CN105878177A - Mesalazine temperature-sensitive gel enema and preparation method thereof - Google Patents
Mesalazine temperature-sensitive gel enema and preparation method thereof Download PDFInfo
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- CN105878177A CN105878177A CN201610310802.1A CN201610310802A CN105878177A CN 105878177 A CN105878177 A CN 105878177A CN 201610310802 A CN201610310802 A CN 201610310802A CN 105878177 A CN105878177 A CN 105878177A
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- 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
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/606—Salicylic acid; Derivatives thereof having amino groups
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0031—Rectum, anus
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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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
Abstract
The invention discloses a temperature-sensitive gel enema capable of prolonging the detention time of mesalazine in colons and a preparation method of the temperature-sensitive gel enema. The mesalazine temperature-sensitive gel enema is prepared from mesalazine as a main drug, temperature-sensitive gel substrate poloxamer, a bio-adhesive material, a stabilizer and an appropriate amount of water. The mesalazine temperature-sensitive gel enema for colons disclosed by the invention is a liquid freely flowing at a room temperature, is injected to the colons in a liquid form, and has the advantages of uniform drug distribution and good spreadability. Then, the mesalazine temperature-sensitive gel enema is subjected to phase transformation fast under a body temperature condition to form non-chemically-crosslinked semisolid gel, thereby prolonging the detention time of the drug in the colons in addition to the mucous membrane adhesion effect of the bio-adhesive material. Compared with a conventional mesalazine enema, the mesalazine temperature-sensitive gel enema disclosed by the invention can be used for effectively reducing drug liquid leakage and improving the curative effect, and has the advantages of simple preparation and low irritation.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of mesalazine thermosensitive hydrogel enema and preparation method thereof.
Background technology
Ulcerative colitis (Ulcerative colitis, UC) is the chronic non-spy that a kind of cause of disease is still not very clear
Opposite sex enteritis, diseased region, mainly at human colorectal mucosa and Submucosa, can form macroscopic erosion and ulcer.
Its extent of disease is many from lower distal colon, and reversibility proximally develops, and even involves total colectomy, involves terminal ileum once in a while,
It is distributed in seriality.This disease is high at European and American areas sickness rate, and Asia and Africa country is relatively low, the case load of recent year report by
Cumulative adding, the sickness rate of China UC has presented ascendant trend.Owing to the cause of disease and the pathogenesis of this disease not yet illustrate, treatment lacks
Specificity, causes protracted inflammation repeatedly, even canceration, has a strong impact on the physical and mental health of patient, is classified as doubtful by World Health Organization (WHO)
Difficult sick.
Drug therapy is the primary treatment regimen of light moderate UC, and the medicine for UC mainly has amino the most clinically
Salicylic acid, steroid hormone, immunosuppressant, antibiotic etc..Mesalazine (mesalamine) is also called 5-aminosalicyclic
Acid (5-aminosalicylic acid, 5-ASA), due to determined curative effect, is a line medicine of light moderate UC of current clinical treatment
Thing.It is to play antiinflammatory action by suppression prostaglandin E and the formation of leukotriene, and its effect is local, i.e. sticks with intestinal
Playing a role when film contact and complexation, drug level and persistent period that its therapeutic effect contacts with inflammatory bowel mucosa are relevant, with
Blood drug level relation is little.
Mesalazine chemical structural formula
Mesalazine is main in clinical treatment UC uses oral and rectally two ways.Oral formulations mostly is can be at intestinal
The slow releasing preparation of location, road release, is mainly used in the treatment that proximal colonic is scorching.First-selection is treated for end and left side colon
It it is the topical formulations of per rectum administration., for mild to moderate proctitis, sigmoiditis, topical application U.S. is husky to have data to show
The curative effect drawing piperazine is better than oral formulations.About 70% is accounted for, the major lesions position of UC in China's proctosigmoiditis or proctitis
At rectum, straight sigmoid colon, left side colon, become a kind of very important administering mode of mesalazine by rectally.
The dosage form that the per rectum used clinically at present is administered has suppository and enema.Suppository enter the internal degree of depth and with
The contact area of focus is the most limited, can only act on rectum position, is generally used only for the treatment of rectum type ulcerative colitis.City
The mesalazine enema sold mainly is made up of carbomer, be one can free-pouring liquid, sigmoid colon can be arrived,
But almost without bioadhesive, easily affected by enterokinesia and occur leaking, limited in diseased region residence time.Therefore,
The exploitation mesalazine per rectum drug-delivery preparation that drug distribution is uniform, bioadhesive is strong, is used for treating end and left side colon
Inflammation has good clinical value.
Situ-gel is that the solution of the problems referred to above provides good solution.Situ-gel (in situ gel) is
After one class is administered with solution state, the change of response environment, at agents area generation phase in version, form half non-chemically cross-linked solid
Body gel preparation.It has merged the advantage of solution and gel, also has preparation technology concurrently simple, easy to use, mucous membrane tissue
Affinity is strong, can extend the advantage such as holdup time at medicine-feeding part as drug-reservoir.Different according to Forming Mechanism, the most solidifying
Glue can be divided into responsive to temperature type, pH responsive type, ion-sensitive type etc..Owing to colon site tissue fluid is few, the buffer capacity of intestinal
Limited, enema is made pH responsive type or the gel of ion-sensitive type and is not suitable for, and enema is made responsive to temperature type
It it is then a good selection.
Chitosan is cross-linked by Bostan etc. with poly-N-isopropyl acrylamide, is prepared for Cross-linked product for gel rubber material
A kind of mesalazine temperature-and pH-sensitivity type gel (Bostan MS, et al. Int J Biol Macromol,
2013,52:177-83.), the research not yet relates to the content such as pharmacodynamics and zest evaluation, in terms of preparation technology, Cross-linked
Course of reaction is complicated, and the organic solvent of introducing have impact on the safety of preparation to a certain extent.Ramadass etc. use collagen
Preparing mesalazine rectally situ-gel for gel-type vehicle, this gel also has pH and temperature sensitivity (Ramadass concurrently
SK, et al. Eur J Pharm Sci, 2013,48 (1-2): 104-10.), due to the collagen-stabilized property of carrier material
Poor reason, this gel rubber system must be maintained in less than 10 DEG C, and this is that the storage of preparation is made troubles.Above two Lazer coagulates
The pH of colloid system all designs 4 ~ 5, occurs the pH of phase in version 7 ~ 8, owing to intestinal buffer capacity is extremely limited, adds once
The volume of coloclysis is relatively big, and during actual medication, preparation pH is difficult to reach pH needed for phase in version at short notice, and therefore pH sensitivity can
Can be difficult to embody.
Summary of the invention
For the deficiency of existing mesalazine rectally preparation, present invention aim at providing a kind of novel U.S. salad
Piperazine thermosensitive hydrogel enema.It is a further object of the present invention to provide the preparation method of a kind of described preparation.
For achieving the above object, the technical solution adopted in the present invention is as follows:
The mesalazine colon thermosensitive hydrogel that the present invention provides, composition includes: principal agent, temperature sensitive hydrogel substrate, bioadhesion
Material, stabilizer and suitable quantity of water composition, wherein principal agent is mesalazine, and the mass percent in prescription is 6.7%.
Described temperature sensitive hydrogel substrate is poloxamer188, PLURONICS F87 and mixture thereof.Poloxamer
(poloxamer) it is a kind of nonionic surfactant, the ABA type formed for polyoxyethylene (PEO) and polyoxypropylene (PPO)
Block copolymer, is to study a most deep class temperature sensitive hydrogel macromolecular material at present, wherein with poloxamer188 and pool
Luo Shamu 188 is the most commonly used.Poloxamer relative molecular mass is big, stable chemical nature, and metabolism will not be occurred in vivo to turn
Change, good biocompatibility.By poloxamer188 and the ratio of PLURONICS F87 in regulation prescription, can be by system gelatine
Temperature controls near body temperature.By mass percentage, the content of poloxamer188 is 16% ~ 19%;Containing of PLURONICS F87
Amount is 3% ~ 12%.
Described mesalazine thermosensitive hydrogel enema, is to be suspended in thermosensitive hydrogel solution by mesalazine, and gel
Stablizing of the suspending characteristic that substrate poloxamer has itself, beneficially system.
In described mesalazine thermosensitive hydrogel enema, mesalazine chemical structural formula is as follows:
OH and NH from structure2It is in para-position, unstable, oxidizable degraded.Finding through overtesting, mesalazine is stable
Property is relevant with pH, and in the solution of pH 4 ~ 5, stability is preferable.Therefore, the pH of gel rubber system is controlled between 4 ~ 5.
Described bioadhesive material is chitosan, hyaluronate sodium, hydroxypropyl methylcellulose, xanthan gum, Konjac glucomannan, the Pseudobulbus Bletillae (Rhizoma Bletillae)
One in glue or polycarbophil or a combination thereof.
By mass percentage, it is content in described mesalazine thermosensitive hydrogel enema for described bioadhesive material
(mass percent) is 0.1% ~ 0.4%, preferably 0.2%.Preferably, described bioadhesive material is by polycarbophil and hyalomitome
Acid sodium composition, the mass ratio of polycarbophil and hyaluronate sodium is 1:3 ~ 3:1, most preferably 3:1.
Polycarbophil (polycarbophil, PCP) is crosslinked polypropylene acids polymers, can be mutual with mucosa glycoprotein
Effect, formation rationality connects, produces stronger mucous gels network structure, when making mucoadhesive system keep longer adhesion
Between, and mucosa will not be produced stimulation, there is good bioadhesive and biocompatibility.In addition PCP is acidulous material,
Having good buffer capacity, the addition of PCP can be that gel rubber system provides weak acid environment.Hyaluronate sodium is a kind of acid
Mucopolysaccharide, it demonstrates multiple important physiological function with unique molecular structure and physicochemical property in body, it is possible to regulation
The permeability of blood vessel wall, also has the effect etc. promoting wound healing.Also a small amount of document report hyaluronate sodium is had to have necessarily
Bioadhesive.The present invention is using Polycarbophil and hyaluronate sodium as bioadhesive polymer, it is possible to playing synergism increases
The adhesion of preparation, the most also has the effect of wound healing concurrently.
Described mesalazine thermosensitive hydrogel enema, it is characterised in that described stabilizer is mainly by water solublity antioxygen
Agent, metal chelating agent and preservative composition, wherein water soluble antioxidants is preferably pyrosulfite, its quality hundred in prescription
Proportion by subtraction is 0.8% ~ 1.2%;The preferred disodium edetate of metal chelating agent, the mass percent in prescription is 0.1% ~ 0.2%.
In described mesalazine thermosensitive hydrogel enema, solvent is water.The weak acid environment of gel rubber system pH 4 ~ 5 can
Being thered is provided by polycarbophil and potassium metabisulfite, therefore directly choosing uses water as solvent, simplifies preparation technology.
The described mesalazine thermosensitive hydrogel enema dynamic viscosity when 25 DEG C ± 0.5 DEG C is less than 500mPa s,
Can meet preparation is free-pouring liquid at ambient temperature, has good injecting property, and medicine is sprawled in being prone to intestinal;
Gelation temperature controls at 30 ~ 38 DEG C, it is ensured that preparation is gelled the most rapidly, reduces seepage;Adhesion is more than 70mNcm-2, can
Extend the preparation holdup time at diseased region further.
The mesalazine thermosensitive hydrogel enema of the present invention is using thermosensitive hydrogel as mesalazine per rectum topical system
The carrier of agent, this gel is at room temperature free-pouring liquid, injects colon in liquid form, has drug distribution equal
Advantage even, that spreadability is good;Under body temperature, there is rapidly phase in version, form the semi-solid gel non-chemically cross-linked, then add
The mucoadhesive effect of upper bioadhesive material, can extend medicine in the intracolic holdup time.Poloxamer in prescription was both
As thermosensitive hydrogel material, may act as again suspending agent, play the effect that maintenance system is stable.Necessarily promote with having with Polycarbophil
Enter the hyaluronate sodium compatibility of wound healing effect as bioadhesive material, the bioadhesion of preparation can be improved further
Property.Pharmacodynamic confirms that the present invention is better than common mesalazine enema.Additionally, mesalazine of the present invention is temperature sensitive
Gel enema compares with existing correlational study, also has the advantage that
(1) compared with liquid bolt temperature sensitive with the mesalazine reported, it is big that the present invention has drug loading, and gelation temperature is suitable, biological
Adhesiveness and the advantage having good stability.Thermosensitive hydrogel mesalazine enema principal agent the most of the present invention is with the form of suspendible
Being dispersed in gel rubber system, relative to by complete drug dissolution, required gel-type vehicle amount is less, can guarantee that preparation is with suitable body
Amass and carry out coloclysis administration, and maintain higher drug level in local;Thermosensitive hydrogel mesalazine coloclysis the most of the present invention
The gelation temperature of liquid at 30 ~ 38 DEG C, slightly less than body temperature, can guarantee that enema is gelled the most rapidly;3. in invention formulation
In addition to the addition of more common bioadhesive material polycarbophil, also added hyaluronate sodium, hyaluronate sodium is that one can
The adhesion material of wound healing, itself and Polycarbophil compatibility, there is under ensureing preparation room temperature good fluidity simultaneously,
Further increasing the adhesion property of preparation, mesalazine thermosensitive hydrogel enema bioadhesion in vitro of the present invention can be more than
70 mN·cm-2, sustainable release 8h;4. have good stability
(3) temperature/pH Dual Sensitive gel prepared with Ramadass etc. relative to Bostan etc., preparation technology of the present invention letter
Single, do not use any organic solvent.Simultaneously, it is thus also avoided that the pH sensitivity caused owing to intestinal buffer capacity is limited is difficult to reality
Existing, the problem affecting phase in version process.
(4) thermosensitive hydrogel material poloxamer and bioadhesive material polycarbophil selected by the present invention are respectively provided with well
Biocompatibility, to mucosa almost without zest, be included by a class of pharmaceutic adjuvant safety, the safety of adjuvant by U.S. FDA
Property and availability also provide important leverage for the popularization and application that this project is following.
Accompanying drawing explanation
Fig. 1: the preparation technology flow chart of mesalazine thermosensitive hydrogel enema.
Fig. 2: the In-vitro release curves of mesalazine colon thermosensitive hydrogel.
Fig. 3: each group Mouse Weight change curve during test.
Fig. 4: each group mice stool scoring during test.
Fig. 5: during test, each group stool in mice is occulted blood scoring.
Fig. 6: each group rat colon pathological observation after being administered 7 days.
A: normal saline group;B: Blank gel group;C: embodiment 1.
Detailed description of the invention
Below in conjunction with specific embodiment, the invention will be further described, so that those skilled in the art can be preferably
Understand the present invention and can be practiced, but illustrated embodiment is not as a limitation of the invention.
In following example of the present invention mesalazine thermosensitive hydrogel enema composition (surplus is water) and at U.S. salad
Mass percent such as following table shared in piperazine thermosensitive hydrogel enema:
Embodiment | Mesalazine | Poloxamer188 | PLURONICS F87 | Bioadhesive material | Metal chelating agent | Preservative | Water soluble antioxidants |
1 | 6.7% | 17.6% | 8.0% | The mass ratio of 0.20%(polycarbophil and hyaluronate sodium is 3:1) | 0.1%(EDTA) | 0.1%(sodium benzoate) | 0.8% potassium metabisulfite |
2 | 6.7% | 16% | 3% | The mass ratio of 0.20%(polycarbophil and hyaluronate sodium is 3:1) | 0.1%(EDTA) | 0.1%(sodium benzoate) | 0.8% potassium metabisulfite |
3 | 6.7% | 19% | 12% | The mass ratio of 0.20%(polycarbophil and hyaluronate sodium is 3:1) | 0.1%(EDTA) | 0.1%(sodium benzoate) | 0.8% potassium metabisulfite |
4 | 6.7% | 17.6% | 8.0% | The mass ratio of 0.1%(polycarbophil and hyaluronate sodium is 3:1) | 0.1%(EDTA) | 0.1%(sodium benzoate) | 0.8% potassium metabisulfite |
5 | 6.7% | 17.6% | 8.0% | The mass ratio of 0.4%(polycarbophil and hyaluronate sodium is 3:1) | 0.1%(EDTA) | 0.1%(sodium benzoate) | 0.8% potassium metabisulfite |
6 | 6.7% | 17.6% | 8.0% | The mass ratio of 0.20%(polycarbophil and hyaluronate sodium is 1:1) | 0.1%(EDTA) | 0.1%(sodium benzoate) | 0.8% potassium metabisulfite |
7 | 6.7% | 17.6% | 8.0% | The mass ratio of 0.20%(polycarbophil and hyaluronate sodium is 1:3) | 0.1%(EDTA) | 0.1%(sodium benzoate) | 0.8% potassium metabisulfite |
8 | 6.7% | 17.6% | 8.0% | 0.20% hyaluronate sodium | 0.1%(EDTA) | 0.1%(sodium benzoate) | 0.8% potassium metabisulfite |
9 | 6.7% | 17.6% | 8.0% | 0.20% polycarbophil | 0.1%(EDTA) | 0.1%(sodium benzoate) | 0.8% potassium metabisulfite |
10 | 6.7% | 17.6% | 8.0% | The mass ratio of 0.20%(polycarbophil and hyaluronate sodium is 3:1) | 0.1%(EDTA) | 0.1%(sodium benzoate) | 1.0 % potassium metabisulfites |
11 | 6.7% | 17.6% | 8.0% | The mass ratio of 0.20%(polycarbophil and hyaluronate sodium is 3:1) | 0.1%(EDTA) | 0.1%(sodium benzoate) | 1.2% potassium metabisulfite |
12 | 6.7% | 17.6% | 8.0% | The mass ratio of 0.20%(polycarbophil and hyaluronate sodium is 3:1) | — | 0.1%(sodium benzoate) | 0.8% potassium metabisulfite |
13 | 6.7% | 17.6% | 8.0% | The mass ratio of 0.20%(polycarbophil and hyaluronate sodium is 3:1) | — | — | — |
Comparative example 1 | 6.7% | 17.6% | 8% | 0.6% polycarbophil | 0.1%(EDTA) | 0.1%(sodium benzoate) | 0.8% potassium metabisulfite |
Comparative example 2 | 6.7% | 17.6% | 8% | — | 0.1%(EDTA) | 0.1%(sodium benzoate) | 0.8% potassium metabisulfite |
As it is shown in figure 1, the preparation method of the mesalazine thermosensitive hydrogel enema of above-described embodiment, step is as follows:
(1) bioadhesive material being placed in water, stirring, to being uniformly dispersed, prepares the first mixture;
(2) in the first mixture, under agitation slowly add temperature sensitive hydrogel substrate so that it is fully moistening, transfer in 4 DEG C
Putting 24 hours, be the clear solution without agglomerate to temperature sensitive hydrogel substrate complete swelling, stirring is allowed to uniform, prepares the second and mixes
Compound;
(3) taking stabilizer to be added slowly with stirring in the second mixture, stirring, to being completely dissolved, is eventually adding principal agent beautiful
Salad piperazine mending adds water to enough, and lucifuge continues stirring until medicaments uniformity suspendible and get final product.
Being measured the character of the mesalazine thermosensitive hydrogel enema that above-described embodiment prepares, result is as follows:
One, evaluation index
Gelation temperature (Tgel) mensuration: use be inverted determination of tube method Tgel, take gel solution 2mL in test tube, be placed in constant temperature
Slowly heating up in water-bath, heating rate is about 0.2 DEG C of min-1, often raise 0.2 DEG C, be inverted rapidly test tube, observe the flowing of solution
Situation, temperature when solution no longer flows in definition test tube is gelation temperature, and each sample determination 3 times is averaged.
The mensuration of viscosity before plastic: use rotational viscometer to measure viscosity before sample plastic, each sample determination 3 times, take
Meansigma methods.
The mensuration of sedimentation volume ratio: apparatus plug graduated cylinder takes medicine-containing gel solution 25mL, close plug, and firmly shaking 1 minute, writes down
The high H of beginning of suspended matter0, stand 3h, write down the final height H of suspended matter, be calculated as follows: sedimentation volume ratio=H/H0。
The mensuration of adhesion: list of references adhesion assay method the adhesion property of slightly modified investigation preparation.Will be straight
Water filled by the glass surface ware of footpath 6cm, and capping is placed in 37 DEG C of water-baths, and top exceeds the water surface about 0.5cm, when balancing one section
Between.Appropriate amount of sample is joined surface plate top, after complete gelation, the slide (2.5cm × 2.5cm) of preheating is placed in sample
On, and make slide fit tightly with gel with 50g counterweight compacting 3min, little hook, fine rule, cuvette and dropping system are installed, open
Drip control valve at the uniform velocity drips water (5mLmin-1) in cuvette until slide starts mobile, takes off cuvette and weighs.Unit are is glued
Attached power computing formula: f=9.8m/s, m are cuvette quality, s is the area of slide.-1
Embodiment | Adhesion (mN.cm-2) | Gelation temperature (DEG C) | Viscosity (mPa s) before plastic | Sedimentation volume ratio (%) | pH |
1 | 76.5±2.2 | 33.73±0.25 | 395.3±2.5 | 99.2 | 4.35 |
2 | 75.3±2.1 | 37.57±0.15 | 264.3±1.0 | 98.6 | 4.53 |
3 | 75.2±2.2 | 30.14±0.15 | 635.3±1.5 | 99.2 | 4.55 |
4 | 49.3±1.1 | 33.17±0.15 | 290.6±0.7 | 98.4 | 4.46 |
5 | 92.1±2.2 | 35.20±0.20 | 1021.0±3.0 | 99.1 | 4.20 |
6 | 68.2±2.1 | 34.65±0.05 | 488.1±3.1 | 98.8 | 4.35 |
7 | 56.8±2.0 | 33.17±0.12 | 432.2±2.0 | 99.6 | 4.38 |
8 | 53.6±2.8 | 34.27±0.12 | 378.3±8.4 | 99.7 | 4.49 |
9 | 68.4±2.1 | 34.73±0.06 | 431.3±3.1 | 98.8 | 4.38 |
10 | 75.1±3.2 | 33.95±0.67 | 391.2±2.8 | 99.4 | 4.32 |
11 | 75.5±1.2 | 33.56±0.29 | 397.5±1.5 | 98.9 | 4.20 |
12 | 75.1±1.6 | 33.75±0.35 | 397.4±2.5 | 98.3 | 5.52 |
13 | 74.9±1.9 | 33.77±0.15 | 395.3±3.1 | 97.9 | 5.53 |
Comparative example 1 | 92.8±2.8 | / | Can not flow freely under room temperature | / | / |
Comparative example 2 | 39.1±3.0 | 35.03±0.21 | 179.0±0.5 | 98.0 | 4.57 |
From upper table, the comprehensive data such as the viscosity before the adhesion of each embodiment, gelling temp and gel of analyzing:
1, comparative example 1 ~ 3 can be seen that, the quality that poloxamer188 is shared in described mesalazine thermosensitive hydrogel enema
Percentage ratio most preferably 17.6%, the mass percent shared in described mesalazine thermosensitive hydrogel enema of PLURONICS F87 is
Good is 8.0%.
2, comparative example 1,4,5 can be seen that, the addition of bioadhesive material can improve the adhesion of system, along with life
The rising of thing adhesion material concentration, adhesion is gradually increased, and along with the rising of bioadhesive material concentration, gelation temperature has risen
Height, but elevation amplitude is little;Before plastic, viscosity and sedimentation volume ratio all increase with the rising of bioadhesive material concentration;Biological
Gel rubber system pH is slightly affected by adhesion material, and along with bioadhesive material concentration raises, system pH is gradually lowered.Work as biological slime
The ratio of enclosure material is more than when increasing to 0.4%, and adhesion is maximum, but before now striking a bargain, viscosity alreadys more than 1000mPa.s,
At room temperature can not flow freely.
3, comparative example 1,6 and 7 can be seen that, bioadhesive material is that the mass ratio of polycarbophil and hyaluronate sodium is
During the mixture of 1:3 ~ 3:1, the viscosity before adhesion, gelling temp and the gel of mesalazine thermosensitive hydrogel enema is the suitableeest
Preferably, the most preferably polycarbophil of bioadhesive material and the mixture of hyaluronic acid mass ratio 3:1.
4, comparative example 1,8 and 9, the bioadhesive material of embodiment 1 is the quality of polycarbophil and hyaluronate sodium
Than the mixture for 3:1, the adhesion performance of embodiment 1 mesalazine thermosensitive hydrogel enema is substantially better than bioadhesive material
Select hyaluronate sodium or the embodiment 9 and 10 of polycarbophil.
5, comparative example 1 and 10 ~ 13, the addition of antioxidant, metal chelating agent and preservative is temperature sensitive solidifying to mesalazine
Before the adhesion of glue enema, gelling temp, plastic, viscosity and sedimentation volume ratio have little to no effect, along with antioxidant Jiao's sulfurous
The increase of acid potassium application rate, pH slightly reduces.
6. comparative example 1 and comparative example 1,2, the interpolation of bioadhesive material can increase the adhesion of system, and adds
Dosage is crossed and system viscosity can be caused at most too high, is not suitable for the application of mesalazine thermosensitive hydrogel enema.
Two release in vitro
Dynamic dialysis method is used to measure mesalazine release from thermosensitive hydrogel.The mesalazine temperature of preparation in Example 1
Quick gel enema 2g is placed in the bag filter of pretreatment, and bag filter two ends are tight in case stopping leak reveals by linear system, 37 DEG C of conditions
Bag filter is put in 37 DEG C of pH7.4 phosphate buffered solution of 100mL, in 37.0 DEG C ± 0.5 DEG C constant temperature after lower fully gelling
With 100 rmin-1 rate oscillations in agitator, respectively at 0.25,0.5,1.0,1.5,2.0,3.0,4.0,6.0,8.0,10.0,
12.0h samples 5mL, and adds 37 DEG C of pH7.4 phosphate buffered solution of equivalent immediately.Sample is after rationally dilution, at 316nm
Measure absorbance, then calculate Accumulation dissolution, each sample determination 3 times, average.It is measured in the same method commercially available mesalazine to fill
Intestinal juice vitro release, result is shown in Fig. 2.
As shown in Figure 2, commercially available mesalazine enema medicine about discharges 79.0% at 2h, and in 4h, release is completely;And embodiment
In the mesalazine thermosensitive hydrogel enema of 1, mesalazine (5-ASA) is 42.8% at the preparation of 2h, and during 4h, release reaches
To 74.2%, in 8h, release completely, illustrates that the 5-ASA thermosensitive hydrogel enema of embodiment 1 has certain slow releasing function.
Three, stability test
1. influence factor's test
The mesalazine thermosensitive hydrogel enema of Example 1 and 10 ~ 13 places stablizing of 5d and 10d in high temperature (60 DEG C) condition
Property data are as follows.Result shows compared with original state (when 0), and 5d drug content has and obviously reduces.
Comparative example 1,10 ~ 12 and embodiment 13, and mesalazine stability has had and is greatly improved, and illustrates to add in prescription
Enter potassium metabisulfite to be necessary.
Comparative example 1,10 and 11, and along with antioxidant potassium metabisulfite consumption in prescription increases, stability is slightly
Improve, but after potassium metabisulfite consumption in prescription reaches 0.8%, be further continued for increasing the consumption of sodium pyrosulfite, to U.S. husky
The contribution drawing piperazine stability is little.
Comparative example 1 and embodiment 12, illustrate that adding metal chelating agent EDTA in prescription is favorably improved stability.
Stability test
The 5-ASA thermosensitive hydrogel enema test sample three batches of Example 1, simulate commercially available back, be placed in temperature 40 DEG C ± 2 DEG C,
Place 6 months under the conditions of relative humidity 25% ± 5%, during test respectively at the 0th, 1,2,3, sampling in 6 months once, observe and remember
Take down a confession or testimony during an interrogation test product appearance character, measure gelation temperature, pH, viscosity, sedimentation volume ratio, 5-ASA content and have related substance.
Result see table:
Compared with original state (when 0), suspension color is gradually become light brown by milky, and pH all controls without significant change
In the range of 4.0 ~ 5.0;Drug content slightly reduces, but the amplitude of reduction is within 3%, still in the range of indicating, has related substance to meet
Requirement;Gelation temperature, viscosity and sedimentation volume ratio are without significant change.Therefore indices stable in properties.
Four, zoopery
Choose Healthy female BALB/c mouse 40,6 ~ 8 week old, body weight 20 ~ 22g, be randomly divided into 4 groups, respectively A: normal group;
B: normal saline group;C: mesalazine enema group (is called for short: commercially available group);The 5-ASA thermosensitive hydrogel enema group of D: embodiment 1
(being called for short: embodiment 1).
The preparation of acute ulcer Colitis Model and medication
The mode freely drinking DSS aqueous solution is used to prepare chmice acute Ulcerative Colitis Model, in addition to A group, other three groups
All modelings, freely drink 3.5%DSS aqueous solution 5 days, and every day changes fresh DSS solution, and A group gives normal drinking water 5 days.Mould
What type was successfully established be masked as mice occurs half loose stool, diarrhoea, fecal occult blood be positive and arbitrary symptom in naked eyes hemafecia.Modeling
Success coloclysis next day gives relative medicine, and two groups of dosages behaviour coloclysis dosage every day of C, D are converted to mice dose,equivalent and are
520mg/kg(is based on 5-ASA), continuous 7 days;B group dosage is the physiology with medicine-containing gel equivalent relative to D group Rapid Dose Calculation
Saline, continuous 7 days;A group normal diet, is left intact.
Disease activity index (disease activity index, DAI) is assessed
Mice general activity situation, record body weight change, stool and fecal occult blood situation, ginseng is observed from every day on-test
Examine documentation standards and do and suitably modified carry out DAI scoring, see table.
Score | Stool | Fecal occult blood |
0 | Normally | Do not develop the color after 2min |
1 | ╲ | Aubergine is the most gradually produced in 1 ~ 2min |
2 | Loose | Aubergine is produced in 1min |
3 | ╲ | Hyacinthine is produced in 10s |
4 | Loose stool | Produce hyacinthine immediately |
The most normally stool: shape stool;Loose stool: be not adhere to the pasty state of anus, half form stool;Loose stool: can adhere to
Dilute water sample in anus is defecated.
From figure 3, it can be seen that during Gei Yaoing, normal saline group Mouse Weight alleviates trend and gradually slows down, commercially available group and enforcement
1 group of mice of example started body weight in the 8th day and no longer alleviates, and increased along with being administered natural law, and some Mouse Weights occur;It is administered knot
Shu Hou, commercially available group with 1 group of Mouse Weight of embodiment obviously higher than normal saline group (P < 0.05), but without notable between two groups
Sex differernce (P > 0.05).Finding by observing each group of mice stool and fecal occult blood situation every day, normal group mice defecates
Normally, scoring maintains zero level all the time;Three groups of mices through modeling started to engender loose, the loose stool of stool at the 3rd day,
Severe patient visual hemafecia, visible bloodstain on bedding and padding, just occult blood in positive in various degree;During administration, along with being administered natural law
Increase, three groups of mice stool are the most on a declining curve with fecal occult blood scoring, and the score value that embodiment is 1 group is substantially less than it
He is two groups.Result is shown in Fig. 4 ~ 5.
The damage of colon mode of appearance and Histological injury's assessment
After mice last is administered, fasting 24h, anesthesia is put to death, and dissects, the whole intestinal segment of taking-up anus end to cap end, observes
Each group colon mode of appearance change, marks with reference to following table standard.
Score | Form |
0 | Not damaged |
1 | Mucosa hyperemia, edema, without ulcer |
2 | Mucosa hyperemia, edema, slight rotten to the corn, without ulcer |
3 | Mucosa hyperemia, edema, moderate is rotten to the corn, have single ulcer |
4 | Mucosa hyperemia, edema, highly rotten to the corn, have many places ulcer |
5 | Mucosa hyperemia, edema, severe is rotten to the corn, have more than 1cm ulcer |
Longitudinally being cut open along mesenteric border by mouse Colon, ice normal saline cleans intestinal contents, in have extensive inflammation or
Tissue specimen is taken after 4% paraformaldehyde is fixing at ulcer, conventional dehydration and paraffin embedding, after 5 μm sections, carry out conventional H E dye
Color, carries out colon's pathological examination, marks with reference to following table standard under optical microscope.
Score | Degree of inflammation | Injured depth | Crypts destroys | Extent of disease (%) |
0 | Nothing | Nothing | Nothing | Nothing |
1 | Slightly | Tela submucosa | Substrate 1/3 crypts is destroyed | 1~25 |
2 | Moderate | Muscle layer | Substrate 2/3 crypts is destroyed | 26~50 |
3 | Severe | Placenta percreta | Only have full surface epithelium | 51~75 |
4 | ╲ | ╲ | All crypts and epithelium are destroyed | 76~100 |
Using SPSS19.0 software that result is carried out statistical analysis, measurement data all represents with mean ± SD, and variance is neat
Property inspection after, the comparison of each group difference uses one factor analysis of variance (One-way ANOVA), with P < 0.05 for difference tool
Statistically significant.
Result see table:
Group | Colon mode of appearance Injury score | Colon histology Injury score |
Normal group | 0.00±0.00 | 0.00±0.00 |
Normal saline group | 3.10±0.88a | 9.50±1.96a |
Commercially available group | 2.00±0.67ab | 6.80±2.10ab |
Embodiment 1 | 1.20±0.42abc | 4.40±1.35abc |
aCompare with normal group, P < 0.05;bCompare with normal saline group, P < 0.05;cCompare with commercially available group, P < 0.05
Mouse Colon mode of appearance is respectively organized in perusal, and normal group mouse Colon mucosa is smooth, and intestinal wall is thin, vascular lake under mucosa
Clearly, without congested, edema, without rotten to the corn and ulcer;Normal saline group mouse Colon rough surface is in granular form, and intestinal wall thickens, and turns round
Bent deformation, intestinal mucosa is congested, edema, it is seen that gently rotten to the corn to severe and ulcer;Commercially available group of mouse Colon intestinal wall thickens, and intestinal mucosa fills
Blood, edema, slightly rotten to the corn, aphtha stove seen from minority;1 group of mouse Colon intestinal wall of embodiment thickens, intestinal mucosa mild hyperaemia, water
Swollen, only slight rotten to the corn seen from 2 mices, but have no ulcer stove.Commercially available group and the colon mode of appearance damage of 1 group of mice of embodiment
Wound scoring is significantly lower than normal saline group (P < 0.05);Embodiment 1 group, compared with commercially available group, has lower colon outward appearance shape
State Injury score, and both differences have statistical significance (P < 0.05).Mouse Colon histological damage score result shows,
The scoring of commercially available group and embodiment 1 group is substantially less than normal saline group (P < 0.05), and embodiment 1 group scoring is minimum, with commercially available group
Comparing, both differences have statistical significance (P < 0.05).
In sum, compared with normal saline group and commercially available group, embodiment 1 group (the mesalazine thermosensitive hydrogel of embodiment 1
Enema) curative effect more excellent.Also find during being administered simultaneously, after normal saline group and commercially available group of mice coloclysis are administered, nearly all
Occur in that leakage in various degree, embodiment 1 group the most occasionally have mice to occur revealing, illustrate using thermosensitive hydrogel as mesalazine
Carrier, then it is aided with bioadhesive material, can effectively extend the mesalazine holdup time at colon site, thus improve curative effect.
Five, pathology
Choose female sd inbred rats 9, body weight 200 ~ 250g, be randomly divided into 3 groups, respectively A: normal saline group;B: blank enforcement
Example 1 group;C: mesalazine colon temperature sensitive embodiment 1 group.C group coloclysis every day gives mesalazine colon thermosensitive hydrogel and (presses
Prepare according to embodiment 3), dosage is that 360mg/kg(is based on mesalazine), continuous 7 days;A group and B group give normal saline every day
With the Blank gel without mesalazine, dosage is that calculate relative to C group radiacmeter with medicine-containing gel equivalent relative medicine,
Continuous 7 days.Every day observes each group of rat body weight, the mental status and active situation.After last is administered, Rat Fast 24h, anesthesia
Put to death.Dissecting, the whole intestinal segment of taking-up anus end to cap end, the change of colon mode of appearance is respectively organized in perusal.By colon
Cut off along mesentery edge, ice normal saline flushing feces, for avoiding the inflammatory caused because of mechanical stimulus in coloclysis administration process to do
Disturbing result of the test, tissue specimen takes away from coloclysis degree of depth upper end about 1cm colon specimen after 4% paraformaldehyde is fixing, conventional dehydration
And paraffin embedding, to cut into slices (5 μm), conventional H E dyes, and carries out colon's pathological examination under optical microphotograph.
Result shows, respectively organize during medication rat body weight, ingest, stool all normal, each group of perusal after dissection
Colon mode of appearance, is showed no the phenomenons such as obvious hyperemia, edema or mucosa bleed bottom.Optical microphotograph Microscopic observation colon is sick
Reason section, is shown in Fig. 6, and three groups of Colon mucosa cells are all without degeneration, necrosis, and the distribution of lamina propria body of gland is normal, has no congested, water
Swelling and cell infiltration, Submucosa, muscularis mucosae and adventitial tissue structural integrity, no abnormality seen changes.Test result indicate that
Mesalazine colon thermosensitive hydrogel has the good vivo biodistribution compatibility.
Embodiment described above is only the preferred embodiment lifted by absolutely proving the present invention, the protection model of the present invention
Enclose and be not limited to this.The equivalent that those skilled in the art are made on the basis of the present invention substitutes or conversion, all in the present invention
Protection domain within.Protection scope of the present invention is as the criterion with claims.
Claims (10)
1. a mesalazine thermosensitive hydrogel enema, it is characterised in that its composition includes: principal agent, temperature sensitive hydrogel substrate, life
Thing adhesion material and water,
Wherein said principal agent is mesalazine, and its mass percent shared in described mesalazine thermosensitive hydrogel enema is
6.7%;
Described temperature sensitive hydrogel substrate is made up of poloxamer188 and PLURONICS F87, and poloxamer188 is at described U.S. salad
Mass percent shared in piperazine thermosensitive hydrogel enema is 16%~19%, and PLURONICS F87 is in described mesalazine temperature
Mass percent shared in quick gel enema is 3%~12%;
Described bioadhesive material of stating is chitosan, hyaluronate sodium, hydroxypropyl methylcellulose, xanthan gum, Konjac glucomannan, Bletilla glucomannan
Or the one in polycarbophil or a combination thereof, described bioadhesion material is shared in described mesalazine thermosensitive hydrogel enema
Mass percent is 0.1%~0.4%, preferably 0.2%.
Mesalazine thermosensitive hydrogel enema the most according to claim 1, it is characterised in that described bioadhesive material by
Polycarbophil and hyaluronate sodium composition, the mass ratio of polycarbophil and hyaluronate sodium is 1:3~3:1.
Mesalazine thermosensitive hydrogel enema the most according to claim 1, it is characterised in that described bioadhesive material by
Polycarbophil and hyaluronate sodium composition, the mass ratio of polycarbophil and hyaluronate sodium is 3:1.
Mesalazine thermosensitive hydrogel enema the most according to claim 1, it is characterised in that poloxamer188 is described
Mass percent shared in mesalazine thermosensitive hydrogel enema is 17.6%;PLURONICS F87 is in described mesalazine temperature
Mass percent shared in quick gel enema is 8.0%.
Mesalazine thermosensitive hydrogel enema the most according to claim 1, it is characterised in that also include stabilizer, described
Stabilizer include: metal chelating agent, preservative and antioxidant.
Mesalazine thermosensitive hydrogel enema the most according to claim 5, it is characterised in that described antioxidant is burnt sulfurous
Acid potassium.
Mesalazine thermosensitive hydrogel enema the most according to claim 5, it is characterised in that described metal chelating agent is for depending on
Ground acid disodium.
Mesalazine thermosensitive hydrogel enema the most according to claim 5, it is characterised in that described preservative is benzoic acid
Sodium.
Mesalazine thermosensitive hydrogel enema the most according to claim 1, it is characterised in that described mesalazine is temperature sensitive solidifying
The pH value of glue enema is 4.0~5.0.
10. the preparation method of the mesalazine colon thermosensitive hydrogel described in any one of claim 1~9, it is characterised in that bag
Include following steps:
(1) bioadhesive material being placed in water, stirring, to being uniformly dispersed, prepares the first mixture;
(2) in the first mixture, under agitation add temperature sensitive hydrogel substrate so that it is fully moistening, transfer in 0~5 DEG C
Putting, be the clear solution without agglomerate to temperature sensitive hydrogel substrate complete swelling, stirring is allowed to uniform, prepares the second mixture;
(3) taking stabilizer and under agitation join in the second mixture, stirring, to being completely dissolved, is eventually adding principal agent and adds
Water is to the most enough, and lucifuge continues stirring until medicaments uniformity suspendible and get final product.
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108478544A (en) * | 2018-05-15 | 2018-09-04 | 杭州易敏生物医药科技有限公司 | A kind of mucous membrane disease treatment system and its application |
CN108553410A (en) * | 2018-06-11 | 2018-09-21 | 成都医学院 | A kind of mesalazine rectum original position thermo-sensitive gel and its preparation method and application |
CN109316441A (en) * | 2018-10-31 | 2019-02-12 | 成都医学院 | A kind of budesonide rectum original position thermo-sensitive gel and its preparation method and application |
CN109682939A (en) * | 2018-12-26 | 2019-04-26 | 四川健能制药有限公司 | A kind of Mesalazine enema fluid dissolution determination method |
CN116173044A (en) * | 2023-03-24 | 2023-05-30 | 优畅达(武汉)医疗科技有限公司 | Composition containing mesalamine, preparation method and application thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006036660A (en) * | 2004-07-23 | 2006-02-09 | Wakamoto Pharmaceut Co Ltd | Hardly soluble pharmaceutical-containing aqueously suspended thermogelling preparation |
CN102258458A (en) * | 2011-07-06 | 2011-11-30 | 陕西新药技术开发中心 | Rectal in-situ gel for abating fever and preparation method thereof |
CN104706582A (en) * | 2013-12-12 | 2015-06-17 | 四川健能制药有限公司 | Mesalazine-containing drug composition |
-
2016
- 2016-05-12 CN CN201610310802.1A patent/CN105878177B/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006036660A (en) * | 2004-07-23 | 2006-02-09 | Wakamoto Pharmaceut Co Ltd | Hardly soluble pharmaceutical-containing aqueously suspended thermogelling preparation |
CN102258458A (en) * | 2011-07-06 | 2011-11-30 | 陕西新药技术开发中心 | Rectal in-situ gel for abating fever and preparation method thereof |
CN104706582A (en) * | 2013-12-12 | 2015-06-17 | 四川健能制药有限公司 | Mesalazine-containing drug composition |
Non-Patent Citations (4)
Title |
---|
ASHISH Y. PAWAR等: "In Vitro and In Vivo Characterization of a Thermoresponsive Rectal Delivery System of Mesalamine", 《LATIN AMERICAN JOURNAL OF PHARMACY》 * |
宋兴龙等: "美沙拉嗪羟丙基β-环糊精包合物温敏型液体栓的制备及性质考察", 《中国药师》 * |
张玲莉等: "美沙拉嗪温敏液体栓的制备及体外性质考察", 《中国药师》 * |
李廷荃等: "《老药新用》", 31 December 2012 * |
Cited By (6)
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CN108478544A (en) * | 2018-05-15 | 2018-09-04 | 杭州易敏生物医药科技有限公司 | A kind of mucous membrane disease treatment system and its application |
CN108553410A (en) * | 2018-06-11 | 2018-09-21 | 成都医学院 | A kind of mesalazine rectum original position thermo-sensitive gel and its preparation method and application |
CN109316441A (en) * | 2018-10-31 | 2019-02-12 | 成都医学院 | A kind of budesonide rectum original position thermo-sensitive gel and its preparation method and application |
CN109316441B (en) * | 2018-10-31 | 2021-04-23 | 成都医学院 | Budesonide rectal in-situ temperature-sensitive gel and preparation method and application thereof |
CN109682939A (en) * | 2018-12-26 | 2019-04-26 | 四川健能制药有限公司 | A kind of Mesalazine enema fluid dissolution determination method |
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