CN1802151A - Formulations of non-steroidal anti-inflammatory agents to treat pathologic ocular angiogenesis - Google Patents
Formulations of non-steroidal anti-inflammatory agents to treat pathologic ocular angiogenesis Download PDFInfo
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- CN1802151A CN1802151A CN 200480015771 CN200480015771A CN1802151A CN 1802151 A CN1802151 A CN 1802151A CN 200480015771 CN200480015771 CN 200480015771 CN 200480015771 A CN200480015771 A CN 200480015771A CN 1802151 A CN1802151 A CN 1802151A
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- angiogenesis
- edema
- retina
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Abstract
Methods for the use of NSAIs in combination with anecortave acetate are disclosed for preventing and treating pathologic ocular angiogenesis and associated edema, retinal edema, PPDR or NPDR.
Description
The application requires the U.S.S.N.60/478 that submits on June 13rd, 2003, and 227 and the U.S.S.N.60/478 that submits on June 13rd, 2003,252 priority.
Technical field
The present invention relates to prevent and treating with edema under pathologic ophthalmic angiogenesis and/or retina or the retina is the ocular disease of feature.Particularly, the present invention relates to nonsteroidal antiinflammatory drug (NSAIs) uses separately and is used for the treatment of the application of edema under this type of ophthalmic angiogenesis and relevant retina or the retina with some preparation that anecortave acetate is united use.
Background technology
Known many medicines can suppress neovascularization (angiogenesis or neovascularization).For example, Crum etc. are at " class suppresses the new steroid of angiogenesis in the presence of heparin or heparin fragment " (Science, the 230th volume, the 1375-1378 page or leaf, on December 20th, 1985) in come out with that steroid has the function that suppresses angiogenesis in the presence of heparin or special heparin fragment.The author claims that this type of steroid is " angiogenesis inhibition (angiostatic) " steroid.The dihydro and the tetrahydro metabolites that comprise hydrocortisone and deoxidation skin alcohol in this type of steroid of angiogenesis inhibition have been found to have.In experiment subsequently, relate to the hypothesis that this type of steroid of checking suppresses angiogenesis mechanism, studies show that heparin/angiogenesis inhibition steroid compositions makes the membrane holder of adhering on the dependency endothelium dissolve, thereby cause blood capillary degeneration (capillary involution); Referring to Ingber etc. " angiogenesis inhibition steroid suppress angiogenesis may mechanism: induce the capillary basement membrane dissolving ", Endocrinology, the 119th volume, 1768-1775 page or leaf, 1986.
The one group of tetrahydro steroids that is used to suppress angiogenesis is disclosed in U.S. Patent No. 4,975,537 (Aristoff etc.).Disclosed chemical compound is used for the treatment of head trauma, spinal trauma, infectivity or traumatic shock, apoplexy and hemorrhagic shock.In addition, this patent has been discussed these chemical compounds in embryo's implantation and the application in cancer, arthritis and arteriosclerosis treatment.Be disclosed in U.S. Patent No. 4,771, some steroid among 042 (Aristoff etc.) and heparin or heparin fragment can be used for homoiothermic animal and suppress angiogenesis.
Hydrocortisone, " Tetrahydrocortisol-S " and U-72 have been proved, the compositions of 745G (each all combines with beta-schardinger dextrin-) can suppress cornea neovascularization: Li's etc. " sulfated cyclodextrin can strengthen the cornea neovascularization inhibitory action of angiogenesis inhibition steroid ", CornealNeovascularization, Investigative Ophthalmology and Visual Science, the the 32nd (11) volume, the 2898-2905 page or leaf, October, 1991.Steroid self neovascularization of can slowing down to a certain extent, but use can not effectively make neovascularization disappear separately.
Tetrahydrocortisol (THF) has been disclosed in " the angiogenesis inhibition steroid " of Folkman etc. as angiogenesis inhibition steroid, Ann.Surg., the 206th volume (3), in 1987, propose angiogenesis inhibition steroid in the article and can be used in the disease that unusual neovascularization causes, comprise diabetic retinopathy, neovascular glaucoma and crystalline lens after fibrous tissue generate.
Exudative is that wet age-related macular degeneration (AMD) and proliferative diabetic retinopathy (PDR) are feature with pathologic ophthalmic angiogenesis, is to cause acquired blind modal reason in developed country.The unusual vessel layer of neovascularity growth source below retinal pigment epithelial cell (RPE) and sensory nerve retina in exudative AMD.This kind neovascularization is called as the choroid neovascularity and generates or CNV.This type of angiogenesis can grow by Bruch ' s film and enter RPE and photoreceptor between the space.Usually fragile CNV leaks out liquid, blood constituent and causes significantly hemorrhage.So during CNV, fluid accumulation is called edema under the retina.On the contrary, neovascularity growth unusual in PDR enters vitreous body from the retina blood capillary and from interior retina, i.e. NV before the retina.The same with exudative AMD, these pathologic vessels also can liquid body exudates and are caused in the retina and vitreous hemorrhage.In addition, compare with the normal human retina blood capillary, the vascular permeability of diabetics may be stronger, causes being called the disease of macular edema.
Diabetes are feature with the hyperglycemia that continues, at the reversible and irreversible pathological change of blood capillary system generation of various organs.So diabetic retinopathy (DR) is the retinal microvascular pathological changes, it demonstrates a succession of symptom that increases the weight of gradually and vision is progressively worsened.Some main hazard factor of the formation diabetic retinopathy of having reported comprises the persistent period of diabetes, the quality of glycemic control and the existence of systemic hypertension.Broadly, DR can be divided into 2 main clinical stages: simple type diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR), wherein term " hypertrophy " is meant and has the preceding neovascularization (NV) of retina.NPDR comprises a series of clinical subcategories, " preliminary (the background) " DR that comprises the starting stage, this stage can be observed little many kitchen ranges and changes (as microaneurysm, the hemorrhage and nerve fibre layer infraction of " circle speckle " property) in retina, through preceding hypertrophy (preproliferative) the DR stage, develop into the preceding NV of retina immediately.During NPDR or PDR, all can see diabetic macular edema, yet just often can observe edema, so it becomes the omen index to development of the most serious stage (PDR) at the NPDR late stage.
Macular edema is the main cause of vision loss in diabetic patients, yet neovascularization (PDR) is (legal) the blind main cause on the legal sense before the retina, macular edema and the retinal ischemia part correlation that comes subsequently, above-mentioned ischemia be since lasting hyperglycemia inductive retinal microvascular pathological changes cause.Data from animal model and the accumulation of human experience's institute show that retinal ischemia is relevant with the increase of the local horizontal of short inflammatory and/or short angiogenic somatomedin and cytokine.For example PGE2, VEGF (VEGF), insulin like growth factor (IGF-1) etc.These molecules can change the retinal microvascular system and cause pathologic to change, as capillary extracellular matrix reconstruct, cause the retinal vessel seepage and the angiogenesis of edema.
Now, do not ratify the treatment that medicine is used for DR and/or macular edema as yet.The standard care of current popular is a laser photocoagulation, and it is used to stable or eliminates macular edema and stop pathological changes NV development before retina.Thereby laser photocoagulation alleviates retinal ischemia and reduces the metabolism needs by destroying health tissues; It also can adjust the expression and the generation of various cytokines and trophic factors.Unfortunately, laser photocoagulation is a cytoclasis method, is treated the visual field of eyes and has irreversibly been damaged.Except diabetic macular edema, in various other posterior segment disease, can observe retinal edema, as posterior uveitis, branch retinal venous occlusion, the inductive inflammation of surgical operation, endophthalmitis (bacillary and non-bacterial), scleritis and episcleritis etc.
Medical circle has been used the disease at glucocorticoid treatment eyes rear portion: particularly Kenalog (omcilon acetone solvate), Celestone Soluspan (betamethasone sodium phosphate), Depo-Medrol (acetic acid methyl meticortelone), Decadron (dexamethasone sodium phosphate), Decadron L.A. (dexamethasone acetate) and Aristocort (omcilon diacetate).These products are administered for the treatment inflammatory diseases by periocular injections usually.Owing to lack effective and safe Therapeutic Method,, adopt glucocorticoid treatment such as retinal edema and senile degeneration of macula (AMD) more and more to cause people's interest by the vitreous body administration.Bausch ﹠amp; Lomb and Control Delivery Systems are implanted into administration to fluocinolone acetonide through vitreous body and estimate with the treatment macular edema.Oculex Pharmaceuticals also is implanted into dexamethasone treatment persistence macular edema to vitreous body and studies.In addition, ophthalmologist oculist is carrying out the intravitreal injection experiment of Kenalog, is used for the treatment of obstinate capsule macular edema and exudative AMD.
Although glucocorticoid is very effective in the many ocular disease of treatment, it also can produce the same serious side effects relevant with present available product.Side effect comprises: endophthalmitis, cataract and intraocular pressure rising (IOP).Produce although some side effect is a glucocorticoid itself, some then is because the excipient in the preparation and pass that the prescription method causes or quilt is increased the weight of.
The eyes topical application of NSAIs is included in to be kept behind platycoria, the cataract extraction and inflammation control behind the argon laser trabeculoplasty in the surgical operation.They also are used for the inflammatory diseases that the eyes non-surgery operation causes, as the pain after anaphylaxis conjunctivitis and radial keratotomy or the myoporthosis operation (excimerlaser procedure).Can obtain some topical ophthalmics at present: flurbiprofen (Ocufen
, Allergan), diclofenac (Voltaren
, Ciba Vision) and ketorolac (Acular
, Allergan), referring to Ophthalmic Drug Facts, 1999, the 82-83 and 90-93 page or leaf.
So people still need effectively to treat the NSAI of pathologic ophthalmic neovascularization diseases, particularly at back segment, it does not have or less side reaction simultaneously.In addition, still do not have NSAIs and be developed out the patient who is used for the treatment of the hardship of enduring ocular edema and/or NPDR to the fullest extent.Preparation of the present invention has satisfied all these requirements.
Summary of the invention
The present invention relates to adopt NSAIs separately and with the preparation of anecortave acetate associating, described preparation can be used to prevent and treat ocular disease and the discomfort that comprises the ophthalmic angiogenesis.The invention still further relates to NSAIs and be used for the treatment of the patient's of the hardship of enduring retinal edema and/or NPDR to the fullest extent application.
Description of drawings
Following accompanying drawing is the part of present specification, and is included in and is used for further proving some aspect of the present invention in the description.With reference to this figure and to the detailed description of specific embodiments, the present invention may be better understood.
Fig. 1. neovascularization (neovascularity generation mark) before the topical of anecortave acetate has suppressed retina in the inductive retinopathy rat model of oxygen.
The present invention is auspicious to be stated
Eye back segment neovascularization (NV) is the pathological change that causes the harm eyesight of acquired blind two modal reasons in developed country: exudative agerelated macular (AMD) and proliferative diabetic retinopathy (PDR). Only be laser photocoagulation or use Visudyne for the approved methods for the treatment of that occurs in eye back segment NV in the exudative AMD at presentThe photodynamic therapy that carries out, two kinds of methods of treatments be all so that affected vascular system is inaccessible, thus the infringement that causes local laser to be induced to retina. For PDR patient, the surgical management that adopts the excision of vitrectomy and preretinal membrane is present available unique selection. There is not proper drug therapy to be approved for antagonism eye back segment NV, although several different compounds are just estimated clinical, comprise, for example, anecortave acetate (the Alcon Research that is used for AMD, Ltd.), EYE 001 (Eyetech) and rhuFabV2 (Genentech), and be used for LY333531 (Lilly) and the FA (Bausch ﹠ Lomb) of exudative AMD and/or diabetic macular edema.
Pathologic ophthalmic angiogenesis (comprising a back segment NV) progressively takes place forward as chain of events, the formation from initial stimulation to unusual new blood capillary.Reason at exudative AMD and PDR moderate stimulation is still unknown, yet it seems that various angiogenesis growth factor be modal stimulating factor.In pathologic ophthalmic angiogenesis patient's isolating tissue and body fluid, found soluble growth factor, for example, VEGF (VEGF), basic fibroblast growth factor (bFGF or FGF-2), type-1 insulin like growth factor (IGF-1) etc.After the angiogenesis cascade firing, capillary basement membrane and extracellular matrix produce degenerates, and capillary endothelial cell propagation and migration have occurred.The endothelium bud connects the inner chamber that forms pipeline and form stretching, extension subsequently.Because jejune barrier action, new blood capillary have the permeability of increase or easily infiltration usually, so can cause tissue edema.In AMD, because the accumulation of the liquid that high osmosis choriocapillary and CNV produce causes in the retina and/or edema down, i.e. edema under the retina, and in DR, the vascular permeability of the retinal capillary of increase causes edema in the retina.Be divided into mature capillary and be characterised in that and between other endotheliocyte and pericyte, exist continuous basement membrane to be connected, yet under pathologic condition, this atomization is often impaired with normal endothelium.
Effective pharmacological treatment method to pathologic ophthalmic angiogenesis and any associated edema thereof provides reliable effect for the patient, thereby has avoided invasive surgical or destructive laser therapy.Effective treatment of pathologic ophthalmic angiogenesis and edema can improve patients ' life quality, improves social productive forces.Simultaneously, will greatly reduce with the social cost relevant that offer help for blind person with healthy care.
The method according to this invention will be used for the mammal that topical drug delivery composition delivers medicine to needs it, said composition in pharmaceutically acceptable carrier, contain NSAI separately or with the associating of anecortave acetate.According to procedures known in the art, compositions formulated is used to expect the special pathway of administration.
The NSAIs that is preferred for treating retinal edema, PPDR and NPDR comprises the NSAIs that is applicable to ophthalmology that all non-commercial approach and commercial sources obtain, include but not limited to amfenac, nepafenac and be disclosed in U.S. Patent No. 5,475,034 and U.S. Patent No. 4, relevant chemical compound, ketorolac, voltaren see diclofenac and the flurbiprofen of 910,225 (being hereby incorporated by).
This preparation can be by following administration: administration or subconjunctival injection administration and back are described by the implanting device administration behind eyes topical, vitreous body administration, the nearly sclera.The patent of all references and publication are all at this as a reference.
Particularly preferred implanting device comprises that various solids and semi-solid medicament transmit implant, comprises two kinds of non-erodible, Nondegradable implant (as adopting ethylene vinyl acetate made) and erodible or biodegradable implants (made as employing polyanhydride or polylactic acid).It is feature to contain at least a component of polymer usually that drug delivery implant, particularly eye medicinal are transmitted implant.In many cases, the drug delivery implant contains more than a kind of component of polymer.
For example, U.S. Patent No. 5,773,019 discloses the implantable controlled-release device that is used for drug delivery is arrived eye, wherein this implantable device has the kernel of the low solubility drug that contains effective dose, said medicine is covered by a kind of abiotic erodable polymer coating layer, and this coatings can allow low solubility drug to see through.
U.S. Patent No. 5,378,475 disclose the slow releasing pharmaceutical transfer device with kernel or bank, and this kernel or bank contain medicine, first coatings (medicine basically not porous) and second coatings (medicine can see through).First coatings covers a part of kernel at least but at least one fraction kernel is not covered by first coatings.Second coatings is basically with first coatings and not coating part covering fully of kernel.
U.S. Patent No. 4,853,224 disclose biodegradable ophthalmic implant, and it comprises the medicine of the microencapsulation that is used to implant eye-chamber front and/or rear.It is the main component of capsule that polymeric encapsulating agent or lipid become wafer.
United States Patent (USP) 5,164,188 disclose the biodegradable implant in the suprachoroid purposes of eye.This implant is capsuleization normally.Most of capsule is a polymeric encapsulating agent.Also can use the material that can be placed in the choroid appointed area and not move as " oxidized cellulose, gelatin, silicone etc. ".
U.S. Patent No. 6,120,789 disclose the purposes of the non-polymeric compositions that the original position that can be used for solid matrix in animal forms and said composition as medical apparatus or as the slow release transmission system of bioactive ingredients purposes, also comprise other purposes.Said composition is made up of the non-polymeric material and the pharmaceutically acceptable organic solvent of biocompatibility.Non-polymeric compositions is biodegradable and/or bioerodible, and water insoluble basically or body fluid.Organic solvent solubilized non-cohesive material, and in water or other aqueous medium, have from mixing to dispersible dissolubility.When placing the animal implantation position, this non-polymeric compositions finally changes solid structure into.The gained implant provides the system of pharmaceutically effective active component to the animal transmission of inciting somebody to action.According to above-mentioned `789 patent, suitable organic solvent has biocompatibility, pharmaceutically acceptable for those and can be partly dissolved the solvent of above-mentioned non-cohesive material at least.This organic solvent has in water from mixing to dispersible dissolubility.This solvent can spread, disperse or be exuded in the aqueous tissue fluid of implantation position from composition in situ, as serum, lymph, cerebrospinal fluid (CSF), saliva etc.According to the `789 patent, preferred solvent has about 9-13 (cal/cm
3) 1/2 Hildebrand (HLB) dissolubility ratio, and the polarity degree of preferred solvent is for having an appointment 5% dissolubility at least in water.
Necessary energy corrosion of polymerization composition in erodible or biodegradability implant or degraded are so that can and eliminate by the part tissue of eye transmission.Low-molecular-weight molecule (4000 or littler) can not need biodegradation or corrosion to eliminate by the part tissue of eye transmission.
Other implantable device that can be used for transmitting preparation of the present invention is a U.S. Patent No. 5,869, the biodegradability implant described in 079.
For the transmission at the nearly sclera of preparation of the present invention rear portion, preferred device is disclosed in the United States Patent (USP) of owning together 6,413, among the 245B1 (cannula).Other preferred transfer device is disclosed in other patent of owning together and patent application: U.S.6, and 416,777B1 and 6,413,540B1 sclera outer surface implanting device).
Exemplary NSAI preparation of the present invention clearly provides among the embodiment 1-3 in the back.Said preparation can transmit as previously mentioned.Preparation of the present invention can comprise that concentration is NSAI, the non-ionic surface active agent of about 0.001 to 4 (preferred 0.01 to 0.5), as polysorbate (being also referred to as tween), pluronic and span.Also can adopt ionic surfactant, as sodium lauryl sulphate or anionic bile salts.Also can adopt amphoteric surfactant such as lecithin and hydrolecithin.PH can be from 5.0 to 8.4, but preferred about 6.8 to 7.8.In preparation of the present invention, can use suitable buffer system, as citrate or borate.Also can use different osmotic pressure regulators such as potassium chloride, calcium chloride, glycerol, glucose or mannitol.Can affirm that not all NSAIs can be used for the treatment of retinal edema, preceding proliferative diabetic retinopathy (PPDR) and/or simple type diabetic renal papillary necrosis (NPDR), particularly nepafenac by topical.
The following example is used to illustrate the preferred specific embodiments of the present invention.It will be understood by those skilled in the art that the technology that is used to implement operational excellence of the present invention that on behalf of the present inventor, disclosed technology find in the following examples, so be considered to implement optimal way of the present invention.Yet it will be appreciated by persons skilled in the art that according to content disclosed by the invention can have in concrete disclosed embodiment and carry out many changes but still can obtain same or analogous result, this does not deviate from the spirit and scope of the present invention.
Embodiment 1
| Nepafenac | 0.01-0.5％ |
| Polysorbate80 | 0.01％ |
| Benzalkonium chloride | 0.01%+10% is excessive |
| The EDTA disodium | 0.1％ |
| Sodium dihydrogen phosphate | 0.03％ |
| Sodium hydrogen phosphate | 0.1％ |
| Sodium chloride | An amount of 290-300mOsm/Kg |
| NaOH and/or HCl regulate PH | pH4.2-7.4 |
| Water | In right amount to 100% |
Embodiment 2
| Nepafenac | 0.01-0.5％ |
| Hydroxypropyl emthylcellulose | 0.5％ |
| Polysorbate80 | 0.01％ |
| Benzalkonium chloride | 0.01%+5% is excessive |
| The EDTA disodium | 0.01％ |
| Sodium hydrogen phosphate | 0.2％ |
| Sodium chloride | An amount of 290-300mOsm/Kg |
| NaOH and/or HCl regulate PH | pH4.2-7.4 |
| Water | In right amount to 100% |
The present invention also comprises the use in conjunction of NSAIs and angiogenesis inhibitor anecortave acetate or other angiogenesis inhibitor.As used herein, anecortave acetate is meant 4,9 (11)-pregnen diethylenes-17 α, 21-glycol-3,20-diketone-21-acetas and corresponding alcohol (4,9 (11)-pregnen diethylenes-17 α, 21-glycol-3,20-diketone) thereof.At present, anecortave acetate is being used for the optical fundus center near region choroidal neovascularization patient's relevant with AMD clinical trial.Anecortave acetate can be by nearly sclera injection to contain the durative action preparation administration of 3-30mg anecortave acetate, preferred 15mg anecortave acetate.It also can 0.1%-6% the concentration range topical.NSAIs can unite the patient who is used for the treatment of retinal edema, PPDR and/or NPDR separately or with anecortave acetate.NSAIs and anecortave acetate can be made preparation and administration together, perhaps make preparation and administration respectively.The following example is preferably through nearly sclera administration.
Embodiment 3
| Composition | Concentration w/v% |
| Anecortave acetate | 3％ |
| The sodium dihydrogen phosphate dihydrate | 0.051％ |
| Disodium hydrogen phosphate | 0.5％ |
| Tyloxapol | 0.05-0.4％ |
| Sodium chloride | 0.76％ |
| NaOH/HCl | PH is adjusted to 5.0-8.4 |
| Water for injection | In right amount to 100% |
Embodiment 4
The angiogenesis of experiment anecortave acetate suppresses effect (Penn etc., Investigative Ophthalmology ﹠amp in the retinopathy rat cub model in early days; Visual Science, " angiogenesis inhibition steroid is to the effect of the neovascularization of early stage retinopathy rat model ", Vol volume, 42 (1): 283-290, January calendar year 2001).The neonate rat cub is placed the environment of different oxygen.When it being put back in the room air (the 14th day) or after 2 days (the 16th day), giving rat single intravitreal injection carrier or anecortave acetate (500 μ g).In the rat of received vector injection, serious retina neovascularization has appearred.The 14th day and 16 days (difference), anecortave acetate suppressed the retina neovascularization significantly.See Fig. 1.
According to the disclosed content of the application, can prepare and be implemented in this open and claimed all compositionss and/or method fully, and need not further experiment.Although the applicant has set forth the present composition and method in this mode with embodiment preferred, but, to those skilled in the art, can change compositions of the present invention and/or method, and the step in step described herein or the method is carried out various variations, and these do not deviate from thought of the present invention, spirit and scope.More particularly, some chemically with structure on relevant composition can replace composition described herein to obtain similar result.It will be appreciated by persons skilled in the art that all these type of replacements and revise and all can think to be included in the defined spirit of the present invention of the application's claim, scope and the thought.
Claims (7)
1. the method for treatment pathologic ophthalmic angiogenesis and any relevant edema, this method comprise the non-steroidal anti-inflammatory agent that contains effective dose and the compositions of angiogenesis inhibitor.
2. claim 1 method required for protection, wherein angiogenesis inhibitor is an anecortave acetate.
3. claim 1 method required for protection, wherein antiinflammatory is a nepafenac.
4. treatment suffers from the method for retinal edema and simple type patients with diabetic retinopathy, and this method comprises the non-steroidal anti-inflammatory agent that gives effective dose.
5. claim 4 method required for protection, this method also comprises the angiogenesis inhibitor that gives effective dose.
6. claim 5 method required for protection, wherein angiogenesis inhibitor is an anecortave acetate.
7. claim 4 method required for protection, wherein non-steroidal anti-inflammatory agent is a nepafenac.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US47825203P | 2003-06-13 | 2003-06-13 | |
| US60/478,227 | 2003-06-13 | ||
| US60/478,252 | 2003-06-13 |
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| Publication Number | Publication Date |
|---|---|
| CN1802151A true CN1802151A (en) | 2006-07-12 |
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| CN 200480015771 Pending CN1802151A (en) | 2003-06-13 | 2004-06-14 | Formulations of non-steroidal anti-inflammatory agents to treat pathologic ocular angiogenesis |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104490861A (en) * | 2014-11-21 | 2015-04-08 | 三明欣茂药业有限公司 | Sustained-release nepafenac eye-drops preparation |
-
2004
- 2004-06-14 CN CN 200480015771 patent/CN1802151A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104490861A (en) * | 2014-11-21 | 2015-04-08 | 三明欣茂药业有限公司 | Sustained-release nepafenac eye-drops preparation |
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