CN106232123A - The optimization of intravitreal injection steroid bioavailability - Google Patents
The optimization of intravitreal injection steroid bioavailability Download PDFInfo
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- CN106232123A CN106232123A CN201480073463.9A CN201480073463A CN106232123A CN 106232123 A CN106232123 A CN 106232123A CN 201480073463 A CN201480073463 A CN 201480073463A CN 106232123 A CN106232123 A CN 106232123A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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Abstract
The present invention relates to a kind of pharmaceutical composition and the method preparing pharmaceutical composition, described pharmaceutical composition comprise one or more therapeutically effective amounts can regulate mineralcorticoid receptor and/or glucocorticoid receptor (GR) activity compound, described method includes the physicochemical property making described compositions comprise one or more improvement.Receptor modulators preferably is selected from triamcinolone acetonide, 11 desoxycortisones, fludrocortisone, desoxycorticosterone acetate (DOCA), desoxycortone, aldosterone, hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone, or it has the analog of therapeutic activity, derivant, congener, pharmaceutically acceptable salt or conjugate.The physicochemical property of described improvement includes dissolubility, porosity, electrokinetic potential (zeta current potential), flocculation and particle diameter.
Description
Technical field
Described herein the present invention relates generally to a kind of pharmaceutical composition and for preparation for treating ocular disease bag
The method including the pharmaceutical composition of care of patients with diabetic ocular disease and ocular tumor.Especially, the present invention relates to one and prepare this type of medicine
The method of compositions and pharmaceutical composition, described pharmaceutical composition comprises one or more can regulate mineralcorticoid receptor
And/or the compound of glucocorticoid receptor (GR) activity, wherein said compositions comprises the physicochemical property of improvement, but the present invention
Scope need not be confined to this.
Background technology
Triamcinolone acetonide (TA) is that one is applicable to local is used the unresponsive multiple diabetic of 17-hydroxy-11-dehydrocorticosterone and new life
Retinal retinitis becomes and the synthesis 17-hydroxy-11-dehydrocorticosterone of inflammatory conditions.Triamcinolone acetonide has been used for the alone therapy of various fundus situation
With combination therapy and also the vision restoration during vitrectomy.Triamcinolone acetonide is widely used in treating diabetic
The choroidal neovascularization formation that retinopathy, uveitis and age-related degeneration of macula are relevant.
Diabetic macular edema (DME) is the main cause causing diabetic retinopathy visual loss.Glass
Internal injection triamcinolone acetonide is successfully used for improving vision and significantly alleviates DME simultaneously and also be used successfully to reduction macula lutea center thickness
Degree.(not yet being approved by clinical trial) that although this type of purposes is outside the U.S. is considered as label, but a lot of retina is special
Family advocates intravitreal injection of triamcinolone acetonide as the main therapy of recurrent DME.
A kind of mechanism of action of having pointed out be TA increase tight junction protein level thus reduce vascular leakage and its
By suppression VEGF (VEGF), there is angiogenesis suppression action.Although there is great potential, but glass
Internal injection triamcinolone acetonide has the sizable risk including Cataractogenesis and glaucoma.
Remain a need for a kind of alternative medicine.
Summary of the invention
The present invention is to be found that inventor to prepare the improved method of pharmaceutical composition and for treating eye
Propose on the basis of the improved pharmaceutical composition of disease and/or situation or its tendency.
A wide in range form, the present invention relates to a kind of method preparing pharmaceutical composition and for treating ocular disease
Or situation or its tendency pharmaceutical composition, described pharmaceutical composition comprises the physicochemical property of one or more improvement.
At first aspect, invention relates generally to a kind of method for preparing pharmaceutical composition, described medicine group
Compound comprise therapeutically effective amount one or more can regulate mineralcorticoid receptor and/or glucocorticoid receptor (GR) activity
Compound, the described composite preparation that described method includes comprises the physicochemical property of one or more improvement.
At second aspect, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises therapeutically effective amount
One or more can regulate mineralcorticoid receptor and/or the compound of glucocorticoid receptor (GR) activity and at least one is molten
Agent, described compositions comprises the physicochemical property of one or more improvement.
At the 3rd aspect, the invention provides a kind of pharmaceutical composition prepared according to the method for first aspect.
At the 4th aspect, the invention provides a kind of for treating ocular disease or situation or the medicine of its tendency purposes
Compositions, described pharmaceutical composition comprise therapeutically effective amount one or more can regulate mineralcorticoid receptor and/or
The compound of glucocorticoid receptor (GR) activity, wherein said compositions comprises the physicochemical property of one or more improvement.
At the 5th aspect, the invention provides a kind of treat in the object needing it ocular disease or situation or its
The method of tendency, described method includes to regulate mineralcorticoid receptor to ocular administration therapeutically effective amount one or more
And/or the compound of glucocorticoid receptor (GR) activity, described compositions comprises the physicochemical property of one or more improvement, thus controls
Treat ocular disease or situation or its tendency.
At the 6th aspect, the invention provides a kind of compositions in preparation for therapeutic and/or prophylactic treatment eye
Purposes in the medicine of portion's disease or situation, described compositions comprise therapeutically effective amount one or more can regulate salt cortex
Hormone receptor and/or the compound of glucocorticoid receptor (GR) activity, described compositions comprises the physics and chemistry of one or more improvement
Matter.
At the 7th aspect, the invention provides a kind of syringe, described syringe comprises the compositions of second aspect.
In an embodiment of any one above-mentioned aspect, the one or more physicochemical property improved is following
In one or more: dissolubility；Porosity；Electrokinetic potential (zeta current potential)；Flocculation and granularity.
In another embodiment of any one above-mentioned aspect, one or more compounds described can be ground with
Just classification and/or control particle diameter.Described granule can be wet grinding.Described wet grinding can comprise homogenizing.Described all
Matter may be embodied in suspendible in wetting agent.Described wetting agent can comprise polysorbate.
Described particle diameter can comprise crystalline size.
In the further embodiment of any one above-mentioned aspect, can by one or more compound dissolutions described or
Heavily it is dissolved in solvent with adjustment aperture size.Described solvent can include acetone.
Porosity can include average pore size and/or total hole area.
In an embodiment of any one above-mentioned aspect, one or more compounds described are optionally by micropowder
Change.In a specific embodiment, described compound is the most micronized.
In another embodiment of any one above-mentioned aspect, can be by comprising dissolubility in the composition
Companion increases dissolubility.Described dissolubility companion may be configured to regulate mineralcorticoid receptor and/or glucocorticoid is subject to
The second compound of body activity.
Described the second compound can include the compound of same type.
In the further embodiment of any one above-mentioned aspect, the one or more physicochemical property improved may
It is that miscible solvent causes.Described miscible solvent can include solvent or solute.
In an embodiment of any one above-mentioned aspect, described dissolubility can be improved by adding cyclodextrin.
Described cyclodextrin can include hydroxypropylβ-cyclodextrin (HP-β CD).
In the further embodiment of any one above-mentioned aspect, the one or more physicochemical property improved may
It is that pH causes.
In another embodiment of any one above-mentioned aspect, the one or more physicochemical property improved may
It is that fractional distillation causes.
In the further embodiment of any one above-mentioned aspect, the one or more physicochemical property improved is permissible
Including one in the intermolecular force of the ionic strength, the colligative property of improvement, the surface chemistry of improvement and/or the improvement that improve
Or it is multiple.
In the further embodiment of any one above-mentioned aspect, the one or more physicochemical property improved is permissible
Including the residence time changed and/or bioavailability.
The residence time of the change of any one above-mentioned aspect can include residence time that is that increase or that reduce.At one
In specific embodiment, the residence time of described change includes the residence time increased.
In a specific embodiment of any one above-mentioned aspect, the bioavailability of described change can include
The bioavailability increased.
In an embodiment of any one above-mentioned aspect, one or more compounds described can include prodrug.
According to any one in above-mentioned aspect, the one or more physicochemical property improved is real by following step
Existing: by wet sieving for described compound particle to D (V, 0.9) less than 20 μMs；Individually one or more chemical combination described in lyophilization
Thing；The solution of all excipient is added in one or more compound powders described；Subpackage is to also lyophilization in medicine bottle；γ
Ray sterilizing；Redissolve with in BSS.
According to any one in above-mentioned aspect, described one or more can regulate mineralcorticoid receptor and/or sugar
Cortical hormone receptor activity compound can be one or more 17-hydroxy-11-dehydrocorticosterone or its there is the analog of therapeutic activity, spread out
Biology, congener, pharmaceutically acceptable salt, prodrug, metabolite or conjugate.
According to any one in above-mentioned aspect, one or more compounds described can include one or more salt cortex
Hormone.
One or more mineralocorticoids described can include one or more of following kind: triamcinolone acetonide (TA)；11-takes off
Oxygen cortisone (11-DC)；Fludrocortisone (FA)；Desoxycorticosterone acetate (DOCA) (DA)；Desoxycortone (DS)；Or aldosterone；Or
Person its there is the analog of therapeutic activity, derivant, congener, pharmaceutically acceptable salt or conjugate.
According to any one in above-mentioned aspect, one or more compounds described can include one or more sugar cortex
Hormone.
One or more glucocorticoids described can include one or more of following kind: hydrocortisone, cortisone, sprinkles Buddhist nun
Pine, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone, deoxidation cortex
Ketone, aldosterone, or it has the analog of therapeutic activity, derivant, congener, pharmaceutically acceptable salt or conjugate.
One or more compounds described can include one or more dual action compounds, wherein every kind of dual function
Compound can regulate the activity of both mineralcorticoid receptor and glucocorticoid receptor (GR) simultaneously.
Described dual action compounds can include following in one or more: hydrocortisone；Cortisone；Prednisone；Sprinkle
Ni Songlong；Methylprednisolone；Fludrocortisone acetate；Desoxycorticosterone acetate (DOCA)；Aldosterone or its there is the similar of therapeutic activity
Thing, derivant, congener, pharmaceutically acceptable salt or conjugate.
In a specific embodiment kind of any of the above-described aspect, one or more compounds described comprise triamcinolone acetonide
Or it has the analog of therapeutic activity, derivant, congener, pharmaceutically acceptable salt or conjugate.
In another particular implementation kind of any of the above-described aspect, one or more compounds described include acetic acid fluorine hydrogen
Cortisone or its there is the analog of therapeutic activity, derivant, congener, pharmaceutically acceptable salt or conjugate.
In another particular implementation kind of any of the above-described aspect, one or more compounds described include triamcinolone acetonide
With there is the analog of therapeutic activity, derivant, congener, pharmaceutically may be used of fludrocortisone acetate or any of which
The salt accepted or conjugate.
According to any one in above-mentioned aspect, described ocular disease and/or situation can be exudative ocular disease and/
Or situation.
Can be optical fundus exudative eye disease according to any one in above-mentioned aspect, described ocular disease and/or situation
Disease and/or situation.
Can be preocular exudative eye according to any one in above-mentioned aspect, described ocular disease and/or situation
Disease and/or situation.
Can be that degeneration of macula includes the age according to any one in above-mentioned aspect, described ocular disease and/or situation
The degeneration of macula that relevant degeneration of macula is relevant with Wet Age.
Can be diabetic macular edema according to any one in above-mentioned aspect, described ocular disease and/or situation
(DME), cystoid macular edema (CMO)；Maculopathy；And/or ocular tumor.
Described ocular tumor can include retinoblastoma and/or melanoma.
Can be diabetic ocular diseases according to any one in above-mentioned aspect, described ocular disease and/or situation
And/or situation.
Other ocular disease and/or situation include (non-infectious) conjunctivitis, anterior uveitis and ocular allergies.
According to any of the above-described aspect present invention can also comprise one or more pharmaceutically acceptable carriers, diluent or
Excipient.
One or more pharmaceutically acceptable carriers described, diluent or excipient can include one or more surfaces
Activating agent or wetting agent.Described surfactant or wetting agent can include polysorbate.Described polysorbate can be wrapped
Include one or more in polysorbas20 and Tween 80.
One or more pharmaceutically acceptable carriers described, diluent or excipient can include that wetting agent and viscosity are adjusted
One or more in joint agent.Described wetting agent can include polysorbate.Described viscosity modifier can include carboxymethyl
Cellulose (CMC).Described polysorbate wetting agent can include Tween 80 or polysorbas20.At a specific embodiment
In, described polysorbate wetting agent includes Tween 80.
One or more pharmaceutically acceptable carriers described, diluent or excipient can include carboxymethyl cellulose
Sodium；Polysorbate80；Sodium chloride；Balanced salt solution；PH regulator compositions；And/or water for injection.Described BSS can comprise
Potassium chloride；Calcium chloride (anhydrous)；Magnesium chloride (six hydrations)；Sodium acetate (three hydrations)；Sodium citrate (anhydrous)；Hydrochloric acid and/or hydrogen
Sodium oxide.Described pH regulator compositions can comprise hydrochloric acid and/or sodium hydroxide.
According to any one in above-mentioned aspect, the compositions of the present invention can include sustained-release composition.
In a specific embodiment of any one above-mentioned aspect, described compound and compositions can be aseptic
's.
In another specific embodiment of any one above-mentioned aspect, the present composition is free from preservative
's.
As used in this specification, unless the context otherwise requires, term " includes (comprise) " and this term
Variant, such as " comprising ", " comprises " and " comprised ", it is not intended that get rid of other additives, component, whole
Body or step.
Accompanying drawing explanation
In order to enable the invention to should be readily appreciated that and try out, now providing accompanying drawing for reference, the most same is attached
The feature that figure numbering expression is same, and wherein:
Fig. 1: (data are with flat in the dissolubility increase of MR compound and TA in the normal saline adding hydroxypropylβ-cyclodextrin
Mean value ± sd represents, n=3).Upper figure: FLU and TA；Figure below: 11-DC；DCS and DCSA.
Fig. 2: when at 37 DEG C store 72 little time, drug solubility change in Tween 80 aqueous solution situation (
Each time point, data represent with meansigma methods ± sd, n=3).
Fig. 3: high pressure and γ ray sterilization process on the impact of medicine stability in aqueous (data with meansigma methods ±
Sd represents, n=3).
Fig. 4: absorbing wavelength is the contour map of y-axis and HPLC that retention time is X-axis, and the intensity of color represents at this ripple
Absorbance (in this research kind for all compound λ max=240) under length and retention time.
Fig. 5: be exposed to MR compound and the stability of TA of dry powder form after 25kGy gamma-rays.
Fig. 6: the SEM image of MR powder during arrival.All images all represent with similar scale, and total difference therebetween is highlighted
Display.
Fig. 7: 11-DC, DCS and DCSA reduces situation (with D (v, 0.5) and D (v, 0.9) with the particle diameter that homogenising time extends
Represent distribution).
Detailed description of the invention
The present invention relates to a kind of pharmaceutical composition for treating ocular disease and the preparation method of described pharmaceutical composition,
Described ocular disease includes diabetic ocular diseases and ocular tumor.
The present invention is based at least partially on a beyond thought discovery, can prepare and can regulate mineralcorticoid receptor
And/or the compound of glucocorticoid receptor (GR) activity is so that it comprises the physicochemical property of one or more improvement.This improvement
Physicochemical property may advantageously improve required therapeutic process, such as, reduce required intraocular injection number of times or extend ophthalmic note
Time between penetrating and/or the easy degree of increase injection.
Especially, the present invention relates to a kind of method preparing this type of pharmaceutical composition and comprise a kind of or all middle salt cortical hormone
The pharmaceutical composition of element, wherein said compositions comprises the physicochemical property of improvement, but the scope of the present invention is not limited thereto.
At a wide in range aspect, the present invention is based at least partially on one surprisingly, it was concluded that to routine preparation side
Method carries out revising and/or change the physicochemical property that can produce improvement.This has significant advantage, because it can cause patient
Compliance increase and improve eye health result.
As used in this specification, term " eye conditions " includes any eye conditions such as early stage or subclinical stage
Ocular disease.
As used in this specification, term " ocular disease " includes any ocular disease such as degeneration of macula, maculopathy
Become and include that the degeneration of macula (AMD) that age relevant maculopathy (ARM), age are relevant includes dryness (geographic atrophy) and wet
Property (choroidal neovascularization generate (CNV)), exudative ocular disease or situation, retinal pigment epithelium come off (PED), age
Relevant degeneration of macula form, diabetic ocular diseases or situation include diabetic retinopathy and Diabetic Macular water
Swollen (DME), cornea rebirth blood vessel generations, cyclitis, Xi Peier-Ernst Linder disease, retinopathy of prematurity is (the most crystalline
Fibroplasia after body), pterygium, histoplasmosis, iris neovascularization generation, glaucoma, glaucoma associated neogenesis blood
Pipe generation, Purtcher retinopathy, ocular hypertension, macular edema, coats disease, uveitis include anterior uveitis, do
Dry syndrome hereditary that intracellular lipid storage/accumulation relevant outer to the born of the same parents increased, juvenile macular degeneration, eye mistake
Quick and ocular tumor.Described ocular tumor can include retinoblastoma and/or melanoma.
Described ocular disease or situation can include rear portion disease or a situation, including the exudative disease in exudative eye rear portion
Disease or situation.Described eye rear portion disease or situation can include relating to retina, macula lutea and/or the fovea centralis in a rear region
Ocular disease or situation.The example of eye rear portion disease includes macular edema, as clinical yellow in caused by the various causes of disease such as diabetes
Speckle edema or angiographic macula lutea capsule edema, by retina being carried out exudative macular degeneration and the Huang that laser therapy causes
Speckle edema, retinal ischemia and choroidal neovascularization generate, and retinopathy, inflammatory diseases, with tumor such as retinoblastoma cell
The uveitis that tumor or false glioma are correlated with, the new vessels generation of Post vitrectomy, angiopathy and optic nerve
New vessels generates.Described retinal diseases can be diabetic retinopathy, diabetic retinal edema, retina
Come off, generated the one or many in the senile degeneration of macula and myopic retinopathy caused by subretinal Neovascularization
Kind.Described angiopathy can be retinal ischemia, choroidal artery functional defect, choroidal thrombosis formation and be lacked by carotid artery
One or more in the neovascular retinopathies change that blood causes.
Described ocular disease or situation can also include preocular disease or situation, and it is chiefly directed to preocular group
Knit, such as cornea, iris, corpus ciliare and conjunctiva, including exudative preocular disease or situation.Under described preocular disease can be
One or more in stating: cornea rebirth blood vessel generates, has the exudative or keratopathy of inflammatory component or muddiness, diffusivity
Stratiform keratitis, penetrate due to eye or new vessels generation, rubosis iritis, Fuch that contusive ocular injury causes are heterochromatic
Property iridocyclitis, chronic uveitis, anterior uveitis, by operation as LASIK, LASEK, Refractive surgery, IOL implantation
The inflammatory conditions caused；Irreversible corneal edema such as Complications of Cataract Surgery, damage or the wound edema caused, inflammation
Disease, infection and non-infectious conjunctivitis, keratoconjunctivitis, iridocyclitis, iritis, scleritis, episcleritis, infection
Property keratitis, superficial punctate keratitis, keratoconus, posterior polymorphous dystrophy, Fuch malnutrition, aphakia and
Intraocular lens's bullous keratopathy, corneal edema, sclera disease, eye cicatricial pemphigoid, pars planitis, green light
Eye cyclitis syndrome, behcets disease, Vogt-Koyanagi-Harada syndrome, anaphylaxis, eye surface diseases, chemosis,
The hyperemia of toxoplasma retinitis, eye socket inflammatory pseudotumor, chemosis, conjunctival veins, socket of the eye week cellulitis, acute dacryocystitis,
Non-specific angiopathy, sarcoidosis and cytomegalovirus infection.
Edema in tumor, swelling and/or new vessels can be generated by the compositions of the present invention has therapeutical effect.?
Know feeling sick when 17-hydroxy-11-dehydrocorticosterone can reduce inflammation and contribute to alleviate chemotherapy.
As used in this specification, 17-hydroxy-11-dehydrocorticosterone includes that it has the analog of therapeutic activity, derivant, pharmaceutically
Acceptable salt, prodrug, metabolite or conjugate.
As used in this specification, derivant includes regulating mineralcorticoid receptor or glucocorticoid receptor (GR) activity
The compound fragment with therapeutic activity or pharmaceutically active.
Analog can be analog or functional analogue.
But congener comprises identical chemical type atom or the different molecule of increment of constant atomic group.One example is
Methanol and ethanol are homologies.
" prevent " or " prevention ", as used in this specification, refer to preventative or precaution measure.Needs prevent or in advance
Those anti-situations include its ocular disease or situation those situations to be stoped, in some embodiments, including may be easily
Suffer from or be prone to those situations that ocular disease or situation occur, such as, there is ocular disease or the individuality of situation family history.
In this application, if the development of ocular disease or situation is stoped wholly or in part or slows down, then prevent or in advance
Anti-is successful.
" treatment " for object refers to therapeutic treatment in this application.Those situations needing treatment include having suffered from
Those situations of ocular disease or situation, and its ocular disease or situation be in progress those situations to be stoped.Thus, described
Object may be made a definite diagnosis suffers from ocular disease or situation, or may suffer from the eye may being in progress in the case of lacking treatment
Disease or situation.Or, described object is probably asymptomatic, but its have the risk developing into ocular disease or situation because of
Element, such as positive family history.In this application, if compared with the situation using front described object, described ocular disease or
Situation is alleviated or is cured, or the progress of described ocular disease or situation includes that its S&S and/or structural damage stop
Or slow down, then treatment is successful.Successful treatment also includes the development stoping described ocular disease or situation wholly or in part.Right
For the purpose of the application, delay or reduce the progress of described ocular disease or situation or described ocular disease or situation with
Retardance, alleviate or reverse described ocular disease or situation is identical.
Express " effective dose " and refer to single dose or as the medicament of the part in a series of or the amount of medicine, it is effectively controlled
Treat or preventing ocular diseases or situation or its tendency.This word include effectively reaching with use before baseline compared with alleviate one
Or the amount of multiple symptom, this amount is determined by such as vision or other detections.This effective dose is change, and it depends on to be treated
Individual health and health, the sorted group of individuality to be treated, the preparation of compositions, to the assessment of medical conditions and other
Correlative factor.This amount anticipated will fall into the relatively wide scope that can be determined by routine test.
Term " object ", " patient " or " individual " exchanges use in this application, refer to treat for it or prevent be
Required, any object, particularly vertebrate subject, be even more particularly mammalian object.Fall into model of the present invention
The suitable vertebrates enclosed includes but not limited to that any member of subphylum chordata includes people and non-human primates, grinding tooth
Class (such as mice, rat, Cavia porcellus), rabbit section (such as rabbit, hare), Bovidae (such as cattle), sheep section (such as sheep), goat
Section (such as goat), Suidae (such as pig), equine (such as horse), Canidae (such as dog), cat family (such as cat), birds (such as chicken,
Turkey, duck, goose, companion bird such as canary, budgerigar etc.), marine mammal (such as dolphin, whale), reptiles (such as
Serpentis, Rana nigromaculata, Eremiatis argi etc.) and Fish.In specific embodiment, described " object ", " patient " or " individual " are to need treatment
Or preventing ocular diseases or the people of situation, including the object suffering from diabetic ocular diseases or situation or ocular tumor.?
In specific embodiment, the subject the most individually human subjects of described " object ", " patient " or " individual " finger, including
Patient, its standing or by ocular disease or situation or its one or more signs being inclined to, symptom or other refer to
Levying, the newly diagnosis that the most e.g. which kind of reason causes or former diagnosis and present the most experience are recurred or are returnd to the past, or
It is among the risk of ocular disease or situation.Be intended to be included in " object ", " patient " or " individual " is to participate in facing
Bed test does not demonstrates any object of clinical sign of any disease, or participates in the object of epidemiological study, or once
Through the object as comparison.Described " object ", " patient " or " individual " can be the most to have accepted for ocular disease or shape
The treatment of the medicine of condition, or do not accepted such treatment.
According to the present invention, the one or more physicochemical property improved be following in one or more: dissolubility；Hole
Porosity；Electrokinetic potential (zeta current potential)；Flocculation and particle diameter.
Can be by one or more compound dissolutions described or be heavily dissolved in solvent with adjustment aperture size.Described solvent can
To include acetone.
Described porosity can include average pore size and/or total hole area.
One or more compounds described be ground so as classification and/or control particle diameter.
Described particle diameter can include crystalline size.
Described compound is micronized alternatively.In a specific embodiment, described compound is not by micropowder
Change.
Described granule can be wet grinding.Described wet grinding can include homogenizing.Described homogenizing can be included in
Suspendible in wetting agent.Described wetting agent can include polysorbate.
The compositions comprising dissolubility companion can be utilized to increase dissolubility.Described dissolubility companion may be configured to adjust
Joint mineralcorticoid receptor and/or the second compound of glucocorticoid receptor (GR) activity.Described the second compound can wrap
Including similar compound, i.e. when one or more compounds described include mineralocorticoid, described dissolubility companion can include
Different mineralocorticoids.
Dissolubility can be improved by adding cyclodextrin.Described cyclodextrin can include hydroxypropylβ-cyclodextrin (HP-β
CD)。
The physicochemical property of described improvement is probably what miscible solvent caused.Described miscible solvent can include solvent or molten
Matter.
The one or more physicochemical property improved is probably pH or ionic strength causes.
The one or more physicochemical property improved is probably what fractional distillation caused.Described fractional distillation can be to take turns or take turns more
Filter, concentrate and separate.Described filtration can include Mi Libo filter.Described concentration can include being centrifuged.Described separation can
To include gradient separations.
The one or more physicochemical property improved can include the ionic strength of improvement, the colligative property of improvement, improvement
Surface chemistry and/or improvement intermolecular force in one or more.
The one or more physicochemical property improved can include the residence time changed.Described change resident permissible
Including the residence time being increased or decreased.In a specific embodiment, the residence time of described change includes increase
Residence time.
The one or more physicochemical property improved can include the bioavailability changed.A specific enforcement
In mode, the bioavailability of described change can include the bioavailability increased.
In one embodiment, described one or more can regulate mineralcorticoid receptor and/or glucocorticoid
The compound of receptor active be one or more 17-hydroxy-11-dehydrocorticosterone or its have the analog of therapeutic activity, derivant, congener,
Pharmaceutically acceptable salt or conjugate.
One or more compounds described can include one or more mineralocorticoids.One or more salt cortex described
Hormone can include following in one or more: triamcinolone acetonide (TA)；11-desoxycortisone (11-DC)；Fludrocortisone
(FA)；Desoxycorticosterone acetate (DOCA) (DA)；Desoxycortone (DS)；Or aldosterone；Or it has the analog of therapeutic activity, spreads out
Biology, congener, pharmaceutically acceptable salt or conjugate.
In another embodiment, one or more compounds described can include one or more glucocorticoids.
One or more glucocorticoids described can include following in one or more: hydrocortisone, cortisone, prednisone, sprinkle Buddhist nun
Song Long, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone, desoxycortone, aldehyde are solid
Ketone, or it has the analog of therapeutic activity, derivant, congener, pharmaceutically acceptable salt or conjugate.
One or more compounds described can include one or more dual action compounds, wherein every kind of dual function
Compound can regulate the activity of both mineralcorticoid receptor and glucocorticoid receptor (GR) simultaneously.Described dual action compounds
Can include following in one or more: hydrocortisone；Cortisone；Prednisone；Prednisolone；Methylprednisolone；Acetic acid fluorine hydrogen can
Pine；Desoxycorticosterone acetate (DOCA)；Aldosterone or its there is the analog of therapeutic activity, derivant, congener, pharmaceutically can connect
The salt being subject to or conjugate.
In a specific embodiment, one or more compounds described include triamcinolone acetonide or its there is treatment
Analog, derivant, congener, pharmaceutically acceptable salt or the conjugate of activity.
In another specific embodiment, one or more compounds described include fludrocortisone acetate or its
There is the analog of therapeutic activity, derivant, congener, pharmaceutically acceptable salt or conjugate.
In another specific embodiment of any of the above-described aspect, how one or more compounds described include Qu An
Moral and fludrocortisone acetate or any of which there is the analog of therapeutic activity, derivant, congener, pharmaceutically
Acceptable salt or conjugate.
Table 1 below shows the mineralocorticoid and glucocorticoid usefulness that some exemplary compounds and detection thereof obtain.
In one embodiment, the compositions of the present invention includes sustained-release composition.Based on teachings of the present application, this
Skilled person can be readily selected and/or prepare suitable sustained-release composition.
In another embodiment, described compound and compositions can be aseptic.From teachings of the present application, this
Skilled person can be readily selected suitable sterilizing methods, such as heat treated.
In another embodiment, the compositions of the present invention is free from preservative.
In a specific embodiment, the compositions of the present invention may be embodied in syringe.An embodiment party
In formula, described syringe allows to be directly injected into into eyes.
Inventor additionally provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises therapeutic agent described herein and appoints
The pharmaceutically acceptable carrier of selection of land, diluent or excipient.
In one embodiment, one or more pharmaceutically acceptable carriers described, diluent or excipient include
Surfactant.
As used in this specification, term " surfactant " refers to any agent, and its Preferential adsorption is in two not phases
The miscible interface between phase, such as the interface between water and organic polymer soln, the interface of water/air or organic solvent/sky
The interface of gas.Surfactant is generally of hydrophilic parts and lipophilic moieties；So, after being adsorbed to microgranule, it tends to
In the part not attracting coated particle is presented in external environment condition, thus reduce particle aggregation.Surfactant also promotees
Enter the bioavailability absorbing and increasing this medicament of therapeutic agent or diagnostic agent.
Described surfactant can include polysorbate, such as one or more in polysorbas20 and Tween 80.
" pharmaceutically acceptable carrier, diluent or excipient " refers to can be safely used for solid or the liquid of systemic administration
Body filler, diluent or encapsulating substance.According to specific route of administration, it is possible to use variety carrier well known in the art.This
A little carriers can be selected from lower group: sugar, starch, cellulose and its derivates, Fructus Hordei Germinatus, gelatin, Pulvis Talci, calcium sulfate, vegetable oil, conjunction
Oil, polyhydric alcohol, alginic acid, phosphate buffer, emulsifying agent, isotonic saline solution and salt such as inorganic acid salt is become to include hydrochlorate, bromination
Thing and sulfate, organic acid such as acetic acid, propanoic acid and malonic acid and apirogen water.
One or more pharmaceutically acceptable carriers described, diluent or excipient can include that wetting agent and viscosity are adjusted
One or more in joint agent.Described wetting agent can include polysorbate.Described viscosity modifier can include carboxymethyl
Cellulose (CMC).Described polysorbate wetting agent can include Tween 80 or polysorbas20.At a specific embodiment
In, described polysorbate wetting agent includes Tween 80.
A useful reference about pharmaceutically acceptable carrier, diluent and excipient is Lei Mingdun pharmaceutical science
(Remington ' s Pharmaceutical Sciences, Mack Publishing Co.N.J.USA, 1991), it passes through
It is incorporated by the application.
Any safe route of administration can be used to patient to provide the compositions of the present invention.It is, for example possible to use oral,
Rectum, parenteral, Sublingual, buccal, intravenous, intraarticular, intramuscular, Intradermal, subcutaneous, suction, ophthalmic, intraperitoneal, Intraventricular and
Transdermal administration.
Dosage form includes tablet, dispersant, suspensoid, injection, solution, syrup, lozenge, capsule, suppository, aerosol
Agent, percutaneous plaster etc..These dosage forms can also include the injection exclusively for this purpose design or the controlled-release device implanted, or
The implant of improved other forms acted on by this way.The control of therapeutic agent can be affected by it being carried out cladding
Release, such as use hydrophobic polymer include acrylic resin, wax, high fatty alcohol, polylactic acid and polyglycolic acid and some
Cellulose derivative such as hydroxypropyl methyl cellulose.Furthermore, it is possible to by using other polymeric matrixs, liposome and/or micro-
Ball impact controlled release.
The pharmaceutical composition of the present invention being suitable to oral or parenteral administration can exist with discrete unit form, such as glue
Capsule, pouch or tablet, it all contains the therapeutic agent of one or more present invention of scheduled volume, powder or granule or in aqueous
Solution in liquid, anhydrous liquid or suspensoid, oil in water emulsion or water in oil emulsion.Arbitrary method of pharmacy system can be used
Standby such composition, but all of method all includes adding by one or more one or more medicaments as described above
Step in the carrier that required composition is constituted.Under normal conditions, by by the medicament of the present invention and liquid carrier or in small, broken bits
Solid-state carrier or both be mixed with said composition equably and closely, then, wanted if it is necessary, product is made
The shape presented.
Above-mentioned composition can be used in the way of adapting with dosage form, and be that pharmacy is effective with such amount.?
Under the background of the present invention, be enough to produce in patients useful response in suitable time section to patient's applied dose.Executed
The amount of medicament can depend on that object to be treated includes the factor of its age, sex, body weight and general health, this
Will depend upon which the judgement of doctor.
Therefore the present invention can easily understand that and try out, it is provided that following non-limiting example.
Embodiment
Water solublity and the use cyclodextrin increase to drug solubility
We have studied hydroxypropylβ-cyclodextrin (HP-β CD) to MR compound dissolubility of dissolubility in normal saline
Increase situation, its object is to investigate the potential use of its amount increasing drug in solution in suspensoid.
Fig. 1 shows and adds the dissolubility increase (number that hydroxypropylβ-cyclodextrin makes MR compound and TA in normal saline
Meansigma methods ± sd represents according to this, n=3).Clearly illustrate, compared with the dissolubility in normal saline, FLU (fluorine hydrogen can
Pine) and the dissolubility increase of TA (triamcinolone acetonide) > 30 times and the most all along with cyclodextrin concentration linearly
Increase.The absolute dissolubility of TA generally reduces.In aqueous suspension, this will provide higher in the solution when being administered
The medicine of ratio, but the problem not havinging activity reduction.The concentration of DCS (desoxycorticosterone acetate (DOCA)) increases closes close to linear
System, and visible maximum in all medicines, its concentration when HP-β CD is 50mM in the solution > 8mg/mL.But,
The concentration of 11-DC (11-desoxycortisone) and DCSA (desoxycorticosterone acetate (DOCA)) reaches level ground at about 2mg/mL.Although its reason is
Indefinite, the difference between this two compounds is FLU and TA is micronized, and the non-micronization of DCS, DCSA and 11-DC,
And the incorporation time of 48hr may reach fully saturated insufficient for medicine in normal saline.This is also close by DCS
Supported by the fact that saturated, because its dissolubility is 4-8 times of 11-DC and DCSA.In view of taking longer for reaching balance,
The dissolubility that it is expected to 11-DC and DCSA will be more than 6mg/mL, and in fact based at relatively low cyclodextrin concentration lower curve
Slope, the dissolubility of DCS can reach more than 20mg/mL.
In all cases, the use of hydroxypropylβ-cyclodextrin (HP-β CD) is considered as so that observing that these are water-soluble
Property poor medicine pharmacotoxicological effect chance maximize.
Medicine storage stability in normal saline
In order to better assure that the aseptic of final dosage form, it is believed that the final sterilization in the glass ampule that flame seals
Method is the prefered method producing " Kenalog " formula product, but needs medicine is in the long period in saltwater environment by this.Cause
This, it is believed that as the instruction of the possible problem of the medicament contg being stored in suspension and/or catabolite, in aqueous
The stability of medicine situation over time is a key character.Carry out an accelerated stability test, wherein given birth to
Reason saline is prepared for saturated drug solution (as the model of BSS) and sample is stored at 60 DEG C up to 14 days.Think
Which reflects the possible degraded character of at least 2-3 month under room temperature/refrigerated storage temperature.By triplicate sample the 1st, 3,7
From baking oven, took out and analyze the content of medicine after loss of activity with 14 days, and in spectrogram the outward appearance at peak (for these
Research uses special diode array detector and HPLC to be used as the powerful of authenticating compound, and described compound exists
Absorption may not be produced at 240nm and therefore will occur not as " peak " in single wavelength chromatogram).
The drug level of each medicine changes over figure and sees Fig. 2.It is apparent that 11-DC was stable at first week,
It is declined slightly at second week, but is still in sample more than the 90% of original concentration.Fludrocortisone demonstrates significant shakiness
Qualitative, it is down to the 20% of only original concentration after two weeks.Residual drug is the most stable within the detection time period.DCSA and
There are some variability in the result of TA, by it, owing to compared with other compounds, it has extremely low water solubility institute for we
Cause.Especially, the unstability of fludrocortisone can get rid of use pre-packaged aqueous suspension as suitable dosage form, at least
For fludrocortisone, owing to the catabolite of higher level may be produced, need to seek other approach.
Medicine stability (autoclaving and gamma-rays irradiate) aseptically
Pharmaceutical aqueous solution
For preclinical study, research material is aseptic the most to a great extent.Lacking completely
In the case of aseptic production facility, in order to suspension sterilizing being had two kinds of predictable possible modes at " in medicine bottle "
By final suspension autoclaving or γ ray sterilization.Therefore, in order to Preliminary detection " wet " environment Chinese medicine to degraded
Opposing, according to above-mentioned bin stability research medicine made saturated solution and apply autoclave conditions (121 DEG C/
30min) or gamma-rays irradiates (at room temperature～25kGy).
It is a company (Steritech in Melbourne that gamma-rays irradiates；160South Gippsland Hwy,
Dandenong Sth) carry out, and the gamma-rays exposure dose accepted is verified by the QC certification certificate that provides.
Sample is exposed to 25kGy roentgenization for a long time, and it causes medicine bottle serious discoloration, when the suitable glass container using gamma ray resistant
Time, this method may be highly applicable to the preparation of sample.
As can be seen from Figure 3 11-DC and DSC is stable to autoclave conditions.TA is that moderate is stable, but it is at this
Unacceptable active degradation still may be had under the conditions of Xie.FLU also Partial digestion is to close with TA or worse level, but DCSA
Degradable.Gamma-rays irradiates and drug level is had damaging influence, does not has medicine still in practice for for any solution
It is so intact, but except 11-DC, after sterilizing, it still retains the initial drug content less than 20%.
Retention time is mapped by absorbance based on 3-dimensional by wavelength, and the use of diode array detector can be at sample
Product there occurs, what is made some and explains.Especially, lower Fig. 4 shows the most degradable one-tenth of DCSA under autoclaving
DCS, but under gamma-rays irradiates, it is degradable, does not i.e. demonstrate DCS and DCSA in 3D contour map.DCSA is degraded to
DCS is important, because the pharmacology's response that must determine in research in vivo is that non-drug is degraded in the solution by DCSA
The DCS produced causes.
Drug powder
Most of medicine under autoclaving or gamma-rays irradiate has poor steady when contacting with aqueous diluent
Qualitative, this causes needing to carry out a series of further stability study and irradiates the shadow to dry medication powder with detection gamma-rays
Ring, to provide the research material of the sterilized powder redissolved immediately before using.
When carry out γ ray sterilization and for subsequently with carry out similar operations, undosed compare the medicine compared
During assay, Fig. 5 shows the stability of powder.Only DCSA seems to demonstrate on medicament contg and slightly reduces, but only
Analyzing a sample, such difference is likely due to what inevitably slight systematic error caused, but when with in Fig. 3
When data compare, it is still the highest.
Particle diameter and refinement
The particle diameter recommending ophthalmically acceptable suspensoid in document should be less than 50 microns and preferably smaller than 25 microns to avoid bigger medicine
Thing crystallization stimulates part tissue of eye.The triamcinolone acetonide and the fludrocortisone that use in these are studied are directly from Farmabios
Micronised powder；And its excess-three kind medicine is from Sigma Alrich, as without micronized commercial samples.Therefore, under
State and be important that (i) identifies the size of its excess-three kind powder before carrying out below step and confirm the size of TA and FLU；
(ii) when needing the material obtaining suitable size to carry out research material research and development, particle diameter is refined.
By determination of laser light scattering particle diameter
Table 2 shows the particle diameter distribution that the powder sample for " arrival " compound records.It will be apparent that three non-micronizations
Sample needs the further refinement can the product of intravitreal injection to be adapted to make.
Raw-material SEM image
Powder is entered also by SEM for morphology, gathering or other phenomenons that possibly cannot show in laser light scattering
Go research.In Fig. 6, the typical image of display is the most consistent with the particle size results obtained in chapters and sections before this.
It is apparent that there is a need of micronised powder non-to all three refines the agent being adapted to prepare the application of eye rear portion
Type.During it will be apparent that use a small amount of powder, utilize the conventional method of ball milling or jet mill can not produce enough effects, and
Low-down powder yield may finally be obtained.Through determining that the wet grinding using homogenizer will be the best approach, and by even
Slurry device (Polytron) is for this purpose.
Use 0.4% Tween 80 (also referred to as polysorbate80) as wetting agent by 11-DC, DCS and DCSA sample system
Become suspensoid, and use Polytron with 6 notch speed degree homogenate different times to determine the required process time.As in lower Fig. 7
Each figure seen in, this process is all effective to all medicines.Target D (v, 0.9) is set to 20 microns, and it represents size
The granule existed less than 90%, reached in all cases within the process time of 20min or shorter, and subsequently by this side
Method is the refinement of granule in remaining preparation R&D work.
Prescription R&D and production and process optimization
Following middle junction opinion is adopted in the method determining final prescription.1. when in aqueous solution form, autoclaving
With the sterilizing methods that γ ray sterilization is not suitable as these compounds.2., when only at dried forms, γ ray sterilization seems
Be suitable to powder.3. need to refine again to meet these research to the particle diameter of 11-DC, DCS and DCSA by wet grinding.
It is achieved in that a kind of extensive method comprising the following stage: be less than wet sieving for drug particles to D (V, 0.9)
20μM；Individually lyophilized medication；The solution of all excipient is added the test tube filling drug powder；It is dispensed in medicine bottle also
Lyophilization；γ ray sterilization also carries out quality control；Redissolve in BSS when research or use.
From table 3 it is observed that our conclusion is in addition to all medicines beyond TA without equal table when CMC and Tween 80
Reveal suspension ability problem, recommend the prescription comprising CMC and Tween 80 the most as shown in Tables 3 and 4.
Thus, using the prescription in table 4 as research material.
The batch production result of the display packing suitability collects
Table 5 shows and collects batch production result.One underproof result is a dosage in medicine bottle
DCSA is slightly below quality standard lower limit 18mg.This is likely due to active component during γ ray sterilization and slightly degrades and cause
, but it does not results in the peak occurring failing to understand in HPLC chromatogram.
Triesence compositions
Table 6 shows the Triesence compositions directly listed with product information sheet form.Therefore, a kind of selection is to make
The fludrocortisone system for redissolving is prepared with above-mentioned technique and Triesence prescription.
Kenalog compositions
Table 7 shows the Kenalog compositions directly listed with product information sheet form.When producing, by container
Air is replaced into nitrogen.Source of data:
http://packageinserts.bms.com/pi/pi_kenalog-10.pdf。
The present invention has significant advantage, because the physicochemical property improved can improve required therapeutic process, such as, subtracts
Lack required intraocular injection number of times or increase the time between intraocular injection and/or make injection be more prone to.
Additionally, the present invention has significant benefit, because the time reduced between frequency injection or increase injection can increase
Add the compliance of patient.This will cause the eye health consequence improved in turn.
The purpose of entire disclosure is to describe the preferred embodiment of the present invention, rather than limits the invention to any one
Embodiment or specific characteristic set.Therefore, it will be appreciated by persons skilled in the art that in the premise without departing from the scope of the invention
Under, according to the present invention it is possible to exemplified particular implementation is carried out different modifying and change.
Table 1: the mineralcorticoid receptor of some corticosterones and glucocorticoid receptor (GR) activity
Abbreviation: MR=mineralcorticoid receptor；GR=glucocorticoid receptor (GR)；
I.m. intramuscular injection
Table 2: particle size distribution measuring
Table 3: the suspension of compound
Table 4: the prescription utilized
Table 5: the batch production of the method for expressing suitability is summed up
Medicine
11-DC
DCS
DCSA
Fludra
T.A
Table 6:Triesecence compositions
Table 7:Kenalog compositions
| Triamcinolone acetonide | 10mg/mL |
| Sodium carboxymethyl cellulose | 0.75%w/v；7.5mg/mL |
| Polysorbate80 | 0.04% (no standard it is contemplated that w/v=0.4mg/mL) |
| Sodium chloride | 0.65% to isotonic |
| Benzyl alcohol | 0.9% (w/v) |
| Hydrochloric acid and/or sodium hydroxide | For regulating pH |
| Water for injection | qs |
Claims (31)
1. the method preparing pharmaceutical composition, described pharmaceutical composition comprise therapeutically effective amount one or more can adjust
Joint mineralcorticoid receptor and/or the compound of glucocorticoid receptor (GR) activity, described method includes making described composite preparation
Comprise the physicochemical property of one or more improvement.
2. a pharmaceutical composition, described pharmaceutical composition comprise therapeutically effective amount one or more can regulate salt cortical hormone
Element receptor and/or glucocorticoid receptor (GR) activity compound and at least one solvent, described compositions comprises one or more
The physicochemical property improved.
3. the pharmaceutical composition that prepared by a method according to claim 1.
4., for treating ocular disease or situation or a pharmaceutical composition for its tendency purposes, described pharmaceutical composition comprises
One or more of therapeutically effective amount can regulate mineralcorticoid receptor and/or the compound of glucocorticoid receptor (GR) activity,
Wherein said compositions comprises the physicochemical property of one or more improvement.
5. treating ocular disease or situation or a method for its tendency in the object needing it, described method includes to eye
One or more of application for the treatment of effective dose can regulate mineralcorticoid receptor and/or the chemical combination of glucocorticoid receptor (GR) activity
Thing, described compositions comprises the physicochemical property of one or more improvement, thus treats described ocular disease or situation or its tendency.
6. a compositions purposes in the medicine that preparation is used for therapeutic and/or prophylactic treatment ocular disease or situation,
Described compositions comprise therapeutically effective amount one or more can regulate mineralcorticoid receptor and/or glucocorticoid receptor (GR)
The compound of activity, described compositions comprises the physicochemical property of one or more improvement.
7. the syringe of the compositions comprised described in claim 2.
8. according to method, compositions, purposes or the syringe described in aforementioned any one claim, wherein said one or many
The physicochemical property of individual improvement be following in one or more: dissolubility；Porosity；Electrokinetic potential (zeta current potential)；Flocculation and
Particle diameter.
9. according to method, compositions, purposes or the syringe described in aforementioned any one claim, wherein said one or many
Kind of compound is ground so that classification and/or control particle diameter.
Method the most according to claim 9, compositions, purposes or syringe, wherein said grinding comprises wet grinding.
11. according to method, compositions, purposes or the syringe described in aforementioned any one claim, wherein said dissolubility
Increase by comprising dissolubility companion in the composition.
12. methods according to claim 11, compositions, purposes or syringe, wherein said dissolubility companion includes ring
Dextrin.
13. according to method, compositions, purposes or the syringe described in aforementioned any one claim, wherein said one or
The physicochemical property of multiple improvement is realized by following step: by wet sieving for described compound particle to D (V, 0.9) less than 20 μ
M；Individually one or more compounds described in lyophilization；All excipient are added in one or more compound powders described
Solution；Subpackage is to also lyophilization in medicine bottle；γ ray sterilization；Redissolve with in BSS.
14. according to method, compositions, purposes or the syringe described in aforementioned any one claim, one or more of which
Can regulate mineralcorticoid receptor and/or glucocorticoid receptor (GR) activity compound be one or more 17-hydroxy-11-dehydrocorticosterone or its
There is the analog of therapeutic activity, derivant, congener, pharmaceutically acceptable salt, prodrug, metabolite or conjugate.
15. according to method, compositions, purposes or the syringe described in aforementioned any one claim, wherein said one or
Multiple compounds includes one or more mineralocorticoids.
16. methods according to claim 15, compositions, purposes or syringe, one or more salt cortex wherein said
Hormone include following in one or more: triamcinolone acetonide (TA)；11-desoxycortisone (11-DC)；Fludrocortisone (FA)；
Desoxycorticosterone acetate (DOCA) (DA)；Desoxycortone (DS)；Or aldosterone；Or its have the analog of therapeutic activity, derivant,
Congener, pharmaceutically acceptable salt or conjugate.
17. according to method, compositions, purposes or the syringe described in aforementioned any one claim, wherein said one or
Multiple compounds includes one or more glucocorticoids.
18. methods according to claim 17, compositions, purposes or syringe, one or more sugar cortex wherein said
Hormone include following in one or more: hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, times
Ta meter Song, triamcinolone, beclometasone, fludrocortisone, desoxycortone, aldosterone, or it has the class of therapeutic activity
Like thing, derivant, congener, pharmaceutically acceptable salt or conjugate.
19. according to method, compositions, purposes or the syringe described in aforementioned any one claim, wherein said one or
Multiple compounds include triamcinolone acetonide or its there is the analog of therapeutic activity, derivant, congener, pharmaceutically acceptable
Salt or conjugate.
20. according to method, compositions, purposes or the syringe described in aforementioned any one claim, wherein said one or
Multiple compounds include fludrocortisone acetate or its there is the analog of therapeutic activity, derivant, congener, pharmaceutically may be used
The salt accepted or conjugate.
21. according to method, compositions, purposes or the syringe described in aforementioned any one claim, wherein said one or
Multiple compounds include triamcinolone acetonide and fludrocortisone acetate or the analog with therapeutic activity of any of which,
Derivant, congener, pharmaceutically acceptable salt or conjugate.
22. according to method, compositions, purposes or the syringe described in aforementioned any one claim, wherein said eye disease
Sick and/or situation includes exudative ocular disease and/or situation.
23. according to method, compositions, purposes or the syringe described in aforementioned any one claim, wherein said eye disease
Sick and/or situation includes the exudative ocular disease in optical fundus and/or situation.
24. according to method, compositions, purposes or the syringe described in aforementioned any one claim, wherein said eye disease
Sick and/or situation includes preocular exudative ocular disease and/or situation.
25. according to method, compositions, purposes or the syringe described in aforementioned any one claim, wherein said eye disease
The sick degeneration of macula with/situation being degeneration of macula and including that age relevant degeneration of macula is relevant with Wet Age.
26. according to method, compositions, purposes or the syringe described in aforementioned any one claim, wherein said eye disease
Sick and/or situation is diabetic macular edema (DME), cystoid macular edema (CMO)；Maculopathy；And/or ocular tumor.
27. swell according to method, compositions, purposes or the syringe described in aforementioned any one claim, wherein said eye
Tumor includes retinoblastoma and/or melanoma.
28. according to method, compositions, purposes or the syringe described in aforementioned any one claim, wherein said eye disease
Sick and/or situation is care of patients with diabetic ocular disease and/or situation.
29. according to method, compositions, purposes or the syringe described in aforementioned any one claim, wherein said eye disease
Sick and/or situation includes that conjunctivitis includes non-infectious conjunctivitis, anterior uveitis and ocular allergies.
30., according to method, compositions, purposes or the syringe described in aforementioned any one claim, also comprise one or many
Plant pharmaceutically acceptable carrier, diluent or excipient.
31. methods according to claim 30, compositions, purposes or syringe, wherein said one or more pharmaceutically
Acceptable carrier, diluent or excipient include one or more wetting agent and/or viscosity modifier.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2013904935 | 2013-12-17 | ||
| AU2013904935A AU2013904935A0 (en) | 2013-12-17 | Optimising bioavailability of injectable steroids | |
| PCT/AU2014/001141 WO2015089559A1 (en) | 2013-12-17 | 2014-12-17 | Optimising bioavailability of intra vitreally injectable steroids |
Publications (1)
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| CN106232123A true CN106232123A (en) | 2016-12-14 |
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| CN201480073463.9A Pending CN106232123A (en) | 2013-12-17 | 2014-12-17 | The optimization of intravitreal injection steroid bioavailability |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111886013A (en) * | 2018-02-26 | 2020-11-03 | 眼力有限公司 | Compositions and methods for treating dry A.M.D (age-related macular degeneration) |
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| WO2019136512A1 (en) * | 2018-01-10 | 2019-07-18 | Eye Co Pty Ltd | Medical device and pharmaceutical composition for treatment of an eye disease or condition |
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| US20040141925A1 (en) * | 1998-11-12 | 2004-07-22 | Elan Pharma International Ltd. | Novel triamcinolone compositions |
| WO2005074942A1 (en) * | 2004-02-04 | 2005-08-18 | Retmed Pty Ltd | Slow release steroid composition |
| US20050234018A1 (en) * | 2004-04-15 | 2005-10-20 | Allergan, Inc. | Drug delivery to the back of the eye |
| WO2006043965A1 (en) * | 2004-10-14 | 2006-04-27 | Allergan, Inc. | Therapeutic ophthalmic compositions containing retinal friendly excipients and related methods |
| CN101180038A (en) * | 2005-03-23 | 2008-05-14 | 伊兰制药国际有限公司 | Nanoparticulate corticosteroid and antihistamine formulations |
| WO2011006079A2 (en) * | 2009-07-10 | 2011-01-13 | Lyotropoic Therapeutics, Inc. | Ophthalmic formulations of reversed liquid crystalline phase materials and methods of using |
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2014
- 2014-12-17 CN CN201480073463.9A patent/CN106232123A/en active Pending
- 2014-12-17 WO PCT/AU2014/001141 patent/WO2015089559A1/en active Application Filing
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|---|---|---|---|---|
| US20040141925A1 (en) * | 1998-11-12 | 2004-07-22 | Elan Pharma International Ltd. | Novel triamcinolone compositions |
| WO2005074942A1 (en) * | 2004-02-04 | 2005-08-18 | Retmed Pty Ltd | Slow release steroid composition |
| US20050234018A1 (en) * | 2004-04-15 | 2005-10-20 | Allergan, Inc. | Drug delivery to the back of the eye |
| WO2006043965A1 (en) * | 2004-10-14 | 2006-04-27 | Allergan, Inc. | Therapeutic ophthalmic compositions containing retinal friendly excipients and related methods |
| CN101180038A (en) * | 2005-03-23 | 2008-05-14 | 伊兰制药国际有限公司 | Nanoparticulate corticosteroid and antihistamine formulations |
| WO2011006079A2 (en) * | 2009-07-10 | 2011-01-13 | Lyotropoic Therapeutics, Inc. | Ophthalmic formulations of reversed liquid crystalline phase materials and methods of using |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111886013A (en) * | 2018-02-26 | 2020-11-03 | 眼力有限公司 | Compositions and methods for treating dry A.M.D (age-related macular degeneration) |
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| WO2015089559A1 (en) | 2015-06-25 |
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