fluid prescription:
Triethyl citrate 3.0g
Pulvis Talci 18.0g
Water 79.0g
Preparation by the following method:
To sieve behind the mesalazine of recipe quantity and microcrystalline Cellulose, the lactose pulverize separately, mix homogeneously is a binding agent system soft material with polyvinylpyrrolidone, soft material is put extruded the wet micropill of system in the spheronizator, and wet 30 ± 5 ℃ of dryings of micropill, screening promptly gets coating ball core; The ball core is placed in the fluid bed, be blown into hot-air, when treating that ball core temperature is 30 ℃ of left and right sides, carry out coating, the coating solution flow velocity is 0.6mL/min, and pressure is 1.0kg/cm
2, temperature is about 35 ℃ in the fluid bed, reaches weightening finish 30-35% to the thickness of ball core outer coatings film, continues to be blown into hot-air dry 15min, then with coated micropill in drying baker 40 ℃ down dry 24h get product.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2004100204556A CN100571694C (en) | 2004-04-26 | 2004-04-26 | Mesalazine colon positioning release pellet preparations and preparation method thereof |
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| CNB2004100204556A CN100571694C (en) | 2004-04-26 | 2004-04-26 | Mesalazine colon positioning release pellet preparations and preparation method thereof |
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| CN100571694C true CN100571694C (en) | 2009-12-23 |
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100562322C (en) * | 2005-08-11 | 2009-11-25 | 中国科学院过程工程研究所 | Colon targeting preparation of a kind of 5-aminosalicylic acid and preparation method thereof |
| CN101590020B (en) * | 2008-05-30 | 2012-02-08 | 上海新菲尔生物制药工程技术有限公司 | Para-aminosalicylate colon positioning drug delivery system |
| CN101721385B (en) * | 2008-10-13 | 2012-10-24 | 重庆医药工业研究院有限责任公司 | Mesalazine oral controlled release medicine composition |
| CN103153944A (en) * | 2010-09-10 | 2013-06-12 | 法莫再尔公司 | Method for producing crystalline 5-aminosalicylic acid |
| CN102784154B (en) * | 2012-09-01 | 2013-10-09 | 朱文军 | Mesalazine enteric coated tablet and preparation method thereof |
| CN109568281B (en) * | 2018-12-21 | 2022-05-10 | 南京济群医药科技股份有限公司 | Sulfasalazine tablet and preparation method thereof |
| CN113855643B (en) * | 2021-11-10 | 2022-11-11 | 葵花药业集团佳木斯鹿灵制药有限公司 | Mesalazine sustained release preparation for colon-specific drug release and preparation process thereof |
-
2004
- 2004-04-26 CN CNB2004100204556A patent/CN100571694C/en not_active Expired - Fee Related
Non-Patent Citations (7)
| Title |
|---|
| .A new 5-aminosalicylic acid multi-unit dosage form for thetherapy of ulcerative colitis. Markus W.Rudolph,Sandra Klein et al.European Journal of Pharmaceutics and Biopharmaceutics,Vol.51 . 2001 |
| .A new 5-aminosalicylic acid multi-unit dosage form for thetherapy of ulcerative colitis. Markus W.Rudolph,Sandra Klein et al.European Journal of Pharmaceutics and Biopharmaceutics,Vol.51 . 2001 * |
| PH-依赖－缓释型美沙拉秦结肠靶向小丸的制备与体外评价. 傅崇东等.中国医药工业杂志，第31卷第12期. 2000 |
| PH-依赖－缓释型美沙拉秦结肠靶向小丸的制备与体外评价. 傅崇东等.中国医药工业杂志，第31卷第12期. 2000 * |
| 药物新剂型. 朱盛山，第175页，第244页例8-9，化学工业出版社. 2003 药物新剂型与新技术. 陆彬，第290页，第294－295页，第296-299页，人民卫生出版社. 1998 |
| 药物新剂型. 朱盛山，第175页，第244页例8-9，化学工业出版社. 2003 * |
| 药物新剂型与新技术. 陆彬，第290页，第294－295页，第296-299页，人民卫生出版社. 1998 * |
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