CN1836670A - Microsphere injection for treating ophthalmopathy - Google Patents
Microsphere injection for treating ophthalmopathy Download PDFInfo
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- CN1836670A CN1836670A CNA2005100166489A CN200510016648A CN1836670A CN 1836670 A CN1836670 A CN 1836670A CN A2005100166489 A CNA2005100166489 A CN A2005100166489A CN 200510016648 A CN200510016648 A CN 200510016648A CN 1836670 A CN1836670 A CN 1836670A
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Abstract
The microballoon injection for treating eye diseases has medicine containing microballoons comprising medicine and microballoon forming material. The medicine is musk, citicoline and Chinese medicine vasodilator or their composition; and the microballoon forming material consists of medicinal polymer material. The microballoon injection may be used in treating several kinds of eye disease, as well as central nerve disease, cardiac vascular diseases, local nerve functional disorder and damage, and ischemic diseases. The present invention has the preferable embodiment of preparing microballoon injection or microballoon powder for injection through an optimized emulsifying-solvent volatilizing process and freeze drying process.
Description
Technical field
The invention belongs to pharmaceutical preparation, specifically, relate to a kind of biodegradable slow release long-acting micro-balloon injection for the treatment of oculopathy, more particularly is a kind of microballoon lyophilized injectable powder or microsphere suspendible injection.
Background technology
Retinal degeneration and optic atrophy class disease are a kind of chronic blinding oculopathy, need to heal with medicine for a long time or throughout one's life.Local eye drip, be coated with eye, oral, intramuscular injection or intravenous injection, be difficult to make medicine in retina and optic nerve, to reach effective Drug therapy concentration.The eye implantation agent of inventor invention (Chinese invention patent number: 01122761.3; Application number: 2004100110807; Application number: 2004100111091), be the treatment of this type of oculopathy, provide a kind of new treatment approach and new product, implantation but this implant need be performed the operation.Retrobulbar injection can improve the drug level of eye, but the injection of using is non-slow releasing preparation, must be for a long time retrobulbar injection continually.The ophthalmic microsphere is implanted or injection can cause serious eye inner tissue's damage and side effect, and the microsphere of being implanted only limits to intraocular inflammation, does not relate to the treatment of retinal degeneration and optic atrophy class oculopathy.
The relevant eye of table 1 patent documentation of microsphere
| Country origin | The patent No. | The inventor | Days |
| The U.S. | 5718922 | Herrero-Vanrell | 1998.2 |
| The U.S. | 5185152 | Peyman | 1993.2 |
| The U.S. | 5641750 | Louis | 1997.6 |
| The U.S. | 6489335 | Peyman | 2002.12 |
| The U.S. | 021024782 | King's body state | 2002.1 |
The relevant eye of table 2 non-patent literature of microsphere
| The author | The pastille microsphere | Source of paper |
| Liu Yuling | Ciclosporin A | The practical ophthalmology magazine 1999 of China, 9:527 |
| Wu Wei | Dexamethasone | Acta Pharmaceutica Sinica 2001,10:766 |
| Li Bin | 5-fluorouracil | The practical ophthalmology magazine of China, 2002,4:279 |
| Al-Kassas R | Gentamycin | J microencapsul，2004，1：71 |
| Saishin y | Midostaurin | Invest ophthalmol Vis sci 2003，11：4989 |
| Tamaki y | Lomerizine | Inveat ophthalmol Vis sci 2003，11：4864 |
| Nour m | INS 37217 | Invest ophthalmol Vis sci 2003，10：4505 |
| Kimara H | Amycin | Invest ophthalmol Vis sci 1992，12：3436 |
Based on above-mentioned technical defective, the inventor is such technical conceive: the active drug composition of selecting treatment retinal degeneration and optic atrophy, adopt modern microsphere pharmaceutical technology, be prepared into biodegradable slow release long-acting injection, this micro-balloon injection is injected in behind patient's the ball or near the eyes, the slow constant release of pastille microsphere forms a kind of new drug administration by injection of microsphere near the eyes system, effectively treats retinal degeneration and optic atrophy class oculopathy.Someone is called injection implant or injection implants with the local injection micro-balloon injection, and eye of the present invention can be described as the injection implant again with micro-balloon injection.
The website of the domestic and international intellectual property of login China national intellectual property website and connection, and login domestic and international medical science website, with Moschus (moschus), muscone (muscone), citicoline (citicoline), puerarin (puerarin), TANSHINONES (tanshinone), breviscapine (Breviscapine), ligustrazine (ligustrazine), Anisodamine (ani sodamine), scopolamine (scopolamine), Anisodine (Anisodine) and micro-balloon injection (Microspheres injection), foreign language patent and non-patent literature retrieval in carrying out, do not detect associated documents, do not have the commodity listing yet.
Up to now, still do not have publication record, therefore, be necessary to develop a kind of micro-balloon injection for the treatment of diseases such as retinal degeneration and optic atrophy by Moschus, citicoline, Chinese medicine extension vascular agent micro-balloon injection as effective ingredient.
Summary of the invention
The objective of the invention is for a kind of micro-balloon injection new product for the treatment of oculopathy is provided.
To achieve these goals, the inventor proposes following technical scheme:
Pastille microsphere in the micro-balloon injection of this treatment oculopathy, by medicine with become ball material to form, its technical characterictic is; Medicine is selected from any or two kinds or three kinds of components in Moschus, citicoline, the Chinese medicine extension vascular agent, become ball material to form by the medicinal organism degraded macromolecular material, medicine accounts for the percentage by weight 0.01-90% of pastille microsphere, surplus becomes ball material to supply 100%, optimum is to be selected from the percentage by weight 5-45% that medicine accounts for the pastille microsphere, and surplus becomes ball material to supply 100%.Pastille microsphere in this micro-balloon injection also is meant microgranule, microcapsule, nanoparticle, nanosphere, nanocapsule.In pastille microsphere preparation process, the Moschus that is selected from is meant muscone or Moschus extract.The Chinese medicine extension vascular agent that is selected from is meant from the single Chinese herbal medicine and extracts or synthetic, has blood vessel dilating, the chemicals of microcirculation improvement effect or effective ingredient, described Chinese medicine extension vascular agent specifically is meant in puerarin, TANSHINONES, breviscapine, ligustrazine, Anisodamine, scopolamine, the Anisodine any.Medicine in this micro-balloon injection can add in inosine or the levodopa any.
This micro-balloon injection is the pastille microsphere for the treatment of effective dose by containing, and suspending agent, osmotic pressure regulator, caffolding agent, wetting agent are formed.Micro-balloon injection technology of preparing by modern is prepared into microballoon lyophilized injectable powder or microsphere suspendible injection.The weight percent content of each component is in this micro-balloon injection: the pastille microsphere accounts for 60-90%, and suspending agent accounts for 0.5-5%, and osmotic pressure regulator accounts for 1-25%, and caffolding agent accounts for 5-25%, and wetting agent accounts for 0.5-5%.
Contain Moschus; citicoline; puerarin; TANSHINONES; breviscapine; ligustrazine; Anisodamine; scopolamine; the micro-balloon injection of Anisodine improves or the treatment retinitis pigmentosa in preparation; senile degeneration of macula; degeneratio,maculae myopia; hereditary macular digeneration; retinal artery occlusion; the retinal vein occlusion; retina is dampened; commotio retinae; diabetic retinopathy; optic neuritis; ischemic optic neuropathy; traumatic optic neuropathy; toxic optic neuropathy becomes; papillitis; optic atrophy; the amblyopia eye; ballet's disease; traumatic mydriasis; the protection of glaucoma retinal ganglial cells; and central nervous system; cardiovascular system, the local nerve dysfunction; use in the medicine of damage and ischemic diseases.
The pastille microsphere Chinese medicine that the present patent application is mentioned is described below its medicament sources and main component below.
Moschus can be synthetic muscone or Moschus extract, muscone is the main effective ingredient of Moschus, but synthetic is so be called the artificial Moschus again, also can purify from the natural Moschus is muscone, and chemical name is a L-3-methyl cyclopentadecanone, molecular weight 238.4, water-soluble hardly, be soluble in alcohol, be little yellow oily liquid, 328 ℃ of boiling points.Described Moschus extract is to select the natural Moschus, and through the vapor distillation or the alcohol reflux method of purification of pharmaceutical technology, the refining purification removed foreign material, gained Moschus extract.Muscone or Moschus extract are the insoluble or insoluble drugs of water, use o/w (oil/water) emulsion process and prepare microsphere.Muscone has the refreshment of having one's ideas straightened out, promoting blood circulation to restore menstrual flow effect, and extremely strong penetration power is arranged, and excited retina and optic cell obviously improve vision and broaden one's vision.
Citicoline is called citicoline, Citicoline again, and its chemical name is a Cytidine Diphosphate Choline, is white powder, and Yi Rongshui is dissolved in ethanol, acetone, chloroform hardly, is water soluble drug.Citicoline is a neurotrophic agents, and the metabolism that promotes retina and optic nerve tissue is arranged, and helps the reparation of injured nerve fiber, thereby strengthens the activity and the conduction function of visual cell.
Puerarin is called puerarin, daizeol-8-C-glycoside again, chemical name is 4,7-dihydroxy-8-D glucone isoflavone, be a kind of monomer that from the dry root of legume pueraria lobata, extracts and separate, belong to isoflavonoid, be brown powdery solid, can be water-soluble, but dissolubility is little, and stronger lipotropy is arranged, and uses the o/w emulsion process and prepares microsphere.
TANSHINONES is the effective ingredient that extracts from the Chinese medicine red sage root, wherein contains 10 kinds of compositions, the general name TANSHINONES, and Tanshinone I, tanshinone, Tanshinone I IR are the main components of Radix Salviae Miltiorrhizae.Usually be selected from tanshinone, these product are cherry red acicular crystal, 202 ℃ of fusing points.Use the o/W emulsion process and prepare microsphere.
Breviscapine is the breviscapine that extracts from the Chinese medicine Herba Erigerontis, the mixture of scutellarin, the breviscapine product of existing synthetic, and chemical name is 4,5,6-trihydroxyflavone-7 glucuronide.Breviscapine is a flavonoids effective constituent, contains volatile oil, uses the o/W emulsion process and prepares microsphere.
Ligustrazine is a kind of alkaloid that extracts from the Chinese herbal medicine Rhizoma Chuanxiong, and chemical name is a tetramethylpyazine, existing synthetic product.Ligustrazine is white or off-white color crystalloid powder, and is soluble in water, is dissolved in ethanol, chloroform, is water soluble drug.
Anisodamine is a kind of alkaloid that extracts from the plant of Solanaceae Radix Anisodi Tangutici,, belong to the tropine Alkaloid, general designation " 654 ", its synthetic product are called as " 654-2 ", and are for white crystals or crystalloid powder, very easily water-soluble, be soluble in ethanol, fusing point 176-181 ℃, slightly soluble in acetone.
Scopolamine is the alkaloid of extraction from previous conviction plant Semen daturae, white Flos Daturae, hyoscyami etc., is anticholinergic agent, acts on similarly to atropine, is white crystals or crystalloid powder, and is easily molten in water, easily molten in chloroform, molten in the ethanol part omitted, is insoluble to ether.
Barrier willow alkali is a kind of alkaloid that extracts from Radix Anisodi Tangutici, and its toxicity for few, is the crystalloid powder more than atropine, scopolamine, Anisodamine.
Inosine is the precursor of synthetic adenine, participates in energy i (in vivo) metabolism and proteinic synthetic. during this patent was implemented, preferred citicoline and inosine prepared micro-balloon injection, the treatment optic atrophy.
Levodopa is a synthetic norepinephrine in the body, the dopamine precursor material.During this patent was implemented, preferred citicoline and levodopa prepared micro-balloon injection, treatment amblyopia eye.
The major technique feature of this micro-balloon injection is, medicine is by Moschus, citicoline, any or two kinds or three kinds of components in the Chinese medicine extension vascular agent, according to above-mentioned technical characterictic, according to the difference that is selected from drug component, can prepare the pastille microsphere or the micro-balloon injection that contain the different pharmaceutical component, that is to say, this micro-balloon injection can prepare the pastille microsphere that contains seven kinds of main drug components, the pastille microsphere that promptly contains Moschus, the pastille microsphere that contains citicoline, the pastille microsphere that contains the Chinese medicine extension vascular agent, contain Moschus, the pastille microsphere of citicoline, contain Moschus, the pastille microsphere of Chinese medicine extension vascular agent contains citicoline, the pastille microsphere of Chinese medicine extension vascular agent contains Moschus, citicoline, the microsphere of Chinese medicine extension vascular agent.Described Chinese medicine extension vascular agent has seven kinds of components, can be prepared into the pastille microsphere of seven kinds of different pharmaceutical components again according to different drug components, the pastille microsphere that promptly contains puerarin, the pastille microsphere that contains TANSHINONES, the pastille microsphere that contains breviscapine contains the pastille microsphere of ligustrazine, contains the pastille microsphere of Anisodamine, the pastille microsphere that contains scopolamine contains the pastille microsphere of Anisodine.The pastille microsphere that will contain the different pharmaceutical component below is listed as follows:
Table 3 contains the pastille microsphere of Moschus
| The component example | Ingredient |
| 1 | Muscone |
| 2 | Moschus extract |
Table 4 contains the pastille microsphere of citicoline
| The component example | Drug component |
| 1 | Citicoline |
Table 5 contains the pastille microsphere of Chinese medicine extension vascular agent
| The component example | Drug component |
| 1 | Puerarin |
| 2 | TANSHINONES |
| 3 | Breviscapine |
| 4 | Ligustrazine |
| 5 | Anisodamine |
| 6 | Scopolamine |
| 7 | Anisodine |
Table 6 contains the pastille microsphere of Moschus, citicoline
| The component example | Drug component |
| 1 | Moschus, citicoline |
Table 7 contains the pastille microsphere of citicoline, Chinese medicine extension vascular agent
| The component example | Drug component |
| 1 | Citicoline, puerarin |
| 2 | Citicoline, TANSHINONES |
| 3 | Citicoline, breviscapine |
| 4 | Citicoline, ligustrazine |
| 5 | Citicoline, Anisodamine |
| 6 | Citicoline, scopolamine |
| 7 | Citicoline, Anisodine |
Table 8 contains the microsphere of the pastille of Moschus, Chinese medicine extension vascular agent
| The component example | Drug component |
| 1 | Moschus, puerarin |
| 2 | Moschus, TANSHINONES |
| 3 | Moschus, breviscapine |
| 4 | Moschus, ligustrazine |
| 5 | Moschus, Anisodamine |
| 6 | Moschus, scopolamine |
| 7 | Moschus, Anisodine |
Table 9 contains the pastille microsphere of Moschus, citicoline, Chinese medicine extension vascular agent
| The component example | Drug component |
| 1 | Moschus, citicoline, puerarin |
| 2 | Moschus, citicoline, TANSHINONES |
| 3 | Moschus, citicoline, breviscapine |
| 4 | Moschus, citicoline, ligustrazine |
| 5 | Moschus, citicoline, Anisodamine |
| 6 | Moschus, citicoline, scopolamine |
| 7 | Moschus, citicoline, Anisodine |
Table 10 adds the pastille microsphere of medicine
| The component example | Drug component |
| 1 | Inosine |
| 2 | Levodopa |
Dissimilar each drug component of pastille microsphere of table 11 account for drug weight percentage ratio
| Contain the medicine microsphere | Each drug component accounts for drug weight percentage ratio (%) |
| The Moschus microsphere | Moschus 100 |
| The citicoline microsphere | Citicoline 100 |
| Chinese medicine extension vascular agent microsphere | Chinese medicine extension vascular agent 100 |
| Moschus, citicoline microsphere | Moschus 1-99 citicoline 99-1 |
| Citicoline, Chinese medicine extension vascular agent microsphere | Citicoline 1-99 Chinese medicine extension vascular agent 99-1 |
| Moschus, Chinese medicine extension vascular agent microsphere | Moschus 1-99 Chinese medicine extension vascular agent 99-1 |
| Moschus, citicoline, Chinese medicine extension vascular agent microsphere | Moschus 1-98 citicoline 98-1 Chinese medicine extension vascular agent 1-98 |
In the preparation process of this micro-balloon injection, the medicament contg of every micro-balloon injection, be by microsphere day the amount of releasing * expectation slow release natural law calculate the medicine input amount of every micro-balloon injection, estimate that the slow release natural law can be from 7-430 days, preferred 15 days, 30 days, 45 days.Day amount of releasing can be calculated day amount of releasing by 100%～0.1% of retrobulbar injection dosage.The slow release natural law depends on into the kind of ball material, the difference of molecular weight.
The day of each drug component of table 12 is released weight range
| Medicine | Day is released weight range | Optimum day is released weight range |
| Muscone | 0.01-50mg | 0.1-1mg |
| Citicoline | 2-200mg | 20-200mg |
| Puerarin | 0.5-50mg | 5-50mg |
| Tanshinone | 0.1-10mg | 1-10mg |
| Breviscapine | 0.05-5mg | 0.5-5mg |
| Ligustrazine | 0.4-40mg | 4-40mg |
| Anisodamine | 0.05-5mg | 0.5-5mg |
| Scopolamine | 0.003-0.3mg | 0.03-0.3mg |
| Anisodine | 0.002-0.2mg | 0.02-0.2mg |
The one-tenth ball material of microsphere is called microsphere supported, microsphere substrate again, be meant selected carrier material in the microsphere preparation process, the one-tenth ball material of this microsphere is formed for the medicinal organism degraded macromolecular material, every can be used as medicinal, biodegradable, injectable macromolecular material all can be used as this microsphere and becomes ball material.This microsphere become ball material optional select as follows: natural or synthesising biological degraded macromolecular material, optional any or more than one components in gelatin, albumin, starch, glucosan, chitin of natural biological degraded macromolecular material.The synthesising biological degraded macromolecular material is optional from polylactic acid, polysaccharide acid, polyglycolic acid, poly butyric ester, lactide-glycolide copolymer, lactic acid-Polyethylene Glycol (polypropylene glycol) copolymer, polycaprolactone, paracyanogen base propylene Arrcostab, polylactic acid-poly-hexanediol block copolymer, ε caprolactone and lactide block copolymer, polyglutamic acid, aminoacid-ethylene glycol copolymer, poe, poly-phosphide, polyurethane, poly-sulfuric ester, any or more than one components in the amino acids polymer.Preferably select polylactic acid, polylactic acid/polyglycolic acid, polycaprolactone one-tenth ball material as microsphere.
Polylactic acid is the one-tenth ball material as micro-balloon injection through FDA's approval, also is to use the most sophisticated at most microsphere in the medical industry to become ball material.Polylactic acid dissolves in the organic solvent, and molecular weight is big more, and decomposition is slow more in vivo, and slow-release time is long more.During this patent is implemented, be selected from the molecular weight 3000-400000 of polylactic acid, preferred polylactic acid molecule amount 10000-60000.Polylactic acid (PLA)/polyglycolic acid (PGA), can be by PLA: PGA=90: 10～50: 50, relative molecular weight 20000-700000.
The main effect of suspending agent is that microsphere is suspended in the injection, and suspending agent commonly used has polyvinyl alcohol, carboxymethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, dextran, and preferably polyethylene alcohol is as suspending agent.Polyvinyl alcohol (PVA) is water-soluble polymer, and is water-soluble, but is insoluble to organic solvent, odorless, nontoxic, and outward appearance is a white or little yellow is cotton-shaped, lamellar or pulverulent solids.In preparation microsphere process, the microsphere effect that is selected from the polyvinyl alcohol molding is better.The preparation of poly-vinyl alcohol solution is that polyvinyl alcohol is dissolved in the aseptic aqueous solution, dissolves under 70-100 rev/min of stirring, after stopping to stir, soaks 30---60 minute again.If stir under 80---90 ℃ of steam heated, dissolving is better, can dissolve fully.Use 0,5% poly-vinyl alcohol solution, the microsphere effect of molding is better.The weight percent content that suspending agent accounts for micro-balloon injection is 0.5-5%, and preferred content is 0.5-2.5%.
The main effect of caffolding agent is to make the microsphere can be not inter-adhesive, and caffolding agent commonly used has glucose, trehalose, mannitol, lactose.The weight percent content that caffolding agent accounts for micro-balloon injection is 5-25%, and preferred content is 5-10%.
The main effect of osmotic pressure regulator is an osmotic pressure of regulating injection, and sodium chloride commonly used is regulated osmotic pressure, and the weight percent content that osmotic pressure regulator accounts for micro-balloon injection is 1-25%.
The main effect of wetting agent is to make that microsphere is reasonable to be dispersed in the injection, tween 80 commonly used.The weight percent content that wetting agent accounts for micro-balloon injection is 0.5-5%.
The main effect of organic solvent is a dissolving medicinal organism degraded macromolecular material, with medicine dissolution or be dispersed among the macromolecular material, is prepared into microsphere, and behind the molding microsphere, the organic solvent volatilization eliminates.Organic solvent commonly used has dichloromethane, chloroform, ethyl acetate, dichloro six rings, dimethyl formamide, ether, chloroform, acetone, dimethyl sulfoxine, tetrachloro furan.Preferred dichloromethane.Dichloromethane, molecular formula: CH2CL2.For water white transparency effumability liquid, be slightly soluble in water, be dissolved in ethanol, ether.In dichloromethane, add acetone more soluble in water, can improve the drug loading of microsphere.Dichloromethane: acetone is 9: 1～7: 3.Behind the preparation microsphere, volatilization eliminates dichloromethane.The residual quantity of dichloromethane, concentration are limited the quantity of with 500/1000000ths; The residual total amount (PDE) that accept every day is lower than 6.0mg/ day.Remove after the dichloromethane in the microsphere with the rotation volatility process, again with microsphere vacuum drying three days, residual dichloromethane conformance with standard in the prepared microsphere.
The technology of preparing of micro-balloon injection is a kind of ripe pharmaceutical technology, the commercialization of its product.But this micro-balloon injection using emulsion-solvent evaporation method, spray drying method, phase separation method, dissolve method, interface sedimentation, chemical polymerization, two step method, freeze-drying.During this patent was implemented, preferably emulsifying-solvent evaporation method and freeze-drying prepared microsphere suspendible injection or microballoon lyophilized injectable powder.
Emulsifying-solvent evaporation method is biphasely not make Emulsion by mechanical agitation or ultrasonic emulsification mode with miscible, and the inner phase solvent evaporates is removed, and becomes ball material to separate out, and is solidified into microsphere.Concrete preparation method is, with medicine and high molecular polymer, adds and is dissolved in the organic solvent in the drug loading ratio, and high molecular polymer occupies the percentage by weight (wt%) of machine solvent, for suitable, forms organic facies with 5-50wt%.Polyvinyl alcohol (PVA) aqueous solution is a water, organic facies: the volume ratio of water is 1: 5-100, ratio of greater inequality is 1: 30.Is syringe needle or No. 16 injection needles of 4.5-9mm with organic facies with the aperture, slowly injects aqueous phase emulsifying, forms droplet, at ice bath, room temperature or elevated temperature, flings to solvent under normal pressure or the decompression, and temperature is usually at 5-40 ℃.Stir, it is diffusing that solvent is waved from established microdroplet, and emulsion droplet begins to stiffen into sphere, obtains solid-state medicine carrying microballoons.Collect microsphere through the membrane filtration with 0.45um, behind distilled water wash, vacuum drying is collected microsphere.Colostrum and emulsion mixing speed are 8000-15000 rev/min, mixing time 10-90 second; The solidified microsphere mixing speed is 200-2000 rev/min, between mixing time 4-18 hour; Centrifugalize microsphere mixing speed is 5000-20000 rev/min, mixing time 5-10 minute.When solidified microsphere stirs, according to the microspheres prepared size, speed up, particle diameter diminishes; Speed is slack-off, and it is big that particle diameter becomes.With suspending agent, wetting agent, caffolding agent, osmotic pressure regulator, with the water for injection dissolving, form injection suspendible substrate, medicine carrying microballoons is incorporated among the suspendible substrate, through freezing, drying makes its moisture reduce to 0.1-5%, lyophilized injectable powder.Freeze-dried powder ethane via epoxyethane or C
0-60 radiation sterilization.The time of ethylene oxide sterilizing is 48 hours, and residual ethylene content is less than 5.0PPm.Injection suspendible substrate is regulated PH with sodium dihydrogen phosphate or sodium hydrogen phosphate, and pH value is controlled between the 6.5-8.5.The type of emulsion during by preparation, emulsifying-solvent evaporation method is divided into o/w again, o/o, three types of w/o/w.Insoluble or the insoluble drug of water is used the o/w emulsion process and is prepared microsphere, and the muscone in the present patent application, puerarin, TANSHINONES and breviscapine are used the o/w emulsion process and prepared microsphere.O/o or w/o/w emulsion process are used to prepare the microsphere of water soluble drug, and the citicoline in the present patent application, ligustrazine, Anisodamine, scopolamine and Anisodine are used o/o or the w/o/w emulsion process prepares microsphere.Freeze-drying is to utilize that liquid towards carries out drying under the low temperature, and finished product is an injectable powder, good stability, easily its effective ingredient of long preservation.
The preferred for preparation technology of this micro-balloon injection is that using emulsion-solvent evaporation method prepares microsphere, through Freeze Drying Technique, is prepared into microballoon lyophilized injectable powder.The framboid warp of preparation is micron order or nanoscale, preferred micron order.The microballoon lyophilized injectable powder of preparation, with the dilution of sterile water for injection or 0.9% normal saline, the injection consumption is the 100-400% of microsphere powder injection weight, uses 1-4ml, do by the superficial temporal artery, under the conjunctiva, behind the ball, ball is other or periocular injections.The microsphere of preparation also can be used as the injection implant, is implanted in anterior chamber, vitreous body.This micro-balloon injection is preferably made retrobulbar injection.This micro-balloon injection, in treatment central nervous system, cardiovascular system diseases, route of administration is intravenous drip; When treating local nerve dysfunction, damage and ischemic diseases, use the local injection route of administration.
Microsphere is a kind of slow release long-acting preparation, the injection that will contain medicine microspheres, be injected near the eyes, the pastille microsphere is forming one " drug storage warehouse " near the eyes, the constant release of drug slow in the microsphere, keep persistent local drug concentration, form a kind of new drug administration by injection of microsphere near the eyes system, effectively treat retinal degeneration and optic atrophy.Moschus in the microsphere has causing resuscitation with aromatic drugs, excited retina and optic cell; Citicoline has the metabolism that promotes retina and optic nerve, strengthens its cytoactive and conduction function; The Chinese medicine extension vascular agent has the blood circulation that improves retina and optic nerve, recovers its function.The drug combination of Moschus, citicoline and Chinese medicine extension vascular agent has the coordination pharmacodynamics effect, obviously improves curative effect and enlarges range of application.
The present invention is a kind of new product of micro-balloon injection, it is the micro-balloon injection of drug component by Moschus, citicoline, Chinese medicine extension vascular agent, and prescription is unique, innovation, also be a kind of pharmaceutical composition of micro-balloon injection, the new solution of preparation method, medical usage.Micro-balloon injection of the present invention is the treatment of retinal degeneration and optic atrophy class oculopathy, has opened up new treatment measure and a kind of new product is provided, and it is convenient to use, and obviously improves curative effect, has a salutary effect.
Specific embodiments
This micro-balloon injection, the one-tenth ball material that is selected from can be different, and the also corresponding difference of its preparation method, clinical application range also can be different.But by any component in Moschus, citicoline, puerarin, TANSHINONES, breviscapine, ligustrazine, Anisodamine, scopolamine, the Anisodine as the micro-balloon injection of active constituents of medicine, within the conspicuous protection domain of the present invention that falls into this description.
Below be specific embodiments of the invention, described embodiment is used to describe of the present invention, rather than limits claim scope of the present invention.
Embodiment 1:
Prescription: (with 1000 radiacmeters)
Muscone 60g
Polylactic acid 300g
Mannitol 100g
Dextran 1 20g
Sodium chloride 10g
Tween 80 8g
Preparation: apparatus for preparation: electronics constant speed blender, ultrasonator, freezer dryer.Muscone and polylactic acid are dissolved among the dichloromethane solution, stir and make it to dissolve fully, form organic facies.Be mixed with 0.5% poly-vinyl alcohol solution, form water.Organic facies is injected among the water, regulated 400 rev/mins of mixing speeds, waving looses eliminates dichloromethane, centrifugal, isolate microsphere, through washing, dry medicine carrying microballoons.With mannitol, dextran, sodium chloride, tween 80, with the water for injection dissolving, regulate PH to 6.5 through sodium dihydrogen phosphate, add medicine carrying microballoons, stir, be filled into bottle, freezing rapidly, open wide bottleneck, lyophilization 72 hours covers plug, sealing, CO-60 sterilization.
Embodiment 2
Prescription: (1000 radiacmeters)
Citicoline 500g
Inosine 250g
Polylactic acid 800g
Mannitol 120g
Dextran 1 40g
Sodium chloride 10g
Tween 80 10g
Preparation: citicoline, inosine and polylactic acid are dissolved among the dichloromethane solution, 8000 rev/mins, stirred 30 seconds, make it to dissolve fully the formation organic facies.Organic facies is injected among 1% poly-vinyl alcohol solution, stirred,, evaporate 12 hours, the centrifugal supernatant that goes, precipitation, distilled water drip washing precipitation, reduced pressure at room temperature, collection medicine carrying microballoons in 25 ℃ with 300 rev/mins of speed.With mannitol, dextran, sodium chloride, tween 80, with the water for injection dilution, sodium dihydrogen phosphate is regulated PH, forms suspension, medicine carrying microballoons is added in this suspension, stir, be filled into bottle, freezing rapidly, lyophilization makes it moisture and reduces to standard.
Embodiment 3
Prescription: (with 1000 radiacmeters)
Anisodine 6g
Polylactic acid 30g
Mannitol 100g
Dextran 1 20g
Sodium chloride 10g
Tween 80 8g
Preparation: implementation step is with embodiment 3.
Claims (10)
1. pastille microsphere, by medicine with become ball material to form, its technical characterictic is: medicine is selected from any or two kinds or three kinds of components in Moschus, citicoline, the Chinese medicine extension vascular agent, become ball material to form by the medicinal organism degraded macromolecular material, medicine accounts for the percentage by weight 0.01-90% of pastille microsphere, and surplus becomes ball material to supply 100%.
2. by the described pastille microsphere of claim 1, its technical characterictic is: described microsphere also refers to microgranule, microcapsule, nanoparticle, nanosphere, nanocapsule.
3. by the described pastille microsphere of claim 1, its technical characterictic is: described Moschus is meant muscone or Moschus extract.
4. by the described pastille microsphere of claim 1, its technical characterictic is: described Chinese medicine extension vascular agent is meant in puerarin, TANSHINONES, breviscapine, ligustrazine, Anisodamine, scopolamine, the Anisodine any.
5. by the described pastille microsphere of claim 1, its technical characterictic is: described medicine, can add in inosine, the levodopa any.
6. by the described pastille microsphere of claim 1, it is characterized in that: medicine accounts for the percentage by weight 5-45% of pastille microsphere, and surplus becomes ball material to supply 100%.
7. micro-balloon injection is characterized in that: by containing any one described pastille microsphere in the claim 1 to 6 for the treatment of effective dose, and suspending agent, osmotic pressure regulator, caffolding agent and wetting agent are formed.
8. by the described a kind of micro-balloon injection of claim 7, its technical characterictic is: described micro-balloon injection is meant microballoon lyophilized injectable powder or microsphere suspensoid.
9. by the described a kind of micro-balloon injection of claim 7, its technical characterictic is: the weight percent content of each component is in this micro-balloon injection: the pastille microsphere accounts for 60-90%, and suspending agent accounts for 0.5-5%, and osmotic pressure regulator accounts for 1-25%, caffolding agent accounts for 5-25%, and wetting agent accounts for 0.5-5%.
10. by the described a kind of micro-balloon injection of claim 7; its technical characterictic is: this micro-balloon injection improves or the treatment retinitis pigmentosa in preparation; senile degeneration of macula; degeneratio,maculae myopia; hereditary macular digeneration; retinal artery occlusion; the retinal vein occlusion; retina is dampened; commotio retinae; diabetic retinopathy; optic neuritis; ischemic optic neuropathy; traumatic optic neuropathy; toxic optic neuropathy becomes; papillitis; optic atrophy; the amblyopia eye; ballet's disease; traumatic mydriasis; the protection of glaucoma retinal ganglial cells; and central nervous system; cardiovascular system, the local nerve dysfunction; use in the medicine of damage and ischemic diseases.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2005100166489A CN1836670A (en) | 2005-03-25 | 2005-03-25 | Microsphere injection for treating ophthalmopathy |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2005100166489A CN1836670A (en) | 2005-03-25 | 2005-03-25 | Microsphere injection for treating ophthalmopathy |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1836670A true CN1836670A (en) | 2006-09-27 |
Family
ID=37014264
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005100166489A Pending CN1836670A (en) | 2005-03-25 | 2005-03-25 | Microsphere injection for treating ophthalmopathy |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1836670A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITRM20120284A1 (en) * | 2012-06-18 | 2013-12-19 | Omikron Italia S R L | CITICOLINE FOR THE TREATMENT OF DIABETIC RETINOPATHY. |
| CN105748520A (en) * | 2016-04-08 | 2016-07-13 | 李君� | Compound preparation for treating ischemic optic neuropathy and preparation method of compound preparation |
| CN108066315A (en) * | 2016-11-11 | 2018-05-25 | 天津中医药大学 | Puerarin and scutellarin lipid nano particle eye-drops preparations and preparation method thereof |
| CN111450044A (en) * | 2020-04-30 | 2020-07-28 | 云南生物谷药业股份有限公司 | Ophthalmic preparation containing scutellarin, preparation method and application thereof |
| CN115634196A (en) * | 2022-12-15 | 2023-01-24 | 成都第一制药有限公司 | Stable-quality anisodine hydrobromide injection and preparation method thereof |
-
2005
- 2005-03-25 CN CNA2005100166489A patent/CN1836670A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITRM20120284A1 (en) * | 2012-06-18 | 2013-12-19 | Omikron Italia S R L | CITICOLINE FOR THE TREATMENT OF DIABETIC RETINOPATHY. |
| CN105748520A (en) * | 2016-04-08 | 2016-07-13 | 李君� | Compound preparation for treating ischemic optic neuropathy and preparation method of compound preparation |
| CN108066315A (en) * | 2016-11-11 | 2018-05-25 | 天津中医药大学 | Puerarin and scutellarin lipid nano particle eye-drops preparations and preparation method thereof |
| CN111450044A (en) * | 2020-04-30 | 2020-07-28 | 云南生物谷药业股份有限公司 | Ophthalmic preparation containing scutellarin, preparation method and application thereof |
| CN111450044B (en) * | 2020-04-30 | 2021-06-25 | 云南生物谷药业股份有限公司 | Ophthalmic preparation containing scutellarin, preparation method and application thereof |
| CN115634196A (en) * | 2022-12-15 | 2023-01-24 | 成都第一制药有限公司 | Stable-quality anisodine hydrobromide injection and preparation method thereof |
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