CN107823178A - Treat Niflumic Acid colon targeting preparation of IBS and preparation method thereof - Google Patents
Treat Niflumic Acid colon targeting preparation of IBS and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
Abstract
The present invention discloses a kind of Niflumic Acid colon targeting preparation for treating IBS and preparation method thereof, the colon targeting preparation of the Niflumic Acid uses two-step method, first Niflumic Acid is contained nano-micelle is formed in high polymer material, further the nano-micelle is wrapped in micropill and obtained.Rear medicine concentrates on colon site release to said preparation by oral administration, improves the adherence rate of medicine and colon lesions position, and then significantly improve the drug concentration of colon site.Reduce side effect of the medicine to intestines and stomach simultaneously, give full play to the therapeutic action of medicine.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, is related to a kind of Niflumic Acid colon targeting preparation and preparation method thereof.More properly
Say, can discharge Niflumic Acid and in the micropill of colitis position delay long period targeted to colon site the present invention relates to a kind of
And preparation method thereof.
Background technology
IBS (IBS) be it is a kind of it is common, spy is changed into bowl evacuation habit with chronic abdominal pain or abdominal discomfort
The functional bowel disease of sign, major function abnormal position is in colon.It is IBS patient's abdomen to generally believe Chronic Visceral Hypersensitivity
Pain and Instestinal motility exception main cause, it may relate to periphery colon and afferent nerve sensitization and spinal cord and above central sensitization two
Kind mechanism（Aguas M., et al., 2011；Tang Hongmei etc., 2009）.15% is up in the illness rate of American-European countries, the whole world is suffered from
Sick rate is in rising trend.IBS clinical treatments are based on medicine at present, but most medicines are only relief of symptoms, it is impossible to thoroughly cure,
Therefore new effective medicine is urgently researched and developed.
Chronic ache is a kind of complicated Physiological Psychology activity, is jointly processed by by brain different parts, generation includes feeling
Distinguish, the function of three aspects of emotion motivation and cognitive appraisal.Chronic persistent pain can influence the function of hippocampus, so as to produce Jiao
Consider a variety of brain disorder diseases such as disease, depression.Research shows that pain is not only to feel, or memory, and hippocampus is memory
Key position.One of the research model of long term potentiation as learning and memory synaptic plasticity, also it is considered as to remember with pain
Recall the Basic of Biology of closely related Synaptic plasticity.It has been reported that nmda receptor blocking agent AP-7 etc. is to IBS internal organ
Pain sensation sensitization has an inhibitory action, but this kind of non-hypospecificity receptor blocking pharmacon is when playing analgesic activity, more with motion
The more serious whole body toxic side effect such as obstacle.Therefore, the hypotype of periphery or central sensitization can directly be suppressed by paying high attention to both at home and abroad
The therapeutic value of specific receptor blocking agent, it is important R＆D direction therefrom to find safely and effectively medicine.
Niflumic Acid（Niflumic acid）It is a kind of non_steroidal anti_inflammatory drug, is clinically used for rheumatic pain etc.
The treatment of somatalgia.Recently research is found, Niflumic Acid is the hyperpolarization activated cyclic nucleotide gate hypotype of cationic channel 2（HCN2）
Specific inhibition agent, can selectively acting in the outskirt of HCN2 S4 voltage sensitive regions, so as to change the gate of pacemaking channels
Effect（Cheng L, et al., 2009）；It has been reported that HCN2 passages in body inflammatory pain with being sent out in neurogenic pain
Wave important function（Papp I., et al., 2012；Emery EC, et al., 2012）, but Niflumic Acid is to IBS internal organ
Whether pain has therapeutic action to remain to be confirmed.Early-stage Study finds that HCN2 albumen is in the related supercentral table of the IBS viscera in rats pain sensation
Up to significantly increasing (Liu Cuiying, 2009)；And Niflumic Acid, its splanchnodynia of energy dose-dependent inhibition is injected intraperitoneally in IBS children mouse
Feel sensitization behavior, improve its nociceptive signals (Lu great Li, 2010)；Further research finds that Niflumic Acid can also significantly inhibit IBS again
Rat hippocampus long-term potentiation (blessing is deposited, 2012).It is slow that these results of study unanimously show that HCN2 may participate in IBS
Property Visceral Hypersensitivity formation, prompt Niflumic Acid may have treatment IBS splanchnodynias new role.
Oral colon specific targeting drug-delivery system is after making medicine by oral administration by different doses of technologies, in Stomach duodenum, sky
Intestines, ileum front end do not discharge, and are discharged after medicine is transported into ileocecus and play a kind of new of locally or systemically therapeutic action
Site-specific delivery of drugs system.The system can make medicine from the effect of gastro-intestinal Fluid, and by drug delivery to colon site and delay exactly
On The Drug Release, not only medicine can be made directly to be discharged in diseased region, increase local drug concentration, improve constipation, intestines easily swash synthesis
The therapeutic effect of the local large intestine diseases such as sign, ulcerative colitis, hemorrhagic colitis, Crohn`s diseases, colon cancer, but also
Its long-acting can be played by medicine in the slow release of colon.
It is well known that Niflumic Acid has more serious intestines and stomach toxic side effect as other NSAIDs.Than intestines
For soluble drug mainly in intestinal absorption, colon targeting drug administration is then there is the carrier of guide effect to be crosslinked a medicine and certain,
The medicine is oriented in colon release, so as to the concentration of the medicine in constantly improve colon, give full play to its drug action
(Vadlamudi H.C.,et al.,2012).Therefore, colon targeting preparation is made in Niflumic Acid, can not only avoids medicine in stomach
Enteron aisle is decomposed destruction, increases its bioavilability；And medicine can be mitigated in itself to the toxic side effect of intestines and stomach, improve simultaneously
Colon local drug concentration, suppresses the periphery sensitization of colon site, and then plays its therapeutic action.
In recent years, it by reducing particle diameter is the effective means that improves segmented intestine targeted property to have document report, is primarily due to inflammation
EEPR (epithelial enhanced permeability and retention) effect be present in intestinal epithelial cell
（Schmidt C, et al., 2013；Collnot E M, et al., 2012）, nanometer particle can be preferentially by areas of inflammation
A large amount of immunocytes absorbed；Secondly, the reduction of particle diameter is also avoided that medicine is often suffered from diarrhoea due to colitis patient
And cause to be quickly discharged in vitro（Beloqui A, et al., 2013）.In addition, nanometer particle can also pass through porous
Suction-operated through epithelium fluff tip gap or aperture and be transported through（Pichai M V, et al., 2012）.Cause
This, this seminar uses two-step method, first contains Niflumic Acid and nano-micelle is formed in high polymer material, further using sharp
Nano-micelle is wrapped in micropill by hole-freezing method, is subtracted again simultaneously in the targeting of colon site so as to reach raising Niflumic Acid
Few destruction of the gastrointestinal tract environment to Niflumic Acid nano-micelle.
The patent No. is that 200119464.X patent document discloses a kind of metronidazole colon-specific enteric-coated tablets preparation, the system
Agent is coated on the tablet of nitroimidazoles medicine；The patent No. is that 200710029476.8 patent document discloses a kind of heart
Colon targeting drug administration preparation of myogen polypeptide and preparation method thereof, said preparation are to containing cardiac muscle using segmented intestine targeted coating solution
Pastille micropill made of the spice of polypeptide composition is coated or is directly loadable into be made in segmented intestine targeted capsule shells；Patent
Number it is that 200710029478.7 patent document discloses a kind of colon targeting preparation of orgotein polypeptide and preparation method thereof, should
Preparation is pastille micropill made of the spice containing orgotein polypeptide moiety to be coated using segmented intestine targeted coating solution or straight
It is hinged with segmented intestine targeted capsule shells and is made.The content of document above report exists basic with the purpose of the present invention with method
It is different.
There is not yet the colon targeting preparation containing Niflumic Acid, also has no the research of this pharmaceutical preparation on domestic market
Report, therefore develop this kind of medicine and do not only have important clinical meaning, it may have wide market prospects.
The content of the invention
It is an object of the invention to provide a kind of Niflumic Acid colon targeting preparation for treating IBS and its preparation side
Method.The Niflumic Acid colon targeting preparation of the present invention can discharge medicine in colon, give full play to drug therapy effect.
Need to be solved the problems, such as according to above-mentioned, devise a kind of colon targeting preparation containing Niflumic Acid, it is first by Niflumic Acid
Contain and nano-micelle formed in high polymer material, further nano-micelle is wrapped in micropill using orifice-freezing method,
Its feature is：
The inventory of Niflumic Acid and high polymer material is 1 by weight：20~1：1, high polymer material, which is dissolved in organic solvent, matches somebody with somebody
The quality concentration of volume percent of manufactured Polymer Solution is 2% ~ 20%；
Wherein described high polymer material is pluronic F127, Poly(D,L-lactide-co-glycolide（PLGA）, polyethylene glycol
The one or two or more kinds of 1000 VE-succinates mix.
Described nano-micelle needs the freeze-dried rear form for forming freeze-dried powder to preserve.
Described micropill is mixed by low-ester pectin, sodium alginate, chitosan, the one or two or more kinds of of ethyl cellulose
Form.
A diameter of 0.5 ~ 1.5mm of manufactured pastille micropill, wherein it is preferred that a diameter of 0.8 ~ 1.2mm.
A kind of preparation method of the colon targeting preparation containing Niflumic Acid is devised according to the above-mentioned Second Problem that need to be solved, its
Step is：
1）The carrier material of the Niflumic Acid of formula ratio and formula ratio is placed in container, then adds methanol thereto, makes Niflumic Acid
It is dissolved in carrier material in methanol, makes the mixture of Niflumic Acid and carrier material in container the step of by removing methanol
Film is formed on wall, then PBS is added into the container（pH=7.4）, the film formed on container inner wall is carried out
Hydration process, ultrasonic wave (240 W, 40 kHz) vibrates aquation to Film Fractionation at 37 DEG C, successively respectively with 0.2 μm of aperture,
0.1 μm of makrolon membrane filtration, is respectively repeated 3 times, frozen dried, that is, obtains the Niflumic Acid nano-micelle.
2）Take the micropill high polymer material of formula ratio to be dissolved in the water, be configured to certain density solution, by formula ratio
Nano-micelle containing Niflumic Acid is uniformly suspended in Polymer Solution and forms suspension, and the suspension is instilled into calcium chloride with droplet-like
In the aqueous solution, solidify, filter, drying, obtain load pill core;
3）Load pill core is taken, is immersed in aq. polyethyleneimine, is soaked, filtering, dries to obtain Niflumic Acid colon targeting preparation.
The inventory of above-mentioned nano-micelle containing Niflumic Acid and micropill high polymer material is 1 by weight：20~1：1；Macromolecule
Material is dissolved in the quality concentration of volume percent of the Polymer Solution that water is configured to as the % of 5 % ~ 15.
The inventory of Niflumic Acid nano-micelle and high polymer material is by weight preferably 1：10；The quality of Polymer Solution
Concentration of volume percent is preferably 8 %.
The above-mentioned Niflumic Acid colon targeting preparation of the present invention is preparing treatment IBS, ulcerative colitis, gone out
Application in the medicines of local large intestine disease such as courageous and upright colitis, Crohn`s diseases, colon cancer.
One of above-mentioned preparation method feature of the present invention：It is first to prepare the organic solvent used in nano-micelle technical process
Alcohol, Niflumic Acid and high polymer material can be dissolved simultaneously, it is ensured that nano-micelle drug content it is uniform accurate.
The two of the above-mentioned preparation method feature of the present invention：Niflumic Acid colon targeting preparation is prepared using two-step method, first by Buddhist nun's fluorine
Nano-micelle is made in acid, and this not only contributes to solve insoluble problem in Niflumic Acid water, also helps promotion and absorbs, improves body
Interior bioavilability.In addition, nano-micelle can ensure that Niflumic Acid exists in colon site with nanoscale size, be advantageous to improve knot
Intestines targeting, attach to colitis tissue with making drug specificity, extend holdup time of the medicine in focal zone.
In view of Niflumic Acid nano-micelle in the presence of the large quantity of moisture and enzyme material of intestines and stomach, it may occur however that nanometer
The wild effects such as the structure of micella is destroyed or surface charge changes.Based on this, nano-micelle is wrapped in micropill by second step,
The protective effect in stomach and small intestine is played, biodegradation, which then occurs, in colon site discharges nano-micelle and then gulped down by cell
Bite, play therapeutic action.Through comparative studies, designer surprisingly has found, preparation, which is made, using two-step method has obvious colon
Targeting drug release performance and bioadhesive.
Beneficial effects of the present invention：
1）The preparation of the present invention is colon site release medicine, and target area drug concentration can be made to be higher than its hetero-organization, also can per rectum
Into blood circulation, effectively avoid side effect of the medicine to intestines and stomach while also avoid the destruction of hydrochloric acid in gastric juice or enzyme to nano-micelle,
Give full play to the therapeutic action of medicine.
2）Invention formulation is to IBS, ulcerative colitis, hemorrhagic colitis, Crohn`s diseases, colon cancer
Therapeutic effect etc. local large intestine disease is obvious.
Brief description of the drawings
Figure 1A is the particle diameter and fractions distribution figure for describing Niflumic Acid nano-micelle.
Figure 1B is the transmission electron microscopy figure for the particle diameter and form for describing Niflumic Acid nano-micelle.
Fig. 2 is the electron microscope scanning figure for describing Niflumic Acid colon-targeted pellets outward appearance, and A is pastille micropill in figure（×
150）；B is micropill surface in figure（×1000）.
Fig. 3 is the figure for describing swelling-corrosion rate of the Niflumic Acid colon targeting preparation in artificial gastro-intestinal Fluid.
Fig. 4 is the figure for describing drug-eluting curve of the Niflumic Acid colon targeting preparation in different artificial digestive juices, A in figure
It is the release profiles of Niflumic Acid colon-targeted pellets；B is the release profiles of Niflumic Acid nano-micelle in figure.
Fig. 5 is the figure for the external adhesion for describing Niflumic Acid nano-micelle.
Embodiment
With reference to specific embodiment, the present invention is furture elucidated.It should be understood that these embodiments are merely to illustrate this hair
Bright rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to routine
Condition, or according to the condition proposed by manufacturer.
Embodiment 1
Carried by medicine than for 1 ︰ 10 (w/w), precision weighs Niflumic Acid and D- alpha-tocopherol cetomacrogol 1000 succinates respectively
（TPGS 1000）It is placed in eggplant-shape bottle, adds proper amount of methanol and dissolved through supersonic oscillations, rotary evaporation removes first at 40 DEG C
Alcohol, treat that eggplant-shape bottle bottom and inwall form one layer of uniform film, add PBS（pH=7.4）50 mL, ultrasound at 37 DEG C
Ripple (240 W, 40 kHz) vibrates aquation to Film Fractionation, successively respectively with 0.2 μm of aperture, 0.1 μm of polycarbonate membrane mistake
Filter, is respectively repeated 3 times, and it is standby to freeze acquisition nano-micelle freeze-dried powder.
It is 1 by the mass ratio of nano-micelle freeze-dried powder and low-ester pectin:10 are fed intake.Low-ester pectin is sprinkled into by several times pure
To change in water, the solution of quality concentration of volume percent 8% is made in dissolving, adds nano-micelle freeze-dried powder, and stirring suspension is uniform, with
This mixed liquor is instilled to the CaCl for the quality concentration of volume percent 10% being slowly stirred with No. 6 injection needles2In solution,
Solidify 30min, filtering, dried in 60 DEG C, then micropill is immersed in the polyethyleneimine of quality concentration of volume percent 1.0%
（PEI）In solution, 6h, filtering are crosslinked, purifying water washing produces colon targeting preparation after 60 DEG C of drying.
Embodiment 2
Carried by medicine than for 1 ︰ 15 (w/w), precision weighs Niflumic Acid and D- alpha-tocopherol cetomacrogol 1000 succinates respectively
（TPGS 1000）It is placed in eggplant-shape bottle, adds proper amount of methanol and dissolved through supersonic oscillations, rotary evaporation removes first at 40 DEG C
Alcohol, treat that eggplant-shape bottle bottom and inwall form one layer of uniform film, add PBS（pH=7.4）50 mL, ultrasound at 37 DEG C
Ripple (240 W, 40 kHz) vibrates aquation to Film Fractionation, successively respectively with 0.2 μm of aperture, 0.1 μm of polycarbonate membrane mistake
Filter, is respectively repeated 3 times, and it is standby to freeze acquisition nano-micelle freeze-dried powder.
It is 1 by the mass ratio of nano-micelle freeze-dried powder and low-ester pectin:8 are fed intake.Low-ester pectin is sprinkled into by several times pure
To change in water, the solution of quality concentration of volume percent 6% is made in dissolving, adds nano-micelle freeze-dried powder, and stirring suspension is uniform, with
This mixed liquor is instilled to the CaCl for the quality concentration of volume percent 8% being slowly stirred with No. 6 injection needles2In solution,
Solidify 30min, filtering, dried in 60 DEG C, then micropill is immersed in the polyethyleneimine of quality concentration of volume percent 1.0%
（PEI）In solution, 6h, filtering are crosslinked, purifying water washing produces colon targeting preparation after 60 DEG C of drying.
Embodiment 3
Carry than precision weighs Niflumic Acid respectively and pluronic F127 is placed in eggplant-shape bottle for 1 ︰ 10 (w/w), add appropriate by medicine
Methanol dissolves through supersonic oscillations, rotates methanol removed by evaporation at 40 DEG C, treats that eggplant-shape bottle bottom and inwall form one layer uniformly
Film, add PBS（pH=7.4）50 mL, ultrasonic wave (240 W, 40 kHz) vibration aquation is molten to film at 37 DEG C
Solution, respectively it is repeated 3 times with 0.2 μm of aperture, 0.1 μm of makrolon membrane filtration respectively successively, the lyophilized nano-micelle that obtains freezes
Powder is standby.
It is 1 by the mass ratio of nano-micelle freeze-dried powder and sodium alginate:8 are fed intake.Sodium alginate is sprinkled into by several times pure
To change in water, the solution of quality concentration of volume percent 8% is made in dissolving, adds nano-micelle freeze-dried powder, and stirring suspension is uniform, with
This mixed liquor is instilled to the CaCl for the quality concentration of volume percent 10% being slowly stirred with No. 6 injection needles2In solution,
Solidify 30min, filtering, dried in 60 DEG C, then micropill is immersed in the polyethyleneimine of quality concentration of volume percent 1.0%
（PEI）In solution, 6h, filtering are crosslinked, purifying water washing produces colon targeting preparation after 60 DEG C of drying.
Embodiment 4
Precision weighs Niflumic Acid 1g, pluronic F127 1g, D- alpha-tocopherol cetomacrogol 1000 succinate 9g, is placed in eggplant
In shape bottle, add 50mL methanol dissolved through supersonic oscillations, rotate methanol removed by evaporation at 40 DEG C, treat eggplant-shape bottle bottom and
Inwall forms one layer of uniform film, adds PBS（pH=7.4）50 mL, ultrasonic wave (240 W, 40 kHz) at 37 DEG C
Aquation is vibrated to Film Fractionation, is respectively repeated 3 times, freezed with 0.2 μm of aperture, 0.1 μm of makrolon membrane filtration respectively successively
It is standby.
It is 1 by the mass ratio of nano-micelle freeze-dried powder and low-ester pectin:8 are fed intake.Sodium alginate is sprinkled into by several times pure
To change in water, the solution of quality concentration of volume percent 8% is made in dissolving, adds nano-micelle freeze-dried powder, and stirring suspension is uniform, with
This mixed liquor is instilled to the CaCl for the quality concentration of volume percent 10% being slowly stirred with No. 6 injection needles2In solution,
Solidify 30min, filtering, dried in 60 DEG C, then micropill is immersed in the polyethyleneimine of quality concentration of volume percent 1.0%
（PEI）In solution, 6h, filtering are crosslinked, purifying water washing produces colon targeting preparation after 60 DEG C of drying.
Embodiment 5
Pastille micropill is made with the method that pastille micropill is prepared in above-described embodiment, then the pastille micropill is filling in capsule shells
In, filling specification is every milligram of 10-50 containing Niflumic Acid, produces the capsule of colon targeting preparation.
Embodiment 6
Niflumic Acid nano-micelle will be obtained in embodiment 1 to take in right amount, is diluted 10 times with purified water, is mixed, through 0.22 μm of micropore
Membrane filtration.Use the particle diameter and Zeta potential of laser particle analyzer measure micella.Each sample determines 20 circulation times, measure
Temperature is set as 25 DEG C.Test result indicates that the average grain diameter of Niflumic Acid nano-micelle is (25.8 ± 0.6) nm, Zeta potential
For（-18.73±0.23）MV, polydispersity coefficient 0.25, show that decentralization is good.As shown in Figure 1A, the grain of the nano-micelle
Footpath is smaller and narrow distribution.
Appropriate Niflumic Acid nano-micelle is taken, is diluted with purified water, after 0.22 μm of filtering with microporous membrane, carbon will be covered with
The copper mesh drift of film is placed on nano micellar solution, takes out copper mesh after 1~2 min, surplus liquid is blotted from copper mesh edge with filter paper.
The copper mesh drift that capture has nano-micelle particle is placed on about 1 min on 1 % uranium acetate dye liquors, takes out, is equally inhaled with filter paper
Dry surplus liquid.After left at room temperature over night, the copper mesh dried is put into transmission electron microscope instrument, observes and receives under the kV of accelerating potential 160
Rice glue beam formalness.As shown in Figure 1B, nano-micelle is spherical outward appearance rounding, uniform particle diameter, about in 20~30 nm
Between, particle size is consistent with the result that laser particle analyzer measures.
Embodiment 7
100 are randomly selected by micropill is obtained in embodiment 1, puts on slide, is put with Motic digit microscopes in batches
Big shooting, particle size determination (scale is calibrated) is carried out by the image analysis softwares of Motic image plus 2.0 one by one, is used
The softwares of Excel 2003 calculate average value.After logarithm normal distribution is fitted, D90, D50, D10 are asked.Calculate span SD=(D90-
D10)/ D50.It is computed, the average grain diameter of micropill is 1.33 ± 0.14 mm, span 0.26.
By after dry micropill metal spraying powder with conductive gluing on sample stage, with SEM observe micropill body
Looks feature.As a result as shown in Fig. 2 micropill more rounding, surface texture is coarse, PEI hydrophobic layers are formed.
Embodiment 8
Weigh in right amount, be suspended in equipped with simulated gastric fluid by sample is obtained in embodiment 1（PH=1.2, it is preheated to 37 DEG C ± 0.2 DEG C）
Test tube in, by test tube be placed in water bath with thermostatic control vibration case（37℃±0.2℃）Middle vibration（100 r·min-1）2h；It will be situated between afterwards
Matter replaces with artificial intestinal fluid successively（Press《Chinese Pharmacopoeia》2015 editions preparations, pH=6.8）, artificial colonic fluid containing 2% pectase
（Press《Chinese Pharmacopoeia》2015 editions preparations, hydrochloric acid adjust pH=6）, 3h is vibrated respectively.Micropill is taken out from test tube every 1h, uses filter paper
Suck the moisture content of micropill excess surface and weigh, calculate the corrosion rate of micropill.As a result as shown in figure 3, micropill is in simulated gastric fluid
Water swelling process is slow, and swelling reaches at utmost during 3h in simulated intestinal fluid, but micropill outward appearance keeps complete, does not occur bright
Aobvious corrosion phenomenon；And in the artificial colonic fluid containing pectase, corrosion rate is gradually reduced, and corrosion phenomenon occurs in micropill, is prompted
Niflumic Acid nano-micelle starts to discharge from micropill.
Embodiment 9
Weigh in right amount, be suspended in equipped with simulated gastric fluid by sample is obtained in embodiment 1（PH=1.2, it is preheated to 37 DEG C ± 0.2 DEG C）
Test tube in, by test tube be placed in water bath with thermostatic control vibration case（37℃±0.2℃）Middle vibration（100rpm）2h；By medium successively afterwards
Replace with artificial intestinal fluid（pH=6.8）, the pectase of concentration of volume percent containing quality 2% artificial colonic fluid（pH=6）, respectively
Vibrate 3h.Period timing sampling, carry out dissolution in vitro experiment.As a result A in Fig. 4 is seen.As illustrated, Niflumic Acid is segmented intestine targeted
Micropill delays Slow release in simulated gastric fluid 2h and simulated intestinal fluid 3h, and cumulative release amount is less than 30%；And containing pectase
In colonic fluid, discharge and accelerate after micropill swelling, release is complete after 2h, illustrates that micropill has segmented intestine targeted effect.
The Niflumic Acid nano-micelle of known content and 2 mL PBS solutions in Example 1（pH=7.4）Load after mixing pre-
In the bag filter first handled well, and bag filter is placed in the artificial colonic fluids of 100 mL（Without pectase, press《Chinese Pharmacopoeia》
2015 editions preparations, pH=7.4）In, in（37.0±0.2）DEG C water bath with thermostatic control vibration（100 r·min-1）, difference timing sampling 1
ML, and supplement equality of temperature equivalent dissolution medium.Remaining is handled as stated above, is drawn drug release profiles, is as a result seen B in Fig. 4.As schemed
Show, Niflumic Acid nano-micelle is accelerated in preceding 2h only cumulative release medicines 15% or so, then release, and 8h is discharged up to 90% or so, 12h
Release is complete.
By barium sulfate alternatives to medication, colon targeting preparation is made, has carried out tracking test in five human bodies, has been examined through X-ray
Look into, film making record result shows：After taking said preparation, wherein the disintegration position for three barium sulfate tracer capsules that three people are taken is
Terminal ileum position, two people take three and are all disintegrated in ileocecus, do not appear in the situation of transverse colon disintegration.
Embodiment 10
Niflumic Acid nano-micelle 10mg is placed in containing 0.1 mg mL in Example 1-1Eosinophile cationic protein and turn
In the PBS solution of ferritin, vibrated in 37 DEG C of water-baths（100 r·min-1）, sampled respectively at 30,60,90,180min, warp
10000 r·min-130min is centrifuged, takes supernatant appropriate, after methyl alcohol process, with HPLC sample detections, calculates adherence rate.Knot
Fruit as shown in figure 5, Niflumic Acid nano-micelle adherence rate with the time in being gradually increasing trend, peak reaches 94.5%, illustrates the glue
Beam has good adhesion with cationic protein.
Embodiment 11
From newborn SD rat, after birth in 8~14 days, the daily set time gives a 60 mmHg Colon and rectums expansion thorn
Swash, establish chronic visceral pain model, control rats are in addition to not all right Colon and rectum is expanded, the same rat model of other situations.By following
Carry out experiment packet：Control group, control blank group, control Niflumic Acid group, model group, model blank control group, model Niflumic Acid
Preparation low dose group, model Niflumic Acid preparation middle dose group, model Niflumic Acid preparation high dose group.Rat starts through stomach on the 28th day
Enteral administration, after continuously giving Niflumic Acid targeting preparation 14 days, the sensitiveness of the enteron aisle pain sensation is assessed using musculus obliquus externus abdominis electric discharge；Enter
And the recording method of brain slice in vitro field potential is used, the young mouse hippocampus CAl areas field potential LTP of observation chronic visceral pain（long-term
Potentiation change).
As a result show, model children mouse musculus obliquus externus abdominis electric discharge is remarkably reinforced, give Niflumic Acid targeting preparation low dosage, middle dose
Amount, high dose group are compared with model group rats, and musculus obliquus externus abdominis electric discharge amplitude significantly drops under 40,60 mmHg CRD pressure
It is low；Record in vitro hippocampus CAl areas field potential LTP to show, model children mouse dramatically increases (P than the peak value of normal young mouse<0.05), Buddhist nun
Fluoric acid preparation significantly reduces model children's mouse hippocampus field potential LTP peak value.Illustrate that Niflumic Acid colon targeting preparation has in treatment
Pain caused by dirty height is quick, suppress the quick effect of model children's mouse splanchnodynia.
Claims (6)
- A kind of 1. Niflumic Acid colon targeting preparation for treating IBS, as made from following two-step methods, first by Buddhist nun's fluorine Acid is contained and nano-micelle is formed in high polymer material, and nano-micelle further is wrapped in into micropill using orifice-freezing method Obtained in high polymer material, it is characterised in that：The inventory of Niflumic Acid and high polymer material is 1 by weight：20~1：1, high polymer material, which is dissolved in organic solvent, matches somebody with somebody The quality concentration of volume percent of manufactured Polymer Solution is 2% ~ 20%；Wherein described high polymer material is pluronic F127, Poly(D,L-lactide-co-glycolide（PLGA）, polyethylene glycol The one or two or more kinds of 1000 VE-succinates mix;Described nano-micelle needs the freeze-dried rear solid form for forming freeze-dried powder to save backup；Described micropill high polymer material be by low-ester pectin, sodium alginate, chitosan, one kind of ethyl cellulose or two kinds with On mix.
- 2. the Niflumic Acid colon targeting preparation for the treatment of IBS according to claim 1, it is characterised in that：It is described A diameter of 0.5 ~ 1.5mm of micropill, preferably 0.8 ~ 1.2mm.
- 3. the preparation method of the Niflumic Acid colon targeting preparation of the treatment IBS described in claim 1 or 2, including with Lower step：1）The high polymer material of the Niflumic Acid of formula ratio and formula ratio is placed in container, then adds proper amount of methanol thereto, is made Niflumic Acid and high polymer material are dissolved in methanol, make the mixing of Niflumic Acid and high polymer material the step of by removing methanol Thing forms film on container inner wall, then the PBS of pH=7.4 is added into the container, to being formed on container inner wall Film carry out hydration process, supersonic oscillations aquation uses 0.2 μm, 0.1 μm of aperture respectively successively to Film Fractionation at 37 DEG C Makrolon membrane filtration, be respectively repeated 3 times, frozen dried, that is, obtain Niflumic Acid nano-micelle；2）Take the micropill high polymer material of formula ratio to be dissolved in the water, be configured to certain density Polymer Solution, by formula ratio Step 1）Obtained Niflumic Acid nano-micelle, which is uniformly suspended in above-mentioned Polymer Solution, forms suspension, by the suspension Instilled in calcium chloride water, solidified with droplet-like, filtered, drying, obtain load pill core;3）Load pill core is taken, is immersed in aq. polyethyleneimine, is soaked, filtering, dries to obtain Niflumic Acid colon targeting preparation.
- 4. the preparation method of the Niflumic Acid colon targeting preparation for the treatment of IBS according to claim 3, it is special Sign is：The inventory of Niflumic Acid nano-micelle and micropill high polymer material is 1 by weight：20~1：1；High polymer material is molten The quality concentration of volume percent for the Polymer Solution that Xie Yushui is configured to is the % of 5 % ~ 15.
- 5. the preparation method of the Niflumic Acid colon targeting preparation for the treatment of IBS according to claim 4, it is special Sign is：The inventory of Niflumic Acid nano-micelle and high polymer material is 1 by weight：10；The quality volume of Polymer Solution Percent concentration is 8 %.
- 6. the Niflumic Acid colon targeting preparation of the treatment IBS described in claim 1 or 2 is preparing treatment intestines easily swash Answering in the medicines of local large intestine disease such as syndrome, ulcerative colitis, hemorrhagic colitis, Crohn`s diseases, colon cancer With.
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| CN112545988A (en) * | 2020-04-03 | 2021-03-26 | 南京农业大学 | Hydrobromic acid halofuginone-TPGS polymer micelle and preparation method thereof |
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| EP2977043A2 (en) * | 2003-08-25 | 2016-01-27 | Foamix Pharmaceuticals Ltd. | Penetrating pharmaceutical foam |
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