CN1377706A - Ocular in-situ gel preparatino with proper phase conversion temperature - Google Patents
Ocular in-situ gel preparatino with proper phase conversion temperature Download PDFInfo
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- CN1377706A CN1377706A CN02109503A CN02109503A CN1377706A CN 1377706 A CN1377706 A CN 1377706A CN 02109503 A CN02109503 A CN 02109503A CN 02109503 A CN02109503 A CN 02109503A CN 1377706 A CN1377706 A CN 1377706A
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Abstract
The gel preparation has the merits of both solution and gel. By means of the combination of different type poloxamers, ocular in-situ gel preparation containing medicine and water soluble polymer supplementary material is prepared. The preparation contains poloxamer 407 and poloxament 188 as well as water soluble polymer supplementary material less than 3%. The preparation has proper phase conversion temperatur and may form gel on the surface of cornea of living body after being applied in liquid state at room temperature. The present invention can delay the disappearance of medicine and raise the biological utilization in some local area and is suitable for various ocular medicines.
Description
Technical field:
The present invention relates to a kind of novel dosage form of eye medicinal-the have ocular in-situ gel preparation of suitable phase transition temperature.Specifically a kind of temperature sensitive macromolecule aqueous solution is liquid condition under the room temperature condition, to form gel at anterior corneal surface rapidly behind the eye drop form administration, eliminates thereby delay medicine, improves local bioavailability.
Background technology:
Many ocular disease as glaucoma, corneal infection and inflammation etc., as can not get treating timely and effectively and cause the serious consequence of losing one's sight the most at last.Use effectively disease controlling of appropriate drug, alleviate or eradicate symptom, and select rational dosage form, assurance medication safe and effective also taken like a shot patient then to be important topic on the Drug therapy.
According to statistics, the agent of solution-type eye accounts for the ratio more than 60% in the ophthalmic preparation that has gone on the market, and is easy to use because of it, seldom causes the dimness of vision and cheap and be subjected to the welcome of extensive patients deeply.Protection mechanisms such as eyes are highstrung organs, and it is reverse to shed tears and blink cause medicine holdup time in conjunctival sac short to the elimination effect of foreign body, and local bioavailability is low, thereby has hindered medicine performance curative effect.In addition, most of medicine arrives nasal cavity with tear, enters systemic circulation via mucosa absorption again, has increased the danger that side effect takes place.Eye ointment or gel be the elimination of blocking medicine significantly, the prolong drug cornea holdup time, and then improve its local bioavailability, but higher viscosity causes preparation difficulty, dosage is inaccurate and use problem such as inconvenience, has seriously limited the development of this type of dosage form.The ophthalmic preparation that exploitation has long-acting and good conformability concurrently is the significant challenge of current ophthalmology rational use of drug all the time.The situ-gel drug-supplying system is a kind of character of utilizing polymer to the environmental factors sensitivity, with the solution state administration, forms the novel dosage form of gel in the part, has not only merged the advantage of solution and gel but also has avoided the two deficiency, shows ideal and application prospect.
The ABA block copolymer of polyoxyethylene/polyoxypropylene, non-proprietary term poloxamer (poloxamer) is the high polymer adjuvant that pharmacopeia is recorded, and has very high safety, non-stimulated anaphylaxis, good biocompatibility.Certain density poloxamer aqueous solution has the reverse agglomerative character of being heated, and forms clear and bright gel when promptly being free-pouring liquid and room temperature or body temperature under the refrigerated storage temperature.Poloxamer can be used for preparing ocular in-situ gel, but the poloxamer that is used alone model can't obtain ideal solution-gel transition temperature, promptly formed gel at ambient temperature as 25% (w/w) poloxamer 407, can use after need cold preservation makes it to be converted into liquid.This not only brings great inconvenience for patient's medication, and formulation temperature crosses and low eyes are caused stimulation, cause shed tears, nictation etc. physiology oppositely promote medicine to eliminate, be unfavorable for improving the local bioavailability of medicine.Patent report (Thermoreversible gel as aliquid pharmaceutical carrier for a galenicformulation.EP0551626 is arranged, 1993-07-21), the carbomer of pH sensitivity (Carbomer) share the gel that can obtain to have suitable phase transition temperature and good rheological property with poloxamer.Said preparation is slant acidity, needs in tear and the formation gel, may cause discomfort after the medication.(Suppository composition of the drug whichundergo the hepatic first-pass effect.WO9730693 1997-08-28) has reported that gelation temperature is between 30-60 ℃ poloxamer liquid suppository prescription to also have patent.Comprehensive all searching documents, with the poloxamer compatibility use of different model, the ocular in-situ gel that preparation has suitable phase transition temperature does not appear in the newspapers as yet.
Summary of the invention:
The purpose of this invention is to provide a kind of ocular in-situ gel preparation with suitable phase transition temperature, it contains the water soluble polymer adjuvant, use the poloxamer of two kinds of different models by compatibility, its phase transition temperature is adjusted to more than the room temperature (25 ℃), still can under body temperature (35 ℃) condition, be formed gel by tear dilution back said preparation.
The objective of the invention is to be achieved by the following scheme: with medicine or be loaded with the microparticulate system of medicine or cyclodextrin clathrate and high polymer adjuvant are dissolved in 80%-50% aseptic buffer solution or the pure water.Take by weighing the poloxamer that total amount is two or more different model of 20%-50% again, slowly join under ice bath and stirring condition in the above-mentioned solution, deepfreeze is preserved, until the solution that forms the clarification homogeneous.Add an amount of antibacterial or antiseptic, the pH of regulator solution and osmotic pressure make it meet the requirement of ophthalmic preparation.Polyoxyethylated content should not be lower than 70% in the poloxamer molecule, and mean molecule quantity is between 5000-16000.According to the ratio between used poloxamer model and the different model poloxamer, the phase transition temperature of said preparation is adjustable between 25-30 ℃.Further the rising phase transition temperature causes said preparation no longer to be formed gel by tear dilution back at 35 ℃.
The medicine that relates in the situ-gel can be a kind of in the following medicine or their compound recipe:
1) anti-glaucoma medicine is as pilocarpine, beta-blocker etc.
2) antibiotic is in beta-lactam, Tetracyclines, aminoglycosides, macro ring
Esters, chloromycetin and derivant thereof etc.
3) antibacterials are as quinolones, imidazoles etc.
4) antiviral drugs is as ucleosides etc.
5) steroidal anti-inflammatory drugs thing is as adrenocortical hormone etc.
6) protein and polypeptide drug.
For the holdup time of prolong drug at anterior corneal surface, regulate the rate of release of medicine, or improve the rheological property of gel, can add concentration in the gel less than 3% water soluble polymer adjuvant, as polyvinyl alcohol, polyvidone, methylcellulose, hypromellose, hyetellose, carboxymethyl cellulose, carbomer, hyaluronate sodium, xanthan gum, chitosan, sodium alginate and phospholipid.
The invention has the advantages that, utilize the responsive to temperature character of poloxamer aqueous solution and the combination of different model poloxamer, prepared ocular in-situ gel preparation, made it form gel with the liquid condition administration and at anterior corneal surface at ambient temperature with suitable phase transition temperature.Make things convenient for patient's medication, delay the medicine elimination simultaneously and then improve local bioavailability.
Description of drawings:
Fig. 1 is the phase transition temperature sketch map of poloxamer situ-gel of the present invention.
Fig. 2 is for containing the Research on The Rheology sketch map of poloxamer 407/ poloxamer 188 situ-gel phase transition processes among the present invention.
Fig. 3 is in the preparation of the present invention
99m 'The process sketch map that Tc-DTPA eliminates from anterior corneal surface.
By the description of front, we have provided the preparation technology of ocular in-situ gel.For the phase transition temperature of investigating situ-gel and the retentivity of eye, we are model with poloxamer 407 and poloxamer 188, have designed following experiment:
Experiment one: the phase transition temperature of situ-gel.In-situ gel preparation before and after simulation tear (STF) dilution places flat cylindrical chamber, adds magnetic stir bar.This container is placed on the constant temperature blender with magnetic force, mixing speed is constant, and slow even heating is carried out in water-bath, measures gelation temperature with precision thermometer, temperature when stopping operating fully with magnetic stir bar is as phase transition temperature, and the result gets the meansigma methods of four repetitive operations.
The phase transition temperature of Fig. 1 poloxamer situ-gel.▲ be to use separately poloxamer 407, ● for poloxamer 407 mixes use with poloxamer 188, △ and zero be corresponding situ-gel after simulating tear and the diluting phase transition temperature of (40: 7).
The phase transition temperature of situ-gel is seen Fig. 1.Experimental result explanation poloxamer 407 mixes with poloxamer 188 and uses the phase transition temperature that significantly improves situ-gel to reach 9 ℃, and the two appropriate combination can make situ-gel simulated tear to dilute the phase transition temperature of front and back between 25 ℃-35 ℃.
Experiment two: the Research on The Rheology of situ-gel phase transition process.Determining instrument is a Couette type flow graph of being furnished with water bath with thermostatic control.Adopt CC17 concentric drums container, application of sample amount 5ml, sample surfaces covers one deck silicone oil and prevents solvent evaporates.With the storage modulus of concussion pattern working sample (G '), heating rate is 1 ℃/30min.
Fig. 2 contains the Research on The Rheology of poloxamer 407/ poloxamer 188 situ-gel phase transition processes.● before simulateding the tear dilution, zero for simulateding tear dilution back (40: 7).
The result of Fig. 2 shows, only is increased to after 25 ℃ in temperature, and the storage modulus of situ-gel just begins rapid increase, shows the characteristic of gel.And same prescription has just formed gel at 35 ℃ after the dilution of simulation tear.
Experiment three: the elimination process of the detection in vivo situ-gel of γ scitiphotograph.Add radioactive marker in the gel in position
99m 'The Tc-Pentetic Acid (
99m 'Tc-DTPA), activity is 2-3MBq/40 μ l.Situ-gel behind the labelling is splashed into white rabbit cornea surface under 20 ℃ of conditions, with the elimination process of single photon emission computerized tomography,SPECT photographing unit (SPECT) monitoring mark thing.Fill 40 μ l one of distance white rabbit tail of the eye 1cm placement and tried the plastic tube of solution as the location object of reference.The image of scitiphotograph adopts 128 * 128 picture element matrix forms, opening entry behind the administration 5s, record 10min, totally 63 frames (being followed successively by 5s * 36 frame 10s * 12 frame 20s * 15 frames).In image, mark 5 significant zones (RIO), be respectively (1) location object of reference, (2) anterior corneal surface, (3) inner eye corner, (4) nasolacrimal duct and (5) background.Mapped area under the calculated curve (AUC) time with anterior corneal surface zone radiation residual quantity.
In Fig. 3 preparation
99m 'The process that Tc-DTPA eliminates from anterior corneal surface.■ is a contrast solution, ● be the poloxamer situ-gel.
As can be seen from Figure 3, in 10min, area is 3.4 times of contrast solution under the radiation residual quantity-time graph of the anterior corneal surface of poloxamer in-situ gel preparation zone, show that situ-gel can significantly suppress medicine and eliminate, that is to say, improve medicine by the present invention and have feasibility in the bioavailability of eye.
The specific embodiment:
Embodiment 1:
The timolol maleate ocular in-situ gel; Get timolol maleate 0.25%, bromo geramine 0.02%, 21% poloxamer 407,10% poloxamers 188, aseptic waits phosphatizing acid buffer solution (pH7.4) to full dose.Medicine and Benzalkonii Chloridum are water-soluble, and poloxamer is slowly added in the above-mentioned solution under ice bath and stirring condition, and deepfreeze is preserved, until forming clear and bright solution.
Embodiment 2:
Contain hyaluronic ofloxacin ocular in-situ gel; Get ofloxacin 0.3%, hyaluronate sodium 0.2%, 21% poloxamer 407,10% poloxamers 188, aseptic waits phosphatizing acid buffer solution (pH7.4) to full dose.Hyaluronate sodium is dissolved in buffer solution, again according to embodiment 1 prepared ofloxacin ocular in-situ gel.
Embodiment 3:
The acyclovir ocular in-situ gel that contains carbomer; Get acyclovir 2%, bromo geramine 0.02%, carbomer 934 P0.2%, mannitol 5%, 22% poloxamer 407,10% poloxamers 188, sterilized water is to full dose.Carbomer is dispersed in the water, regulates pH to neutral with sodium hydroxide solution, adds medicine, Benzalkonii Chloridum and mannitol, and poloxamer is slowly added in the above-mentioned solution under ice bath and stirring condition, and deepfreeze is preserved, until forming clear and bright solution.
Embodiment 4:
The pilocarpine ocular in-situ gel that contains chitosan; Get pilocarpine 1%, bromo geramine 0.02%, chitosan 1%, 21% poloxamer 407,10% poloxamers 188, aseptic waits phosphatizing acid buffer solution (pH7.4) to full dose.Chitosan is dissolved in buffer solution, again according to embodiment 1 prepared pilocarpine ocular in-situ gel.
Embodiment 5:
The ocular in-situ gel that contains the gentamycin plasmalogen; Gentamycin plasmalogen 1%, bromo geramine 0.02%, 21% poloxamer 407,10% poloxamers 188, aseptic waits phosphatizing acid buffer solution (pH7.4) to full dose.The ocular in-situ gel that the gentamycin plasmalogen is arranged according to embodiment 1 prepared.
Embodiment 6:
The ocular in-situ gel that contains the amphotericin B plasmalogen; Amphotericin B plasmalogen 0.5%, bromo geramine 0.02%, hydroxypropyl methylcellulose K4M 2%, 20% poloxamer 407,10% poloxamers 188, aseptic waits phosphatizing acid buffer solution (pH7.4) to full dose.Hydroxypropyl emthylcellulose is dissolved in buffer solution, contains the ocular in-situ gel of amphotericin B plasmalogen again according to embodiment 1 prepared.
Embodiment 7:
The ocular in-situ gel that contains ground thiophene rice DNA releaxed circular DNA cyclodextrin inclusion compound; Hydroxypropyl-beta-cyclodextrin inclusion 0.1%, 21% poloxamer 407,10% poloxamers 188 of ground thiophene rice pine, aseptic waits phosphatizing acid buffer solution (pH7.4) to full dose.The ocular in-situ gel that contains ground thiophene rice DNA releaxed circular DNA cyclodextrin inclusion compound according to embodiment 1 prepared.
Embodiment 8:
The ocular in-situ gel that contains the hydrocortisone microsphere; Hydrocortisone microsphere 0.5%, polyvinyl alcohol 3%, 21% poloxamer 407,10% poloxamers 188, aseptic waits phosphatizing acid buffer solution (pH7.4) to full dose.The hydrocortisone microsphere is dispersed in the poly-vinyl alcohol solution, contains the ocular in-situ gel of hydrocortisone microsphere again according to embodiment 1 prepared.
Claims (10)
1, the ocular in-situ gel preparation that has suitable phase transition temperature, it is characterized in that: utilize the combination of different model poloxamer, prepared the ocular in-situ gel preparation that contains medicine and water soluble polymer adjuvant, this situ-gel has suitable phase transition temperature, can form gel with the liquid condition administration and on the live cornea surface at ambient temperature.
2, a kind of ocular in-situ gel preparation according to claim 1 with suitable phase transition temperature, it is characterized in that: related poloxamer is poloxamer 407 and poloxamer 188 in the preparation, wherein poloxamer 407 accounts for 15%-25% (w/w), and poloxamer 188 accounts for 5%-25% (w/w).Water accounts for 80%-50%.According to the ratio between the different model poloxamer, the phase transition temperature of said preparation is adjustable between 25-30 ℃.
3, a kind of ocular in-situ gel preparation according to claim 1 with suitable phase transition temperature, it is characterized in that: can add concentration in the preparation and come the holdup time of prolong drug at anterior corneal surface less than 3% water soluble polymer adjuvant, regulate the rate of release of medicine, or improve the rheological property of gel, as polyvinyl alcohol, polyvidone, methylcellulose, hypromellose, hyetellose, hyprolose, carboxymethyl cellulose, carbomer, hyaluronate sodium, xanthan gum, chitosan, sodium alginate and phosphide.
4, a kind of ocular in-situ gel preparation with suitable phase transition temperature according to claim 1 is characterized in that: can add medicine in the preparation, be loaded with the microparticulate system and the cyclodextrin clathrate of medicine.
5, a kind of ocular in-situ gel preparation according to claim 4 with suitable phase transition temperature, it is characterized in that: related medicine can be a kind of in the anti-glaucoma medicine or their compound recipe in the preparation, as pilocarpine, beta-blocker etc.
6, a kind of ocular in-situ gel preparation according to claim 4 with suitable phase transition temperature, it is characterized in that: related medicine can be a kind of in the antibiotics or their compound recipe in the preparation, as beta-lactam, Tetracyclines, aminoglycosides, Macrolide, chloromycetin and derivant thereof etc.
7, a kind of ocular in-situ gel preparation with suitable phase transition temperature according to claim 4 is characterized in that: related medicine can be a kind of in the antibacterials or their compound recipe in the preparation, as quinolones, and imidazoles etc.
8, a kind of ocular in-situ gel preparation with suitable phase transition temperature according to claim 4 is characterized in that: related medicine can be a kind of in the disease-resistant plain medicine or their compound recipe in the preparation, as ucleosides etc.
9, a kind of ocular in-situ gel preparation with suitable phase transition temperature according to claim 4 is characterized in that: related medicine can be a kind of in the steroidal anti-inflammatory class medicine or their compound recipe in the preparation, as adrenocortical hormone etc.
10, a kind of ocular in-situ gel preparation with suitable phase transition temperature according to claim 4 is characterized in that: related medicine can be a kind of in protein and the polypeptide drug or their compound recipe in the preparation.
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