CN105878177B - Mesalazine thermo-sensitive gel enema fluid and preparation method thereof - Google Patents
Mesalazine thermo-sensitive gel enema fluid and preparation method thereof Download PDFInfo
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- CN105878177B CN105878177B CN201610310802.1A CN201610310802A CN105878177B CN 105878177 B CN105878177 B CN 105878177B CN 201610310802 A CN201610310802 A CN 201610310802A CN 105878177 B CN105878177 B CN 105878177B
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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 one kind can extend mesalazine in the thermosensitive gel type enema fluid and preparation method thereof of colon residence time, and said preparation is made of main ingredient mesalazine, temperature sensitive hydrogel matrix poloxamer, bioadhesive material, stabilizer and suitable quantity of water.Mesalazine colon thermo-sensitive gel enema fluid provided by the invention is at room temperature the liquid flowed freely, injects colon in liquid form, has the advantages that drug distribution is uniform, spreadability is good；Phase transition occurs rapidly under body temperature therewith, forms the semi-solid gel of non-chemical crosslinking, in addition the mucoadhesive of bioadhesive material acts on, to extend drug in the residence time of colon.Compared with conventional mesalazine enema fluid, said preparation can effectively reduce liquid leakage and improve curative effect, and have preparation simply, bland advantage.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, it is related to a kind of mesalazine thermo-sensitive gel enema fluid and preparation method thereof.
Background technique
Ulcerative colitis (Ulcerative colitis, UC) is a kind of still not very clear chronic non-spy of cause of disease
Anisotropic intestinal inflammatory, diseased region mainly in human colorectal mucous membrane and submucosa, can form macroscopic rotten to the corn and ulcer.
Mostly since lower distal colon, invertibity proximally develops its extent of disease, or even involves total colectomy, involves terminal ileum once in a while,
It is distributed in continuity.The disease European and American areas disease incidence height, Asia and Africa country is relatively low, in recent years the case load of domestic report by
Cumulative to add, ascendant trend has been presented in the disease incidence of China UC.Since the cause of disease and pathogenesis of the disease not yet illustrate, treatment lacks
Specificity causes protracted inflammation repeatedly or even canceration, seriously affects the physical and mental health of patient, is classified as by the World Health Organization doubtful
Difficult disease.
Drug therapy is the primary treatment regimen of light moderate UC, clinically mainly has amino for the therapeutic agent of UC at present
Salicylic acid, steroid hormone, immunosuppressor, antibiotic etc..Mesalazine (mesalamine) is also known as 5- aminosalicyclic
Sour (5-aminosalicylic acid, 5-ASA) is a line medicine of the light moderate UC of current clinical treatment due to curative for effect
Object.It is by inhibiting the formation of prostaglandin E and leukotriene to play anti-inflammatory effect, and it is local for acting on, i.e., glutinous with intestines
It playing a role when film contact and complexing, the drug concentration and duration that therapeutic effect is contacted with inflammatory intestinal mucosa are related, with
Blood concentration relationship is little.
Mesalazine chemical structural formula
Mesalazine is in clinical treatment UC mainly using oral and rectally two ways.Oral preparation is mostly can
In the sustained release preparation of enteron aisle positioning release, it is mainly used for the treatment of proximal colonic inflammation.It is first for the treatment of end and left side colon
What is selected is the topical formulations of per rectum administration.There is data to show for mild to moderate rectitis, sigmoiditis, topical application
The curative effect of mesalazine is better than oral preparation.The major lesions of 70% or so, UC are accounted in Chinese proctosigmoiditis or rectitis
Position in rectum, straight-sigmoid colon, left side colon, a kind of very important administration of mesalazine is become by rectally
Mode.
The dosage form of the per rectum administration clinically used at present has suppository and enema fluid.Suppository enter intracorporal depth and with
The contact area of lesion is limited, can only act on rectum position, is generally used only for the treatment of rectum type ulcerative colitis.City
The mesalazine enema fluid sold mainly is made of carbomer, is a kind of liquid that can be flowed freely, can be reached sigmoid colon,
But almost without bioadhesive, the influence vulnerable to enterocinesia is leaked, limited in diseased region residence time.Therefore,
The exploitation mesalazine per rectum drug-delivery preparation that drug distribution is uniform, bioadhesive is strong, for treating end and left side colon
Inflammation has good clinical value.
Situ-gel provides good solution for the solution of the above problem.Situ-gel (in situ gel) is
After one kind is administered with solution state, the change of environment is responded, phase transition occurs in agents area, form non-chemical crosslinking half is solid
Body gel preparation.It has merged the advantages of solution and gelling agent, and it is simple also to have both preparation process, easy to use, mucous membrane tissue
Affinity is strong, can be used as drug-reservoir and extends the residence time of medicine-feeding part the advantages that.It is in situ solidifying according to Forming Mechanism difference
Glue can be divided into responsive to temperature type, pH responsive type, ion-sensitive type etc..Since colon site tissue fluid is few, the buffer capacity of enteron aisle
It is limited, the gel of pH responsive type or ion-sensitive type is made in enema fluid and is not suitable for, and responsive to temperature type is made in enema fluid
It is then a good selection.
Chitosan and poly-N-isopropyl acrylamide are crosslinked by Bostan etc., are prepared for using Cross-linked product as 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 is not yet related to the contents such as pharmacodynamics and irritation evaluation, in terms of preparation process, Cross-linked
Reaction process is complicated, and the organic solvent of introducing affects the safety of preparation to a certain extent.Ramadass etc. uses collagen
Mesalazine rectally situ-gel is prepared for gel-type vehicle, which also has both pH and temperature sensitivity (Ramadass
SK, et al. Eur J Pharm Sci, 2013,48 (1-2): 104-10.), due to the collagen-stabilized property of carrier material
Poor reason, the gel rubber system must be maintained in 10 DEG C hereinafter, this makes troubles for the storage of preparation.Above two Lazer is solidifying
The pH of colloid system is designed 4 ~ 5, and the pH of phase transition occurs 7 ~ 8, since enteron aisle buffer capacity is extremely limited, along with primary
The volume of bowel lavage is larger, and preparation pH is difficult to reach pH needed for phase transition in a short time when practical medication, therefore pH sensibility can
It can be difficult to embody.
Summary of the invention
For the deficiency of existing mesalazine rectally preparation, it is an object of that present invention to provide a kind of novel U.S. salads
Piperazine thermo-sensitive gel enema fluid.It is a further object of the present invention to provide a kind of preparation methods of preparation.
To achieve the above object, the technical solution adopted in the present invention is as follows:
Mesalazine colon thermo-sensitive gel provided by the invention, ingredient include: main ingredient, temperature sensitive hydrogel matrix, biology
Adhesion material, stabilizer and suitable quantity of water composition, wherein main ingredient is mesalazine, and the mass percent in prescription is 6.7%.
The temperature sensitive hydrogel matrix is poloxamer188, PLURONICS F87 and its mixture.Poloxamer
(poloxamer) it is a kind of nonionic surface active agent, is the ABA type that polyoxyethylene (PEO) and polyoxypropylene (PPO) form
Block copolymer is the more deep a kind of temperature sensitive hydrogel high molecular material of current research, wherein with poloxamer188 and pool
Luo Shamu 188 is the most commonly used.Poloxamer relative molecular mass is big, and chemical property is stablized, and metabolism will not occur in vivo and turn
Change, good biocompatibility.It, can be by system gelatine by adjusting the ratio of poloxamer188 and PLURONICS F87 in prescription
Temperature controls near body temperature.By mass percentage, the content of poloxamer188 is 16% ~ 19%；PLURONICS F87 contains
Amount is 3% ~ 12%.
The mesalazine thermo-sensitive gel enema fluid is suspended in mesalazine in thermo-sensitive gel solution, and gel
The suspending characteristic that matrix poloxamer itself has, is conducive to the stabilization of system.
In the mesalazine thermo-sensitive gel enema fluid, mesalazine chemical structural formula is as follows:
From structure-OH and-NH2It is unstable in contraposition, oxidizable degradation.It is found through overtesting, mesalazine
Stability is related with pH, and stability is preferable in the solution of pH 4 ~ 5.Therefore, the pH of gel rubber system is controlled between 4 ~ 5.
The bioadhesive material is chitosan, Sodium Hyaluronate, hypromellose, xanthan gum, konjac glucomannan, the bletilla striata
One of glue or polycarbophil or combinations thereof.
The bioadhesive material by mass percentage, the content in the mesalazine thermo-sensitive gel enema fluid
(mass percent) is 0.1% ~ 0.4%, preferably 0.2%.Preferably, the bioadhesive material is by polycarbophil and hyalomitome
The mass ratio of sour sodium composition, polycarbophil and Sodium Hyaluronate is 1:3 ~ 3:1, most preferably 3:1.
Polycarbophil (polycarbophil, PCP) is crosslinked polypropylene acids polymers, can be mutual with mucous membrane glycoprotein
Effect forms physical connection, generates stronger mucous gels reticular structure, when mucoadhesive system being made to keep longer adherency
Between, and stimulation will not be generated to mucous membrane, there is good bioadhesive and biocompatibility.Furthermore PCP is acidulous material,
With good buffer capacity, the addition of PCP can provide weak acid environment for gel rubber system.Sodium Hyaluronate is a kind of acidity
Mucopolysaccharide, it shows a variety of important physiological functions with unique molecular structure and physicochemical property in body, can adjust
The permeability of vascular wall also has the function of promoting wound healing etc..Also a small amount of document report Sodium Hyaluronate has certain
Bioadhesive.The present invention can play synergistic effect and increase using Polycarbophil and Sodium Hyaluronate as bioadhesive polymer
The adhesion strength of preparation, while also having the effect of wound healing concurrently.
The mesalazine thermo-sensitive gel enema fluid, it is characterised in that the stabilizer is mainly by water-soluble antioxygen
Agent, metal chelating agent and preservative composition, wherein water soluble antioxidants are preferably pyrosulfite, the quality hundred in prescription
Divide than being 0.8% ~ 1.2%；The preferred natrium adetate of metal chelating agent, the mass percent in prescription are 0.1% ~ 0.2%.
In the mesalazine thermo-sensitive gel enema fluid, solvent is water.The weak acid environment of gel rubber system pH 4 ~ 5 can
It is provided by polycarbophil and potassium metabisulfite, therefore directly selects water as solvent, simplify preparation process.
Dynamic viscosity of the mesalazine thermo-sensitive gel enema fluid at 25 DEG C ± 0.5 DEG C be less than 500mPas,
It is the liquid flowed freely that preparation, which can be met, at room temperature, has good injecting property, drug is easy to sprawl in enteron aisle；
Gelation temperature is controlled at 30 ~ 38 DEG C, it is ensured that preparation is gelled rapidly in vivo, reduces leakage；Adhesion strength is greater than 70mN cm-2, can
Further extend preparation in the residence time of diseased region.
Mesalazine thermo-sensitive gel enema fluid of the invention is using thermo-sensitive gel as mesalazine per rectum local administration system
The carrier of agent, the gel are at room temperature the liquid flowed freely, inject colon in liquid form, have drug distribution equal
Advantage even, spreadability is good；Phase transition occurs rapidly under body temperature, forms the semi-solid gel of non-chemical crosslinking, then plus
The mucoadhesive of upper bioadhesive material acts on, and can extend drug in the residence time of colon.Poloxamer in prescription was both
It as thermo-sensitive gel material, and may act as suspending agent, play the stable effect of maintenance system.With Polycarbophil and there is certain promote
The Sodium Hyaluronate compatibility acted on into wound healing can be further improved the bioadhesion of preparation as bioadhesive material
Property.Pharmacodynamic confirms that the present invention is better than common mesalazine enema fluid.In addition, mesalazine of the present invention is temperature sensitive
Gel enema fluid also has the advantage that compared with existing correlative study
(1) compared with the temperature sensitive liquid bolt of reported mesalazine, the present invention has drugloading rate big, and gelation temperature is suitable,
Bioadhesive and the advantages of having good stability.1. thermo-sensitive gel mesalazine enema fluid main ingredient of the present invention is to be suspended
Form is dispersed in gel rubber system, and relative to by complete drug dissolution, required gel-type vehicle amount is less, can guarantee preparation to be suitable for
Volume carry out bowel lavage administration, and locally maintaining higher drug concentration；2. thermo-sensitive gel mesalazine of the present invention
The gelation temperature of enema fluid can guarantee that enema fluid is gelled rapidly under body temperature in 30 ~ 38 DEG C, slightly less than body temperature；3. present invention system
In agent in addition to being added to more common bioadhesive material polycarbophil, Sodium Hyaluronate also added, Sodium Hyaluronate is one
The adhesion material that kind can promote wound healing, and Polycarbophil compatibility, same with good fluidity in the case where guaranteeing preparation room temperature
When, the adhesion property of preparation is further improved, mesalazine thermo-sensitive gel enema fluid bioadhesion in vitro of the present invention can
Greater than 70 mNcm-2, sustainable drug release 8h；4. having good stability
(3) relative to Bostan etc. and the temperature of the preparations such as Ramadass/pH Dual Sensitive gel, preparation process of the present invention
Simply, any organic solvent is not used.Simultaneously, it is thus also avoided that since the limited caused pH sensibility of enteron aisle buffer capacity is difficult to reality
Now, the problem of influencing phase transition process.
(4) the selected thermo-sensitive gel material poloxamer of the present invention and bioadhesive material polycarbophil all have well
Biocompatibility, it is almost nonirritant to mucous membrane, one kind of pharmaceutic adjuvant safety, the safety of auxiliary material are included by by U.S. FDA
Property and popularization and application of the availability also for this project future provide important leverage.
Detailed description of the invention
Fig. 1: the preparation technology flow chart of mesalazine thermo-sensitive gel enema fluid.
Fig. 2: the In-vitro release curves of mesalazine colon thermo-sensitive gel.
Fig. 3: each group mouse weight change curve during test.
Fig. 4: each group mouse stool scores during test.
Fig. 5: each group stool in mice is occulted blood scoring during test.
Fig. 6: each group rat colon pathological observation after administration 7 days.
A: physiological saline group；B: Blank gel group；C: embodiment 1.
Specific embodiment
The present invention is further explained in the light of specific embodiments, 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.
The ingredient (surplus is water) of mesalazine thermo-sensitive gel enema fluid and its in U.S. salad in following embodiment of the present invention
Shared mass percent is as follows: in piperazine thermo-sensitive gel enema fluid
| Embodiment | It is U.S. husky Draw piperazine | Moor Lip river Sha Mu 407 | It is husky to moor Lip river Nurse 188 | Bioadhesive material | Metal network Mixture | Preservative | Water solubility is anti- Oxygen agent |
| 1 | 6.7% | 17.6% | 8.0% | 0.20%(polycarbophil and thoroughly The mass ratio of bright matter acid sodium is 3:1) | 0.1% (EDTA) | 0.1%(benzene Sodium formate) | 0.8% is burnt sub- Potassium sulfate |
| 2 | 6.7% | 16% | 3% | 0.20%(polycarbophil and thoroughly The mass ratio of bright matter acid sodium is 3:1) | 0.1% (EDTA) | 0.1%(benzene Sodium formate) | 0.8% is burnt sub- Potassium sulfate |
| 3 | 6.7% | 19% | 12% | 0.20%(polycarbophil and thoroughly The mass ratio of bright matter acid sodium is 3:1) | 0.1% (EDTA) | 0.1%(benzene Sodium formate) | 0.8% is burnt sub- Potassium sulfate |
| 4 | 6.7% | 17.6% | 8.0% | 0.1%(polycarbophil and thoroughly The mass ratio of bright matter acid sodium is 3:1) | 0.1% (EDTA) | 0.1%(benzene Sodium formate) | 0.8% is burnt sub- Potassium sulfate |
| 5 | 6.7% | 17.6% | 8.0% | 0.4%(polycarbophil and thoroughly The mass ratio of bright matter acid sodium is 3:1) | 0.1% (EDTA) | 0.1%(benzene Sodium formate) | 0.8% is burnt sub- Potassium sulfate |
| 6 | 6.7% | 17.6% | 8.0% | 0.20%(polycarbophil and thoroughly The mass ratio of bright matter acid sodium is 1:1) | 0.1% (EDTA) | 0.1%(benzene Sodium formate) | 0.8% is burnt sub- Potassium sulfate |
| 7 | 6.7% | 17.6% | 8.0% | 0.20%(polycarbophil and thoroughly The mass ratio of bright matter acid sodium is 1:3) | 0.1% (EDTA) | 0.1%(benzene Sodium formate) | 0.8% is burnt sub- Potassium sulfate |
| 8 | 6.7% | 17.6% | 8.0% | 0.20% Sodium Hyaluronate | 0.1% (EDTA) | 0.1%(benzene Sodium formate) | 0.8% is burnt sub- Potassium sulfate |
| 9 | 6.7% | 17.6% | 8.0% | 0.20% polycarbophil | 0.1% (EDTA) | 0.1%(benzene Sodium formate) | 0.8% is burnt sub- Potassium sulfate |
| 10 | 6.7% | 17.6% | 8.0% | 0.20%(polycarbophil and thoroughly The mass ratio of bright matter acid sodium is 3:1) | 0.1% (EDTA) | 0.1%(benzene Sodium formate) | 1.0 % are burnt Potassium sulfite |
| 11 | 6.7% | 17.6% | 8.0% | 0.20%(polycarbophil and thoroughly The mass ratio of bright matter acid sodium is 3:1) | 0.1% (EDTA) | 0.1%(benzene Sodium formate) | 1.2% is burnt sub- Potassium sulfate |
| 12 | 6.7% | 17.6% | 8.0% | 0.20%(polycarbophil and thoroughly The mass ratio of bright matter acid sodium is 3:1) | — | 0.1%(benzene Sodium formate) | 0.8% is burnt sub- Potassium sulfate |
| 13 | 6.7% | 17.6% | 8.0% | 0.20%(polycarbophil and thoroughly The mass ratio of bright matter acid sodium is 3:1) | — | — | — |
| Comparative example 1 | 6.7% | 17.6% | 8% | 0.6% polycarbophil | 0.1% (EDTA) | 0.1%(benzene Sodium formate) | 0.8% is burnt sub- Potassium sulfate |
| Comparative example 2 | 6.7% | 17.6% | 8% | — | 0.1% (EDTA) | 0.1%(benzene Sodium formate) | 0.8% is burnt sub- Potassium sulfate |
As shown in Figure 1, the preparation method of the mesalazine thermo-sensitive gel enema fluid of above-described embodiment, steps are as follows:
(1) bioadhesive material is placed in water, stirs to being uniformly dispersed, the first mixture is made；
(2) temperature sensitive hydrogel matrix is slowly added into the first mixture under stiring, soaks it sufficiently, in 4 DEG C
Lower to place 24 hours, until temperature sensitive hydrogel matrix complete swelling is the clear solution without agglomerate, stirring is allowed to uniformly, be made second
Kind mixture；
(3) it takes stabilizer to be added slowly with stirring into second of mixture, stirs to being completely dissolved, be eventually adding master
Medicine mesalazine and water supplement are protected from light and continue stirring until medicaments uniformity is suspended to enough to obtain the final product.
The property of mesalazine thermo-sensitive gel enema fluid made from above-described embodiment is measured, as a result as follows:
One, evaluation index
Gelation temperature (Tgel) measurement: using be inverted determination of tube method Tgel, take gel solution 2mL in test tube, be placed in
It slowly heats up in water bath with thermostatic control, heating rate is about 0.2 DEG C of min-1, it is every to increase 0.2 DEG C, it is inverted test tube rapidly, observes solution
Mobility status, defining temperature when solution no longer flows in test tube is gelation temperature, and each sample is measured 3 times, is averaged.
The measurement of viscosity before plastic: using viscosity before rotational viscometer measurement sample plastic, each sample is measured 3 times, is taken
Average value.
The measurement of sedimentation volume ratio: apparatus plug graduated cylinder takes medicine-containing gel solution 25mL, and close plug firmly shakes 1 minute, writes down
The high H of the beginning of suspended matter0, 3h is stood, the final height H of suspended matter is write down, is calculated as follows: sedimentation volume ratio=H/H0。
The measurement of adhesion strength: bibliography adhesion strength measuring method and the slightly modified adhesion property for investigating preparation.It will be straight
The glass surface ware of diameter 6cm fills water, and capping is placed in 37 DEG C of water-baths, and top is higher by the water surface about 0.5cm, when balancing one section
Between.Appropriate amount of sample is added to surface plate top, after complete gelation, the slide (2.5cm × 2.5cm) of preheating is placed in sample
On, and slide is fitted closely with gel with 50g counterweight compacting 3min, small hook, filament, cuvette and dropping system are installed, opened
Water (5mL min is at the uniform velocity added dropwise into cuvette for drip control valve-1) until slide starts to move, remove cuvette weighing.Unit area
Adhesion strength calculation formula: f=9.8m/s, m are cuvette quality, and s is the area of slide.
| Embodiment | Adhesion strength (mN.cm-2) | Gelation temperature (DEG C) | Viscosity (mPas) 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 | / | It cannot flow freely at 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 data such as viscosity before the adhesion strength of each embodiment of comprehensive analysis, gelling temp and gel:
1, comparative example 1 ~ 3 can be seen that, poloxamer188 is shared in the mesalazine thermo-sensitive gel enema fluid
Mass percent most preferably 17.6%, PLURONICS F87 quality percentage shared in the mesalazine thermo-sensitive gel enema fluid
Than most preferably 8.0%.
2, comparative example 1,4,5 can be seen that, the addition of bioadhesive material can be improved the adhesion strength of system, with life
The raising of object adhesion material concentration, adhesion strength are gradually increased, and with the raising of bioadhesive material concentration, gelation temperature is risen
Height, but elevation amplitude is little；Viscosity and sedimentation volume ratio increase with the raising of bioadhesive material concentration before plastic；Biology
Adhesion material slightly influences gel rubber system pH, and as bioadhesive material concentration increases, system pH is gradually decreased.Work as biological slime
For the ratio of enclosure material greater than when increasing to 0.4%, adhesion strength is maximum, but viscosity alreadys exceed 1000mPa.s before striking a bargain at this time,
It cannot flow freely at room temperature.
3, comparative example 1,6 and 7 can be seen that, bioadhesive material is that the mass ratio of polycarbophil and Sodium Hyaluronate is
When the mixture of 1:3 ~ 3:1, the viscosity before the adhesion strength of mesalazine thermo-sensitive gel enema fluid, gelling temp and gel is relatively suitable
Preferably, the mixture of the most preferably polycarbophil of bioadhesive material and hyaluronic acid mass ratio 3:1.
4, comparative example 1,8 and 9, the bioadhesive material of embodiment 1 are the quality of polycarbophil and Sodium Hyaluronate
Than the mixture for 3:1, the adhesion strength performance of 1 mesalazine thermo-sensitive gel enema fluid of embodiment is substantially better than bioadhesive material
Select the embodiment 9 and 10 of Sodium Hyaluronate or polycarbophil.
5, comparative example 1 and 10 ~ 13, the addition of antioxidant, metal chelating agent and preservative are temperature sensitive to mesalazine solidifying
Viscosity and sedimentation volume ratio have little effect before the adhesion strength of glue enema fluid, gelling temp, plastic, with antioxidant coke sulfurous
The increase of sour potassium application rate, pH are slightly reduced.
6. the addition of comparative example 1 and comparative example 1,2, bioadhesive material can increase the adhesion strength of system, and add
It is excessively high that dosage excessively then will lead to system viscosity, is not suitable for the application of mesalazine thermo-sensitive gel enema fluid.
Two release in vitro
Mesalazine is measured from the release in thermo-sensitive gel using dynamic dialysis method.The U.S. salad prepared in Example 1
Piperazine thermo-sensitive gel enema fluid 2g is placed in by pretreated bag filter, bag filter both ends are tightly revealed with linear system to prevent stopping leak, and 37 DEG C
Under the conditions of sufficiently be gelled after bag filter is put into 37 DEG C of pH7.4 phosphate buffer solutions of 100mL, in 37.0 DEG C ± 0.5 DEG C
With 100 r min-1 rate oscillations in constant temperature oscillator, 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 buffer solutions of equivalent immediately.After sample is rationally diluted,
Absorbance is measured at 316nm, then calculates Accumulation dissolution, and each sample is measured 3 times, is averaged.It is measured in the same method commercially available beauty
Salad piperazine enema fluid vitro release, is as a result shown in Fig. 2.
As shown in Figure 2, commercially available mesalazine enema fluid drug is about discharged in 79.0%, 4h in 2h and is discharged completely；And embodiment
Mesalazine (5-ASA) release when the preparation of 2h is 42.8%, 4h reaches in 1 mesalazine thermo-sensitive gel enema fluid
Release completely, illustrates that the 5-ASA thermo-sensitive gel enema fluid of embodiment 1 has certain slow releasing function in 74.2%, 8h.
Three, stability test
1. influence factor is tested
The mesalazine thermo-sensitive gel enema fluid of Example 1 and 10 ~ 13 places 5d's and 10d in high temperature (60 DEG C) condition
Stability data is as follows.As the result is shown compared with original state (when 0), 5d drug content has and obviously reduces.
Comparative example 1,10 ~ 12 and embodiment 13, mesalazine stability, which has, to be greatly improved, and illustrates to add in prescription
Entering potassium metabisulfite is necessary.
Comparative example 1,10 and 11, as dosage of the antioxidant potassium metabisulfite in prescription increases, stability slightly has
It improves, but after dosage of the potassium metabisulfite in prescription reaches 0.8%, is further continued for increasing the dosage of sodium pyrosulfite, to U.S. husky
Draw the contribution of piperazine stability little.
Comparative example 1 and embodiment 12 illustrate that metal chelating agent EDTA is added in prescription helps to improve stability.
Stability test
The 5-ASA thermo-sensitive gel enema fluid of Example 1 test sample three batches simulates commercially available back, is placed in 40 DEG C ± 2 of temperature
DEG C, place 6 months under the conditions of relative humidity 25% ± 5%, primary respectively at sampling in the 0th, 1,2,3,6 month during test, observation
And test sample appearance character is recorded, measurement gelation temperature, pH, viscosity, sedimentation volume ratio, 5-ASA content and related substance.
As a result it see the table below:
Compared with original state (when 0), suspension color gradually becomes light brown by milky, and pH is controlled without significant change
System is in 4.0 ~ 5.0 ranges；Drug content slightly reduces, but reduces amplitude within 3%, still in mark range, related substance
It meets the requirements；Gelation temperature, viscosity and sedimentation volume ratio are without significant change.Therefore indices property is stablized.
Four, zoopery
Healthy female BALB/c mouse 40 are chosen, 6 ~ 8 week old, 20 ~ 22g of weight is randomly divided into 4 groups, respectively A: just
Normal group；B: physiological saline group；C: mesalazine enema fluid group (referred to as: commercially available group)；D: the 5-ASA thermo-sensitive gel of embodiment 1 fills
Intestinal juice group (referred to as: embodiment 1).
The preparation and medication of acute ulcer Colitis Model
Chmice acute Ulcerative Colitis Model is prepared by the way of freely drinking DSS aqueous solution, in addition to A group, other
Three groups of equal modelings, freely drink 3.5%DSS aqueous solution 5 days, replace fresh DSS solution daily, and A group gives normal drinking water 5
It.Model foundation successfully indicates any disease occurred in half loose stools, diarrhea, the fecal occult blood positive and naked eyes bloody stool for mouse
Shape.Modeling success next day bowel lavage gives relative medicine, and it is equivalent that two groups of daily bowel lavage dosage of dosages behaviour of C, D are converted to mouse
Dosage is 520mg/kg(based on 5-ASA), continuous 7 days；B group dosage is relative to D group Rapid Dose Calculation and medicine-containing gel equivalent
Physiological saline, continuous 7 days；A group normal diet, it is without any processing.
Disease activity index (disease activity index, DAI) assessment
Observe mouse general activity situation, record changes of weight, stool and fecal occult blood feelings daily from on-test
Condition, bibliography standard are simultaneously done suitably modified progress DAI scoring, be see the table below.
| Score | Stool | Fecal occult blood |
| 0 | Normally | It does not develop the color after 2min |
| 1 | ╲ | Aubergine is just gradually generated in 1 ~ 2min |
| 2 | Loosely | Aubergine is generated in 1min |
| 3 | ╲ | Hyacinthine is generated in 10s |
| 4 | Loose stools | Hyacinthine is generated immediately |
* normal to defecate: forming stool；Loose stool: paste, the half form stool of anus are not adhere to；Loose stools: adhesive
It defecates in dilute water sample of anus.
From figure 3, it can be seen that physiological saline group mouse weight mitigates trend and gradually slows down during administration, commercially available group and implementation
1 group of mouse of example no longer mitigated in the 8th day beginning weight, and as administration number of days increases, some mouse weights go up；Administration knot
Shu Hou, commercially available group obviously higher than physiological saline group (P < 0.05), but between two groups, nothing is significant with example 1 group mouse weight
Sex differernce (P > 0.05).It is normal to organize mouse stool by observing each group mouse stool and the discovery of fecal occult blood situation daily
Normally, scoring maintains zero level always；Three groups of mouse by modeling start to gradually appear loose, loose stools of defecating on day 3,
Serious person's visual bloody stool, visible bloodstain on padding, stool occult blood is in positive in various degree；During administration, with administration number of days
Increase, three groups of mouse stools and fecal occult blood scoring it is on a declining curve, the score value of example 1 group is substantially less than it
He is two groups.As a result see Fig. 4 ~ 5.
The damage of colon mode of appearance and Histological injury's assessment
Mouse after the last administration, for 24 hours, put to death for fasting, and the entire intestinal segment at anus end to cap end is taken out in dissection by anesthesia,
The variation of each group colon mode of appearance is observed, is scored referring to following table standard.
| Score | Form |
| 0 | It is not damaged |
| 1 | Mucous membrane hyperemia, oedema, without ulcer |
| 2 | Mucous membrane hyperemia, oedema, it is slight rotten to the corn, without ulcer |
| 3 | Mucous membrane hyperemia, oedema, moderate is rotten to the corn, has single ulcer |
| 4 | Mucous membrane hyperemia, oedema, height is rotten to the corn, has many places ulcer |
| 5 | Mucous membrane hyperemia, oedema, severe is rotten to the corn, has 1cm or more ulcer |
Mouse Colon is longitudinally splitted along mesenteric border, ice physiological saline clean intestinal contents, in have extensive inflammation or
Take tissue specimen after 4% paraformaldehyde is fixed at ulcer, conventional dehydration and paraffin embedding after 5 μm are sliced, carry out conventional H E dye
Color carries out colonic tissue pathological examination under optical microscopy, scores referring to following table standard.
| Score | Degree of inflammation | Injured depth | Crypts destroys | Extent of disease (%) |
| 0 | Nothing | Nothing | Nothing | Nothing |
| 1 | Slightly | Submucosa | 1/3 crypts of substrate is destroyed | 1~25 |
| 2 | Moderate | Muscle layer | 2/3 crypts of substrate is destroyed | 26~50 |
| 3 | Severe | Placenta percreta | Only full surface epithelium | 51~75 |
| 4 | ╲ | ╲ | Whole crypts and epithelium are destroyed | 76~100 |
Statistical analysis is carried out to result using SPSS19.0 software, measurement data uses mean ± SD to indicate, variance is neat
Property examine after, the comparison of each group difference uses one-way analysis of variance (One-way ANOVA), is that difference has with P < 0.05
It is statistically significant.
As a result it see the table below:
| Group | Colon mode of appearance Injury score | Colon histology Injury score |
| Normal group | 0.00±0.00 | 0.00±0.00 |
| Physiological 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 |
aCompared with normal group, P < 0.05；bCompared with physiological saline group, P < 0.05；cCompared with commercially available group, P < 0.05
Each group mouse Colon mode of appearance is visually observed, normal group mouse Colon mucous membrane is smooth, and intestinal wall is thin, blood vessel under mucous membrane
Clean mark, no congested, oedema, no rotten to the corn and ulcer；Physiological saline group mouse Colon rough surface is in granular form, and intestinal wall increases
Thickness, torsional deformation, intestinal mucosa hyperemia, oedema, it is seen that gently to severe erosion and ulcer；Commercially available group of mouse Colon intestinal wall thickens, intestines
Mucous hyperemia, oedema, slight rotten to the corn, a small number of visible aphtha stoves；Example 1 group mouse Colon intestinal wall thickens, and intestinal mucosa is slight
Congested, oedema, the visible slight erosion of only 2 mouse, but have no ulcer stove.Outside the colon of commercially available group and example 1 group mouse
It sees form Injury score and is significantly lower than physiological saline group (P < 0.05)；Example 1 group has lower knot compared with commercially available group
Intestines mode of appearance Injury score, and the two difference has statistical significance (P < 0.05).Mouse Colon histological damage score knot
Fruit shows that the scoring of commercially available group and example 1 group is substantially less than physiological saline group (P < 0.05), and example 1 group scoring is minimum,
Compared with commercially available group, the two difference has statistical significance (P < 0.05).
In conclusion compared with physiological saline group and commercially available group, example 1 group (the mesalazine thermo-sensitive gel of embodiment 1
Enema fluid) curative effect it is more excellent.It also found during being administered simultaneously, after physiological saline group and commercially available group of mouse bowel lavage administration, nearly all
There is different degrees of leakage, and example 1 group then occasionally has mouse to reveal, and illustrates using thermo-sensitive gel as mesalazine
Carrier, then it is aided with bioadhesive material, it can effectively extend mesalazine in the residence time of colon site, so as to improve curative effect.
Five, pathology
Female sd inbred rats 9 are chosen, 200 ~ 250g of weight is randomly divided into 3 groups, respectively A: physiological saline group；B: blank
Example 1 group；C: the temperature sensitive example 1 group of mesalazine colon.The daily bowel lavage of C group gives mesalazine colon thermo-sensitive gel
(preparing according to embodiment 3), dosage are 360mg/kg(based on mesalazine), continuous 7 days；Physiology salt is given once daily in A group and B group
Water and Blank gel without mesalazine, dosage is the medicine corresponding to medicine-containing gel equivalent calculated relative to C group dosimeter
Object, continuous 7 days.Observation each group rat body weight, the state of mind and activity condition daily.In after the last administration, Rat Fast for 24 hours,
Anesthesia is put to death.The entire intestinal segment at anus end to cap end is taken out in dissection, visually observes the variation of each group colon mode of appearance.It will
Colon is cut off along mesenterium edge, ice normal saline flushing excrement, to avoid because of mechanical stimulus in bowel lavage administration process caused by it is scorching
Property interference test as a result, tissue specimen takes away from bowel lavage depth upper end 1cm or so colon sample after 4% paraformaldehyde is fixed, it is conventional
Dehydration and paraffin embedding are sliced (5 μm), conventional H E dyeing, carry out colonic tissue pathological examination under optical microphotograph.
The results show that each group rat body weight during medication, ingest, stool it is normal, each group is visually observed after dissection
Colon mode of appearance, phenomena such as being showed no obvious congested, oedema or mucous membrane bleed bottom.Optical microphotograph microscopic observation colonic tissue disease
Reason slice is shown in Fig. 6, and for three groups of Colon mucosa cells without denaturation, necrosis, the distribution of lamina propria body of gland is normal, has no congested, water
Swollen and cell infiltration, submucosa, muscularis mucosae and adventitial tissue structural integrity, no abnormality seen change.The experimental results showed that
Mesalazine colon has good vivo biodistribution compatibility with thermo-sensitive gel.
Embodiment described above is only to absolutely prove preferred embodiment that is of the invention and being lifted, protection model of the invention
It encloses without being limited thereto.Those skilled in the art's made equivalent substitute or transformation on the basis of the present invention, in the present invention
Protection scope within.Protection scope of the present invention is subject to claims.
Claims (8)
1. a kind of mesalazine thermo-sensitive gel enema fluid, which is characterized in that its ingredient includes: main ingredient, temperature sensitive hydrogel matrix, life
Object adhesion material and water,
Wherein the main ingredient is mesalazine, and shared mass percent is in the mesalazine thermo-sensitive gel enema fluid
6.7%；
The temperature sensitive hydrogel matrix is made of poloxamer188 and PLURONICS F87, and poloxamer188 is in the U.S. salad
Shared mass percent is 16%~19% in piperazine thermo-sensitive gel enema fluid, and PLURONICS F87 is temperature sensitive in the mesalazine
Shared mass percent is 3%~12% in gel enema fluid；
Bioadhesion material mass percent shared in the mesalazine thermo-sensitive gel enema fluid is 0.2%；
The bioadhesive material is made of polycarbophil and Sodium Hyaluronate, and the mass ratio of polycarbophil and Sodium Hyaluronate is
3:1。
2. mesalazine thermo-sensitive gel enema fluid according to claim 1, which is characterized in that poloxamer188 is described
Shared mass percent is 17.6% in mesalazine thermo-sensitive gel enema fluid；PLURONICS F87 is in the mesalazine temperature
Shared mass percent is 8.0% in quick gel enema fluid.
3. mesalazine thermo-sensitive gel enema fluid according to claim 1, which is characterized in that it further include stabilizer, it is described
Stabilizer include: metal chelating agent, preservative and antioxidant.
4. mesalazine thermo-sensitive gel enema fluid according to claim 3, which is characterized in that the antioxidant is burnt sulfurous
Sour potassium.
5. mesalazine thermo-sensitive gel enema fluid according to claim 3, which is characterized in that the metal chelating agent be according to
Ground acid disodium.
6. mesalazine thermo-sensitive gel enema fluid according to claim 3, which is characterized in that the preservative is benzoic acid
Sodium.
7. mesalazine thermo-sensitive gel enema fluid according to claim 1, which is characterized in that the mesalazine is temperature sensitive solidifying
The pH value of glue enema fluid is 4.0~5.0.
8. the preparation method of the described in any item mesalazine thermo-sensitive gel enema fluids of claim 1~7, which is characterized in that packet
Include following steps:
(1) bioadhesive material is placed in water, stirs to being uniformly dispersed, the first mixture is made；
(2) temperature sensitive hydrogel matrix is added into the first mixture under stiring, soaks it sufficiently, is transferred in 0~5 DEG C
It sets, until temperature sensitive hydrogel matrix complete swelling is the clear solution without agglomerate, stirring is allowed to uniformly, second of mixture be made；
(3) it takes stabilizer to be added in second of mixture under stiring, stirs to being completely dissolved, be eventually adding main ingredient and add
Water is protected from light and continues stirring until medicaments uniformity is suspended to enough to obtain the final product.
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| 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 |
| 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 |
| 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 |
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| CN104706582A (en) * | 2013-12-12 | 2015-06-17 | 四川健能制药有限公司 | Mesalazine-containing drug composition |
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