CN103784394A - Intelligent temperature-sensitive sustained-release gel and preparation method thereof - Google Patents

Abstract

The invention discloses an intelligent temperature-sensitive sustained-release gel and a preparation method thereof. The intelligent temperature-sensitive sustained-release gel comprises the following components in percentage by weight: 15-25 percent basic remedy, in-situ gel material and water, 2-3 percent of poloxamer 188, 0.5-1 percent of polyethylene glycol-6000, 5-7 percent of ornidazole and 60-70 percent of distilled water. An intelligent temperature-sensitive sustained-release in-situ gel drug-loading system is prepared by combining medicaments with different types of high molecular carrier materials, and is applied to root canal treatment for the first time, so that the defects that the lasting time of the conventional root canal disinfecting and sterilizing effects is short, root canals cannot be fully filled with medicaments under the limitation of dosage form and the like are overcome, the root canal disinfecting operation is simplified, and the double effects of sustained-release long-acting treatment and root canal enclosing are achieved. The one-time success rate of root canal treatment is increased, and the intelligent temperature-sensitive sustained-release gel has an important practical value on the treatment of pulposis, pulpitis and periapical periodontitis and the like.

Description

Intelligence temperature sensitive type sustained-release gel and preparation method thereof

Technical field

The present invention relates to a kind of pharmaceutical preparation, relate in particular to a kind of intelligent temperature sensitive type sustained-release gel and preparation method thereof.

Background technology

At present, odontopathy is ubiquity in crowd, and it is weaker that majority prevent and treat consciousness, is easy to cause deterioration, causes the profound pathological changes of tooth, the pain endurable of generation, and common such as dental pulp disease and periapical disease, its arch-criminal is that antibacterial infects.

Root canal is the primary treatment means of department of stomatology treatment dental pulp disease and periapical disease, and root canal disinfection is an important step of root canal.The root pipe of crossing through Mechanical Method and chemical Treatment, its sidewall dentin deep layer, collateral pulp canal and the tip of a root around wait the existence that still has some downright bad materials or microorganism, are further to eliminate or minimizing microorganism, promote periapical tissue's healing, should carry out root canal disinfection thoroughly.Conventional medication has traditional cotton to twist with the fingers phenol camphor (CP), formaldehyde cresol formocresol (FC), calcium hydroxide paste clinically at present, iodoform paste envelope medicine, polymeric gel agent etc.

Tradition root canal disinfection means, having very large deficiency aspect medication and long-term bacteriostasis, need further be improved.Much research shows that FC has whole body toxic and side effects, and fuse is subject to the impact of saliva, blood, blood plasma, transudate and many bacterial products after 24 hours, can lose bacteriostasis at inclosure root pipe; Calcium hydroxide paste, iodoform paste, high-molecular gels etc. are because preparation is certainly as solid or semisolid, and the very little and tiny branch in root canal aperture is many, therefore paste, polymeric gel agent are in carrying out root of the tooth canal sealant, operate limited, be difficult to be full of root pipe completely, do not enclose the position of medicine and cannot play sterilization effect.

The more route of administration of research has both at home and abroad at present: mucosa delivery, and drug administration by injection, tympanum administration, percutaneous dosings etc., do not have no report so far in root canal treatment field.

Summary of the invention

Object of the present invention is just to provide in order to address the above problem a kind of intelligent temperature sensitive type sustained-release gel and preparation method thereof.

The present invention is achieved through the following technical solutions above-mentioned purpose:

A kind of intelligent temperature sensitive type sustained-release gel, comprise principal agent, situ-gel material, water, PLURONICS F87, PEG-4000, ornidazole and distilled water, wherein: principal agent, situ-gel material and water account for 15～25%, described PLURONICS F87 accounts for 2～3%, described PEG-4000 accounts for 0.5～1%, described ornidazole accounts for 5～7%, and described distilled water accounts for 60～70%.

Situ-gel material of the present invention is that PLURONICS F87, poloxamer188, polyethylene glycol-polylactic acid block copolymer, polyethylene glycol-ε caprolactone segmented copolymer, cellulose derivative class are if ethyl-hydroxyethyl fiber, polysaccharide derivatives are as the wherein one or wherein several in chitosan or poly-N-isopropyl acrylamide.

Situ-gel material of the present invention is ornidazole, and tinidazole, iodoform, acetyl Roxithromycin, Chinese medicine are as the wherein one or wherein several in SHUANGHUANLIAN, rubescensine A, ester.

A kind of preparation method of intelligent temperature sensitive type sustained-release gel is: cold cut preparation method and film dispersion method;

Cold cut preparation method: principal agent and the PEG-4000 of getting recipe quantity are dissolved in appropriate distilled water, stirring and dissolving, then add poloxamer188 and the PLURONICS F87 dispersed with stirring of recipe quantity, after put into 4 ℃ of refrigerator cold-storages 24 hours, obtain clear solution;

Film dispersion method: the principal agent and the PLGA-PEG-PLGA block copolymer that take recipe quantity, dissolve by proper amount of acetone, then vacuum rotary steam is removed acetone, and medicine is dispersed in the thin film of polymer formation uniformly, add distilled water or buffer hydrated films, form polypeptide drug-loaded micelle solution.

Beneficial effect of the present invention is:

The present invention is a kind of intelligent temperature sensitive type sustained-release gel and preparation method thereof, compared with prior art, the present invention adds some antibacterials take temperature sensitive type in-situ gel as carrier, the medicine carrying temperature sensitive type in-situ gel being prepared into is at normal temperatures for can flowing liquid, syringeability is good, medicine is fully contacted with root canal, avoid dead angle, stop antibacterial intrusion and cause superinfection, and sterilizing that can be slowly lasting, and remove simple to operation, be convenient to dispenser repeatedly, in reducing root dressing operation easier, greatly improve the efficiency of kill bacteria, can fill and lay the first stone for later stage root pipe, only by an asepsis injector, adopt the method for an injection head of a patient, operate handy and safe more with respect to traditional disinfection way, effect is better, the material that this research is selected, all without obvious stimulation abnormal smells from the patient, has certain biocompatibility, puts into mouth and is convenient to patient's acceptance, effectively make up the deficiency of traditional root canal disinfection method, greatly improved root canal one-time success rate, the treatments such as dental pulp disease have been had to material impact.

Especially the present invention adopts medicine is combined with dissimilar polymer carrier, prepare intelligent temp-sensitive, slow-releasing situ-gel drug-loading system, and be applied to first root canal, effectively made up that traditional root canal disinfection fungistatic effect is short, medicine is subject to dosage form restriction cannot be full of the drawback of root canal etc., simplify root canal sterilizing operation, there is the dual function for the treatment of and the root canal sealing of slow release long-acting; Improve the one-time success rate of root canal treatment, the treatments such as dental pulp disease, all diseases of apex of root of tooth have been had to great practical value.

The specific embodiment

Below in conjunction with embodiment, the invention will be further described:

The present invention includes principal agent, situ-gel material, water, PLURONICS F87, PEG-4000, ornidazole and distilled water, wherein: principal agent, situ-gel material and water account for 15～25%, described PLURONICS F87 accounts for 2～3%, described PEG-4000 accounts for 0.5～1%, described ornidazole accounts for 5～7%, and described distilled water accounts for 60～70%.

Situ-gel material of the present invention is that PLURONICS F87, poloxamer188, poly-7 glycol-polylactic-acid block copolymer, polyethylene glycol-ε caprolactone segmented copolymer, cellulose derivative class are if ethyl-hydroxyethyl fiber, polysaccharide derivatives are as the wherein one or wherein several in chitosan or poly-N-isopropyl acrylamide.

Situ-gel material of the present invention is ornidazole, and tinidazole, iodoform, acetyl Roxithromycin, Chinese medicine are as the wherein one or wherein several in SHUANGHUANLIAN, rubescensine A, ester.

Preparation method of the present invention is: cold cut preparation method and film dispersion method;

Cold cut preparation method: principal agent and the PEG-4000 of getting recipe quantity are dissolved in appropriate distilled water, stirring and dissolving, then add poloxamer188 and the PLURONICS F87 dispersed with stirring of recipe quantity, after put into 4 ℃ of refrigerator cold-storages 24 hours, obtain clear solution;

Film dispersion method: the principal agent and the PLGA-PEG-PLGA block copolymer that take recipe quantity, dissolve by proper amount of acetone, then vacuum rotary steam is removed acetone, and medicine is dispersed in the thin film of polymer formation uniformly, add distilled water or buffer hydrated films, form polypeptide drug-loaded micelle solution.

Embodiment mono-:

5 parts of ornidazoles are dissolved in appropriate distilled water with 0.5 part of PEG-4000, and then stirring and dissolving adds 20 parts of poloxamer188s and 2.5 parts of dispersed with stirring of PLURONICS F87, after put into 4 ℃ of refrigerator cold-storages 24 hours, obtain clear solution.

Gelation temperature is measured:

Adopt magnet rotor method to measure, getting appropriate gel solution packs in cillin bottle, add stirrer, insertion precision is the precision thermometer of 0.1 ℃, and the mercury ball of thermometer is immersed in gel solution completely, put it in low temperature (10 ℃) water-bath, rotating speed 300rpm, keeps water-bath to continue slowly to heat up, and makes the temperature rate-of-rise of gel be about 1-2 ℃/min, with temperature rise, the temperature in the time that stirrer stops operating is gelation temperature.

The irritant experiment of situ-gel material:

Carry out skin irritation test with rabbit, get 8 of healthy rabbits (male and female half and half), be divided into two groups, adopt depilatory to be lost hair or feathers by hair to rabbit spinal column both sides, the about 25cm2 of every side depilation area, after depilation 24h, check whether baring skin has erythema, edema and breakage, first group 4 (male and females half and half) carry out intact skin irritation test, second group 4 (male and females half and half) set up injured skin model, draw " well " word at unhairing place with aseptic syringe needle, be advisable to scratch epidermis oozing of blood, the damaged degree of controlling both sides skin is consistent, adopt the method for spinal column both sides contrast, one side is smeared the gel solution of preparation, opposite side is smeared normal saline, the observation of comparing after a period of time.

The vitro release of the situ-gel material of pastille is measured:

Preparation Isolated Tooth, get the fresh root development of pulling out 10 of single pipe teeth completely, clip corona, clean and remove soft dirt, soft tissue, the upper and lower calculus of gum of the agomphiasis of pulling out by ultrasonic scaler removal part periodontal disease, is stored in 4 ℃, stand-by in pH7.4 normal saline, period of storage adds experimental period and is no more than 4 weeks.Release test: the liquid pastille situ-gel of preparation is injected in ready isolated tooth root pipe, and seal temporarily hole with Oleum Caryophylli cement, Isolated Tooth is placed in to test tube, and 1 of every pipe, adds 300ul to steam radium water, 0.5 ℃ of water-bath of 37 ℃ of scholars, every 24 hours, 4 ℃ of preservations of taking-up 300ul sample were to be measured, then add equivalent distilled water to continue by above-mentioned condition water-bath, continue 10 days, after measure situ-gel release situation by high performance liquid chromatogram.

Claims (4)

1. an intelligent temperature sensitive type sustained-release gel, comprise principal agent, situ-gel material and water, it is characterized in that: also comprise PLURONICS F87, PEG-4000, ornidazole and distilled water, wherein: principal agent, situ-gel material and water account for 15～25%, described PLURONICS F87 accounts for 2～3%, described PEG-4000 accounts for 0.5～1%, and described ornidazole accounts for 5～7%, and described distilled water accounts for 60～70%.

2. intelligent temperature sensitive type sustained-release gel according to claim 1, is characterized in that: described situ-gel material is that PLURONICS F87, poloxamer188, polyethylene glycol-polylactic acid block copolymer, polyethylene glycol-ε caprolactone segmented copolymer, cellulose derivative class are if ethyl-hydroxyethyl fiber, polysaccharide derivatives are as the wherein one or wherein several in chitosan or poly-N-isopropyl acrylamide.

3. according to the intelligent temperature sensitive type sustained-release gel of claim 1, it is characterized in that: described situ-gel material is ornidazole, tinidazole, iodoform, acetyl Roxithromycin, Chinese medicine are as the wherein one or wherein several in SHUANGHUANLIAN, rubescensine A, ester.

4. a preparation method for intelligent temperature sensitive type sustained-release gel, is characterized in that, comprises cold cut preparation method and film dispersion method;

Cold cut preparation method: principal agent and the PEG-4000 of getting recipe quantity are dissolved in appropriate distilled water, stirring and dissolving, then add poloxamer188 and the PLURONICS F87 dispersed with stirring of recipe quantity, after put into 4 ℃ of refrigerator cold-storages 24 hours, obtain clear solution;

Film dispersion method: the principal agent and the PLGA-PEG-PLGA block copolymer that take recipe quantity, dissolve by proper amount of acetone, then vacuum rotary steam is removed acetone, and medicine is dispersed in the thin film of polymer formation uniformly, add distilled water or buffer hydrated films, form polypeptide drug-loaded micelle solution.