CN101502485A - Nano cubic liquid crystal dexamethasone preparation for eye and preparation method thereof - Google Patents
Nano cubic liquid crystal dexamethasone preparation for eye and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a dexamethasone ophthalmic nano-cubic liquid-crystal preparation and a preparation method thereof. The dexamethasone ophthalmic nanocube crystal preparation is prepared from lipid materials, an emulsifying agent, a thickening agent, an osmotic pressure regulating agent, a bacteriostatic agent, a pH value regulating agent and purified water and characterized in that the amphipathic lipid capable of forming the cubic liquid-crystal morphology, one or more out of glyceryl monooleate (GMO), phytantriol and lecithin are adopted as the lipid materials; and the safe and non-irritant ophthalmic surfactant, one or more out of poloxamer 407 and polyvinyl alcohol (PVA) are adopted as the emulsifying agent. .The invention realizes the ophthalmic administration of dexamethasone, a fat-soluble drug, and has the advantages of high comfort level and non-irritant administration; and the invention can promote the drug to permeate into the corneal barriers after the ophthalmic administration, thereby achieving the effect of improving the ophthalmic bioavailability.
Description
Technical field
The present invention relates to a kind of novel ophthalmic preparation of dexamethasone---be specifically related to a kind of nano cubic liquid crystal dexamethasone preparation for eye.The invention still further relates to the preparation method of this nano cubic liquid crystal dexamethasone preparation for eye.
Background technology
Uveitis is a kind of common ophthalmic diseases, causes that in the west uveitis accounts for 10%-15% in the blind oculopathy.Its clinical iridocyclitis, choroiditises etc. of mainly showing as.Uveitic pathogenesis complexity, except infectious factors, the overwhelming majority is because due to the autoimmune response.Uveitis is regarded as ophthalmology " difficult miscellaneous diseases ", and its treatment is difficulty quite.
The dead ahead of eyeball is fine and close cornea tissue, the normal cornea epithelial layer is made up of 6～7 layers of epithelial cell, and exist between epithelial cell and be tightly linked, in the physical protection function of bringing into normal play, also become the main barrier of most ophthalmic preparations after the administration of eye table, it has often limited the ocular tissue performance drug effect of many medicines in the deep.And the medicine of lipophilic molecules type (LogD2～3) enters ocular tissue inside than the easier corneal epithelium that sees through of the Ionized medicine of hydrophilic.
Dexamethasone is a kind of adrenocortical hormone of synthetic, is the medicine of slightly solubility, and the ophthalmic preparation that adopts clinically mainly is dexamethasone sodium phosphate eye drop and Eye ointments at present.Test shows: even prolong in holdup time of eye table organization, the bioavailability of Eye ointments is still than eye drop difference (people such as Cox, Arch Ophthalmol.91,373 (1972); People such as Kupferman, Arch Ophthalmol.91.373 (1974)).Behind the eye drop topical, dexamethasone exists with ionic form, is difficult to see through lipophilic corneal epithelium and enters eyeball inside, so be mainly used in the inflammation treatment of a table organization; Then curative effect is not good enough for ocular tissue's deep inflammation (as inflammation such as iris, corpus ciliaries).Patent (CN1266369) discloses a kind of dexamethasone gel, though gel can prolong the holdup time of preparation in eye table organization, yet active component is still the sodium salt of dexamethasone, and medicine exists with ionic species, is difficult to see through the cornea barrier.
Certain density amphipathic lipoid is the thermodynamically stable lipid bilayer of the spontaneous formation of meeting in water, and then reassembles into the cubic liquid crystal system with different shape and structure.Successive cubic liquid crystal can disperse to form independently nanoparticle in the presence of big water gaging, is called nano cubic liquid crystal (Cubosome).Nano cubic liquid crystal (Cubosome) has bioadhesive, because the two channel structures in its unique inside can discharge the medicine of sealing lentamente, has therefore caused people's common concern.Bibliographical information (Larsson K.Cubic lipid-water phases:Structures and biomembrane aspects[J] .Phys Chem, 1989,93:7304-7314), liquid crystal has and the biomembrane similar microstructure, can promote medicine to see through the biomembrane barrier.At present, existing this carrier is at the research report in percutaneous drug delivery, intravenous injection and field such as oral; But the application with carrier formulation does not appear in the newspapers as yet as novel eye with nano cubic liquid crystal.
Summary of the invention
The object of the present invention is to provide a kind of nano cubic liquid crystal dexamethasone preparation for eye and preparation method thereof.
According to the present invention, a kind of dexamethasone nano cubic liquid crystal preparation is provided, based on 1000ml eye nano cubic liquid crystal preparation, mainly be grouped into by following one-tenth:
Dexamethasone 10～1800mg
Matrix material 5～300g
Emulsifying agent 0.25～60g
Thickening agent 0～200g
Osmotic pressure regulator is an amount of
Antibacterial 0.0～0.5g
The pH regulator agent is an amount of
Purified water adds to 1000ml
Matrix material comprises in glyceryl monooleate (GMO), phytantriol and the lecithin one or more for forming the amphipathic lipoid of cubic liquid crystal form in the prescription; Emulsifying agent selects to be fit to be applied to the safe and non-stimulating surfacant of eye, comprises in poloxamer 407 and the polyvinyl alcohol (PVA) one or more.
Thickening agent in the prescription is one or more in hyaluronic acid sodium, carbomer, poloxamer, hypromellose (HPMC), methylcellulose (MC), polyvinylpyrrolidone (PVP) and the polyvinyl alcohol.
Osmotic pressure regulator is one or more in glycerol, glucose, mannitol and the propylene glycol.Osmotic pressure regulator content in the present invention, for the osmotic pressure that makes said preparation in the scope of 0.280-0.320mOsmol/Kg (freezing point osmotic pressure method).
Adoptable antibacterial is: quaternary ammonium salt, for example benzalkonium chloride, Benzoxonium Chloride or poly quaternary ammonium salt (polyquats); The alkyl mercuric salt of thiosalicylic acid; Chlorobutanol or guanidine derivatives; And be preferably quaternary ammonium salt, alkyl mercuric salt or chlorobutanol.
The pH regulator agent is one or more in hydrochloric acid, sodium hydroxide, phosphate, boric acid, borate, Tris, citric acid, citrate and the triethanolamine.PH regulator agent content in the present invention, for the pH value that makes said preparation in 6～8 scopes that physiology can tolerate.
The present invention also provides the preparation method of nano cubic liquid crystal dexamethasone preparation for eye, and this method may further comprise the steps: matrix material, emulsifier is even, then dexamethasone is dissolved in this mixture, and make oil phase; Get an amount of purified water as water; Oil phase is added the water emulsification pretreatment, and then use the high pressure homogenizer homogenizing, obtain the nano cubic liquid crystal preparation, the gained preparation is with the filtering with microporous membrane of 0.45 μ m.Add the aqueous solution contain an amount of osmotic pressure regulator, antibacterial and thickening agent again, regulate pH value to 6～8 with the pH regulator agent at last, with purified water mend to capacity promptly.Wherein, high pressure homogenize pressure is more than or equal to 200 crust.
Nano cubic liquid crystal dexamethasone preparation for eye provided by the invention has following beneficial effect:
1, the present invention's eye of containing dexamethasone can form the amphipathic lipoid of cubic liquid crystal form with nano cubic liquid crystal preparation employing, comprises that glyceryl monooleate, phytantriol or lecithin are as matrix material; Be fit to be applied to the safe and non-stimulating surfacant of eye, comprise that poloxamer 407 or polyvinyl alcohol are as emulsifying agent; The eye that has prepared dexamethasone is used the nano cubic liquid crystal preparation, has solved dissolving, the scattering problem of this fat-soluble medicine, makes it be fit to be applied to the eye sensitive part, has comfort level height, non-irritating advantage.
2, the present invention is wrapped in dexamethasone in the nano cubic liquid crystal carrier, behind the dosing eyes, utilize nano cubic liquid crystal and biomembrane similar microstructure, the glyceryl monooleate bilayer in its particle and the lipid bilayer of corneal epithelial cell merge.Be accompanied by the fusion of lipid layer, the effect of nano cubic liquid crystal performance bank, the two channel structures by its uniqueness slowly discharge medicine, provide power for striding the film diffusion, thereby promote medicine to see through the cornea barrier, improve the bioavailability of eye.
3, compare with liposome, nano cubic liquid crystal inside is made up of amphipathic lipid components, to the bag loading capability of fat-soluble medicine dexamethasone, is significantly higher than the inner liposome of water that is.In addition, the stability of nano cubic liquid crystal also significantly is better than liposome, and in the storage process, medicine is not easy to leak.
Description of drawings
Fig. 1 has shown the different preparation unit are accumulation of dexamethasone transit dose-time plot (n=3).
The specific embodiment
The present invention is further elaborated below in conjunction with specific embodiment, but do not limit the present invention.Mean diameter is measured with the particle size analyzer (Nicomp388/ZetaPALS, PSS, the U.S.) of dynamic light scattering principle.
At first according to the composition that provides embodiment 1 in the following table 1,500mg dexamethasone, 10g poloxamer 407 are dissolved among the 100g GMO, 60 ℃ of mix homogeneously are made oil phase; The 700ml purified water is preheated to 60 ℃, makes water; Oil phase is added the water emulsification pretreatment, and (T25basic IKA high shear dispersing emulsification machine 10000rpm), and then with high pressure homogenizer homogenizing (under the 350bar pressure, homogenizing 5 times), obtains nano cubic liquid crystal solution, with the filtering with microporous membrane of 0.45 μ m.
The 5g hyaluronic acid sodium is dissolved in the 200ml purified water, stirs and make dissolving fully, add 0.05g Benzalkonii Chloridum, 18g glycerol, stir, add to above-mentioned nano cubic liquid crystal solution, stir; Be that the hydrochloric acid solution of 0.5M is adjusted to pH7.2 with concentration at last, mend to 1000ml, promptly with purified water.
Adopt the preparation method identical,, make the nano cubic liquid crystal preparation of embodiment 2～6 by forming and technological parameter of providing in the table 1 with embodiment 1.
Table 1 embodiment 1～6 dexamethasone nano cubic liquid crystal preparation is formed and technological parameter
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | |
| Dexamethasone | 500mg | 10mg | 500mg | 400mg | 200mg | 1800mg |
| Matrix material | GMO100g | Phytantriol 150g | Lecithin 200g | GMO 100g lecithin 100g | GMO 5g | GMO 300g |
| Emulsifying agent | Poloxamer 40710g | Poloxamer 40715g | Poloxamer 4078g PVA4g | PVA 20g | PVA 0.25g | Poloxamer 40760g |
| Thickening agent | Hyaluronic acid sodium 50g | Carbomer 10g | HPMC 100g | MC 80g | PVP 40g | Hyaluronic acid sodium 200g |
| Antibacterial | Benzalkonii Chloridum 0.05g | Buddhist nun uncle tortoise beetle ester 0.2g | Benzalkonii Chloridum 0.5g | Chlorobutanol 0.2g | Thimerosal 0.3g | Benzalkonium bromide 0.1g |
| Osmotic pressure regulator | Glycerol 18g | Propylene glycol 20g | Glycerol 21g | Mannitol 45g | Glycerol 20g | Glycerol 16g |
| The pH regulator agent | HCL 0.5M | NaOH 0.5M | / | NaOH 0.5M | Tris 0.5M | Sodium borate |
| Purified water | To 1000ml | To 1000ml | To 1000ml | To 1000ml | To 1000ml | To 1000ml |
| pH | 7.2 | 7.0 | 7.4 | 6.8 | 6.0 | 7.6 |
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | |
| Mean diameter | 253nm | 187nm | 208nm | 236nm | 268nm | 279nm |
| PI | 0.135 | 0.161 | 0.144 | 0.176 | 0.163 | 0.189 |
PI: be the particle diameter polydispersity coefficient, adopt particle size analyzer to record.
The eye safety testing of experimental example 1 dexamethasone nano cubic liquid crystal preparation
1, test material and condition:
The dexamethasone nano cubic liquid crystal preparation of trial drug: embodiment 1 preparation, each dosage is 100 μ l;
Experimental animal: 4 of cleaning level New Zealand white rabbit, male and female half and half, body weight 2-3 kilogram (available from the extraordinary animals and plants of peace breeding farm, Shanghai);
Animal feeding environment: room temperature: 20 ℃
Humidity: 30%-70%
Illumination: artificial light rays, 12 hours daylight, 12 hours dark
2, test method:
Draw back tame lagophthalmos conjunctival sac gently, 100 μ l trial drugs are splashed in the eye conjunctival sac of right side, the left side gives normal saline in contrast.Made eyes after the administration passive closed 5～10 seconds (action is light), medicinal liquid is had fully with the part contact.Be administered twice every day, one week of successive administration.The degree of impairment of 6,24,48,72,96,120,144,168 hours the eye in one week of record administration back is with Draize eye irritant test scoring expression (according to the 208th page of " new drug (Western medicine) clinical research guideline compilation (pharmacology pharmacology's toxicology) " eye irritant test).Check corneal injury with fluorescein sodium during observation, change with slit lamp examination corneal transparence and iris texture.
3, result of the test: each test period is put tame lagophthalmos stimulates score value to see Table 2.
Each test period of table 2 is put tame lagophthalmos stimulates score value
According to Draize eye irritation evaluation criterion, 0-3 is divided into nonirritant, and as can be seen from Table 1, stimulating a score value at the eye of each test period point is 0～0.5, so preparation of the present invention is put equal nonirritant to the rabbit eyes in each test period.Through slit lamp and fluorescein sodium inspection, cornea and iris are all normal simultaneously.Because this pilot system is than human eye irritant reaction sensitivity, so the irritant reaction feminine gender can be determined the human eye nonirritant.
Experimental example 2 dexamethasone nano cubic liquid crystal preparation rabbit cornea permeabilitys are estimated
1, test material and condition:
Experimental animal: 3 of cleaning level New Zealand white rabbit, male and female half and half, body weight 2-3 kilogram (available from the extraordinary animals and plants of peace breeding farm, Shanghai);
Animal feeding environment: room temperature: 20 ℃
Humidity: 30%-70%
Illumination: artificial light rays, 12 hours daylight, 12 hours dark
The dexamethasone nano cubic liquid crystal preparation of trial drug: embodiment 1 preparation; Commercially available dexamethasone sodium phosphate eye drop (Wuhu three beneficial pharmaceutical Co. Ltds)
2, test method
After rabbit auricular vein injection pneumatic needle is put to death, separate cornea, rinse well, be placed on (effective diffusion area 0.785cm on the Franz infiltration disperser after the improvement with the Ringer's solution of 37 ℃ of preheatings
2), on the cornea lateral, put the 2ml Ringer's solution in the reception tank, add the sample of pre-metering in the supply pool respectively: dexamethasone sodium phosphate eye drop and dexamethasone nano cubic liquid crystal preparation; Begin experiment in 37 ℃ of waters bath with thermostatic control, measure the concentration of dexamethasone with HPLC from reception tank sampling 0.2ml at setting-up time point 30,60,90,120,150,180,210,240,270,300,330,420min, mend the Ringer's solution of 0.2ml37 ℃ of preheating simultaneously, to keep the diffusion cell inner volume constant.
3, result of the test
Each is organized the preparation isolated cornea and sees through result such as accompanying drawing 1.The cornea transit dose of dexamethasone nano cubic liquid crystal preparation group medicine is apparently higher than regular solution agent group, and the prompting nano cubic liquid crystal can be brought into play the effect that remarkable promotion medicine cornea sees through.
Experimental example 3 dexamethasone nano cubic liquid crystal preparation preliminarily stabilised evaluations
1, accelerated test
Dexamethasone nano cubic liquid crystal preparation according to embodiment 1 described prescription and method preparation is put in the glass cillin bottle, in temperature is 40 ℃ ± 2 ℃, relative humidity is to place 6 months in 20 ± 5% the environment, and timing sampling is checked indexs such as outward appearance, medicament contg, envelop rate, pH value and particle diameter.Its result of the test sees Table 3:
Table 3 accelerated test result
As can be seen from Table 3, under the accelerated test condition of 40 ℃ of relative humiditys 20%, temperature, placed 6 months, every indexs such as appearance character, medicament contg, envelop rate, pH value and particle diameter of dexamethasone nano cubic liquid crystal preparation of the present invention all do not take place obviously to change steady quality.
2, the room temperature test that keeps sample
Dexamethasone nano cubic liquid crystal preparation according to embodiment 1 described prescription and method preparation is put in the glass cillin bottle, in temperature is 25 ℃ ± 2 ℃, relative humidity is to place 6 months in 60 ± 10% the environment, and timing sampling is checked indexs such as outward appearance, medicament contg, envelop rate, pH value and particle diameter.Its result of the test sees Table 4:
The table 4 room temperature long-term test results that keeps sample
As can be seen from Table 4, under the approaching actual storage requirement of 25 ℃ of relative humiditys 60%, temperature, placed 6 months, every indexs such as appearance character, medicament contg, envelop rate, pH value and particle diameter of dexamethasone nano cubic liquid crystal preparation of the present invention all do not take place obviously to change steady quality.
Claims (9)
1, a kind of nano cubic liquid crystal dexamethasone preparation for eye is characterized in that, based on 1000ml eye nano cubic liquid crystal preparation, is grouped into by following one-tenth:
Dexamethasone 10～1800mg
Matrix material 5～300g
Emulsifying agent 0.25～60g
Thickening agent 0～200g
Osmotic pressure regulator is an amount of
Antibacterial 0.0～0.5g
The pH regulator agent is an amount of
Purified water adds to 1000ml
2, nano cubic liquid crystal dexamethasone preparation for eye according to claim 1 is characterized in that, described matrix material is one or more in glyceryl monooleate, phytantriol and the lecithin.
3, nano cubic liquid crystal dexamethasone preparation for eye according to claim 1 is characterized in that, described emulsifying agent is one or more in poloxamer 407 and the polyvinyl alcohol.
4, nano cubic liquid crystal dexamethasone preparation for eye according to claim 1, it is characterized in that described thickening agent is one or more in hyaluronic acid sodium, carbomer, poloxamer, hypromellose, methylcellulose, polyvinylpyrrolidone and the polyvinyl alcohol.
5, nano cubic liquid crystal dexamethasone preparation for eye according to claim 1 is characterized in that, described osmotic pressure regulator is one or more in glycerol, glucose, mannitol and the propylene glycol.
6, nano cubic liquid crystal dexamethasone preparation for eye according to claim 1 is characterized in that, described antibacterial is one or more in alkyl mercuric salt, chlorobutanol or the guanidine derivatives of quaternary ammonium salt, thiosalicylic acid.
7, nano cubic liquid crystal dexamethasone preparation for eye according to claim 1, it is characterized in that described pH regulator agent is one or more in hydrochloric acid, sodium hydroxide, phosphate, boric acid, borate, Tris, citric acid, citrate and the triethanolamine.
8, the preparation method of the described nano cubic liquid crystal dexamethasone preparation for eye of claim 1 is characterized in that may further comprise the steps: matrix material, emulsifier is even, then dexamethasone is dissolved in this mixture, and make oil phase; Get an amount of purified water as water; Oil phase is added the water emulsification pretreatment, and then use the high pressure homogenizer homogenizing, obtain the nano cubic liquid crystal preparation, the gained preparation is with the filtering with microporous membrane of 0.45 μ m.Add the aqueous solution that contains an amount of osmotic pressure regulator, antibacterial and thickening agent again,
Regulate pH value to 6～8 with the pH regulator agent at last, with purified water mend to capacity promptly.
9, the preparation method of nano cubic liquid crystal dexamethasone preparation for eye according to claim 8 is characterized in that high pressure homogenize pressure is more than or equal to 200 crust.
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Application publication date: 20090812 |