CN103169649A - Temperature and ion dual-sensitive in-situ gel nasal cavity drug delivery system - Google Patents
Temperature and ion dual-sensitive in-situ gel nasal cavity drug delivery system Download PDFInfo
- Publication number
- CN103169649A CN103169649A CN201310125441XA CN201310125441A CN103169649A CN 103169649 A CN103169649 A CN 103169649A CN 201310125441X A CN201310125441X A CN 201310125441XA CN 201310125441 A CN201310125441 A CN 201310125441A CN 103169649 A CN103169649 A CN 103169649A
- Authority
- CN
- China
- Prior art keywords
- situ
- temperature
- gel
- sensitive type
- ion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses a temperature and ion dual-sensitive in-situ gel nasal cavity drug delivery system, comprising a main drug and a temperature and ion dual-sensitive in-situ gel matrix, wherein the temperature and ion dual-sensitive in-situ gel matrix is mainly prepared from the following raw materials of temperature sensitive in-situ gel matrix, ion sensitive in-situ gel matrix, and a penetration enhancer. The drug delivery system disclosed by the invention is especially suitable for a drug of achieving the central pivot through a BBB (blood brain barrier) to play a role, has good sprayable property and good in-situ gel property and drug slow-release effect, and benefits for playing the drug effect.
Description
Technical field
The present invention relates to a kind of local medicine-applying system, particularly relate to a kind of temperature and ion Dual Sensitive type in-situ gel nasal-cavity administration system.
Background technology
Blood brain barrier (Blood-Brain Barriers, BBB) is that medicine enters the main barrier in brain, adopts nasal-cavity administration can walk around BBB.Nasal cavity is maintained close ties with brain anatomically, and drug molecule enters cerebrospinal fluid by olfactory bulb after being absorbed by the regio olfactoria mucosa, then enters brain performance drug effect by cerebrospinal fluid-brain barrier.Due to cerebrospinal fluid-brain barrier to the barrier effect of medicine than BBB a little less than 5000 times of left and right, so nasal drug delivery system to be used for the brain drug delivery with the obvious advantage.
In recent years, in the ascendant with thermosensitive in situ gel and the systematic research of ion-sensitive type in-situ gel nasal-cavity administration.Situ-gel (in-situ gel) claims again at body gel, gel in place, be macromolecular material with solution or semi-solid state administration after, stimulate to external world (temperature of agents area, pH value, ionic species and concentration at medicine-feeding part.The variations such as illuminance) respond, the reversible conversion of dispersity or conformation occurs, form semisolid or solid preparation.Wherein, better with the physiological compatibility to the responsive to temperature type gel of variations in temperature response.Responsive to temperature type gel preparation (room temperature) before storage and administration exists with liquid or semisolid form, and after topical, Yin Wendu raises (body temperature) and gel solution is condensed, and forms to have good adhesiveness and the gel of sustained release performance.Because the responsive to temperature type gel has that manufacture is comparatively simple, physiological compatibility is good, dosage is easy to control and the advantage such as adhesiveness is good, novel eye, nose, rectum and drug administration by injection system have been widely used in recent years.But there is the shortcoming that the gel phase temperature is low, gel erosion is fast in simple thermosensitive in situ gel, with the gel that also do not have enough time to form after solution form spray delivery, runs off, and can not embody the advantage that the gel Local Residence Time is long, be conducive to drug absorption.Ionic strength sensitive in situ gels research material refers to that material character is relevant with environment intermediate ion intensity, and the variation of ionic strength directly affects the viscosity of material in solution, namely forms the degree of gel.Ion is generally Na
+, K
+, Ca
2+, Zn
2+But simple ion-sensitive type situ-gel drug-supplying system gelation time in nasal cavity is long and the burst drug release phenomenon is serious.
Ketorolac tromethamine (ketorolac tromethamine, be called for short ketorolac) is novel nonsteroidal analgesia, anti-inflammatory drug, and this medicine analgesic activity produce effects is fast, longer duration, and action intensity and morphine, Pethidine is similar but without addiction.The listing product is Ketoralac ammonia butanediol nasal mist at present, is to be used at present acute moderate to the most frequently used medicine of severe pain short term therapy.But spray easily runs off, and is short in the nasal mucosa local action time, is unfavorable for the drug effect performance.
Summary of the invention
In order to overcome the problem of prior art, the object of the present invention is to provide a kind of temperature and ion Dual Sensitive type in-situ gel nasal-cavity administration system, described nasal drug delivery system comprises principal agent and temperature and ion Dual Sensitive type situ-gel substrate, and wherein said temperature and ion Dual Sensitive type situ-gel substrate are mainly made by following raw material:
Thermosensitive in situ gel substrate, described thermosensitive in situ gel substrate is selected from poloxamer188 (PoloXamer407, P407), any one or a few in PLURONICS F87 (PoloXamer188, P188), methylcellulose, hypromellose, chitosan derivatives, polylactic acid-polyethylene glycol block copolymer, polylactic-co-glycolic acid-polyethyleneglycol block copolymer, second hydroxy ethyl cellulose, polycaprolactone polyethyleneglycol block copolymer, poly-N-isopropyl acrylamide;
Ion-sensitive type situ-gel substrate, described ion-sensitive type situ-gel substrate are selected from alginate, gellan gum any one or two kinds; And
penetration enhancer, described penetration enhancer is selected from oleyl alcohol, lauryl alcohol, hexadecanol, oleic acid, lauric acid, linoleic acid, isopropyl cetylate, the isopropyl myristin, lanoline, cineole, menthol, the dodecane Azone, Camphora, liquid paraffin, dimethicone, methanol, ethanol, glycerol, isopropyl alcohol, Polyethylene Glycol, thymol, dimethyl sulfoxide, glycocholate, N, N-dimethyl cresol amine, N, the N-dimethyl acetylamide, carbamide, EDTA-2Na, cyclodextrin, HP-β-CD, sulfobutyl ether-beta-schardinger dextrin-, 1-Methyl-2-Pyrrolidone, N, N-two (α-ethoxy) oleamide, sodium laurylsulfate, dodecyl dimethyl propyl group ammonium sulfate, tween 80, SUNSOFT 700P-2, in azone any one or a few.
Preferably, described thermosensitive in situ gel substrate is selected from poloxamer188, PLURONICS F87, methylcellulose, polylactic acid-polyethylene glycol block copolymer, polylactic-co-glycolic acid-polyethyleneglycol block copolymer, polycaprolactone-polyethylene glycol block copolymer, poly-N-isopropyl acrylamide, more preferably any one or a few in poloxamer188, PLURONICS F87, methylcellulose.
The major advantage that temperature of the present invention and ion Dual Sensitive type in-situ gel nasal-cavity administration system have compare simple thermosensitive in situ gel or ion-sensitive type situ-gel drug-supplying system is: gel phase temperature and nasal cavity temperature approach, plastic speed is fast, have the medicament slow release effect, and the nasal mucosa Local Residence Time is long, be conducive to drug absorption.The temperature that responsive to temperature is combined with ion-sensitive mechanism and prepare and ion Dual Sensitive type in-situ gel nasal-cavity administration system are specially adapted to need to see through the medicine that BBB arrival maincenter plays a role.Have good spray property, good gelling property in place and medicament slow release effect, be conducive to bring into play drug effect.
The principal agent of temperature of the present invention and ion Dual Sensitive type in-situ gel nasal-cavity administration system can be selected from the medicine that need enter maincenter and play a role.For example: central nervous system stimulant, as nikethamide, lobeline etc.; Analgesic is as morphine, Pethidine etc.; Antuepileptic is as phenytoin Sodium, carbamazepine etc.; Tranquilizer and anticonvulsant are as quazepam, haloxazolam, armillaria mellea etc.; Antiparkinsonian drug is as levodopa, profenamine etc.; The sick medicine of resisting cerebrovascular; Anti-senile dementia medicine and improve brain metabolism medicine, etc.
Preferably, described penetration enhancer is sulfobutyl ether-beta-schardinger dextrin-and/or azone.
preferably, described temperature and ion Dual Sensitive type situ-gel substrate also comprise antibacterial, described antibacterial is selected from chlorobutanol, benzalkonium bromide, ethanol, sorbic acid, potassium sorbate, methyl salicylate, sodium salicylate, propylene glycol, propanoic acid, propionic aldehyde, cresol, formic acid, ethylparaben, benzyl p-hydroxybenzoate, methyl parahydroxybenzoate, isopropyl alcohol, arabo-ascorbic acid, cinnamyl alcohol, styracin, resorcinol, phenethanol, phenoxyethanol, Benzalkonii Chloridum, benzalkonium bromide, benzoic acid, sodium benzoate, Potassium Benzoate, benzyl alcohol, phenol, o-phenyl phenol, lactic acid, zinc oxide, Oleum Eucalypti, thimerosal, Borax, boric acid, tetradecyl trimethylammonium bromide, bromination myristyl pyridine, povidone iodine, acetic acid, chlorhexidine acetate, in chlorhexidine hydrochloride any one or a few.
Preferably, the described thermosensitive in situ gel substrate poloxamer188 that is mass fraction 0.1-1.0%; Described ion-sensitive type situ-gel substrate is the gellan gum of mass fraction 14%-20%.
More preferably, the described thermosensitive in situ gel substrate poloxamer188 that is mass fraction 0.3%; Described ion-sensitive type situ-gel substrate is the gellan gum of mass fraction 18%.
Preferably, described principal agent be selected from water soluble drug ketorolac tromethamine, quinalbarbitone, sodium valproate,
Dimefline, Pethidine, or one or more in fat-soluble medicine pentazocine, zopiclone, carbamazepine.
Temperature of the present invention and ion Dual Sensitive type in-situ gel nasal-cavity administration system are not only applicable to water soluble drug, are applicable to fat-soluble medicine yet.
More preferably, described principal agent is ketorolac tromethamine.
Preferred, described absorption enhancer is sulfobutyl ether-beta-schardinger dextrin-, and described antibacterial is chlorobutanol.
After ketorolac tromethamine is made temperature and ion Dual Sensitive type in-situ gel nasal-cavity administration and is administered systemically, the nasal mucosa part based on nose liquid in contained ion and nasal cavity temperature inversion become gel, be attached on nasal mucosa, can the long period rest on the part and prolong drug action time, be conducive to medicine and enter maincenter performance analgesic activity.
More preferably, when described principal agent was selected from fat-soluble medicine, the preparation method of described nasal drug delivery system comprised the following steps:
Step 1, preparation temperature and ion Dual Sensitive type situ-gel substrate;
Employing contains temperature and the ion Dual Sensitive type in-situ gel nasal-cavity administration system of absorption enhancer, greatly improves the absorbance of medicine, promotes medicine to walk around the BBB cross-docking and enters brain; Realized in the non-intruding mode transmitting in the brain of medicine, safe; Especially can increase the brain volume that enters of the macromolecular drugs such as many skins, protein, polar medicine, reduce the toxic and side effects of periphery; Rapid-action, independently medication of patient.
Description of drawings
Fig. 1 is that the concentration (W/V) of poloxamer188 is 18%, the change curve of gellan gum concentration (W/V) and pluralgel gelling time;
Fig. 2 is that the gellan gum mass fraction is 0.3%, the change curve of the poloxamer188 solution of different quality mark and the gelling time of pluralgel;
Fig. 3 is that the mass fraction of poloxamer188 is 18%, adds the gellan gum solution of different quality mark after artificial nose liquid and the change curve of gel viscosity;
Fig. 4 is that the gellan gum mass fraction is 0.3%, adds the poloxamer188 solution of different quality mark after artificial nose liquid and the change curve of gel viscosity;
Fig. 5 is the phase transition temperature curve chart of the compound situ-gel of temperature-ion-sensitive of poloxamer188 solution and 0.3% (W/V) the gellan gum preparation of different quality mark (16%, 18%, 20%);
Fig. 6 adds the average cumulative penetration curve figure that sees through nasal mucosa after different penetrating agents; And
Fig. 7 be not on the same group Dichlorodiphenyl Acetate cause the block diagram that affects of mouse writhing number of times.
The specific embodiment
Below the present invention is described in further detail, can implement according to this with reference to the description word to make those skilled in the art.
The preparation of embodiment 1. ion-sensitive type nasal in situ gel
Take appropriate gellan gum, in beaker, add appropriate deionized water, abundant swelling in the hot bath of 70-80 ° of C, then as for obtaining clear and bright solution in 4 ° of C refrigerators, prepare respectively the gel-type vehicle that the gellan gum mass fraction is 0.2%, 0.5%, 0.75%, 1.0% (w/v), in the water bath with thermostatic control of 36.5 ° of C, mix the gel situation that (v/v=1:1) observes each gel-type vehicle with artificial nose liquid, the results are shown in Table 1.
The mixed gel situation of table 1 different quality mark gellan gum and artificial nose liquid
Result shows, when using merely gellan gum as nasal in situ gel substrate, can't form gel when concentration is too low at all; Concentration is too high, and poor fluidity can't nose spray administration.Therefore need to use with the responsive to temperature type matrix composite.
The variation of the compound situ-gel gelling time of embodiment 2. variable concentrations
Get appropriate gellan gum in beaker, add appropriate amount of deionized water, abundant swelling, then be placed in 4 ° of C refrigerators and obtain clear and bright solution in 70-80 ° of C hot bath; Separately get appropriate poloxamer188, add in mentioned solution, stir, 4 ° of C placed 48 hours, made Recombination gel.Prepare respectively the Recombination gel of 0.1% gellan gum+18% poloxamer188,0.2% gellan gum+18% poloxamer188,0.3% gellan gum+18% poloxamer188,0.4% gellan gum+18% poloxamer188,14% poloxamer188+0.3% gellan gum, 16% poloxamer188+0.3% gellan gum, 18% poloxamer188+0.3% gellan gum, 20% poloxamer188+0.3% gellan gum, V
Recombination gel: V
Artificial nose liquid=4:1 in 36.5 ° of C waters bath with thermostatic control, investigates the gelling time of each Recombination gel, the results are shown in Table 2.
The gelling time of table 2 different proportion Recombination gel
When the concentration (W/V) of poloxamer188 is 18%, the change curve of the gelling time of gellan gum concentration and pluralgel is seen Fig. 1.Increase with gellan gum concentration, gelling time obviously shortens.
When fixed knot cold glue mass fraction is 0.3%, the change curve of the gelling time of poloxamer188 mass fraction and pluralgel is seen Fig. 2.Increase with poloxamer188 concentration, gelling time obviously shortens.
Gelling time is oversize is unfavorable for the drug effect performance, may also not have enough time to form gel, and drug solution runs off in a large number.Result of study shows that the concentration (W/V) when poloxamer188 solution is respectively 18%, 20%, when the gellan gum solution concentration is 0.3% (W/V) gelling time be respectively 2.65,2.2Omin, gelation time is shorter, is suitable for use as temperature and ion Dual Sensitive nasal in situ gel substrate.
The variation of the compound situ-gel viscosity of embodiment 3. variable concentrations
Recombination gel is mixed with artificial nose liquid, and under circulator bath, controlling reaction temperature with thermometer is 36.5 ° of C, surveys its k value with RVDVIII (rotational viscometer).When the concentration of poloxamer188 solution is 18% (W/V), adds the gellan gum solution of different quality mark after artificial nose liquid and the change curve of situ-gel viscosity and see Fig. 3.Increase with the gellan gum solution concentration, the situ-gel viscosity obviously increases.
Poloxamer188 concentration (W/V) is seen Fig. 4 with the change curve of situ-gel viscosity after the gellan gum mass fraction is 0.3%, adds artificial nose liquid.Increase with poloxamer188 concentration, the situ-gel viscosity obviously increases.
The investigation of embodiment 4. situ-gel critical phase temperatures
The compound situ-gel of temperature-ion-sensitive of the gellan gum preparation take the poloxamer188 of different quality mark (16%, 18%, 20%) and mass fraction as 0.3%, in the water bath with thermostatic control of different temperatures, fully gelling, with its k value of digital display viscosity apparatus side, measure the phase transition temperature of gel, the phase transition temperature curve of the compound situ-gel of ion-responsive to temperature of variable concentrations is seen Fig. 5.
Poloxamer188 concentration is remarkable to the viscosity of situ-gel, and concentration is larger, and viscosity is larger.And extend in time, viscosity obviously increases.
The impact that embodiment 5. penetration enhancers absorb the saturating nasal mucosa of ketorolac tromethamine composite in-situ gel
Reception tank is full of normal saline, the sheep nasal mucosa is fixed between diffusion cell, 36.5 ° C circulator bath, add 100 μ l artificial nose liquid in the dosing pond, add again 200 μ l pluralgel, be placed in 36.5 ° of C baking oven gel 10min, in 15,30,45,60,90,120,180min takes a sample and mend isothermal equivalent normal saline.
To contain 2% azone, 2.5% sulfobutyl ether-beta-schardinger dextrin-and (sulfobutyl ether-β-CD), three kinds of absorption enhancers of 5%HP-β-CD, and carry out the tablets in vitro experiment without the ketorolac tromethamine composite in-situ gel of absorption enhancer by the sheep nasal mucosa, press the content of content assaying method working sample Chinese medicine after sampling, the accumulation infiltration capacity of unit of account area the results are shown in Table 3, table 4 and Fig. 6.
Unit are is accumulated infiltration capacity the time is carried out linear regression, straight slope is infiltration rate; Useful enhancing rate is weighed absorption enhancer to the size of medicine facilitation, and its value is the intrinsic infiltration rate of infiltration rate/medicine.
Table 3 adds the average accumulated infiltration capacity that sees through nasal mucosa after different penetrating agents
Penetration enhancer generally is used for transdermal delivery system, is applied in the nasal in situ gel drug-supplying system, and the step of can spouting increases drug absorption.As seen from Table 3, the short assimilation effect of sulfobutyl ether-β-CD and azone is remarkable.
Table 4 ketorolac tromethamine pluralgel adds regression equation and the regression coefficient after different penetrating agents
The infiltration rate of 2% azone, 2.5% sulfobutyl ether-β-CD, 5%HP-β-CD is respectively 0.0277.0.0266,0.0184mgcm
-2Min
-1, urge to ooze multiple and be respectively 2.16,2.09,1.44.The short assimilation effect of azone and sulfobutyl ether-β-CD is suitable.By the further safety of estimating azone and sulfobutyl ether-β-CD of Bufo siccus nose fibre swing time.
Get 33 of Bufo siccuss, be divided at random 11 groups, 3 every group.After the Bufo siccus broken end, cut its palate with operating scissors, be fixed on frog board, cut the approximately upper palatine mucosa of 3mm*3mm with sharp ophthalmologic operation rapidly, clean clot and foreign material with normal saline, mucomembranous cilium is tiled on microscope slide facing up.Drip the 0.1ml medicinal liquid in mucosal surface, (10*40) observes the ciliary movement situation under optical microscope.With being placed in the chromatography cylinder that is added with a small amount of normal saline, airtight, make steam near saturated, ambient temperature is 20-25 ° of C.After this take out every appropriate time and observe, continue motion as cilium and put back in chromatography cylinder, begin to stop duration to ciliary movement from administration until ciliary movement stops rear record.Wherein 2% azone, 2.5% sulphur butyl-β-CD are as absorption enhancer, and 0.01% benzalkonium bromide, 0.5% chlorobutanol are as antibacterial.Different antibacterial and different absorption enhancer the results are shown in Table 5 to the impact of Isolated Toad nose fibre swing time.
The different antibacterial of table 5 and different absorption enhancer are on the Bufo siccus nose impact of fibre swing time of leaving one's post
Sulfobutyl ether-β-CD toxicity is less than azone, proved that also sulfobutyl ether-β-CD toxicity is less than azone after adding benzalkonium bromide, chlorobutanol as antibacterial.Chlorobutanol toxicity is less than benzalkonium bromide.In conjunction with mechanism and toxicity test data, preferred absorption enhancer is sulfobutyl ether-β-CD, and antibacterial is chlorobutanol.
The pharmacodynamic experiment of embodiment 7. ketorolac tromethamine temperature and ion Dual Sensitive type situ-gel
Get 30 of BALB/C mice, male and female are standby half, are divided at random 3 groups, and 10 every group, i.e. negative control group, positive control-ketorolac tromethamine nasal spray group, ketorolac tromethamine temperature and ion Dual Sensitive type situ-gel group.Organize the mice intranasal administration with microsyringe respectively, dosage is 7.56mg/kg to each, and negative control group gives the equal volume normal saline.After administration 30 minutes, lumbar injection 0.6% (v/v) acetum 0.2ml observes and records experiment mice the number of times of writhing response occured in 15 minutes.
Respectively negative control group, positive controls, situ-gel group Dichlorodiphenyl Acetate are caused the mouse writhing number of times and add up.The results are shown in Table 6 and Fig. 7.
Table 6 not on the same group Dichlorodiphenyl Acetate cause the impact of mouse writhing number of times
The reverse effect of ketorolac tromethamine temperature and ion Dual Sensitive type situ-gel group Dichlorodiphenyl Acetate induced mice writhing is remarkable.
The preparation of embodiment 8. dimefline temperature and ion Dual Sensitive type situ-gel
Take the 0.3g gellan gum in beaker, add appropriate deionized water, abundant swelling in the hot bath of 70-80 ° of C is then as for obtaining clear and bright solution in 4 ° of C refrigerators; Separately take the 18g poloxamer188, add in mentioned solution, stir, 4 ° of C placed 48 hours, made Recombination gel substrate.Take the 0.4g dimefline and add in above-mentioned blank substrate and dissolve, deionized water adds to 100ml, is made into temperature and ion Dual Sensitive type nasal in situ gel that dimefline concentration is 4mg/ml.
The preparation of embodiment 9. Pethidine temperature and ion Dual Sensitive type situ-gel
Take the 0.3g gellan gum in beaker, add appropriate deionized water, abundant swelling in the hot bath of 70-80 ° of C is then as for obtaining clear and bright solution in 4 ° of C refrigerators; Separately take the 18g poloxamer188, add in mentioned solution, stir, 4 ° of C placed 48 hours, made Recombination gel substrate.Take the 5g Pethidine and add in above-mentioned blank substrate and dissolve, deionized water adds to 100ml, is made into temperature and ion Dual Sensitive type nasal in situ gel that Pethidine concentration is 50mg/ml.
The preparation of embodiment 10. water solublity quinalbarbitone temperature and ion Dual Sensitive type situ-gel
Take the 0.3g gellan gum in beaker, add appropriate deionized water, abundant swelling in the hot bath of 70-80 ° of C is then as for obtaining clear and bright solution in 4 ° of C refrigerators; Separately take the 18g poloxamer188, add in mentioned solution, stir, 4 ° of C placed 48 hours, made Recombination gel substrate.Take the 5g quinalbarbitone and add in above-mentioned blank substrate and dissolve, add the 0.2ml Tween 80, deionized water adds to 100ml, is made into temperature and ion Dual Sensitive type nasal in situ gel that quinalbarbitone concentration is 50mg/ml.
The tranquilizing soporific effect assessment of embodiment 11. quinalbarbitone temperature and ion Dual Sensitive type situ-gel
60 of male ICR mouses, 18-22g is divided into 3 groups at random, and 20 every group, i.e. negative control group, 50mg/ml quinalbarbitone solution group, 50mg/ml quinalbarbitone temperature and ion Dual Sensitive type nasal in situ gel group.Every day 2 intranasal administrations, dosage is 20mg/kg, negative control group gives the same dose normal saline, successive administration 3 days.45min after the last administration measures the autonomic activities number of times in mice 15min, the results are shown in Table 7.
The tranquilizing soporific effect of the different quinalbarbitone preparations of table 7 to mice
Quinalbarbitone situ-gel group shows obvious sedation, and the number of times of mice autonomic activities per minute is compared obvious minimizing with negative control group.
The system of the fat-soluble hypnotic and sedative assistant gram cooling degree of embodiment 12. and ion Dual Sensitive type situ-gel
Standby
Take the 0.3g gellan gum in beaker, add appropriate deionized water, abundant swelling in the hot bath of 70-80 ° of C is then as for obtaining clear and bright solution in 4 ° of C refrigerators; Separately take the 18g poloxamer188, the 1g sodium laurylsulfate adds in mentioned solution, stirs, and 4 ° of C placed 48 hours, made Recombination gel substrate.
Take the 500mg zopiclone, use appropriate dissolve with ethanol.Add 3gPEG6000, stir evenly, heat in water-bath, make melting, and boil off ethanol.Subsequently, fused mass is poured on the stainless steel disc that is placed in ice bath, made straticulation, blow with cold wind, make its rapid cooling curing, be placed in exsiccator inner drying 24h, pulverized 80 mesh sieves.
The zopiclone solid dispersion for preparing is added in above-mentioned blank substrate, and deionized water adds to 100ml, is made into temperature and ion Dual Sensitive type nasal in situ gel that zopiclone concentration is 5mg/ml.
The town of embodiment 13. fat-soluble hypnotic and sedative zopiclone temperature and ion Dual Sensitive type situ-gel
The indigo hypnotic effect is estimated
60 of male ICR mouses, 18-22g is divided into 3 groups at random, and 20 every group, i.e. negative control group, 5mg/ml zopiclone suspension group, 5mg/ml zopiclone temperature and ion Dual Sensitive type nasal in situ gel group.Every day 2 intranasal administrations, dosage is 1.5mg/kg, negative control group gives the same dose normal saline, successive administration 3 days.45min after the last administration measures the autonomic activities number of times in mice 15min, the results are shown in Table 8.
The tranquilizing soporific effect of the different zopiclone preparations of table 8 to mice
Zopiclone situ-gel group shows obvious sedation, and the number of times of mice autonomic activities per minute is compared obvious minimizing with negative control group.
The system of the fat-soluble antiepileptic of embodiment 14.-carbamazepine temperature and ion Dual Sensitive type situ-gel
Standby
Take the 0.3g gellan gum in beaker, add appropriate deionized water, abundant swelling in the hot bath of 70-80 ° of C is then as for obtaining clear and bright solution in 4 ° of C refrigerators; Separately take the 18g poloxamer188, add in mentioned solution, stir, 4 ° of C placed 48 hours, made Recombination gel substrate.
Take the 2g carbamazepine and be dissolved in appropriate dehydrated alcohol, add to rapidly in the deionized water that is stirring, Precipitation is arranged.Get the suspension lyophilizing, namely get micronized carbamazepine.
The carbamazepine micropowder for preparing is added in above-mentioned blank substrate, and deionized water adds to 100ml, is made into temperature and ion Dual Sensitive type nasal in situ gel that Carbamazepine is 20mg/ml.
The medicine of the fat-soluble antiepileptic of embodiment 15.-carbamazepine temperature and ion Dual Sensitive type situ-gel
Effect is learned and is estimated
30 of healthy male mouse of kunming, 18-22g is divided into 3 groups at random, and 10 every group, i.e. negative control group, carbamazepine suspension group, carbamazepine temperature and ion Dual Sensitive type nasal in situ gel group.Every day 2 intranasal administrations, dosage is 20mg/kg, negative control group gives the same dose normal saline, successive administration 7 days.Lh after the last administration, lumbar injection strychnine nitrate solution, dosage are 1.5mg/kg, observe convulsions incubation period and the death incident of respectively organizing mice, the results are shown in Table 9.
The pharmacodynamic evaluation of the different molecusol-carbamazepines of table 9
Carbamazepine situ-gel group is compared with negative control group, can obviously extend faint from fear incubation period and death time, compares also with carbamazepine suspension group to be significantly improved.
The system of embodiment 16. water solublity antiepileptic-sodium valproate temperature and ion Dual Sensitive type situ-gel
The standby pharmacodynamic evaluation that reaches
Take the 0.3g gellan gum in beaker, add appropriate deionized water, abundant swelling in the hot bath of 70-80 ° of C is then as for obtaining clear and bright solution in 4 ° of C refrigerators; Separately take the 18g poloxamer188, add in mentioned solution, stir, 4 ° of C placed 48 hours, made Recombination gel substrate.
Take the 2g sodium valproate and be dissolved in appropriate dehydrated alcohol, add to rapidly in the deionized water that is stirring, Precipitation is arranged.Get the suspension lyophilizing, namely get micronized sodium valproate.
The sodium valproate micropowder for preparing is added in above-mentioned blank substrate, and deionized water adds to 100ml, is made into temperature and ion Dual Sensitive type nasal in situ gel that sodium valproate concentration is 20mg/ml.
30 of healthy male mouse of kunming, 18-22g is divided into 3 groups at random, and 10 every group, i.e. negative control group, sodium valproate solution group, sodium valproate temperature and ion Dual Sensitive type nasal in situ gel group.Every day 2 intranasal administrations, dosage is 20mg/kg, negative control group gives the same dose normal saline, successive administration 7 days.1h after the last administration, lumbar injection strychnine nitrate solution, dosage are 1.5mg/kg, observe convulsions incubation period and the death incident of respectively organizing mice, the results are shown in Table 10.
The pharmacodynamic evaluation of the different sodium valproate preparations of table 10
Sodium valproate situ-gel group is compared with negative control group, can obviously extend faint from fear incubation period and death time, compares also with sodium valproate solution group to be significantly improved.
The preparation of embodiment 17. fat-soluble analgesic pentazocine temperature and ion Dual Sensitive type situ-gel reaches
Pharmacodynamic evaluation
Take the 0.3g gellan gum in beaker, add appropriate deionized water, abundant swelling in the hot bath of 70-80 ° of C is then as for obtaining clear and bright solution in 4 ° of C refrigerators; Separately take the 18g poloxamer188, add in mentioned solution, stir, 4 ° of C placed 48 hours, made Recombination gel substrate.
Under 50 ° of C conditions, take the 5g HP-β-CD and be dissolved in 40% alcoholic solution and make saturated solution, add 1g pentazocine (mol ratio of pentazocine and HP-β-CD is 1:1).Magnetic stirrer stirs 2h, cooling after, be placed in 4 ° of C cold preservations of refrigerator crystallization that spends the night.After the crystallization sucking filtration, use cold water washing, be drying to obtain the pentazocine cyclodextrin clathrate in exsiccator.
The pentazocine clathrate for preparing is added in above-mentioned blank substrate, and deionized water adds to 100ml, is made into temperature and ion Dual Sensitive type nasal in situ gel that pentazocine concentration is 10mg/ml.
Get 30 of BALB/C mice, male and female half and half are divided into 3 groups at random, and 10 every group, i.e. negative control group, pentazocine suspensoid group, pentazocine clathrate nasal in situ gel.Organize the mice intranasal administration with microsyringe respectively, dosage is 20 μ g/kg to each, and negative control group gives the equal volume normal saline.After administration 30 minutes, lumbar injection 0.6% (v/v) acetum 0.2ml observes and records experiment mice the number of times of writhing response occured in 15 minutes, the results are shown in Table 11.
The analgesic effect evaluation of the different pentazocine preparations of table 11
Compare with negative control group, pentazocine clathrate nasal in situ gel can obviously reduce the mouse writhing number of times, compares also with pentazocine suspensoid group to be significantly increased.
The major advantage that temperature of the present invention and ion Dual Sensitive type in-situ gel nasal-cavity administration system have compare simple thermosensitive in situ gel or ion-sensitive type situ-gel drug-supplying system is: gel phase temperature and nasal cavity temperature approach, plastic speed is fast, have the medicament slow release effect, and the nasal mucosa Local Residence Time is long, be conducive to drug absorption.The temperature that responsive to temperature is combined with ion-sensitive mechanism and prepare and ion Dual Sensitive type in-situ gel nasal-cavity administration system are specially adapted to need to see through the medicine that BBB arrival maincenter plays a role.Have good spray property, good gelling property in place and medicament slow release effect, be conducive to bring into play drug effect.
The principal agent of temperature of the present invention and ion Dual Sensitive type in-situ gel nasal-cavity administration system can be selected from the medicine that need enter maincenter and play a role.For example: central nervous system stimulant, as nikethamide, lobeline etc.; Analgesic is as morphine, Pethidine etc.; Antuepileptic is as phenytoin Sodium, carbamazepine etc.; Tranquilizer and anticonvulsant are as quazepam, haloxazolam, armillaria mellea etc.; Antiparkinsonian drug is as levodopa, profenamine etc.; The sick medicine of resisting cerebrovascular; Anti-senile dementia medicine and improve brain metabolism medicine, etc.
Although embodiment of the present invention are open as above, but it is not restricted to listed utilization in description and embodiment, it can be applied to various suitable the field of the invention fully, for those skilled in the art, can easily realize other modification, therefore do not deviating under the general concept that claim and equivalency range limit, the present invention is not limited to specific details and illustrates here and the embodiment that describes.
Claims (10)
1. a temperature and ion Dual Sensitive type in-situ gel nasal-cavity administration system, it is characterized in that, described nasal drug delivery system comprises principal agent and temperature and ion Dual Sensitive type situ-gel substrate, and wherein said temperature and ion Dual Sensitive type situ-gel substrate are mainly made by following raw material:
Thermosensitive in situ gel substrate, described thermosensitive in situ gel substrate is selected from any one or a few in poloxamer188, PLURONICS F87, methylcellulose, hypromellose, chitosan derivatives, polylactic acid-polyethylene glycol block copolymer, polylactic-co-glycolic acid-polyethyleneglycol block copolymer, second hydroxy ethyl cellulose, polycaprolactone polyethyleneglycol block copolymer, poly-N-isopropyl acrylamide;
Ion-sensitive type situ-gel substrate, described ion-sensitive type situ-gel substrate are selected from alginate, gellan gum any one or two kinds; And
penetration enhancer, described penetration enhancer is selected from oleyl alcohol, lauryl alcohol, hexadecanol, oleic acid, lauric acid, linoleic acid, isopropyl cetylate, the isopropyl myristin, lanoline, cineole, menthol, the dodecane Azone, Camphora, liquid paraffin, dimethicone, methanol, ethanol, glycerol, isopropyl alcohol, Polyethylene Glycol, thymol, dimethyl sulfoxide, glycocholate, N, dinethylformamide, N, the N-dimethyl acetylamide, carbamide, EDTA-2Na, cyclodextrin, HP-β-CD, sulfobutyl ether-beta-schardinger dextrin-, 1-Methyl-2-Pyrrolidone, N, N-two (α-ethoxy) oleamide, sodium laurylsulfate, dodecyl dimethyl propyl group ammonium sulfate, tween 80, SUNSOFT 700P-2, in azone any one or a few.
2. temperature as claimed in claim 1 and ion Dual Sensitive type in-situ gel nasal-cavity administration system, it is characterized in that, wherein said thermosensitive in situ gel substrate is selected from poloxamer188, PLURONICS F87, methylcellulose, polylactic acid-polyethylene glycol block copolymer, polylactic-co-glycolic acid-polyethyleneglycol block copolymer, polycaprolactone-polyethylene glycol block copolymer, poly-N-isopropyl acrylamide, more preferably any one or a few in poloxamer188, PLURONICS F87, methylcellulose.
3. temperature as claimed in claim 2 and ion Dual Sensitive type in-situ gel nasal-cavity administration system, is characterized in that, described penetration enhancer is sulfobutyl ether-beta-schardinger dextrin-and/or ammonia ketone.
4. temperature as claimed in claim 3 and ion Dual Sensitive type in-situ gel nasal-cavity administration system, it is characterized in that, wherein said temperature and ion Dual Sensitive type situ-gel substrate also comprise antibacterial, described antibacterial is selected from chlorobutanol, benzalkonium bromide, ethanol, sorbic acid, potassium sorbate, methyl salicylate, sodium salicylate, propylene glycol, propanoic acid, propionic aldehyde, cresol, formic acid, ethylparaben, benzyl p-hydroxybenzoate, methyl parahydroxybenzoate, isopropyl alcohol, arabo-ascorbic acid, cinnamyl alcohol, styracin, resorcinol, phenethanol, phenoxyethanol, Benzalkonii Chloridum, benzalkonium bromide, benzoic acid, sodium benzoate, Potassium Benzoate, benzyl alcohol, phenol, o-phenyl phenol, lactic acid, zinc oxide, Oleum Eucalypti, thimerosal, Borax, boric acid, tetradecyl trimethylammonium bromide, bromination myristyl pyridine, povidone iodine, acetic acid, chlorhexidine acetate, in chlorhexidine hydrochloride any one or a few.
5. described temperature as arbitrary in claim 1-4 and ion Dual Sensitive type in-situ gel nasal-cavity administration system, is characterized in that, described thermosensitive in situ gel substrate is the poloxamer188 of mass fraction 0.1-1.0%; Described ion-sensitive type situ-gel substrate is the gellan gum of mass fraction 14%-20%.
6. temperature as claimed in claim 5 and ion Dual Sensitive type in-situ gel nasal-cavity administration system, is characterized in that, described thermosensitive in situ gel substrate is the poloxamer188 of mass fraction 0.3%; Described ion-sensitive type situ-gel substrate is the gellan gum of mass fraction 18%.
7. temperature as claimed in claim 5 and ion Dual Sensitive type in-situ gel nasal-cavity administration system, is characterized in that, described principal agent be selected from water soluble drug ketorolac tromethamine, quinalbarbitone, sodium valproate,
Dimefline, Pethidine, or one or more in fat-soluble medicine pentazocine, zopiclone, carbamazepine.
8. temperature as claimed in claim 7 and ion Dual Sensitive type in-situ gel nasal-cavity administration system, is characterized in that, described principal agent is ketorolac tromethamine.
9. temperature as claimed in claim 8 and ion Dual Sensitive type in-situ gel nasal-cavity administration system, is characterized in that, described absorption enhancer is sulfobutyl ether-beta-schardinger dextrin-, and described antibacterial is chlorobutanol.
10. temperature as claimed in claim 7 and ion Dual Sensitive type in-situ gel nasal-cavity administration system, is characterized in that, when described principal agent was selected from fat-soluble medicine, the preparation method of described nasal drug delivery system comprised the following steps:
Step 1, preparation temperature and ion Dual Sensitive type situ-gel substrate;
Step 2, by micronization or nanocrystal or altogether grinding technique make the fat-soluble medicine particle diameter be reduced to nanoscale;
Step 3 improves the fat-soluble medicine dissolubility by preparation clathrate or solid dispersion; And
Step 4 is distributed to the fat-soluble medicine after processing in the temperature and ion Dual Sensitive type situ-gel substrate for preparing, and adds deionized water to predetermined, and get final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310125441XA CN103169649A (en) | 2013-04-11 | 2013-04-11 | Temperature and ion dual-sensitive in-situ gel nasal cavity drug delivery system |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310125441XA CN103169649A (en) | 2013-04-11 | 2013-04-11 | Temperature and ion dual-sensitive in-situ gel nasal cavity drug delivery system |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103169649A true CN103169649A (en) | 2013-06-26 |
Family
ID=48630144
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310125441XA Pending CN103169649A (en) | 2013-04-11 | 2013-04-11 | Temperature and ion dual-sensitive in-situ gel nasal cavity drug delivery system |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103169649A (en) |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104721234A (en) * | 2013-12-20 | 2015-06-24 | 舒梅 | Periplaneta Americana extract product ion-activated in-situ gel and preparation method thereof |
| CN105111466A (en) * | 2015-09-17 | 2015-12-02 | 华南理工大学 | Environmentally-sensitive hydrogel and method and application for preparing hydrogel by using bamboo shoot scraps |
| WO2015192772A1 (en) * | 2014-06-18 | 2015-12-23 | 上海翰森生物医药科技有限公司 | Medical application of nmda receptor antagonist and pharmaceutical composition thereof |
| CN105641103A (en) * | 2016-01-07 | 2016-06-08 | 西安医学院 | Preparation method and application of medicament for treating insomnia and gel thereof |
| CN106178111A (en) * | 2016-08-31 | 2016-12-07 | 山东赛克赛斯药业科技有限公司 | A kind of nose section gel filled preparation of Thermo-sensitive and preparation method thereof and the application in nasal surgery |
| CN106727276A (en) * | 2015-11-22 | 2017-05-31 | 中国人民解放军第三军医大学 | In-situ gel preparation and application thereof |
| CN106727277A (en) * | 2015-11-22 | 2017-05-31 | 中国人民解放军第三军医大学 | A kind of mentholated nasal cavity in-situ gel spray and preparation method thereof |
| CN107847604A (en) * | 2015-10-25 | 2018-03-27 | 艾威医药有限公司 | Ocular in-situ gel prescription |
| CN108785260A (en) * | 2018-06-20 | 2018-11-13 | 华中科技大学 | Thermo-sensitive non-steroidal anti-inflammatory drugs solid dispersions and rapidly dissolving tablet and preparation method thereof |
| CN109793705A (en) * | 2019-02-02 | 2019-05-24 | 中国人民解放军军事科学院军事医学研究院 | Timosaponin BII temperature/ion-sensitive type nasal in situ gel and its application |
| CN110433133A (en) * | 2019-08-19 | 2019-11-12 | 中国人民解放军军事科学院军事医学研究院 | The cannabidiol nasal formulations for treating posttraumatic stress disorder |
| WO2020072602A1 (en) * | 2018-10-02 | 2020-04-09 | Frequency Therapeutics, Inc. | Pharmaceutical compositions comprising otic therapeutic agents and related methods |
| CN111298188A (en) * | 2019-12-04 | 2020-06-19 | 戴建英 | Self-curing double-component ion and temperature double-sensitive digestive tract mucosa protective adhesive and application thereof |
| CN111643719A (en) * | 2020-06-15 | 2020-09-11 | 中国人民解放军海军特色医学中心 | Cyclo-gamma-polyglutamic acid modified hydrogel loaded nano sponge detoxification system and preparation method thereof |
| CN112263546A (en) * | 2020-09-29 | 2021-01-26 | 南京大学 | Zopiclone suspension nanometer preparation administrated through nasal cavity and preparation method thereof |
| CN112870156A (en) * | 2021-03-25 | 2021-06-01 | 深圳前海九华国际投资控股有限公司 | Etoricoxib in-situ gel and preparation method thereof |
| US11033546B2 (en) | 2016-03-02 | 2021-06-15 | Frequency Therapeutics, Inc. | Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using a GSK3 inhibitor: I |
| US11160868B2 (en) | 2016-03-02 | 2021-11-02 | Frequency Therapeutics, Inc. | Thermoreversible compositions for administration of therapeutic agents |
| CN113877055A (en) * | 2021-08-10 | 2022-01-04 | 中国人民解放军军事科学院军事医学研究院 | Radiation-sensitive wearable drug controlled release system |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101053550A (en) * | 2007-04-25 | 2007-10-17 | 昆明制药集团股份有限公司 | Rhizoma Gastrodiae nasal gel preparation |
| CN101810562A (en) * | 2009-11-26 | 2010-08-25 | 天津金耀集团有限公司 | Nasal in situ gel containing cortical hormone |
| CN101912355A (en) * | 2010-04-29 | 2010-12-15 | 佟丽 | Recombinant human interleukin-1 receptor antagonist in-situ gel |
-
2013
- 2013-04-11 CN CN201310125441XA patent/CN103169649A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101053550A (en) * | 2007-04-25 | 2007-10-17 | 昆明制药集团股份有限公司 | Rhizoma Gastrodiae nasal gel preparation |
| CN101810562A (en) * | 2009-11-26 | 2010-08-25 | 天津金耀集团有限公司 | Nasal in situ gel containing cortical hormone |
| CN101912355A (en) * | 2010-04-29 | 2010-12-15 | 佟丽 | Recombinant human interleukin-1 receptor antagonist in-situ gel |
Non-Patent Citations (3)
| Title |
|---|
| 栾琳 等: "利巴韦林温度-离子敏感型鼻用原位凝胶喷雾剂的制备及体外性质考察", 《沈阳药科大学学报》 * |
| 王建华 等: "一种新型辅料磺丁基醚-β-环糊精的药学应用进展", 《材料导报》 * |
| 钱家健 等: "鼻用原位凝胶给药系统中药物吸收的影响因素与改进措施", 《中国新药杂志》 * |
Cited By (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104721234A (en) * | 2013-12-20 | 2015-06-24 | 舒梅 | Periplaneta Americana extract product ion-activated in-situ gel and preparation method thereof |
| WO2015192772A1 (en) * | 2014-06-18 | 2015-12-23 | 上海翰森生物医药科技有限公司 | Medical application of nmda receptor antagonist and pharmaceutical composition thereof |
| CN106413708A (en) * | 2014-06-18 | 2017-02-15 | 上海翰森生物医药科技有限公司 | Medical application of nmda receptor antagonist and pharmaceutical composition thereof |
| CN105111466A (en) * | 2015-09-17 | 2015-12-02 | 华南理工大学 | Environmentally-sensitive hydrogel and method and application for preparing hydrogel by using bamboo shoot scraps |
| CN107847604A (en) * | 2015-10-25 | 2018-03-27 | 艾威医药有限公司 | Ocular in-situ gel prescription |
| CN107847604B (en) * | 2015-10-25 | 2020-11-10 | 艾威药业(珠海)有限公司 | Ophthalmic in situ gel formulations |
| CN106727276A (en) * | 2015-11-22 | 2017-05-31 | 中国人民解放军第三军医大学 | In-situ gel preparation and application thereof |
| CN106727277A (en) * | 2015-11-22 | 2017-05-31 | 中国人民解放军第三军医大学 | A kind of mentholated nasal cavity in-situ gel spray and preparation method thereof |
| CN105641103A (en) * | 2016-01-07 | 2016-06-08 | 西安医学院 | Preparation method and application of medicament for treating insomnia and gel thereof |
| US11160868B2 (en) | 2016-03-02 | 2021-11-02 | Frequency Therapeutics, Inc. | Thermoreversible compositions for administration of therapeutic agents |
| US11033546B2 (en) | 2016-03-02 | 2021-06-15 | Frequency Therapeutics, Inc. | Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using a GSK3 inhibitor: I |
| CN106178111A (en) * | 2016-08-31 | 2016-12-07 | 山东赛克赛斯药业科技有限公司 | A kind of nose section gel filled preparation of Thermo-sensitive and preparation method thereof and the application in nasal surgery |
| CN108785260A (en) * | 2018-06-20 | 2018-11-13 | 华中科技大学 | Thermo-sensitive non-steroidal anti-inflammatory drugs solid dispersions and rapidly dissolving tablet and preparation method thereof |
| CN108785260B (en) * | 2018-06-20 | 2020-06-02 | 华中科技大学 | Temperature-sensitive non-steroidal anti-inflammatory drug solid dispersion and instant tablet and preparation method thereof |
| WO2020072602A1 (en) * | 2018-10-02 | 2020-04-09 | Frequency Therapeutics, Inc. | Pharmaceutical compositions comprising otic therapeutic agents and related methods |
| WO2020072601A1 (en) * | 2018-10-02 | 2020-04-09 | Frequency Therapeutics, Inc. | Pharmaceutical compositions comprising otic therapeutic agents and related methods |
| CN109793705A (en) * | 2019-02-02 | 2019-05-24 | 中国人民解放军军事科学院军事医学研究院 | Timosaponin BII temperature/ion-sensitive type nasal in situ gel and its application |
| CN110433133A (en) * | 2019-08-19 | 2019-11-12 | 中国人民解放军军事科学院军事医学研究院 | The cannabidiol nasal formulations for treating posttraumatic stress disorder |
| CN111298188A (en) * | 2019-12-04 | 2020-06-19 | 戴建英 | Self-curing double-component ion and temperature double-sensitive digestive tract mucosa protective adhesive and application thereof |
| CN111643719A (en) * | 2020-06-15 | 2020-09-11 | 中国人民解放军海军特色医学中心 | Cyclo-gamma-polyglutamic acid modified hydrogel loaded nano sponge detoxification system and preparation method thereof |
| CN112263546A (en) * | 2020-09-29 | 2021-01-26 | 南京大学 | Zopiclone suspension nanometer preparation administrated through nasal cavity and preparation method thereof |
| CN112263546B (en) * | 2020-09-29 | 2021-08-10 | 南京大学 | Zopiclone suspension nanometer preparation administrated through nasal cavity and preparation method thereof |
| CN112870156A (en) * | 2021-03-25 | 2021-06-01 | 深圳前海九华国际投资控股有限公司 | Etoricoxib in-situ gel and preparation method thereof |
| CN113877055A (en) * | 2021-08-10 | 2022-01-04 | 中国人民解放军军事科学院军事医学研究院 | Radiation-sensitive wearable drug controlled release system |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103169649A (en) | Temperature and ion dual-sensitive in-situ gel nasal cavity drug delivery system | |
| Watts et al. | PecSys: in situ gelling system for optimised nasal drug delivery | |
| Wang et al. | Design of a long-term antipsychotic in situ forming implant and its release control method and mechanism | |
| Li et al. | Nasal delivery of analgesic ketorolac tromethamine thermo-and ion-sensitive in situ hydrogels | |
| Rasool et al. | Development and evaluation of ibuprofen transdermal gel formulations | |
| Mahajan et al. | Nasal administration of ondansetron using a novel microspheres delivery system Part II: ex vivo and in vivo studies | |
| EP2922581B1 (en) | Mucoadhesive compositions comprising hyaluronic acid and chitosan for topical application | |
| CN102406594A (en) | Curcumin nasal jelly, as well as preparation method and application thereof | |
| Gulati et al. | Fabrication and in vitro characterization of polymeric nanoparticles for Parkinson's therapy: a novel approach | |
| Kamel et al. | Self-assembled carbohydrate hydrogels for prolonged pain management | |
| Zhang et al. | Sustained delivery of prilocaine and lidocaine using depot microemulsion system: in vitro, ex vivo and in vivo animal studies | |
| ALQuadeib et al. | The oral administration of lidocaine HCl biodegradable microspheres: formulation and optimization | |
| CN102657602A (en) | 3,5-dyhydroxyl-4-isopropyl diphenylethene chitosan gel and preparation method thereof | |
| RU2699674C1 (en) | Percutaneous absorption composition | |
| CN100502850C (en) | Medicinal composition of total capsicine compounds and beta-cyclodextrin or derivative of beta-cyclodextrin | |
| CN101151028A (en) | Topical gels compositions | |
| KR20200138730A (en) | Composition and method for treating itching | |
| CN103446045B (en) | A kind of stable Busulfan injection | |
| Gaddam et al. | Systemic delivery of diclofenac sodium after topical application of gels incorporated with drug-loaded solid lipid nanoparticles (SLN) | |
| TW202202129A (en) | Transdermal preparation containing active ingredient of anesthetic drug and preparation method thereof | |
| Hassan | A long acting ophthalmic gel formulations of atenolol | |
| EP3563843A1 (en) | Topical composition | |
| JP2020508992A (en) | Formulations of cannabinoids for the treatment of acne | |
| CN103908463B (en) | A kind of lincomycin hydrochloride and lidocaine hydrochloride gel agent and preparation technology thereof | |
| CN103349651B (en) | Nifedipine sustained release tablet and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20130626 |