CN1850062A - Fatty acid eye nano preparations for dry eye disease - Google Patents
Fatty acid eye nano preparations for dry eye disease Download PDFInfo
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- CN1850062A CN1850062A CNA2006100384952A CN200610038495A CN1850062A CN 1850062 A CN1850062 A CN 1850062A CN A2006100384952 A CNA2006100384952 A CN A2006100384952A CN 200610038495 A CN200610038495 A CN 200610038495A CN 1850062 A CN1850062 A CN 1850062A
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Abstract
The present invention relates to a nano emulsion for curing xerophthalmia and related diseases. The described emulsion composition includes fatty acid, emulsifier and water. Said invention also provides its preparation method.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that is used for the treatment of xerophthalmia and relevant disease thereof, and the application in the treatment xerophthalmia.Particularly, the present invention relates to a kind of fatty acid or derivatives thereof of the 0.0001-50 of containing weight portion, the pharmaceutical composition of analog, and the application aspect treatment of dry eye.
Background technology
" xerophthalmia " the generation eye is shown the general name of one group of disease of epithelial lesion by the tear film that lacrimal secretion reduces, evaporation is too fast or pathologic tear film causes is unusual.Clinically, its pathogeny is varied, and owing to generally there is not the definite diagnosis cause of disease, therefore think that at present xerophthalmia is not only a kind of single disease, but a class is commonly referred to as the eye surface diseases of dry eye syndrome.
Still needleless is to the treatment means of the concrete cause of disease in the treatment of xerophthalmia at present, and what carry out only is to alleviate discomfort, smooth eye surface is provided, to prevent that the cornea structure infringement from being the symptomatic treatment of purpose.Present stage, adopting artificial tear preparation to come the Therapeutic Method of mitigation symptoms is the main means of treatment xerophthalmia.
The outermost layer of people's tear liquid is an oil layer.Although this layer lipid layer is very thin, has the effect in lower eyelid gap in the sealing in preventing tear liquid evaporation, prevent foreign body, sterilize, make eyeball surface to keep a level and smooth optical flat and closing one's eyes process in the long period.The shortage of lipid or be one of reason that causes dry eye syndrome unusually in the tear is set up stable tear layer and is helped the alleviating dry eye symptom.Fatty acid or derivatives thereof, the contained oils and fats of analog can be used for stablizing the tear film, thereby keep the moisture of tear film.
At present, existing polarity fat, non-polar lipid, lipoprotein and be used for the report of treatment of dry eye through the fat of chemical modification in the prior art.
What use in the xerophthalmia medicine is the bioactive fat of tool.For example, gonadal hormone and derivant thereof and analog are used for alleviating dry eye syndrome (EP 0652754 A1, US 6096733 A); 2, the 4-pentadienoic acid derivates has class xanthoplane activity (EP 0848696 B1).The Gilbard of U.S. Advanced Vision Research has declared two parts by the edible patent that is rich in oil (for example fish oil) health product of ω-3 with the treatment xerophthalmia, and its open time was respectively 2004 and 2005.In addition, the patent that Troyer and Spencer are are accepting also relates to the oral ω of containing-3 and ω-6 fatty acid, vitamin and water soluble antioxidant etc. in order to the treatment xerophthalmia, and its open time was respectively 2002 and 2004.Many disclosed patents all relate to uses eicosapentaenoic acid (EPA) and derivant and analog, 12-HETE phospholipid thereof to treat xerophthalmia.Eicosapentaenoic acid is a kind of omega-fatty acid that is rich in the fish oil, can change into the knob Ke Chun B5 (LTB5) of antiinflammatory intermediate product PGE3 (PEG3) and antiinflammatory.U.S. Pat 6846499 B2 are patents that portion relates to Jojoba oil treatment xerophthalmia.Biolipid, the WO 2005067892 A1 patents that the Tseng of Inc. declares relate to C
12-C
24Medium chain or long-chain fatty acid, C
10-C
24Fatty acid and C
10-C
20Cholesteryl ester or C that alcohol constitutes
10-C
20Fatty acid and C
20-C
34The fat ointment that the cholesteryl ester that alcohol constitutes, glycerol are formed.
The fat of chemical modification also is widely used in the treatment of xerophthalmia.It is the pharmaceutical composition of surfactant that the patent that Weimer of Alcon Universal Ltd. and Gamache declare relates to the polyoxyethylene castor oil.
Although these methods have obtained certain success, but because the lipid layer thickness of normal tear film only is about 0.1 μ m, and at present on the market xerophthalmia therapeutic agent often only is conceived to replenish the unusual fat layer that lacks in the xerophthalmia patient tear film, attempts to reach the evaporation that reduces tear.But thicker lipid layer and tear itself exists dilution and flushing action to medicine, makes medicine be difficult to rest on surface of tear-film for a long time, thereby reduced the curative effect of medicine.Therefore, how prolong drug has just become a difficult problem and breach in the present xerophthalmia treatment in the time of staying of surface of tear-film.
Summary of the invention
The object of the invention is to provide the pharmaceutical composition and the application thereof of fatty acids, derivative of fatty acid or the analog of a kind of prevention that is used for xerophthalmia and treatment.
Another object of the present invention provides a kind of method of the present invention, that pharmaceutical composition that the time of staying obviously prolongs is treated xerophthalmia that adopts.
Concrete, pharmaceutical composition of the present invention is the composition of recoverable tear liquid and tear film not only,, improve the stability of tear film by contained lipid, reduce losing unusually of xerophthalmia human eye moisture, keep competent tear liquid.More particularly, because pharmaceutical emulsion prescription of the present invention is unique, employing nanotechnology preparation, its greasy particle diameter is between the 10-100 nanometer, thereby with respect to commercially available medicament, oil layer wherein can be detained the longer time at surface of tear-film, thereby better reduces the evaporation of tear, alleviating dry eye symptom.
Technical scheme of the present invention is: nanotechnology (CN 1720900 A that adopt Jesse's medicine, open day is on January 8th, 2006) prepared the nano-emulsion of the fatty acids, derivative of fatty acid or the analog that are specifically designed to xerophthalmia, the mean diameter of its oil phase is between 1-500nm, preferable between 10-100nm, best between 10-30nm.
The invention provides a kind of oil-in-water type nano-emulsion that is used for the treatment of xerophthalmia, this Emulsion contains following composition:
(a) fatty acid of 0.0001-50 weight portion, derivative of fatty acid or analog;
(b) emulsifying agent of 5-300 weight portion, described emulsifying agent is selected from down group:
(b1) be selected from down the chemical compound of organizing: VE succinic acid macrogol ester, Polyethylene Glycol, polyethylene glycol monolaurate, polyoxyethylene poly-oxygen propylene aether block polymer poloxamer, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hyaluronic acid, polyvinylpyrrolidone, polyvinyl alcohol, glyceryl monooleate, acetoglyceride;
(b2) phospholipid: lecithin, soybean phospholipid, synthetic phospholipid;
(b3) at least two kinds of mixture that emulsifying agent constitutes by (b1) and (b2);
(c) water of 500-1500 weight portion;
And the mean diameter of breast grain is between 1-500nm in the Emulsion.
In another preference, described fatty acid, derivative of fatty acid or analog are selected from down group:
(i) eicosapentaenoic acid (EPA), docosahexenoic acid (DHA), linoleic acid, dimerized linoleic acid, arachidonic acid, α-linoleic acid or its salt, fat, ester, amine;
(ii) vitamin E, vitamin A, phylloxanthin (Lutein), zeaxanthin (Zeaxanthin), prostaglandin (PGE) or its salt, fat, ester, amine;
(iii) at least two kinds of mixture that fatty acid, derivative of fatty acid or analog constitute by (i) and (ii).
In another preference, described emulsifying agent is VE succinic acid macrogol ester, hydroxypropyl methylcellulose, Pluronic F-127, the sodium carboxymethyl cellulose of 30-130 weight portion.
In another preference, described fatty acid, derivative of fatty acid or analog are eicosapentaenoic acid, docosahexenoic acid, vitamin E, vitamin A, phylloxanthin, the zeaxanthins of 0.001-20 weight portion; Described emulsifying agent is VE succinic acid macrogol ester, hypromellose 2910, poloxamer F-127, low-viscosity Carboxymethyl cellulose sodium.
In another preference, this Emulsion also contains the additive of following group of being selected from of 1-200 weight portion: the antiseptic of isoosmotic adjusting agent, pH regulator agent, cosolvent, trace element, 0-50 weight portion.
In another preference, described isoosmotic adjusting agent is selected from following group: glycerol, sodium chloride, potassium chloride, ethylene glycol, propylene glycol, glucose, maltose, maltodextrin or its combination.
Described pH regulator agent is selected from but is not limited only to down group: sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium hydroxide, potassium hydroxide, hydrochloric acid.
Described antiseptic is selected from but is not limited to down group: benzalkonium chloride, benzalkonium bromide, sorbic acid, disodium edetate or the two combination.
Described cosolvent is alpha-tocopherol and/or alpha-tocopherol acetate.
Described trace element is zinc, copper, selenium, manganese, chromium, magnesium, ferrum.
In another preference, the mean diameter of oil phase is between 10-100nm in the Emulsion.
In another preference, the mean diameter of oil phase is between 10-30nm in the Emulsion.
In another preference, described Emulsion is eye drop.
Described Emulsion also can be used as other local applications, as ear drop.
Description of drawings
Fig. 1 has shown the particle size distribution situation of oil phase among the nano-emulsion embodiment in the embodiment of the invention 1.Abscissa is a particle diameter, and unit is (nm), and vertical coordinate is a percent by volume.
The specific embodiment
The inventor on the basis of a large amount of experiments, by the choose reasonable to emulsifying agent, has prepared the nano-emulsion that contains fatty acid, derivative of fatty acid or analog that a kind of effectively prolong drug stops at surface of tear-film through extensive and deep research.Its particle size distribution of medicinal Emulsion of the present invention is even, is a kind of medicinal Emulsion of stable oil-in-water type.
Pharmaceutical composition of the present invention is a kind of Emulsion that contains fatty acid, derivative of fatty acid or analog and correlative, and its composition mainly comprises: (a) fatty acid, derivative of fatty acid or analog; (b) emulsifying agent; (c) water.
Fatty acid, derivative of fatty acid or analog: being used for fatty acid of the present invention, derivative of fatty acid or analog can make from the natural goods extraction, also can be to be raw material, make through synthetic with the prodrug of being accepted in the nontoxic pharmaceuticals industry.Fatty acid, derivative of fatty acid or analog can be one or more:
(i) eicosapentaenoic acid (EPA), docosahexenoic acid (DHA), linoleic acid, dimerized linoleic acid, arachidonic acid, α-linoleic acid or its salt, fat, ester, amine;
(ii) vitamin E, vitamin A, phylloxanthin (Lutein), zeaxanthin (Zeaxanthin), prostaglandin (PGE) or its salt, fat, ester, amine;
(iii) by (i) and the (ii) mixture that constitute of at least two kinds of fatty acids, derivative of fatty acid or analog.
Wherein, the consumption of fatty acid, derivative of fatty acid or analog is the 0.0001-50 weight portion, more preferably is the 0.001-20 weight portion.
In final Emulsion, the total concentration of fatty acid, derivative of fatty acid or analog is 0.01mg/g-10.0mg/g normally, wherein preferable range 0.1mg/g-1.0mg/g.
Emulsifying agent: in pharmaceutical composition of the present invention, play emulsification.Emulsifying agent is owing to have a hydrophilic and oleophilic gene simultaneously, thus can disperse to be enclosed in fatty acid, derivative of fatty acid or analog around, and then hinder the coalescent again of fatty acid, derivative of fatty acid or analog.Emulsifying agent can be the chemical compound of following group of being selected from of one or more:
1, VE succinic acid macrogol ester, Polyethylene Glycol, polyethylene glycol monolaurate, polyoxyethylene poly-oxygen propylene aether block polymer poloxamer, hydroxypropyl methylcellulose sodium, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hyaluronic acid, polyvinylpyrrolidone, polyvinyl alcohol, glyceryl monooleate, acetoglyceride;
2, phospholipid: comprise the phospholipid of tissues such as being derived from egg yolk, Semen sojae atricolor, cattle, pig, as lecithin, soybean phospholipid etc.; Can also comprise the phospholipid that obtains with synthesis mode, as phospholipid.
Wherein, preferably VE succinic acid macrogol ester, poloxamer F-127, hypromellose 2910.
The consumption of emulsifying agent is generally the 5-300 weight portion, and better is the 30-130 weight portion.In final Emulsion, the concentration of emulsifying agent is 5mg/g-300mg/g normally, wherein preferable range 30mg/g-130mg/g.
Water: water is solvent of the present invention, can form successive water in Emulsion.Can be used for water of the present invention and have no particular limits, can be pure water, distilled water or water for injection, also can be normal saline.
Optional additive: Emulsion prescription of the present invention can add the normal additive that uses in this area, as isoosmotic adjusting agent, pH regulator agent, cosolvent, antiseptic, antioxidant, correctives etc.
PH regulator agent: the pH value of regulating product.Can be salt such as phosphate, carbonate, citrate, tartrate; Can also be alkali such as sodium hydroxide, potassium hydroxide; Also can be acid such as hydrochloric acid, glycine, lysine.
Isoosmotic adjusting agent: regulate the osmotic pressure of product, so that the osmotic pressure of product is close with the human body osmotic pressure or equate.It can be glycerol, sodium chloride, potassium chloride, ethylene glycol, propylene glycol, glucose, maltose, maltodextrin or its combination.Wherein, preferably glycerol, sodium chloride, potassium chloride.
Antiseptic: suppress bacterial reproduction, go bad because of the microbial contamination of chance to prevent product.Can be benzalkonium chloride, benzalkonium bromide, sorbic acid, disodium edetate or the combination of the two.
The preparation method of Emulsion
Under nitrogen protection, the VE succinic acid macrogol ester is heated to 50～55 ℃ of fusings by concrete formula proportion; add docosahexenoic acid (and/or vitamin A, eicosapentaenoic acid, vitamin E, beta-carotene, phylloxanthin, zeaxanthin) and glycerol; mix homogeneously; be heated to 50～55 ℃; add the warm poloxamer F-127 of fusing in advance while stirring, ultrasonic 10 minutes.In another container, add about 100g60～70 ℃ water recently distilled, under shearing blender (IKA T18 Ultra Tberrax) stirs, slowly add benzalkonium chloride, sodium hydrogen phosphate, potassium dihydrogen phosphate and sodium chloride, continue to stir.After treating that institute adds the whole dissolvings of material, oil phase is slowly added water with wire, continue to stir 10 minutes.Gained Emulsion filters the back branch with filter and is filled in the eye drop bottle of sterilization through moist heat sterilization, adds a cover.(further details can be referring to CN 1720900 A, and open day is on January 8th, 2006).
The Emulsion mean diameter is measured
(Malvern UK) measures the mean diameter that obtains concrete Emulsion for Mastersizer S, Malvern Instruments Ltd. to use light scattering particle size determination instrument.
Preliminarily stabilised investigation experiment
Get the Emulsion of the present invention after the sterilization, be sub-packed in the 5ml cillin bottle, 15 bottles every batch.Room temperature is placed, and sample appearance, the color and luster observed respectively the 0th, 1,3,6,12,18 month change.The sample appearance, color and luster that experimental result shows preparation among embodiment 1, embodiment 2, embodiment 4, embodiment 5 and the embodiment 7 equal no change in 18 months experiment periods still is the liquid of clarification, transparent, homogeneous.(concrete experimental technique can be referring to LeonLachman, The Theory and Practice of Industry Pharmacy, 3rd Ed, 760-803, LEA﹠amp; Febiger, Philadelphia, USA, 1986)
The experiment of tear film integrality
The curative effect that this experiment finally comes comparative control thing and sample of the present invention by reference substance and sample tear film surface detention time relative value.(concrete experimental technique can further referring to " All in the blink of aneye ", Review of Ophthalmology, 82-85, March, 2002)
(1) interval (the inter-blink interval in a short time, IBI) mensuration: to select the xerophthalmia patients of making a definite diagnosis some at every turn, at controlled (the Controlled AdverseEnvironment of poor environment, CAE) (relative humidity is less than 5% for indoor, temperature 21-28 ℃, laminar-flow air, fully illumination, television set or computer are arranged) use ET-220LH camera photography and the eye imaging after another indoor Real Time Observation is amplified, be capped 95% as once blinking with pupil, write down the interval in a short time.
(2) medicine is in the mensuration of the holdup time on tear film surface: experiment divides matched group and test group, every group of six to ten patients.During experiment, at first measure all experimenters' interval in a short time, as basis interval IBI (0) in a short time.Then by different groups, give control sample (eye drop of present commercially available treatment xerophthalmia best results is the Refresh of U.S. Allergan company, in the test in contrast) and test specimen respectively with it.After the administration, an IBI value was measured in timing immediately later on every 5 minutes.When measuring for the n time, find IBI (n)=IBI (0), then off-test (in the whole mensuration process, the experimenter puts on earphone and watches TV).Medicine in holdup time=5 on tear film surface * (n-1).
(3) sample is in tear film surface detention time relative value's calculating: with reference substance (Refresh) holdup time on tear film surface as 100, sample tear film surface detention time relative value=(sample tear film surface the holdup time/to impinging upon the holdup time on tear film surface) * 100.
Beneficial effect compared with prior art: 1, tear film integrality experimental result shows: with respect to commercially available long-acting xerophthalmia agent, pharmaceutical composition of the present invention can effectively prolong the time that is stranded in tear film surface, thus alleviating dry eye symptom better.2, owing to adopt nanotechnology to prepare Emulsion of the present invention, so the particle diameter of oil phase is in nanometer range, the Emulsion particle diameter that obtains less than prior art.3, because Emulsion of the present invention breast grain is little, particularly particle diameter is between the Emulsion of 10-100nm, so solution is not only transparent, and stable, and the holding time is long.4, tear film integrality experimental result shows, Emulsion of the present invention has obviously improved the stability of tear films.
Pharmaceutical composition provided by the invention can effectively be treated xerophthalmia, and described pharmaceutical composition can also contain all suitable additives that adopted in the fish oil of effective dose or its component or its component derivant, analog and other pharmaceuticals industries.Consummate drug manufacture technology comprises uses the extraction from natural goods nontoxic, that pharmaceuticals industry is accepted or fish oil, its component, component derivant and/or the analog of synthetic.Be in conjunction with specific embodiments below, further set forth the present invention.Should be appreciated that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Unreceipted actual conditions and experimental technique among the embodiment, usually according to normal condition, or the condition of advising according to manufacturer.
According to preparation method mentioned above, according to following formulation Emulsion 1.
| Component | Weight (g) |
| DHA (DHA) VE succinic acid macrogol ester glycerine poloxamer F-127 benzalkonium chloride sodium hydrogen phosphate potassium dihydrogen phosphate sodium chloride water | 0.1 1.0 0.5 1.0 0.001 0.223 0.012 0.3 add to 100g |
Use light scattering particle size determination instrument (Mastersizer S, Malvern Instruments Ltd., Malvern, UK) measuring the mean diameter that obtains this Emulsion is 26nm.
Clinical effectiveness and discussion:
Example 1 has only been used a kind of component of fatty acid, derivative of fatty acid or analog.Although the prescription less complex, tear film integrality experimental result shows: this prescription surpasses commercially available long-acting xerophthalmia preparation in the holdup time on tear film surface, can more effective relief of symptoms.
| The test prescription | Medicine is at the relative ratio of tear film holdup time |
| Refresh (U.S. Allergan company) | 100 |
| | 220 |
Embodiment 2
According to preparation method mentioned above, according to following formulation Emulsion 2.
| Component | Weight (g) |
| Eicosapentaenoic acid (EPA) VE succinic acid macrogol ester glycerine poloxamer F-127 benzalkonium chloride sodium hydrogen phosphate potassium dihydrogen phosphate | 0.1 1.0 0.5 1.0 0.001 0.223 0.012 |
| Sodium chloride water | 0.3 add to 100g |
Use light scattering particle size determination instrument (Mastersizer S, Malvern Instruments Ltd., Malvern, UK) measuring the mean diameter that obtains this Emulsion is 28nm.
Clinical effectiveness and discussion: example 2 has also only been used a kind of component of fatty acid, derivative of fatty acid or analog.Although the prescription less complex, tear film integrality experimental result shows: this prescription surpasses commercially available long-acting xerophthalmia preparation in the holdup time on tear film surface, can more effective relief of symptoms.
| The test prescription | Medicine is at the relative ratio of tear film holdup time |
| Refresh (U.S. Allergan company) | 100 |
| Embodiment 2 Emulsions | 225 |
Embodiment 3
According to preparation method mentioned above, according to following formulation Emulsion 3.
| Component | Weight (g) |
| Vitamin A vitamin E vitamin(e) C palmitate zinc gluconate VE succinic acid macrogol ester poloxamer F-127 sodium hydrogen phosphate potassium dihydrogen phosphate sodium chloride water | 0.05 0.05 0.025 0.02 1.0 1.0 0.223 0.012 0.3 adds to 100g |
Clinical effectiveness and discussion: example 3 has been used vitamin A and vitamin E.The structure of vitamin E and surfactant structure have similar part.Tear film integrality experimental result shows: this prescription surpasses commercially available long-acting xerophthalmia preparation in the holdup time on tear film surface, can more effective relief of symptoms.
| The test prescription | Medicine is at the relative ratio of tear film holdup time |
| Refresh (U.S. Allergan company) | 100 |
| Embodiment 3 Emulsions | 260 |
Embodiment 4
According to preparation method mentioned above, according to following formulation Emulsion 4.
| Component | Weight (g) |
| Docosahexenoic acid (DHA) VE succinic acid macrogol ester vitamin E glycerol poloxamer F-127 benzalkonium chloride | 0.05 0.5 0.05 0.5 2.0 0.001 |
| Sodium hydrogen phosphate potassium dihydrogen phosphate sodium chloride water | 0.223 0.012 0.3 adds to 100g |
Use light scattering particle size determination instrument (Mastersizer S, Malvern Instruments Ltd., Malvern, UK) measuring the mean diameter that obtains this Emulsion is 27nm.
Clinical effectiveness and discussion: example 4 is improved prescriptions on example 1 and example 3 bases.Owing to use docosahexenoic acid (DHA) simultaneously and the vitamin E of similar part arranged, further prolonged the tear film holdup time with surfactant structure.Tear film integrality experimental result shows: this prescription far surpasses commercially available long-acting xerophthalmia preparation in the holdup time on tear film surface, and is effective especially to relief of symptoms.
| The test prescription | Medicine is at the relative ratio of tear film holdup time |
| Refresh (U.S. Allergan company) | 100 |
| Embodiment 4 Emulsions | 600 |
According to preparation method mentioned above, according to following formulation Emulsion 5.
| Component | Weight (g) |
| Eicosapentaenoic acid (EPA) VE succinic acid macrogol ester vitamin E glycerine poloxamer F-127 benzalkonium chloride sodium hydrogen phosphate potassium dihydrogen phosphate sodium chloride water | 0.05 0.3 0.05 0.5 1.0 0.001 0.225 0.012 0.3 add to 100g |
Use light scattering particle size determination instrument (Mastersizer S, Malvern Instruments Ltd., Malvern, UK) measuring the mean diameter that obtains this Emulsion is 29nm.
Clinical effectiveness and discussion: example 5 also is the improvement prescription on example 2 and example 3 bases.Owing to use eicosapentaenoic acid (EPA) simultaneously and the vitamin E of similar part arranged, further prolonged the tear film holdup time with surfactant structure.Tear film integrality experimental result shows: this prescription far surpasses commercially available long-acting xerophthalmia preparation in the holdup time on tear film surface, and is effective especially to relief of symptoms.
| The test prescription | Medicine is at the relative ratio of tear film holdup time |
| Refresh (U.S. Allergan company) | 100 |
| | 625 |
Embodiment 6
According to preparation method mentioned above, according to following formulation Emulsion 6.
| Component | Weight (g) |
| Eicosapentaenoic acid (EPA) vitamin E beta carotene vitamin(e) C palmitate lutein luteole zinc sulfate VE succinic acid macrogol ester poloxamer F-127 sodium hydrogen phosphate potassium dihydrogen phosphate sodium chloride water | 0.05 0.05 0.25mg, 0.075 0.5mg 0.1mg 0.02 1.0 1.0 0.223 0.012 0.3 adds to 100g |
Clinical effectiveness and discussion: compare with example 5, example 6 has further increased beta-carotene, phylloxanthin and zeaxanthin and trace element zinc sulfate, tear film integrality experimental result shows: this prescription surpasses commercially available long-acting xerophthalmia preparation in the holdup time on tear film surface, and is effective especially to relief of symptoms.
| The test prescription | Medicine is at the relative ratio of tear film holdup time |
| Refresh (U.S. Allergan company) | 100 |
| Embodiment 6 Emulsions | 640 |
Embodiment 7
According to preparation method mentioned above, according to following formulation Emulsion 7.
| Component | Weight (g) |
| DHA (DHA) eicosapentaenoic acid (EPA) VE succinic acid macrogol ester glycerine poloxamer F-127 benzalkonium chloride sodium hydrogen phosphate potassium dihydrogen phosphate sodium chloride water | 0.025 0.025 0.3 0.5 1.0 0.001 0.225 0.012 0.3 adds to 100g |
Use light scattering particle size determination instrument (Mastersizer S, Malvern Instruments Ltd., Malvern, UK) measuring the mean diameter that obtains this Emulsion is 26nm.
Clinical effectiveness and discussion: example 7 prescriptions use docosahexenoic acid (DHA) and eicosapentaenoic acid (EPA) simultaneously, and tear film integrality experimental result shows: this prescription holdup time within the eye is 7.5 times of reference product ophthalmic holdup time.This shows that the prescription of being made up of docosahexenoic acid (DHA) and eicosapentaenoic acid (EPA) has not only significantly increased the stability of tear films, also may obviously improve the uniformity of tear film.
| The test prescription | Medicine is at the relative ratio of tear film holdup time |
| Refresh (U.S. Allergan company) | 100 |
| Embodiment 7 Emulsions | 750 |
Embodiment 8
According to preparation method mentioned above, according to following formulation Emulsion 8.
| Component | Weight (g) |
| DHA (DHA) eicosapentaenoic acid (EPA) VE succinic acid macrogol ester poloxamer F-127 hydroxypropyl methylcellulose (HPMC) vitamin E glycerine benzene first chloramines sodium hydrogen phosphate potassium dihydrogen phosphate sodium chloride water | 0.025 0.025 1.0 1.0 0.3 0.05 0.5 0.001 0.223 0.012 0.2 adds to 100g |
Clinical effectiveness and discussion: example 8 prescriptions use DHA and EPA simultaneously, have increased vitamin E and hydroxypropyl emthylcellulose simultaneously again.Tear film integrality experimental result shows: this prescription holdup time within the eye is long more than the reference product ophthalmic holdup time, and doing well,improving is obvious.
| The test prescription | Medicine is at the relative ratio of tear film holdup time |
| Refresh (U.S. Allergan company) | 100 |
| Embodiment 8 Emulsions | 710 |
Embodiment 9
According to preparation method mentioned above, according to following formulation Emulsion 9.
| Component | Weight (g) |
| DHA (DHA) eicosapentaenoic acid (EPA) vitamin E vitamin A lutein luteole VE succinic acid macrogol ester poloxamer F-127 glycerine benzalkonium chloride | 0.05 0.05 0.05 0.25mg 0.5mg 0.1mg 1.0 1.0 0.5 0.001 |
| Sodium hydrogen phosphate potassium dihydrogen phosphate sodium chloride water | 0.223 0.012 0.3 adds to 100g |
Clinical effectiveness and discussion: example 9 prescriptions use docosahexenoic acid (DHA) and eicosapentaenoic acid (EPA) simultaneously, have increased vitamin E, vitamin A, phylloxanthin and zeaxanthin again.Tear film integrality experimental result shows: the holdup time comparison within the eye of this prescription is long according to the product ophthalmic holdup time, and effect is obvious especially.
| The test prescription | Medicine is at the relative ratio of tear film holdup time |
| Refresh (U.S. Allergan company) | 100 |
| Embodiment 9 Emulsions | 725 |
The list of references that following additional copy literary composition is quoted, its in full mode be incorporated herein by reference.
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15.Roshantha A.Chandraratna(Allergan)“Phenyl or heternaryl and tetrahydronaphthyl substituteddiene activity”US5607135A
16.Thomas Glonek，Jack V.Greiner，Donald R.Korb，“Dry eye treatment process andsolution”，US5578586
17.Donald R.Korb，Thomas Glonek，“Dry eye treatment process and solution”，US5371108
18.Thomas Glonek，Jack V.Greiner，Donald R.Korb，“Dry eye treatment process andsolution”，US5294607
19.Thomas Glonek，Jack V.Greiner，Donald R.Korb，“Dry eye treatment solution andmethod”，US4914088
20.Thomas Glonek，Donald R.Korb，Jack V.Greiner，“Dry eye treatment composition”EP0459148B1
21.Donald R.Korb，Thomas Glonek，“Treatment and solution for dry eye”，JP07002647A
Claims (14)
1, a kind of oil-in-water type nano-emulsion that is used for the treatment of xerophthalmia and relevant disease thereof is characterized in that described Emulsion contains following composition:
(a) fatty acid of 0.0001-50 weight portion, derivative of fatty acid and analog thereof;
(b) emulsifying agent of 5-300 weight portion, described emulsifying agent are selected from following group:
(b1) VE succinic acid macrogol ester, Polyethylene Glycol, polyethylene glycol monolaurate, polyoxyethylene poly-oxygen propylene aether block polymer poloxamer, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hyaluronic acid, polyvinylpyrrolidone, polyvinyl alcohol, glyceryl monooleate, acetoglyceride;
(b2) phospholipid: lecithin, soybean phospholipid, synthetic phospholipid;
(b3) at least two kinds of mixture that emulsifying agent constitutes by (b1) and (b2);
(c) water of 500～1500 weight portions.
2, oil-in-water type nano-emulsion as claimed in claim 1 is characterized in that, described fatty acid, derivative of fatty acid and analog thereof are selected from following group:
(i) eicosapentaenoic acid EPA, docosahexenoic acid DHA, linoleic acid, dimerized linoleic acid, arachidonic acid, α-linoleic acid, its salt, fat, ester, amine;
(ii) vitamin E, vitamin A, phylloxanthin, zeaxanthin, prostaglandin or its salt, fat, ester, amine;
The (iii) mixture that at least two kinds of fatty acids or derivative of fatty acid and analog thereof constitute by (i) and (ii).
3, nano-emulsion as claimed in claim 1 is characterized in that:
(a) described fatty acid, derivative of fatty acid and analog thereof are preferably eicosapentaenoic acid or docosahexenoic acid or vitamin E or vitamin A or phylloxanthin or zeaxanthin or its combination of 0.001-20 weight portion;
(b) described emulsifying agent is preferably VE succinic acid macrogol ester or hydroxypropyl methylcellulose or poloxamer F-127 or low-viscosity sodium carboxymethyl cellulose or its combination of 30-130 weight portion.
4, nano-emulsion as claimed in claim 1 is characterized in that, this Emulsion also contains the additive of following group of being selected from of 1-200 weight portion: isoosmotic adjusting agent, pH regulator agent, cosolvent, trace element, antiseptic.
5, nano-emulsion as claimed in claim 4 is characterized in that, described isoosmotic adjusting agent is selected from down group: glycerol, sodium chloride, potassium chloride, ethylene glycol, propylene glycol, glucose, maltose, maltodextrin or its combination.
6, nano-emulsion as claimed in claim 4 is characterized in that, described pH regulator agent is selected from down group: sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium hydroxide, potassium hydroxide, hydrochloric acid.
7, nano-emulsion as claimed in claim 4 is characterized in that, described antiseptic is selected from down group: benzalkonium chloride, benzalkonium bromide, sorbic acid, disodium edetate or the two combination.
8, nano-emulsion as claimed in claim 4 is characterized in that, described cosolvent is alpha-tocopherol and/or alpha-tocopherol acetate.
9, nano-emulsion as claimed in claim 4 is characterized in that, described trace element is selected from down group: zinc, copper, selenium, manganese, chromium, magnesium, ferrum.
10, nano-emulsion as claimed in claim 1 is characterized in that, the mean diameter of oil phase is between 1-500nm in the Emulsion.
11, nano-emulsion as claimed in claim 1 is characterized in that, the mean diameter of oil phase is between 10-100nm in the Emulsion.
12, nano-emulsion as claimed in claim 1 is characterized in that, the mean diameter of oil phase is between 10-30nm in the Emulsion.
13, nano-emulsion as claimed in claim 1 is characterized in that, described Emulsion is local application, as eye drop or ear drop etc.
14, be used for the treatment of application in the medicine of xerophthalmia and relevant disease thereof as any described nano-emulsion in the claim 1 to 13 in preparation.
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| CN2006100384952A CN1850062B (en) | 2006-02-24 | 2006-02-24 | Fatty acid eye nano preparations for dry eye disease |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2006100384952A CN1850062B (en) | 2006-02-24 | 2006-02-24 | Fatty acid eye nano preparations for dry eye disease |
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| CN1850062A true CN1850062A (en) | 2006-10-25 |
| CN1850062B CN1850062B (en) | 2010-11-03 |
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| CN2006100384952A Expired - Fee Related CN1850062B (en) | 2006-02-24 | 2006-02-24 | Fatty acid eye nano preparations for dry eye disease |
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| CN106420454A (en) * | 2016-09-28 | 2017-02-22 | 北京瑞济善健康科技有限公司 | Composition for alleviating dry eyes and visual fatigue, preparation method and application of composition, and roll applicator |
| CN106692187A (en) * | 2015-11-16 | 2017-05-24 | 浙江医药股份有限公司新昌制药厂 | Composition for improving visuognosis persistence and protecting eye health |
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| CN106963728A (en) * | 2016-01-13 | 2017-07-21 | 汤欣 | A kind of preparation method and applications of docosahexaenoic acid subconjunctival injection liquid |
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| CN106420454B (en) * | 2016-09-28 | 2019-02-22 | 北京瑞济善健康科技有限公司 | Composition for alleviating xerophthalmia and visual fatigue and its preparation method and application and ballpoint applicator |
| JP2020508695A (en) * | 2017-01-20 | 2020-03-26 | ジャージャン メディスン カンパニー リミテッド シンチョン ファーマシューティカル ファクトリー | Stable fat-soluble active ingredient composition, microcapsule and method for producing the same and application |
| CN107137379A (en) * | 2017-04-21 | 2017-09-08 | 武汉理工大学 | Natural hydrophilic gel loads the preparation method of nanometer xanthophyll composite membrane |
| CN107137379B (en) * | 2017-04-21 | 2020-01-31 | 武汉理工大学 | Preparation method of natural hydrophilic gel loaded nanocrystallized lutein composite membrane |
| CN109820825A (en) * | 2017-11-23 | 2019-05-31 | 河北嘉硕生物科技有限公司 | It is a kind of for treating the pharmaceutical composition of eye disease |
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