WO2014114255A2 - 一种定位速释生物粘附剂及应用 - Google Patents

一种定位速释生物粘附剂及应用 Download PDF

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Publication number
WO2014114255A2
WO2014114255A2 PCT/CN2014/071294 CN2014071294W WO2014114255A2 WO 2014114255 A2 WO2014114255 A2 WO 2014114255A2 CN 2014071294 W CN2014071294 W CN 2014071294W WO 2014114255 A2 WO2014114255 A2 WO 2014114255A2
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WIPO (PCT)
Prior art keywords
microparticles
bioadhesive
immediate release
gastric
coating
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PCT/CN2014/071294
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English (en)
French (fr)
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WO2014114255A3 (zh
Inventor
万平
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Wan Ping
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Application filed by Wan Ping filed Critical Wan Ping
Priority to AU2014210266A priority Critical patent/AU2014210266B2/en
Priority to NZ710654A priority patent/NZ710654A/en
Priority to CA2898742A priority patent/CA2898742C/en
Priority to US14/764,046 priority patent/US20150359750A1/en
Priority to GB1513741.7A priority patent/GB2524701A/en
Publication of WO2014114255A2 publication Critical patent/WO2014114255A2/zh
Publication of WO2014114255A3 publication Critical patent/WO2014114255A3/zh

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5036Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5073Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00Foods or foodstuffs containing additives; Preparation or treatment thereof
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/20Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891Coated capsules; Multilayered drug free capsule shells
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5084Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32Alcohol-abuse
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00General protective or antinoxious agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5031Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5036Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5052Proteins, e.g. albumin
    • A61K9/5057Gelatin

Definitions

  • the present invention relates to a biocompatible medical device for internal or external use, and in particular to a preventive or And targeted rapid release bioadhesives for the treatment of diabetes, obesity, alcoholism, inflammation of the stomach and intestinal mucosa, and/or ulcers.
  • gastric bypass surgery can be used to treat obese patients with type 2 diabetes and to reduce the occurrence and development of chronic complications of diabetes (China Medical Sciences, 2011, 1 (22): 1-2 ). This kind of surgery can also significantly improve the complications of hypertension, obesity, and dyslipidemia (China Medical Science, 2011, 1 (21): 3-5 ).
  • gastric bypass surgery has clinical risks, such as death, intestinal obstruction, anastomotic leakage, pulmonary embolism, deep vein thrombosis, portal vein injury, respiratory diseases, etc. (Chinese Journal of Diabetes, 2011, 3 (3): 205-208 ).
  • Restricting food intake and reducing gastric and intestinal absorption are the basic mechanisms for surgical treatment of obesity, and the corresponding prior art invention patents ' Tissue conveyor used in stomach reduction surgery and related methods of use ' (Application date April 30, 2009, publication date April 13, 2011), prior art invention patent ' Releasable gastroplasty ring ' (Application date December 21, 2000, authorization notice date September 1, 2004), prior art invention patent ' A single controlled gastroplasty ring ' (application date January 19, 2001, authorization announcement date October 20, 2004), etc., or placement of a balloon or gastric band in the stomach cavity (Yang Kejun Advantages of adjustable gastric band slimming surgery. Shanghai Medical Journal, 2012, 33(8): 11; Tang Shen et al.
  • Prior art invention patent 'duodenal cannula and its conveyor' application date April 9, 2010) , Authorized Announcement Date, January 11, 2012
  • the prior art invention patent 'A duodenal inner membrane made of biodegradable biocompatible materials and its application' Application Date 2012 5 On the 5th of May, the announcement date of August 8, 2012
  • the prior art invention patent 'an intraduodenal membrane made of electrospinning' application date August 21, 2012
  • the publication date of November 21, 2012 affects the compliance of the user, and (compared with the present invention) also adds complexity to the operation.
  • the positioning and immediate release bioadhesive agent of the present invention is used after oral administration.
  • the pH-sensitive coating material will be said enteric instant release bioadhesive (particles or / and capsules or / depending on the pH difference in the gastrointestinal tract) And tablets) localized to the upper part of the duodenum and jejunum, reaching the upper part of the duodenum and the jejunum, the enteric instant release bioadhesive coating material rapidly or / and degraded in high pH environment .
  • the adhesive material in the enteric instant release bioadhesive agent rapidly and completely releases, disintegrates, floats, dissolves, and swells (the speed at which the tablets are compressed into tablets) Bioadhesive
  • the agent is rapidly and completely released, disintegrated, floated, dissolved, and swollen due to the release of the disintegrating agent, etc., and the mucous membranes of the duodenum and the jejunum are contacted with mucin or/and mucosal epithelial cells.
  • the duodenal ascending part reduces the empty and ileal contents reflux, Also extended the adhesion material The time spent in the duodenum.
  • Adhesive material Determine the amount and duration of the superimposed dose as the time of gradual degradation or / and dissolution or / and dissolution in the body.
  • Prior art invention patent 'tissue conveyor used in stomach reduction surgery and related methods of use' (Application Date 2009 4 On the 30th of the month, the announcement date of April 13, 2011), the prior art invention patent 'Releasable gastroplasty ring' (application date December 21, 2000) , Authorization Announcement Date, September 1, 2004), the prior art invention patent 'single-controlled gastroplasty ring' (application date January 19, 2001, authorization notice day October 20, 2004) Etc., or place a balloon or gastric band in the stomach cavity (Yang Kejun. The advantages of adjustable gastric band slimming surgery. Shanghai Medical Journal, 2012, 33(8): 11 Tang Shen et al. Clinical study of intragastric water balloon therapy for obesity.
  • the positioning and immediate release bioadhesive agent according to the invention is not required to go to the hospital by the user (obesity patient, diabetic patient, etc.), does not need surgery, does not need endoscopy, has no pain, only needs to take oral, after taking,
  • the pH-sensitive coating material delivers the gastric-soluble immediate release bioadhesive (particles or/and capsules and/or tablets) to the stomach according to the pH difference in the gastrointestinal tract, reaching the stomach for gastric dissolution. Immediate release bioadhesion The coating material rapidly or / and degrades in the pH environment of the stomach.
  • the adhesive material in the gastric-soluble immediate release bioadhesive agent is rapidly Fully fully released, disintegrated, floated, dissolved, and swollen (positioned immediate release bioadhesives compressed into tablets are also rapidly and fully released, disintegrated, floated, dissolved, and swollen due to immediate release disintegrants), Touch the stomach mucosa In terms of interaction with mucin or/and mucosal epithelial cells, etc., adhered thereto, until all adhered, covered the gastric mucosa or/and embedded in the mucosal folds; the gastric pylorus was reduced by twelve Finger gut The reflux of the contents also further prolongs the time the adhesive material stays in the stomach.
  • the adhesion of the adhesive material to the gastric mucosa reduces the absorption of the stomach.
  • it gradually degrades in the body or /
  • the time of dissolution or / and dissolution determine the amount and period of superimposed dose.
  • Prior art invention patent 'a recipe for hangover oral drugs and preparation process' (Application Date December 20, 2010 Japanese, the publication date July 11, 2012), the prior art invention patent 'an anti-drunk hangover composition and its preparation method' (Application Date May 18, 2012 , the publication date September 19, 2012), the prior art invention patent 'oral absorption solid hangover effervescent preparation' (application date July 12, 2010, publication date December 22, 2010), etc.
  • the nodes of the hangover are basically after the body absorbs the wine, which has increased the burden on the organs related to the body.
  • the hangover substances will increase the liver through absorption, metabolism and other internal pathways. or / The burden of organs such as the kidneys.
  • the pH-sensitive coating material will be said to be gastric or/and enteric-release bioadhesive (particles or/and capsules or according to pH differences in the gastrointestinal tract). / And tablets) localized to the stomach or / and duodenum and jejunum, to the stomach or / and duodenum and jejunum gastric or / and enteric instant release bioadhesive in the corresponding pH environment Coating material quickly or / And sudden degradation.
  • Adhesive material in the gastric or/and enteric instant release bioadhesive agent rapidly in the gastric cavity or / and duodenum and jejunal cavity Fully fully released, disintegrated, floated, dissolved, and swollen (positioned immediate release bioadhesives compressed into tablets are also rapidly and fully released, disintegrated, floated, dissolved, and swollen due to immediate release disintegrants), Touch the stomach or / And the duodenal and jejunal mucosa interacts with mucin or/and mucosal epithelial cells, etc., until they adhere, cover the stomach or / and duodenum and jejunal mucosa or / And embedded in the mucosal folds in the seam.
  • the gastric or/and enteric-release bioadhesive agent only adheres to the stomach or / and duodenum and jejunal mucosa, neither absorbs nor actively prevents the stomach or / and duodenal and jejunal absorption of wine; because it covers the stomach or / and duodenum and jejunal mucosa, it can also protect the stomach or / and duodenum and jejunal mucosa to prevent or / and treat the stomach or / And duodenum and jejunum or / and ulcers.
  • the amount and period of the superimposed dose are determined.
  • a positioning immediate release bioadhesive characterized by preparing a microparticle with a biocompatible bioadhesive material, an external accelerated release disintegrant, an enteric coating after tableting, or an enteric coating of the microparticles, or Filled into enteric hollow capsules, or bioadhesive materials, immediate release disintegrants and other additives directly after tableting, enteric coating, adhere to cover the duodenum and upper jejunum mucosa after taking, can prevent or / and treatment of diabetes and obesity, reduced alcohol absorption, can also prevent or / and treat duodenal inflammation or / and ulcers.
  • a positioning immediate release bioadhesive characterized by preparing a microparticle with a biocompatible bioadhesive material, externally releasing a disintegrating agent, applying a gastric coating after tableting, or coating the microparticles with a stomach, or Filled into stomach-soluble hollow capsules, or bioadhesive materials, immediate release disintegrants and other additives directly after tableting, gastric coating, adhesion to cover the gastric mucosa after taking, can reduce gastric alcohol absorption, prevention or / and treatment of obesity can also prevent or / and treat gastritis or / and ulcers.
  • the enteric-coated rapid release bioadhesive agent can be obtained by the following steps and methods:
  • polyisobutylene, ethyl cellulose, cyclohexane formed a ternary system, dissolved at 80 ° C into a homogeneous solution, slowly cooled to 45 ° C , and then quickly cooled to 25 ° C, into particles.
  • chitosan dissolved in dilute aqueous acetic acid solution, swell overnight, formulated into 0.3-1.0% (w / v)
  • the chitosan solution sodium tripolyphosphate dissolved in distilled water, is formulated into a 0.3-1.0% (w/v) solution, and continuously magnetically stirred at a dropping rate of about 2-5 ml/min.
  • the sodium tripolyphosphate solution was added to the chitosan solution, and the solution was changed from clarification to light blue opalescence, and the formation of the nanoparticles was judged based on the opalescence.
  • the adhesive can be selected from 3-10% PVP K30 in 60-80% ethanol solution, the lubricant can be magnesium stearate (1-5%), and the filler can be pre-gelatinized starch. .
  • the original auxiliary material can pass 100 mesh sieve, mix well, add adhesive 3-15% PVP aqueous solution soft material, granulation, 60 ° C drying 0.5-2 h; add magnesium stearate or / and thinner or / and wetting agent, etc., and granules are obtained.
  • the core is observed, the edge is smooth, no defects or lobes, the coated tablets are not bonded, and the film is evenly flat; after the coating is completed, it is taken out and dried in an oven at about 60 ° C; weighed, and the coating weight gain percentage is used as a coating. Control indicators.
  • the coating solvent is 60-90% ethanol aqueous solution
  • core-coated coating pan preheating, coating pan angle 45', nozzle inner diameter 0.5-1.0 mm
  • spray gun atomization pressure about 137.3 kPa, inlet air temperature 35 ⁇ 5 °C, sheet temperature 35 ⁇ 2°C
  • speed 13-36 r/nin spray rate 0.5-1.0ml/min.
  • the core is immersed in 1-5% (W/V) Eudragit L100-55 acetone solution, 2-10min Remove and dry, repeat 3-6 times, and control the thickness to about 50 ⁇ m.
  • the prepared microparticles can be fluidized in a fluidized bed coating device, and the spray gun is sprayed 4-8%.
  • the acrylic liquid of the acrylic resin is air-dried, and the volatile solvent is discharged from the exhaust port to obtain an enteric coated fine particle having a uniform coating thickness and no adhesion.
  • High-efficiency coating machine can be used, nozzle diameter 0.5-1.5 mm, atomization pressure 0.1 MPa, air volume 50-120 m 3 /h, material temperature 23-25 ° C, spray speed 0.5-5.5 g/min, digital micrometer The thickness was measured, and the mixture was aged at 25 ° C for 20-60 min, the coating was completed, and the enteric coated capsule was taken out and dried at room temperature.
  • the enteric-coated hollow capsules were filled, sealed with 5-15% ethylcellulose solution, and placed in a desiccator for use.
  • An appropriate amount of an anti-adhesive agent such as magnesium stearate or silica, or a diluent, a lubricant, a disintegrator or the like may be added.
  • CAP Cellulose Acetate
  • CAT 1,2,4-Benzene Tricarboxylate
  • CAS Cellulose Acetate
  • HPMCT hydroxypropyl methylcellulose succinate acetate
  • HPMCAS hydroxypropyl methylcellulose succinate acetate
  • the gastric-soluble localized immediate release bioadhesive agent can be obtained by the following steps:
  • polyisobutylene, ethyl cellulose, cyclohexane formed a ternary system, dissolved at 80 ° C into a homogeneous solution, slowly cooled to 45 ° C , and then quickly cooled to 25 ° C, into particles.
  • chitosan dissolved in dilute aqueous acetic acid solution, swell overnight, formulated into 0.3-1.0% (w / v)
  • the chitosan solution sodium tripolyphosphate dissolved in distilled water, is formulated into a 0.3-1.0% (w/v) solution, and continuously magnetically stirred at a dropping rate of about 2-5 ml/min.
  • the sodium tripolyphosphate solution was added to the chitosan solution, and the solution was changed from clarification to light blue opalescence, and the formation of the nanoparticles was judged based on the opalescence.
  • the adhesive can be selected from 3-10% PVP K30 in 60-80% ethanol solution, the lubricant can be magnesium stearate (1-5%), and the filler can be pre-gelatinized starch. .
  • the original auxiliary material can pass 100 mesh sieve, mix well, add adhesive 3-15% PVP aqueous solution soft material, granulation, 60 ° C drying 0.5-2 h; add magnesium stearate or / and thinner or / and wetting agent, etc., and granules are obtained.
  • the air blower preheats the core of the air, the temperature is about 50 ° C, the air inlet position and the air outlet speed are adjusted, so that the coating liquid is evenly sprayed out.
  • the prepared microparticles can be fluidized in a fluidized bed coating device, and sprayed by a spray gun 5-7 % ethanol hydroxypropyl methylcellulose solution, blast dried, and the volatile solvent is discharged from the vent to obtain a coating of gastric coating particles with uniform thickness and no adhesion.
  • High-efficiency coating machine can be used, nozzle diameter 0.5-1.5 mm, atomization pressure 0.1 MPa, air volume 50-120 m 3 /h, material temperature 23-25 ° C, spray speed 0.5-5.5 g/min, digital micrometer The thickness was measured and aged at 25 ° C for 20-60 min. The coating was completed, and the gastric-coated capsule was taken out and dried at room temperature. The stomach-soluble hollow capsules were filled, sealed with 5-15% ethyl cellulose solution, and placed in a desiccator for use. An appropriate amount of an anti-adhesive agent such as magnesium stearate or silica, or a diluent, a lubricant, a disintegrator or the like may be added.
  • an anti-adhesive agent such as magnesium stearate or silica, or a diluent, a lubricant, a disintegrator or the like may be added.
  • HPMC hydroxypropyl methylcellulose
  • MC methylcellulose
  • PVA polyvinyl alcohol
  • HPC hydroxypropyl cellulose
  • HPC polyethylene glycol
  • PEG polyvinyl acetal diethylamine acetate
  • Eudragit E type stomach soluble acrylic resin and other materials.
  • bioadhesive material of the enteric or gastric-soluble positioning immediate release bioadhesive according to the present invention:
  • the amount of adhesive material is 10%-90%.
  • the filler may be a material such as lactose, microcrystalline cellulose, sucrose, starch, pregelatinized starch or the like.
  • the binder may be water, different concentrations of ethanol, different concentrations of PVP K30 and the
  • the preparation of the microparticles can also be carried out by solvent evaporation method, spray drying method, phase separation method, electrospray method, sonic excitation atomization method, emulsion polymerization method, interfacial polymerization method, in situ polymerization method, polymer rapid insolubilization method, Atomization solvent extraction method, single emulsion method, double emulsion method, medium phase separation method, solution drying method, solution evaporation method, powder bed method, air suspension coating method, vacuum spraying method, electrostatic aerosol method, porous centrifugation method And other methods are obtained.
  • the amount and period of the superimposed dose are determined.
  • the adhesive material in the enteric instant release bioadhesive agent rapidly and completely releases, disintegrates, floats, dissolves, and swells (the speed at which the tablets are compressed into tablets) Bioadhesive
  • the agent is rapidly and completely released, disintegrated, floated, dissolved, and swollen due to the release of the disintegrating agent, etc., and the mucous membranes of the duodenum and the jejunum are contacted with mucin or/and mucosal epithelial cells.
  • the duodenal ascending part reduces the empty and ileal contents reflux, Also extended the adhesion material The time spent in the duodenum.
  • Adhesive material Determine the amount and duration of the superimposed dose as the time of gradual degradation or / and dissolution or / and dissolution in the body.
  • the application of immediate release bioadhesives is not required to go to the hospital, without surgery, without endoscopy, without pain, just by oral administration, after taking the pH sensitive
  • the coating material delivers the gastric-soluble immediate release bioadhesive agent (microparticles or/and capsules and/or tablets) to the stomach according to the pH difference in the gastrointestinal tract, and reaches the stomach of the gastric-soluble immediate release organism.
  • Adhesive in stomach pH The coating material in the environment is rapidly or / and degraded.
  • the adhesive material in the gastric-soluble immediate release bioadhesive agent is rapidly Fully fully released, disintegrated, floated, dissolved, and swollen (positioned immediate release bioadhesives compressed into tablets are also rapidly and fully released, disintegrated, floated, dissolved, and swollen due to immediate release disintegrants), Touch the stomach mucosa In terms of interaction with mucin or/and mucosal epithelial cells, etc., adhered thereto, until all adhered, covered the gastric mucosa or/and embedded in the mucosal folds; the gastric pylorus was reduced by twelve Finger gut The reflux of the contents also further prolongs the time the adhesive material stays in the stomach.
  • the adhesion of the adhesive material to the gastric mucosa reduces the absorption of the stomach.
  • it gradually degrades in the body or /
  • the time of dissolution or / and dissolution determine the amount and period of superimposed dose.
  • the pH-sensitive coating material is adapted to the gastric or/and enteric-release bioadhesive agent (microparticles or/and capsules or according to pH differences in the gastrointestinal tract) / And tablets) localized to the stomach or / and duodenum and jejunum, to the stomach or / and duodenum and jejunum gastric or / and enteric instant release bioadhesive in the corresponding pH environment Coating material quickly or / And sudden degradation.
  • Adhesive material in the gastric or/and enteric instant release bioadhesive agent rapidly in the gastric cavity or / and duodenum and jejunal cavity Fully fully released, disintegrated, floated, dissolved, and swollen (positioned immediate release bioadhesives compressed into tablets are also rapidly and fully released, disintegrated, floated, dissolved, and swollen due to immediate release disintegrants), Touch the stomach or / And the duodenal and jejunal mucosa interacts with mucin or/and mucosal epithelial cells, etc., until they adhere, cover the stomach or / and duodenum and jejunal mucosa or / And embedded in the mucosal folds in the seam.
  • the gastric or/and enteric-release bioadhesive agent only adheres to the stomach or / and duodenum and jejunal mucosa, neither absorbs nor actively prevents the stomach or / and duodenal and jejunal absorption of wine; because it covers the stomach or / and duodenum and jejunal mucosa, it can also protect the stomach or / and duodenum and jejunal mucosa to prevent or / and treat the stomach or / And duodenum and jejunum or / and ulcers.
  • the amount and period of the superimposed dose are determined.
  • Figure 1 positioning of the immediate release bioadhesive sheet
  • Figure 2 positioning of the immediate release bioadhesive capsule
  • the parts or parts indicated by the reference numerals in Figure 1 are: 1- Bioadhesive particles; 2- Immediate release disintegrant or / and diluent or / and lubricant or / and wetting agent; 3- stomach or enteric coating.
  • Enteric coating of microparticles the prepared microparticles are fluidized in a fluidized bed coating device, sprayed with a spray gun 6%
  • the acrylic liquid of the acrylic resin is air-dried, and the volatile solvent is discharged from the exhaust port to obtain an enteric coated fine particle having a uniform coating thickness and no adhesion.
  • Direct compression 1 part of Carbomer 934P, 1 part of sodium carboxymethylcellulose 2000cp, uniformly mixed, powder directly compressed, thickness 1mm, diameter 3mm, hardness about 4kg /mm 2 . It can also be granulated by wet granulation.
  • the adhesive can be selected from 5% PVP K30 in 70% ethanol solution, the lubricant can be magnesium stearate (3%), and the filler can be pre-gelatinized starch.
  • Pelletizing of microparticles original excipients pass through 100 mesh sieve, mix well, add binder 10% PVP aqueous solution made of soft material, granulation, 60 °C Dry for 1 h; add magnesium stearate or / and thinner or / and wetting agent, etc., and granules are obtained.
  • enteric coated capsules and microparticles high-efficiency coating machine, nozzle diameter l mm, atomization pressure 0.1MPa, air volume 60-80m 3 /h, material temperature 23-25°C, spray speed 1.5-3.5g/min The thickness of the micrometer was measured, and the ripening was carried out at 25 ° C for 30-50 min. The coating was completed, and the enteric coated capsule was taken out and dried at room temperature. The enteric hollow capsule was filled, sealed with 10% ethyl cellulose solution, and placed in a desiccator for use. An appropriate amount of an anti-adhesive agent such as magnesium stearate or silica, or a diluent, a lubricant, a disintegrator or the like may be added.
  • an anti-adhesive agent such as magnesium stearate or silica, or a diluent, a lubricant, a disintegrator or the like may be added.
  • the isopropanol solution of formaldehyde is cross-linked and solidified, dehydrated, and vacuum dried to obtain fine particles.
  • water can be used as a diluent, and after repeated aggregation and deagglomeration, the shape is observed under an optical microscope until a suitable shape is formed, and then cross-linked and solidified.
  • Preparation of microparticles by complex coacervation 10% gelatin, 10% gum arabic, 80% The mixture of water is gradually diluted with water, and the shape is observed under an optical microscope until a suitable shape is formed, and then cross-linked and solidified.
  • microparticles by adjusting the temperature method: polyisobutylene, ethyl cellulose, cyclohexane to form a ternary system, dissolve into a homogeneous solution at 80 °C, and slowly cool to At 45 °C, it is rapidly cooled to 25 °C to form particles.
  • gelatin nanospheres by physicochemical method: 300g / L
  • the gelatin solution is placed in an equal amount of sesame oil and emulsified in an ice bath emulsion to gelatinize the gelatin emulsion, diluted with acetone, filtered through a 50 nm filter, and the oil on the nanosphere is rinsed with acetone, 10% formaldehyde in acetone cross-linking, 10 min. Dry is available.
  • Preparation of PLGA nanoparticles by precipitation 100 mg PLGA Ultrasonic solution in 6 ml of acetone, dripped under magnetic stirring 40 ml of 0.03% carbomer in aqueous solution, stir at room temperature for 500 rpm, until the organic solvent is exhausted, and centrifuge at 30 °C for 1 min. Discard the supernatant, remove residual surfactant, reconstitute the precipitate in Milipore water, wash it 3 times, and dry it to obtain PLGA nanoparticles.
  • PLGA was dissolved in trifluoroethanol at room temperature for 48 hr, magnetic stirring, 15% w/v, Transfer this solution to a micro syringe pump with a high voltage generator, adjust the voltage V 5-35kV, the receiving distance L 9cm, the solution flow rate f 0.6ml / h , EFI, aluminum foil receiving plate or glass slide to receive the obtained particles, dried in a drying oven for 2d, to obtain nanoparticles. The morphology of the prepared particles was observed by scanning electron microscopy.
  • Preparation of immediate release tablets mannitol 40%, microcrystalline cellulose 35%, appropriate amount of lactose, over 100 mesh sieve, equal amount of incremental mixing, plus 5% polyvinylpyrrolidone K30 solution is a binder, granulated, dried at 60 °C for 1 h, whole granules, and then mixed with appropriate amount of sodium carboxymethyl cellulose, micro-powder silica gel, and compressed.
  • Gastric coating The instant release tablets are placed in a coating pan, the coating pan is inclined at 45 o , the inlet air temperature is 35 ⁇ 5 °C, the spray gun atomizing air pressure is 414 KPa, the spray rate is 10 g/min, and the immediate release sheet temperature is controlled at 25. ⁇ 2 °C, speed 15r/min.
  • Gastric coating Take gastric-soluble acrylic resin (VI No.) with pH sensitive point at 1-2, with acetone / ethanol (1/1, v / v) Formulated into a 2.0% solution, the amount of the additive is 10-20%, and the mixture is adjusted to increase the weight of the coating by 3%. Adjust the rotation speed of the coating pan so that the core is parabolically rolled, rotated and polished, about 60 ⁇ 5 r / min. The air blower preheats the core of the air, the temperature is about 50 °C, adjusts the air inlet position, and the air outlet speed, so that the coating liquid is evenly sprayed out.
  • Gastric coating of microparticles the prepared microparticles are fluidized in a fluidized bed coating device, and sprayed by a spray gun 5-7 % ethanol hydroxypropyl methylcellulose solution, blast dried, and the volatile solvent is discharged from the vent to obtain a coating of gastric coating particles with uniform thickness and no adhesion.
  • gastric-coated capsules and microparticles high-efficiency coating machine, nozzle diameter 0.5-1.5 mm, atomization pressure 0.1 MPa, air volume 60-80 m 3 /h, material temperature 23-25 ° C, spray speed 1.5- 2.5g/min, the thickness of the micrometer was measured, and the ripening was carried out at 25 °C for 30-40 min.
  • the coating was completed, and the gastric-coated capsule was taken out and dried at room temperature.
  • the stomach-soluble hollow capsules were filled, sealed with 10% ethyl cellulose solution, and placed in a desiccator for use.
  • An appropriate amount of an anti-adhesive agent such as magnesium stearate or silica, or a diluent, a lubricant, a disintegrator or the like may be added.
  • Determination of disintegration of enteric-coated instant release tablets refer to the static method of the Drug Evaluation Center of the State Food and Drug Administration, the sieve basket (hole diameter 400 ⁇ m) Put into a test tube containing 2ml artificial intestinal juice, and then put it vertically into a 37 °C water bath. After the internal temperature of the test tube rises, 1 The enteric-coated instant release tablets were placed in the sieve basket, and the enteric instant release tablets were contacted with the artificial intestinal juice to start timing, and when the complete disintegration was stopped, the sieve basket was immediately taken out of the test tube, and the sieve mesh was not obviously retained, and 6 pieces were tested, both ⁇ 15s. .
  • Determination of disintegration of gastric-soluble immediate release tablets refer to the static method of the Drug Evaluation Center of the State Food and Drug Administration, the sieve basket (hole diameter 400 ⁇ m) Put into a test tube containing 2ml artificial gastric juice, and then put it vertically into a 37 °C water bath. After the temperature inside the test tube rises, 1 In the sieve basket, the gastric-soluble instant release tablets were started from the contact with the artificial gastric juice, and the complete disintegration was stopped. The sieve basket was immediately taken out of the test tube, and the sieve mesh was not obviously retained. 6 pieces were tested, both ⁇ 15s. .
  • Acute toxicity test 20 Kunming mice, weighing 22.75 ⁇ 2.63g, were randomly divided into 2 groups, the experimental group ip Bioadhesive material extract, 50ml/Kg, control ip equal amount of normal saline. 24h, 48h, 72h after injection Observe the general condition, toxicity and number of dead animals. The results showed that all the animals in the test group had no signs of exercise retardation, weight loss, diarrhea, paralysis, respiratory depression, convulsions, and death.
  • Subacute toxicity test 24 SD rats, weighing 214.61 ⁇ 18.72g, randomly divided into 2 Group.
  • the fine powder of the bioadhesive material, the physiological saline is formulated into a 5% suspension, the qod is 9:00 am, and the control group is the same amount of normal saline.
  • Observe general condition and weight 2W, 4W
  • 6 rats in each group were taken, heart, liver, kidney and spleen tissues were weighed and fixed for pathological tissue section.
  • SPSS12.0 statistical analysis software was used to analyze organ index (organ weight/animal weight). Analysis of variance was used between groups, and t test was used in the group. The difference was significant at p ⁇ 0.05.
  • the organ index of the test group was 0.454 ⁇ 0.062 for the heart and 3.203 ⁇ 0.254 for the liver. 0.869 ⁇ 0.077, spleen 0.269 ⁇ 0.085, control organ index: heart 0.463 ⁇ 0.039, liver 3.317 ⁇ 0.472, kidney 0.878 ⁇ 0.071, spleen 0.273 ⁇ 0.064, compared with the control group, there was no significant difference in heart, liver, kidney and spleen index (P>0.05). ). No obvious abnormalities were found in the pathological tissue sections.
  • Skin irritation test 3 New Zealand rabbits, weighing 2.75 ⁇ 0.13kg, sterile bioadhesive material powder 10g Add 50ml of normal saline, autoclave at high temperature, extract at 37 °C for 72h, centrifuge at 2500rpm for 5min, and take the supernatant. Skin preparation on both sides of the back, about 10 ⁇ 10cm , 10 points on one side with extract id, 0.5ml, the same amount of normal saline on the other side, observe each point after lh, 24h, 48h, 72h after injection After signs. The results showed that there were no obvious signs of redness, ulceration and exudation on the test side and the control side at lh, 24h, 48h, and 72h after injection, and no obvious skin irritation was observed.
  • Ex vivo gastric mucosa adhesion test 8 Kunming mice, weighing 21.36 ⁇ 2.41g, fasting for 24h (Water supply), cervical dislocation and death, immediately take the stomach, cut from the sacral door along the stomach to the pylorus, tiled on the slide, evenly spread the gastric-soluble positioning of the immediate release bioadhesive particles, set the container of saturated sodium chloride solution Medium, closed moisturizing for 10min , remove, rinse with hydrochloric acid sodium chloride solution of pH 1.3 at 20ml/min for 5min Observe the area of particle shedding, and take a digital photograph of the same distance. If necessary, the image analysis compares the shedding area. The results showed that only the naked eye observation showed that the gastric-soluble localized immediate release bioadhesive particles did not significantly fall off.
  • Ex vivo gastric mucosa adhesion test 10 SD rats, weighing 227.83 ⁇ 19.41g, fasting for 24h (Water supply), take the stomach as above, compress the gastric-soluble immediate release bioadhesive into a flat piece, and moisten with artificial gastric juice for 10 min. After that, the bridge is connected to the torsion balance and fixed, and the balance pointer is zeroed. Place the petri dish with the gastric mucosa (moisturizing) on the lifting platform, adjust the lifting platform, and make the gastric mucosa just adhere to the wet gastric juice release bioadhesive, 10 min.
  • the gastric-soluble immediate release bioadhesive agent was pulled at a rate of 2 mg/s until the mucosa was separated from the gastric-soluble immediate release bioadhesive agent, and the balance reading was recorded.
  • the results show that the gastric-soluble immediate release bioadhesive has a good adhesion to the gastric mucosa.
  • enteric instant release bioadhesive Place the petri dish with small intestinal mucosa (moisturizing) on the lifting platform, adjust the lifting platform, and make the small intestine mucosa just adhere to the wetted enteric instant release bioadhesive, 10 min. After, enteric instant release bioadhesive 2mg/s Pull the force until the mucosa is separated from the enteric instant release bioadhesive and record the balance reading. The results show that the enteric instant release bioadhesive has a good adhesion to the mucosa from the duodenum to the upper part of the jejunum.
  • In vivo perfusion mucosal adhesion test enteral solution: 6 SD rats, weighing 253.10 ⁇ 19.24g, fasting 24h (water supply), Ulatan anesthesia, abdominal midline incision, ligation of the cardia, blunt separation of the stomach, small intestine of the entire intestine, washing the contents, distal ligation, the proximal end of the stomach and the distal end of the small intestine respectively connected to the glass tube, stomach proximal glass tube Connect the peristaltic pump.
  • Enteric instant release bioadhesive particles 200 capsules, suspended in 100 ml In the physiological saline, the enteric-coated immediate-release bioadhesive particle suspension was poured, the effluent was collected, and the number of the enteric-coated immediate-release bioadhesive particles was counted, and the retention rate of the coated particles at different sites was calculated.
  • the adhesive properties of enteric-coated immediate-release bioadhesive particles in different parts are different, and the adhesion properties in the stomach and small intestine are respectively 3.53 ⁇ 0.21%, 87.36 ⁇ 5.59%.
  • In vivo perfusion mucosal adhesion test (stomach solution): 6 SD rats, weighing 244.31 ⁇ 17.37g, fasting 24h (water supply), Ulatan anesthesia, abdominal midline incision, ligation of the cardia, blunt separation of the stomach, small intestine of the entire intestine, washing the contents, distal ligation, the proximal end of the stomach and the distal end of the small intestine respectively connected to the glass tube, stomach proximal glass tube Connect the peristaltic pump.
  • Gastric dissolution immediate release bioadhesive particles 200 capsules, suspended in 100 ml In the physiological saline, the gastric-soluble immediate-release bioadhesive microparticle suspension was poured, the effluent was collected, and the number of the gastric-soluble immediate-release bioadhesive particles was counted, and the retention rate of the coated particles at different sites was calculated.
  • the gastric-coated immediate release bioadhesive particles have different adhesion properties in different parts, and the adhesion properties in the stomach and small intestine are respectively 90.13 ⁇ 3.74%, 8.45 ⁇ 0.67%.
  • bioadhesive group 20 Kunming mice, weighing 23.47 ⁇ 2.11g, fasted for 12 hours, randomly divided into 2 Group: bioadhesive group, control group.
  • the bioadhesive group was first gavaged with an enteric instant release bioadhesive agent of 20 g/kg body weight, followed by 20 g/kg.
  • the body weight of the gastric-soluble immediate-release bioadhesive was intragastrically administered, and the control group was intragastrically administered with an equal volume of normal saline. After 30 minutes, each group was administered with Erfutou wine with an alcohol content of 56% (v/v), 10 ml/kg.
  • Oral administration after 20 g/kg body weight of gastric-soluble immediate release bioadhesive was intragastrically administered, A control group was intragastrically administered with equal volume of normal saline; each group was administered with Erfutou wine with alcohol content of 56% (v/v), 15 mL/kg body weight; After 60 minutes, the post-bioadhesive group was first gavaged with 20 g/kg body weight of the enteric instant release bioadhesive agent, and then administered with 20 g/kg body weight of the gastric-soluble immediate release bioadhesive agent. The control group was intragastrically administrated with an equal volume of normal saline.
  • the cervical spine was dislocated and the midline of the abdomen was cut open.
  • the stomach and duodenum were removed, cut along the stomach, rinsed with saline, and blotted with filter paper. Mucosal damage was observed by the naked eye, and the gastric mucosa and duodenal mucosa were cut out, 3.7% paraformaldehyde fixed, conventional paraffin embedded, sectioned, HE The pathological changes of gastric mucosa and duodenal mucosa were observed under light microscope.
  • the gastric mucosa and duodenal mucosa were clearly damaged, and the B control group was more; See the pathological section
  • the gastric mucosa and duodenal mucosa of group A and group B were extensively hyperemic and edematous, inflammatory cells infiltrated, mainly neutrophils, and epithelial cells were necrotic, B
  • the mucosal erosion ulcer and hemorrhagic necrosis were more.
  • the gastric mucosa and duodenal mucosa of the Mr. adhesive group were intact, the glands were arranged neatly, and the layers were clear. Edema and inflammatory cell infiltration were observed in the gastric mucosa and duodenal submucosa.
  • control group was significantly obese (136.25 ⁇ 15.08g), and the bioadhesive group had no obvious obesity ( 109.84 ⁇ 12.23g), the difference between the two groups was extremely significant (P ⁇ 0.01).
  • the body weight of the enteric-coated immediate-release bioadhesive was intragastrically administered, and then 20 g/kg body weight of the gastric-soluble immediate release bioadhesive was administered to the stomach, bid, and the control group was intragastrically administered with an equal volume of normal saline.
  • SPSS12.0 statistical analysis software analysis Analysis of variance was used between groups, and t test was used in the group. The difference was significant at p ⁇ 0.05.
  • the bioadhesive group had a blood glucose level of 9.43 ⁇ 3.75 mM / L
  • the blood glucose of the control group was 25.71 ⁇ 5.93 mM/L, and the difference between the two groups was extremely significant (P ⁇ 0.01).
  • the present invention is not intended to include the same prior art, or may be implemented using the prior art.

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Abstract

本发明提供了一种定位速释生物粘附剂,涉及一种预防或/和治疗糖尿病、肥胖病、酒精中毒、胃与肠粘膜炎症或/和溃疡等的医疗器械;该定位速释生物粘附剂,用生物相容的生物粘附材料制备成微粒,外加速释崩解剂,压片后肠溶或胃溶包衣,或将微粒肠溶或胃溶包衣,或填充至肠溶或胃溶空心胶囊,或生物粘附材料、速释崩解剂等附加剂直接压片后肠溶或胃溶包衣;服用后,定位、速释,并迅速粘附覆盖十二指及空肠上段或/和胃粘膜,减弱了十二指及空肠上段或/和胃的吸收;该定位速释生物粘附剂经口服用,携带方便,储存方便,使用方便,不必去医院、不必手术、不必用内镜、没有痛苦,增强了被使用者的顺应性、避免了操作的繁复性。

Description

一种定位速释生物粘附剂及应用 技术领域
本发明涉及一种内服或 / 和外用的生物相容医疗器械,特别是涉及一种预防或 / 和治疗糖尿病、肥胖病、酒精中毒、胃与肠粘膜炎症或 / 和溃疡等的定位速释 生物粘附 剂。
背景技术
2011 年 3 月,美国纽约召开的第二届国际 2 型糖尿病介入治疗大会上,国际糖尿病联盟( IDF )首次声明,认为胃流转手术可用于治疗肥胖的 2 型糖尿病患者,并可减少糖尿病慢性并发症的发生与发展(中国医药科学 ,2011,1(22):1-2 )。这种手术也可使患者的高血压、肥胖、血脂紊乱等并发症均有明显改善(中国医药科学 ,2011,1(21):3-5 )。但胃转流手术有临床风险,如死亡、肠梗阻、吻合口漏、肺栓塞、深静脉血栓、门静脉损伤、呼吸系统疾病等(中华糖尿病杂志 ,2011,3(3):205-208 )。近来,在体置入十二指肠内覆膜以覆盖十二指肠和空肠上段粘膜进而治疗糖尿病与肥胖病,趋向替代上述 ' 胃转流手术 ' 。但现有技术的发明专利 ' 十二指肠套管及其输送器 ' (申请日 2010 年 4 月 9 日 ,授权公告日 2012 年 1 月 11 日 ),现有技术的发明专利 ' 一种用可降解生物相容材料制成的十二指肠内覆膜及应用 ' (申请日 2012 年 5 月 5 日 ,公布日 2012 年 8 月 8 日 ),现有技术的发明专利 ' 一种用静电纺制成的十二指肠内覆膜 ' (申请日 2012 年 8 月 21 日 ,公布日 2012 年 11 月 21 日 )均为植入体内的医疗器械,其植入操作要依赖内镜,不可降解的材料还要延期取出,(与本发明相比)这不仅影响了被使用者的顺应性,也增添了操作的繁复性。
限制进食量、减少胃与肠吸收,是手术治疗肥胖病的基本机理,相应的现有技术的发明专利 ' 缩胃手术中使用的组织传送器以及相关使用方法 ' (申请日 2009 年 4 月 30 日 ,公布日 2011 年 4 月 13 日 ),现有技术的发明专利 ' 可松开的胃成形术环 ' (申请日 2000 年 12 月 21 日 ,授权公告日 2004 年 9 月 1 日 ),现有技术的发明专利 ' 单一控制的胃成形术环 ' (申请日 2001 年 1 月 19 日 ,授权公告日 2004 年 10 月 20 日 )等,或在胃腔中置放球囊或胃束带(杨柯君 . 可调节胃束带减肥手术的优点 . 上海医药 , 2012,33(8):11 ;汤深等 . 肥胖症胃内水球疗法的临床研究 . 中国医药科学 ,2011,1(6):23-24 ;梅力文等 . 胃内水球治疗肥胖症患者的疗效与安全性评估 . 中华医学杂志 ,2007,87(6):388-391 ),虽可以限制每餐的进食量、减少胃的吸收,但被使用者的顺应性、操作的繁复性及风险度不言而喻。
常见的解酒思路,多在饮酒之后如何被动地解除或降低其作用,相应的现有技术的发明专利 ' 一种解酒口服药物的组方及制备工艺 ' (申请日 2010 年 12 月 20 日 ,公布日 2012 年 7 月 11 日 ),现有技术的发明专利 ' 一种防醉解酒组合物及其制备方法 ' (申请日 2012 年 5 月 18 日 ,公布日 2012 年 9 月 19 日 ),现有技术的发明专利 ' 口腔吸收固体解酒泡腾制剂 ' (申请日 2010 年 7 月 12 日 ,公布日 2010 年 12 月 22 日 )等,且不评价这些物质对解酒的效用,其经吸收、代谢等体内途径,亦会增加肝脏或 / 和肾脏等脏器的负担,更主要的是其被动解酒的节点基本都在机体吸收酒之后,这已经增加了机体相关脏器的负担。
技术问题
现有技术的发明专利 ' 十二指肠套管及其输送器 ' (申请日 2010 年 4 月 9 日 ,授权公告日 2012 年 1 月 11 日 ),现有技术的发明专利 ' 一种用可降解生物相容材料制成的十二指肠内覆膜及应用 ' (申请日 2012 年 5 月 5 日 ,公布日 2012 年 8 月 8 日 ),现有技术的发明专利 ' 一种用静电纺制成的十二指肠内覆膜 ' (申请日 2012 年 8 月 21 日 ,公布日 2012 年 11 月 21 日 )既影响了被使用者的顺应性,(与本发明相比)也增添了操作的繁复性。本发明所述的定位速释生物粘附剂,经口服用后, pH 敏感的 包衣材料依胃肠道内的 pH 值差异将所述的肠溶 速释生物粘附 剂(微粒或 / 和胶囊或 / 和片剂)定位传递到十二指肠和空肠上段,到达十二指肠和空肠上段的肠溶 速释生物粘附 剂在高 pH 环境中包衣材料迅速 或 / 和 突跃 降解 。在十二指肠和空肠上段肠腔内,所述的肠溶 速释生物粘附 剂中的 粘附材料迅速 充分完全地释放、崩解、漂浮、溶出、溶胀(压制成片剂的定位 速释生物粘附 剂因有速释崩解剂等也 迅速 充分完全地释放、崩解、漂浮、溶出、溶胀),触及十二指肠和空肠上段粘膜 就与膜粘蛋白或 / 和粘膜上皮细胞等之间相互作用而 即粘附其上,直至全部粘附、覆盖十二指肠和空肠上段粘膜或 / 和嵌入粘膜皱褶谷缝中; 十二指肠升部在减少 空、回肠的内容物反流的同时,也进一步延长了 粘附材料 在十二指肠停留的时间。 该 定位 速释生物粘附 剂 经口服用,携带方便,储存方便,使用方便,服用时不必去医院、不必手术、不必用内镜、没有痛苦,增强了被使用者(肥胖病患者、糖尿病患者、酒精中毒预防者、十二指肠炎症或 / 和溃疡等人群)的顺应性、几乎归零了操作的繁复性。因为覆盖了 十二指肠和空肠上段粘膜,也可以减少酒精在十二指肠和空肠上段粘膜的吸收从而减少酒精中毒; 因为覆盖了 十二指肠和空肠上段粘膜,也可以保护十二指肠和空肠上段从而 预防或 / 和治疗十二指肠或 / 和空肠炎症或 / 和溃疡。依 粘附材料 在体内逐渐降解或 / 和溶蚀或 / 和溶出的时间,确定叠加服用的量与周期。
现有技术的发明专利 ' 缩胃手术中使用的组织传送器以及相关使用方法 ' (申请日 2009 年 4 月 30 日 ,公布日 2011 年 4 月 13 日 ),现有技术的发明专利 ' 可松开的胃成形术环 ' (申请日 2000 年 12 月 21 日 ,授权公告日 2004 年 9 月 1 日 ),现有技术的发明专利 ' 单一控制的胃成形术环 ' (申请日 2001 年 1 月 19 日 ,授权公告日 2004 年 10 月 20 日 )等,或在胃腔中置放气囊或胃束带(杨柯君 . 可调节胃束带减肥手术的优点 . 上海医药 , 2012,33(8):11 ;汤深等 . 肥胖症胃内水球疗法的临床研究 . 中国医药科学 ,2011,1(6):23-24 ;梅力文等 . 胃内水球治疗肥胖症患者的疗效与安全性评估 . 中华医学杂志 ,2007,87(6):388-391 ),虽可以限制每餐的进食量、减少胃的吸收,但被使用者的顺应性、操作的繁复性及风险度不言而喻。本发明所述的定位速释生物粘附剂,被使用者(肥胖病患者、糖尿病患者等人群)不必去医院、不必手术、不必用内镜、没有痛苦,只需口服,服用后, pH 敏感的 包衣材料依胃肠道内的 pH 值差异将所述的胃溶 速释生物粘附 剂(微粒或 / 和胶囊或 / 和片剂)定位传递到胃部,到达胃部的胃溶 速释生物粘附 剂在胃 pH 环境中包衣材料迅速 或 / 和 突跃 降解 。在胃腔内,所述的胃溶 速释生物粘附 剂中的 粘附材料迅速 充分完全地释放、崩解、漂浮、溶出、溶胀(压制成片剂的定位 速释生物粘附 剂因有速释崩解剂也 迅速 充分完全地释放、崩解、漂浮、溶出、溶胀),触及胃粘膜 就与膜粘蛋白或 / 和粘膜上皮细胞等之间的相互作用而 即粘附其上,直至全部粘附、覆盖胃粘膜或 / 和嵌入粘膜皱褶谷缝中; 胃幽门部在减少十二指肠 内容物反流的同时,也进一步延长了 粘附材料 在胃部停留的时间。这样,粘附材料 粘附覆盖在胃粘膜上,即可减少胃的吸收。依 粘附材料 在体内逐渐降解或 / 和溶蚀或 / 和溶出的时间,确定叠加服用的量与周期。
现有技术的发明专利 ' 一种解酒口服药物的组方及制备工艺 ' (申请日 2010 年 12 月 20 日 ,公布日 2012 年 7 月 11 日 ),现有技术的发明专利 ' 一种防醉解酒组合物及其制备方法 ' (申请日 2012 年 5 月 18 日 ,公布日 2012 年 9 月 19 日 ),现有技术的发明专利 ' 口腔吸收固体解酒泡腾制剂 ' (申请日 2010 年 7 月 12 日 ,公布日 2010 年 12 月 22 日 )等,其解酒的节点基本都是在机体吸收酒之后,这已经增加了机体相关脏器的负担,解酒的物质经吸收、代谢等体内途径,亦会增加肝脏或 / 和肾脏等脏器的负担。正常情况下,酒精摄入后,约 80 %由十二指肠及空肠粘膜吸收,其余部分由胃粘膜吸收(《内科学 · 上册》 789 页)。本发明所述的 定位 速释生物粘附 剂 经口服用后, pH 敏感的 包衣材料依胃肠道内的 pH 值差异将所述的胃溶或 / 和肠溶 速释生物粘附 剂(微粒或 / 和胶囊或 / 和片剂)定位传递到胃部或 / 和十二指肠及空肠,到达胃部或 / 和十二指肠及空肠的胃溶或 / 和肠溶 速释生物粘附 剂在相应 pH 环境中包衣材料迅速 或 / 和 突跃 降解 。在胃腔或 / 和十二指肠及空肠腔内,所述的胃溶或 / 和肠溶 速释生物粘附 剂中的 粘附材料迅速 充分完全地释放、崩解、漂浮、溶出、溶胀(压制成片剂的定位 速释生物粘附 剂因有速释崩解剂也 迅速 充分完全地释放、崩解、漂浮、溶出、溶胀),触及胃或 / 和十二指肠及空肠粘膜 就与膜粘蛋白或 / 和粘膜上皮细胞等之间的相互作用而 即粘附其上,直至全部粘附、覆盖胃或 / 和十二指肠及空肠粘膜或 / 和嵌入粘膜皱褶谷缝中。这样,所述的胃溶或 / 和肠溶 速释生物粘附 剂 只是粘附覆盖在胃 或 / 和十二指肠及空肠 粘膜上,既不吸收,也期前主动阻止了胃 或 / 和十二指肠及空肠 对酒的吸收;因为覆盖了 胃或 / 和十二指肠及空肠粘膜,也可以保护胃或 / 和十二指肠及空肠粘膜从而 预防或 / 和治疗胃 或 / 和十二指肠及空肠 炎或 / 和溃疡。依 粘附材料 在体内逐渐降解或 / 和溶蚀或 / 和溶出的时间,确定叠加服用的量与周期。
技术解决方案
一种定位速释生物粘附剂,其特征在于用生物相容的生物粘附材料制备成微粒,外加速释崩解剂,压片后肠溶包衣,或将微粒肠溶包衣,或填充至肠溶空心胶囊,或生物粘附材料、速释崩解剂与其他附加剂直接压片后肠溶包衣,服用后粘附覆盖十二指肠及空肠上段粘膜,可以预防或 / 和治疗糖尿病和肥胖病、减弱酒精吸收, 也可预防或 / 和治疗 十二指肠 炎症或 / 和溃疡。
一种定位速释生物粘附剂,其特征在于用生物相容的生物粘附材料制备成微粒,外加速释崩解剂,压片后胃溶包衣,或将微粒胃溶包衣,或填充至胃溶空心胶囊,或生物粘附材料、速释崩解剂与其他附加剂直接压片后胃溶包衣,服用后粘附覆盖胃粘膜,可以减弱胃部酒精吸收、预防或 / 和治疗肥胖病, 也可预防或 / 和治疗胃炎或 / 和溃疡。
所述的肠溶 定位 速释生物粘附 剂 ,可以由以下步骤和方式得到:
微粒的制备:
1-5g 丙交酯 - 聚乙二醇共聚物 (PELA) ,丙交酯 : 聚乙二醇重量比为 80-90:20-10 ,聚乙二醇分子量 6000 , 15-25ml 无水乙醇溶解,此为内相; 2% 司盘 85 的液体石蜡 100 ml ,此为外相;磁力高速搅拌下,内相缓慢滴入外相, 60℃ 减压除去乙醇,立即冰浴,冷却成固体;离心分离液体石蜡,沉淀,石油醚洗涤,真空干燥;过 100 目筛,不可过 200 目筛。光学显微镜下观察形状。
或,分子量 5 万的 A 型明胶,配置成 3-8% 溶液, 45℃ 中,搅拌中加入凝聚剂硫酸钠,静置,分离,用冷异丙醇洗后,用 5-15% 甲醛的异丙醇液交联固化,脱水,真空干燥,得微粒。其间,可以水为稀释剂,经反复凝聚与解凝聚,光学显微镜下观察形状,直到形成适宜形状,再交联固化。
或, 5-15% 明胶, 5-15% 阿拉伯胶, 70-90% 水的混合液,加水逐渐稀释,光学显微镜下观察形状,直到形成适宜形状,再交联固化。
或,聚异丁烯,乙基纤维素,环己烷组成三元系统, 80℃ 溶解成均匀溶液,缓慢冷却至 45℃ ,再迅速冷却至 25℃ ,即成微粒。
或(制备纳米粒), 300g/L 明胶溶液置入等量芝麻油中乳化,冰浴乳液,使明胶乳滴胶凝,丙酮稀释, 50nm 滤膜过滤,丙酮漂洗纳米球上的油, 5-15% 甲醛的丙酮液交联, 5-15min ,干燥即得。
或(制备纳米粒), 100 mg PLGA 超声溶于 5-15 ml 丙酮,磁力搅拌下滴入 30-50 ml 的 0.01-0.05% 卡泊姆水溶液中,室温 500 rpm 搅拌,至有机溶剂挥尽, 4 ℃ 、 15000 rpm 离心 20-40 min ,弃上清,去除残余表面活性剂,沉淀物复溶于 Milipore 水中, 3 次水洗,干燥,即得 PLGA 纳米粒。
或(制备纳米粒),壳聚糖溶于稀醋酸水溶液,过夜溶胀,配成 0.3-1.0%(w/v) 的壳聚糖溶液,三聚磷酸钠溶于蒸馏水,配成 0.3-1.0%(w/v) 的溶液,不断磁力搅拌,以滴速约为 2-5ml/min 将三聚磷酸钠液加入壳聚糖液中,溶液由澄清渐变为淡蓝色乳光,根据乳光判断纳米粒的形成。
或(制备纳米粒),常温, PLGA 溶解在三氟乙醇中 36-72hr ,磁力搅拌, 5-50 %w/v , 将此溶液转入连有高压发生器的微量注射泵中,调节电压 V 5-35kV ,接收距离 L 1-20cm ,溶液流速 f 0.1-2.0ml/h ,电喷,铝箔接收板或载玻片接收所得微粒,干燥箱中干燥 2d ,即得纳米粒。扫描电镜观察所制微粒形貌。
直接压片:
1 份卡泊姆 934P , 1 份羧甲基纤维素钠 2000cp ,均匀混合,粉末直接压片,厚度 1-3 mm ,直径 3-13mm ,硬度约 4kg /mm2 。也可以湿法制粒压片,粘合剂可选用 3-10%PVP K30 的 60-80% 乙醇溶液,润滑剂可选用硬脂酸镁( 1-5% ),填充剂可选用预胶化淀粉 。
或,甘露醇 30-50% 、微晶纤维素 30-40% 、适量乳糖,过 100 目筛,等量递增混匀,加 5% 聚乙烯吡咯烷酮 K30 溶液为黏合剂,制粒, 60℃ 烘干 0.5-2h ,整粒,再与适量羧甲基纤维素钠、微粉硅胶混匀,压片。
或,碳酸氢钠 : 氢氧化镁 =1:2 ,硬脂酸镁 0.5-2% 、交联羧甲基纤维素钠 1-5% 、 Starch 1500 5-15% , 100 目过筛,全部混合均匀,压片,硬度为 4-10 kg/mm2
微粒的压片:
可以原辅料过 100 目筛,混匀,加粘合剂 3-15%PVP 水溶液制软材,制粒, 60℃ 干燥 0.5-2 h ;加入硬脂酸镁或 / 和稀释剂或 / 和润湿剂等,整粒,压片即得。
肠溶包衣:
取 pH 敏感点在 5-6 的羟丙基甲基纤维素酞酸酯,用丙酮 / 乙醇 (1/1,v /v) 配成 1.0-3.0% 的溶液,附加剂用量 10-30% ,混匀,调节包衣增重为 1-5% 。调节包衣锅转速,使片芯呈抛物线滚动、旋转、打磨,约 60±5 r/min 。吹风机进风预热片芯,温度约 50℃ ,调节进风位置,出风速度,使包衣液均匀喷出。 10-30min 后,观察片芯,边缘光滑,无缺损或裂片,包衣片不粘片,衣膜均匀平整;包衣完毕,取出,约 60℃ 烘箱干燥;称重,以包衣增重百分比作为包衣控制指标。
或, 3-5%EC , 0.3-1.0%DEP 和 0.1-0.6%PEG400 ,包衣溶剂为 60-90% 乙醇水溶液;片芯置包衣锅内,预热,包衣锅倾角 45' ,喷嘴内径 0.5-1.0 mm ;喷枪雾化压力约 137.3 kPa ,进风温度 35±5 ℃ ,片温 35±2℃ ;转速 13-36 r/nin ,喷速 0.5-1.0ml/min 。
或,片芯浸入 1-5%(W/V)Eudragit L100-55 丙酮溶液, 2-10min ,取出干燥,反复 3-6 次,控制厚度约 50μm 。
微粒的肠溶包衣:
可以制得的微粒置流化床包衣装置中沸腾流化,喷枪喷洒 4-8% 丙烯酸树脂的乙醇液,鼓风干燥,排气口排出挥发溶剂,得包衣厚度均匀、无粘连的肠溶包衣微粒。
肠溶包衣胶囊及微粒的填充:
可以用高效包衣机,喷嘴直径 0.5-l.5 mm ,雾化压力 0.1MPa ,风量 50-120m3/h ,物料温度 23-25℃ ,喷液速度 0.5-5.5g/min ,数显千分尺测定厚度, 25℃ 下熟化 20-60 min ,包衣完成,取出肠溶包衣胶囊,室温干燥。灌装肠溶空心胶囊, 5-15% 乙基纤维素溶液封口,置干燥器备用。可加入适量抗粘剂硬脂酸镁或二氧化硅等,或稀释剂、润滑剂、崩解剂等。
肠溶包衣材料:
可以是 Eudragit L 型、 Eudragit S 型、丙烯酸树脂 Ⅰ 号、丙烯酸树脂 Ⅱ 号、丙烯酸树脂 Ⅲ 号、丙烯酸树脂 Ⅳ 号、邻苯二甲酸醋酸纤维素 (CAP) 、 1,2,4- 苯三甲酸醋酸纤维素 (CAT) 、琥珀酸醋酸纤维素 (CAS) 、邻苯二甲酸羟丙基甲基纤维素 (HPMCP) 、 l,2,4- 苯三甲酸羟丙基甲基纤维素 (HPMCT) 、琥珀酸醋酸羟丙基甲基纤维素 (HPMCAS) 等材料。
所述的胃溶 定位 速释生物粘附 剂 ,可以由以下步骤得到:
微粒的制备:
1-2 份 5-25% 乙基纤维素 - 卡泊姆 934P 共聚物无水乙醇溶解液, 5-15℃ 水浴搅拌 20-30min ,缓慢匀速滴入到 5-7 份 5-15℃ 的 1-10% 司盘 85 的液体石蜡中,搅拌 30-40 min , 60℃ 减压挥发去除乙醇,立即冰浴,冷却成固体,离心分离液体石蜡,沉淀,石油醚洗涤, 37 ℃ 干燥箱中干燥 12-24 h ,过 100 目筛 , 不可过 200 目筛。光学显微镜下观察形状。
或,分子量 5 万的 A 型明胶,配置成 3-8% 溶液, 45℃ 中,搅拌中加入凝聚剂硫酸钠,静置,分离,用冷异丙醇洗后,用 5-15% 甲醛的异丙醇液交联固化,脱水,真空干燥,得微粒。其间,可以水为稀释剂,经反复凝聚与解凝聚,光学显微镜下观察形状,直到形成适宜形状,再交联固化。
或, 5-15% 明胶, 5-15% 阿拉伯胶, 70-90% 水的混合液,加水逐渐稀释,光学显微镜下观察形状,直到形成适宜形状,再交联固化。
或,聚异丁烯,乙基纤维素,环己烷组成三元系统, 80℃ 溶解成均匀溶液,缓慢冷却至 45℃ ,再迅速冷却至 25℃ ,即成微粒。
或(制备纳米粒), 300g/L 明胶溶液置入等量芝麻油中乳化,冰浴乳液,使明胶乳滴胶凝,丙酮稀释, 50nm 滤膜过滤,丙酮漂洗纳米球上的油, 5-15% 甲醛的丙酮液交联, 5-15min ,干燥即得。
或(制备纳米粒), 100 mg PLGA 超声溶于 5-15 ml 丙酮,磁力搅拌下滴入 30-50 ml 的 0.01-0.05% 卡泊姆水溶液中, 500 rpm 室温搅拌,至有机溶剂挥尽, 4 ℃ 、 15000 rpm 离心 20-40 min ,弃上清,去除残余表面活性剂,沉淀物复溶于 Milipore 水中, 3 次水洗,干燥,即得 PLGA 纳米粒。
或(制备纳米粒),壳聚糖溶于稀醋酸水溶液,过夜溶胀,配成 0.3-1.0%(w/v) 的壳聚糖溶液,三聚磷酸钠溶于蒸馏水,配成 0.3-1.0%(w/v) 的溶液,不断磁力搅拌,以滴速约为 2-5ml/min 将三聚磷酸钠液加入壳聚糖液中,溶液由澄清渐变为淡蓝色乳光,根据乳光判断纳米粒的形成。
或(制备纳米粒),常温, PLGA 溶解在三氟乙醇中 36-72hr ,磁力搅拌, 5-50 %w/v , 将此溶液转入连有高压发生器的微量注射泵中,调节电压 V 5-35kV ,接收距离 L 1-20cm ,溶液流速 f 0.1-2.0ml/h ,电喷,铝箔接收板或载玻片接收所得微粒,干燥箱中干燥 2d ,即得纳米粒。扫描电镜观察所制微粒形貌。
直接压片:
1 份卡泊姆 934P , 1 份羧甲基纤维素钠 2000cp ,均匀混合,粉末直接压片,厚度 1-3 mm ,直径 3-13mm ,硬度约 4kg /mm2 。也可以湿法制粒压片,粘合剂可选用 3-10%PVP K30 的 60-80% 乙醇溶液,润滑剂可选用硬脂酸镁( 1-5% ),填充剂可选用预胶化淀粉 。
或,甘露醇 30-50% 、微晶纤维素 30-40% 、适量乳糖,过 100 目筛,等量递增混匀,加 5% 聚乙烯吡咯烷酮 K30 溶液为黏合剂,制粒, 60℃ 烘干 0.5-2h ,整粒,再与适量羧甲基纤维素钠、微粉硅胶混匀,压片。
或,碳酸氢钠 : 氢氧化镁 =1:2 ,硬脂酸镁 0.5-2% 、交联羧甲基纤维素钠 1-5% 、 Starch 1500 5-15% , 100 目过筛,全部混合均匀,压片,硬度为 4-10 kg/mm2
微粒的压片:
可以原辅料过 100 目筛,混匀,加粘合剂 3-15%PVP 水溶液制软材,制粒, 60℃ 干燥 0.5-2 h ;加入硬脂酸镁或 / 和稀释剂或 / 和润湿剂等,整粒,压片即得。
胃溶包衣:
可以取 pH 敏感点在 1-2 的胃溶型丙烯酸树脂( Ⅵ 号),用丙酮 / 乙醇 (1/1,v /v) 配成 2.0% 的溶液,附加剂用量为 10-50% ,混匀,调节包衣增重为 1-5% 。调节包衣锅转速,使片芯呈抛物线滚动、旋转打磨,约 60±5 r/min 。吹风机进风预热片芯,温度约 50℃ ,调节进风位置,出风速度,使包衣液均匀喷出。 10-15min 后,观察片芯,边缘光滑,无缺损或裂片,包衣片不粘片,衣膜均匀平整;包衣完毕,取出,约 60℃ 烘箱干燥;称重,以包衣增重百分比作为包衣控制指标。
微粒的胃溶包衣:
可以将制得的微粒置流化床包衣装置中沸腾流化,喷枪喷洒 5-7 %的乙醇羟丙基甲基纤维素液,鼓风干燥,排气口排出挥发溶剂,得包衣厚度均匀、无粘连的胃溶包衣微粒。
胃溶包衣胶囊及微粒的填充:
可以用高效包衣机,喷嘴直径 0.5-l.5 mm ,雾化压力 0.1MPa ,风量 50-120m3/h ,物料温度 23-25℃ ,喷液速度 0.5-5.5g/min ,数显千分尺测定厚度, 25℃ 下熟化 20-60 min ,包衣完成,取出胃溶包衣胶囊,室温干燥。灌装胃溶空心胶囊, 5-15% 乙基纤维素溶液封口,置干燥器备用。可加入适量抗粘剂硬脂酸镁或二氧化硅等,或稀释剂、润滑剂、崩解剂等。
胃溶包衣材料:
可以是羟丙基甲基纤维素 (HPMC) 、甲基纤维素 (MC) 、聚乙烯醇 (PVA) 、羟丙基纤维素 (HPC) 、聚乙二醇 (PEG) 、聚乙烯缩乙醛二乙胺醋酸酯 (AEA) 、 Eudragit E 型、胃溶型丙烯酸树脂等材料。
本发明所述的肠溶或 胃溶 定位 速释生物粘附 剂的 生物粘附 材料:
可以是卡波姆 (CP) 、羟丙基甲基纤维素 (HPMC) 、羟丙基纤维素 (HPC) 、乙二胺改性聚乳酸 (EMPLA) 、聚四氟乙烯、聚乳酸 - 羟基乙酸 (PLGA) 、聚乳酸 - 己内酯 (PCL-b-LA) 、聚 ε- 己内酯 (PCL) 、硅油、硅橡胶、聚酯 - 聚醚共聚物、接枝聚乳酸、明胶、白芨胶、海藻酸盐、纤维素衍生物、壳聚糖、外源凝集素 ( 植物血凝素 ) 、西红柿凝集素、 N-(2- 羟丙基 ) 甲基丙烯胺共聚物等材料。粘附材料 用量为 10%-90% 。填充剂可以是乳糖、微晶纤维素、蔗糖、淀粉、预胶化淀粉等材料。粘合剂可以是水、不同浓度的乙醇、不同浓度的 PVPK30 等材料 。
本发明所述的肠溶或 胃溶 定位 速释生物粘附 剂微粒的制备,还可以由溶剂挥发法、喷雾干燥法、相分离法、电喷法、声波激发雾化法、乳液聚合法、界面聚合法、原位聚合法、聚合物快速不溶解法、雾化溶剂萃取法、单乳液法、双乳液法、中相分离法、溶液中干燥法、溶液蒸发法、粉末床法、空气悬浮涂层法、真空喷涂法、静电气溶胶法、多孔离心法等方法得到。
依 粘附材料 在体内逐渐降解或 / 和溶蚀或 / 和溶出的时间,确定叠加服用的量与周期。
有益效果
提供一种 肠溶 定位 速释生物粘附 剂 ,与现有技术相比(发明专利 ' 十二指肠套管及其输送器 ' ;发明专利 ' 一种用可降解生物相容材料制成的十二指肠内覆膜及应用 ' ;发明专利 ' 一种用静电纺制成的十二指肠内覆膜 ' ),该 定位 速释生物粘附 剂 经口服用后, pH 敏感的 包衣材料依胃肠道内的 pH 值差异将所述的肠溶 速释生物粘附 剂(微粒或 / 和胶囊或 / 和片剂)定位传递到十二指肠和空肠上段,到达十二指肠和空肠上段的肠溶 速释生物粘附 剂在高 pH 环境中包衣材料迅速 或 / 和 突跃 降解 。在十二指肠和空肠上段肠腔内,所述的肠溶 速释生物粘附 剂中的 粘附材料迅速 充分完全地释放、崩解、漂浮、溶出、溶胀(压制成片剂的定位 速释生物粘附 剂因有速释崩解剂等也 迅速 充分完全地释放、崩解、漂浮、溶出、溶胀),触及十二指肠和空肠上段粘膜 就与膜粘蛋白或 / 和粘膜上皮细胞等之间相互作用而 即粘附其上,直至全部粘附、覆盖十二指肠和空肠上段粘膜或 / 和嵌入粘膜皱褶谷缝中; 十二指肠升部在减少 空、回肠的内容物反流的同时,也进一步延长了 粘附材料 在十二指肠停留的时间。 该 定位 速释生物粘附 剂 经口服用,携带方便,储存方便,使用方便,服用时不必去医院、不必手术、不必用内镜、没有痛苦,增强了被使用者(肥胖病患者、糖尿病患者、酒精中毒预防者、十二指肠炎症或 / 和溃疡等人群)的顺应性、几乎归零了操作的繁复性。因为覆盖了 十二指肠和空肠上段粘膜,也可以减少酒精在十二指肠和空肠上段粘膜的吸收从而减少酒精中毒; 因为覆盖了 十二指肠和空肠上段粘膜,也可以保护十二指肠和空肠上段从而 预防或 / 和治疗十二指肠或 / 和空肠炎症或 / 和溃疡。依 粘附材料 在体内逐渐降解或 / 和溶蚀或 / 和溶出的时间,确定叠加服用的量与周期。
提供一种 胃溶 定位 速释生物粘附 剂 ,与现有技术相比(发明专利 ' 缩胃手术中使用的组织传送器以及相关使用方法 ' ;发明专利 ' 可松开的胃成形术环 ' ;发明专利 ' 单一控制的胃成形术环 ' ;杨柯君 . 可调节胃束带减肥手术的优点 . 上海医药 , 2012,33(8):11 ;汤深等 . 肥胖症胃内水球疗法的临床研究 . 中国医药科学 ,2011,1(6):23-24 ;梅力文等 . 胃内水球治疗肥胖症患者的疗效与安全性评估 . 中华医学杂志 ,2007,87(6):388-391 )等,该 定位 速释生物粘附 剂 的应用,被使用者(肥胖病患者、糖尿病患者等人群)不必去医院、不必手术、不必用内镜、没有痛苦,只需经口服,服用后, pH 敏感的 包衣材料依胃肠道内的 pH 值差异将所述的胃溶 速释生物粘附 剂(微粒或 / 和胶囊或 / 和片剂)定位传递到胃部,到达胃部的胃溶 速释生物粘附 剂在胃 pH 环境中包衣材料迅速 或 / 和 突跃 降解 。在胃腔内,所述的胃溶 速释生物粘附 剂中的 粘附材料迅速 充分完全地释放、崩解、漂浮、溶出、溶胀(压制成片剂的定位 速释生物粘附 剂因有速释崩解剂也 迅速 充分完全地释放、崩解、漂浮、溶出、溶胀),触及胃粘膜 就与膜粘蛋白或 / 和粘膜上皮细胞等之间的相互作用而 即粘附其上,直至全部粘附、覆盖胃粘膜或 / 和嵌入粘膜皱褶谷缝中; 胃幽门部在减少十二指肠 内容物反流的同时,也进一步延长了 粘附材料 在胃部停留的时间。这样,粘附材料 粘附覆盖在胃粘膜上,即可减少胃的吸收。依 粘附材料 在体内逐渐降解或 / 和溶蚀或 / 和溶出的时间,确定叠加服用的量与周期。
提供一种 胃溶或 / 和肠溶 定位 速释生物粘附 剂 ,与现有技术相比(发明专利 ' 一种解酒口服药物的组方及制备工艺 ' ;发明专利 ' 一种防醉解酒组合物及其制备方法 ' ;发明专利 ' 口腔吸收固体解酒泡腾制剂 ' )等,本发明的产品经口服用后, pH 敏感的 包衣材料依胃肠道内的 pH 值差异将所述的胃溶或 / 和肠溶 速释生物粘附 剂(微粒或 / 和胶囊或 / 和片剂)定位传递到胃部或 / 和十二指肠及空肠,到达胃部或 / 和十二指肠及空肠的胃溶或 / 和肠溶 速释生物粘附 剂在相应 pH 环境中包衣材料迅速 或 / 和 突跃 降解 。在胃腔或 / 和十二指肠及空肠腔内,所述的胃溶或 / 和肠溶 速释生物粘附 剂中的 粘附材料迅速 充分完全地释放、崩解、漂浮、溶出、溶胀(压制成片剂的定位 速释生物粘附 剂因有速释崩解剂也 迅速 充分完全地释放、崩解、漂浮、溶出、溶胀),触及胃或 / 和十二指肠及空肠粘膜 就与膜粘蛋白或 / 和粘膜上皮细胞等之间的相互作用而 即粘附其上,直至全部粘附、覆盖胃或 / 和十二指肠及空肠粘膜或 / 和嵌入粘膜皱褶谷缝中。这样,所述的胃溶或 / 和肠溶 速释生物粘附 剂 只是粘附覆盖在胃 或 / 和十二指肠及空肠 粘膜上,既不吸收,也期前主动阻止了胃 或 / 和十二指肠及空肠 对酒的吸收;因为覆盖了 胃或 / 和十二指肠及空肠粘膜,也可以保护胃或 / 和十二指肠及空肠粘膜从而 预防或 / 和治疗胃 或 / 和十二指肠及空肠 炎或 / 和溃疡。依 粘附材料 在体内逐渐降解或 / 和溶蚀或 / 和溶出的时间,确定叠加服用的量与周期。
附图说明
图 1 (定位 速释生物粘附片 )和图 2 (定位 速释生物粘附胶囊 )是本发明的结构示意图。
图 1 (定位 速释生物粘附片 )中标号所表示的部件或部位为: 1- 生物粘附微粒 ; 2- 速释崩解剂或 / 和稀释剂或 / 和润滑剂或 / 和润湿剂等; 3- 胃溶或肠溶包衣。
图 2 (定位 速释生物粘附胶囊 )中标号所表示的部件或部位为: 1- 生物粘附微粒 ; 2- 抗粘剂或 / 和稀释剂或 / 和润滑剂或 / 和崩解剂等; 3- 胃溶或肠溶胶囊壳。
本发明的最佳实施方式
本发明的实施方式
下面结合具体实例对本发明作进一步说明:
实施例 1
微粒的制备: 1 份 10% 乙基纤维素 - 卡泊姆 934P 共聚物无水乙醇溶解液, 10 ℃ 水浴搅拌 20min ,缓慢匀速滴入到 5 份 10 ℃ 的 3% 司盘 85 的液体石蜡中,搅拌 30 min , 60 ℃ 减压挥发去除乙醇,立即冰浴,冷却成固体,离心分离液体石蜡,沉淀,石油醚洗涤, 37 ℃ 干燥箱中干燥 24 h ,过 100 目筛,不可过 200 目筛。光学显微镜下观察形状。
实施例 2
微粒的肠溶包衣:制得的微粒置流化床包衣装置中沸腾流化 , 喷枪喷洒 6% 丙烯酸树脂的乙醇液,鼓风干燥 , 排气口排出挥发溶剂,得包衣厚度均匀、无粘连的肠溶包衣微粒。
实施例 3
直接压片: 1 份卡泊姆 934P , 1 份羧甲基纤维素钠 2000cp ,均匀混合,粉末直接压片,厚度 1mm ,直径 3mm ,硬度约 4kg /mm2 。也可以湿法制粒压片,粘合剂可选用 5%PVP K30 的 70% 乙醇溶液,润滑剂可选用硬脂酸镁( 3% ),填充剂可选用预胶化淀粉。
实施例 4
微粒的压片:原辅料过 100 目筛,混匀,加粘合剂 10%PVP 水溶液制软材,制粒, 60 ℃ 干燥 1h ;加入硬脂酸镁或 / 和稀释剂或 / 和润湿剂等,整粒,压片即得。
实施例 5
肠溶包衣胶囊及微粒的填充:高效包衣机,喷嘴直径 l mm ,雾化压力 0.1MPa ,风量 60-80m3/h ,物料温度 23-25℃ ,喷液速度 1.5-3.5g/min ,数显千分尺测定厚度, 25 ℃ 下熟化 30-50 min ,包衣完成,取出肠溶包衣胶囊,室温干燥。灌装肠溶空心胶囊, 10% 乙基纤维素溶液封口,置干燥器备用。可加入适量抗粘剂硬脂酸镁或二氧化硅等,或稀释剂、润滑剂、崩解剂等。
实施例 6
液中干燥法制备微粒: 1.5g 丙交酯 - 聚乙二醇共聚物 (PELA) ,丙交酯 : 聚乙二醇重量比为 90:10 ,聚乙二醇分子量 6000 , 20ml 无水乙醇溶解 , 此为内相; 2% 司盘 85 的液体石蜡 100 ml ,此为外相;磁力高速搅拌下,内相缓慢滴入外相, 60 ℃ 减压除去乙醇,立即冰浴,冷却成固体;离心分离液体石蜡,沉淀,石油醚洗涤,真空干燥;过 100 目筛 , 不可过 200 目筛。光学显微镜下观察形状。
实施例 7
单凝聚法制备微粒:分子量 5 万的 A 型明胶,配置成 5% 溶液, 45 ℃ 中,搅拌中加入凝聚剂硫酸钠,静置,分离,用冷异丙醇洗后,用 10% 甲醛的异丙醇液交联固化,脱水,真空干燥,得微粒。其间,可以水为稀释剂,经反复凝聚与解凝聚,光学显微镜下观察形状,直到形成适宜形状,再交联固化。
实施例 8
复凝聚法制备微粒: 10% 明胶, 10% 阿拉伯胶, 80% 水的混合液,加水逐渐稀释,光学显微镜下观察形状,直到形成适宜形状,再交联固化。
实施例 9
调节温度法制备微粒:聚异丁烯,乙基纤维素,环己烷组成三元系统, 80 ℃ 溶解成均匀溶液,缓慢冷却至 45 ℃ ,再迅速冷却至 25 ℃ ,即成微粒。
实施例 10
物理化学法制备明胶纳米球: 300g /L 明胶溶液置入等量芝麻油中乳化,冰浴乳液,使明胶乳滴胶凝,丙酮稀释, 50nm 滤膜过滤,丙酮漂洗纳米球上的油, 10% 甲醛的丙酮液交联, 10min ,干燥即得。
实施例 11
沉淀法制备 PLGA 纳米粒: 100 mg PLGA 超声溶于 6 ml 丙酮,磁力搅拌下滴入 40 ml 的 0.03% 卡泊姆水溶液中,室温搅拌 500 rpm ,至有机溶剂挥尽, 4 ℃ 、 15000 rpm 离心 30 min ,弃上清,去除残余表面活性剂,沉淀物复溶于 Milipore 水中, 3 次水洗,干燥,即得 PLGA 纳米粒。
实施例 12
离子交联法制备微粒:壳聚糖溶于稀醋酸水溶液,过夜溶胀,配成 0.5%(w/v) 的壳聚糖溶液,三聚磷酸钠溶于蒸馏水,配成 0.5%(w/v) 的溶液,不断磁力搅拌,以滴速约为 3ml/min 将三聚磷酸钠液加入壳聚糖液中,溶液由澄清渐变为淡蓝色乳光,根据乳光判断纳米粒的形成。
实施例 13
静电喷雾法制备微粒:常温,将 PLGA 溶解在三氟乙醇中 48hr ,磁力搅拌, 15%w/v , 将此溶液转入连有高压发生器的微量注射泵中,调节电压 V 5-35kV ,接收距离 L 9cm ,溶液流速 f 0.6ml/h ,电喷,铝箔接收板或载玻片接收所得微粒,干燥箱中干燥 2d ,即得纳米粒。扫描电镜观察所制微粒形貌。
实施例 14
速释片的制备:碳酸氢钠 : 氢氧化镁 =1:2 ,硬脂酸镁 1% 、交联羧甲基纤维素钠 3% 、 Starch 1500 10% , 100 目过筛,将上述制备的微粒适量,全部混合均匀,直接压片,硬度为 6 kg /mm2
实施例 15
速释片的制备:甘露醇 40% 、微晶纤维素 35% 、适量乳糖,过 100 目筛,等量递增混匀,加 5% 聚乙烯吡咯烷酮 K30 溶液为黏合剂,制粒, 60 ℃ 烘干 1 h ,整粒,再与适量羧甲基纤维素钠、微粉硅胶混匀,压片。
实施例 16
胃溶包衣 : 将速释片置包衣锅内,包衣锅倾角 45o ,进风温度 35±5 ℃ ,喷枪雾化空气压力 414KPa ,喷雾速率 10g/min ,速释片温度控制在 25±2 ℃ ,转速 15r/min 。
实施例 17
胃溶包衣:取 pH 敏感点在 1-2 的胃溶型丙烯酸树脂( Ⅵ 号),用丙酮 / 乙醇 (1/1,v /v) 配成 2.0% 的溶液,附加剂用量 10-20% ,混匀,调节包衣增重为 3% 。调节包衣锅转速,使片芯呈抛物线滚动、旋转打磨,约 60±5 r/min 。吹风机进风预热片芯,温度约 50 ℃ ,调节进风位置,出风速度,使包衣液均匀喷出。 15min 后,观察片芯,边缘光滑,无缺损或裂片,包衣片不粘片,衣膜均匀平整;包衣完毕,取出,约 60 ℃ 烘箱干燥;称重,以包衣增重百分比作为包衣控制指标。
实施例 18
微粒的胃溶包衣:制得的微粒置流化床包衣装置中沸腾流化 , 喷枪喷洒 5-7 %的乙醇羟丙基甲基纤维素液,鼓风干燥 , 排气口排出挥发溶剂,得包衣厚度均匀、无粘连的胃溶包衣微粒。
实施例 19
胃溶包衣胶囊及微粒的填充:高效包衣机,喷嘴直径 0.5-l.5 mm ,雾化压力 0.1MPa ,风量 60-80m3/h ,物料温度 23-25℃ ,喷液速度 1.5-2.5g/min ,数显千分尺测定厚度, 25 ℃ 下熟化 30-40 min ,包衣完成,取出胃溶包衣胶囊,室温干燥。灌装胃溶空心胶囊, 10% 乙基纤维素溶液封口,置干燥器备用。可加入适量抗粘剂硬脂酸镁或二氧化硅等,或稀释剂、润滑剂、崩解剂等。
实施例 20
肠溶速释片崩解测定:参考国家食品药品监督管理局药品审评中心的静态方法,将筛篮 ( 孔内径 400 µ m) 放入装有 2ml 人工肠液的试管中,再垂直放入 37 ℃ 水浴中,待试管内温上升后,将 1 片肠溶速释片置筛篮中,从肠溶速释片接触人工肠液开始计时,至完全崩解停止,立刻将筛篮提离试管,筛网上无明显留存,测试 6 片,均 <15s 。
实施例 21
胃溶速释片崩解测定:参考国家食品药品监督管理局药品审评中心的静态方法,将筛篮 ( 孔内径 400 µ m) 放入装有 2ml 人工胃液的试管中,再垂直放入 37 ℃ 水浴中,待试管内温上升后,将 1 片胃溶速释片置筛篮中,从胃溶速释片接触人工胃液开始计时,至完全崩解停止,立刻将筛篮提离试管,筛网上无明显留存,测试 6 片,均 <15s 。
实施例 22
大鼠体内定位试验 : SD 大鼠, 30 只,体重 216.37±17.53g ,禁食 5h , 200 粒肠溶 速释生物粘附 微粒用水灌胃,分别在灌胃后即刻, 10' , 20' 后处死,打开腹腔,从贲门起锐性分离暴露胃肠腔,至回盲处,肉眼观察肠溶 速释生物粘附 微粒在胃肠道的分布。结果显示,灌胃后即刻胃中完整和少量溶胀肠溶 速释生物粘附 微粒 160.70±17.33 粒 ,十二指肠溶胀或溶出肠溶 速释生物粘附 微粒 35.90±15.47 粒, 灌胃后 10' 胃中完整和少量溶胀肠溶 速释生物粘附 微粒 1.40±1.96 粒,十二指肠溶胀或溶出肠溶 速释生物粘附 微粒 186.40±7.76 粒, 灌胃后 20' 胃中完整和少量溶胀肠溶 速释生物粘附 微粒 0.70±0.82 粒,十二指肠溶胀或溶出肠溶 速释生物粘附 微粒 191.50±4.03 粒。可见, 所述的 肠溶 速释生物粘附 剂在十二指肠定位溶出。
实施例 23
大鼠体内定位试验: SD 大鼠, 20 只,体重 223.17±20.04g ,禁食 5h , 200 粒胃溶 速释生物粘附 微粒用水灌胃,分别在灌胃后 5' , 15' ,打开腹腔,从贲门起锐性分离暴露胃肠腔,肉眼观察胃溶 速释生物粘附 微粒在胃肠道的分布。结果显示,灌胃后 5' ,胃中溶胀或溶出胃溶 速释生物粘附 微粒 190.92±13.12 粒,灌胃后 15' 胃中溶胀或溶出肠溶 速释生物粘附 微粒 193.75±7.84 粒。可见, 所述的 胃溶 速释生物粘附 剂在胃部定位溶出。
实施例 24
急性毒性试验:昆明鼠 20 只,体重 22.75±2.63g ,随机分为 2 组,试验组 ip 生物粘附材料浸提液, 50ml/Kg ,对照组 ip 等量生理盐水。注射后 24h 、 48h 、 72h 观察一般状况、毒性反应和死亡动物数。结果显示,所有试验组动物均无运动迟缓、体重下降、腹泻、瘫痪、呼吸抑制、惊厥、死亡等体征。
实施例 25
亚急性毒性试验: SD 大鼠 24 只,体重 214.61±18.72g ,随机分为 2 组。生物粘附材料细粉,生理盐水配成 5% 混悬液, qod 上午 9 时 ig ,对照组 ig 等量生理盐水。观察一般状况和体重, 2W 、 4W 时每组各处死 6 只,取心、肝、肾、脾组织,称重,并固定作病理组织切片, SPSS12.0 统计分析软件分析 器官指数 ( 器官重量 / 动物重量 ) , 组间采用方差分析,组内采用 t 检验,以 p<0.05 为差异有显著性意义 。 结果显示,所有试验组动物均无运动迟缓、体重下降等体征,试验组器官指数:心脏 0.454±0.062 ,肝脏 3.203±0.254 ,肾脏 0.869±0.077 ,脾脏 0.269±0.085 ,对照组器官指数:心脏 0.463±0.039 ,肝脏 3.317±0.472 ,肾脏 0.878±0.071 ,脾脏 0.273±0.064 ,与对照组相比,心、肝、肾、脾各器官指数的差异均无显著性意义( P>0.05 )。病理组织切片未发现明显异常。
实施例 26
皮肤刺激试验:新西兰兔 3 只,体重 2.75±0.13kg ,无菌生物粘附材料细粉 10g ,加入 50ml 生理盐水,高温高压消毒, 37 ℃ 浸提 72h , 2500rpm 离心, 5min ,取上清。脊背两侧备皮,面积约 10×10cm ,一侧 10 个位点用浸提液 id , 0.5ml ,另一侧等量生理盐水,观察各位点在注射后 lh 、 24h 、 48h 、 72h 后体征。结果显示,注射后 lh 、 24h 、 48h 、 72h 试验侧及对照侧均无明显红肿、溃烂及渗液等体征出现,未见明显皮肤刺激症状。
实施例 27
离体胃粘膜粘附试验:昆明鼠 8 只,体重 21.36±2.41g ,禁食 24h (供水),颈椎脱位处死,立即取胃,自贲门沿胃大弯切开至幽门,平铺于载玻片,均匀铺撒胃溶定位速释生物粘附微粒,置饱和氯化钠溶液容器中,密闭保湿 10min ,取出,用 pH1.3 的盐酸氯化钠溶液 20ml/min 冲洗 5min ,观察微粒脱落面积,并等距离数码拍照,必要时图像分析比较脱落面积。结果显示,仅肉眼观察即胃溶定位速释生物粘附微粒无明显脱落。
实施例 28
离体胃粘膜粘附试验: SD 大鼠 10 只,体重 227.83±19.41g , 禁食 24h (供水),同上取胃, 将胃溶速释生物粘附剂压成平片,用人工胃液润湿 10 min 后,桥连扭力天平并固定,天平指针调零。升降平台放置存有胃粘膜的培养皿(保湿),调节升降平台,使胃粘膜恰与润湿后的胃溶速释生物粘附剂接触粘附, 10 min 后,予胃溶速释生物粘附剂 2mg/s 拉力,直至粘膜与胃溶速释生物粘附剂恰好分开,记录天平读数。结果显示,胃溶速释生物粘附剂对胃粘膜具有良好粘附作用。
实施例 29
离体肠粘膜粘附试验: SD 大鼠 10 只,体重 231.42±15.89g , 禁食 24h (供水),颈椎脱位处死,立即 取十二指肠至空肠上段,平铺, pH6.8 的磷酸盐缓冲液冲洗,置饱和氯化钠溶液容器中,密闭保湿。将肠溶速释生物粘附剂压成平片,用 pH6.8 的磷酸盐缓冲液润湿 10 min 后,桥连扭力天平并固定,天平指针调零。升降平台放置存有小肠粘膜的培养皿(保湿),调节升降平台,使小肠粘膜恰与润湿后的肠溶速释生物粘附剂接触粘附, 10 min 后,予肠溶速释生物粘附剂 2mg/s 拉力,直至粘膜与肠溶速释生物粘附剂恰好分开,记录天平读数。结果显示,肠溶速释生物粘附剂对十二指肠至空肠上段粘膜具有良好粘附作用。
实施例 30
在体灌注粘膜粘附试验(肠溶): SD 大鼠 6 只,体重 253.10±19.24g , 禁食 24h (供水), 乌拉坦麻醉,腹部中线切开,贲门部结扎,钝性分离胃、小肠整个肠段,冲洗内容物,远端结扎,胃近端与小肠远端两端分别接玻璃管,胃近端玻璃管接蠕动泵。取肠溶速释生物粘附微粒 200 粒,混悬于 100 ml 生理盐水中,将肠溶速释生物粘附微粒混悬液灌入,收集流出物并计数流出肠溶速释生物粘附微粒粒数,计算不同部位的包衣微粒滞留率。肠溶速释生物粘附微粒在不同部位的粘附性能不同,在胃、小肠的粘附性能分别为 3.53±0.21% , 87.36±5.59% 。
实施例 31
在体灌注粘膜粘附试验(胃溶): SD 大鼠 6 只,体重 244.31±17.37g , 禁食 24h (供水), 乌拉坦麻醉,腹部中线切开,贲门部结扎,钝性分离胃、小肠整个肠段,冲洗内容物,远端结扎,胃近端与小肠远端两端分别接玻璃管,胃近端玻璃管接蠕动泵。取胃溶速释生物粘附微粒 200 粒,混悬于 100 ml 生理盐水中,将胃溶速释生物粘附微粒混悬液灌入,收集流出物并计数流出胃溶速释生物粘附微粒粒数,计算不同部位的包衣微粒滞留率。胃溶速释生物粘附微粒在不同部位的粘附性能不同,在胃、小肠的粘附性能分别为 90.13±3.74% , 8.45±0.67% 。
实施例 32
离体灌注粘膜粘附试验(肠溶): SD 大鼠 10 只,体重 230.07±15.83g , 颈椎脱位处死, 腹部中线切开,取出十二指肠,用 pH6.8 的磷酸盐缓冲液冲洗内容物,并附于倾斜的固定管中,将微粒混悬液从斜管上口滴入,从下口记录洗脱下来的微粒数,按滞留率的公式计算微粒滞留率,微粒滞留率为 85.15±7.46% 。
实施例 33
对猪小肠粘附性能的测定:巴马猪小肠,磷酸盐缓冲液冲洗,浆膜侧固定于培养皿,培养皿固定于电子天平,磷酸盐缓冲液润湿足量肠溶粘附微粒, 2min ,压力面板 5g 压力下与小肠粘膜接触, 5min ,缓慢匀速调节压力面板,移除压力并分离,记录肠溶粘附微粒粘膜恰好分离时天平读数,将所记录克数转换为以牛顿为单位再除以粘附面面积即得粘附力。结果显示,肠溶粘附微粒对粘膜具有良好粘附作用。
实施例 34
防治酒精中毒:昆明鼠 20 只,体重 23.47±2.11g ,禁食 12 h ,随机分为 2 组:生物粘附剂组,对照组。生物粘附剂组先以 20g/kg 体重的肠溶速释生物粘附剂灌胃,后以 20g/kg 体重的胃溶速释生物粘附剂灌胃,对照组以等容积生理盐水灌胃, 30 min 后,各组以酒精度 56% ( v/v )的二锅头酒灌胃, 10ml/kg 体重,记录翻正反射消失及时间(灌酒后,将其仰卧,若保持 30s 以上 , 则为翻正反射消失 , 即醉酒,反之为未醉)。结果显示,生物粘附剂组有 7 只未醉,而对照组的 10 只均醉酒。
实施例 35
防治胃与肠粘膜炎症或 / 和溃疡:昆明鼠 40 只,体重 25.13±2.79g ,随机分为 4 组( A 对照组, B 对照组,先生物粘附剂组,后生物粘附剂组),禁食 12 h ,先生物粘附剂组先以 20g/kg 体重的肠溶速释生物粘附剂灌胃,后以 20g/kg 体重的胃溶速释生物粘附剂灌胃, A 对照组以等容积生理盐水灌胃;各组以酒精度 56% ( v/v )的二锅头酒灌胃, 15mL/kg 体重; 60min 后,后生物粘附剂组先以 20g/kg 体重的肠溶速释生物粘附剂灌胃,再以 20g/kg 体重的胃溶速释生物粘附剂灌胃, B 对照组以等容积生理盐水灌胃; 5h 后, 颈椎脱位处死 ,腹部中线切开,取出胃和十二指肠,沿胃大弯剪开 , 生理盐水漂洗 , 滤纸吸干 , 肉眼观察粘膜损伤情况,剪取胃粘膜与十二指肠粘膜, 3.7% 多聚甲醛固定,常规石蜡包埋,切片, HE 染色,光镜下观察胃粘膜和十二指肠粘膜组织病理变化。结果显示,肉眼见 先生物粘附剂组的 胃粘膜和十二指肠粘膜覆盖有生物粘附剂薄层且无 明显损伤,后生物粘附剂组的 胃粘膜和十二指肠粘膜覆盖有生物粘附剂薄层且可见轻度 损伤, A 对照组与对 B 照组的 胃粘膜和十二指肠粘膜明显可见损伤,且 B 对 照组甚些;病理切片见对 A 照组与 B 对照组的 胃粘膜和十二指肠粘膜广泛 充血水肿,炎细胞浸润,以中性粒细胞为主,上皮细胞坏死脱落, B 对照组粘膜糜烂溃疡、出血坏死多些,先生物粘附剂组的 胃粘膜和十二指肠粘膜 组织结构完整,腺体排列整齐,层次清楚,后生物粘附剂组的 胃粘膜和十二指肠粘膜下层可见水肿、 炎细胞浸润。
实施例 36
防治肥胖: 21 d 断乳 SD 鼠,雄性, 20 只,体重 54.77±6.13g ,随机分为 2 组(对照组,生物粘附剂组), 2 组均喂养高脂高营养饲料, 3 周,其间,生物粘附剂组先以 20g/kg 体重的肠溶速释生物粘附剂灌胃,再以 20g/kg 体重的胃溶速释生物粘附剂灌胃, bid ,对照组以等容积生理盐水灌胃 。 SPSS12.0 统计分析软件分析 , 组间采用方差分析,组内采用 t 检验,以 p<0.05 为差异有显著性意义 。 喂养高脂高营养饲料 3 周后,对照组肥胖明显( 136.25±15.08g ),生物粘附剂组无明显肥胖( 109.84±12.23g ), 2 组的差异有极显著性意义( P<0.01 )。
实施例 37
防治肥胖: 21 d 断乳 SD 鼠,雄性, 20 只,体重 52.96±5.87g ,随机分为 2 组(对照组,生物粘附剂组),前 3 周, 2 组均喂养高脂高营养饲料,后 3 周, 2 组均改喂普通饲料。在后 3 周起,生物粘附剂组先以 20g/kg 体重的肠溶速释生物粘附剂灌胃,再以 20g/kg 体重的胃溶速释生物粘附剂灌胃, bid ,对照组以等容积生理盐水灌胃 。 SPSS12.0 统计分析软件分析 , 组间采用方差分析,组内采用 t 检验,以 p<0.05 为差异有显著性意义 。 结果显示,对照组体重为 286.13±19.45g ,生物粘附剂组体重为 247.23±25.76g , 2 组的差异有极显著性意义( P<0.01 )。
实施例 38
防治糖尿病: SD 鼠,雄性, 30 只,体重 224.14±9.92g ,饲养 1 周,观察大鼠的体重、血糖等生理指标,使其适应新环境,利于造模。 1 周后,开始造模,禁食 6h 。避光和冰浴条件下,柠檬酸缓冲液配制 STZ , 50mg/kg ip ,注射后在注射部位涂抹少许金霉素软膏。注射后即刻可进水, 4h 后,开始进食。 72h 后,测血糖,血糖值 ≥16.7mM/L 的,确定为造模成功。随机取造模成功 SD 鼠 20 只,随机分为 2 组(对照组,生物粘附剂组),生物粘附剂组先以 20g/kg 体重的肠溶速释生物粘附剂灌胃,再以 20g/kg 体重的胃溶速释生物粘附剂灌胃, bid ,对照组以等容积生理盐水灌胃。 SPSS12.0 统计分析软件分析 , 组间采用方差分析,组内采用 t 检验,以 p<0.05 为差异有显著性意义 。 6 周后,生物粘附剂组血糖值为 9.43±3.75mM/L ,对照组血糖值为 25.71±5.93mM/L , 2 组的差异有极显著性意义( P<0.01 )。
本发明未涉及部分包含相同的现有技术,或可以采用现有技术加以实现。
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  1. 一种定位速释生物粘附剂,其特征在于用生物相容的生物粘附材料制备成微粒,外加速释崩解剂,压片后肠溶包衣,或将微粒肠溶包衣,或填充至肠溶空心胶囊,或生物粘附材料、速释崩解剂等附加剂直接压片后肠溶包衣,服用后粘附覆盖十二指肠及空肠上段粘膜,可以预防或 / 和治疗糖尿病和肥胖病、减弱酒精吸收, 也可预防或 / 和治疗 十二指肠 炎症或 / 和溃疡。
  2. 一种定位速释生物粘附剂,其特征在于用生物相容的生物粘附材料制备成微粒,外加速释崩解剂,压片后胃溶包衣,或将微粒胃溶包衣,或填充至胃溶空心胶囊,或生物粘附材料、速释崩解剂等附加剂直接压片后胃溶包衣,服用后粘附覆盖胃粘膜,可以减弱胃部酒精吸收、预防或 / 和治疗肥胖病, 也可预防或 / 和治疗胃炎或 / 和溃疡。
  3. 根据权利要求 1 所述的定位速释生物粘附剂,其中生物相容的生物粘附材料包括但不限于卡波姆 (CP) 、羟丙基甲基纤维素 (HPMC) 、羟丙基纤维素 (HPC) 、乙二胺改性聚乳酸 (EMPLA) 、聚四氟乙烯、聚乳酸 - 羟基乙酸 (PLGA) 、聚乳酸 - 己内酯 (PCL-b-LA) 、聚 ε- 己内酯 (PCL) 、硅油、硅橡胶、聚酯 - 聚醚共聚物、接枝聚乳酸、明胶、白芨胶、海藻酸盐、纤维素衍生物、壳聚糖、外源凝集素 ( 植物血凝素 ) 、西红柿凝集素、 N-(2- 羟丙基 ) 甲基丙烯胺共聚物等材料。
  4. 根据权利要求 1 所述的定位速释生物粘附剂,其中速释崩解剂包括但不限于聚乙烯吡咯烷酮、羧甲基纤维素钠 CMC-Na 、羧甲基纤维素钙、羧甲基淀粉钠 CMS-Na 、微晶纤维素、低取代羟丙纤维素、硬脂酸镁、海藻酸盐、预凝胶淀粉、葡聚糖等材料及其交联。 根据权利要求 1 所述的定位速释生物粘附剂,其中肠溶包衣材料包括但不限于 Eudragit L 型、 Eudragit S 型、邻苯二甲酸醋酸纤维素 (CAP) 、 1,2,4- 苯三甲酸醋酸纤维素 (CAT) 、琥珀酸醋酸纤维素 (CAS) 、邻苯二甲酸羟丙基甲基纤维素 (HPMCP) 、 l,2,4- 苯三甲酸羟丙基甲基纤维素 (HPMCT) 、琥珀酸醋酸羟丙基甲基纤维素 (HPMCAS) 、 PAVHB 、海藻酸钙、乙醇接枝苯乙烯马来酸酐共聚物、壳聚糖、海藻酸钠、 pH 敏感水凝胶聚甲基丙烯酸 (PMAA) 、瓜胶 / 聚丙烯酸 (GG/PAA) 、丙烯酸和丙烯酰胺共聚接枝半纤维素水凝胶、羧甲基壳聚糖水凝胶 (CMCSG) 、甲基丙烯酸多聚物、乙基纤维素、欧巴代、丙烯酸树脂 II 号 III 号及 Ⅳ 号等材料。 根据权利要求 1 所述的定位速释生物粘附剂,其微粒的制备包括但不限于溶剂挥发法、喷雾干燥法、相分离法、电喷法和声波激发雾化法等方法;其制备步骤可以是 a 用生物相容的生物粘附材料制备成微粒,外加速释崩解剂等附加剂,压片,肠溶包衣; b 用生物相容的生物粘附材料制备成微粒,将该微粒直接肠溶包衣; c 用生物相容的生物粘附材料制备成微粒,将该微粒与附加剂一起填充至肠溶空心胶囊; d 用生物相容的生物粘附材料制备成微粒,将该微粒与速释崩解剂等附加剂一起直接压片,肠溶包衣。
  5. 根据权利要求 1 所述的定位速释生物粘附剂,其微粒的制备包括但不限于溶剂挥发法、喷雾干燥法、相分离法、电喷法和声波激发雾化法等方法;其制备步骤可以是 a 用生物相容的生物粘附材料制备成微粒,外加速释崩解剂等附加剂,压片,肠溶包衣; b 用生物相容的生物粘附材料制备成微粒,将该微粒直接肠溶包衣; c 用生物相容的生物粘附材料制备成微粒,将该微粒与附加剂一起填充至肠溶空心胶囊; d 用生物相容的生物粘附材料制备成微粒,将该微粒与速释崩解剂等附加剂一起直接压片,肠溶包衣。
  6. 根据权利要求 2 所述的定位速释生物粘附剂,其中生物相容的生物粘附材料包括但不限于卡波姆 (CP) 、羟丙基甲基纤维素 (HPMC) 、羟丙基纤维素 (HPC) 、乙二胺改性聚乳酸 (EMPLA) 、聚四氟乙烯、聚乳酸 - 羟基乙酸 (PLGA) 、聚乳酸 - 己内酯 (PCL-b-LA) 、聚 ε- 己内酯 (PCL) 、硅油、硅橡胶、聚酯 - 聚醚共聚物、接枝聚乳酸、明胶、白芨胶、海藻酸盐、纤维素衍生物、壳聚糖、外源凝集素 ( 植物血凝素 ) 、西红柿凝集素、 N-(2- 羟丙基 ) 甲基丙烯胺共聚物等材料。 根据权利要求 2 所述的定位速释生物粘附剂,其中速释崩解剂包括但不限于聚乙烯吡咯烷酮、羧甲基纤维素钠 CMC-Na 、羧甲基纤维素钙、羧甲基淀粉钠 CMS-Na 、微晶纤维素、低取代羟丙纤维素、硬脂酸镁、海藻酸盐、预凝胶淀粉、葡聚糖等材料及其交联。
  7. 根据权利要求 2 所述的定位速释生物粘附剂,其中胃溶包衣材料包括但不限于羟丙基甲基纤维素 (HPMC) 、甲基纤维素 (MC) 、聚乙烯醇 (PVA) 、羟丙基纤维素 (HPC) 、聚乙二醇 (PEG) 、聚乙烯缩乙醛二乙胺醋酸酯 (AEA) 、 Eudragit E 型、胃溶型丙烯酸树脂等材料。
  8. 根据权利要求 2 所述的定位速释生物粘附剂,其微粒的制备包括但不限于溶剂挥发法、喷雾干燥法、相分离法、电喷法和声波激发雾化法等方法;其制备步骤可以是 a 用生物相容的生物粘附材料制备成微粒,外加速释崩解剂等附加剂,压片,胃溶包衣; b 用生物相容的生物粘附材料制备成微粒,将该微粒直接胃溶包衣; c 用生物相容的生物粘附材料制备成微粒,将该微粒与附加剂一起填充至胃溶空心胶囊; d 用生物相容的生物粘附材料制备成微粒,将该微粒与速释崩解剂等附加剂一起直接压片,胃溶包衣。
  9. 根据权利要求 1 所述的定位速释生物粘附剂,其特征在于可以制备成预防或 / 和治疗糖尿病和肥胖病、十二指肠 炎症或 / 和溃疡以及 减弱酒精吸收的医疗器械。
  10. 根据权利要求 2 所述的定位速释生物粘附剂,其特征在于可以制备成预防或 / 和治疗肥胖病、胃 炎或 / 和溃疡以及 减弱酒精吸收的医疗器械。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113209382A (zh) * 2021-04-13 2021-08-06 浙江理工大学 一种三维网状壳聚糖缓释涂层及其制备方法
US11154521B2 (en) 2016-03-15 2021-10-26 Acer Therapeutics Inc. Palatable compositions including sodium phenylbutyrate and uses thereof

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103070844A (zh) * 2013-01-28 2013-05-01 万平 一种定位速释生物粘附剂及其应用
CN107684550B (zh) * 2016-08-03 2020-04-10 徐天宏 糖尿病治疗产品及其制备与应用
CN107684551A (zh) * 2016-08-03 2018-02-13 徐天宏 糖尿病或肥胖疾病治疗产品及其制备与应用
CN108295038B (zh) * 2018-03-12 2020-08-28 江苏凌云药业股份有限公司 一种兽用肠溶组合物及其制备方法
CN108976678B (zh) * 2018-06-11 2021-02-05 河南城建学院 Pbat微纳米纤维增强羧甲基壳聚糖/聚乙烯醇复合水凝胶的制备方法
EP3829666B1 (en) * 2018-08-01 2023-08-30 Boston Scientific Scimed Inc. Drug release coating compositions
CN112515085B (zh) * 2020-11-30 2023-06-30 四川农业大学 一种新型保鲜卡及其制备方法
CN114794309B (zh) * 2022-06-01 2023-07-28 江苏翼邦生物技术有限公司 一种含酸化剂的饲料添加剂及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102281771A (zh) * 2008-11-18 2011-12-14 万有限责任公司 用于体重管理和改善血糖控制的方法和组合物
CN103070844A (zh) * 2013-01-28 2013-05-01 万平 一种定位速释生物粘附剂及其应用

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6531152B1 (en) * 1998-09-30 2003-03-11 Dexcel Pharma Technologies Ltd. Immediate release gastrointestinal drug delivery system
KR20040076203A (ko) * 2003-02-24 2004-08-31 주식회사 엘지생명과학 음식물-약물 상호작용을 방지하기 위한 경구 투여용약제학적 조성물 및 방법
AU2005219443A1 (en) * 2004-03-03 2005-09-15 Spherics, Inc. Polymeric drug delivery system for hydrophobic drugs
CN101084921A (zh) * 2007-06-12 2007-12-12 中南大学湘雅二医院 活性炭肠生物黏附制剂及其制备方法
US20090053309A1 (en) * 2007-08-24 2009-02-26 Axiomedic Ltd., Gibraltar Adhesive compositions for the treatment of xerostomia
CN101543482A (zh) * 2009-05-06 2009-09-30 中南大学湘雅二医院 纳米碳酸钙肠溶生物粘附片及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102281771A (zh) * 2008-11-18 2011-12-14 万有限责任公司 用于体重管理和改善血糖控制的方法和组合物
CN103070844A (zh) * 2013-01-28 2013-05-01 万平 一种定位速释生物粘附剂及其应用

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11154521B2 (en) 2016-03-15 2021-10-26 Acer Therapeutics Inc. Palatable compositions including sodium phenylbutyrate and uses thereof
US11202767B2 (en) 2016-03-15 2021-12-21 Acer Therapeutics Inc. Methods of treating urea cycle disorders and maple syrup urine disease
US11433041B2 (en) 2016-03-15 2022-09-06 Acer Therapeutics Inc. Palatable compositions including sodium phenylbutyrate and uses thereof
CN113209382A (zh) * 2021-04-13 2021-08-06 浙江理工大学 一种三维网状壳聚糖缓释涂层及其制备方法

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CA2898742C (en) 2017-10-03
AU2014210266A1 (en) 2015-08-20
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CN103070844A (zh) 2013-05-01
AU2014210266B2 (en) 2017-01-12
CA2898742A1 (en) 2014-07-31
CN105560203A (zh) 2016-05-11
US20150359750A1 (en) 2015-12-17
GB201513741D0 (en) 2015-09-16
GB2524701A (en) 2015-09-30
CN110302168A (zh) 2019-10-08

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