CN101185650B - Penciclovir ophthalmic temperature sensitivity in situ gel preparation and preparation method thereof - Google Patents
Penciclovir ophthalmic temperature sensitivity in situ gel preparation and preparation method thereof Download PDFInfo
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Abstract
The invention provides an in situ eye gel preparation of penciclovir. The compositions and weight percentages thereof are 0.01-2.0wt% of penciclovir, 5-40wt% of poloxamer, 0.1-5wt% of tackifier high polymer base, 0.8-10wt% of osmotic regulation agent, 0.001-0.5wt% of antiseptics and the rest is distilled water. Meanwhile, the preparation method is also provided. The in situ gel preparation has good biocompatibility and glutinousness; compared with a liquid preparation, the invention can increase retention time of drug in the eyes and delay elimination, thus improving the bioavailability of theeyes and reducing the times of administration; meanwhile, the invention avoids weaknesses that operation is inconvenient during gel administration, the preparation is not easy to spread in eyes, the dosage can not be controlled accurately, etc.
Description
Technical field
The present invention relates to a kind of dosing eyes system of novelty, promptly in-situ gel preparation specifically, relates to a kind of Penciclovir ophthalmic temperature sensitivity in situ gel preparation and preparation method thereof.
Background technology
Penciclovir (Penciclovir is called for short PCV) is a kind of antiviral drugs that Britain SKB company succeeds in developing, and it is the metabolite of its oral prodrug famciclovir, chemistry 9-[4-hydroxyl-3-(methylol) butyl by name]-guanine.PCV be used for the treatment of herpes simplex virus (HSV-1, HSV-2) and varicella zoster virus (VZV) infect.In virus infected cell, viral thymidine kinases turns to the PCV monophosphate with this product phosphoric acid, and cell kinase is translated into the PCV triphosphate more then.Curative effect and the acyclovir of PCV are suitable, but its triphosphate is longer than the half-life of acyclovir triphosphate.Except that thymidine kinase suddenlys change the HSV separated strain to this product drug resistance, the Strain of many anti-acyclovirs is to this product sensitivity.PCV is usually with the form administration of emulsifiable paste or used for intravenous injection solution.Its ointment in 1996 in Britain's Initial Public Offering, injectable powder also in 1998 the listing.The dosing eyes dosage form (eye drop) of PCV is although still be in the clinical research stage at present, in other dosage form better therapeutic that demonstrate aspect the treatment herpes ophthalmicus viral infection than PCV.
Common ophthalmic preparation mostly is the eye drop that water soluble drug is made, and its major defect comprises: medicine is short in eye holdup time and action time, needs frequent drug administration; The medicine pulsed enters after the medication; Systemic adverse reactions that the nasolacrimal duct drain causes and shortage effectively enter the drug delivery system of a back segment.The bioavailability of ophthalmic solution is very low, and partly cause is medicine rapid reduction of concentration in the tear before cornea, and since the speed that water soluble drug diffuses through cornea cause more slowly.And the rapid reduction of concentration mainly is because the absorption of conjunctiva and shed tears and medicine that normal tear circulation is caused is discharged.
Traditional eye drop is after splashing into eye, the medicine of significant proportion is diluted by tear film immediately, excessive liquid overflows from the eyelid next door, remaining medicine is drained in the nasolacrimal duct road fast, these times that cause eye drop to contact with people's cornea have only 1～2 minute usually, and the eye bioavailability is usually less than 10%.Because the bioavailability of eye is very low, many eye medicinals will use with very high concentration, and this can cause the untoward reaction of eye and whole body.
Early stage research mainly concentrates on and improves eye bioavailability and controlled release drug administration aspect.As using tackifier, hydrophilic polymer, cellulose families etc. are to improve the eye bioavailability of eye drop.But the human research proves, these methods to the raising of bioavailability seldom, so its clinical practice is restricted.Eyes foreign body to external world are relatively responsive, and to shed tears and protection mechanism such as eye blink response is eliminated foreign body, this can cause the holdup time of medicine very short usually, and local bioavailability is low, hinders the performance of curative effect.At present, the research of ophthalmic preparation concentrates on the time of contact between prolong drug and corneal epithelium or the conjunctiva, when reducing systemic adverse reactions, improves the eye bioavailability, local positioning administration or continue medication.The form of splashing into of ocular in-situ gel preparation is a liquid, enters an arched roof through being transformed into the viscoelasticity colloid mutually, has not only merged the advantage of solution and gel but also has avoided the two deficiency.
In recent years, the report quantity of using about situ-gel system (in situ gel forming systems) increases, and has reported the application of some biomedical aspects, comprises drug delivery system, cytocystization and tissue repair etc.These systems are the form administrations with aqueous solution, but at agents area, by ionomer, perhaps change pH value or temperature after, the gelling phenomenon can take place form gel.A kind of method in back is to utilize thermoinducible transformation mutually.
The ABA type triblock copolymer that poloxamer (poloxamer) is made up of polyoxyethylene (PEO) and polyoxypropylene (PPO) is a kind of high polymer adjuvant that pharmacopeia is recorded, and has very high safety, non-stimulated anaphylaxis, good biocompatibility.Poloxamer has the specification of a series of different molecular quality and different PEO/PPO ratios.The poloxamer series of products are widely used in liquid preparation, patch and solid preparation, wherein the aqueous solution of some specification is when concentration surpasses marginal value, having temperature sensitive reverse agglomerative character, is free-pouring solution at low temperatures promptly, then forms clear gel when high temperature.Poloxamer 407 (being PF127) molecular weight is about 11500, and the PEO/PPO ratio is 7:3, and its solution is a kind of flowable viscous liquid under room temperature (25 ℃), changes semi-solid transparent gel when body temperature (37 ℃) into.The preparation of poloxamer can increase the holdup time of medicine at application site usually, thereby improves bioavailability and curative effect.The possible shortcoming of poloxamer gel comprises the non-biodegradation of gel bad mechanical strength, fast corrosion (promptly from surperficial dissolving), PEO-PPO-PEO chain, therefore, necessary poloxamer and other biological adhesion polymer is used jointly.
Poloxamer can be used to prepare ocular in-situ gel, but be difficult to obtain concentration and the simultaneously suitable system of phase transition temperature when using separately, high concentration then phase transition temperature is low, bring inconvenience to the patient, the temperature of preparation is crossed and low eyes is easily caused discomfort, cause shed tears and nictation etc. physiological reaction be unfavorable on the contrary absorbing.
By literature search, do not find poloxamer and bio-adhesive agent are used, preparation has suitable phase transition temperature and has the report of the PCV ocular in-situ gel of the ability of necessarily sticking.
Summary of the invention
The purpose of this invention is to provide a kind of PCV ocular in-situ gel preparation with suitable phase transition temperature, it forms dual system by the compound use of heat-sensitive gel substrate poloxamer and bioadhesive high molecular polymer, regulate its phase transition temperature between 28～34 ℃, have higher bioavailability and lower zest.
Another object of the present invention provides the preparation method of PCV ocular in-situ gel preparation.
In order to realize purpose of the present invention, penciclovir ocular in-situ gel of the present invention, composition and weight percentage are: 0.01～2.0wt% penciclovir, 5～40wt% poloxamer, 0.1～5wt% viscosifier polymer matrix, 0.8～10wt% osmotic pressure regulator, 0.001～0.5wt% antiseptic, all the other are distilled water.
It is preferably: 0.1～1.0wt% penciclovir, 10～24wt% poloxamer, 0.5～3wt% viscosifier polymer matrix, 0.9～5wt% osmotic pressure regulator, 0.01～0.5wt% antiseptic, all the other are distilled water.
The molecular weight ranges of described heat-sensitive gel substrate poloxamer is 5000～20000, oxygen ethyl and oxygen propyl group proportion are 4:1～1:4, preferably poloxamer 407 (being PF127), poloxamer 188 (being F68), or the two a certain proportion of mixture.
For the holdup time of prolong drug at anterior corneal surface, regulate the rate of release of medicine, improve the rheological property of gel rubber system, added in the gel and be no more than 5% viscosifier polymer matrix, as polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, sodium alginate and derivant thereof, arabic gum, tragcanth, guar gum, carbomer, phytohemagglutinin, hyaluronic acid, xanthan gum, chitosan, dextrin and derivant or the like.Preferably carbomer or hydroxypropyl emthylcellulose.
Described osmotic pressure regulator is mannitol, sorbitol, sodium chloride, Polyethylene Glycol, glycerol, propylene glycol, glucose.
Described antiseptic is esters and different ester admixture, quaternary amines such as benzalkonium chloride or the benzalkonium bromide of sorbic acid and salt thereof, benzyl alcohol, phenethanol, nipalgin.
The preparation method of ocular in-situ gel preparation of the present invention comprises the steps: to take by weighing in proportion the viscosifier polymer matrix, adds distilled water, fully stirs, and is placed to whole dissolvings; Take by weighing poloxamer more in proportion, add in the distilled water, stirring makes and is partly dissolved, and is placed to whole dissolvings in cold compartment of refrigerator; Penciclovir, osmotic pressure regulator, antiseptic are dissolved in the distilled water, stir and make its dissolving, through 0.30 μ m filtering with microporous membrane, filtrate and above-mentioned macromolecular solution are merged, and are 6.5～7.5 with the pH value of pH regulator agent regulator solution, and adding distil water is to full dose, stir, promptly.
Be in particular: get 0.1～5wt% viscosifier polymer matrix, add distilled water, fully stir, place, to all dissolvings; Get 5～40wt% heat-sensitive gel substrate poloxamer, add in the distilled water, stirring makes and is partly dissolved, and is placed to whole dissolvings in cold compartment of refrigerator; 0.01～2.0wt%PCV, 0.8～10wt% osmotic pressure regulator, 0.001～0.5wt% antiseptic are dissolved in the distilled water, stirring makes its dissolving, through 0.30 μ m filtering with microporous membrane, filtrate and above-mentioned macromolecular solution are merged, pH value with pH regulator agent regulator solution is 6.5～7.5, adding distil water stirs to full dose.
Described pH regulator agent is sodium hydroxide, hydrochloric acid, boric acid, Borax, carbonate, phosphate, acetate or their mixture.
The present invention utilizes the temperature-sensitive character of poloxamer and the character of viscosity high molecular polymer, has prepared the PCV ocular in-situ gel preparation with suitable phase transition temperature.Penciclovir ophthalmic temperature sensitivity in situ gel preparation of the present invention has suitable phase transition temperature, be liquid condition at ambient temperature, form with solution makes things convenient for dropleting medicine-feeding, is easy to accurately control dosage, changes gel in anterior corneal surface when temperature is elevated near body temperature, thereby increase the holdup time of medicine at eye, delay to eliminate, improve the eye bioavailability, reduce administration number of times, make things convenient for patient's medication, delay the elimination of medicine and the bioavailability of raising eye.Simultaneously, this in-situ gel preparation has excellent biological compatibility, and is non-stimulated to eye.
Description of drawings
Fig. 1 is viscosity--the shearing curve chart that contains the PF127 prescription of different additives;
Fig. 2 is the release profiles (n=3) of PCV in different prescriptions;
Fig. 3 is the PCV concentration in the sample liquid in vivo.(n＝6，error?bars?representstandard?error)◆—0.2％PCV；□—0.2％PCV-1％HPMC?K4M；△—0.2％PCV-12％pluronic?F127；×—0.2％PCV-0.3％carbopol934P；
*—0.2％PCV-12％pluronic?F127-1％HPMC?K4M；○—0.2％PCV-12％pluronic?F127-0.3％carbopol934P
The specific embodiment
Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
The PCV ocular in-situ gel that contains carbomer: take by weighing 0.3% carbomer 934 P, add distilled water, fully stir, place, to all dissolvings, as solution I; Take by weighing 18%PF127, add in the distilled water, stirring makes and is partly dissolved, and places at least 24 hours in cold compartment of refrigerator, to all dissolvings, as solution II; 0.2%PCV, 5% mannitol, 0.01% benzalkonium chloride are dissolved in the distilled water, stir and make its dissolving, through 0.30 μ m filtering with microporous membrane, filtrate and solution I and solution II are merged, regulate pH value to 6.5 with the 1mol/L sodium hydroxide solution, adding distil water is to full dose, stir, promptly.
The PCV ocular in-situ gel that contains hydroxypropyl emthylcellulose (HPMC): take by weighing 0.4%HPMC K4M, add distilled water, be heated to 70 ℃, fully stir, place, to all dissolvings, as solution I; Take by weighing 18%PF127, add in the distilled water, stirring makes and is partly dissolved, and places at least 24 hours in cold compartment of refrigerator, to all dissolvings, as solution II; 0.1%PCV, 0.9% sodium chloride, 0.01% benzalkonium chloride are dissolved in the distilled water, stir and make its dissolving, through 0.30 μ m filtering with microporous membrane, filtrate and solution I and solution II are merged, regulate pH value to 7.5 with the 1mol/L sodium hydroxide solution, adding distil water is to full dose, stir, promptly.
The PCV ocular in-situ gel that contains polyvinylpyrrolidone (PVP): take by weighing 20%PF127, add in the distilled water, stirring makes and is partly dissolved, and places at least 24 hours in cold compartment of refrigerator, to all dissolvings, as solution I; 0.1%PCV, 0.8%PVP K30,0.9% sodium chloride, 0.01% benzalkonium chloride are dissolved in the distilled water, stirring makes its dissolving, through 0.30 μ m filtering with microporous membrane, filtrate and solution I are merged, regulate pH value to 6.5～7.5 with the 1mol/L sodium hydroxide solution, adding distil water stirs to full dose, promptly.
Contain hyaluronic PCV ocular in-situ gel: take by weighing 20%PF127, add in the distilled water, stirring makes and is partly dissolved, and places at least 24 hours in cold compartment of refrigerator, to all dissolvings, as solution I; 0.1%PCV, 0.5% hyaluronic acid, 5% sorbitol, 0.01% benzalkonium chloride are dissolved in the distilled water, stirring makes its dissolving, through 0.30 μ m filtering with microporous membrane, filtrate and solution I are merged, regulate pH value to 6.5～7.5 with the 1mol/L sodium hydroxide solution, adding distil water stirs to full dose, promptly.
The PCV ocular in-situ gel that contains carboxymethyl cellulose: take by weighing 0.5% carboxymethyl cellulose, add distilled water, be heated to 80 ℃, fully stir, place, to all dissolvings, as solution I; Take by weighing 22%PF127, add in the distilled water, stirring makes and is partly dissolved, and places at least 24 hours in cold compartment of refrigerator, to all dissolvings, as solution II; 0.3%PCV, 0.9% sodium chloride, 0.01% benzalkonium bromide are dissolved in the distilled water, stir and make its dissolving, through 0.30 μ m filtering with microporous membrane, filtrate and solution I and solution II are merged, regulate pH value to 6.5～7.5 with 2% borax soln, adding distil water is to full dose, stir, promptly.
The PCV ocular in-situ gel that contains hydroxypropyl: take by weighing 22%PF127, add in the distilled water, stirring makes and is partly dissolved, and places at least 24 hours in cold compartment of refrigerator, to all dissolvings, as solution I; 0.1%PCV, 2% hydroxypropyl, 5% sorbitol, 0.01% benzalkonium chloride are dissolved in the distilled water, stirring makes its dissolving, through 0.30 μ m filtering with microporous membrane, filtrate and solution I are merged, regulate pH value to 6.5～7.5 with the 1mol/L sodium hydroxide solution, adding distil water stirs to full dose, promptly.
The PCV ocular in-situ gel that contains sodium alginate: take by weighing 18%PF127, add in the distilled water, stirring makes and is partly dissolved, and places at least 24 hours in cold compartment of refrigerator, to all dissolvings, as solution I; 0.2%PCV, 1% sodium alginate, 5% sorbitol, 0.01% benzalkonium chloride are dissolved in the distilled water, stirring makes its dissolving, through 0.30 μ m filtering with microporous membrane, filtrate and solution I are merged, regulate pH value to 6.5～7.5 with 1mol/L sodium hydroxide solution or 1mol/L hydrochloric acid solution, adding distil water stirs to full dose, promptly.
The PCV ocular in-situ gel that contains arabic gum: take by weighing 24%PF127, add in the distilled water, stirring makes and is partly dissolved, and places at least 24 hours in cold compartment of refrigerator, to all dissolvings, as solution I; 0.1%PCV, 0.5% arabic gum, 5% mannitol, 0.01% benzalkonium chloride are dissolved in the distilled water, stirring makes its dissolving, through 0.30 μ m filtering with microporous membrane, filtrate and solution I are merged, regulate pH value to 6.5～7.5 with 0.2mol/L sodium hydroxide solution or 0.2mol/L hydrochloric acid solution, adding distil water stirs to full dose, promptly.
Embodiment 9
Preparation process is with embodiment 1, and the composition and the weight percentage of different is gel preparation are: 0.05wt%PCV, 9wt%PF127 and 1wt%F68,2wt% polyvinyl alcohol, 0.8% sodium chloride, 0.05wt% potassium sorbate preservative.
Preparation process is with embodiment 1, and the composition and the weight percentage of different is gel preparation are: 1.0wt%PCV, 40wt%F68,3wt% hydroxypropyl cellulose, 2.0wt% Polyethylene Glycol, 0.5wt% antiseptic phenethanol.
Embodiment 11
Preparation process is with embodiment 1, and the composition and the weight percentage of different is gel preparation are: 2.0wt%PCV, 10wt%PF127 and 20wt%F68,0.1wt% tragcanth, 2wt% glycerol, 0.02wt% propylparaben.
Preparation process is with embodiment 1, and the composition and the weight percentage of different is gel preparation are: 0.01wt%PCV, 5wt%PF127,5wt% hydroxypropyl, 10wt% glucose, 0.001wt% benzalkonium bromide.
Experimental example 1
This experimental example is to investigate the quality of situ-gel, with gelation temperature, rheological properties, drug release characteristics, pharmacokinetics and eye zest etc. is index, system is optimized, and screening obtains the PCV ocular in-situ gel preparation that optimized prescription is formed.Designed following experiment:
1. the phase transition temperature of situ-gel is measured.
Gel sample is put in the clear glass bottle, the inside put magnet rotor (15mm * 6mm), with said preparation since 20 ℃ of heating, 1 ℃/minute of programming rate, stir speed (S.S.) is 100rpm, the temperature when magnet rotor stops operating is as gelation temperature.Result of the test sees Table 1.
The PCV gel preparation that table 1 contains different bio-adhesive agent is 34 ℃ ftheoloqical measurements result (n=3)
Table 1 is the result show: add the gelation temperature that HPMC K4M or carbomer 934 P can reduce PF127 to a certain extent.Compare with single PF127 with same concentrations, add the viscosity that above-mentioned two kinds of binders can increase gel, the effect that viscosity increases is relevant with addition.
2. situ-gel rheological property research.
Adopt cone viscosimeter (DV-3 type, Brookfield, USA) rheological properties of mensuration gel.Utilize the circulator bath contact with viscosimeter that sample is heated to 34 ℃, in 15 minutes shear rate was increased to 20 seconds-1 from 0, the rheological curve that obtains during according to different shear rate records viscosity.Result of the test is seen Fig. 1.
Fig. 1 result shows that all test recipes all have rare effect of cutting, and with the raising of rotating speed (angular velocity), viscosity descends thereupon, and this illustrates that the rheological curve of all prescriptions all has the feature of pseudoplastic fluid.Compare with the solution that only contains PF127, add the rheological charactristics of bio-adhesive agent change gel.
3. the extracorporeal releasing test of situ-gel.
(6mm diameter, MWCO12000-14000 USA) carry out the extracorporeal releasing test of PCV to adopt bag filter, with the accurate 1ml formulation samples of drawing of pipette, join in the bag filter of anticipating, after the sealing, bag filter is immersed in the 40ml release medium, and temperature is controlled at 37 ℃.Release medium for the simulation tear (STF, composed as follows: NaCl0.67g, NaHCO
30.20g, CaCl
22H
2O0.008g, distilled water adds to 100g), with 100rpm rotating speed magnetic agitation.Get 1ml at every turn and discharge sample liquid, and additional equal volume simulation tear, discharge sample liquid after 0.45 μ m syringe filter filters, carry out HPLC and analyze, to measure wherein PCV concentration.Result of the test is seen Fig. 2.
Fig. 2 result shows, increases HPMC K4M or carbomer 934 P consumption and all can reduce the rate of release of PCV in gel.With bioadhesive material and the compound use of PF127 can prolong drug in action time of eye.Gel phase ratio with independent use PF127 adds the release characteristics that HPMCK4M or carbomer 934 P do not change PCV.The release in vitro of medicine in these polymer supports belongs to non-fick diffusion mainly by DIFFUSION CONTROLLED.
4. the eye irritation test of situ-gel.
The research of eye zest adopts the female New Zealand white rabbits of six heavy 2～3kg to carry out, administration every day 2 times, and successive administration 21 days, rubescent, the swelling of routine observation lagophthalmos portion and water-filling situation are estimated and are undertaken by per Draize technique.Result of the test sees Table 2.
Table 2 eye irritation test result
Table 2 is the result show, the prescription of PF127 and HPMC K4M or the compound use of carbomer 934 P does not all have zest, demonstrates good eye toleration.Do not see the damage of corneal, iris and conjunctiva and unusual clinical symptoms yet.
5. the eye bioavailability study of situ-gel.
In this research, select for use 6 not sex-limited not, the New Zealand white rabbit of healthy no ophthalmics, weight 2～2.5kg is as animal pattern, before the experiment beginning under controlled condition one week of nursing.24h fasting before the test, but can't help water.All tests of use animal all meet the requirement of animal for research Managed Solution.Test specimen liquid with 14 ℃ of 50 μ (is respectively the 0.2%PCV aqueous solution respectively, and contain 0.2%PCV+12%PF127 respectively, 0.2%PCV+0.3% carbomer 934 P, 0.2%PCV+1%HPMC K4M, the situ-gel solution of 0.2%PCV+12%PF127+1%HPMC K4M or 0.2%PCV+12%PF127+0.3% carbomer 934 P) splash into and test the conjunctiva liquid Nang Chu that uses rabbit.Sample liquid is inserted the corneal-scleral junction by the syringe needle that is fixed in No. 27 1.3cm on the 1ml disposable syringe, and slightly upwards enters the anterior chamber and gather, and draws then and transfers in the teat glass.
With the sample liquid (200ul) and 200ul acetaminophen/methanol solution (inner mark solution) of gathering, the trichloroacetic acid of 200ul20% (protein precipitant) and 3ml chloroform (extractant) mix.Mixed solution vibrated 5 minutes on WH-2 micro-whirlpool agitator, under 10000rpm centrifugal 10 minutes then.Get supernatant, the following 40 ℃ of evaporates to dryness of nitrogen add the mobile mutual-assistance of 150 μ l and dissolve in residue, measure 20 μ l injection chromatograph of liquid and measure.Result of the test is seen Fig. 3.
Fig. 3 result shows, the time (Tmax) that reaches peak concentration except that 0.2% PCV aqueous solution, the peak time of all the other gel preparations (Tmax) was 1.5h for the 1h, illustrates that gel preparation has all prolonged the action time of medicine at eye.The gel preparation of all PCV all time points after administration, the equal corresponding vivo sample liquid concentration (P≤0.05) after the administration of 0.2%PCV aqueous solution of the concentration of PCV in its vivo sample liquid.No matter be the eye bioavailability that heat-sensitive gel (as PF127) or bioadhesive gel (carbomer 934 P) all can improve PCV.
Therefore, ocular in-situ gel preparation of the present invention can improve the bioavailability of penciclovir at eye, has feasibility.
Though above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (5)
1. Penciclovir ophthalmic temperature sensitivity in situ gel preparation, its composition and weight percentage are: 0.01～2.0wt% penciclovir, 5～40wt% poloxamer 407,0.1～5wt% viscosifier polymer matrix, 0.8～10wt% osmotic pressure regulator, 0.001～0.5wt% antiseptic, the pH value of pH regulator agent regulator solution is 6.5～7.5, and all the other are distilled water; Described viscosifier polymer matrix is carbomer or hydroxypropyl emthylcellulose; Described osmotic pressure regulator is any one in mannitol, sorbitol, sodium chloride, Polyethylene Glycol, glycerol, propylene glycol or the glucose.
2. ocular in-situ gel preparation according to claim 1, it is characterized in that composition and weight percentage are: 0.1～1.0wt% penciclovir, 10～24wt% poloxamer 407,0.5～3wt% viscosifier polymer matrix, 0.9～5wt% osmotic pressure regulator, 0.01～0.5wt% antiseptic, the pH value of pH regulator agent regulator solution is 6.5～7.5, and all the other are distilled water.
3. ocular in-situ gel preparation according to claim 1 and 2 is characterized in that: described antiseptic is esters and the different ester admixture or the quaternary amines of sorbic acid and salt thereof, benzyl alcohol, phenethanol, nipalgin; Described quaternary amines is benzalkonium chloride or benzalkonium bromide.
4. the preparation method of any described ocular in-situ gel preparation of claim 1-3 is characterized in that, comprises the steps: to take by weighing in proportion the viscosifier polymer matrix, adds distilled water, fully stirs, and is placed to whole dissolvings; Take by weighing poloxamer more in proportion, add in the distilled water, stirring makes and is partly dissolved, and is placed to whole dissolvings in cold compartment of refrigerator; Penciclovir, osmotic pressure regulator, antiseptic are dissolved in the distilled water, stir and make its dissolving, through 0.30 μ m filtering with microporous membrane, filtrate and above-mentioned macromolecular solution are merged, pH value with pH regulator agent regulator solution is 6.5～7.5, and adding distil water stirs to full dose.
5. the preparation method of ocular in-situ gel preparation according to claim 4 is characterized in that: described pH regulator agent is sodium hydroxide, hydrochloric acid, boric acid, Borax, carbonate, phosphate, acetate or their mixture.
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| CN109316440B (en) * | 2018-09-29 | 2020-12-29 | 华中科技大学 | Temperature-sensitive liquid crystal nano hydrogel and preparation method and application thereof |
| CN112646209B (en) * | 2019-10-11 | 2021-11-23 | 天津大学 | Double-network physical crosslinking ionic gel electrolyte system based on polyvinyl alcohol-poloxamer and preparation method thereof |
| CN113041215A (en) * | 2021-03-17 | 2021-06-29 | 清华大学深圳国际研究生院 | Eye surface in-situ medicine and preparation method thereof |
| CN113520995B (en) * | 2021-08-16 | 2023-03-10 | 海南鑫开源医药科技有限公司 | Ion-sensitive in-situ gel for eyes, and preparation method and application thereof |
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| CN1377706A (en) * | 2002-04-22 | 2002-11-06 | 沈阳药科大学 | Ocular in-situ gel preparatino with proper phase conversion temperature |
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