Summary of the invention
For the deficiency of prior art, the purpose of the present invention is to provide a kind of medication coat groups for ureter bracketClose object and its preparation method and application.
To achieve this purpose, the present invention adopts the following technical scheme:
In a first aspect, the medication coat composition is by weight the present invention provides a kind of medication coat compositionIncluding following component:
Medication coat composition provided by the invention passes through rapamycin, Puerarin and anti-infectives three kinds of ingredientsIt is reasonably combined, not only have the function of good expansion ureter, but also the effect with antibacterial anti-inflammatory, treatment injury of ureterFruit, while passing through the adjusting of hydrophilic polymer and additive, so that composition has the effect of long-acting slow-release, reach more persistentlyCurative effect.
The parts by weight of rapamycin be 0.3~1.3 part, such as can be 0.3 part, 0.4 part, 0.5 part, 0.6 part, 0.7 part,0.8 part, 0.9 part, 1.0 parts, 1.1 parts, 1.2 parts or 1.3 parts etc..
The parts by weight of Puerarin be 0.02~0.09 part, such as can be 0.02 part, 0.03 part, 0.04 part, 0.05 part,0.06 part, 0.07 part, 0.08 part or 0.09 part etc..
Puerarin is the isoflavonoid derivatives with coronary dilatation effect separated from Chinese medicament kudzu-vine root.With bring down a fever, it is calmWith make the increased effect of coronary blood flow, have protective effect to Acute myocardial bleeding caused by pituitrin.ClinicallyFor coronary disease and angina pectoris, hypertension.Currently, proving that Puerarin can be gentle to rabbit arterial smooth muscle in vitro test in vivoRoad smooth muscle generates emulative beta-receptor antagonism.
Puerarin itself has angiectatic effect, but there is presently no any research shows that Puerarin can achieveExpand the effect of ureter.
And it is an unexpected discovery of the invention that Puerarin can promote promoted rapamycin treatment and expand ureter effect,Compared to rapamycin is used alone, effect is more prominent, and will not generate excessive toxic side effect.
The parts by weight of Formoterol are 0.01~0.05 part, such as can be 0.01 part, 0.02 part, 0.03 part, 0.04 partOr 0.05 part etc..
Formoterol has strongly and lasting bronchiectatic activity, is a kind of long-acting β2Receptor stimulating agent, moleculeThere is longer side chain in structure, therefore have stronger fat-soluble and to β2Receptor higher selectivity.Such drug can be withβ on air flue target cell membrane2Receptor combines, activation excitability G-protein, adenosine cyclase of acid, ATP conversion in activated cellFor cAMP, intracellular cAMP level increases, and then activates cAMP dependent kinases (PKA), dense by intracellular free calciumThe decline of degree, the approach such as myosin light chain kinase (MCLK) inactivation and potassium channels opening, final relaxing smooth muscle.But it is suchDrug does not have anti-inflammatory effect.
A small amount of Formoterol is added in the present invention, and the bronchiectatic activity having using Formoterol itself canPromote the mixture of rapamycin and Puerarin, further promotes the effect of expansion ureter.
The parts by weight of anti-infectives are 0.2~1.5 part, such as can be 0.2 part, 0.3 part, 0.4 part, 0.5 part, 0.6Part, 0.7 part, 0.8 part, 0.9 part, 1.0 parts, 1.1 parts, 1.2 parts, 1.3 parts, 1.4 parts or 1.5 parts etc..
In the present invention, due to drug relevant to expansion ureter, hardly there is anti-inflammatory, antibacterial effect, therefore in groupIt closes in object and is added to suitable anti-infectives, to have the function that antibacterial anti-inflammatory.
Preferably, the anti-infectives include glucocorticoid, sulphadiazine, rifampin, chlorhexidine, triclosan or saltAny one in sour minocycline.
Wherein, glucocorticoid can be dexamethasone, momestasone furoate, prednisone, meprednisone, betamethasone or hydrogenChange cortisone etc..Generally preferably use dexamethasone or momestasone furoate.
The parts by weight of natural products be 2~6 parts, such as can be 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, 5 parts,5.5 parts or 6 parts etc..
Preferably, the natural products includes chingma abutilon seed, lophatherum gracile, rhizoma imperatae, semen plantaginis, endothelium corneum gigeriae galli, Lygodium japonicum or stoneIn dry measure used in former times any one or at least two combination.
Preferably, the natural products is chingma abutilon seed, lophatherum gracile, rhizoma imperatae and the combination of semen plantaginis.
In the present invention, it is preferred to above-mentioned four kinds of natural products collaboration has reducing fever and causing diuresis, invigorates the spleen and benefits qi, the function that excreting dampness is treating stranguriaEffect, can play good reparation damaging action in ureter.
The parts by weight of hydrophilic polymer are 1~2 part, such as can be 1 part, 1.1 parts, 1.2 parts, 1.3 parts, 1.4 parts, 1.5Part, 1.6 parts, 1.7 parts, 1.8 parts, 1.9 parts or 2 parts etc..
Preferably, the hydrophilic polymer includes polyvinylpyrrolidone and/or polyoxyethylene hydrophilic polymer.
Polyoxyethylene hydrophilic polymer can be polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitol acid anhydrideMonopalmitate, polyoxyethylene sorbitan monostearate etc..
The parts by weight of additive are 1.3~4.5 parts, such as can be 1.3 parts, 1.5 parts, 1.8 parts, 2 parts, 2.3 parts, 2.5Part, 2.8 parts, 3 parts, 3.4 parts, 3.5 parts, 3.8 parts, 4 parts, 4.2 parts, 4.3 parts, 4.4 parts or 4.5 parts etc..
Preferably, the additive includes any one in D-sorbite, anhydrous sorbitol or xylitol or at least twoThe combination of kind.
D-sorbite has good performance of keeping humidity, and food can be made to keep certain moisture, prevents drying, can also prevent sugar,The precipitations such as salt crystallization.Anhydrous sorbitol is existed in the form of sorbitan fatty acid ester.Xylitol has hygroscopicity, is dissolved inAmount of heat is can absorb when water.
Above-mentioned small molecule can promptly be spread.They easily can discharge itself from delivering sacculus, to make drugRelease accelerate, and they can diffuse out drug in the tissue of drug conjugates chamber, improve or promote drug mobileTissue is penetrated across the polar head group of water barrier and double-layer of lipoid.Hydroxyl is as hydrophilic segment, because it can notIt is reacted with water soluble drug such as rapamycin.D-sorbite and xylitol have in spatial configuration all in the same side of moleculeOn three neighbouring hydroxyls, by the improved compatibility for bringing water soluble drug and hydrophilic additive and improved drugTissue intake and absorb.
Preferably, the mass ratio of the additive and hydrophilic polymer be (0.05~3): 1, for example, can be 0.05:1,0.06:1、0.08:1、0.1:1、0.3:1、0.4:1、0.8:1、0.9:1、1:1、1.5:1、1.6:1、1.9:1、2.3:1、2.5:1,2.8:1 or 3:1 etc..
In the present invention, additive and hydrophilic polymer can form inflated condition in reaching ureter behind target position,It ensure that the expansion state of ureter, and rapamycin, anti-infectives and natural products smoothly can be discharged and be absorbed, haveThere is positive therapeutic effect.
Preferably, the solvent includes water, methanol, ethyl alcohol, normal propyl alcohol, isopropanol, acetone, methylene chloride, dimethyl AsiaIn sulfone or acetonitrile any one or at least two combination.
Second aspect, the present invention provides a kind of preparation methods of medication coat composition as described in relation to the first aspect, willRapamycin, Puerarin, Formoterol, anti-infectives, natural products are dissolved in solvent according to the ratio, then by the parent of proportional quantityAqueous polymer, additive are added in solvent, and mixing forms uniform mixed solution and obtains the medication coat composition.
Preferably, the mixed temperature is 40~60 DEG C, such as can be 40 DEG C, 43 DEG C, 45 DEG C, 48 DEG C, 49 DEG C, 50DEG C, 53 DEG C, 54 DEG C, 55 DEG C, 56 DEG C, 57 DEG C, 58 DEG C, 59 DEG C or 60 DEG C etc..
Preparation method provided by the invention, it is simple and easy.But in mixing, should keep within the said temperature range, it is noThen hydrophilic polymer, additive and the aqueous solution containing drug are unable to reach optimal solute effect, will cause shape when in useAt coating unevenness consequence, influence play curative effect.
The third aspect, the present invention provides a kind of ureter bracket, the ureter bracket includes rack body, bracket sheetThe medication coat and slow release layer that the medication coat composition as described in first aspect that body surface face is set gradually from inside to outside is formed.
Preferably, the rack body is linear hollow tubular structure, and the both ends of the rack body have positioning functionStructure, the medication coat composition are attached on the outer surface of rack body.
In the present invention, location structure is generally cricoid structure, is set to the both ends of rack body.
Preferably, the rack body is single layer structure or multilayered structure.
In the present invention, rack body is that single layer refers to the rack body that monolayer material is prepared；And multilayered structureRack body be then, using identical material, to overlap to form multilayered structure in preparation process.
Preferably, the rack body is provided with anti-recirculation device in tail end.
Preferably, it includes several protrusions and the layer for having at least one aperture that the slow release layer, which is surface,.
Preferably, the raw material for preparing of the slow release layer is any one in polylactic acid, copolymer of poly lactic acid or chitosan.Use polylactic acid or chitosan to prepare raw material as slow release layer, can reach biodegradable effect.
Wherein, it is total to can be poly lactide-glycolide acid, polyethylene glycol monomethyl ether-polylactic acid for copolymer of poly lactic acidPolymers or polyethylene glycol-polylactic acid copolymer etc..
In the present invention, the meaning that several protrusions are contained on surface is to be bonded on medication coat surface by polylactic acid shapeAt slow release layer, the layer of a formation not instead of smooth layer, the state that height rises and falls can shape also, in each protrusionAt at least one aperture, when fluid passes through protrusion, biggish active force can be generated, into aperture, such medication coat can lead toSmall holes are contacted with the formation of the fluid of target site, achieve the purpose that sustained-release administration.And the existing coating stent of medicine of mesh, it isMedication coat is directly directly acted on into region of interest, drug effect is shorter, is unfavorable for sustained-release and controlled release.
In the present invention, the size of slow release layer protrusions can be uniform or inhomogenous.Generally protrusion is bigIt is small between 0.02~2mm.
In the present invention, ureter bracket is optionally provided with the devices such as boost tube, convenient for it is actual operation and it is subsequentIt uses.
There are many ways to being attached to medication coat composition on ureter bracket, such as spraying, dip-coating, Electrostatic AbsorptionEtc..It selects which kind of attachment techniques to depend primarily on the viscosity and surface tension of composition, and is generally preferred to spray or soakIt applies.And the coating uniform that final composition should be made to be formed on ureter bracket.The thickness of the coat of formation is usually0.1~20 μm is differed.
Fourth aspect, the present invention provides a kind of medication coat compositions as described in relation to the first aspect to treat urine output in preparationManage the purposes in narrow and damage drug.
Currently, the effect that treatment ureterostenosis and the drug of damage have very much, but be single use can not reach mostGood effect, and act on more single.And medication coat composition provided by the invention, it not only can be used as ureter bracketMedication coat use, drug can also be developed into and used.
Medication coat composition is such as prepared into liquid preparation or is baked to be prepared into solid pharmaceutical preparation, is applied toClinical treatment.The preparation method of related preparations can be realized by the preparation process of those skilled in the art's routine.
Compared with the existing technology, the invention has the following advantages:
Medication coat composition provided by the invention passes through rapamycin, Puerarin and anti-infectives three kinds of ingredientsReasonably combined, the reasonably combined use of glucocorticoid especially in anti-infectives not only has good expansion ureterEffect, but also have the effect of antibacterial anti-inflammatory, treatment injury of ureter, while passing through the tune of hydrophilic polymer and additiveSection, so that composition has the effect of long-acting slow-release, reaches more lasting curative effect.
Medication coat composition provided by the invention can expand the drug for being prepared into a variety for the treatment of related diseases, to grindStudy carefully developing new drug and provide new strategy, has a good application prospect.
Ureter bracket provided by the invention, by being provided with special slow release layer, so that medication coat can either be formedEffectively administration, and slow release effect can be reached, action time is extended, the guarantor provided for practical application and control related symptomsBarrier.