CN104771354B - For the ophthalmically acceptable pharmaceutical preparation based on non-polar and polar lipid - Google Patents

For the ophthalmically acceptable pharmaceutical preparation based on non-polar and polar lipid Download PDF

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CN104771354B
CN104771354B CN201510119588.7A CN201510119588A CN104771354B CN 104771354 B CN104771354 B CN 104771354B CN 201510119588 A CN201510119588 A CN 201510119588A CN 104771354 B CN104771354 B CN 104771354B
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oil
pharmaceutical composition
acid
emulsion
water
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CN104771354A (en
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玛丽亚·格拉齐亚·马佐内
瓦莱里娅·玛丽亚·卡尔梅拉·莫斯凯蒂
福斯托·朱塞佩·米亚诺
格拉索 莱蒂齐娅·加埃塔纳·洛
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Abstract

The present invention relates to for the ophthalmically acceptable pharmaceutical preparation based on non-polar and polar lipid, including emulsifying the phospholipid composition being made of natural zwitterionic phospholipid and the oil components being made of natural oil in water.Especially, the present invention relates to eye-drops preparations, it can be used for for example delivering drugs to eye and for treating xerophthalmia scheorma, the lipid layer of tear film can be restored.Especially, in non-transitory but under pathological conditions, such as dry eye syndrome, such preparation also can successfully reduce ever-present inflammatory component.

Description

For the ophthalmically acceptable pharmaceutical preparation based on non-polar and polar lipid
The application be the applying date be on December 24th, 2007 it is entitled " for ophthalmically acceptable based on non-polar and polar lipid The divisional application of the Chinese patent application No.200780052387.3 of pharmaceutical preparation "
Technical field
The present invention relates to for the ophthalmically acceptable pharmaceutical preparation based on lipid.Especially, the present invention relates to can be used for for example to Drug is transported to eye and the eye-drops preparations for treating xerophthalmia scheorma, because they can restore the lipid layer of tear film.Especially It is that in non-transitory but under pathological conditions, such as dry eye syndrome, such preparation also can successfully reduce ever-present inflammation Property ingredient (inflammatory component).
Background technique
It is known that the function of tear film is to maintain, ocular surface is wet, and protecting cornea and conjunctival epithelium and transporting can be used for eye The bioactive substance (nutrition, oxygen) of eyeball physiological function.In order to maintain the physical characteristic of an epithelium, tear film must have appropriate Surface tension (mucous layer allows the appropriate ability that extends on epithelium of water phase) and there must be physiology evaporation rate.These property The change of energy determines the generation and possible dry eye syndrome of xerophthalmia scheorma.
Tear film substantially consists of three layers.First layer is attached to eye surface (cornea, conjunctiva) and mainly by mucoprotein structure At；Middle layer is substantially made of the aqueous solution comprising ion, protein etc.；Third layer (contacting with air) is mainly by different spies Property non-polar and polar lipid (cholesterol, cholesteryl ester, phosphatide triglycerides, ceramide, cerebroside etc.) constitute, tool The function of avoiding middle aqueous layer (or water-bearing layer, aqueous layer) from evaporating suddenly.
In fact, such multiple layers are in dynamic equilibrium each other since eyelid blinks, this results in entirety more Add crisscross and homogeneous tear film.
One of the breaking-out of xerophthalmia scheorma and especially dry eyes the reason is that tear film water layer excessive evaporation, this is because at it Composition occur qualitative-quantitative change after outer lipid layer bad function caused by.
The polymer that ophthalmic composition in the market is included is due to that can reduce tear film with certain levels of viscosity Evaporation.
Often have using based on other of phosphatide or oil emu composition in water to restore the natural lipid layer of tear film It is reduced the function of moisture film evaporation.These compositions are for example reported in Glonek patent, in United States Patent (USP) 5,578,586.
Especially, the aforementioned patent describes a kind of specific metastable preparation (formulation), by with determine concentration and The phospholipid composition and oil components composition of ratio emulsification in water.
In pointed patent, phospholipid composition is made of electrically charged phosphatide (net positive charge or negative electrical charge), is based on group The total weight of object is closed, dosage is in the range of 0.01%-7% by weight, and oil components are made of mineral oil, is based on group The total weight of object is closed, dosage is between 0.1%-12.5% by weight.
The patent especially illustrates that this oil type for being defined as " nonpolarity ", which is preferable over, is defined as " polarity " (because of it Include a large amount of acid and/or ester group) animal or plant source oil type because the latter will cause eye-blurred and group Close the undesirable influence of object unstability (relative to synthetic oil).
It should be pointed out that about phosphatide, amphoteric ion molecule (zwitterionic molecule) such as phosphatidyl ethanol Amine and phosphatidyl choline (lecithin) are explicitly excluded except the range of United States Patent (USP) 5,578,586, because they have just Charge can offset the negative electrical charge of phosphate group in pH 7.According to the patent, negatively charged phosphatide be preferably as The negative electrical charge (passing through the light electrostatic repulsion with negatively charged eye surface) that they are assigned will promote composition in eye surface Extend.
In addition, all preparations comprising lipid that can be obtained currently on the market need to be stored under low temperature (4 DEG C), this is Since the stability of lipid components is poor, can generate at room temperature rancid.
Summary of the invention
Therefore, the technical problem for constituting present invention basis be find it is such for ophthalmically acceptable pharmaceutical composition, it is different In known composition, and it is stable and tolerance is good, furthermore can be used as active principle (active Principle carrier).Especially, composition of the invention has best effect in terms for the treatment of xerophthalmia scheorma and/or dry eyes (small-scale even (size's)).
The above problem is that pharmaceutical composition in this way solves, which includes to natural specific The selection of lipid (phosphatide and oil).In fact, it was surprisingly found that especially plant or animal come using non-polar lipid The non-polar lipid (such as soya-bean oil, olive oil, fish oil) and polar lipid in source, such as derived from yolk or the phosphatide of soybean lecithin Or the mixture of phospholipids of such as phosphatidyl choline, phosphatidyl-ethanolamine, sphingomyelins, allow to be similar to Meibomian gland (or Mai Bomu Gland, Meibomian gland) mode of (the natural lipid layer of tear) reduces the evaporation containing water section of tear film, and with than Currently there are emulsification or preparation more efficient way comprising polymer reduce such evaporation.
As will be seen that by embodiment, composition of the invention is in terms of the evaporation for efficiently reducing tear film than other groups It is more successful to close object.In addition, the preparation of other tests, the product that finds on the market cannot in conjunction with natural Meibomian gland, such as with Under described composition on the other hand.
In addition, being surprisingly observed that, numerous compositions of the invention can be effectively prevented inflammatory or change in eye level Venereal disease disease is answered, it is related or uncorrelated to dry eye condition.
Furthermore composition may be used as the carrier of active principle, and wherein active principle is used for eye diseases (glaucoma, age phase Closing property macular degeneration AMD, diabetic retinopathy, neuropathy, bacterium or virus infection etc.), and especially as in this way Substance carrier, answered with resistance and/or anti-inflammatory activity (equally unrelated with dry eyes), can be by the inherence effect of emulsion The assistance of power.
It should be noted that pharmaceutical composition can be advantageously used for due to the structure of its improvement with the ability for carrying the component The carrier of active principle, due to the therapeutic effect of above-mentioned determination itself be used as active principle and/or be used as with anti-inflammatory or Resistance answers the active principle of active active principle presentation additivity or synergistic effect.
Therefore, the first purpose of the invention is to provide be used for ophthalmically acceptable medicine group as described in the following claims Close object.
Second purpose is even to ensure the stability of the preparation at room temperature.
Third purpose is to provide the method for producing described pharmaceutical composition.
4th purpose is that the composition is being produced for treating eye diseases such as, for example, glaucoma, age related are yellow Spot is denaturalized answering in the drug of AMD, diabetic retinopathy, neuropathy, bacterium or virus infection, xerophthalmia scheorma and dry eyes With.
5th purpose be the composition treatment and dry eye syndrome or eye allergic effect illness in relation to or unrelated inflammation Application in venereal disease disease.
6th purpose includes composition as the application for being used for ophthalmically acceptable active principle carrier, and in particular for it Effect those of can be assisted by the pharmacological activity (resistance answer, anti-inflammatory) for characterizing required composition.
Detailed description of the invention
According to the description of the multiple embodiments provided referring to the drawings with non-limiting embodiment, it is of the invention in addition Feature and advantage will become apparent, wherein the stability about required composition:
Figure 1A show in relation to pH process (course) of the three kinds of preparations of the invention at 25 DEG C, during preservation into The curve graph that row compares, it illustrates pH stability at T=25 DEG C；
Figure 1B is shown in relation to being compared to the pH process of three kinds of preparations of the invention at 30 DEG C, during preservation Curve graph, it illustrates pH stability at T=30 DEG C；
Fig. 1 C is shown in relation to being compared to the pH process of three kinds of preparations of the invention at 40 DEG C, during preservation Curve graph, it illustrates pH stability at T=40 DEG C；
Fig. 2 shows the tables of the percentage composition of aliphatic ester in the triglycerides of separate sources；
Fig. 3 is shown in which that tear (tear) water layer steams compared between a variety of commodity in product of the invention, Meibomian gland The figure of the delay percentage of hair；
Fig. 4, which is shown, compares the dexamethasone sodium phosphate of various concentration about controlling in carrying out vitreum with bacteria lipopolysaccharide The figure of validity in terms of the inhibition that PGE2 (prostaglandin E2) is accumulated in the hydratoid (aqueous humour) of the rabbit for the treatment of, Show the eyes that dexamethasone sodium phosphate gives inflammation；
Fig. 5 shows different treatment (processing) the infiltration sides of PMN in rabbit conjunctiva in about surface inflammation model of comparison The figure of the validity in face, it illustrates treatments several in surface inflammation model to penetrate into the effect in rabbit conjunctiva to PMN, wherein Each cylindricality indicates the average value ± SD of 4-12 animal；
Fig. 6 be shown in which in rat body in allergic effect model to answer according to resistance validity glucocorticoid and emulsion it Between the figure that is compared, it illustrates in rat body in allergic effect model steroids compared with resistance answers effect between emulsion, Wherein * * * p ﹤ 0.001. treatment and PBS (unidirectional ANOVA adds Dunnett after test)；
Fig. 7 show glucocorticoid with carrier of the invention in ocular tissue EB (Evans blue) extravasation compared with figure, It illustrates EB to be seeped into ocular tissue outside, wherein * * * p ﹤ 0.001. treatment and 0.05 dexamethasone palmitate of PBS, ξ p ﹤ and emulsion Carrier (unidirectional ANOVA adds Bonferroni after test).
Specific embodiment
Ophthalmic composition of the invention includes the phosphatide being made of natural zwitterionic phospholipid of emulsification in water Ingredient and the oil components being made of natural oil.
Exploitation composition (purpose of the present invention) during shockingly observe, be not composition charge (by comprising Phosphatide assign) cause it in eye surface efficiently and the ability that is extended of effective means, to evaporate to reduce tear film, and It is as caused by the specific composition (according to the percentage and their inverse ratio of identity and preferred phosphatide and oil) of oily phase.
Ratio between oil components and phospholipid composition can be 4:1-1:1, preferably 3:1, and the more preferable ratio is about 2.3:1。
Generally, based on the total weight of composition, phosphatide is present in ophthalmically acceptable combination with the amount of 0.01%-7% by weight In object, preferably 0.1%-5%, more preferably between 0.3%-3%.
Especially, phospholipid composition includes the phosphatidyl gallbladder that natural zwitterionic phospholipid is such as usually 50-70% amount Alkali and other less amount of phosphatide comprising the phosphatidyl-ethanolamine of 5-20%, the sphingomyelins of 1-10%, 1-10% it is molten The neutral lipid etc. of serium inorganic phosphorus phosphatidylcholine, 2%-15% (relative to total phospholipids).For example, a kind of phosphatide including above-mentioned phosphatide at Divide available from Fresenius Kabi company, trade name is egg phosphatide 90 (Egg Phospholipid 90).
Advantageously, the stability and validity of required composition in order to further increase, in phospholipid fatty part The ester of existing fatty acid is preferably with the selection of following amount: myristic acid≤1%, palmitinic acid 20-40%, palmitoleic acid≤5%, hard Resin acid≤30%, oleic acid 20-40%, linoleic acid (LA)≤30%, eicosenoic acid≤10%, arachidonic acid (AA)≤5%, Other fatty acid of docosahexaenoic acid (DHA)≤20% and Ω -3 series.
Wherein, double bond containing fatty acid meeting stable emulsion (or emulsion, emulsion) is wrapped, antioxidation is carried out.
Oil components include substantially natural oil, such as such as soya-bean oil, olive oil, sunflower oil, fish oil, Common Borage Oil, sesame oil, hemp-seed oil, corn oil, cottonseed oil.It should be understood that oil components must only include nonpolar triglycerides form Natural oil, and exclude the oil of synthetic oil and mineral origin.
In the present specification, term nonpolarity triglycerides refers to the lipid macromolecular being made of glycerol molecule, hydroxyl Group (- OH) is esterified by three fatty acid, and wherein fatty acid, which can be, is same or different to each other.
Total weight based on composition, triglycerides are present in composition (this with the amount of 0.01%-28% by weight The purpose of invention) in, preferably 0.3%-15%, more preferably between 0.7%-7%.
As recorded in the table in fig. 2, it is observed that being different from mineral oil, in natural animal and plant oil In, with the long-chain comprising one or more double bonds fatty acid ester triglycerides be it is common, mainly have: linoleic acid C18: 2, oleic acid C18:1, palmitoleic acid C16:1, linolenic acid C18:3 and Ω -3 series fatty acid such as eicosapentaenoic acid C20: 5n3, docosenoic acid C22:6.Such oil further stabilizes composition (purpose of the present invention).
In particular, it is known that Ω -3 series fatty acid (EFA) (such as alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) with And docosenoic acid (BHA)) and the fatty acid (such as linoleic acid (LA) and arachidonic acid (AA)) of Ω -6 series be considered There is modulator effect in inflammation and immunologic process.
It is furthermore observed that advantageouslying allow for obtaining comprising the composition of above-mentioned triglycerides and phosphatide with described percentage More evenly distribution of the lipid components in eye surface is obtained, the formation of oil droplet is avoided, thus avoids covering due to the non-homogeneous of eye surface It covers and causes eye-blurred.
As recorded above, the ratio between triglycerides and phosphatide is in the range of 4:1-1:1, preferably 3:1, also More preferably 2.3:1.
And it was unexpectedly observed that the buffer with low ionic forces, which is added in composition, can advantageously allow in room temperature Under keep pH a very long time (storage life) compatible with the physiological pH of tears in a stable manner, without interfering Chemical Physics The tolerance of property and product itself.
Preferably, buffer can be selected from by Tris, NaOH, histidine, three (methylol) methylglycines (tricine), the group of lysine, glycine, serine composition, is adjusted using the acid ingredient with low ionic forces to appropriate PH.
Especially, it is being intended to develop in emulsion in the different phase of composition, in developed preparation, from stability angle Degree considers, best preparation be those with the preparation of Tris buffering and those use the preparation of histidine buffer.
In order to test such performance of the preparation relative to non-buffer preparation (non-buffered formulation), During stability study (non-buffer preparation is buffered with histidine buffer or with Tris), the measurement based on pH has carried out experiment and has surveyed Examination.As shown in figs. 1A-1 c, acquisition the result shows that not buffering the pH of emulsion (or emulsion, lotion, emulsions) at any time It can reduce suddenly, wherein free fatty acid is formed at room temperature, and in room temperature in the emulsion with histidine or with Tris buffering Under (25 DEG C) and under higher temperature (30 and 40 DEG C), within the time for not being shorter than 24 months, pH is more stable.
Moreover, composition of the invention may include the nonionic or low ionic forces regulator of osmotic pressure, so that finished product Osmotic pressure is in the range of 0.100-0.320Osmol/kg (osmole/kg).Especially, the regulator of osmotic pressure is selected from sweet Oil, sorbierite, mannitol, ethylene glycol, propylene glycol, glucose.The regulator of osmotic pressure is present in an amount sufficient, similar to obtain In the osmotic pressure of tear.
Composition can also include stabilizer, surfactant, antioxidant and/or anti-microbial preservative, thickener, Linear or ramified chain polymer, amino acid such as, such as: tocopherol, free fatty acid and their salt, polysorbate, Pluronic (addition polymers of polypropylene glycol and ethylene oxide)Cremophor (cremophor)HPMC, hyaluronic acid, Xanthan gum, parabens, benzalkonium chloride, poly hexamethylene biguanide (PHMB), arginine, lysine, glycine etc..
As described above, composition of the invention has the form of oil hydrosol, can change when with ocular face contact, it Structure be rearranged.This shows that composition can be distributed in eye surface, especially in conjunction with Meibomian gland, is such as retouched by following Shown by the experiment in vitro about the evaporation flow reduction of tears stated.
In addition, observed by means of the experiment in vivo carried out to male, only when composition include previously described oil simultaneously And when preferably having specified specific ratios between these oil and phosphatide, lipid film is just formed in eye surface in an uniform way On.For example, mixture between medium chain triglyceride (MCT) or short chain triglycerides or MCT and long chain triglycerides is deposited Determining distribution of the lipid part in non-homogeneous tear film, which determine eye-blurred and undesirable eye tolerance, this causes In the specific length of oil carbon chain.
The following describe the method examples for producing the composition as the purpose of the present invention.
The preparation method for ophthalmically acceptable pharmaceutical preparation based on non-polar and polar lipid
The preparation method of pharmaceutical preparation as described above based on non-polar and polar lipid the following steps are included:
Water phase is prepared in a vessel at about 70 ± 15 DEG C, which includes water and may be described water-soluble Property ingredient；
Be prepared separately at about 70 ± 15 DEG C comprising phospholipid composition and oil components and may be all liposoluble constituent Oily phase, stirring is homogeneous until obtaining；
Oil is added in water phase or vice versa；
It is set to reach desired volume with water；
Thick emulsion is prepared by using turbine；
If it is necessary, pH is adjusted to biological value with acid or alkaline solution；
It is homogenized by means of high-pressure homogenizer and stable emulsion；
Sterilizing is carried out to emulsion at 120 ± 10 DEG C and reaches F0(microorganism needed for ensuring the aseptic of product is dead Rate) needed for time；
Emulsion is cooled to 20 ± 10 DEG C.
Preferably, those of previous description water soluble ingredient is selected from according to the water soluble ingredient of first step.
Preferably, those of previous description liposoluble constituent is selected from according to the liposoluble constituent of second step.
Comprising the emulsion of lipophilic active principle, this can be added before adding phosphatide in oiliness step Enter.
Both sexes active principle, which can replace, is added into (or merging, mixing, incorporate) to completely oily phase (oil+phosphorus Rouge) in.
Both sexes active principle can be added in complete combination object (if heat-resisting), or sterile before sterilization Under, it is added in previously sterilized complete preparation.
According to the stabilization of required composition, it is contemplated that the oiliness part of emulsion may be during preparation step Become rancid and then its stability at room temperature, observed, if raw material and semi-finished product operational sequence (or process, Working operations) until the sterilizing of final products is under no oxygen or atmosphere with the oxygen pressure value less than 3% It carries out, then can obtain more stable product.The rouge of this natural phospholipid in fact allowing to avoid constituting preparation and triglycerides Double bond in fat acid chain aoxidizes.The possible oxidation of product in fact can cause preparation unstability (to become rancid, phase Separation) and toxic molecule (peroxide radical) formation.In addition, after sterilization must be immediately by protecting composition to exempt from The packaging of product is carried out by air impact.
Specific embodiment according to the method described above, preparation method is (in no oxygen or with low-down oxygen pressure value Carried out in atmosphere) it include that two containers under magnetic stirring are placed under controlled temperature (70 °), a container accommodates oil Phase, the oil is mutually comprising phosphatide and all fat or liposoluble constituent with above-mentioned specified ratio and amount, the receiving of another container There is water phase, which includes water and all water soluble ingredients.When two-phase is all uniform, by utilizing turbo emulsifier or high pressure Oil is mutually slowly added into water phase by homogenizer with 5000 revs/min of speed.Stirring mixture about 15 minutes, at the end, It sterilized, cooled down to mixture, then being packed.
It is in any case possible to think that most suitable condition carries out all modifications using those skilled in the art.
The preferred but non-limiting embodiment report of composition according to the present invention is in the following table.
Table 1
10% does not buffer emulsion (%w/w)
Soya-bean oil 7.0%
The phosphatide of yolk 3.0%
Glycerol 2.0%
Water (as needed) 100ml
Table 2
5% does not buffer emulsion (%w/w)
Soya-bean oil 3.5%
The phosphatide of yolk 1.5%
Glycerol 2.2%
Water (as needed) 100ml
Table 3
1% does not buffer emulsion (%w/w)
Soya-bean oil 0.7%
The phosphatide of yolk 0.3%
Glycerol 2.2%
Water (as needed) 100ml
Table 4
With 10% emulsion of histidine buffer (%w/w)
Soya-bean oil 7.0%
The phosphatide of yolk 3.0%
Glycerol 1.7%
L-Histidine 0.4%
HCl (as needed) is used for pH 7.5 -
Water (as needed) 100ml
Table 5
10% emulsion buffered with Tris (%w/w)
Soya-bean oil 7.0%
The phosphatide of yolk 3.0%
Glycerol 1.8%
Tris alkali 0.242%
HCl (as needed) is used for pH 7.6 -
Water (as needed) 100ml
Table 6
5% emulsion buffered with three (methylol) methylglycines (%w/w)
Fish oil 3.5%
The phosphatide of yolk 1.5%
Glycerol 2.0%
Three (methylol) methylglycines 0.32%
HCl (as needed) is used for pH 7.6 -
Water (as needed) 100ml
Table 7
With 10% emulsion of glycine buffer (%w/w)
Fish oil 7.0%
The phosphatide of yolk 3.0%
Glycerol 1.8%
Glycine 0.16%
HCl (as needed) is used for pH 7.6 -
Water (as needed) 100ml
Table 8
10% emulsion buffered with NaOH (%w/w)
Soya-bean oil 7.0%
The phosphatide of yolk 3.0%
Glycerol 1.8%
0.01M NaOH 0.05%
HCl (as needed) is used for pH 7.6 -
Water (as needed) 100ml
Table 9
Table 10
The 10% drug containing emulsion buffered with TRIS (%w/w)
Levocabastine (levocabastine) 0.05%
Soya-bean oil 7.0%
The phosphatide of yolk 3.0%
Glycerol 1.8%
TRIS alkali 0.24%
HCl (as needed) is used for pH 7.2 -
Water (as needed) 100ml
Table 11
The 10% drug containing emulsion buffered with L-Histidine (%w/w)
Olopatadine 0.1% or 0.2%
Soya-bean oil 6.0%
The phosphatide of yolk 4.0%
Glycerol 1.7%
L-Histidine 0.60%
HCl (as needed) is used for pH 7.0 -
Water (as needed) 100ml
Table 12
The 10% drug containing emulsion buffered with L-Histidine (%w/w)
Latanoprost 0.005%
Soya-bean oil 6.0%
The phosphatide of yolk 4.0%
Glycerol 1.7%
L-Histidine 0.60%
HCl (as needed) is used for pH 7.0 -
Water (as needed) 100ml
It can also be with the different salt of active principle or with different from the effective of active principle those of specified in embodiment Component executes such embodiment.
Furthermore it is also possible to between 0.02% to 0.2% concentration be used alone be combined with each other or with sugared cortical hormone Element combination comes using olopatadine and levocabastine, and Latanoprost can be in the dense of 0.002% to 0.01% range Degree uses.For example, glucocorticoid can be selected from fluocinolone acetonide, fluticasone propionate, fludroxycortide, Difluprednate, flumethasone Pivalate, beclomethasone dipropionate, betamethasone, budesonide (budesonide), alclometasone diproionate, propionic acid chlorine times he Rope, clobetasone butyrate, desonide, Desoximetasone, double acetic acid diflorasones, Fluocinonide (fluocinonide), halogen rice His rope propionic ester, Amcinonide, clocortolone pivalate, dexamethasone, diflucortolone, acetic acid fluorine hydrogen of pine, Triamcinolone acetonide, Unio margarita Cortisone, fluprednidene acetate, Halcinonide, Mometasone Furoate (mometasone furoate), prednicarbate, Flucloronide, vinegar Acid dichloride pine, fluocortolone, methylprednisolone, hydrocortisone, fluocortin butyl, their salt and ester and its mixture.
In the experiment uveitis model of rabbit, we illustrate dexamethasone sodium phosphate is in the concentration down to 0.001% Significant anti-inflammatory effect (Fig. 4) can be played.
It can be with intraocular hypertension it is believed that giving (> 2 weeks) glucocorticoid with the usually used long-term eye for the treatment of concentration Increase with the risk of lenticular opacifiation.In fact, the clinical use of ophthalmically acceptable glucocorticoid be limited to two weeks courses for the treatment of (treat into Journey).Notably, the adverse effect of ophthalmically acceptable glucocorticoid is directly related with the amount for the drug for being delivered to eyes.
According to the line of reasoning, select the concentration of the lower part of range (0.001%-1%) can be particularly for using us Long-term treatment eye surface illness (is characterized in that inflammation such as allergy, dry eyes), or for photorefractive keratectomy (PRK) or The later treatment of corneal transplantation.
Finally, particularly for ocular surface inflammatory disease, the sugar that has equally selected the adjacent bottom portions concentration of range to use with us Cortin will keep their effect, while show improved eye safety distribution, therefore allow the longer course for the treatment of.
Other active principle can be selected from fluoroquinolones, preferably second, third and forth generation such as Ciprofloxacin, oxygen Flucloxacillin, lavo-ofloxacin, trovafloxacin, Moxifloxacin, gemifloxacin or their mixture or they and anti-inflammatory drug such as sugar Cortin or with other antimicrobials such as macrolides, cephalosporins or beta-lactam (betalattamines) " fixation " combination (preparation comprising at least two different active principles (actives)) group.The concentration of fluoroquinolones can To change between 0.1% to 0.6%.
The following characteristic of numerous compositions (purpose of the present invention) has been determined: stability, reduces tear film evaporation at tolerance Validity, the diffusivity in Meibomian gland, resistance answer/anti-inflammatory validity.
Stability and tolerance
All compositions reported in the description of the purpose of the present invention are all resistant to very well in ophthalmically acceptable level.
The stability of preparation through buffering is at least 24 months at room temperature.
Composition resists the validity of the aqueous ingredients evaporation of tear film
Ophthalmologist, oculist is it is known that can reduce the surface tension of tear film by the tear lipid layer that Meibomian gland generates and slow down water significantly From the evaporation rate of lower layer.
It is described below and in 16 (2004) S2461-S2467 of Miano F.et al, J.Phys:Condens.Matter Works in the hanging drop system reported, emulsion as the object of the invention is relative to including other of lipid and/or polymer Special performance is presented in eye-drops preparations, especially after relative to drops addition by volume about 1%, keeps balance salt water-soluble The surface tension of liquid reduces at least special ability of 30mN/m.
In addition, by existing or lacking natural lipid layer and by the volume ratio between solution and emulsion, as this hair The composition of bright purpose is surprisingly able to maintain the evaporation rate of lower balanced salt solution, and with temperature condition, Relative humidity is unrelated.
In order to confirm the ability of evaporation stream of the composition reduction tear as the purpose of the present invention containing water section, it is determined that flat Weighing apparatus saline solution (HBSS) (without or there are Meibomian gland), the emulsion of the purpose of the present invention or business comparative product Evaporation rate.
In optical contact angle (OCA20, Dataphysics, Germany), the model of hanging drop is used, two tools are connected to There are the Hamilton syringe of electronic measurement and the room with controlled temperature and relative humidity (RH), drops to distribute in it Portion.
Evaporation rate is calculated as hanging drop size in given interval (15 seconds) by the image that CCD camera provides by handling Difference.In each experiment, in 20 minutes in total, the monitoring of repeated evaporation speed 80 times.
By means of following formula, experimental data is expressed as the reduction of the evaporation rate relative to balanced salt solution:
Wherein JWIt is evaporation stream, usesIt indicates, R.H. is the constant that relative humidity and K are to rely on temperature.
There are Meibomian gland or Meibomian gland+ophthalmic compositions (composition or business comparative product of the purpose of the present invention) In the case of evaporation stream JmWith Jw(the evaporation stream of solution is usedIndicate) between ratio be defined as:
φ=1- (Jm/Jw)
φ of its intermediate value within the scope of 0-1 indicates identified to steaming in being uniformly distributed for the interface with water layer by lipid The resistance of hair.Data are pocessed [Miano F.et al, J.Phys:Condens.Matter 16 with DATAPHYSICS software (2004)S2461-S2467].Experiment described below, the evaporation referring to the tears in the patient influenced by vapo(u)rability dry eyes are existing As, it is determined that the evaporation rate of aqueous solution.Together with evaporation rate, the surface tension of fluid is had detected, is the weight of tear Want performance.The data of offer and evaporation rate of a variety of ophthalmically acceptable prepared products (preparations) to the model system for representing tear film Influence it is related.
In the HBSS for having distributed 12 μ l volume of a drop, (Hanks balanced salt solution, it includes CaCl2·H2O, 0.19mg/mL； MgSO4, 0.098mg/mL；KCl, 0.40mg/mL；H2PO4, 0.06mg/mL；NaHCO3, 0.35mg/mL；NaCl, 8.0mg/ml And D-Glucose, 1.0mg/mL) after, expertly add known volume, such as the natural lipid in chloroform of 1 μ l is molten Then liquid waits two minutes so as to chloroform evaporated and be formed simultaneously lipid layer in liquid-air boundary.Then to be by volume The range of the volume of the drop of 10%-50% adds the ophthalmic solution of known volume checked.It tests in following table 13 The preparation of record.
Table 13
Embodiment 1
Under conditions of different temperature and relative humidity, balanced salt solution (HBSS) and ophthalmic composition are measured Evaporation rate.
Condition: T=25 ± 1 DEG C；R.H.=66%, by means of NaNO2Saturated solution be controlled.
Table 14
Composition Jw
HBSS 8.26×10-5±3.1×10-6g/m2/s
HBSS+ Meibomian gland 4.46×10-5±1.67×10-6g/m2/s
10% emulsion 6.37×10-5±2.54×10-6g/m2/s
Condition: T=36 ± 1 DEG C, R.H.=15% are controlled by means of LiCl saturated solution.
Table 15
Composition Jw
HBSS 3.919×10-4±4.1×10-5g/m2/s
HBSS+ Meibomian gland 2.555×10-4±5.4×10-5g/m2/s
10% emulsion 2.802×10-4±4.01×10-5g/m2/s
This embodiment illustrates, as the purpose of the present invention composition how with the mode similar with Meibomian gland, It is under difficult environmental conditions and especially (frequent such as in office, airport, aircraft, automobile when relative humidity is lower Occur), reduce the evaporation rate of aqueous solution.
Embodiment 2
Hold under different temperatures and relative humidities and adding different components being studied or for comparing In the case where product, compared with the solution with Meibomian gland, the evaporation rate of balanced salt solution (HBSS) is measured.
Condition: T=36 ± 1 DEG C；R.H.=15%.
Add composition that 1 μ l/10 μ l is studied or for comparing.
Table 16
Meibomian gland Refresh Endura 1%TSP 10% emulsion
Φ 0.337±0.086 0.341±0.050 0.032±0.061 0.322±0.097
Condition: T=36 ± 1 DEG C；R.H.=15%.
Add composition that 5 μ l/10 μ l are studied or for comparing.
The ratio between prepared product ophthalmically acceptable in eye and fluid is more closely similar to the drops of eyewash (compared to addition only 1 μ l)。
Table 17
Meibomian gland Refresh Endura 1%TSP 10% emulsion
Φ 0.337±0.086 0.041±0.077 0.120±0.048 0.325±0.080
The optimal value of Φ is the value provided by Meibomian gland.The Φ of compound is tested closer to this value, then these compounds will More effectively physiologically reduce the evaporation containing water section of tear film.According to this embodiment, it is inferred that Refresh Endura, Adding low volume is effective into drops, if lipid film can be restored to approach the addition of the volume of the drops of eyewash, and TSP does not always reach physiology Φ value.On the other hand, emulsion is reducing aqueous solution evaporation side under all experiment conditions used Physiological availability is presented in face.
Embodiment 3
Balanced salt solution (HBSS), salting liquid are measured (there are Mai Bomu lipid (or tarsus lipid, Meibomian Lipids in the case where)), the surface tension of ophthalmic solution and above-mentioned emulsion.
Condition: T=25 DEG C；U.R.=95%, for the solution being saturated with 12 hydrated sulfuric acid disodiums.
Table 18
* 0.4% solution.
The description of test surprising characteristic of emulsion of the invention: when them and include bivalent cation (Ca2+； Mg2+) saline solution contact when, surface tension can be reduced.
From the experiment it is apparent that the simple of normal surfactant (Refresh Endura or TSP preparation) exists simultaneously The reduction of active surface tension is not determined, and the emulsion as the purpose of the present invention then can be such.
For Refresh Endura or TSP obtain statistics indicate that, when they are introduced into natural system with similar system When system, they can not be successfully distributed in well in Mai Bomu lipid.
On the other hand, for as the purpose of the present invention emulsion acquisition surface tension reduced value and be added to The ratio of volume in aqueous solution show such composition well with Mai Bomu lipid binding.
Embodiment 4
In order to evaluate the ability of the composition integration of the purpose of the present invention and the function of reproduction Meibomian gland lipid, have rated logical Cross compare at home with different components currently available on international market and composition of the invention and nature Meibomian gland rouge The reduction of matter and the evaporation rate of determination.Hanging drop system is also used in this case.Compare in the table 19 of following record Specified composition.
Table 19
* ophthalmic composition
* intravenous nutrition composition
As being observed that from the figure recorded in Fig. 5, it is different from other test compositions, as the purpose of the present invention Liplid emulsions (SIFI) can be reduced to evaporate and be similar to step in statistically significant mode in our external model and be won Nurse lipid (respectively 28% and 31%), and statistically validity is poor for the product caning be found that on the market.
By means of flow measurement, it was further observed that, there are surface compression (from the eyelid during blink), from Right Mai Bomu lipid film mainly has elastic property, the reconstruction for the later tear film that is conducive to blink.
It can be found that the composition of the purpose of the present invention significantly correspond to characterization nature Mai Bomu lipid film air/ The physical property of the diffusion of water termination.
Such distinctive mobility is conducive to blink the correct reconstruction of later tear film.This it is not obvious that as a result, because For discovery, other compositions comprising phosphatide and certain business emulsions generate dramatically different interface.
Composition in SIFI emulsion shows there is such physical property, characterizes nature Mai Bomu lipid film in sky The diffusion at gas water interface.
The special characteristic makes composition of the invention particularly suitable for carrying eye medicinal, which needs quick Diffusion, integration and the compatibility with tear, which dictates that good distribution and dynamics in ocular tissue and cooperateing with reinforce it is more The effect of kind drug.
After giving in conjunctival sac, in fact, the ion as present in tear, the phase for forming emulsion is separated, and is released Put active principle.
Especially, when changing the qualitative-quantitative composition of lipid layer, such as in subject by xerophthalmia scheorma, dry eye syndrome In the case that (passing through evaporation), allergy, bacterium or virus infection etc. influence, composition of the invention can be with insufficient rouge Matter layer combines, and restores its physiological condition.
Resistance should be with anti-inflammatory validity
As mentioned in the preamble part of this specification, the numerous compositions presentation as the purpose of the present invention is made us Surprised resistance should be with anti-inflammatory performance.It is also observed, answers the composition of the invention of drug comprising anti-inflammatory or resistance by giving, Relative to the drug prepared in known compositions is used, therapeutic response that is significant and surprisingly improving can be obtained.With In the experiment that internal surface inflammatory model carries out glucocorticoid, composition of the invention unexpectedly has can be with sugared cortical hormone The validity (Fig. 6) that element is compared.
Then, with vivo immunization allergic effect model, such effect especially is had studied to the initiative eye anaphylaxis in rat. Rat ocular tissue, in fact, in response to systemic anaphylaxis phenomenon.The experimental model used, which has, to be similar in Human pathology The characteristic observed, clinical sign are: expansion, chemosis and the increased vasopermeability (Bloch of capillary JK,Ohman J,Waltin J,and Cygan RN.“Potentiated reagin response:Initiation with minute doses of antigen and alum followed by infection with Nippostrongylus brasiliensis”J Immunol 110:197,1973)。
20 Male Wistar rats (wistar rat) of about 150-175g weight are used.Existed by intraperitoneal injection The ovalbumin of 100mg in the sterile 0.9%NaCl of 1ml adds the alum of 20mg, makes animal immune.After 14 days, it will move Object is divided into multiple groups and receives the local assault (challenge) of antigen (the 100mg/ml ovalbumin of the 10ml in PBS).It is attacking It is preceding at once, Evans blue (EB) colorant (PBS of 1.25mg/100g/1ml) is injected into the tail of the animal of previous ether anesthesia In vein.
After eye allergic reaction occurs, determine the allergy of above-mentioned clinical sign medium (histamine, serotonin, Leukotriene, platelet activating factor-PAF, eosinocyte chemotactic factor (CF) etc.) it is discharged by mast cell and basocyte.
Especially, the increase of vasopermeability can be caused by the histamine that the mast cell of activation and basocyte discharge, And the extravasation of Evans blue-albumin is then occurred by blood circulation and is accumulated in ocular tissue, so as to cause oedema (Baird RS,Bloch JK,and Allansmith MR.“Edema test for assessing ocular anaphylaxis”.Curr Eye Res 2:657,1983)。
Although vasopermeability is the suitable parameter for evaluating allergy intensity, induced hypersensitivity 30 minutes with The extravasation of the colorant in ocular tissue measured afterwards is used as the label of allergy.
Test these compositions:
Control: water and 2.2% glycerol
10% emulsion
5% emulsion
1% emulsion
0.15% dexamethasone sodium phosphate solution
0.14% dexamethasone palmitate in 10% emulsion
By the substance local application (15 μ l) into the right eye of animal, (processing) left eye is not treated.
5,4,3,2,1 hours before eye attacks (ocular challenge), according to about cortex glucocorticoid (corticoglucocorticoid) program reported in the literature (Calonge MC, Pastor JC, Herreras JM and Gonzales JL.“Pharmacologic modulation of vascular permeability in ocular Allergy in the rat " .Invest Ophthalmol Vis Sci 28:264,1987) give emulsion.
After attack, animal generates allergy in conjunctiva level, after initial 5 minutes, it is already possible to see, and In longest 30 minutes, it can be seen that conjunctiva and blepharedema.
30 minutes after attack, animal is put to death by cervical dislocation.Remove eye and eyelid, weigh and immerse by acetone and In the extraction solution that 0.5% sodium sulphate (respectively with 14:6 ratio) forms, then it is kept at room temperature under stiring.24 hours with Afterwards, with 2000rpm Centrifuge A sample 10 minutes, the color intensity of supernatant is then read at 620nm with spectrophotometer.
For each experiment, canonical reference curve (standard reference curve) is prepared, is used for extinction list Bit map is mg/ml solution, is then every mg tissue by data normalization (normalise).Data are expressed as, relative to non-medicine The control-animal for managing treatment, the EB extravasation percentage in the ocular tissue through treating animal.
As known in Fig. 7, in the model utilized, dose dependent validity is observed in test composition, Statistical significance is presented for the emulsion of the concentrate comprising the oil components greater than 1% in it.
Especially, it observes, relative to control, 10% emulsion shows that the 50% of colorant extravasation inhibits, and 5% cream Agent applies about 37% for allergy and inhibits.It is also observed from experiment, wherein having dexamethasone palmitate comprising (carrying) Emulsion there is synergistic effect to the effect of active principle, wherein active principle (although being 0.14%) has than 0.15% plug The bigger effect of the loose sodium radio-phosphate,P-32 solution of rice.
Moreover, especially, if emulsion is to dexamethasone palmitate compared with the validity of its carrier (10% emulsion) The synergistic effect of effect, relative to by comparing caused by 0.15% solution and PBS, statistical significance is bigger (Fig. 8).
As from above-mentioned can be appreciated that, present patent application can be obtained for ophthalmically acceptable pharmaceutical composition, allow to use Natural materials.
In addition, those skilled in the art can carry out many modifications to composition, and all modifications are appended by this paper In scope of protection of the claims.

Claims (35)

1. being used for ophthalmically acceptable pharmaceutical composition, the composition includes:
The phospholipid composition being made of amphoteric ion yolk phospholipid, and
By being substantially that natural one or more oil are constituted and oil components without any synthetic oil or mineral oil, Wherein
Weight ratio between the oil components and the phospholipid composition is 4:1-1:1,
The phospholipid composition exists with 0.1%-5% by weight, and
The oil components exist with 0.3%-15% by weight, and
Buffer with low ionic forces presents in an amount at least sufficient to and maintains the pH of finished product in the range of 6.5-8, and the buffer is selected from group The group that propylhomoserin and Tris and their combination are constituted, to maintain the stability of the composition.
2. pharmaceutical composition according to claim 1, wherein the ratio between the oil components and phospholipid composition is 3: 1。
3. pharmaceutical composition according to claim 1, wherein the ratio between the oil components and phospholipid composition is 2.3:1。
4. pharmaceutical composition according to any one of claim 1-3, wherein the phospholipid composition is deposited with 0.3%-3% , and the oil components exist with 0.7%-7%.
5. pharmaceutical composition according to any one of claim 1-3, wherein relative to the total weight of the phosphatide, institute State the phosphatidyl choline for the amount that phospholipid composition includes 50-70%, the phosphatidyl-ethanolamine of 5-20%, the sphingomyelins of 1-10%, 1- The neutral lipid of 10% lysophosphatidyl choline, 2%-15%.
6. pharmaceutical composition according to any one of claim 1-3, wherein the oil components are including being substantially day The oil in right source.
7. pharmaceutical composition according to claim 6, wherein described is substantially natural oily for soya-bean oil, olive Oil, sunflower oil, fish oil, borage oil, sesame oil, hemp-seed oil, corn oil, cottonseed oil.
8. pharmaceutical composition according to any one of claim 1-3, wherein the oil components include nonpolar glycerol The oil of three ester-formins.
9. pharmaceutical composition according to claim 8, wherein the fatty acid for constituting the nonpolar triglycerides is selected from meat Myristic acid, linoleic acid, oleic acid, linolenic acid, palmitinic acid, palmitoleic acid, stearic acid, eicosapentaenoic acid, arachidonic acid, 20 Two carbon enoic acids.
10. pharmaceutical composition according to any one of claim 1-3 also comprises the nonionic or low ion of osmotic pressure Power regulator, for adjusting the osmotic pressure of the composition until obtaining the value within the scope of 0.100-0.320Osmol/kg.
11. pharmaceutical composition according to claim 10, wherein the regulator of the osmotic pressure be selected from glycerol, sorbierite, Mannitol, ethylene glycol, propylene glycol, glucose.
12. pharmaceutical composition according to any one of claim 1-3, also comprise from stabilizer, surfactant, Cosurfactant, antioxidant and/or anti-microbial preservative, thickener, in linear or ramified chain polymer, amino acid At least one medicament.
13. pharmaceutical composition according to claim 12, wherein the stabilizer, surfactant, cosurfactant Agent, antioxidant, anti-microbial preservative, thickener, linear or ramified chain polymer, amino acid are selected from: tocopherol, free rouge Fat acid and their salt, polysorbate, pluronic, cremophor, HPMC, hyaluronic acid, xanthan gum, para hydroxybenzene first Esters of gallic acid, benzalkonium chloride, poly hexamethylene biguanide (PHMB), arginine, lysine, glycine, alcohols.
14. pharmaceutical composition according to any one of claim 1-3 further comprises active principle or active principle Fixed Combination.
15. pharmaceutical composition according to claim 14, wherein the active principle be selected from olopatadine, left kappa this Spit of fland, Latanoprost, glucocorticoid, second, third or forth generation fluoroquinolones and their mixture.
16. pharmaceutical composition according to claim 15, wherein can with beta-lactam, cephalosporins and big The fixed Combination of cyclic lactone class is come using the active principle.
17. pharmaceutical composition according to claim 15, wherein olopatadine and levocabastine with 0.02% to Concentration between 0.2% uses, and Latanoprost is used with the concentration between 0.002% to 0.01%, glucocorticoid with Concentration between 0.001% to 1% uses, and the fluoroquinolones of second, third or forth generation are 0.1% to 0.6% Between concentration use.
18. medical composite for eye is made up of:
With 10% emulsion of histidine buffer (%w/w) Soya-bean oil 7.0% The phosphatide of yolk 3.0% Glycerol 1.7% L-Histidine 0.4% HCl (as needed), until pH 7.5 - Water (as needed) 100ml
。
19. medical composite for eye is made up of:
10% emulsion buffered with Tris (%w/w) Soya-bean oil 7.0% The phosphatide of yolk 3.0% Glycerol 1.8% Tris alkali 0.242% HCl (as needed), until pH 7.6 - Water (as needed) 100ml
。
20. medical composite for eye is made up of:
The 10% drug containing emulsion buffered with L-Histidine (%w/w) 21 β of dexamethasone-palmitate 0.16% Soya-bean oil 7.0% The phosphatide of yolk 3.0% Glycerol 1.7% L-Histidine 0.40% HCl (as needed), until pH 7.2 - Water (as needed) 100ml
。
21. medical composite for eye is made up of:
The 10% drug containing emulsion buffered with TRIS (%w/w) Levocabastine 0.05% Soya-bean oil 7.0% The phosphatide of yolk 3.0% Glycerol 1.8% TRIS alkali 0.24% HCl (as needed), until pH 7.2 - Water (as needed) 100ml
。
22. medical composite for eye is made up of:
The 10% drug containing emulsion buffered with L-Histidine (%w/w) Olopatadine 0.1% or 0.2% Soya-bean oil 6.0% The phosphatide of yolk 4.0% Glycerol 1.7% L-Histidine 0.60% HCl (as needed), until pH 7.0 - Water (as needed) 100ml
。
23. medical composite for eye is made up of:
The 10% drug containing emulsion buffered with L-Histidine (%w/w) Latanoprost 0.005% Soya-bean oil 6.0% The phosphatide of yolk 4.0% Glycerol 1.7% L-Histidine 0.60% HCl (as needed), until pH 7.0 - Water (as needed) 100ml
。
24. pharmaceutical composition according to claim 14, wherein the active principle is by any the one of the active principle Kind salt or ester composition.
25. the method for being used to prepare pharmaceutical composition described in any one of -24 according to claim 1, comprising the following steps:
Prepare water phase in a vessel at 70 ± 15 DEG C, the water phase includes water；
Be prepared separately oily phase at 70 ± 15 DEG C, the oil mutually includes the phospholipid composition and the oil components, stirring until It obtains homogeneous；
The oil is added in the water phase or vice versa；
Desired volume is reached with water；
Thick emulsion is prepared by using turbine；
If it is necessary, pH is adjusted to biological value with acid or alkaline solution；
The emulsion is homogenized and stablized by means of high-pressure homogenizer；
Sterilizing is carried out to the emulsion at 120 ± 10 DEG C and reaches F0The required time, wherein the F0Refer to the nothing for ensuring product The microorganism death rate needed for bacterium property；
The emulsion is cooled to 20 ± 10 DEG C.
26. the method for being used to prepare pharmaceutical composition described in any one of -24 according to claim 1, comprising the following steps:
Prepare water phase in a vessel at 70 ± 15 DEG C, the water phase includes water and as remembered in claim 1-12 The water soluble ingredient of record；
Oily phase is prepared separately at 70 ± 15 DEG C, the oil mutually includes the phospholipid composition and the oil components and such as weighing Benefit requires liposoluble constituent recorded in 6-8 and 11-12, and stirring is homogeneous until obtaining；
The oil is added in the water phase or vice versa；
Desired volume is reached with water；
Thick emulsion is prepared by using turbine；
If it is necessary, pH is adjusted to biological value with acid or alkaline solution；
The emulsion is homogenized and stablized by means of high-pressure homogenizer；
Sterilizing is carried out to the emulsion at 120 ± 10 DEG C and reaches F0The required time, wherein the F0Refer to the nothing for ensuring product The microorganism death rate needed for bacterium property；
The emulsion is cooled to 20 ± 10 DEG C.
27. the method for being used to prepare pharmaceutical composition described in any one of -24 according to claim 1, wherein raw material and half at The operational sequence of product is in atmosphere of the pressure value less than 3% for lacking oxygen or oxygen until the sterilizing of final products and packaging It carries out.
28. the method for being used to prepare the pharmaceutical composition according to any one of claim 20-24, wherein in addition institute Phosphatide is stated hydrophobicity active principle was added in the oily phase in the past.
29. the method for being used to prepare the pharmaceutical composition according to any one of claim 20-24, wherein if heat-resisting, Both sexes active principle in the complete fatty phase that sterilizing is previously joined comprising oil and phosphatide or is added in complete combination object, Or if thermo-labile, it is added in previously sterilized complete preparation under sterile.
30. according to claim 1-3, pharmaceutical composition described in any one of 18-23, described pharmaceutical composition is as drug.
31. pharmaceutical composition described in any one of -19 is preparing answering in eye medicinal as carrier according to claim 1 With.
32. pharmaceutical composition described in any one of -20 and 24 is in preparation for treating xerophthalmia scheorma or dry eyes according to claim 1 Application in the drug of syndrome.
33. pharmaceutical composition described in any one of -19 and 24 inhibits the water layer evaporation of tear film in preparation according to claim 1 Application in drug.
34. pharmaceutical composition described in any one of -19 and 24 in preparation there is anti-inflammatory/resistance to answer activity according to claim 1 Eye medicinal in application, wherein relative to the total weight of the composition, the amounts of the phosphatide and oil components is by weight Meter is greater than or equal to 1%.
35. according to claim 1 pharmaceutical composition described in any one of -19 as carrier answering in preparation system drug With.
CN201510119588.7A 2007-03-30 2007-12-24 For the ophthalmically acceptable pharmaceutical preparation based on non-polar and polar lipid Active CN104771354B (en)

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PCT/IT2007/000239 WO2008120249A1 (en) 2007-03-30 2007-03-30 Pharmaceutical formulations based on apolar and polar lipids for ophthalmic use
ITPCT/IT2007/000239 2007-03-30
CN200780052387A CN101657184A (en) 2007-03-30 2007-12-24 Be used for a usefulness based on nonpolar and pharmaceutical preparation polar lipid

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1200298A (en) * 1996-11-06 1998-12-02 罗纳－布朗克罗勒股份两合公司 Phospholipid composite, prepn. method and application thereof
WO2006002050A1 (en) * 2004-06-15 2006-01-05 Encore Therapeutics, Inc. Phospholipid compositions and methods for their preparation and use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1200298A (en) * 1996-11-06 1998-12-02 罗纳－布朗克罗勒股份两合公司 Phospholipid composite, prepn. method and application thereof
WO2006002050A1 (en) * 2004-06-15 2006-01-05 Encore Therapeutics, Inc. Phospholipid compositions and methods for their preparation and use

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