CN100444897C - Nano complex eye drops containing liposoluble compound drug and its preparing method - Google Patents
Nano complex eye drops containing liposoluble compound drug and its preparing method Download PDFInfo
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- CN100444897C CN100444897C CNB2006100386002A CN200610038600A CN100444897C CN 100444897 C CN100444897 C CN 100444897C CN B2006100386002 A CNB2006100386002 A CN B2006100386002A CN 200610038600 A CN200610038600 A CN 200610038600A CN 100444897 C CN100444897 C CN 100444897C
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Abstract
The present invention relates to nano complex eyedrop containing liposoluble compound drugs and a preparing method thereof. Medlar active substances encapsulate nano particles and are used as carriers for transferring liposoluble compound drugs. The nano complex eyedrop comprises calcium phosphate nano particles, the medlar active substances, the liposoluble compound drugs, distilled water, an osmotic pressure regulating agent and a preservative; a pH value is from 6.2 to 7.5. The preparing method comprises the steps that the calcium phosphate nano particles are prepared; the medlar active substances are encapsulated on the nano particles; the liposoluble compound drugs are used for encapsulating outside the calcium phosphate nano particles for encapsulating Chinese medicine of the medlar active substances to form the nano complex eyedrop which comprises the liposoluble compound drugs. The present invention has the advantages that the diffusion coefficient of the liposoluble compound drugs in water solution is improved; an administration approach is changed to make the drugs pass through corneas for increasing drug concentration in room water; the nano complex eyedrop extends the time of the drugs of maintaining treatment concentration in eyes, and has high biologic utilization degree, without a side effect.
Description
Technical field
The present invention relates to a kind of eye medicine combination that contains liposoluble compound medicine and preparation method thereof, especially a kind of with the matrimony vine active material seal the calcium phosphate nano particle as the carrier transfer medicine, can penetrate the thing barrier that looks unfamiliar contain nano complex eye drops of liposoluble compound medicine and preparation method thereof.
Background technology
Drug therapy occupies an important position on clinical ophthalmology.In recent years, the experimentation and the clinical treatment of opthalmological have been obtained gratifying results, for the treatment of ophthalmic diseases is laid a good foundation.Because most of liposoluble compound medicine are used for the influence that a local time is subjected to the special pharmacokinetics characteristics of eyeball such as tear barrier and cornea barrier, can not effectively enter ophthalmic and play a role, have only not only to have water solublity but also have fat-soluble medicine that could to be used for eye effectively local.Many liposoluble compound medicine whole bodies are taken the side effect that can cause a series of complexity, can't play a role and change local the use because of low aqueous solubility, low bioavailability of eye into.People urgently are desirable to provide a kind of new drug-loading system
The research of Nano medication is the very vital new direction of in the drug research, because pharmaceutical carrier is nanoscale, thus have some special nature, as improve the slow-releasing, hypotoxicity of rate of dissolution, the enhancing medicine of medicine and intelligent etc.Drug-carrying nanometer particle can also change the film transporting mechanism, increases medicine to biomembranous permeability, helps the performance of drug effect in drug transdermal absorption and the cell.
The calcium nanoparticle is a kind of biodegradable nanometer transmission system, has excellent biological compatibility, human body is had no side effect, and the research report is recently arranged both at home and abroad, and the adjuvant during as vaccination alleviates local irritant effect and prolongs the immunization time with the calcium nanoparticle.Preparing eye drop such as the calcium nano-complex that includes carbonic anhydrase inhibitors is used for the treatment of glaucoma and reduces intraocular pressure (IOP).
Glaucoma is second the irreversible blinding sexually transmitted disease (STD) in the whole world, and the whole world had 6,680 ten thousand primary open-angles and primary angle-closure glaucoma patient approximately in 2000, and about 6,000,000 patients with secondary glaucoma, 6,700,000 patients was wherein arranged approximately because of the glaucoma blinding.China has about 9,400,000 glaucoma patients, 5,200,000 simple eye blindings wherein, 1,700,000 eyes blindings.The intraocular pressure lowering treatment is glaucomatous main therapeutic purposes.Normal person's intraocular pressure (10mmHg-21mmhg) is owing to the generation of aqueous humor and leaches the result who keeps dynamic equilibrium.Most of aqueous humor leaches generation from the corpus ciliare of eye, and wherein the carbonic anhydrase of nonpigmented epithelium cell plays an important role in aqueous humor generates.What glaucomatous hazardness was its blinding can not healing property, but as long as early discovery, rational therapy, most patients can maintain the visual function of usefulness all the life, and Drug therapy has the status of not replacing.
Carbonic anhydrase inhibitors (CAI) treatment glaucoma and the history in existing more than 40 year of reduction intraocular pressure (IOP), its mechanism of action is the carbonic anhydrase II that suppresses eye, reduces the generation of aqueous humor, thereby plays the effect of lowering intraocular pressure.Carbonic anhydrase inhibitors poorly water-soluble now commonly used clinically can not local application, can only be oral, such as: methazolamide, acetazolamide, diclofenamide (dichlorphenamide), ethoxzolamide, for reach the concentration of using of therapeutic effect at eye, oral dose is bigger, thereby causes a series of side effect.Existing report is as mental disorder, macule, and johnson syndrome, or the like.At present, local uses clinically with carbonic anhydrase inhibitors collyrium brinzolamide and dorzolamide, but reported: eye stimulates, blurred vision, and conjunctival congestion and corneal edema can not return that contrary cornea loses side effect such as compensatory and can not be by patient's withstand long term exposure.Implement the ancillary drug of short-term control when at present, carbonic anhydrase inhibitorss such as methazolamide, acetazolamide, diclofenamide (dichlorphenamide), ethoxzolamide, brinzolamide and dorzolamide can only be as various glaucoma acute attack.
Summary of the invention
The objective of the invention is to: at methazolamide, acetazolamide, diclofenamide (dichlorphenamide), liposoluble compound medicine such as ethoxzolamide can not be directly used in eye, can produce a series of side effect again after oral, or be used for the ocular drug heterodyne and with irritation, such as: the practical situation of implementing the ancillary drug of short-term control when many azoles amine or brinzolamide etc. can only be as various glaucoma acute attacks, can be directly used in eye safely and effectively for solving liposoluble compound medicine, improve bioavailability of medicament, provide a kind of with lycium barbarum polysaccharide calcium phosphate nano particle as liposoluble compound medicine eye medicine combination of carrier and preparation method thereof.
The object of the present invention is achieved like this: a kind of nano complex eye drops that includes the about thing of liposoluble compound, it is characterized in that: it seals the calcium phosphate nano particle as the carrier transfer liposoluble compound medicine with the matrimony vine active material, contains following ingredients in every 100ml eye drop:
Calcium phosphate nano particle 0.01～2g,
Matrimony vine active material 0.1～50mg,
Liposoluble compound medicine 5～50mg,
Antiseptic 0～0.1g,
Distilled water is an amount of;
The pH value of complex eye drops is 6.2～7.5.
In the present invention, described matrimony vine active material is a lycium barbarum polysaccharide; Described liposoluble compound medicine is: methazolamide, or acetazolamide, or diclofenamide (dichlorphenamide), or ethoxzolamide, or many azoles amine, or brinzolamide, or pilocarpine, or dexamethasone, or meticortelone, or timolol, or betaxolol, or atropine, or tropicamide, or ketoconazole, or streptomycin, or metronidazole, or sulfadiazine, or sulphanilamide, or chloromycetin, or clarithromycin, or ketotifen; Described antiseptic is the organic mercury class, or quaternary ammonium salt, or alcohols, or esters, or the oxybenzene esters, or the acids antiseptic; Described osmotic pressure regulator is sodium chloride or boric acid or glucose.
Realize the preparation method of above-mentioned complex eye drop, it is characterized in that:
A) preparation calcium phosphate nano particle:
After 0.01～1.0 mole calcium chloride solution, 0.01～1.0 mole phosphoric acid solution mixed by 1: 1, at room temperature stirred 48 hours, 4 ℃ of ambient temperatures, centrifugal 15 minutes of 8500rpm, removal contains free calcium and phosphorus supernatant, uses the deionized water suspended particles, and supersound process is 45 minutes again, form the calcium phosphate nano particle, its size dimension is 10-850nm;
B) on the calcium phosphate nano particle, seal Chinese medicine matrimony vine active material again:
Under the room temperature with nanoparticle again with after Chinese medicine matrimony vine active material mixes by 1: 10 weight ratio, concentration by 10mg/ml is suspended in pH value 6.8-7.0,0.01 in the phosphate buffer of mole, on shaking table, shook 2 hours under 4 ℃, form the nanoparticle of sealing Chinese medicine matrimony vine active material;
C) the reuse liposoluble compound medicine is sealed outside the calcium phosphate nano particle of sealing Chinese medicine matrimony vine active material, forms the nano complex eye drops that includes liposoluble compound medicine:
Sealing the nanoparticle of Chinese medicine matrimony vine active material and the mass ratio of liposoluble compound medicine is 1: 2～6, after in appropriate amount of organic, all dissolving in the liposoluble compound medicine, add in the phosphate buffer that has been suspended with the nanoparticle of sealing middle pharmaceutically active substance again, 4 ℃ are continued down to shake on shaking table 2 hours, under 4 ℃, 8500rpm centrifugal at least twice, each 15 minutes, remove supernatant, acquisition contains the nanoparticle that liposoluble compound medicine and Chinese medicine matrimony vine active material are sealed calcium phosphate, add distilled water diluting again, form the nano complex eye drops that includes liposoluble compound medicine, pH value is 6.2～7.5.
The calcium phosphate nano particle that obtains in the above-mentioned preparation method a step, pH value are 6.2～7.5.
Liposoluble compound medicine in the above-mentioned preparation method c step is selected a selection: methazolamide, acetazolamide, diclofenamide (dichlorphenamide), ethoxzolamide, many azoles amine or brinzolamide, pilocarpine, dexamethasone, meticortelone, timolol, betaxolol, atropine, tropicamide, ketoconazole, streptomycin, metronidazole, sulfadiazine, sulphanilamide, chloromycetin, clarithromycin, ketotifen; Described organic solvent is a dehydrated alcohol, or methanol, or chloroform, or acetone, or dimethyl sulfoxide.
In the above-mentioned preparation method, the described nano-scale magnitude range 10～850nm that includes liposoluble compound medicine, wherein the granule more than 50% is 56～258nm, concentration range 400～500ug/ml, its zeta potential (mv)-14～-28, viscosity scope 5～10 (mPas).
In the above-mentioned preparation method, after formation includes the nano complex eye drops of liposoluble compound medicine, select to use phosphate buffer or borate buffer or hydrochloric acid or sodium hydroxide to adjust pH value.
In the above-mentioned preparation method, in preparation process, add osmotic pressure regulator and antiseptic according to conventional method, wherein, described osmotic pressure regulator is sodium chloride or boric acid or glucose, and described antiseptic is selected a selection: quaternary ammonium salt, alcohols, esters, oxybenzene esters, acids antiseptic.Wherein, described quaternary ammonium salt antiseptic is a benzalkonium chloride, or the benzalkonium bromide cationic surfactant; Described alcohols antiseptic is a benzyl alcohol, or chlorobutanol; Described acids antiseptic is a sorbic acid.
The invention has the advantages that: because the special list area effect of nanometer improves the diffusion coefficient of liposoluble compound medicine in aqueous solution that is insoluble in water; Utilize the transfer function of nanometer, make medicine can pass through cornea, increased aqueous humor Chinese medicine concentration; Because the slow releasing function of nanometer has prolonged the time that medicine is kept treatment concentration within the eye; Nanometer itself can biodegradation, and its by-product is phosphorus and carbon, and the constituent for tissues such as human body bone and teeth has no side effect to human body; Change traditional liposoluble compound medicine route of administration, directly splashed into eye, not only easy to use, and reduce dosage and by the side effect of its generation.Side effect such as with the nano complex eye drops that includes methazolamide is example, compares with similar cloth Yin assistant amine eye drop, and all there are the raising on the statistical significance its antihypertensive effect and blood pressure lowering time, and local hyperemia, the secretions that does not have Pai Liming to cause of eye is many.When bioavailability height, clinical normal oral methazolamide were used for the treatment of glaucoma and reduce intraocular pressure, the dosage of systemic administration every day was 830ug/kg, was 33ug/kg and include the dosage of nano complex eye drops normal every day of methazolamide.Preparation technology of the present invention is simple, and cost is low; And pH value 6.2-7.5 is a physiological range.
Description of drawings
Fig. 1 be 1% nanometer methazolamide put drops in one's eyes put drops in one's eyes with 1% Pai Liming, the effectiveness of the intraocular pressure lowering of distilled water relatively.
The specific embodiment
Preparation before the preparation
Saline solution: with the calcium chloride of 0.01～1.0 mole of deionized water preparation.
Phosphoric acid solution: with the phosphoric acid solution of 0.01～1.0 mole of deionized water preparation.
The active substance solution of Chinese medicine: the active substance solution (lycium barbarum polysaccharide outsourcing) for preparing the Chinese medicine lycium barbarum polysaccharide in the every 100ml normal saline+ratio of 1mg lycium barbarum polysaccharide.
PH value is 6.8-7.0, and 0.01 mole phosphate buffer can outsourcing.
Capital equipment:
Swinging vibration constant incubator (the 760/760R U.S.).
Preparation process
A) preparation calcium phosphate nano particle:
After 0.01～1.0 mole calcium chloride solution, 0.01～1.0 mole phosphoric acid solution mixed by 1: 1, at room temperature stirred 48 hours, 4 ℃ of ambient temperatures, centrifugal 15 minutes of 8500rpm, remove supernatant, use the deionized water suspended particles, supersound process is 45 minutes again, concentration at 0.4712mg/ml forms the calcium phosphate nano particle, and its size dimension is 10～850nm;
B) under the room temperature with the calcium phosphate nano particle again with after the Chinese medicine lycium barbarum polysaccharide was mixed by 1: 10, concentration by 10mg/ml is suspended in pH value 6.8-7.0,0.01 in the phosphate buffer of mole, on shaking table, shook 2 hours under 4 ℃, form the calcium phosphate nano particle of sealing Chinese medicine matrimony vine active material.
(nanometer methazolamide eye drop is the nano complex eye drops that includes liposoluble compound medicine that the present invention relates to embodiment 21% nanometer methazolamide eye drop, down together) preparation
Capital equipment:
Swinging vibration constant incubator (the 760/760R U.S.);
Refrigerated centrifuge (the BECKMAN U.S.).
Bioactive substance solution:, guarantee that methazolamide all dissolves in the ratio of every 1ml dehydrated alcohol+2mg methazolamide.
The nanoparticle that is encapsulated with the Chinese medicine lycium barbarum polysaccharide (is obtained by embodiment 1, down together) mass ratio with methazolamide is 1: 2, methazolamide is added dehydrated alcohol to medicine all to be dissolved, add in the phosphate buffer that is suspended with the nanoparticle of sealing middle pharmaceutically active substance that the b step obtains among the embodiment 1,4 ℃ are continued down to shake on shaking table 2 hours, under 4 ℃, centrifugal three times of 8500rpm, each 15 minutes, remove supernatant, add distilled water 20ml dilution precipitation, obtain 1% nanometer methazolamide and put drops in one's eyes, nanometer concentration is 5mg/ml, surveys pH value 6.8-7.0.
The preparation of embodiment 33% nanometer methazolamide eye drop
Bioactive substance solution:, guarantee that methazolamide all dissolves in the ratio of every 1ml dehydrated alcohol+2mg methazolamide.
Being encapsulated with the nanoparticle of Chinese medicine matrimony vine active material and the mass ratio of methazolamide is 1: 6, methazolamide is added dehydrated alcohol to medicine all to be dissolved, add in the phosphate buffer that is suspended with the nanoparticle of sealing middle pharmaceutically active substance that the b step obtains among the embodiment 1,4 ℃ are continued down to shake on shaking table 2 hours, under 4 ℃, centrifugal three times of 8500rpm, each 15 minutes, remove supernatant, add distilled water 20ml dilution precipitation, obtain 3% nanometer methazolamide eye drop, nanometer concentration is 5mg/ml, surveys pH value 6.8-7.0.
15 of the livid purple blue rabbits of normal intraocular tension, female, the about 1.8KG-2.0KG of body weight; Livid purple blue rabbit is divided into 3 groups at random, and 5 every group, one group is used 1% nanometer methazolamide eye drop, and one group is used 1% Pai Liming (brinzolamide) to put drops in one's eyes, and one group is used distilled water.
Tried thing:
The 1% nanometer methazolamide 100ul (according to embodiment 2 preparation, down with) that puts drops in one's eyes;
1% Pai Liming put drops in one's eyes 100ul (brinzolamide, U.S. Alcon Universal Ltd., down with);
Distilled water 100ul (outsourcing, down together).
Equipment:
Indentation tonometers is available from the bright core company limited of Suzhou medical apparatus and instruments (attached intraocular pressure conversion table).
Experimental technique:
In the experiment, in each organizes the conjunctival sac of livid purple blue lagophthalmos eyeball, click and enter respectively and tried thing 100ul accordingly, and behind a medicine 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, respectively each group was surveyed intraocular pressure in 12 hours, survey 3 times at every turn, get its meansigma methods.It the results are shown in Figure 1.In Fig. 1, abscissa is the time, and vertical coordinate is the intraocular pressure drop-out value, and represents 1% nanometer methazolamide eye drop with methazolamide.As seen from the figure, use 1% nanometer methazolamide eye drop and Pai Liming to put drops in one's eyes, the intraocular pressure of livid purple blue rabbit all can descend, and in the time of 2 hours, be in the intraocular pressure lowering peak value, in the time of 2 hours, use Pai Liming to put drops in one's eyes and the effect of distilled water does not have significant difference (p＞0.05), there were significant differences (p≤0.05) to use the effect of 1% nanometer methazolamide eye drop and distilled water, and also there were significant differences for the effect of using 1% nanometer methazolamide eye drop and Pai Liming to put drops in one's eyes (p≤0.05).Use distilled water and the Pai Liming group intraocular pressure value rise of putting drops in one's eyes in the time of 6 hours, both no difference of science of statistics (p＞0.05), still there were significant differences (p≤0.05) to use the effect of 1% nanometer methazolamide eye drop and distilled water.Use 1% nanometer methazolamide eye drop that the intraocular pressure lowering effect was arranged in the time of 12 hours.
1, single stimulation and repeatedly stimulation test
The foundation of animal model:
Select 5 of new zealand rabbits for use, female, body weight 1.8KG～2.0KG.Every rabbit a glance medication, another eye is done contrast, and the medication eye uses 1% nanometer methazolamide eye drop, contrast eye use distilled water.
Tried thing:
Be 1% nanometer methazolamide eye drop, distilled water.
Standards of grading: State Food and Drug Administration 2005 " eye irritant reaction score value standard ".
In the experiment, every rabbit one eyespot medicine, another eye is done contrast, uses 1% nanometer methazolamide eye drop, distilled water respectively.
The single stimulation test be every medication eye conjunctival sac point medicine once, 100ul, some medicine finish the back observed the scoring record 1 hour, 24 hours.Each medication eye of single stimulation test compares corneal transparency with the contrast eye, and iris is clear, and conjunctiva is not congested, no edema and secretions, scoring is 0, according to " eye irritant reaction score value standard ", 0-3 is non-stimulated, and the single stimulation test proves 1% nanometer methazolamide eye drop nonirritant.The results are shown in Table 1.
Table 1 nanometer methazolamide eye drop single is to lagophthalmos local response macroscopy n=5 as a result
| Group | Cornea (integration) | Iris (integration) | Conjunctiva (integration) | Secretions (integration) | Fluorescence body (integration) | Total points (integration) | Divide equally (integration) |
| The |
0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Matched |
0 | 0 | 0 | 0 | 0 | 0 | 0 |
Repeatedly stimulation test is every medication eye conjunctival sac point medicine 7 days, every day 1 time, and each 100ul, the some medicine finishes the back observed the scoring record 2 days, 7 days.According to " eye irritant reaction score value standard ", 0-3 is non-stimulated, and repeatedly stimulation test proves 1% nanometer methazolamide eye drop nonirritant.Air embolism is got eyeball and is done pathologic finding after putting to death animal.The results are shown in Table 2.
A continuous week of table 2 nanometer methazolamide eye drop is to lagophthalmos local response macroscopy n=5 as a result
| Group | Cornea (integration) | Iris (integration) | Conjunctiva (integration) | Secretions (integration) | Fluorescence body (integration) | Total points (integration) | Divide equally (integration) |
| The |
0 | 0 | 0 | 1 | 0 | 1 | 0.25 |
| Matched |
0 | 0 | 0 | 0 | 0 | 0 | 0 |
Table 3 nanometer methazolamide eye drip drips the pathologic finding n=4 A4 contrast to tame lagophthalmos stimulation
2, anxious poison experiment
A, select 5 of new zealand rabbits for use, female, the about 1.8KG～2.0KG of body weight.
Being tried thing is 3% nanometer methazolamide eye drop (according to embodiment 3 preparations, down together), distilled water.
In the experiment, 4 rabbit point medicines use 3% nanometer methazolamide to put drops in one's eyes as the medication group, and 1 rabbit is used distilled water in contrast.The point medicine is 10 times in the medication group 24 hours, and each 0.2ml 1 hour 1 time, puts the record of marking behind the medicine at every turn.The point medicine finishes the back to be observed 7 days, 14 days.
There is not animal dead in the experiment, it is no abnormal that general pharmacology is learned observation, eye maximum tolerated dose 70mg/KG, the normal eye is clinical (to be equivalent to the 1% nanometer methazolamide eye dripping of putting drops in one's eyes with dosage 0.15mg/kg, three times on the one), be 466 times of normal clinical consumption. Cmax, heap(ed) capacity does not have animal dead, and the result is referring to table 4.14 day convalescent period observed, and total points is 0 minute.Inflammatory reaction such as cornea, iris are not seen in slit lamp examination.
40 of b, selection ICR mices, male and female half and half, body weight 18g～19g is divided into 2 groups at random, matched group, medication group.Being tried thing is 3% nanometer methazolamide eye drop, distilled water.Matched group uses distilled water, medication group to use the 3% nanometer methazolamide solution of putting drops in one's eyes.
In the experiment: every mice 9:00PM in the morning of each group respectively lumbar injection 0.4ml tried thing, observed 1 hour, afternoon, 14:00AM injected the thing that tried of 0.4ml in the abdominal cavity respectively again, observed 1 hour.Then each group mice is continued to observe 14 days.
N/R general pharmacology behavior is observed in the anxious poison experiment of whole body medication for the first time after 1 hour, no animal dead is considered this complex low toxicity low irritant, carry out the maximum tolerated dose experiment, observe for the second time no abnormally after the medication, no animal dead is observed 14 days no dead mouses.Cmax, heap(ed) capacity does not have animal dead.Maximum tolerated dose 116mg/KG, people's clinical oral administration usual amounts is 0.8mg/KG, is 145 times of positive usual amounts, the result is referring to table 5.
Table 4 nanometer methazolamide eye drop acute toxicity LD
50And 95% fiducial limit interval
Table 5 nanometer methazolamide eye drop acute toxicity LD
50And 95% fiducial limit interval (IP)
3, skin allergy experiment
Select 16 of Cavia porcelluss, female, the about 40g of body weight is divided into low dose group, high dose group, positive controls, negative control group at random.Tried thing and be that 1% nanometer methazolamide is put drops in one's eyes, 3% nanometer methazolamide is put drops in one's eyes, two-Methylnitrobenzene, distilled water.
Standards of grading: food and medicine Surveillance Authority 2005 " skin hypersensitivity evaluation criterion ".In the experiment, low dose group uses 1% nanometer methazolamide to put drops in one's eyes, and high dose group uses 3% nanometer methazolamide to put drops in one's eyes, and positive controls is used two-Methylnitrobenzene, and negative control group is used distilled water.
Phase I: in the sensitization stage, every Cavia porcellus skin of abdomen is coated with and is tried thing accordingly, and 1 time every other day, be coated with 3 times, observe skin and have or not flushing, anaphylaxiss such as edema, and record scoring.Low dose group, high dose group and negative control group animal skin do not have erythema, edema anaphylaxis.
Enter second stage after 14 days: phase of the attack, every Cavia porcellus skin of abdomen is coated with and is tried thing accordingly, and method is identical with the phase I.Observe skin and have or not flushing, anaphylaxiss such as edema, and record scoring.Phase of the attack, low dose group, high dose group and negative control group animal skin do not have erythema, edema anaphylaxis; Serious erythema 3 minutes appear in positive controls, intermediate edema 2 minutes, and experimental result sees Table 6.
Table 6 receives the methazolamide eye drop to guinea pig skin hypersensitive test result
According to " skin hypersensitivity evaluation criterion ", 1% nanometer methazolamide eye drop and 3% nanometer methazolamide eye drop do not have skin allergy.
The foregoing description that the present invention relates to is example with the methazolamide only, is not to unique restriction of the present invention.By the foregoing description as can be seen, seal the calcium phosphate nano particle improves liposoluble compound medicine as carrier transfer liposoluble compound medicine (methazolamide) drug effect with lycium barbarum polysaccharide.In the specific implementation, can in preparation method, can select one and select following his liposoluble compound medicine, as: methazolamide, acetazolamide, diclofenamide (dichlorphenamide), ethoxzolamide, many azoles amine or brinzolamide, pilocarpine, dexamethasone, meticortelone, timolol, betaxolol, atropine, tropicamide, ketoconazole, streptomycin, metronidazole, sulfadiazine, sulphanilamide, chloromycetin, clarithromycin, ketotifen; Described organic solvent also can be selected a selection to the dissolution characteristics of organic solvent according to above-mentioned each liposoluble compound medicine: dehydrated alcohol, methanol, chloroform, acetone, dimethyl sulfoxide routinely except dehydrated alcohol; Contain following ingredients in satisfying every 100ml eye drop: calcium phosphate nano particle 0.01～2g, matrimony vine active material 0.1～50mg during liposoluble compound medicine 5～50mg, can realize purpose of the present invention equally, obtains satisfied effect.
PH value in order to ensure complex eye drops is 6.2～7.5, include the nano complex eye drops of liposoluble compound medicine in formation after, in case pH value departs from, can select to use phosphate buffer, or borate buffer, or hydrochloric acid, or sodium hydroxide is adjusted to above-mentioned physiological range with pH value.
For the osmotic pressure that makes complex eye drops and the physiological osmotic pressure close (280～310mOsm/L) of people's tear, reduce the sense of discomfort of ophthalmic administration, include the nano complex eye drops of liposoluble compound medicine in formation after, can add osmotic pressure regulator according to conventional method, osmotic pressure is adjusted in the scope close with the physiological osmotic pressure of people's tear.The addition of osmotic pressure regulator should be controlled in the scope of 0～1.0g in every 100ml eye drop, and described osmotic pressure regulator can select to use sodium chloride or boric acid or glucose.
In order to prevent that microorganism from growing and breeding in the complex eye drop, can adopt the daily dose packaged form, every loading amount is 0.4ml～0.8ml only, and is disposable one of every day, avoids pollution problem in use.Pack for the needs single, nonexpondable, in order to prolong the effective storage life after complex eye drops breaks a seal, can in the complex eye drop, add antiseptic, described antiseptic can be selected: quaternary ammonium salt, as cationic surfactants such as benzalkonium chloride, benzalkonium bromides; Alcohols is as benzyl alcohol, chlorobutanol; Esters, the oxybenzene esters; Acids, sorbic acid etc., the addition of antiseptic is can add 0～0.1g in every 100ml eye drop, for example: select methyl hydroxybenzoate can add 0.023g, select propylparaben can add 0.011g, select phenylmercuric nitrate can add 0.002g, selective chlorination benzene first hydroxylammonium solution 0.02g selects phenylmercuric acetate can add 0.002g.
Claims (9)
1, a kind of nano complex eye drops that includes liposoluble compound medicine is characterized in that: it seals the calcium phosphate nano particle as the carrier transfer liposoluble compound medicine with the matrimony vine active material, contains following ingredients in every 100ml eye drop:
Calcium phosphate nano particle 0.01～2g,
Matrimony vine active material 0.1～50mg,
Liposoluble compound medicine 5～50mg,
Osmotic pressure regulator 0～1.0g,
Antiseptic 0～0.1g,
Distilled water is an amount of;
The pH value of complex eye drops is 6.2～7.5, and described matrimony vine active material is a lycium barbarum polysaccharide.
2, the nano complex eye drops that includes liposoluble compound medicine according to claim 1, it is characterized in that: described liposoluble compound medicine is: methazolamide, or acetazolamide, or diclofenamide (dichlorphenamide), or ethoxzolamide, or many azoles amine, or brinzolamide, or pilocarpine, or dexamethasone, or meticortelone, or timolol, or betaxolol, or atropine, or tropicamide, or ketoconazole, or streptomycin, or metronidazole, or sulfadiazine, or sulphanilamide, or chloromycetin, or clarithromycin, or ketotifen; Described antiseptic is the organic mercury class, or quaternary ammonium salt, or alcohols, or the oxybenzene esters, or the acids antiseptic; Described osmotic pressure regulator is sodium chloride or boric acid or glucose.
3, the preparation method of complex eye drops as claimed in claim 1 or 2 is characterized in that:
A) preparation calcium phosphate nano particle:
After 0.01～1.0 mole calcium chloride solution, 0.01～1.0 mole phosphoric acid solution mixed by 1: 1, at room temperature stirred 48 hours, 4 ℃ of ambient temperatures, centrifugal 15 minutes of 8500rpm, removal contains free calcium and phosphorus supernatant, uses the deionized water suspended particles, ultrasonic again place 45 minutes, form the calcium phosphate nano particle, its size dimension is 10-850nm;
B) on the calcium phosphate nano particle, seal Chinese medicine matrimony vine active material again:
Under the room temperature with the calcium phosphate nano particle again with after Chinese medicine matrimony vine active material mixes by 1: 10 weight ratio, concentration by 10mg/ml is suspended in pH value 6.8-7.0,0.01 in the phosphate buffer of mole, on shaking table, shook under 4 ℃ 2 hours, and formed the calcium phosphate nano particle of sealing Chinese medicine lycium barbarum polysaccharide active substance;
C) the reuse liposoluble compound medicine is sealed outside the calcium phosphate nano particle of sealing Chinese medicine matrimony vine active material, forms the nano complex eye drops that includes liposoluble compound medicine:
Sealing the nanoparticle of Chinese medicine matrimony vine active material and the mass ratio of liposoluble compound medicine is 1: 2～6, liposoluble compound medicine is all dissolvings in appropriate amount of organic, add again and be suspended with in the phosphate buffer of the nanoparticle of sealing lycium barbarum polysaccharide, 4 ℃ are continued down to shake on shaking table 2 hours, under 4 ℃, 8500rpm centrifugal at least twice, each 15 minutes, remove supernatant, acquisition contains the nanoparticle that liposoluble compound medicine and Chinese medicine matrimony vine active material are sealed calcium phosphate, add distilled water diluting again, form the nano complex eye drops that includes liposoluble compound medicine, pH value is 6.2～7.5.
4, according to the preparation method of the described complex eye drops of claim 3, it is characterized in that: the calcium phosphate nano particle that obtains in a step, pH value are 6.2～7.5.
5, according to the preparation method of the described complex eye drops of claim 3, it is characterized in that: described organic solvent is a dehydrated alcohol, or methanol, or chloroform, or acetone, or dimethyl sulfoxide.
6, the preparation method of complex eye drops according to claim 3, it is characterized in that: the granular size size range 10～850nm of described liposoluble compound medicine, concentration range 400～500ug/ml, its zeta potential be-14～-28mv, viscosity scope 5～10mPas.
7, according to the preparation method of the described complex eye drops of claim 3, it is characterized in that: after formation includes the nano complex eye drops of liposoluble compound medicine, select to use phosphate buffer or borate buffer or hydrochloric acid or sodium hydroxide to adjust pH value.
8, the preparation method of complex eye drops according to claim 3, it is characterized in that: add osmotic pressure regulator and antiseptic according to conventional method in preparation process, described antiseptic is selected a selection: quaternary ammonium salt, alcohols, esters, acids antiseptic.
9, the preparation method of complex eye drop according to claim 8 is characterized in that: described quaternary ammonium salt antiseptic is a benzalkonium chloride, or the benzalkonium bromide cationic surfactant; Described alcohols antiseptic is a benzyl alcohol, or chlorobutanol; Described acids antiseptic is a sorbic acid.
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| CN1389475A (en) * | 2002-06-14 | 2003-01-08 | 张平 | Wolfberry polysaccharide and its prepn. and application |
| CN1448408A (en) * | 2002-04-03 | 2003-10-15 | 敖尔戈勒 | Wolfberry fruit polysaccharide separating and purifying technology |
| CN1488574A (en) * | 2003-07-28 | 2004-04-14 | 浙江大学 | Method for preparing biomedical amorphous nano calcium phosphate |
| CN1709511A (en) * | 2005-03-23 | 2005-12-21 | 华南理工大学 | Drug-carrier calcium phosphate hano line and its preparing method |
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| CN1448408A (en) * | 2002-04-03 | 2003-10-15 | 敖尔戈勒 | Wolfberry fruit polysaccharide separating and purifying technology |
| CN1389475A (en) * | 2002-06-14 | 2003-01-08 | 张平 | Wolfberry polysaccharide and its prepn. and application |
| CN1488574A (en) * | 2003-07-28 | 2004-04-14 | 浙江大学 | Method for preparing biomedical amorphous nano calcium phosphate |
| CN1709511A (en) * | 2005-03-23 | 2005-12-21 | 华南理工大学 | Drug-carrier calcium phosphate hano line and its preparing method |
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