CN105311641A - Slowly released type sirolimus eye-drops preparation and preparation method thereof - Google Patents
Slowly released type sirolimus eye-drops preparation and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a slowly released type sirolimus eye-drops preparation and a preparation method thereof. The slowly released type sirolimus eye-drops preparation is characterized in that the slowly released type preparation is prepared by using sirolimus as a pharmacodynamic raw material, using salviae miltiorrhizae and polycarbophil as a mucosa adhesion polymer drug releasing system, and using auxiliary materials which can be received by eyes locally, and the weight ratio of the using amount of the sirolimus, the salviae miltiorrhizae and the polycarbophil is 1:0.5-5.0: 0.5-2. The related dosage forms comprise eye drops, ophthalmic gel, eye ointment or any pharmaceutic external dosage forms suitable for eyes locally. The salviae miltiorrhizae and the polycarbophil serve as the mucosa adhesion polymer drug releasing system, and the problem that the sirolimus is poor in solubility and stability when used in a pure aqueous solution is solved. Meanwhile, the salviae miltiorrhizae facilitates improvement of immunosuppressive effect and eye tissue penetrability of the sirolimus, and a pharmacology experiment shows that the eye-drops preparation can be used for treating eye immune diseases well.
Description
Technical field
The invention belongs to drug world, more specifically relate to a kind of sirolimus ophthalmic preparation and preparation method thereof.
Background technology
Sirolimus (Sirolimus) is also known as rapamycin (Rapamycin), it is a kind of macrolides antibiotics immunosuppressant, its mechanism is that late phase reaction (propagation) T suppression cell that it can block T lymphocyte activation enters the S phase from the G1 phase, the combination of blocking leukocyte Jie element-2 (IL-2) and its receptor, Tc, Td cell can not be become have the sensitization T lymphocyte of immunne response effect, play its immunization.As third generation immunosuppressant, sirolimus is the novel potent immunosuppressant that the toxicity that finds up to now is less, is just becoming the essential drugs of Organ Transplantation Patients permanent immunity suppression therapy.Can be used for the autoimmune disease such as the anti-repulsive interaction of organ transplantation and treatment rheumatoid arthritis, lupus erythematosus, psoriasis clinically, its immunosuppressive action is stronger than ciclosporin 100 times, stronger than tacrolimus 30 times.Studies have found that FKBPL (FKBP) exists high expressed in cornea and retinal tissue, prompting sirolimus is applied to the immunosuppressant potential value of eye.
For ocular disease, local application has many benefits than systemic administration.Can reach effective drug level in ocular tissue with intravitreal injection medication under conjunctiva, but intraocular injection administration is a kind of traumatic medication after all, repeatedly duplicate injection administration can increase the incidence rate of infectious endophthalmitis greatly.The best mode of ophthalmology local application is eye drop, but because sirolimus treatment window is narrow, the adverse reaction rate such as hypertriglyceridemia, hypercholesterolemia is high, and sirolimus is insoluble in water, and be easy to degraded in aqueous, limit its extensive use clinically especially on clinical ophthalmology.In contemporary ophthalmic medical, relate to the intraocular inflammation of moderate to severe, especially as the ophthalmology autoimmune diseasees such as uveitis need respond well immunosuppressant badly.
Water and bioactive molecule sirolimus, as mucoadhesive polymer medicine-releasing system, can be embedded in wherein by Radix Salviae Miltiorrhizae and polycarbophil, form stable aqueous gel shape eye drop, solve the problem of sirolimus dissolubility and poor stability in simple aqueous solutions.Meanwhile, Radix Salviae Miltiorrhizae, as a kind of Chinese medicine material, has blood circulation promoting and blood stasis dispelling, calming heart and tranquilizing mind, evacuation of pus, and effect of pain relieving is used it for and prepared sirolimus ophthalmic preparation, contributes to the immunosuppressive effect and the ocular tissue's penetrance that strengthen sirolimus.
Therefore, sirolimus, as mucoadhesive polymer medicine-releasing system, is prepared into a kind of spacetabs type department ophthalmic preparation and has certain science by interpolation Radix Salviae Miltiorrhizae and polycarbophil.
Summary of the invention
The object of the present invention is to provide a kind of opthalmological accessory formula, be made into appropriate dosage forms with itself and principal agent sirolimus, both facilitated Clinical practice, the drug effect of sirolimus can be retained again.
Spacetabs type sirolimus ophthalmic preparation of the present invention, take sirolimus as pharmacodynamic raw materials, using Radix Salviae Miltiorrhizae and polycarbophil as mucoadhesive polymer medicine-releasing system, be equipped with the slow release type preparation of the prepared one-tenth of said pharmaceutical adjunct on the acceptable pharmaceutics of eye local, the content of every 100 weight portion medicament sirolimuss is 0.01 ~ 1.0 weight portion, and the consumption of sirolimus and bletilla striata polyoses glue is expressed as by its weight ratio: sirolimus: Radix Salviae Miltiorrhizae: polycarbophil=1: 0.5 ~ 5.0: 0.5 ~ 2.
Radix Salviae Miltiorrhizae is as a kind of Chinese medicine material, there is blood circulation promoting and blood stasis dispelling, calming heart and tranquilizing mind, evacuation of pus, effect of pain relieving, using it for the extracting method preparing sirolimus ophthalmic preparation is: get Radix Salviae Miltiorrhizae and extract 3 times, add alcohol reflux 1.5 hours 1st time, filter, filtrate recycling ethanol, being concentrated into relative density is 1.30 (55 ~ 60 DEG C); Add 50% alcohol reflux 1.5 hours 2nd time, filter.Add water for 3rd time backflow 2 hours, filters, merge the 2nd time, the 3rd time filtrate, reclaim ethanol, being concentrated into relative density is 1.40 (55 ~ 60 DEG C), merges with the concentrated solution of the 1st time, mixed Uniform, makes the extractum that relative density is 1.35 ~ 1.39 (55 DEG C).The method can make most of effective ingredient of Radix Salviae Miltiorrhizae be retained, and also can remove the impurity of a great deal of, can improve Radix Salviae Miltiorrhizae purity further in addition by the method such as membrane separation technique and ultrafiltration.
Apply spacetabs type sirolimus ophthalmic preparation prepared by above medicinal raw material and adjuvant to comprise said any one on eye drop, gel for eye use, spongaion or pharmaceutics and be suitable for the dosage form of a local topical.With regard to its function, belong to spacetabs type ophthalmology immunosuppressant.
The adjuvant preparing spacetabs type sirolimus ophthalmic preparation of the present invention comprises osmotic pressure regulator, pH adjusting agent, antibacterial, thickening agent, cosolvent.Their Fruit variety and consumption are described below respectively.
1. when made dosage form be eye drop or gel for eye use time, raw material components also comprises antibacterial.Described antibacterial is the combination in any of any one or described kind in thimerosal, quaternary ammonium salt, oradol, Xian Bitai, chlorobutanol, parabens, three pears acid; The consumption of antibacterial to be expressed as with the weight ratio of sirolimus, sirolimus: antibacterial=1.0: 0.002 ~ 0.5.
2., when made dosage form is eye drop, raw material components also comprises thickening agent.Described thickening agent is the combination in any of any one in hypromellose, methylcellulose, hyaluronic acid sodium, polyvinyl alcohol, polyvinylpyrrolidone, polycarbophil, carboxymethyl cellulose, carbomer, chondroitin sulfate or described kind; The consumption of thickening agent to be expressed as with the weight ratio of sirolimus, sirolimus: thickening agent=1.0: 0.1 ~ 1.0.Can different polymerization degree be adopted, finally make eye drop reach suitable viscosity.
3., when made dosage form 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 expressed as with the weight ratio of sirolimus, sirolimus: thickening agent=1.0: 0.5 ~ 5.0.
4. when made dosage form be eye drop or gel for eye use time, use pH adjusting agent to regulate the pH value of finished product medicament to be 5.5 ~ 7.5; Described pH adjusting agent is the combination in any of any one in sodium hydroxide, hydrochloric acid, sodium citrate, the minor official acid of Chinese holly, boric acid, Borax or described kind.
5., when made dosage form is eye drop, use osmotic pressure regulator to regulate the osmotic pressure molar density of eye drop to be 250 ~ 350mOsmol/kg.Described osmotic pressure regulator is a kind of combination in any of or two kinds of sodium chloride, mannitol.
6. when made dosage form be eye drop or gel for eye use time, Xi Moluosi dissolves to use cosolvent to promote, described cosolvent is a kind of combination in any of or two kinds of Tween-80, castor oil hydrogenated.
7. when made dosage form is spongaion, raw material components also comprises the adjuvant of following kind and consumption: raw material components and supplementary product consumption part by weight are: sirolimus: Radix Salviae Miltiorrhizae: anhydrous lanolin: liquid Paraffin: Yellow Vaselin=1: 0.5 ~ 5.0: 8 ~ 15: 2 ~ 10: 75 ~ 95.
The present invention uses Radix Salviae Miltiorrhizae as mucoadhesive polymer medicine-releasing system, can be embedded in wherein by water and bioactive molecule sirolimus, forms stable aqueous gel shape eye drop, solves the problem of sirolimus dissolubility and poor stability in simple aqueous solutions.Meanwhile, Radix Salviae Miltiorrhizae, as a kind of Chinese medicine material, has blood circulation promoting and blood stasis dispelling, calming heart and tranquilizing mind, evacuation of pus, and effect of pain relieving is used it for and prepared sirolimus ophthalmic preparation, contributes to the immunosuppressive effect and the ocular tissue's penetrance that strengthen sirolimus.
The sirolimus ophthalmic preparation local topical prepared by the inventive method has good intraocular penetration, ophthalmic bioavailability is higher, adverse reaction rate is low, improve clinical drug safety, and raw material is easy to get, preparation technology's simple possible, productive rate is high, cost is low, industrialization large-scale production can be realized, there is significant economic benefit.
Detailed description of the invention
By the following examples and experimental example the invention will be further described.
Embodiment 1-3 prepares 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 kind listed by table, can also have multiple choices, such as antibacterial, and can use any antibacterial alleged on pharmaceutics, its consumption presses 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 namely every hundred milliliters contain grams.
Preparation method is, sirolimus full dose is dissolved with Radix Salviae Miltiorrhizae, make it disperse to let cool thickening agent water for injection, separately dissolve pH adjusting agent, osmotic pressure regulator, antibacterial with water for injection, stir evenly filtration, merge two liquid, add the sirolimus dissolved again, add to the full amount of water for injection, filter, subpackage, to obtain final product.PH adjusting agent is used to regulate the pH value of finished product eye drop to be 5.5 ~ 7.5.
Embodiment 4-6 prepares 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 kind listed by table, and can also have following multiple choices: wherein, the Fruit variety of antibacterial and consumption are with embodiment 1 ~ 3.The amount ratio of described thickening agent and sirolimus is 0.5 ~ 5.0: 1.0.
Preparation method is, dissolves sirolimus full dose with Radix Salviae Miltiorrhizae, dissolves thickening agent make it disperse to let cool with water for injection, another water for injection dissolves pH adjusting agent, antibacterial, then adds the thickening agent and sirolimus that have dissolved, and benefit injects water to volume required, aseptic subpackaged, to obtain final product.PH adjusting agent is used to regulate the pH value of finished product eye drop to be 5.5 ~ 7.5.
Embodiment 7-9 prepares spacetabs type sirolimus spongaion raw material components and consumption
Preparation method: dissolve sirolimus full dose with Radix Salviae Miltiorrhizae, adds in right amount through the liquid Paraffin of sterilizing, cooling, grinds to form thin pasty state, cross 200 mesh sieves, then adds aseptic, that filter lanoline, Yellow Vaselin mixture gradually, and mixing, to obtain final product.Usedly prepare utensil and packing container must sterilizing.
Experimental example 1 spacetabs type sirolimus eye drop compares with the stability of plain edition sirolimus eye drop
Medicament prepared by the method recorded by the embodiment of the present invention 2 is as trial target, the sirolimus eye drop product in contrast adopting commonsense method (not selecting mucoadhesive polymer medicine-releasing system) to prepare, compare the stability of spacetabs type sirolimus eye drop and plain edition sirolimus eye drop by accelerated stability test.
Because this product is to sensitive, therefore determine that the accelerated test condition of this product is temperature 25 DEG C ± 2 DEG C, relative humidity 20% ± 5%.Respectively by test agent (lot number: 20120701,20120702,201210703) in three batches of spacetabs type sirolimus eye drop and plain edition sirolimus eye drop, under commercially available back condition, put into climatic chamber, place under the condition of temperature 25 DEG C ± 2 DEG C, relative humidity 20% ± 5%, respectively at the 1st, within 2,3,6 months, sample on time, measure according to the quality standard draft drafted before experiment.Measurement result compares with 0 month measurement result, the results are shown in subordinate list.
Spacetabs type sirolimus eye drop is temperature 25 DEG C ± 2 DEG C, and investigated through 6 months under the condition of relative humidity 20% ± 5%, single impurity and total impurities content obviously do not change, and within first 3 months, sirolimus content does not have significant change, decreases when 6 months; And the single impurity of plain edition sirolimus eye drop and total impurities content obviously increase, sirolimus content obviously reduces.Above result of the test all shows: spacetabs type sirolimus eye drop stability is better.The results are shown in following table.
Accelerated stability test result
Experimental example 2 spacetabs type sirolimus eye drop compares with the release of plain edition sirolimus eye drop
Medicament prepared by the method recorded by the embodiment of the present invention 2, as trial target, adopts sirolimus eye drop product in contrast prepared by commonsense method (not selecting mucoadhesive polymer medicine-releasing system).Adopt Radix Salviae Miltiorrhizae the active medicine (sirolimus) for the treatment of level can be made at eye table increased retention as mucoadhesive polymer medicine-releasing system, significantly reduce administration number of times.By measuring the release of eye drop, thus spacetabs type sirolimus eye drop and the plain edition sirolimus eye drop holdup time at eye table can be predicted.
The release inspection of spacetabs type sirolimus eye drop and plain edition sirolimus eye drop is carried out according to drug release determination method (" Chinese Pharmacopoeia " version in 2010 two annex XD).UV-VIS spectrophotometry (UV method) is adopted to carry out drug release determination.Measure eye drop 10g, put at the bottom of 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, adds 0.1mol/L hydrochloric acid solution and shakes up and standardize solution.Precision measures each 5ml of this solution and is placed in 10ml volumetric flask respectively again, adds sulfuric acid solution 5ml and shakes up, leave standstill 30min in room temperature.Get the solution after above-mentioned colour developing, with 0.1mol/L hydrochloric acid solution for 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, the release of plain edition sirolimus eye drop is very fast, within 1 hour, just release about 85%, and spacetabs type sirolimus eye drop release ratio is slower, and be discharge gradually, higher drug level can be kept for a long time on eye surface, thus greatly improve the bioavailability of sirolimus at eye.
Experimental example 3 spacetabs type sirolimus eye drop compares in the pharmacokinetics of eye with plain edition sirolimus eye drop
Medicament prepared by the method recorded by the embodiment of the present invention 2, as trial target, adopts sirolimus eye drop product in contrast prepared by commonsense method (not selecting mucoadhesive polymer medicine-releasing system).
Give by reagent spacetabs type sirolimus eye drop or plain edition sirolimus eye drop, the administration simultaneously of rabbit right and left eyes, dosage is 50 μ L.Respectively at 0.0762 after administration, 0.5,2,6,12,24,48,72,96, the tear of 120h Ge Qu 1 group (4 animals, male and female half and half) animal.After tear has gathered, air tap inserting method puts to death rabbit immediately, gets aqueous humor, cornea, retina in order.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 the concentration of ocular tissue's sirolimus after spacetabs type sirolimus eye drop
New zealand rabbit single dose gives the concentration of ocular tissue's sirolimus after plain edition sirolimus eye drop
New zealand rabbit eye single dose gives the pharmacokinetic parameters after spacetabs type sirolimus eye drop in ocular tissue
New zealand rabbit eye single dose gives the pharmacokinetic parameters after plain edition sirolimus eye drop in ocular tissue
Result shows: after new zealand rabbit single dose gives spacetabs type sirolimus eye drop, still sirolimus can be measured in ocular tissue after 120h, half-life in aqueous humor, cornea, retina all can reach more than 30 hour, therefore is administered once every day and can reaches effective drug level in ocular tissue.
After new zealand rabbit single dose gives plain edition sirolimus eye drop 48h, substantially sirolimus is not detected in ocular tissue, about 8 hours half-life in aqueous humor, cornea, retina, single dose give plain edition sirolimus eye drop reach peak concentration and area under curve is all starkly lower than spacetabs type sirolimus eye drop.In order to maintain effective drug level, within one day, need administration 2-3 time.
Experimental example 4 spacetabs type sirolimus eye drop compares with the pharmacodynamics of plain edition sirolimus eye drop
The spacetabs type sirolimus eye drop of our development is mainly used in treating uveitis, therefore observes its therapeutical effect to experimented autoimmune myositis (EAU), and carries out pharmacodynamics with plain edition sirolimus eye drop and compare.Medicament prepared by the method recorded by the embodiment of the present invention 2, as trial target, adopts sirolimus eye drop product in contrast prepared by commonsense method (not selecting mucoadhesive polymer medicine-releasing system),
The extraction of 1 bovine retina soluble antigen (solubleantigen, S-Ag)
Fresh bovine retina 50, homogenate, saltout, dialyse, centrifugal, get supernatant, use diethylamide ethyl-agarose gel (DEAESepharoseFF, 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 about 85ml gel), after washing balanced gel post, adds bovine retina supernatant samples with the hydrochloric acid column buffer liquid stream containing trihydroxy aminomethane of pH7.5.Continue chromatography buffer and wash post (flow velocity 50ml/h) to foreign protein peak falling baseline.0 ~ 0.4mol/LNaCl linear elution, 10 column volumes (100ml/h), every 5ml collects a pipe (ultraviolet 280nm monitors).S-Ag peak sample 4 DEG C of distilled water dialysis 24h, move in vial, put-30 DEG C of preservations.Sodium dodecyl sulfate-polyacrylamide gel electrophoresis Silver stain display 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 terminates rear lyophilizing ,-30 DEG C of preservations.
2EAU Animal Model
Closed colony Wistar rat, male, about body weight 150g is healthy without oculopathy.Random digits table is divided into experimental group and matched group at random.Freund's complete adjuvant (completefreund ' sadjuvant, CFA, Gibco) mix with equivalent bovine retina S-Ag, makes Emulsion, S-Ag final concentration 1.35mg/ml, respectively inject 0.1ml bottom the two metapedes of rat, count 270 μ g/.Previous experiments brings out EAU with 100,200,300 μ gS-Ag immune rats respectively, is optimum immuning dose through comparing S-Ag200 ~ 300 μ g.
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 eye drop, administration every day 1 time, each 1-2 drips.
Plain edition sirolimus eye drop, 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, record 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 crystalline lens center point-like is muddy, how to disappear after continuing 2 ~ 4d; Or pupil is to mydriatic Low Response, the light moderate inflammatory cell of anterior lens capsule is calm, and in vitreous body, focal dirt shape is muddy; Or the obvious aqueous flare of anterior chamber, a large amount of inflammatory cell of anterior lens capsule is calm, and crystalline lens center is obviously muddy, and vitreous body is obviously muddy; Or bulbar conjunctiva is treating serious edema caused, ciliary congestion, iris vessels is expanded, and posterior synechia is seclusion of pupil even, and ophthalmic cannot be peeped into, visible limitation detachment of retina in some rat courses of disease and the rapid full detachment of retina of generation.For the rat occurring 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 is put to death.Extract eyeball immediately after execution, 2.5% glutaraldehyde fixes more than 24h, eyeball is pressed meridian direction and cuts, be divided into two parts, removing crystalline lens, conventional gradients alcohol fixation is dewatered, paraffin embedding, 3 ~ 4 μm of sections, HE dyes, and 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, 20 μ gS-Ag being dissolved in 10 μ l0.01mol/L phosphate buffer (phosphatebuffersaline, PBS), injecting auris dextra edge; Left ear edge injects 10 μ lPBS in contrast.Respectively at before injection and after injection 24,48,72,96h, use micron meter to measure bilateral ear edge buildup thickness.Wherein often organize 6 left ears of rat and contain 10 μ lPBS of 20 μ g bovine serum albumin in contrast at another injection location simultaneously.The following formulae discovery of the ear swelling extent of reaction: 24h specificity ear swelling=(injection after 24h auris dextra measuring value-injection front right otometry value) after injection/(the rear left otometry value of the 24h-injection front left otometry value of injection), 48,72,96h specificity ear swelling survey calculation method analogizes.
6 results
6.1 Histological change
After S-Ag immunity, 2 groups of rat major parts all have the outer section (receptoroutersegment, ROS) of photoreceptor to destroy, normal pectination texture disappears, notably ROS thinning, show as conjunctival congestion, anterior chamber is muddy, posterior synechia, eye ground edema is congested.Pathological section is shown in vitreous chamber inflammatory cell, retinal edema, and each Rotating fields is disorderly, inflammatory infiltration, periangiitis, nethike embrane internal granuloma etc.Wherein, the lighter's inner limiting membrane thickens, and inflammatory reaction homogenizing sample powder contaminates electrodeposition substance and (or) formed with partial cavity; Ganglionic cell and inner plexiform layer of retina cavity sample become; Retinal pigment epithelium (retinalpigmentepithelium, 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, inner nuclear layer visible limitation inflammation stove (inflammatory cell gathering); Choroidal artery tube wall thickening, vasculitis sample reacts.Severe person on above-mentioned change basis, inflammatory cell infiltration increasing number in each layer tissue of iris, corpus ciliare, choroid and retina, vitreous body diffuse inflammation sexual cell oozes out; Some ocular choroids are obviously struvite to be thickened, based on lymphocytic infiltration; Ocular tissue's structure visible damage.Pole severe person's ophthalmic massive inflammatory cells infiltrated (neutrophilic leukocyte is main), infiltrating sites is extensive, even involves conjunctiva, cornea, sclera, eye muscle; Ocular tissue's structure is destroyed completely: especially retina each layer tissue diffuse inflammation 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 actually to there occurs EAU.Spacetabs type sirolimus eye drop group EAU histology inflammatory reaction scoring is lower than plain edition sirolimus eye drop group, and the two difference has the meaning (P < 0.001) (seeing the following form) of significance.
2 groups of rat EAU histologys and DTH scoring
6.2DTH reaction
2 groups of rat auris dextras all there occurs the DTH reaction of S-Ag induction, and full ear is obviously red and swollen; Left ear does not have DTH to react, and local mild swelling, does not involve full ear, not rubescent, and disappears rapidly.Take PBS as the meaning (P > 0.05) of 2 groups of rat specificity ear swelling value no significant differences of contrast.Each time point compares, and 24h specificity ear swelling is the most obvious, and 48h starts to disappear, and substantially recovers normal to 96h.
Add with the bovine serum albumin person of comparing, spacetabs type sirolimus eye drop group-specific ear swelling value is all lower than plain edition sirolimus eye drop 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).
2 groups of rat bovine serum albumin contrast DTH scoring
7 conclusions
In integral level, spacetabs type sirolimus eye drop (administration every day 1 time) and plain edition sirolimus eye drop (administration every day 3 times) all can suppress the generation of rat EAU and alleviate the state of an illness of EAU, but daily number of times is less for spacetabs type sirolimus eye drop, and curative effect is obviously better than plain edition sirolimus eye drop.
The present inventor has also carried out the checking of stability, release, pharmacokinetics and pharmacodynamics to spacetabs type sirolimus gel for eye use and spacetabs type sirolimus eye ointment, its stability, release, in the Pharmacokinetic Characteristics of eye and parameter, and the therapeutic effect there was no significant difference compared with spacetabs type sirolimus eye drop to ocular immune diseases such as uveitis.
Claims (9)
1. spacetabs type sirolimus ophthalmic preparation and preparation method thereof, it is characterized in that, it take sirolimus as pharmacodynamic raw materials, using Radix Salviae Miltiorrhizae and polycarbophil as mucoadhesive polymer medicine-releasing system, be equipped with the slow release type preparation of the prepared one-tenth of said pharmaceutical adjunct on the acceptable pharmaceutics of eye local, the content of every 100 weight portion medicament sirolimuss is 0.01 ~ 1.0 weight portion, and the consumption of sirolimus and Radix Salviae Miltiorrhizae and polycarbophil by its weight ratio is: sirolimus: Radix Salviae Miltiorrhizae: polycarbophil=1: 0.5 ~ 5.0: 0.5 ~ 2.
2. spacetabs type sirolimus ophthalmic preparation according to claim 1, is characterized in that, its dosage form is the dosage form that on eye drop, gel for eye use, spongaion or pharmaceutics, said any one is suitable for a local topical.
3. spacetabs type sirolimus ophthalmic preparation according to claim 2, it is characterized in that, when made dosage form is spongaion, raw material components and supplementary product consumption part by weight are: sirolimus: Radix Salviae Miltiorrhizae: anhydrous lanolin: liquid Paraffin: Yellow Vaselin=1: 0.5 ~ 5.0: 8 ~ 15: 2 ~ 10: 75 ~ 95.
4. spacetabs type sirolimus ophthalmic preparation according to claim 2, it is characterized in that, when made dosage form be eye drop or gel for eye use time, raw material components also comprises the combination in any of any one antibacterial or described antibacterial in thimerosal, quaternary ammonium salt, oradol, Xian Bitai, chlorobutanol, parabens, three pears acid; The consumption of antibacterial to be expressed as with the weight ratio of sirolimus, sirolimus: antibacterial=1.0: 0.002 ~ 0.5.
5. spacetabs type sirolimus ophthalmic preparation according to claim 2, it is characterized in that, when made dosage form is eye drop, raw material components also comprises the combination in any of any one thickening agent in hypromellose, methylcellulose, hyaluronic acid sodium, polyvinyl alcohol, polyvinylpyrrolidone, polycarbophil or described thickening agent; The consumption of thickening agent to be expressed as with the weight ratio of sirolimus, sirolimus: thickening agent=1.0: 0.1 ~ 1.0.
6. spacetabs type sirolimus ophthalmic preparation according to claim 2, it is characterized in that, when made dosage form is gel for eye use, raw material components also comprises the combination in any of a kind of thickening agent in hypromellose, methylcellulose, hyaluronic acid sodium, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethyl cellulose, carbomer, chondroitin sulfate, polycarbophil or described thickening agent; The consumption of thickening agent to be expressed as with the weight ratio of sirolimus, sirolimus: thickening agent=1.0: 0.5 ~ 5.0.
7. the spacetabs type sirolimus ophthalmic preparation according to claim 4 or 5 or 6, is characterized in that, when made dosage form be eye drop or gel for eye use time, use pH adjusting agent to regulate the pH value of finished product medicament to be 5.5 ~ 7.5; Described pH adjusting agent is the combination in any of any one in sodium hydroxide, hydrochloric acid, sodium citrate, the minor official acid of Chinese holly, boric acid, Borax or described kind.
8. the spacetabs type sirolimus ophthalmic preparation according to claim 4 or 5 or 6, it is characterized in that, when made dosage form be eye drop or gel for eye use time, Xi Moluosi dissolves to use cosolvent to promote, described cosolvent is a kind of combination in any of or two kinds of Tween-80, castor oil hydrogenated.
9. the spacetabs type sirolimus ophthalmic preparation according to claim 4 or 5, is characterized in that, when made dosage form is eye drop, uses osmotic pressure regulator to regulate the osmotic pressure molar density of eye drop to be 250 ~ 350mOsmol/kg; Described osmotic pressure regulator is a kind of combination in any of or two kinds of sodium chloride, mannitol.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107320446A (en) * | 2017-08-03 | 2017-11-07 | 广东莱恩医药研究院有限公司 | A kind of forsythin eye drops and preparation method thereof |
| CN107375197A (en) * | 2017-08-03 | 2017-11-24 | 广东莱恩医药研究院有限公司 | A kind of forsythin eye ointment and preparation method 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 |
| CN108283622A (en) * | 2018-04-03 | 2018-07-17 | 广州君博医药科技有限公司 | A kind of slow-release Linezolid eye medicinal and preparation method thereof |
| CN112569187A (en) * | 2019-09-27 | 2021-03-30 | 武汉科福新药有限责任公司 | Tacrolimus nano eye emulsion and preparation method thereof |
| CN112641733A (en) * | 2020-12-30 | 2021-04-13 | 北京华氏开元医药科技有限公司 | Sirolimus sustained-release pellet and preparation method thereof |
| CN113332228A (en) * | 2021-04-29 | 2021-09-03 | 杭州中美华东制药有限公司 | Sirolimus gel preparation |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102670498A (en) * | 2012-06-09 | 2012-09-19 | 广东宏盈科技有限公司 | Sustained-release sirolimus ophthalmic preparation |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102670498A (en) * | 2012-06-09 | 2012-09-19 | 广东宏盈科技有限公司 | Sustained-release sirolimus ophthalmic preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107320446A (en) * | 2017-08-03 | 2017-11-07 | 广东莱恩医药研究院有限公司 | A kind of forsythin eye drops and preparation method thereof |
| CN107375197A (en) * | 2017-08-03 | 2017-11-24 | 广东莱恩医药研究院有限公司 | A kind of forsythin eye ointment and preparation method 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 |
| CN108283622A (en) * | 2018-04-03 | 2018-07-17 | 广州君博医药科技有限公司 | A kind of slow-release Linezolid eye medicinal and preparation method thereof |
| CN112569187A (en) * | 2019-09-27 | 2021-03-30 | 武汉科福新药有限责任公司 | Tacrolimus nano eye emulsion and preparation method thereof |
| CN112569187B (en) * | 2019-09-27 | 2022-04-12 | 武汉科福新药有限责任公司 | Tacrolimus nano eye emulsion and preparation method thereof |
| CN112641733A (en) * | 2020-12-30 | 2021-04-13 | 北京华氏开元医药科技有限公司 | Sirolimus sustained-release pellet and preparation method thereof |
| CN113332228A (en) * | 2021-04-29 | 2021-09-03 | 杭州中美华东制药有限公司 | Sirolimus gel preparation |
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