CN101584666A - Preparing method of proton pump inhibitor biological adhesive preparation - Google Patents
Preparing method of proton pump inhibitor biological adhesive preparation Download PDFInfo
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- CN101584666A CN101584666A CNA2008100376071A CN200810037607A CN101584666A CN 101584666 A CN101584666 A CN 101584666A CN A2008100376071 A CNA2008100376071 A CN A2008100376071A CN 200810037607 A CN200810037607 A CN 200810037607A CN 101584666 A CN101584666 A CN 101584666A
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Abstract
The invention discloses a preparing method of a proton pump inhibitor biological adhesive preparation, which comprises the following steps: selecting peroral proton pump inhibitor medicaments, alkaline substances, carrier materials and biological adhesive materials to prepare the adhesive preparation by a preparation preparing method; making enteric coating on the outer layer of the preparation; and finally, preparing the medical preparation containing the adhesive materials. The proton pump inhibitor biological adhesive preparation prepared by the preparing method has the advantages of indissolvableness in gastric acid, coating film degradation in intestinal juice, and the like, is adhered to the intestinal mucosa for slowly releasing, and is suitable for treating gastric ulcer and duodenal ulcer.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of bioadhesive drug formulations preparation method of proton pump inhibitor.
Background technology
From the early eighties in last century, promptly there are some researches show, the carboxylated polymers of high bear electricity (as acrylic polymer) has significantly high bioadhesion effect and low bio-toxicity [Park K.et al to the human eye conjunctival epithelial cell of In vitro culture, Int J Pharm 1984,19:107-127]; The inside and outside gastrointestinal tract of animal body adheres to and experimental results show that, acrylic polymer (as Polycarbophil) and the gastrointestinal tract mucinous interaction in surface, gastrointestinal tract is obviously prolonged its emptying time, thereby draw the bioadhesive material that this base polymer can be used as oral positioning release medicine preparation [Ch ' ng H.S.et al, J Pharm Sci 1985,74:399-405].What the bioadhesion effect was thought in research is a successive process, mainly divides two stages.At first be the imbibition of bioadhesive polymer or moistened surface effect produced with the surface between tight the contact, and then adhesive agent infiltrates the tissue surface slit or interpenetrates with mucus and take place to interact and produce adhesiveness.Bioadhesive material at present commonly used have Polycarbophil [Polycarbophil (
EX-55resin)], carbomer (Carbomer,
934P), chitosan (chitosan), hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), hyaluronate sodium etc.Known medicine with following character is relatively more suitable makes biologic adhesion preparation, little as dissolubility in the body, absorption window is narrow, infiltration rate is slow or saturated absorption is arranged, and biological half-life is lacked; Maybe need to treat local disease.Medicine with above-mentioned character is after making biologic adhesion preparation, and pharmaceutical preparation can as adhesive retentions such as gastrointestinal tract, eye, oral cavity, nasal cavities, reach positioning release medicine setting medicine-feeding part, improves curative effect; Or improve absorption, improve bioavailability.Report is arranged, metronidazole and clotrimazole are made adhesion preparation be used for the treatment of vaginal infection [Alam MAet al, AAPS PharmSciTech.200714; 8 (4): E109], or dexamethasone chitosan adhesion preparation is used for oral administration [Pignatello R et al, J Drug Target.200715 (9): 603-10], or ketoconazole is made adhesion preparation be used for vagina administration [Wang L et al, Int JPharm.200828; 350 (1-2): 181-7]; or theophylline made biological adhesive tablet [Peppas NA et al; Adv Drug Deliv Rev 1993; 11 (1-2): 1-7]; or chlorothiazide made behind the albumin granule mix encapsulated [the Longer MA et al in back with the PVP granule; J Pharm Sci 1985; 74 (4): 406-415]; or be that substrate prepares nimodipine gel for nose [Park K et al with PEG400 and Carbopol; Int JPharm 1984; 19 (2): 107-127]; or be sotalol hydrochloride floating in stomach agent [the Chueh HR et al of adhesive agent preparation with CMC-Na and HPMC; Drug Dev Ind Pharm 1995,21 (15): 1725-1747], or single with Polycarbophil; the Carbomer coating; or with Carbomer and
The small intestinal of RL100 mixing coating adheres to microsphere [Lehr CM et al, J Controlled Release 1990,13:51-57], or be scattered in the stomach that four glycerol the five kinds of stiffness in infant fat acids (TGPS) and four glyceryl monostearates (TGMS) make with Carbomer and adhere to microsphere [Akiyama Y et al, Pharm Res 1995,12 (3): 397-405], or Aciclovir eye epithelial adherence microsphere [the GentaIet al that makes with chitosan, J Pharm Pharmacol 1997,49:737-42], equal proofs, above-mentioned biologic adhesion preparation or obviously prolong preparation in the medicine-feeding part holdup time, or significantly improve bioavailability of medicament.Biologic adhesion preparation comprises tablet, microsphere and granule etc.
The mechanism of action of proton pump inhibitor is the generation of blocking-up gastric acid, and the latter can cause mucous membrane of esophagus, gastric mucosa and duodenal mucosa infringement.Proton pump inhibitor comprises omeprazole, lansoprazole, Tenatoprazole, rabeprazole and pantoprazole etc.Existing report, pantoprazole is made slow releasing preparation and antimicrobial drug drug combination treatment helicobacter pylori infections and digestive tract ulcer [United States Patent:6274173], or lansoprazole is made enteric coated preparation (tablet, micropill or granule), contain alkaline matter (sodium hydroxide in the preparation, potassium hydroxide or sodium carbonate) alkaline environment that is used to keep preparation keeps stability of drug, prepared preparation is used for gastrointestinal ulceration treatment [Uni ted States Patent:7276253], yet there are no proton pump inhibitor is made adhesion preparation (tablet, microsphere, granule etc.) pertinent literature of aspect report and patent.
Summary of the invention
The preparation method that the purpose of this invention is to provide the proton pump inhibitor biologic adhesion preparation.The present invention selects oral administration proton pump inhibitor medicine, alkaline matter, carrier material and bioadhesive material for use, makes adhesion preparation by formulation preparation method, and adhesion preparation comprises tablet, microsphere, granule etc.Carry out enteric coating at the preparation skin, the obtained preparation not release in gastric acid that contains adhesion material, coating membrane degraded in intestinal juice, preparation sticks to the slow release in mucous membrane of small intestine place, treatment gastric ulcer and duodenal ulcer.
The medicine that the present invention relates to is a proton pump inhibitor, includes but are not limited to omeprazole, lansoprazole, Tenatoprazole, rabeprazole and pantoprazole.
The alkaline matter that the present invention relates to comprises sodium hydroxide, potassium hydroxide, sodium carbonate etc.
The drug carrier material that the present invention relates to is selected for use and is included but not limited to ethyl cellulose, polylactic acid, polylactic acid-glycolic guanidine-acetic acid copolymer, polyglycolic acid, methyl acrylate copolymer, lactose, starch, microcrystalline Cellulose, hydroxypropyl methylcellulose, methylcellulose, mannitol etc.
The bioadhesive material that the present invention relates to comprises: acrylic polymer and derivant thereof, and as Polycarbophil and carbomer etc., hydroxypropyl cellulose, chitin and chitosan, alginic acid and sodium salt thereof, hyaluronic acid and sodium salt thereof, carboxymethyl cellulose and sodium salt thereof, carboxymethyl dextran and sodium salt, carboxymethyl cellulose and sodium salt thereof and polyisobutylene blend, polyvinyl alcohol and copolymer thereof, polyvidone and copolymer, guar gum etc.
Above-mentioned one or more the blended pharmaceutic adjuvants that adhere to of the optional usefulness of bioadhesive drug formulations involved in the present invention.Its amount ranges preferred 10～30%.
Bioadhesive drug formulations involved in the present invention comprises tablet, microsphere, granule.
The bioadhesive drug formulations that makes involved in the present invention carries out enteric coating, and used coating material includes but are not limited to copolymer, phthalic acid polyvinyl alcohol ester, cellulose acetate-phthalate, Hydroxypropyl Methylcellulose Phathalate, cellulose acetate benzenetricarboxylic acid ester, the carboxylic first and second basic celluloses of methacrylic acid/methyl methacrylate copolymer, methacrylic acid/ethyl methacrylate.Used enteric-coating material can be wherein one or more.
The bioadhesive drug formulations that makes involved in the present invention is used for the treatment of gastrointestinal ulceration.
The bioadhesive drug formulations that makes involved in the present invention not release under the gastric acid condition, outer enteric coating membrane degradation under the intestinal juice condition.
The bioadhesive drug formulations that makes involved in the present invention adhesion preparation behind outer enteric coating membrane degradation under the intestinal juice condition is detained slowly release at the mucous membrane of small intestine place.
The inventive method is with respect to existing proton pump inhibitor preparation, as Lansoprazole enteric-coated tablet, pantoprazole enteric-coated sustained-release preparation, has following advantage: 1. prolonged the holdup time of preparation at mucous membrane of small intestine, slowly release, help the action time of prolong drug, improve curative effect at the sufferer place.2. add alkaline matter in the adhesion preparation, keep the alkali condition of adhesion preparation, help keeping medicine stability.
The specific embodiment
Embodiment 1 preparation lansoprazole biological adhesive tablet
Label prepares lansoprazole 30g, lactose 114g, mannitol 30g, sodium carbonate 15g, carbomer 934 P20g, hydroxypropyl emthylcellulose K
15MThe 40g mix homogeneously, polyvinylpyrrolidone K
30Alcoholic solution is the binding agent wet granulation, 1000 of oven dry back compressed tabletses.
The label coating is got 76g water, adds EudragitL100-5513g, makes it moistening, fully disperses, and adds 1N NaOH 5g, mixing.Taking polyethylene glycol 2g is dissolved in the 4g water, and is with Polyethylene Glycol aqueous solution, Pulvis Talci 3g and titanium dioxide 1.6g and EudragitL100-55 solution mix homogeneously, standby.40 ℃ of coating inlet temperature, 30 ℃ of sheet bed tempertaures, atomisation pressure 0.15MPa, spray velocity 11g/min.Tablet appearance is good behind the coating, and it is complete to soak 2 hours clothing films in pH1 hydrochloric acid, slowly release in the pH6.8 phosphate buffer.
The lansoprazole adhesion tablet is got in the investigation of tablet adhesion and lansoprazole tablet is investigated it to rat small intestine mucosal adhesive power size, the results are shown in Table 1
| Sample | Force(N，X±SD) |
| Lansoprazole adhesion tablet (n=5) | 39.26±6.13 |
| Lansoprazole ordinary tablet (n=5) | 14.87±4.53 |
P＜0.05
The omeprazole enteric-coated adhered particles of embodiment 2 preparations
Get omeprazole 10g, chitosan 30g, microcrystalline Cellulose 100g, micropowder silica gel 3g, PVPK
30Behind 10g, the lactose 80g mixing, adopt phthalic acid polyvinyl alcohol ester (10%) ethanol liquid fluidized bed with spraying coating, coating weightening finish 30%, the enteric coated adhered particles that obtains is distributed into 1000 bags.
Embodiment 3 preparation pantoprazole bioadhesion microspheres
It is dissolve medium that anhydrous propanone is adopted in the preparation of medicine-material suspendible Colloidal fluid, and ethyl cellulose (20cps) is configured to the transparent Colloidal fluid that concentration is 100mg/ml, standby.Get above-mentioned ethyl cellulose liquid and become variable concentrations with acetone diluted again, add carbomer 934 P stirring and evenly mixing on magnetic stirring apparatus, obtain the ethyl cellulose-carbomer suspension of fine dispersion.Add pantoprazole, continue to stir, the pantoprazole dissolving is dispersed in the above-mentioned suspendible Colloidal fluid, standby.
Microsphere preparation utilization solvent evaporation prepares pantoprazole bioadhesion microsphere, is continuous phase with the liquid paraffin, and sorbester p17 is an emulsifying agent, and hierarchy of control temperature is at 30 ℃, and stirring is removed acetone and obtained pantoprazole adhesion microsphere.
Microsphere coating cellulose acetate-phthalate is an enteric coating liquid, fluidized bed coating, and coating weightening finish 15% makes the pantoprazole enteric and adheres to microsphere.
Claims (10)
1, a kind of preparation method of proton pump inhibitor bioadhesive drug formulations, its feature is selected oral administration proton pump inhibitor medicine, alkaline matter, carrier material and bioadhesive material for use, make adhesion preparation by formulation preparation method, carry out enteric coating at the preparation skin, the obtained preparation not release in gastric acid that contains adhesion material, coating membrane degraded in intestinal juice, preparation sticks to the slow release in mucous membrane of small intestine place, treatment gastric ulcer and duodenal ulcer.
2, proton pump inhibitor bioadhesive drug formulations according to claim 1 is characterized in that described proton pump inhibitor is omeprazole, lansoprazole, Tenatoprazole, rabeprazole and pantoprazole.
3, by the proton pump inhibitor bioadhesive drug formulations of claim 1, it is characterized in that described pharmaceutical preparation is tablet, microsphere and granule.
4, be sodium hydroxide, potassium hydroxide, sodium carbonate etc. according to the alkaline matter in the pharmaceutical preparation of claim 1
5, be in ethyl cellulose, polylactic acid, polylactic acid-glycolic guanidine-acetic acid copolymer, polyglycolic acid, methyl acrylate copolymer, lactose, starch, microcrystalline Cellulose, hydroxypropyl methylcellulose, the methylcellulose one or more according to the carrier material in the pharmaceutical preparation of claim 1.
6, be in acrylic polymer and derivant, hydroxypropyl cellulose, chitin and chitosan, alginic acid and sodium salt thereof, hyaluronic acid and sodium salt thereof, carboxymethyl cellulose and sodium salt thereof, carboxymethyl dextran and sodium salt, carboxymethyl cellulose and sodium salt thereof and polyisobutylene blend, polyvinyl alcohol and copolymer thereof, polyvidone and copolymer thereof, the guar gum one or more according to the bioadhesive material in the pharmaceutical preparation of claim 1.
7, preparation according to claim 3 will carry out enteric coating.
8, be in the copolymer, phthalic acid polyvinyl alcohol ester, cellulose acetate-phthalate, Hydroxypropyl Methylcellulose Phathalate, cellulose acetate benzenetricarboxylic acid ester, the carboxylic first and second basic celluloses of methacrylic acid/methyl methacrylate copolymer, methacrylic acid/ethyl methacrylate one or more according to the enteric-coating material of the described preparation of claim 3.
9, bioadhesive drug formulations according to claim 1 is used for the treatment of gastrointestinal ulceration.
10, bioadhesive drug formulations according to claim 1 not release under the gastric acid condition, outer enteric coating membrane degradation under the intestinal juice condition, biologic adhesion preparation adheres to the mucous membrane of small intestine place under the intestinal juice condition, slowly release, and adhesion preparation has good adhesiving effect to mucous membrane of small intestine.
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| CNA2008100376071A CN101584666A (en) | 2008-05-19 | 2008-05-19 | Preparing method of proton pump inhibitor biological adhesive preparation |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103211780A (en) * | 2013-04-17 | 2013-07-24 | 沈阳药科大学 | Oral mesalazine colon-specific adhesive pellet |
| CN108042506A (en) * | 2018-01-09 | 2018-05-18 | 上海祺宇生物科技有限公司 | A kind of enteric plant capsule and its capsule |
| CN114099471A (en) * | 2021-11-03 | 2022-03-01 | 海南海灵化学制药有限公司 | Omeprazole enteric-coated pellet and preparation process thereof |
-
2008
- 2008-05-19 CN CNA2008100376071A patent/CN101584666A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103211780A (en) * | 2013-04-17 | 2013-07-24 | 沈阳药科大学 | Oral mesalazine colon-specific adhesive pellet |
| CN103211780B (en) * | 2013-04-17 | 2015-10-14 | 沈阳药科大学 | Oral mesalazine colon-specific adhesive pellet |
| CN108042506A (en) * | 2018-01-09 | 2018-05-18 | 上海祺宇生物科技有限公司 | A kind of enteric plant capsule and its capsule |
| CN114099471A (en) * | 2021-11-03 | 2022-03-01 | 海南海灵化学制药有限公司 | Omeprazole enteric-coated pellet and preparation process thereof |
| CN114099471B (en) * | 2021-11-03 | 2023-01-06 | 海南海灵化学制药有限公司 | Omeprazole enteric-coated pellet and preparation process thereof |
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