CN105395488B - A kind of matrine colon targeted pellet and preparation method thereof, purposes - Google Patents
A kind of matrine colon targeted pellet and preparation method thereof, purposes Download PDFInfo
- Publication number
- CN105395488B CN105395488B CN201510837540.XA CN201510837540A CN105395488B CN 105395488 B CN105395488 B CN 105395488B CN 201510837540 A CN201510837540 A CN 201510837540A CN 105395488 B CN105395488 B CN 105395488B
- Authority
- CN
- China
- Prior art keywords
- parts
- matrine
- pellet
- solution
- colon
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of compositions for preparing alkaline drug colon-targeted pellets separation layer, it is grouped as by the group of following weight proportion: 10 parts of EC, 1 part~2.5 parts of DEP.Matrine colon targeted pellet that the present invention also provides a kind of to be prepared using the composition as separation layer and preparation method thereof, purposes.The result shows that said preparation cumulative release amount in simulate the gastric juice, intestinal fluid is 14% or so, 10h cumulative release amount 90% or so after drug release is prepared easy, it can be achieved that colon targeting drug administration in vitro test.Compared with common oral preparation, matrine colon targeted preparation can reduce toxic side effect and adverse reaction；Compared with rectum agent and suppository, patient has more preferable tolerance.The matrine colon targeted pellet of the present invention treat colitis, in terms of have a clear superiority.
Description
Technical field
The present invention relates to a kind of matrine colon targeted pellets and preparation method thereof, purposes, belong to field of medicaments.
Background technique
Oral colon-target positioning release medicine system is after making drug oral by several formulations technology, stomach and small enteral not
Release, a kind of novel controlled release system of release could be positioned by only reaching ileocecus position or colon site.Segmented intestine targeted positioning is released
Medicine through the disease of large intestine drug treatment for that need to have special meaning.After common oral preparation administration, some drugs reach knot
Will be absorbed or degrade before intestines and rectum, and drug can be fed directly to colon by oral colon-specific drug release, drug can with compared with
High concentration is scattered in entire colon.
To realize colon-targeted delivery system, a kind of method being widely used at present is will to carry tablet/capsule core enteric coating material
Material is coated；It since enteric polymer has acid resistance, is only dissolved in intestinal juice, drug is made to discharge to send out in colon site
Wave curative effect.However, often needing to carry out spacer layer coating to core material, reason has: 1. preventing from wrapping before packet site specific DDS for colon coating solution
When enteric layer, drug improves the stability of preparation and improves mechanical performance with the evaporation of moisture and to external migration；2. for easy
It is dissolved in the drug of water, separation layer can prevent moisture from immersing label/ball heart, and avoid drug from evaporating with moisture and migrate into clothing film,
The profile pattern of core material is improved, porosity is reduced, guarantees clothing film continuity；3. for alkaline drug, after enteric coated,
It is had in gastro-intestinal Fluid in liquid infiltration clothing film and forms alkaline environment, accelerated clothing film rupture, wrapped between enteric coating and medicine layer
Upper separation layer can prevent enteric clothing film from internal corrosion.As barrier gown material, at present preferably using relatively wide, effect
HPMC, its main feature is that filming performance is good, clothing film is very stable under heat, light, air and certain humidity；However, the material can be dissolved in
In water, easily make enteric clothing film from internal corrosion under alkaline environment, to cannot achieve colon targeting drug administration.
Matrine (molecular formula C15H24N2O, CAS:519-02-8) it is the medium-height grass such as leguminous plant kuh-seng, root of subprostrate sophora and Sophora alopecuroide
The active constituent of medicine, is white, needle-shaped crystals or crystalline powder, is long placed in have in air and draws moist, and becomes faint yellow,
It is dissolved in water.Matrine has the effects that antitumor, antiviral, anti-inflammatory；Modern pharmacological studies have shown that matrine is to treatment ulcer
Property colitis have good curative effect；Confirmation is studied simultaneously, matrine can inhibit the proliferation and transfer of Partial tumors, to colon cancer
There is inhibiting effect.Therefore, which has wide potential applicability in clinical practice.Currently, clinically widely used kuh-seng alkali preparation
Mainly there are injection, tablet, capsule and suppository, for treating acute, chronic hepatitis, enteritis and auxiliary for treating cancer.In order to adapt to
The characteristics of various disease, meets the needs of clinical treatment, needs to develop new matrine dosage form, to give full play to drug effect, subtract
Few toxic side effect.CN101176724A discloses a kind of matrine sustained-release pellet and preparation method thereof, and the sustained release pellet is in vitro
Energy sustained release can extend the maintenance of drug blood medicine effective concentration in human body, and reduce blood concentration up to 12 hours in test
Peak valley phenomenon, alleviate the toxicity of drug；However, experiment in vitro shows the matrine sustained-release pellet in 0.1mol/L
2h dissolution rate cannot achieve colon drug delivery up to 42.46% in hydrochloric acid solution.CN101700227A provides a kind of matrine colon target
To adhesive pellet, it is allowed to not absorb by stomach and small intestine, and release could be positioned by reaching ileocecus position or colon site, be realized
Colon-targeted delivery system.However, the pellet preparations use wax material as separation layer, coating between enteric coating and drug capsule core
When need to use melt coating method, be carried out under 80 DEG C of high temperature, condition is harsh, energy consumption is excessively high.
Therefore, a kind of matrine pellet with good colon-targeted delivery system characteristic and preparation simplicity is developed, becomes one
A urgent problem to be solved.
Summary of the invention
The purpose of the present invention is to provide a kind of compositions for preparing alkaline drug colon-targeted pellets separation layer.The present invention
Another object be to provide a kind of matrine colon targeted pellet and preparation method thereof, purposes, to solve existing matrine system
The problem that agent cannot achieve colon-targeted delivery system and preparation condition is harsh, energy consumption is excessively high.
The present invention provides a kind of compositions for preparing alkaline drug colon-targeted pellets separation layer, it is by following weight
The group of proportion is grouped as: 10 parts of ethyl cellulose (EC), 1 part~2.5 parts of diethyl phthalate (DEP).
Further, the composition is grouped as by the group of following weight proportion: 10 parts of ethyl cellulose (EC), neighbour
1.5 parts of diethyl phthalate (DEP).
The present invention provides a kind of matrine colon targeted pellets, are made of load pill core, separation layer and enteric coat layer,
Wherein,
The load pill core is prepared by the supplementary material that following weight matches: 5 parts of matrine, hydroxypropyl methylcellulose
(HPMC) 1 part, 20 parts of 1mol/L HCL aqueous solution, 5 parts of water, 6 parts of blank capsule core, matrine content is in load pill core obtained
39.47%~40.76%；
The separation layer is made of the above-mentioned composition for preparing alkaline drug colon-targeted pellets separation layer, and separation layer is to carry
The 5.34%~11.10% of pill core weight；
The enteric coat layer is grouped as by the group that following weight matches: 7 parts of Eudragit S100, ethyl cellulose
(EC) 3 parts, 1 part~2.5 parts of diethyl phthalate (DEP), enteric coating layer weight are to carry pill core and separation layer gross weight
The 31.56%~40.03% of amount.
Eudragit S100 (EudragitS100) is copolymerized for methacrylic acid and methyl methacrylate with 35: 65 ratios
Made of polymer.
Further, the blank capsule core is sucrose or microcrystalline cellulose；The separation layer is to carry pill core weight
11.10%；The enteric coat layer is grouped as by the group that following weight matches: 7 parts of Eudragit S100, ethyl cellulose
(EC) 3 parts, 1.5 parts of diethyl phthalate (DEP), enteric coating layer weight are to carry pill core and separation layer total weight
40.03%.
The present invention also provides the preparation methods of the pellet, it is comprised the following steps:
(1) matrine, hydroxypropyl methylcellulose a, pellet solution loading: are taken in the load pill core each component ratio
(HPMC), 1mol/L HCL aqueous solution, water, blank capsule core；B, matrine is dissolved in 1mol/L HCL aqueous solution, hydroxypropyl is added
Methylcellulose (HPMC), water, are made drug solution；C, the drug solution of b step is splined on blank capsule core through bed spray
On, that is, it is prepared into matrine vegetable pill；
(2) matrine vegetable pill packet barrier gown: ethyl cellulose (EC) a, is taken, adds 95% ethanol water that ethyl cellulose is made
The solution that the mass percent of plain (EC) is 8%；B, 52% ethanol water for preparing 160 parts of volumes, by 1.5 parts by weight
Diethyl phthalate washing is added in the solution of a step, mixes, it is spare that coating solution is made；C, the coating prepared with b step
Liquid through bed spray be wrapped in matrine vegetable pill to get；
(3) pellet is enteric coated: a, taking totally 10 parts of Eudragit S100, ethyl cellulose (EC) in proportion, adds 160 parts
95% ethanol water of volume impregnates；B, be added into a step solution 1.5 parts by weight diethyl phthalate, 90
52.8% ethanol water of part volume, mixes, and Eudragit S100 and ethyl cellulose (EC) gross mass percentage is made
It is spare for 4% coating solution；C, the coating solution prepared with b step is enteric coated through fluidized bed.
Further, the condition of fluidized bed loading is used in the step (1) are as follows: air inlet rate 20-25m3/ h100g,
68 DEG C -72 DEG C of inlet air temperature, 49 DEG C -52.5 DEG C of temperature of charge, atomizing pressure 0.7-1MPa, feed liquor rate 1.5-2ml/min
100g；The condition of fluidized bed coating is used in the step (2) are as follows: air inlet rate 18-22m3/ h100g, inlet air temperature 50
DEG C -55 DEG C, 33 DEG C -34 DEG C of temperature of charge, feed liquor rate 1-2ml/min100g, atomizing pressure 0.7-1MPa；The step
(3) condition of fluidized bed coating is used in are as follows: air inlet rate 18-22m3/ h100g, 50 DEG C -55 DEG C of inlet air temperature, material temperature
33 DEG C -34 DEG C of degree, feed liquor rate 1-2ml/min100g, atomizing pressure 0.7-1MPa.
The present invention also provides use of the pellet in the drug of preparation treatment and/or prevention colitis or colon cancer
On the way.
The present invention provides a kind of composition for preparing alkaline drug colon-targeted pellets separation layer, additionally provide it is a kind of with
Matrine colon targeted pellet that the composition is prepared as separation layer and preparation method thereof, purposes.In vitro test knot
Fruit shows that said preparation cumulative release amount in simulate the gastric juice, intestinal fluid is 14% or so, and 10h cumulative release amount 90% is left after drug release
It is right, it can be achieved that colon targeting drug administration, and prepare easy.Compared with common oral preparation, invention formulation can reduce toxic side effect
And adverse reaction；Compared with rectum agent and suppository, patient has more preferable tolerance.The matrine colon targeted pellet of the present invention is being treated
Colitis, colon cancer etc. have a clear superiority.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
Detailed description of the invention
Fig. 1 is drug-eluting curve comparison figure under the conditions of weight gains different after packet barrier gown；
Fig. 2 is that the dissolution curve of prescription 3-1 pellet and prescription 3-2 pellet in 0.1mol/L HCL aqueous medium compares
Figure；
Fig. 3 is prescription 3-1 pellet and dissolution curve comparison diagram of the prescription 3-2 pellet in pH6.8 phosphate buffer；
Fig. 4 is prescription 3-1 pellet and dissolution curve comparison diagram of the prescription 3-2 pellet in pH7.6 phosphate buffer；
Fig. 5 is dissolution curve comparison diagram of the prescription 3-2 pellet in different dissolution mediums；
Fig. 6 is by pellet dissolution curve comparison diagram made from different enteric coating prescriptions；
Fig. 7 is drug-eluting curve comparison figure under the conditions of enteric coated rear different weight gains；
Fig. 8 is the matrine colon targeted pellet In-vitro release curves figure of the present invention.
Specific embodiment
Raw material, equipment used in the specific embodiment of the invention are known product, are obtained by purchase commercial product.
The preparation of the 1 matrine colon targeted pellet of the present invention of embodiment
1, pellet solution loading
Take matrine 80g, HPMC E5 16g, 1mol/L HCL aqueous solution 320ml, water 80ml；
Matrine is dissolved in 1mol/L HCL aqueous solution, HPMC E5 dissolution dispersion is added, adds water dilution and drug is made
Solution for standby；
Blank sucrose ball heart 100g is taken, is put into Mini fluidized bed, presses in airspeed 20-25m3/ h100g, air inlet temperature
68 DEG C -72 DEG C of degree, 49 DEG C -52.5 DEG C of temperature of charge, atomizing pressure 0.7MPa, feed liquor rate 1.5-2ml/min, jet diameters
0.3mm condition carries out loading, and medicine-feeding 90% matrine vegetable pill of weight gain is made.
2, matrine vegetable pill packet barrier gown
EC20 10g is taken to add 95% ethanol water soaked overnight, it is 8% that EC20 mass percent, which is made, in ultrasonic dissolution
Solution 125ml；52% ethyl alcohol 160ml is prepared again, 1g diethyl phthalate is washed and is added in EC20 solution, and ultrasound mixes
EC20 mass percent 3.51% is made, the coating solution of Solid content mass percent 4% is spare；
Mini fluidized bed is reused, airspeed 18-22m is pressed in3/ h100g, 50 DEG C -55 DEG C of inlet air temperature, temperature of charge
33 DEG C -34 DEG C, feed liquor rate 1-2ml/min100g, atomizing pressure 0.7-1MPa, jet diameters 0.3mm condition is coated；
When coating, a bit of 70% ethyl alcohol is first passed through in pipeline；After starting fluidisation, with the rate feed liquor of 1ml/min；Object
After material temperature degree reaches 31 DEG C, flow velocity is adjusted to 1.5ml/min；After temperature of charge reaches 33 DEG C, flow velocity is adjusted to 2ml/min；Pass through tune
Whole inlet air temperature controls temperature of charge at 33 DEG C -34 DEG C；70% ethyl alcohol flushing pipeline and spray head are passed through after the completion of hydrojet；Coating
Weight gain 5.34%.
3, pellet is enteric coated
Eudragit S100 42g, EC20 18g is taken to add 95% ethyl alcohol 960ml soaked overnight；Pipette phthalic acid two
Above-mentioned ethanol solution is added in ethyl ester 6g；52.8% ethanol water 540ml is added, ultrasound, which mixes, is made EudragitS100:
The coating solution that EC20=7:3, EudragitS100 and EC20 gross mass percentage are 4% is spare；
Mini fluidized bed is reused, rate 18-22m is entered the wind3/ h100g, 50 DEG C -55 DEG C of inlet air temperature, temperature of charge 33
DEG C -34 DEG C, feed liquor rate 1-2ml/min100g, atomizing pressure 0.7-1MPa, jet diameters 0.3mm condition is coated；
When coating, air inlet rate is adjusted to 22m3/ h, atomizing pressure 0.7MPa, 55 DEG C of wind-warm syndrome, material starts to fluidize, and has faint
When electrostatic phenomenon, start to spray into 80% ethyl alcohol with 1ml/min, electrostatic phenomenon disappears；When temperature of charge rises to 30.5 DEG C, it is adjusted to
1.5ml/min；When temperature of charge rises to 33.5 DEG C, it is adjusted to 2ml/min；Adjustment wind-warm syndrome stablizes temperature of charge at 33 DEG C -34
Between DEG C；After coating solution hydrojet is complete, with appropriate 95% ethyl alcohol with 2ml/min flushing pipeline and spray head；Coating weight gain
31.56%.
The preparation of the 2 matrine colon targeted pellet of the present invention of embodiment
1, pellet solution loading
Take matrine 80g, HPMC E5 16g, 1mol/L HCL aqueous solution 320ml, water 80ml；
Matrine is dissolved in 1mol/L HCL aqueous solution, HPMC E5 dissolution dispersion is added, adds water dilution and drug is made
Solution for standby；
Blank sucrose ball heart 100g is taken, is put into Mini fluidized bed, presses in airspeed 20-25m3/ h100g, air inlet temperature
68 DEG C -72 DEG C of degree, 49 DEG C -52.5 DEG C of temperature of charge, atomizing pressure 0.7MPa, feed liquor rate 1.5-2ml/min, jet diameters
0.3mm condition carries out loading, and medicine-feeding 90% matrine vegetable pill of weight gain is made.
2, matrine vegetable pill packet barrier gown
EC20 15g is taken to add 95% ethanol water soaked overnight, it is 8% that EC20 mass percent, which is made, in ultrasonic dissolution
Solution 188ml；52% ethyl alcohol 240ml is prepared again, and 2.25g diethyl phthalate is washed and is added in EC20 solution, ultrasound
EC20 mass percent 3.52% is made in mixing, and the coating solution of Solid content mass percent 4% is spare；
Mini fluidized bed is reused, airspeed 18-22m is pressed in3/ h100g, 50 DEG C -55 DEG C of inlet air temperature, temperature of charge
33 DEG C -34 DEG C, feed liquor rate 1-2ml/min100g, atomizing pressure 0.7-1MPa, jet diameters 0.3mm condition is coated；
When coating, appropriate 70% ethyl alcohol is first passed through in pipeline；After starting fluidisation, with the rate feed liquor of 1ml/min；Material
After temperature reaches 31 DEG C, flow velocity is adjusted to 1.5ml/min；After temperature of charge reaches 33 DEG C, flow velocity is adjusted to 2ml/min；By adjusting
Inlet air temperature controls temperature of charge at 33 DEG C -34 DEG C；70% ethyl alcohol flushing pipeline and spray head are passed through after the completion of hydrojet；Coating increases
Weigh 7.66%.
3, pellet is enteric coated
Eudragit S100 46g, EC20 19.7g is taken to add 95% ethyl alcohol 1051ml soaked overnight；Pipette phthalic acid
Above-mentioned ethanol solution is added in diethylester 9.9g；52.8% ethanol water 591ml is added, ultrasound, which mixes, to be made
The coating solution that EudragitS100:EC20=7:3, EudragitS100 and EC20 gross mass percentage are 4% is spare；
Mini fluidized bed is reused, rate 18-22m is entered the wind3/ h100g, 50 DEG C -55 DEG C of inlet air temperature, temperature of charge 33
DEG C -34 DEG C, feed liquor rate 1-2ml/min100g, atomizing pressure 0.7-1MPa, jet diameters 0.3mm condition is coated；
When coating, air inlet rate is adjusted to 22m3/ h, atomizing pressure 0.7MPa, 55 DEG C of wind-warm syndrome, material starts to fluidize, and has faint
When electrostatic phenomenon, start to spray into 80% ethyl alcohol with 1ml/min, electrostatic phenomenon disappears；When temperature of charge rises to 30.5 DEG C, it is adjusted to
1.5ml/min；When temperature of charge rises to 33.5 DEG C, it is adjusted to 2ml/min；Adjustment wind-warm syndrome stablizes temperature of charge at 33 DEG C -34
Between DEG C；After coating solution hydrojet is complete, with appropriate 95% ethyl alcohol with 2ml/min flushing pipeline and spray head；Coating weight gain
35.73%.
The preparation of the 3 matrine colon targeted pellet of the present invention of embodiment
1, pellet solution loading
Take matrine 80g, HPMC E5 16g, 1mol/L HCL aqueous solution 320ml, water 80ml；
First matrine is dissolved in 1mol/L HCL aqueous solution, HPMC E5 dissolution dispersion is added, adds water dilution and medicine is made
Object solution for standby；
Blank sucrose ball heart 100g is taken, is put into Mini fluidized bed, presses in airspeed 20-25m3/ h100g, air inlet temperature
68 DEG C -72 DEG C of degree, 49 DEG C -52.5 DEG C of temperature of charge, atomizing pressure 0.7MPa, feed liquor rate 1.5-2ml/min, jet diameters
0.3mm condition carries out loading, and medicine-feeding 90% matrine vegetable pill of weight gain is made.
2, matrine vegetable pill packet barrier gown
EC20 20g is taken to add 95% ethyl alcohol soaked overnight, the solution that EC20 mass percent is 8% is made in ultrasonic dissolution
250ml；52% ethyl alcohol 320ml is prepared again, 5g diethyl phthalate is washed and is added in EC20 solution, and ultrasound is mixed and is made
EC20 mass percent is 3.52%, and the coating solution of Solid content mass percent 4% is spare；
Mini fluidized bed is reused, airspeed 18-22m is pressed in3/ h100g, 50 DEG C -55 DEG C of inlet air temperature, temperature of charge
33 DEG C -34 DEG C, feed liquor rate 1-2ml/min100g, atomizing pressure 0.7-1MPa, jet diameters 0.3mm condition is coated；
When coating, appropriate 70% ethyl alcohol is first passed through in pipeline；After starting fluidisation, with the rate feed liquor of 1ml/min；Material
After temperature reaches 31 DEG C, flow velocity is adjusted to 1.5ml/min；After temperature of charge reaches 33 DEG C, flow velocity is adjusted to 2ml/min；By adjusting
Inlet air temperature controls temperature of charge at 33 DEG C -34 DEG C；70% ethyl alcohol flushing pipeline and spray head are passed through after the completion of hydrojet；Coating increases
Weigh 11.10%.
3, pellet is enteric coated
Eudragit S100 52g, EC20 22.3g is taken to add 95% ethyl alcohol 1189ml soaked overnight；Pipette phthalic acid
Ethanol solution is added in diethylester 18.6g；52.8% ethanol water 670ml is added, ultrasound, which mixes, is made EudragitS100:
The coating solution that EC20=7:3, EudragitS100 and EC20 gross mass percentage are 4% is spare；
Mini fluidized bed is reused, rate 18-22m is entered the wind3/ h100g, 50 DEG C -55 DEG C of inlet air temperature, temperature of charge 33
DEG C -34 DEG C, feed liquor rate 1-2ml/min100g, atomizing pressure 0.7-1MPa, jet diameters 0.3mm condition is coated；
When coating, air inlet rate is adjusted to 22m3/ h, atomizing pressure 0.7MPa, 55 DEG C of wind-warm syndrome, material starts to fluidize, and has faint
When electrostatic phenomenon, start to spray into 80% ethyl alcohol with 1ml/min, electrostatic phenomenon disappears；When temperature of charge rises to 30.5 DEG C, it is adjusted to
1.5ml/min；When temperature of charge rises to 33.5 DEG C, it is adjusted to 2ml/min；Adjustment wind-warm syndrome stablizes temperature of charge at 33 DEG C -34
Between DEG C；After coating solution hydrojet is complete, with appropriate 95% ethyl alcohol with 2ml/min flushing pipeline and spray head；Coating weight gain
40.03%.
Beneficial effects of the present invention are proved below by way of comparative experiments and drug quality evaluation result.
[experimental material, reagent and instrument]
Experimental material, reagent
Matrine reference substance (matrine >=98%HPLC, Chengdu Man Site Biotechnology Co., Ltd), matrine raw material
Medicine (matrine >=98%, K140510, come bioengineering Co., Ltd in Xi'an), cane sugar core (F20060074, Hangzhou height at
Nutritional Technologies, INC.), Eudragit S100 (B100405198, German Degussa company), HPMC E5
(0001691515, U.S. Ya Shilan), EC20 (DOW Chemical), concentrated hydrochloric acid, diethyl phthalate, sodium oxide molybdena, sodium phosphate,
Potassium dihydrogen phosphate, acetonitrile are chromatographically pure, and water is ultrapure water, remaining is that analysis is pure.
Laboratory apparatus
Mini fluidized bed (German Glatt company)；Dissolution rate test instrument (Tianjin name of the country medical equipment Co., Ltd, RC-
6 types) assay balance (sartorius, BP211D type)；Ultrasonic cleaner (Tianjin Ao Tesaiensi Instrument Ltd.,
AS5150BD-1 type) electric drying oven with forced convection (Shanghai Yiheng Scientific Instruments Co., Ltd, DHG-9123A type), acidometer (Chengdu
ShiJiFangZhou Science and Technology Ltd., pHS-4C+ are intelligent), excellent spectrum Superpure water machine (Chengdu Ultra Pure Science & Technology Co., Ltd, UPH-1-
20T type), digital display thermostat water bath (Shanghai Chang Si Trade Co., Ltd., HH-2 type)
[detection method]
Matrine vegetable pill quality evaluating method
By observing pellet appearance, if there is viscous ball phenomenon；Vegetable pill medicine assay: accurately weighed matrine vegetable pill is ground
Powder 1g, adds pure water 50ml, ultrasonic extraction 30min that supernatant is taken to be diluted with water 100 times after thin；In C18 column, acetonitrile: PH3.0
Phosphate buffer=5:95, flow velocity 1ml/min, 40 DEG C of column temperature, detected [8] under the conditions of Detection wavelength 205nm.Vegetable pill
Dissolution determination: using " Chinese Pharmacopoeia 2010 editions " second method, take sample 0.1g, at 37.5 DEG C, revolving speed 75r/min, dissolution
Medium is 910ml 0.1mol/L HCL, under the conditions of PH6.8, PH7.6 phosphate buffer, sampling time point 5min,
10min, 15min, 30min, 45min, 60min, sampling amount 1ml cross 0.45um microfiltration membranes in C18 column, acetonitrile: the phosphorus of PH3.0
Acid buffer=5:95, flow velocity 1ml/min, are detected under the conditions of Detection wavelength 205nm by 40 DEG C of column temperature.
Dissolution determination method after pellet packet barrier gown
Using " Chinese Pharmacopoeia 2010 editions " the second method, take sample appropriate, at 37.5 DEG C, revolving speed 75r/min, dissolution medium
Under the conditions of 910ml ultrapure water, sampling time point 5min, 10min, 15min, 30min, 45min, 60min, 120min are taken
Sample amount 1ml crosses 0.45um microfiltration membranes, in C18 column, acetonitrile: phosphate buffer=5:95 of PH3.0, flow velocity 1ml/min, column
It is 40 DEG C warm, it is detected under the conditions of Detection wavelength 205nm.
Dissolution determination method after pellet is enteric coated
Using " Chinese Pharmacopoeia 2010 editions " the second method, take sample appropriate, at 37.5 DEG C, revolving speed 75r/min, dissolution medium
For 1. 910ml 0.1mol/L HCL, PH6.8, PH7.6 phosphate buffer；2. being used after 0.1mol/L HCL750ml, 120min
It is added 250ml sodium radio-phosphate,P-32 solution (0.2mol/L), uses 2mol/L sodium hydroxide solution by PH tune after PH is adjusted to 6.8,360min
To 7.6 to simulate digestive tract environment；3. " Chinese Pharmacopoeia 2010 editions " first method of using, takes sample appropriate, at 37.5 DEG C, revolving speed is
75r/min, in simulation simulated gastric fluid: dissolving out 120min in 0.1mol/L HCL and move back to artificial intestinal fluid (simulated gastric fluid 750ml
Middle addition 0.2mol/L sodium phosphate 250ml, adjusts pH value to 6.8), then dissolve out 180min move back to artificial colonic fluid (referring to " in
State's pharmacopeia two " pH7.8 phosphate in annex XVD buffer, it is arranged to 1000ml).1. 2. sampling time point be 30min,
60min,120min,240min,300min,360min,480min；3. sampling time point be 120min, 180min, 240min,
300min,360min,420min,480min,540min,600min；Sampling amount 1ml crosses 0.45um microfiltration membranes in C18 column, second
Nitrile: phosphate buffer=5:95 of PH3.0, flow velocity 1ml/min, are examined under the conditions of Detection wavelength 205nm by 40 DEG C of column temperature
It surveys.
1 main ingredient solvent comparative experiments of experimental example
Water, 95% ethyl alcohol, 1mol/L HCL aqueous solution are used respectively as matrine solvent, and loading is carried out to blank capsule core,
It the results are shown in Table 1.
The comparative experiments of 1 main ingredient solvent of table
The experimental results showed that matrine can be completely dissolved in 1mol/L HCL aqueous solution of the present invention, and pellet obtained
Fluidized state is good, therefore only 1mol/L HCL aqueous solution of the present invention is suitable main ingredient solvent, other common main ingredient solvents
It cannot obtain the ideal matrine vegetable pill of quality.
2 barrier gown prescription comparative experiments of experimental example
The different barrier gown prescriptions tested are shown in Table 2, and dissolution rate measurement result is shown in Table 3.
The comparative experiments of 2 barrier gown prescription of table
Note: coating solution solvent is selected according to the dissolubility of auxiliary material each in prescription, coating solution concentration is glutinous according to configuration coating solution
Degree is adjusted.
Table 3 uses different barrier gown prescription drug dissolution rate measurement results
As barrier gown filmogen, HPMC is now mostly used；However use water solubility HPMC as film forming according to prescription 2-1
Pellet is made almost without time lag effect in material.It is only bigger using viscosity by prescription 2-2,2-3,2-4,2-5 of the present invention
EC20, EC45, EC100 make plasticizer as film forming agent, the DEP of mass percent 15%, and drug-eluting is obviously postponed, and can play
The effect that drug is isolated with solution.
3 barrier gown of experimental example weight gain comparative experiments
Coating solution is prepared with the prescription 2-2 drafted, its coating weight gain is investigated, drug-eluting rate measurement result is shown in Table
4, drug-eluting curve is shown in Fig. 1 under the conditions of each weight gain.
Drug-eluting rate measurement result (%) under the conditions of different weight gains after 4 packet barrier gown of table
The result shows that pellet has apparent time lag effect when barrier gown gain in weight reaches 5.34%；When barrier gown increases weight
When amount reaches 11.10%, time lag effect is optimal.
4 enteric coating prescription of experimental example and gain in weight comparative experiments
4.1, use acrylic resin III, EudragitS100 as enteric coating material respectively
Specific prescription is shown in Table 5, and dissolution rate measurement result is shown in Table 6, and drug-eluting curve is shown in Fig. 2~5.
Table 5 uses the prescription of acrylic resin III, EudragitS100 respectively
Dissolution rate (%) in the different dissolution mediums of table 6
Table 5,6 and Fig. 2~5 show to use even if in the situation similar in coating weight gain amount by prescription of the present invention
EudragitS100 is compared with using polyacrylic resin III, and under the conditions of simulated gastrointestinal tract, the former dissolution is more slow, i.e.,
Clothing film is more complete.Use EudragitS100 as enteric coating main material as can be seen from Figure 5, pellet pH sensibility is obvious,
Release amount of medicine, which is considerably less than, in simulation stomach, small intestine condition simulates burst size in colon (alkalescent) environment.
4.2, in enteric coating prescription each component different ratio comparative experiments
Specific prescription is shown in Table 7, is 2. dissolved out by the enteric coated rear dissolution determination method of pellet under [detection method] item
Degree measurement, dissolution rate measurement result are shown in Table 8, and drug-eluting curve is shown in Fig. 6.
The comparative experiments of each component different amounts ratio in 7 enteric coating prescription of table
Note: according to coating solution viscosity, coating solution concentration is made the appropriate adjustments.
The dissolution rate measurement result of each component different amounts ratio in 8 enteric coating prescription of table
The result shows that: 1. with the increase of EC20 ratio in prescription, subtract in simulate the gastric juice, the total 6h drug leakage amount of intestinal fluid
It is few；2. can be seen that leakage rate is obvious after EC20 is added in coating material from prescription 3-3 and prescription 3-4 simulate the gastric juice dissolution result
It reduces；3. finding out from prescription 3-5 and prescription 3-6 Comparative result, simulated if continuing increase EC ratio under the conditions of prescription 3-5
Drug leakage rate increases in gastric juice, simulates drug releasing rate in colonic fluid and slows down；Therefore, only of the invention
EudragitS100:EC20:DEP=7:3:1.5 is suitable prescription.
4.3, enteric coating is coated the comparative experiments of different gains in weight
Each prescription is shown in Table 9,2. carries out dissolution rate by the enteric coated rear dissolution determination method of pellet under [detection method] item
Measurement, dissolution rate measurement result are shown in Table 10, and drug-eluting curve is shown in Fig. 7.
9 enteric coating of table is coated the comparative experiments of different gains in weight
Dissolution rate under the conditions of 10 enteric coating difference coating weight gain of table
The result shows that: when coating weight gain 31.56%, drug total 6h drug accumulation leakage rate in simulation stomach, small intestine condition
It reduces；When coating weight gain 40.03%, drug accumulates leakage rate in 20% or so, 80% drug energy in simulation stomach, small intestine condition
Colon site is reached, shows good colon-targeted delivery system performance.
The 5 matrine colon targeted pellet dissolution rate confirmatory experiment in Imitative gastroenteric environments of the present invention of experimental example
Above-mentioned 4.3 the result shows that, gained preparation simulate colonic environment in 2h when accumulation the amount of dissolution it is on the low side, but because accumulate it is molten
The time is less than 10h out, it cannot be said that bright drug drug release in simulation colonic environment is insufficient.This experimental example presses [detection method] item
3. to gained preparation, dissolution rate is measured dissolution determination method in Imitative gastroenteric environments after lower pellet is enteric coated, molten
Extracting rate measurement result is shown in Table 11, and drug-eluting curve is shown in Fig. 8.
The matrine colon targeted pellet of table 11 dissolves out result in simulated gastrointestinal tract
The result shows that the matrine colon targeted pellet of present invention cumulative release amount in simulate the gastric juice, intestinal fluid is 14%
Left and right, 10h cumulative release amount 90% or so is, it can be achieved that colon targeting drug administration after drug release.
The above experimental example shows pellet preparations formula of the present invention rationally, and the pellet dissolved corrosion being prepared is ideal, can subtract
The generation of few toxic side effect and adverse reaction, treat colitis, in terms of have a clear superiority.
Claims (6)
1. a kind of matrine colon targeted pellet, is made of load pill core, separation layer and enteric coat layer, it is characterized in that:
The load pill core is prepared by the supplementary material that following weight matches: 5 parts of matrine, 1 part of hydroxypropyl methylcellulose,
20 parts of Imol/L HCL aqueous solution, 5 parts of water, 6 parts of blank capsule core, in load pill core obtained matrine content be 39.47%~
40.76%；
The separation layer is grouped as by the group that following weight matches: 10 parts of ethyl cellulose, 1 part of diethyl phthalate~
2.5 parts, separation layer is carry pill core weight 5.34%~11.10%；
The enteric coat layer is grouped as by the group that following weight matches: 7 parts of Eudragit Sl00,3 parts of ethyl cellulose, neighbour
1 part~2.5 parts of diethyl phthalate, enteric coating layer weight be carry pill core and separation layer total weight 31.56%~
40.03%.
2. isolation layer composition as described in claim 1, it is characterized in that: being grouped as by the group that following weight matches: ethyl is fine
10 parts, 1.5 parts of diethyl phthalate of dimension element.
3. pellet as described in claim 1, it is characterized in that: the blank capsule core is sucrose or microcrystalline cellulose；The isolation
Layer is the 11.10% of load pill core weight；The enteric coat layer is grouped as by the group that following weight matches: Eudragit
7 parts of Sl00,3 parts of ethyl cellulose, 1.5 parts of diethyl phthalate, enteric coating layer weight are to carry pill core and separation layer
The 40.03% of total weight.
4. a kind of preparation method of claim 1 or 3 pellet, it is characterized in that: comprising the following steps:
(1) matrine, hydroxypropyl methylcellulose, 1mol/L a, pellet solution loading: are taken in the load pill core each component ratio
Matrine, blank capsule core .b, is dissolved in 1mol/L HCL aqueous solution water by HCL aqueous solution, and hydroxypropyl methylcellulose, water is added,
Drug solution is made；C, the drug solution of b step is splined in blank capsule core through bed spray, that is, is prepared into matrine element
Ball；
(2) matrine vegetable pill packet barrier gown: a, taking ethyl cellulose, adds 95% ethanol water that the quality of ethyl cellulose is made
The solution that percentage is 8%；B, 52% ethanol water for preparing 160 parts of volumes, by the phthalic acid two of 1.5 parts by weight
Ethyl ester washing is added in the solution of a step, mixes, it is spare that coating solution is made；C, it is sprayed with coating solution prepared by b step through fluidized bed
Mist be wrapped in matrine vegetable pill to get；
(3) pellet is enteric coated: a, taking Eudragit Sl00, ethyl cellulose total in the enteric coat layer each component ratio
10 parts, the O-phthalic for adding 95% ethanol water of 160 parts of volumes to impregnate .b, 1.5 parts by weight are added into a step solution
52.8% ethanol water of diethyl phthalate, 90 parts of volumes mixes, and Eudragit Sl00 and the total matter of ethyl cellulose is made
It is spare to measure the coating solution that percentage is 4%；C, the coating solution prepared with b step is enteric coated through fluidized bed.
5. preparation method as claimed in claim 4, it is characterized in that: using the condition of fluidized bed loading in the step (1) are as follows:
Enter the wind rate 20-25m3/ h100g, 68 DEG C -72 DEG C of inlet air temperature, 49 DEG C -52.5 DEG C of temperature of charge, atomizing pressure 0.7-
1MPa, feed liquor rate 1.5-2ml/min100g；The condition of fluidized bed coating is used in the step (2) are as follows: air inlet rate
18-22m3/ h100g, 50 DEG C -55 DEG C of inlet air temperature, 33 DEG C -34 DEG C of temperature of charge, feed liquor rate 1-2ml/min100g,
Atomizing pressure 0.7-1MPa；The condition of fluidized bed coating is used in the step (3) are as follows: air inlet rate 18-22m3/ h100g,
50 DEG C -55 DEG C of inlet air temperature, 33 DEG C -34 DEG C of temperature of charge, feed liquor rate 1-2ml/min100g, atomizing pressure 0.7-1MPa.
6. purposes of the pellet described in claim 1 or 3 in the drug of preparation treatment and/or prevention colitis or colon cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510837540.XA CN105395488B (en) | 2015-11-25 | 2015-11-25 | A kind of matrine colon targeted pellet and preparation method thereof, purposes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510837540.XA CN105395488B (en) | 2015-11-25 | 2015-11-25 | A kind of matrine colon targeted pellet and preparation method thereof, purposes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105395488A CN105395488A (en) | 2016-03-16 |
| CN105395488B true CN105395488B (en) | 2019-03-29 |
Family
ID=55461488
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510837540.XA Active CN105395488B (en) | 2015-11-25 | 2015-11-25 | A kind of matrine colon targeted pellet and preparation method thereof, purposes |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105395488B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107811990A (en) * | 2017-11-10 | 2018-03-20 | 杨鹏 | The oral colon targeting preparation and preparation method and purposes of a kind of double-layer coatings |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101455655B (en) * | 2009-01-04 | 2011-08-17 | 北京康比特体育科技股份有限公司 | Creatine sustained-release preparation and preparation process thereof medication |
| CN101700227B (en) * | 2009-09-27 | 2011-08-10 | 宁夏医科大学 | Matrine colon targeted adhesive pellet and preparation method thereof |
| CN103405395B (en) * | 2013-08-23 | 2015-04-22 | 山东省医药工业研究所 | Sodium picosulfate enteric-coated tablet and preparation method thereof |
-
2015
- 2015-11-25 CN CN201510837540.XA patent/CN105395488B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN105395488A (en) | 2016-03-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101596166B (en) | Aspirin enteric-coated pellet | |
| CN103550158B (en) | Emodin solid dispersion, drug-containing pellet core, colonic targeted micropill, and applications of three | |
| CN101780055A (en) | Controlled-release colon targeting drug administration preparation and preparation method thereof | |
| CN101108171A (en) | Budesonide intestines sustained release dextromethorphan pellets and method of manufacturing the same | |
| CN101700227A (en) | Matrine colon targeted adhesive pellet and preparation method thereof | |
| CN109044977A (en) | A kind of pleasure is cut down for Buddhist nun's solid dispersions and preparation method thereof and preparation | |
| Ji et al. | Guar gum as potential film coating material for colon-specific delivery of fluorouracil | |
| CN105395488B (en) | A kind of matrine colon targeted pellet and preparation method thereof, purposes | |
| CN101301455A (en) | Chinese medicine compound turmeric rhizome solid dispersion for treating hyperlipemia | |
| CN107982241B (en) | Potassium sodium dehydroandroan drographolide succinate enteric preparation and preparation method thereof | |
| CN109589311A (en) | Pharmaceutical composition, preparation and the preparation method and medical usage of a kind of curcumin phosplate and its salt | |
| Naikwade et al. | Development of time and pH dependent controlled release colon specific delivery of tinidazole | |
| CN105496967B (en) | Ranitidine hydrochloride controlled release dry suspensoid agent and preparation method thereof | |
| CN101164537B (en) | High-efficient oral silibinin sustained-release preparation and preparation method thereof | |
| CN107982240B (en) | Potassium sodium dehydroandroan drographolide succinate enteric coated granules capable of being accurately dissolved out and preparation method thereof | |
| CN102552163B (en) | Metoprolol tartrate sustained release pellet and preparation method thereof | |
| CN110882258A (en) | Use of qi-tonifying pulse-restoring (freeze-dried) or ruscogenin for injection in preventing bleeding of drug-induced organ | |
| CN109875971A (en) | A kind of Berberine hydrochloride sustained release tablets and preparation method thereof | |
| CN103948558B (en) | A kind of posaconazole double-layer osmotic pump controlled-release tablet and preparation method thereof | |
| CN103520226B (en) | A kind of pH dependent form conlon targeting hard capsule | |
| CN108685870A (en) | Jamaicin and its can forming salt enteric-coated micro-pill, its prepare and application | |
| CN105617391B (en) | A kind of scutelloside colon specific drug preparation and preparation method thereof | |
| CN101167765B (en) | Colon targeting drug delivery soft capsule and preparation method thereof | |
| CN102727445A (en) | Sophocarpidine pH/ magnetic dual-sensitive hydrogel globule and preparation method thereof | |
| CN106491556A (en) | A kind of stable montelukast sodium enteric-coated pellet |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |