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Objective To study the eye irritation and the pharmacokinetics of tacrolimus-loaded cationic nanoemulsion-based in-situ gel in rabbits. Methods The eye irritation of tacrolimus-loaded cationic nanoemulsion-based in-situ gel in rabbits was observed by histological cross-sections of external ocular tissues stained with HE. The aqueous humor of rabbit eyes was extracted by corneal puncture and analyzed by HPLC-MS for pharmacokinetic study. Results Tacrolimus-loaded cationic nanoemulsion-based in-situ gel had no significant irritation on rabbit eyes. The pharmacokinetic parameter showed that the AUC of tacrolimus-loaded cationic nanoemulsion-based in-situ gel was (128.34±13.09) ng·h/ml, which was 1.13 times of tacrolimus-loaded cationic nanoemulsion (113.61±12.36) ng·h/ml and 1.88 times of Talymus® (68.25±10.82) ng·h /ml. Conclusion Tacrolimus-loaded cationic nanoemulsion-based in-situ gel had the advantages of low irritation, long retention time and high bioavailability in rabbit eyes. It has a good potential for clinical application.
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Cancer is the most important leading cause of death worldwide, with about 10 million deaths caused by cancer in 2020. In situ gel drug delivery systems have attracted much attention in the field of pharmacy and biotechnology due to their good histo-compatibility, excellent injectability, high drug delivery capacity, slow-release drug delivery, and less influence by the in vivo environment. Meanwhile, in situ gel can be combined with chemotherapy, photo-thermal therapy, chemokinetic therapy, immunotherapy and so on to deliver drugs into the tumor site in a less invasive way without surgical operation, forming a semi-solid gel reservoir in the tumor site to realize in situ tumor combined therapy. In this paper, the author summarized the research progress of anti-tumor in situ gel delivery system in the past 10 years, introduced its commonly used polymer materials, classification principles and specific application examples, and finally summarized and discussed the key issues, in order to provide reference for the development of new anti-tumor drug delivery system in the future.
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@#Recently, in situ gel has been widely used as a local delivery system for periodontitis treatment because of its lesion injectability, local drug depot function, and drug sustained-release effect.Different therapeutic purposes can be achieved by loading different types of drugs such as antibiotics, bioactive factors, etc.In this review, different types of in situ gel with temperature-sensitive, ion-sensitive, pH-sensitive and solvent-exchanged characteristics were introduced for their applications and limitations in the delivery of drug for periodontitis;and the elimination of periodontal inflammation, periodontal tissue repair and the long-term role after loading microsphere achieved by the in situ gel system were also reviewed.
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The present study aimed to formulate a mucoadhesive in situ gel with mucilage extracted from Corchorus olitoriusfor the intranasal route. Propranolol HCl used as a model drug. For the comparative study, the mucoadhesive in situgels were prepared using two different concentration 0.4% and 0.5% of C. olitorius mucilage, Carbopol P-934 andhydroxypropyl methylcellulose. The prepared in situ gel was subjected to characterization test, such as pH, appearance,gelation temperature, spreadability, viscosity, mucoadhesive strength, and in vitro study. From the comparative study,0.5% mucilage containing in situ gel formulation can be considered as optimum formulation.
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Bacterial Vaginosis (BV) is the leading cause of vaginal discharge. Because of its big surface area, wealthy blood supply, avoidance of the first-pass effect and high permeability to many drugs, the vagina offers a promising location for local impact as well as systemic drug delivery. In situ gels give several benefits, such as ease of administration in the respective body cavities, elevated spreadability at certain temperatures, reduced administration frequency, improved patient compliance and comfort compared to standard dosage forms. Tinidazole (TNZ) can give effective treatment over the BV. In situ gel of TNZ containing polaxomer 407and HPMC E100 or carbopol 941NF was optimized on the basis of various evaluation parameters. Gelation temperature (Tgel) and pH of all batches was found in range of 36.6 to38.0 ºC and 4.20 to 5.03, viscosity was found in range of 1100-2050 cps at 25ºC and 4800-6530 cps at 37ºC. The Spredability was found in range of 16-20 cm. From these evaluation parameters we selected best combination for the mucoadhesive property, antimicrobial study, in vitro drug release and for HET CAM irritation study. The optimized formulation gives satisfactory results. In this study we also compare the performance of two mucoadhesive polymer. Based on maximum desirability and cost effectiveness, in situ vaginal gel containing 20% polaxomer and 0.5% HPMC E100 could be considered as a highly promising treatment for bacterial vaginosis.
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Objective In order to improve the problems of poor water-solubility and low bioavailability of ocular tacrolimus, a cationic nanoemulsion in-situ gel of tacrolimus was developed and its drug release behavior in vitro was studied to provide a basis for further research. Methods Tacrolimus-loaded cationic nanoemulsion was prepared by high pressure homogenization and dispersed in poloxamer 407 and poloxamer 188 to prepare tacrolimus-loaded cationic nanoemulsion-based in-situ gel. The membraneless dissolution model was used to study the in vitro drug release behavior. Results The inverse glass bottle method was used to determine the gelation temperature. The optimal formulation of gel matrix was screened out as 26% poloxamer 407 and 12% poloxamer 188. The in vitro release results showed that the rate of gel dissolution determined the in vitro drug release. Conclusion Tacrolimus-loaded cationic nanoemulsion-based in-situ gel is successfully prepared. Its in vitro drug release is stable. It meets the requirement of ophthalmic formulation and shows good prospects for ocular application.
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The aim of the investigation was to develop and evaluate thermoreversible in situ nasal gel formulations of repaglinide (REP) and to establish correlation between its in vitro release and ex vivo permeation profiles. The solubility of REP was enhanced by preparing solid dispersions (SDs) with hydrophilic carriers (PVP K30/ PEG 6000/ poloxamer 188) in different weight ratios. REP: PVP K30 (1:5) was selected as the optimized SD as it showed highest enhancement in solubility (405%). The optimized SD was characterized by SEM and DSC and incorporated into a blend of thermoreversible and mucoadhesive polymers (poloxamer 407 and carbopol 934 P) by cold technique to form in situ gels (F1-F6). The prepared in-situ gels were evaluated for various pharmacotechnical features and the formulation F3 exhibited least gelling time of 6.1± 0.20, good mucoadhesive property to ensure sufficient residence time at the site of application and a %CDR of 82.25%. The ex vivo permeation characteristics across goat mucosa can be summarized as CDP of 78.7%, flux = 6.80 mg/cm2/h; permeability coefficient of 2.02 mg/h and zero order kinetics. On correlating the CDR profile of F3 with that of its CDP profile, a R2 value of 0.991 (slope= 0.921) was observed. The value of slope approximating one, suggested that almost entire amount of drug released from F3 was capable of permeating across the nasal mucosa, ex-vivo indicating that in-situ nasal gels of REP for systemic action can be successfully developed for the management non-insulin dependent type-II diabetes mellitus.
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In this paper, a new type of preparation for treatment of initial dry eye disease, thermosensitive in situ gel, was prepared using levocarnitine as a model drug. Poloxamer 407 and poloxamer 188 were used as the gel matrix, and sodium hyaluronate and sodium carboxymethylcellulose were used as bioadhesive materials. Gelation temperature was determined by a rotor method and the prescription was optimized by central composite design-response surface methodology. The pH value, viscosity value and gelation temperature of the optimal prescription were measured. The release of the drug in vitro was examined by dialysis membrane permeation, and retention time of the thermosensitive in situ gel preparation on the rabbit's ocular surface was observed by a slit lamp microscope. The results showed that the dosage of the poloxamer 407 and poloxamer 188 were 20.81% and 3.46%, respectively, and sodium hyaluronate was 0.02%, sodium carboxymethyl cellulose was 0.10% of the optimal formulation of levocarnitine thermosensitive in situ gel. The pH value was 6.90 ± 0.06 at room temperature and the viscosity value started to rise sharply at 27 ℃ of the optimal formulation. The gelation temperature of the optimal preparation before and after dilution by simulated tear fluid were (26.37 ± 0.06) ℃ and (33.57 ± 0.21) ℃, respectively. In the first 240 min, in vitro release rate per unit area of levocarnitine thermosensitive in situ gel was lower than that of solution (P<0.05), and after 600 min, the cumulative release rate of levocarnitine thermosensitive in situ gel could reach more than 80%. The retention time of the thermosensitive in situ gel preparation on rabbit's ocular surface reached about 25 min, at least 5 times as much as that of the solution. The animal experiment was conducted following the National Institutes of Health Guidelines for the use of experimental animals, and approved by the Ethics Committee of the Experimental Animal Center of Beijing University of Chinese Medicine. The levocarnitine thermosensitive in situ gel showed good characteristics and sustained release property and significantly improved the retention time of the drug on the rabbit's ocular surface.
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Objective: In this paper,the effect of microemulsion in Chuanqi ophthalmic microemulsion in situ gel was investigated. Method: The effect of microemulsion was confirmed by the parallel comparison between the Chuanqi microemulsion in situ gel and normal in situ gel,including study of pharmaceutical characterization and tissue distribution. Result: The average particle sizes of Chuanqi microemulsion in situ gel and normal in situ gel were (38.20±0.13) nm and (985±37) nm,respectively.Microemulsion could maintain the properties of nanocarrier in a microemulsion in situ gel composite system.The result of tissue distribution study showed that only ligustilide could be detected.This was related to the nature of these three indicator components(ligustrazine,ligustilide and astragaloside A).The common logarithm of oil and water partition coefficient of ligustilide(lgP) was 2.87,which was consistent with the range of lgP of ideal ophthalmic drugs(lgP=2.0-3.0).The ligustilide from Chuanqi microemulsion in situ gel could be detected in the cornea,vitreous body and retina,and this compound from normal in situ gel could only be detected in the cornea with low content.At the same time,microemulsion could increase the content of ligustilide in corneal tissues. Conclusion: The characteristics of microemulsion nanocarriers can increase the solubility of ligustilide,compared with normal in situ gel,it can be better distributed in the tears outside the corneal,it reaches the cornea with a higher concentration,and forms a corneal concentration gradient,and ligustilide is transported from the anterior ocular region to the posterior ocular region through the transocular barrier.
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Objective To investigate the preparation process of Kucha gynecological gel and prepare a temperature-sensitive in situ gel capable of rapid phase change in vagina. Methods Poloxamer P188 and Poloxamer P407 were used as gel matrix, Lactic acid and sodium lactate were used as the acid buffer solution. The central composite design was performed to optimize the prescription and technology, and the gelation temperature (GT), gelation time, and the effects of different acid buffer solutions on GT, gel stability, and related rheological properties were determined. Results Within a certain concentration range, the gelation temperature was gradually increased with the increase of poloxamer 188 concentration, and the gelation temperature was gradually decreased with the increase of poloxamer 407 concentration, and the optimized prescription by central composite design was poloxamer P188 with a concentration of 3.51% and poloxamer P407 with a concentration of 17.16%. The addition of different buffers has a deviation of 5% of the gelation temperature of the gel in vitro, but the variation in the vaginal fluid is large. The gelation temperatures of the citric acid-sodium citrate buffer and the lactic acid-sodium lactate buffer solution in the vaginal fluid were 68.5 ℃ and 35.8 ℃, respectively, and the rheological data showed that the gel retained better in vivo. Conclusion The Kucha gynecological gel preparation corresponded with the model employed by central composite design, and the screened process can prepare situ gels with good retention and stable properties.
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Objective: To prepare nerve growth factor(NGF) temperature sensitive in situ gel and investigate its therapeutic effect on sciatic nerve injury of rats.Method: NGF thermosensitive gel was prepared and its prescription was optimized by central composite design-response surface methodology.Fifty rats were randomly divided into the normal group,model group,NGF injection group(10 mg·L-1),NGF low-dose(10 mg·L-1) and high-dose(20 mg·L-1) thermosensitive gel groups,and sciatic nerve injury model of rats was established.The effect of NGF thermosensitive gel on the injury of sciatic nerve were comprehensively examined by taking rat behavior,sciatic nerve function index(SFI),time of withdrawal reflex,wet weight ratio of gastrocnemius muscle,and histomorphological changes as indicators.Result: The gelation temperature of NGF thermosensitive gel was 35.2℃ after the formulation being optimized,which was in line with the standard for injection.Four-eight weeks after operation,the SFI and wet weight ratio of gastrocnemius muscle in rats of NGF high-dose thermosensitive gel group were significantly higher than those in the model group and NGF injection group,but its time of withdrawal reflex was significantly lower than those in the model group and NGF injection group,and the effect was in a dose-dependent manner.Arrangement of regenerated nerve fibers in sciatic nerve injury area of rats from NGF high-dose thermosensitive gel group was more tidy,dense and continuous than that of the model group.Conclusion: NGF thermosensitive gel can promote repair of sciatic nerve injury in rats.
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Objective: Optimize to obtain the in situ gel of matrine with thermosensitivity and rectal retention of bioadhesion rectum. Methods: Thermosensitive gel was prepared by cold method, and then using gelation temperature as an indicator, central combination design-response surface method (CCD-RSM) was used to optimize the dosage of P407, P188, and CMC-Na. Texture Analyzer was used to measure the gel strength and adhesion of prescription, the rectal retention was investigated by rectal administration, and the release rate was explored by modified paddle method. Results: The optimal prescription was matrine 2%, CMC-Na 1.0%, P188 1.3%, P407 16.5%, and benzalkonium bromide 0.02%. The prescription gel did not leak after rectal administration in rats, which can remain in the body for more than 6 h, in vitro release in line with Weibull model. Conclusion: The optimized matrine-loaded thermosensitive in situ gel could meet the requirement of rectal administration.
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objective To optimize the preparation technology of sulfuric in situ gel and study the infiltration experiment of different dosage forms. Methods Shufei in situ gel was prepared by cold cut method with poloxamer 188 (P188) and poloxamer 407 (P407) as gel base. Using gelling temperature index, the dosage range of gel matrix P407 and P188 in Shufei in situ gel was determinated by the single factor and star design-response surface methods to get the best prescription of Shufei in situ gel. The transdermal diffusion process of Shufei in situ gel was carried out in Franz diffusion cells to explore the permeation mechanism. Results The optimized prescription of Shufei in situ gel was as follow: The ratio of gel matrix to drug at 1:3, P188 dosage of 4%, P407 dosage of 22.5%, and the phase transition temperature within 32-36 ℃ to form gel. The releases of sinapine thiocyanate and genkwanin in Shufei in situ gel were all in line with the Higuchi release model. Conclusion The preparation process of Shufei in situ gel is stable and feasible with reliable product quality and good application prospect, which is suitable for industrial production and clinical application.
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OBJECTIVE: To prepare curcumin (CUR) -Poly (lactic-co-glycolic acid) (PLGA) nanoparticles (CUR-PLGA) thermosensitive in-situ gel (CUR-PLGA-GEL), and to study pharmacokinetic characteristics of it in aqueous humor of rabbits.METHODS: CUR-PLGA was prepared with modified emulsion-solvent evaporation method. CUR-PLGA-GEL was prepared by cold-dissolving method using poloxamer407 (P407) and poloxamer 188 (P188) as gel matrix. The level of CUR in gel was determined by HPLC, and the irritation of it to rabbit eyes was investigated (self-control of left and right eyes of 5 rabbits were taken, while the Draize test was used to evalvate the irritation). 10 New Zealand white rabbits were randomly divided into 2 groups, with 5 rabbits in each group. Left eyes were given CUR-PLGA-GEL and CUR suspension (containing CUR 8 mg), respectively. The concentrations of CUR in aqueous humor of rabbits were determined before medication and 1, 2, 4, 6, 8, 10, 12, 24 h after medication. The pharmacokinetic parameters were calculated by using DAS 2. 0 software. RESULTS: CUR-PLGA-GEL was successfully prepared and the total score of irritation was 0, which indicated irritative to rabbits. In aqueous humor of rabbits, cmax and AUC0-24 h of CUR-PLGA-GEL were 2. 48 and 2. 71 fold of CUR suspension. CONCLUSIONS: Prepared CUR-PLGA-GEL can be used for ophthalmic delivery and can improve the utilization of CUR in the eye.
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Objective:To prepare norfloxacin thermosensitive in situ gel and investigate its in vitro drug release behavior. Meth-ods:Poloxamer 407 and poloxamer 188 were used as the matrix of norfloxacin thermosensitive in situ gel,and the gel was prepared by a cold dissolving method. The formula was optimized by a central composite design-response surface method. In vitro drug release be-havior of norfloxacin thermosensitive in situ gel was studied as well. Results:Within a certain concentration range, the gelation tem-perature decreased gradually with the amount increase of poloxamer 407, and that increased gradually with the amount increase of poloxamer 188. The optimal formula was as follows:the concentration of poloxamer 407 was 20.6%(w/v),and that of poloxamer 188 was 5.7%(w/v),which obtained suitable gelling temperature. The release of norfloxacin from the thermosensitive in situ gel reached up to (87.5% ± 5.4% 7 in 6 h. Conclusion: Norfloxacin thermosensitive in situ gel has excellent temperature sensitivity, and can slow down the drug release,which shows potential use for vaginal drug delivery system.
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The unique solution-gel transition property of in-situ gel makes it have advantages of good histocompatibility, long residence time, high local concentration, promising bioavailability and so on.This paper summarized the different types and the latest research progress in Chinese medicine targeting preparations of in-situ gel in order to provide reference for the application of in-situ gel in Chinese medicines.
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Objective:To study the pharmacokinetic parameters of gastrodin nasal in situ gel ( ISG) with the base of TMC-P407-P188-carbomer, and evaluate its brain-targeting ability preliminarily. Methods:Rats were used as the model animals. The experiment group was treated with gastrodin nasal in situ gel, and the control group was treated with gastrodin solution with intravenous administra-tion. The plasma sample and brain tissue ( cerebrum and cerebellum) were taken out at the predetermined time points, and the concen-tration of gastrodin in plasma and gastrodigenin in brain tissues were determined by HPLC to draw the curve of concentration vs time. The pharmacokinetic parameters such as MRT and AUC were calculated by 3P97 software. The bioavailability F (%) and the brain-targeting index BTI were compared between the groups. Results:The concentration of gastrodigenin in the brain tissues of grastrodin in situ gel was higher than that of gastrodin solution with intravenous administration (P<0. 05). AUC of cerebrum and cerebellum both increased significantly with BTI of 2. 38 and 1. 93, respectively. MRT increased by nearly two-fold in the gel group when compared with that in the control group, and F(%) increased significantly in cerebrum and cerebellum as well. Conclusion:Gastrodin nasal in situ gel with the base of TMC-P407-P188-carbomer has promising effectiveness. Meanwhile, it can improve the brain-targeting ability of gastrodin with sustained release.
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Objective:To evaluate the nasal safety of gastrodin nasal temperature-sensitive in situ gel through the studies on cilia toxicity in toads and mucosal irritation in rats. Methods:The toads were randomly divided into four groups, saline group, gastrodin in situ gel group, blank gel matrix group and sodium deoxycholate group, and the cilia toxicity was observed in vivo by a toad palate meth-od. The rats were randomly divided into three groups, saline group, gastrodin in situ gel group and blank gel matrix group, and the mucosal irritation was studied in rats through the observation of nasal mucosal pathological changes and behavioral indices. Results:Compared with the saline group, gastrodin in situ and blank gel matrix showed no notable effect on the cilia movement function in toads, and the effect on cilia movement of sodium deoxycholate showed statistically significant difference when compared with that of sa-line, gastrodin in situ gel and blank gel matrix (P0. 05), and after the 2-day withdrawal, that in the gastrodin in situ gel group and blank gel matrix group decreased significantly when compared with that at the last administration (P0. 05). The number of inflammatory cells in the nasal mucosa in the gastrodin in situ gel group and blank gel matrix group increased complicated with congestion and cilia falling off, and after the with-drawal, the mucosal morphology in the three groups showed no significant difference. Conclusion:The local application of gastrodin in situ gel has high security, which is valuable to be studied further.
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Objective To prepare an in situ gel system for nasal delivery of menthol and to evaluate the safety of this formulation.Methods Menthol in situ gel was prepared with deacetylatedgellan gum.The nasal mucocilia toxicities of this formulation was evaluated using in situ toad palate model.Guinea pig skin sensitization test and the rabbit skin irritation test were conducted.Skin allergy and irritation reaction were monitored and scored.Results No significant effect on nasal mucosa ciliary movement and the morphology of rat nasal mucosa were observed.The formulation did not induce any dermal irritation in rabbits.Skin allergic reaction was not found in guinea pigs.Conclusion The preparation of menthol in situ nasal gel with low ciliary toxicity was easily achieved.This gel has good physiological flexibility.The further investigation was warranted for this formulation as an intranasal drug delivery system.
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Objective: To optimize the formula and preparation process of metronidazole thermosensitive in situ gel.Methods: The temperature of gelation and 24-h cumulative release were used as the evaluation indices, and the orthogonal tests were carried out to investigate the amounts of poloxamer 407 (P407), poloxamer 188 (P188), sodium alginate and polyethylene glycol 4000 (PEG 4000) to screen the best formula of thermosensitive in situ gel.The in vitro release of metronidazole thermosensitive in situ gel was determined by HPLC and compared with that of commercially available gel.Results: The optimum formula of thermosensitive in situ gel was P407 of 20%, P188 of 18%, sodium alginate of 0.1% and PEG 4000 of 1.5%.The release rate of metronidazole thermosensitive in situ gel was high, and the temperature of gelation was suitable.Compared with that of the commercially available gel, the vaginal retention of the in situ gel was significantly improved.Conclusion: The formula of the in situ gel is reasonable and the preparation process is feasible.