CN103860745B - A kind of medical composite for eye containing sirolimus - Google Patents
A kind of medical composite for eye containing sirolimus Download PDFInfo
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- CN103860745B CN103860745B CN201410090503.2A CN201410090503A CN103860745B CN 103860745 B CN103860745 B CN 103860745B CN 201410090503 A CN201410090503 A CN 201410090503A CN 103860745 B CN103860745 B CN 103860745B
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Abstract
The present invention discloses a kind of medical composite for eye containing sirolimus, included composition and effectiveness is sirolimus, astragalus polysaccharides, sodium tanshinon IIA silate injection and Radix Rehmanniae extract, eye external preparation is made into by usual way, be applicable to treatment uveitis, the ocular immune disease such as rejection after corneal transplantation, compared with the ophthalmic preparation good drug efficacy of plain edition sirolimus, side effect is little.
Description
Technical field
The present invention relates to medicinal preparation, particularly relate to the pharmaceutical composition being used for the treatment of the ocular immune disease such as rejection after uveitis, corneal transplantation.
Background technology
Uveitis is the general name of a class intraocular inflammation disease, comprises and betides tunica uvea, retina, retinal vessel and Vitrea inflammation, is worldwide common diseases causing blindness.Most uveitis is caused by immunologic mechanism, and its treatment mainly uses immunosuppressant, as glucocorticoid.But immunosuppressant mostly is systemic administration, can cause multiple side effect, some medicines also have liver toxicity, nephrotoxicity and gastrointestinal reaction.
There is graft-rejection in corneal transplantation postoperative about 30%, is the main cause of corneal graft failure.Hormone therapy, ciclosporin in treating have certain effect, but usually can not the development of symptom management completely, and cause the multiple untoward reaction of whole body and eye local.Therefore, research and development a new generation highly effective and safe immunosuppressant has become suppression high-risk keratoplasty immunological rejection, improves the important directions of success rate of operation.
If immunosuppressant is made a local application, diseased region can be made to reach enough drug level to play curative effect better, and compared with Formulations for systemic administration, topical can keep lower blood drug level, thus reduce the generation of whole body toxic and side effects.
201210188186.9, No. 201210188187.3 Chinese patent application of the present inventor, be applied to significant immunosuppressive action in Organ Transplantation Patients based on sirolimus, slow-released system is used to prepare sirolimus eye drop, be applied to treatment uveitis, though there is certain curative effect, but its drug effect is very undesirable, also has more untoward reaction simultaneously.
Summary of the invention
The object of the present invention is to provide and be a kind ofly applicable to treat uveitis, the pharmaceutical composition of the ocular immune disease such as rejection after corneal transplantation, the ophthalmic preparation drug effect prepared with this pharmaceutical composition is good, and side effect is little.
Composition and effectiveness included by pharmaceutical composition of the present invention is: sirolimus, astragalus polysaccharides, sodium tanshinon IIA silate injection, Radix Rehmanniae extract.
Described sirolimus (Sirolimus, SRL), i.e. rapamycin is the macrolide antibiotics produced by damp streptocin (Streptomyceshygroscopicus).
Described astragalus polysaccharides is one of main active of the Radix Astragali, be the dry root of leguminous plant Radix Astagali or Radix Astragali through extracting, the water solublity heteropolysaccharide of concentrated, purification.
Described sodium tanshinon IIA silate injection is through the sulfonated water-soluble substances obtained isolate diterpene quinone TANSHINONES from Radix Salviae Miltiorrhizae after.
Described Radix Rehmanniae extract extracts by the following method: get Radix Rehmanniae medical material 12 times amount water soaking 30 minutes, extraction time is 1.5 hours, extracts 3 times continuously, and three times extracting solution mixes, concentrates, and to obtain final product.
The proportioning that pharmaceutical composition of the present invention is suitable for is expressed as by weight, sirolimus 1 part, astragalus polysaccharides 1 ~ 10 part, sodium tanshinon IIA silate injection 1 ~ 10 part, Radix Rehmanniae extract 1 ~ 10 part.
The preferred proportioning of pharmaceutical composition of the present invention is expressed as by weight, sirolimus 1 part, astragalus polysaccharides 3 ~ 7 parts, sodium tanshinon IIA silate injection 5 ~ 10 parts, Radix Rehmanniae extract 1 ~ 5 part.
Pharmaceutical composition optimum proportioning of the present invention is expressed as by weight, sirolimus 1 part, astragalus polysaccharides 5 parts, sodium tanshinon IIA silate injection 8 parts, Radix Rehmanniae extract 3 parts.
In pharmaceutical composition of the present invention, sirolimus has potent immune suppression function, and to various non-T cell, propagation as isocellular in B cell, macrophage, granulocyte and endotheliocyte and cell function all have certain effect.In glaucoma filtration surgery, apply sirolimus have significant anti-proliferative effect; Sirolimus is applied to corneal transplantation patient, there is the effect of resisting transplant rejection, and untoward reaction is relatively less.
The present invention draws the modern scientific and technical result of Chinese medicine west system simultaneously, chemicals sirolimus and Chinese medicine is merged and uses, respectively get the chief, synergism.Theoretical by the traditional Chinese medical science " liver opening at eye ", uveitis is equivalent to " iridocyclitis " demonstrate,proves, and be due to retention of damp-heat in the interior, pathogenic factor returns liver and gall with in few sun, three Jiao; Or diseases caused by exogenous pathogenic factor rheumatism, strongly fragrant heat-transformation of a specified duration, rheumatism is fought mutually with heat, follows on Liver Channel and violates caused by clear key.Under this theoretical direction, the present invention chooses the pointed effect of the Radix Astragali, Radix Salviae Miltiorrhizae, Radix Rehmanniae.
The Radix Astragali has effect of strengthening vital QI to eliminate pathogenic factors, nourishing the liver and kidney, nourishing YIN to lower pathogenic fire, and the Uveitis Patients Radix Astragali can balance body negative and positive, and healthy energy is vigorous, " healthy energy deposit in, heresy can not be done ".And the Radix Astragali can also strengthen superoxide dismutase (SOD) activity, alleviates the effect of lipid peroxy damage, thus accelerate disease recovery, shorten the course of disease, reduce and recur.Astragalus polysaccharides is one of main active of the Radix Astragali, and because it is at adjustment immunity of organism, blood sugar lowering, there is stronger activity defying age aspect and receives much concern.
Sodium Tanshinone Ⅱ-A sulfonate can reduce lipid peroxide contents, stabilate film, and can improve SOD activity, has anti-radical action.Uveitis Patients, by using activating blood and removing stasis drug blood vessel dilating, improves tunica uvea microcirculation, has both been beneficial to the absorption of Inflammatory substances, also can the resistance against diseases of enhancing body.Sodium tanshinon IIA silate injection has dual regulation, adds the activating blood and removing stasis drugs such as sodium tanshinon IIA silate injection over the course for the treatment of, really can improve drug effect, reduces recurrence.
Radix Rehmanniae extract has clearing away heat and cooling blood, yin nourishing, and the effect of promoting the production of body fluid, also has immunoregulation effect, can improve the breeder reaction ability of T cell.
In sum, this three tastes Chinese medicine of astragalus polysaccharides, sodium tanshinon IIA silate injection, Radix Rehmanniae extract all has immunoregulation effect, itself and sirolimus merge and use by the present invention, and the immune suppression function of collaborative sirolimus, has heightening the effect of a treatment, reduces effect of side effect.
Pharmaceutical composition of the present invention can be equipped with said pharmaceutical adjunct on the acceptable pharmaceutics of eye local and be mixed with eye external preparation, comprises said any one on eye drop, gel for eye use, spongaion or pharmaceutics and is suitable for the dosage form of a local topical.Wherein adjuvant antibacterial, 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, hibitane etc., valid density is 0.002% ~ 0.02%; 3. alcohols, conventional 0.3 ~ 0.6% chlorobutanol; 4. parabens, conventional 0.03 ~ 0.06% ethyl hydroxybenzoate; 5. acids, as 0.01 ~ 0.08% sorbic acid.Each material concentration is volume-percentage by weight above, and namely every hundred milliliters contain grams.
Detailed description of the invention
The invention will be further described by the following examples.
embodiment 1-3prepare compound recipe sirolimus eye drop
Prepare the raw materials used component of compound recipe sirolimus eye drop and consumption as following table:
Preparation method: take a morsel water for injection, first adds cosolvent, then add sirolimus, astragalus polysaccharides, sodium tanshinon IIA silate injection and Radix Rehmanniae extract, stirring and dissolving is A liquid, for subsequent use; Make it disperse to let cool thickening agent and surfactant water for injection, this liquid is B liquid, for subsequent use; Another water for injection solution pervasion pressure regulator, antibacterial, stirring evenly filtration, is C liquid.Merge B, C bis-liquid, then add the A liquid dissolved, add to the full amount of water for injection, filtration, 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 4-6prepare compound recipe sirolimus gel for eye use
Prepare the raw materials used component of compound recipe sirolimus gel for eye use and consumption as following table:
Preparation method: take a morsel water for injection, first adds cosolvent, then add sirolimus, astragalus polysaccharides, sodium tanshinon IIA silate injection and Radix Rehmanniae extract, stirring and dissolving is A liquid, for subsequent use; Make it disperse to let cool thickening agent and surfactant water for injection, this liquid is B liquid, for subsequent use; Another water for injection solution pervasion pressure regulator, antibacterial, stirring evenly filtration, is C liquid.Merge B, C bis-liquid, then add the A liquid dissolved, add to the full amount of water for injection, filtration, 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.Preparation method: take a morsel water for injection, first adds cosolvent, then add sirolimus, astragalus polysaccharides, sodium tanshinon IIA silate injection and Radix Rehmanniae extract, stirring and dissolving is A liquid, and aseptic filtration is for subsequent use; Another water for injection solution pervasion pressure regulator, antibacterial, stirring evenly, aseptic filtration, is B liquid, for subsequent use; Aseptically, the thickening agent of sterilizing and surfactant water for injection are dissolved, make it disperse to let cool, this liquid is C liquid; Aseptically, A liquid and B liquid are added in C liquid, then add to the full amount of water for injection, 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 7-9prepare compound recipe sirolimus spongaion
Prepare the raw materials used component of compound recipe sirolimus spongaion and consumption as following table:
preparation method: take a morsel water for injection, first adds cosolvent, adds sirolimus, astragalus polysaccharides, sodium tanshinon IIA silate injection and Radix Rehmanniae extract, stirring and dissolving, aseptic filtration; Add in right amount through the liquid Paraffin of sterilizing, cooling, grind to form thin pasty state, cross 200 mesh sieves, then add aseptic, that filter lanoline, Yellow Vaselin mixture gradually, mixing, to obtain final product.
By technical solution of the present invention, the available adjuvant kind of preparation sirolimus ophthalmic preparation is not limited to kind listed by table, can also have following multiple choices.
experimental examplecompound recipe sirolimus eye drop compares with the pharmacodynamics of plain edition sirolimus eye drop
The present invention is mainly used in treating uveitis containing the ophthalmic preparation prepared by medical composite for eye of sirolimus, therefore this laboratory observation its to the therapeutical effect of experimented autoimmune myositis (EAU), and carry out pharmacodynamics with plain edition sirolimus eye drop and compare.
Adopt the medicament prepared by method recorded by description embodiment 2 of the present invention as trial target, be called " compound recipe sirolimus eye drop "; In the raw material of the preparation eye drop of description embodiment 2 record of the present invention, remove astragalus polysaccharides, sodium tanshinon IIA silate injection and Radix Rehmanniae extract, other all by the method preparation eye drop of embodiment 2, as positive reference substance, are called " plain edition sirolimus eye drop ".Contained by trial target and reference substance, sirolimus concentration is identical.
Experimental procedure is as follows:
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.
2 set up EAU 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, the deactivation bordetella pertussis solution of every rat tail vein injection 10 × 109 thalline; Supernatant after lumbar injection 0.1ml escherichia coli Ultrasonic Pulverization liquid is centrifugal.
3 dosage regimens
Compound recipe sirolimus eye drop, administration every day 3 times, 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, and 3 ~ 4mm cuts into slices, 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, 20mgS-Ag being dissolved in 10ml0.01mol/L phosphate buffer (phosphatebuffersaline, PBS), injecting auris dextra edge; Left ear edge injects 10mlPBS 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 the 10mlPBS of 20mg 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, and normal pectination texture disappears, notably ROS thinning, disappear; 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 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.Compound recipe sirolimus eye drop group EAU histology inflammatory reaction scoring is lower than plain edition sirolimus eye drop group, and the two difference has meaning (P<0.001) (the seeing the following form) of significance.
2 groups of rat EAU histologys and DTH scoring
6.2 delayed metamorphosis (DTH) reactions
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, compound recipe 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, compound recipe sirolimus eye drop and plain edition sirolimus eye drop all can suppress the generation of rat EAU and alleviate the state of an illness of EAU, but compound recipe sirolimus eye drop curative effect is obviously better than plain edition sirolimus eye drop, and untoward reaction is relatively less.
The present inventor has also carried out pharmacodynamics checking to the compound recipe sirolimus gel for eye use prepared by the inventive method, compound recipe sirolimus eye ointment and plain edition sirolimus gel for eye use, plain edition sirolimus eye ointment, show its therapeutic effect to ocular immune diseases such as uveitis, the former is obviously better than the latter.
Claims (5)
1. the medical composite for eye containing sirolimus, be applicable to treat uveitis, the ocular immune disease of rejection after corneal transplantation, it is characterized in that, composition and effectiveness is: sirolimus, astragalus polysaccharides, sodium tanshinon IIA silate injection, Radix Rehmanniae extract; Suitable proportioning is expressed as by weight, sirolimus 1 part, astragalus polysaccharides 1 ~ 10 part, sodium tanshinon IIA silate injection 1 ~ 10 part, Radix Rehmanniae extract 1 ~ 10 part;
Described Radix Rehmanniae extract extracts by the following method: get Radix Rehmanniae medical material 12 times amount water soaking 30 minutes, extraction time is 1.5 hours, extracts 3 times continuously, three extracting solution mixing, concentrated gained.
2. pharmaceutical composition according to claim 1, is characterized in that, the proportioning of pharmaceutical composition is expressed as by weight, sirolimus 1 part, astragalus polysaccharides 3 ~ 7 parts, sodium tanshinon IIA silate injection 5 ~ 10 parts, Radix Rehmanniae extract 1 ~ 5 part.
3. pharmaceutical composition according to claim 1, is characterized in that, the proportioning of pharmaceutical composition is expressed as by weight, sirolimus 1 part, astragalus polysaccharides 5 parts, sodium tanshinon IIA silate injection 8 parts, Radix Rehmanniae extract 3 parts.
4. pharmaceutical composition according to claim 1, is characterized in that, is equipped with said pharmaceutical adjunct on the acceptable pharmaceutics of eye local and is mixed with eye external preparation.
5. pharmaceutical composition according to claim 4, is characterized in that, described eye external preparation is eye drop or gel for eye use or spongaion.
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| CN1596914A (en) * | 2003-09-15 | 2005-03-23 | 徐万富 | Medicine for treating eye disease caused by visceral disease |
| CN102670499A (en) * | 2012-06-09 | 2012-09-19 | 广东宏盈科技有限公司 | Slow-release sirolimus ophthalmic preparation |
| CN102670498A (en) * | 2012-06-09 | 2012-09-19 | 广东宏盈科技有限公司 | Sustained-release sirolimus ophthalmic preparation |
| CN103055112A (en) * | 2012-11-07 | 2013-04-24 | 山东施尔明眼科医院 | Traditional Chinese medicine compound composition for treating uveitis |
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2014
- 2014-03-13 CN CN201410090503.2A patent/CN103860745B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1596914A (en) * | 2003-09-15 | 2005-03-23 | 徐万富 | Medicine for treating eye disease caused by visceral disease |
| CN102670499A (en) * | 2012-06-09 | 2012-09-19 | 广东宏盈科技有限公司 | Slow-release sirolimus ophthalmic preparation |
| CN102670498A (en) * | 2012-06-09 | 2012-09-19 | 广东宏盈科技有限公司 | Sustained-release sirolimus ophthalmic preparation |
| CN103055112A (en) * | 2012-11-07 | 2013-04-24 | 山东施尔明眼科医院 | Traditional Chinese medicine compound composition for treating uveitis |
Non-Patent Citations (2)
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| 中药丹参注射液治疗外伤性玻璃体浑浊的观察;汤喜成等;《眼外伤职业眼病杂志(附眼科手术)》;20031231;第25卷(第08期);540－541 * |
| 丹参在眼科的应用;张丽琼等;《中国中医眼科杂志》;20051231;第15卷(第04期);242－244 * |
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