CN102670499B - Slow-release sirolimus ophthalmic preparation - Google Patents
Slow-release sirolimus ophthalmic preparation Download PDFInfo
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Abstract
The invention relates to an external slow-release sirolimus ophthalmic preparation for ophthalmology, which is prepared by sirolimus as a pharmacodynamic raw material, bletilla striata as a slow release formulation, and appropriate excipients according to a ratio of sirolimus to bletilla striata of 1.0: (0.1 to 10.0). According to the external slow-release sirolimus ophthalmic preparation for the ophthalmology, the bletilla striata is used as a mucoadhesive polymer drug release system, so that the problems that solubility and stability of the sirolimus in a pure aqueous solution are poor are solved; and the convergence, hemostasis, heat clearing and diuresis promoting, detumescence and granulation promoting effects of the bletilla striata are utilized to enhance the immunosuppressive effect and the eye tissue penetration of the sirolimus.
Description
Technical field
The present invention relates to medicinal preparation, relate in particular to treatment ophthalmic diseases eye local topical preparation used.
Background technology
Sirolimus (Sirolimus, SRL), it is rapamycin, it is the macrolide antibiotics being produced by damp streptocin (Streptomyces hygroscopicus), to various non-T cells, propagation as isocellular in B cell, macrophage, granulocyte and endotheliocyte and cell function all have certain effect.Clinical trial shows, sirolimus is applied to Organ Transplantation Patients and has significant immunosuppressive action.
In contemporary ophthalmic medical, relate to the intraocular inflammation of moderate to severe, especially as the ophthalmology autoimmune diseasees such as uveitis are needed respond well immunosuppressant badly.Studies have found that FKBPL in cornea and retinal tissue (FKBP) exists high expressed, prompting sirolimus is applied to the immunosuppressant potential value of eye.
For ocular disease, local application has many benefits than systemic administration.Under conjunctiva, can in ocular tissue, reach effective drug level with intravitreal injection medication, but intraocular injection administration is a kind of traumatic medication after all, repeatedly duplicate injection administration meeting increases the incidence rate of infectious endophthalmitis greatly.The best mode of ophthalmology local application is eye drop, is also like this for the ophthalmic applications of Xi Moluosi.But sirolimus is insoluble in water, and in aqueous solution, be easy to degraded, making to make a kind of clinical sirolimus easy to use becomes a difficult thing.
Summary of the invention
The object of the present invention is to provide a kind of accessory formula, be made into appropriate dosage forms with itself and principal agent sirolimus, both facilitated clinical use, can retain again the drug effect of sirolimus.
Spacetabs type sirolimus ophthalmic preparation of the present invention, taking sirolimus as pharmacodynamic raw materials, using the Pseudobulbus Bletillae (Rhizoma Bletillae) [Bletillastriata (Thunb.) Reichb.f.] as mucosa-adherent polymeric drug delivery system, be equipped with the slow release type preparation of the prepared one-tenth of said pharmaceutical adjunct on the local acceptable pharmaceutics of eye, the content of every 100 weight portion medicament sirolimus is 0.01～1.0 weight portion, and the consumption of sirolimus and the Pseudobulbus Bletillae (Rhizoma Bletillae) is expressed as by its weight ratio: sirolimus: the Pseudobulbus Bletillae (Rhizoma Bletillae)=1: 0.1～10.0.
Apply spacetabs type sirolimus ophthalmic preparation prepared by above pharmacodynamic raw materials and adjuvant and comprise said any dosage form that is suitable for a local topical on eye drop, gel for eye use, spongaion or pharmaceutics.With regard to its function, belong to spacetabs type ophthalmology immunosuppressant.
The adjuvant of preparing spacetabs type sirolimus ophthalmic preparation of the present invention comprises osmotic pressure regulator, pH adjusting agent, antibacterial, thickening agent, cosolvent.Their kind is selected and consumption is described below respectively.
In the time that the dosage form of made is eye drop or gel for eye use, raw material components also comprises antibacterial.Described antibacterial is the combination in any of any in thimerosal, quaternary ammonium salt, oradol, Xian Bitai, chlorobutanol, parabens, three pears acid or described kind; The consumption of antibacterial to be to be expressed as with the weight ratio of sirolimus, sirolimus: antibacterial=1.0:0.002～0.5.
In the time that the dosage form of made is eye drop, raw material components also comprises thickening agent.Described thickening agent is the combination in any of any or described kind in hypromellose, methylcellulose, hyaluronic acid sodium, polyvinyl alcohol, polyvinylpyrrolidone, polycarbophil, carboxymethyl cellulose, carbomer, chondroitin sulfate; The consumption of thickening agent to be to be expressed as with the weight ratio of sirolimus, sirolimus: thickening agent=1.0:0.1～1.0, can adopt different polymerization degree, and finally make eye drop reach suitable viscosity.
In the time that the dosage form of made is gel for eye use, raw material components also comprises thickening agent; Described thickening agent is selected from the combination in any of a kind of or described kind in hypromellose, methylcellulose, hyaluronic acid sodium, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose, carbomer, chondroitin sulfate, polycarbophil; The consumption of thickening agent to be to be expressed as with the weight ratio of sirolimus, sirolimus: thickening agent=1.0:0.5～5.0.
In the time that the dosage form of made is eye drop or gel for eye use, using pH adjusting agent to regulate the pH value of finished product medicament is 5.5～7.5; Described pH adjusting agent is the combination in any of any or described kind in sodium hydroxide, hydrochloric acid, sodium citrate, the minor official acid of Chinese holly, boric acid, Borax.
In the time that the dosage form of made is eye drop, using osmotic pressure regulator to regulate the osmotic pressure molar density of eye drop is 250～350mOsmol/kg.Described osmotic pressure regulator is the combination in any of a kind of of sodium chloride, mannitol or two kinds.
In the time that the dosage form of made is eye drop or gel for eye use, use cosolvent to promote Xi Moluosi to dissolve, described cosolvent is the combination in any of a kind of of Tween-80, castor oil hydrogenated or two kinds.
In the time that the dosage form of made is spongaion, raw material components also comprises the adjuvant of following kind and consumption: every 1 weight portion sirolimus is equipped with anhydrous lanolin 8～15 weight portions, liquid Paraffin 2～10 weight portions, Yellow Vaselin 75～95 weight portions.
The present invention uses the Pseudobulbus Bletillae (Rhizoma Bletillae) as mucosa-adherent polymeric drug delivery system, can by water and the embedding of bioactive molecule sirolimus wherein, form stable aqueous gel shape eye drop, solves the problem of sirolimus dissolubility and poor stability in simple aqueous solution.In addition, this system can make the active medicine for the treatment of level extend in the eye table holdup time, significantly reduces administration number of times, contributes to increase patient's compliance and treatment success rate.
Meanwhile, the Pseudobulbus Bletillae (Rhizoma Bletillae), as a kind of Chinese medicine material, has effect of convergence, hemostasis, clearing away heat-damp and promoting diuresis, detumescence and promoting granulation, uses it for and prepares sirolimus ophthalmic preparation, contributes to strengthen immunosuppressive effect and ocular tissue's penetrance of sirolimus.
The sirolimus ophthalmic preparation eye local topical of preparing by the inventive method has good intraocular penetration, ophthalmic bioavailability is higher, toxic and side effects is little, the eye immune related diseases such as treatment and prevention autoimmunity tunica uvea retinitis, the graft-rejection of allogeneic corneal, the reaction of eye allergic inflammation.
Detailed description of the invention
The invention will be further described by the following examples.
embodiment 1-3prepare spacetabs type sirolimus eye drop raw material components and consumption
By technical solution of the present invention, the available adjuvant of preparation sirolimus eye drop is not limited to the listed kind of table, can also have multiple choices, and for example antibacterial, can use any antibacterial alleged on pharmaceutics, and its consumption is pressed routine dose on pharmaceutics.As, 1. 0.002%～0.005% thimerosal; 2. quaternary ammonium salt (comprising benzalkonium chloride, benzalkonium bromide), oradol, Xian Bitai etc., valid density is 0.002%～0.01%; 3. alcohols, conventional 0.3～0.6% chlorobutanol; 4. parabens, conventional 0.03～0.06% ethyl hydroxybenzoate; 5. acids, as 0.01～0.08% 3 pears acid.Each material concentration is volume-percentage by weight above, and every hundred milliliters contain grams.
Preparation method is, gets the Pseudobulbus Bletillae (Rhizoma Bletillae) and adds 80% ethanol, and reflux secondary, each 2 hours, merge alcohol extract, filter, decompression recycling ethanol, gained clear paste is for subsequent use.
By Pseudobulbus Bletillae (Rhizoma Bletillae) clear paste or bletilla striata polyoses glue dissolving sirolimus full dose, with water for injection, its dispersion is let cool thickening agent, separately dissolve pH adjusting agent, osmotic pressure regulator, antibacterial with water for injection, stir evenly filtration, merge two liquid, then add the sirolimus having dissolved, add to the full amount of water for injection, filter, subpackage, to obtain final product.Using pH adjusting agent to regulate the pH value of finished product eye drop is 5.5～7.5.
embodiment 4-6prepare spacetabs type sirolimus gel for eye use raw material components and consumption
By technical solution of the present invention, the available adjuvant kind of preparation sirolimus gel for eye use is not limited to the listed kind of table, can also have following multiple choices:
Wherein, the selection of the kind of antibacterial and consumption are with embodiment 1～3.
The weight ratio of described thickening agent and sirolimus is 0.5～5.0:1.0.
Preparation method adds 80% ethanol for getting the Pseudobulbus Bletillae (Rhizoma Bletillae), reflux secondary, and each 2 hours, merge alcohol extract, filter, decompression recycling ethanol, gained clear paste is for subsequent use.
First dissolve sirolimus full dose with Pseudobulbus Bletillae (Rhizoma Bletillae) clear paste or bletilla striata polyoses glue, dissolve thickening agent with water for injection its dispersion is let cool, separately dissolve pH adjusting agent, antibacterial with water for injection, add again the thickening agent and the sirolimus that have dissolved, benefit injects water to volume required, aseptic subpackaged, to obtain final product.Using pH adjusting agent to regulate the pH value of finished product eye drop is 5.5～7.5
embodiment 7-9prepare spacetabs type sirolimus spongaion raw material components and consumption
Preparation method: get the Pseudobulbus Bletillae (Rhizoma Bletillae) and add 80% ethanol, reflux secondary, each 2 hours, merge alcohol extract, filter, decompression recycling ethanol, gained clear paste is for subsequent use.
Dissolve sirolimus full dose with Pseudobulbus Bletillae (Rhizoma Bletillae) clear paste or bletilla striata polyoses glue, add in right amount through sterilizing, cooling liquid Paraffin, grind to form thin pasty state, cross 200 mesh sieves, then add gradually lanoline, Yellow Vaselin mixture aseptic, that filter, mix, to obtain final product.Usedly prepare utensil and packing container must sterilizing.
experimental example 1the stability comparison of spacetabs type sirolimus ophthalmic preparation and plain edition sirolimus ophthalmic preparation
The prepared medicament of the method recorded by the embodiment of the present invention 2 is as trial target, adopt the sirolimus ophthalmic preparation product in contrast prepared of commonsense method (not selecting mucosa-adherent polymeric drug delivery system), compare the stability of spacetabs type sirolimus ophthalmic preparation and plain edition sirolimus ophthalmic preparation by accelerated stability test.
Because this product is to sensitive, therefore determine that the accelerated test condition of this product is 25 DEG C ± 2 DEG C of temperature, relative humidity 20% ± 5%.Respectively by test agent (lot number: 20110901,20110902,20110903) in three batches of spacetabs type sirolimus ophthalmic preparations and plain edition sirolimus ophthalmic preparation, under commercially available back condition, put into climatic chamber, under the condition of 25 DEG C ± 2 DEG C of temperature, relative humidity 20% ± 5%, place, respectively at the 1st, sampling on time in 2,3,6 months, measure by the quality standard of drafting before experiment.Measurement result and measurement result comparison in 0 month, the results are shown in subordinate list.
Spacetabs type sirolimus ophthalmic preparation, 25 DEG C ± 2 DEG C of temperature, was investigated through 6 months under the condition of relative humidity 20% ± 5%, and single impurity and total impurities content obviously do not change, and within first 3 months, sirolimus content does not have significant change, 6 months time, decreases; And the single impurity of plain edition sirolimus ophthalmic preparation and total impurities content obviously increase, sirolimus content obviously reduces.Above result of the test all shows: spacetabs type sirolimus ophthalmic preparation stability is better.The results are shown in following table.
Accelerated stability test result
experimental example 2the release comparison of spacetabs type sirolimus ophthalmic preparation and plain edition sirolimus ophthalmic preparation
The prepared medicament of the method recorded by the embodiment of the present invention 2 is as trial target, the sirolimus ophthalmic preparation product in contrast that adopt commonsense method (not selecting mucosa-adherent polymeric drug delivery system) to prepare.Adopt the Pseudobulbus Bletillae (Rhizoma Bletillae) can make the active medicine (sirolimus) for the treatment of level extend in the eye table holdup time as mucosa-adherent polymeric drug delivery system, significantly reduce administration number of times.By measuring the release of eye drop, thereby can predict spacetabs type sirolimus ophthalmic preparation and the plain edition sirolimus ophthalmic preparation holdup time at eye table.
Carry out the release inspection of spacetabs type sirolimus ophthalmic preparation and plain edition sirolimus ophthalmic preparation according to drug release determination method (two annex X D of " Chinese Pharmacopoeia " version in 2010).Adopt UV-VIS spectrophotometry (UV method) to carry out drug release determination.Measure eye drop 10g, at the bottom of putting beaker, carefully add 100ml normal saline, put 37 DEG C of insulations, as drug release determination solution.Get supernatant 5ml respectively at 1,3,7,12 hour and carry out drug release determination, supplement the normal saline of equivalent volumes simultaneously.Assay method: get supernatant 5ml and be placed in 50ml volumetric flask, add 0.1mol/L hydrochloric acid solution and shake up also standardize solution.Precision measures the each 5ml of this solution and is placed in respectively 10ml volumetric flask again, adds sulfuric acid solution (75 → 100) 5ml and shakes up, and leaves standstill 30min in room temperature.Get the solution after above-mentioned colour developing, taking 0.1mol/L hydrochloric acid solution as blank, according to spectrophotography, measure trap at the wavelength place of 482nm, calculate content and the release of sirolimus.The results are shown in following table.
Drug release determination result (%)
Result shows, plain edition sirolimus ophthalmic preparation discharges very fast, within 1 hour, just discharge approximately 85%, and spacetabs type sirolimus ophthalmic preparation release ratio is slower, and be to discharge gradually, can keep for a long time higher drug level on eye surface, thereby greatly improve the bioavailability of sirolimus at eye.
experimental example 3spacetabs type sirolimus ophthalmic preparation and plain edition sirolimus ophthalmic preparation are in the pharmacokinetics comparison of eye
The prepared medicament of the method recorded by the embodiment of the present invention 2 is as trial target, the sirolimus ophthalmic preparation product in contrast that adopt commonsense method (not selecting mucosa-adherent polymeric drug delivery system) to prepare.
Be subject to reagent spacetabs type sirolimus ophthalmic preparation or plain edition sirolimus ophthalmic preparation, the administration simultaneously of rabbit right and left eyes, dosage is that 50 μ L(adopt the accurate administration of liquid-transfering gun).Respectively at the tear of 0.0833 after administration, 0.5,2,6,12,24,48,72,96,120 h Ge Qu 1 groups (4 animals, male and female half and half) animal.After tear has gathered, air tap inserting method is put to death rabbit immediately, gets in order aqueous humor, cornea, retina.Measure the drug level of ocular tissue's sirolimus, calculate pharmacokinetic parameters.The results are shown in following table.
New zealand rabbit single dose gives after spacetabs type sirolimus ophthalmic preparation, after 120h, in ocular tissue, still can measure sirolimus, half-life in aqueous humor, cornea, retina all can reach more than 30 hour, can in ocular tissue, reach effective drug level therefore be administered once every day.
New zealand rabbit single dose gives after plain edition sirolimus ophthalmic preparation 48h, in ocular tissue, substantially do not detect sirolimus, approximately 8 hours half-life in aqueous humor, cornea, retina, single dose give plain edition sirolimus ophthalmic preparation reach peak concentration and area under curve is all starkly lower than spacetabs type sirolimus ophthalmic preparation.In order to maintain effective drug level, within one day, need administration 2-3 time.
New zealand rabbit single dose gives the concentration of ocular tissue's sirolimus after spacetabs type sirolimus ophthalmic preparation
New zealand rabbit single dose gives the concentration of ocular tissue's sirolimus after plain edition sirolimus ophthalmic preparation
New zealand rabbit eye single dose gives the pharmacokinetic parameters in ocular tissue after spacetabs type sirolimus ophthalmic preparation
New zealand rabbit eye single dose gives the pharmacokinetic parameters in ocular tissue after plain edition sirolimus ophthalmic preparation
experimental example 4the pharmacodynamics comparison of spacetabs type sirolimus ophthalmic preparation and plain edition sirolimus ophthalmic preparation
Spacetabs type sirolimus ophthalmic preparation of the present invention is mainly used in treating uveitis, thus observe its therapeutical effect to experimental autoimmune tunica uvea retinitis (EAU), and carry out pharmacodynamics comparison with plain edition sirolimus ophthalmic preparation.The prepared medicament of the method recorded by the embodiment of the present invention 2 is as trial target, the sirolimus ophthalmic preparation product in contrast that adopt commonsense method (not selecting mucosa-adherent polymeric drug delivery system) to prepare.
The extraction of 1 bovine retina soluble antigen (soluble ant igen, S-Ag)
50 of fresh bovine retinas, homogenate, saltout, dialysis, centrifugal, get supernatant, use diethylamide ethyl-agarose gel (DEAESepharose FF, Pharmacia, Sweden), C post (2.6cm × 10.0cm), put 4 DEG C of cryosphere analysis apparatus (LKB, Sweden) row ion-exchange chromatography separation and purification S-Ag.Dress post (filling approximately 85 ml gels), washes after balanced gel post with the buffering of the hydrochloric acid chromatography containing the trihydroxy aminomethane liquid stream of pH7. 5, adds bovine retina supernatant samples.Continuation chromatography buffer is washed post, and (flow velocity 50 ml/ are h) to foreign protein peak falling baseline.0～0. 4mol/L NaCl linear elution, (h), every 5 ml collect a pipe (ultraviolet 280 nm monitorings) to 100 ml/ to 10 column volumes.4 DEG C of distilled waters of S-Ag peak sample, 24 h that dialyse, move in vial, put-30 DEG C of preservations.The dyeing of sodium dodecyl sulfate-polyacrylamide gel electrophoresis silver shows that S-Ag is a master tape, relative molecular mass 52 × 103.Isoelectric focusing electrophoresis S-Ag mono-band, isoelectric point, IP 6. 2.Antigenic analysis finishes rear lyophilizing ,-30 DEG C of preservations.
2 EAU Animal Models
Closed colony Wistar rat, male, body weight 150g left and right, healthy without oculopathy.Table of random number method is divided into experimental group and matched group at random.Freund's complete adjuvant (complete freund ' s adjuvant, CFA, Gibco) is mixed with equivalent bovine retina S-Ag, make Emulsion, S-Ag final concentration 1. 35 mg/ ml, the rat each injection in two metapedes bottom 0.1 ml, meter 270mg/ is only.Previous experiments respectively with 100,200,300mg S-Ag immune rat brings out EAU, is optimum immuning dose through S-Ag 200～300 mg relatively.
Meanwhile, every rat tail vein injection 10 × 10
9the deactivation bordetella pertussis solution of individual thalline; Supernatant after lumbar injection 0. 1ml escherichia coli Ultrasonic Pulverization liquid is centrifugal.
3 dosage regimens
Spacetabs type sirolimus ophthalmic preparation, administration every day 1 time, each 1-2 drips.
Plain edition sirolimus ophthalmic preparation, administration every day 3 times, each 1-2 drips.
4 observation index and histological examination
After rat immunity, conventional raising, plays mydriasis every day on the 2nd day after immunity, carries out clinical examination with ophthalmoscope, slit lamp microscope, records clinical manifestation.After rat immunity the 12nd day to the 23rd day, can be observed inflammatory reaction.Visible anterior lens capsule is dispersed in inflammatory cell calmness, and how crystalline lens center point-like muddiness disappears after lasting 2～4 d; Or pupil is to mydriatic Low Response, the light moderate inflammatory cell of anterior lens capsule calmness, focal dirt shape muddiness in vitreous body; Or the obvious aqueous flare of anterior chamber, a large amount of inflammatory cell calmnesses of anterior lens capsule, crystalline lens center is obviously muddy, and vitreous body is obviously muddy; Or bulbar conjunctiva is treating serious edema caused, ciliary congestion, iris vessels expansion, posterior synechia is seclusion of pupil even, and ophthalmic cannot be peeped into, visible limitation detachment of retina full detachment of retina occurs rapidly in some rat courses of disease.For the rat that occurs obvious EAU clinical manifestation, the excessive lumbar injection of 10% chloral hydrate is put to death, and after other rat immunity, the 23rd day same method put to death.After execution, extract immediately eyeball, more than the fixing 24h of 2.5% glutaraldehyde, eyeball is pressed to meridian direction and cut, be divided into two parts, remove crystalline lens, conventional gradient alcohol fixation dehydration, paraffin embedding, 3～4mm section, HE dyeing, observation by light microscope, carries out histology's inflammatory reaction scoring.
5 delayed allergies
In order to evaluate delayed allergy (DTH), after rat immunity the 15th day, 20mg S-Ag is dissolved in to 10ml 0. 01mol/L phosphate buffer (phosphate buffer saline, PBS), inject auris dextra edge; Left ear edge injects 10mlPBS in contrast.Front and rear 24,48,72,96 h of injection respectively at injection, use micron meter measurement bilateral ear edge buildup thickness.Wherein every group of 10ml PBS that has the left ears of 6 rats to inject at another position to contain 20mg bovine serum albumin in contrast simultaneously.The ear swelling extent of reaction is calculated with following formula: 24h specificity ear swelling after injection=(24h auris dextra measuring value-injection front right otometry value after injection)/(the left otometry value-injection of 24h front left otometry value after injection), 48,72,96 h specificity ear swellings are measured computational methods and analogized.
6 results
6.1 Histological change
After S-Ag immunity, 2 groups of rat major parts all have the outer section of photoreceptor (receptor outer segment, ROS) to destroy, and normal pectination texture disappears, very person ROS attenuation, disappearance; In addition, the kind of inflammatory cell infiltration, quantity and position, organizational structure change and destructiveness not etc.Wherein, the lighter's inner limiting membrane thickens, and inflammatory reaction homogenizing sample powder dyes electrodeposition substance and (or) forms with partial cavity; Ganglionic cell and inner plexiform layer of retina cavity sample become; Retinal pigment epithelium (ret inal pigment epithelium, RPE) cellular swelling, the degeneration of cavity sample, structure disturbance; Iris or ciliary body congestion, choroid thickens (epithelioid cell infiltration), accidental inflammatory cell infiltration (being mainly lymphocyte).Moderate person's a small amount of inflammatory cell infiltration in visible iris, corpus ciliare or vitreous chamber on above-mentioned change basis; Internal limiting membrane, inner molecular layer, the visible limitation inflammation of inner nuclear layer kitchen range (inflammatory cell gathering); Choroidal artery tube wall thickens, the reaction of vasculitis sample.Severe person is on above-mentioned change basis, and in the each layer tissue of iris, corpus ciliare, choroid and retina, inflammatory cell infiltration quantity increases, and vitreous body diffuse inflammation sexual cell oozes out; Some ocular choroids are struvite thickening obviously, taking lymphocytic infiltration as main; Ocular tissue's structure visible damage.Utmost point severe person ophthalmic massive inflammatory cells infiltrated (neutrophilic leukocyte is main), infiltrates position extensive, even involves conjunctiva, cornea, sclera, eye muscle; Ocular tissue's structure is destroyed completely: the especially each layer tissue diffuse inflammation of retina sexual cell, inflammatory exudation material, slough, visible neuroepithelial layer detachment of retina, full detachment of retina or detachment of choroid.In addition, many without the visible mile abnormality of clinical manifestation person's histological examination, prove that EAU has occurred reality.Spacetabs type sirolimus ophthalmic preparation group EAU histology inflammatory reaction is marked lower than plain edition sirolimus ophthalmic preparation group, and the two difference has the meaning (P < 0. 001) (seeing the following form) of significance.
two groups of rat EAU histologys and DT H scoring
6.2 DT H reactions
All there is the DT H reaction of S-Ag induction in 2 groups of rat auris dextras, full ear is obviously red and swollen; Left ear does not have DT H reaction, and local mild swelling, does not involve full ear, not rubescent, and disappears rapidly.Meaning (P > 0. 05) taking PBS as 2 groups of rat specificity ear swelling value no significant differences of contrast.Each time point comparison, 24 h specificity ear swellings are the most obvious, and 48 h start to disappear, and substantially recover normal to 96 h.
Add with the bovine serum albumin person of comparing, spacetabs type sirolimus ophthalmic preparation group-specific ear swelling value is all lower than plain edition sirolimus ophthalmic preparation group, but the meaning of no significant difference (P >0. 05), when each time point ear swelling rule compares with PBS identical (seeing the following form).
two groups of rat bovine serum albumin contrast DT H scoring
7 conclusions
In integral level, spacetabs type sirolimus ophthalmic preparation (administration every day 1 time) and plain edition sirolimus ophthalmic preparation (administration every day 3 times) all can suppress the generation of rat EAU and alleviate the state of an illness of EAU, but spacetabs type sirolimus ophthalmic preparation administration number of times every day is less, and curative effect is obviously better than plain edition sirolimus ophthalmic preparation.
Inventor has also carried out stability, release, pharmacokinetics and pharmacodynamics checking to sirolimus gel for eye use and sirolimus eye ointment, its stability, release, in Pharmacokinetic Characteristics and the parameter of eye, and similar to the therapeutic effect of the eye immune diseases such as uveitis result compared with sirolimus eye drop.
Claims (1)
1. the uveitic eye drop for the treatment of, it is characterized in that, it is 0.1% sirolimus eye drop, its component is taking sirolimus as pharmacodynamic raw materials, using the Pseudobulbus Bletillae (Rhizoma Bletillae) as mucosa-adherent polymeric drug delivery system, is equipped with adjuvant mannitol and makes osmotic pressure regulator, sodium citrate is made PH regulator, benzalkonium chloride is made antibacterial, and hypromellose is made thickening agent, and castor oil hydrogenated is made cosolvent; Each amounts of components is expressed as by the content in 100 milliliters of medicinal liquids, 0.1 gram of sirolimus, 1.0 grams of the Pseudobulbus Bletillae (Rhizoma Bletillae)s, 0.85 gram, mannitol, 0.1 gram of sodium citrate, 0.01 gram of benzalkonium chloride, 0.2 gram of hypromellose, 2.0 grams of castor oil hydrogenated; Its preparation method is, gets the Pseudobulbus Bletillae (Rhizoma Bletillae) and adds 80% ethanol, and reflux secondary, each 2 hours, merge alcohol extract, filter, decompression recycling ethanol, gained clear paste is for subsequent use; By Pseudobulbus Bletillae (Rhizoma Bletillae) clear paste dissolving sirolimus full dose, with water for injection, its dispersion is let cool thickening agent, separately dissolve pH adjusting agent, osmotic pressure regulator, antibacterial with water for injection, stir evenly filtration, merge two liquid, then add the sirolimus having dissolved, add to the full amount of water for injection, filter, subpackage, to obtain final product; Using pH adjusting agent to regulate the pH value of finished product eye drop is 5.5～7.5.
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| CN103860745B (en) * | 2014-03-13 | 2016-03-16 | 中山大学中山眼科中心 | A kind of medical composite for eye containing sirolimus |
| CN108553407A (en) * | 2018-04-03 | 2018-09-21 | 广州君博医药科技有限公司 | A kind of slow-release Linezolid eye-drops preparations and the preparation method and application thereof |
| CN108210450A (en) * | 2018-04-03 | 2018-06-29 | 广州君博医药科技有限公司 | Medicine-releasing system and azithromycin eye-drops preparations and preparation method comprising its composition |
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| CN1634046A (en) * | 2004-10-29 | 2005-07-06 | 山东省眼科研究所 | Use of rapamycin in preparation of intraocularly embedded drug |
| CN101284006A (en) * | 2007-04-13 | 2008-10-15 | 华北制药集团新药研究开发有限责任公司 | Medicine composition for treating eye disease |
| CN101269220A (en) * | 2008-04-25 | 2008-09-24 | 山东省眼科研究所 | Rapamycin eye-in implantation type medicine release system with bletilla striata glue as carrier |
| CN101518511A (en) * | 2009-03-26 | 2009-09-02 | 中山大学中山眼科中心 | Method for preparing ophthalmic preparation containing tacrolimus |
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| CN102670499A (en) | 2012-09-19 |
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