CN106344587A - Lanosterol compound preparation for eyes - Google Patents
Lanosterol compound preparation for eyes Download PDFInfo
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- CN106344587A CN106344587A CN201610720166.XA CN201610720166A CN106344587A CN 106344587 A CN106344587 A CN 106344587A CN 201610720166 A CN201610720166 A CN 201610720166A CN 106344587 A CN106344587 A CN 106344587A
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- ophthalmic preparation
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- lanosterol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
Abstract
The invention discloses a lanosterol compound preparation for eyes, particularly a pharmaceutical composition comprising 5-250mM lanosterol compounds and a preparation method of the pharmaceutical composition, and application of the pharmaceutical composition in the aspects of prevention and treatment of ophthalmic diseases.
Description
Technical field
The present invention relates to ocular drug field, specifically, the invention discloses a kind of lanosterol class compound is ophthalmically acceptable
Dosage form, and its purposes for treatment or prevention.
Background technology
Cataract is a kind of often property sent out diseases causing blindness with blurred vision, visual deterioration as cardinal symptom, in the whole world 4000
In ten thousand to 4,500 ten thousand blind persons, because of cataract, blinding person accounts for 60%.Cataract betides on eye crystal, due to aging, hereditary, office
Portion's malnutrition, immunity and the factor such as Developmental and Metabolic Disorder, wound, radiation, the crystal metabolism disorder of individual patients, lead to crystalline lenses egg
Leucismus makes a mistake accumulation, reaches retina thus affecting light and entering ophthalmic, is eventually exhibited as blurred vision or even vision
The symptom (bloemendal, de jong et al.2004) completely losing.
Pathogenesis of cataract is not limited only to the mankind, and a lot of mammalian species (horse, Canis familiaris L., monkey etc.) all can occur cataract
(chauke,magwebu et al.2016；sande,alvarez et al.2016).Cataract can be divided according to the different causes of disease
For senile cataract, congenital cataract, traumatic cataract and complicated cataract.
At present, clinical medicine is there is no can to carry out effectively treatment to cataract, diseased individuals more can only be substituted by operation
Work crystal is improving vision.Current paper proves, sterin quasi-molecule can mitigate the cataract order of severity of animal eyes
(quinlan 2015).Wherein, lanosterol (lanosterol) is proved to cataract crystalline protein can be reversed in vitro wrong
Pile up by mistake, so that crystal transparency is recovered as before；In zoopery, cooperation high frequency time ophthalmic glass chamber injection lanosterol and its
On the premise of slow releasing agent, it is simultaneously added dropwise the eye drop containing lanosterol and can mitigate Cataract turbidity
(zhao,chen et al.2015).
By the ocular administration route of Deca medicament for the eyes, biological utilization ratio of drug only has 5-10%, effective in eye drop
Composition is difficult to reach within the eye or the long period keeps treating the concentration of diseases demands, and most of ingredient is with channels such as lachrymal glands
It is discharged outer (scruggs, the wallace et al.1978 of eye at short notice；chetoni,mariotti bianchi et
al.1996).Lanosterol is soluble in organic solvent, such as dmso etc., but extremely difficult be dissolved in water, this makes it as ophthalmic administration master
When wanting effective ingredient, it is difficult in the form of eye dropping of eye drops, individually reach healing cataractous purpose (makley, mcmenimen
Et al.2015, shanmugam pm, barigali a et al.2015).
Content of the invention
It is an object of the invention to provide a kind of high concentration, there is suitable osmotic pressure, Ocular Tolerability is good, is suitable for
The lanosterol class compound ophthalmic preparation of dosing eyes.
It is a further object of the present invention to provide described ophthalmic preparation is being treated or is being prevented people or non-human mammal cataract
The application of aspect.
In a first aspect of the present invention, there is provided the ophthalmic preparation that a kind of non-wound (non-invasive) is administered, its feature
It is, described ophthalmic preparation includes: (a) pharmaceutically acceptable carrier, and (b) is as the lanosterol of the first active component
Class compound；
Wherein, in described ophthalmic preparation, the concentration of lanosterol class compound is 5～250mm.
In another preference, described lanosterol class compound is selected from the group:
(i) lanosterol or itself or its pharmaceutically acceptable salt or its pharmaceutically acceptable ester；
(ii) lanostenol or itself or its pharmaceutically acceptable salt or its pharmaceutically acceptable ester；
(iii) combination of said components (i) and (ii).
In another preference, described lanosterol class compound is lanosterol.
In another preference, described lanosterol class compound is lanostenol.
In another preference, described lanosterol class compound is the mixing of lanosterol and lanostenol
Thing.
In another preference, in the mixture of described lanosterol and lanostenol, the content of lanosterol
C1 is 1:500 to 500:1, preferably 5:90 to 500:1 with the ratio c1/c2 of content c2 of lanostenol, more preferably for 80:
1 to 200:1, most preferably for 85:1 to 100:1.
In another preference, in described ophthalmic preparation, all or essentially all of lanosterol class compound is molten
Solution.
In another preference, described " all or essentially all of " refer to 90-100%, preferably 95-100%, more
Good ground 99-100%.
In another preference, in described ophthalmic preparation, the concentration of lanosterol class compound is 10～200mm, preferably
Ground 15～150mm, more preferably 20～50mm；Most preferably 20～30mm.
In another preference, the concentration of described lanosterol class compound is about 25mm.
In another preference, described ophthalmic preparation is selected from the group: eye drop, Emulsion, gel, spongaion, slow release are micro-
Ball, intraocular slow-released plant piece, eye slow-release medicine-membrane.
In another preference, described eye drop is solution form.
In another preference, described eye drop is emulsion form.
In another preference, described ophthalmic preparation is uniform solution.
In another preference, it is (i.e. described that described ophthalmic preparation also includes the solid pharmaceutical dosage forms that restructural is liquid
Dosage form, after the pharmaceutically acceptable carrier adding liquid, can directly reconstruct (reconstruct) and become liquid ophthalmic preparation).
In another preference, the pharmaceutically acceptable carrier of described liquid is water.
In another preference, described ophthalmic preparation also includes: (c) second active component, and wherein said second is alive
Property composition is selected from the group: azole compounds, glucocorticoidss compound, antibiotic or a combination thereof.
In another preference, the second described active component is azole compounds.
In another preference, the concentration of described azole compounds is 0.05～40 μm, preferably 0.5～10 μm.
In another preference, described azole compounds are selected from econazole, isoconazole, Bifonazole, clotrimazole, A Li
Piperazine azoles, Ketoconazole, fluconazol, phenylimidazole, miconazole, SSF109, Triadimenol, Tebuconazole, propiconazole or a combination thereof.
In another preference, described azole compounds are econazole.
In another preference, described glucocorticoid compound is selected from the group: dexamethasone, hydrocortisone or
A combination thereof.
In another preference, described antibiotic is selected from the group: tobramycin, gentamycin sulfate, chlortetracycline, chlorine are mould
Element or a combination thereof.
In another preference, in described ophthalmic preparation, the second described active component is dissolved form.
In another preference, in described ophthalmic preparation, the content of the second described active component is 0.01-5wt%,
Preferably 0.1-1wt%, by the gross weight meter of ophthalmic preparation.
In another preference, described pharmaceutically acceptable carrier is to eye irritation.
In another preference, described pharmaceutically acceptable carrier includes one or more carrier being selected from the group:
(a1) water；
(a2) solubilizing agent；
(a3) surfactant；
(a4) thickening agent.
(a5) osmotic pressure regulator；
(a6) buffer of buffer agent or described buffer agent composition；
(a7) preservative；
(a8) chelating agen；
(a9) slow releasing agent.
In another preference, described solubilizing agent includes: polyol.
In another preference, described polyol with the ratio of the consumption of the first active component is: 50:1-1:
50.
In another preference, described polyol is selected from the group: polyhydric alcohols, cyclodextrin, polyethylene
Alcohol or a combination thereof.
In another preference, described polyol has the skeleton that carbon, hydrogen and hetero atom (as n) are constituted, and
And active group is substantially or completely hydroxyl.
In another preference, described polyol includes alcohols polyol (units as many in c2-c10
Alcohol) and cyclodextrin and cyclodextrin derivative.
In another preference, described polyol is selected from: propylene glycol (polyene glycol), glycerol
(glycerol), Polyethylene Glycol (polyethylene glycol), alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, cyclodextrin spread out
Biological, polyvinyl alcohol (polyvinyl alcohol, pva), or a combination thereof.
In another preference, described polyol is HP-β-CD.
In another preference, described surfactant is selected from: anion surfactant, cationic surfactant,
Nonionic surfactant, chaotropic type (chaotropic) surfactant or a combination thereof.
In another preference, described nonionic surfactant is selected from: tween, span, fatty glyceride, polyoxy second
Alkenes, Pluronic F68, or a combination thereof.
In another preference, described thickening agent is selected from: shitosan, hydroxypropyl methyl cellulose (hpmc), Methyl cellulose
Plain (mc), polyvidone (pvp), gelatin, sodium carboxymethyl cellulose (cmc-na) or a combination thereof.
In another preference, described thickening agent is shitosan.
In another preference, described osmotic pressure regulator is selected from: saccharide compound, salt compounds or a combination thereof.
In another preference, described saccharide compound is selected from Sorbitol, glucose, Mannitol or a combination thereof.
In another preference, described salt compounds are selected from sodium chloride, potassium chloride, boric acid or a combination thereof.
In another preference, described buffer is selected from: phosphate buffer, borate buffer solution, and citrate delays
Rush liquid, tartaric acid buffer, ammonium acetate salt buffer, or a combination thereof.
In another preference, described preservative is selected from: benzalkonium bromide, chlorobutanol, parabenses, mountain
Pears acid, antibiotic or a combination thereof；It is preferred that the content of preservative is 0-1wt%；
In another preference, described ophthalmic preparation does not contain preservative.
In another preference, described chelating agen is selected from: edta, egta, cdta, citrate, or a combination thereof；Preferably
The content of ground intercalating agent is 0-0.1wt%；
In another preference, described ophthalmic preparation contains: polyol, optional surfactant and optional
Thickening agent,
Wherein, by the gross weight meter of described ophthalmic preparation,
The content of polyol is 0.1-50wt%；
The content of surfactant is 0-2wt%；
The content of thickening agent is 0-6wt%.
In another preference, the content of polyol is 25-40wt%.
In another preference, the content of surfactant is 0.1-1wt%.
In another preference, the content of thickening agent is 0.1-5wt%.
In another preference, the osmotic pressure of described ophthalmic preparation is 240～510mosm.
In another preference, described ophthalmic preparation ph value is 5.5～8.5, preferably 6.0～8.0, more preferably 6.5-
7.5.
It is characterised in that described ophthalmic preparation is the aqueous solution for dosing eyes in another preference.
In another preference, described ophthalmic preparation is the aqueous solution for dosing eyes, and azole chemical combination in solution
The concentration of thing is 0.05～40 μm, more preferably 0.5～10 μm.
In another preference, described ophthalmic preparation contains following component:
10～50mm lanosterol class compound；
0.05～40 μm of azole compounds；
The polyol of 0.1-50wt%, preferably propylene glycol or beta cyclodextrin；
0-1wt% solubilizing agent, preferably Polysorbate；
0.2-0.4wt% thickening agent, preferably shitosan；
0-0.5wt% preservative, preferred antibiotics；
With the water of surplus,
And described ophthalmic preparation ph value about 6.5-7.5, and osmotic pressure is 240～510mosm.
In a second aspect of the present invention, there is provided a kind of preparation side of the ophthalmic preparation that first aspect present invention is provided
Method is it is characterised in that comprise the following steps:
(1) by (a) pharmaceutically acceptable carrier；(b) the lanosterol class compound as the first active component enters
Row mixing, thus form the ophthalmic preparation that first aspect present invention is provided.
In another preference, in step (1), including by (a) pharmaceutically acceptable carrier；(b) as first
The lanosterol class compound of active component and the second active component described in (c) are mixed, thus forming the present invention first
The ophthalmic preparation that aspect is provided.
In another preference, described method includes:
I () will be scattered in polyhydroxy as the lanosterol class compound of the first active component and the second optional active component
In based compound, form the first dispersion；
(ii) described first dispersion is mixed with the carrying out of remaining pharmaceutically acceptable carrier, thus forming this
The ophthalmic preparation that bright first aspect is provided.
In another preference, in step (ii), first remaining pharmaceutically acceptable carrier is mixed, formed
Then described first dispersion is mixed by the second solution or the second dispersion with described second solution or the second dispersion, thus
Make the ophthalmic preparation that first aspect present invention is provided.
In another preference, the solvent of described second solution is water.
In another preference, the solute of described second solution is selected from the group: solubilizing agent, surfactant, thickening agent, oozes
Pressure regulator, buffer agent, preservative, chelating agen, slow releasing agent or a combination thereof thoroughly.
In a third aspect of the present invention, there is provided a kind of purposes of the ophthalmic preparation that first aspect present invention is provided, its
It is characterised by, described ophthalmic preparation is used for preparation prevention or treatment people or the cataractous medicine of non-human mammal.
In another preference, described non-human mammal include horse, Canis familiaris L., cat, panda, monkey, orangutan, rodent,
Rabbit, pig, as.
In another preference, described rodent includes mice, rat.
In another preference, described cataract is selected from the group: senile cataract, congenital cataract, traumatic white
Cataract and complicated cataract.
In another preference, described cataract is traumatic cataract.
In a fourth aspect of the present invention, there is provided a kind of prevention or the cataractous method for the treatment of need it is characterised in that giving
Object eyes non-invasively apply a first aspect of the present invention provide ophthalmic preparation.
In another preference, described " non-invasively administration " refers to Deca in eyes.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and having in below (eg embodiment)
Can be combined with each other between each technical characteristic of body description, thus constituting new or preferred technical scheme.As space is limited, exist
This no longer tires out one by one states.
Brief description
Fig. 1 shows the therapeutic effect suffering from eye to the cataract of Canis familiaris L. in the embodiment of the present invention 2, before left figure is treatment, right figure
After treatment.Result shows, this cataract is cured completely.
Specific embodiment
The present inventor through long-term and in-depth study it has unexpectedly been found that, containing a class specific compound (i.e. lanosterol
Class compound) as active component the ophthalmic preparation that is administered of non-wound (non-invasive), unexpectedly can extremely efficient subtract
The cataract symptom of light mammal, even completely eliminates the cataract symptom of mammal.Additionally, by adding specific medicine
On, acceptable carrier (especially polyol) and extra active component (as azole compounds), can be obtained thorn
Sharp property is little, eye toleration high, the medicine holdup time within the eye is longer and curative effect more preferably ophthalmic preparation.On the basis of the above,
Inventor completes the present invention.
Ophthalmic preparation
The invention provides a kind of ophthalmic preparation, by from suitable pharmaceutical composition (such as azole compounds, polyhydroxy
Compound, surfactant, thickening agent etc.), not only successfully meet the particular/special requirement (as osmotic pressure) of ophthalmic administration, also notable
Improve or increased the concentration of active component.
The ophthalmic preparation of the present invention includes pharmaceutically acceptable carrier and the Pilus Caprae seu Oviss steroid of the effective dose as active component
Alcohol compound, and press the total volume meter of preparation, the concentration of (dissociating) lanosterol class compound of dissolving is 5～
250mm.
Generally, the ophthalmic preparation of the present invention include water or aqueous solvent and be dissolved in active component in described solvent and
Following components: azole compounds, polyol, optional surfactant and optional thickening agent.Described ophthalmic preparation
Also optionally add pharmaceutically acceptable other components, other pharmaceutically acceptable components above-mentioned include but is not limited to,
Osmotic pressure regulator, buffer agent, preservative, chelating agen, slow releasing agent etc..
First active component
As used herein, term " the first active component " or " lanosterol class compound " are used interchangeably, and refer to Pilus Caprae seu Oviss steroid
Alcohol compound.The active component of the present invention can be the various crystal formations, no of pharmaceutically acceptable lanosterol class compound
Setting, dehydrate, solvate, hydrate, enantiomer, in the present invention, lanosterol class compound refers to first work of the present invention
Property composition.
Lanosterol is tetracyclic triterpenoids compound, and structural formula is as follows:
Lanosterol is an important product on steroid biosynthetic metabolism path in people or other mammal.So
And, lanosterol water solublity is very poor, in water maxima solubility can only achieve 0.000376mg/ml (http: //
Www.drugbank.ca/drugs/db03696), much do not reach the clinically concentration needed for dosing eyes.
However, the research of the present inventor shows, using specific pharmaceutical formulation, the dissolving of lanosterol can be significantly improved
Degree, thus under keeping ophthalmic higher concentration, make lanosterol have very effective therapeutic effect to cataract.
Second active component
As used herein, term " the second active component " refers to azole compounds, glucocorticoidss compound, antibiosis
Element or a combination thereof.In ophthalmic preparation in the present invention, the second active component can be dissolved form.Ophthalmically acceptable in the present invention
In preparation, the content of the second active component is 0.01-5wt%, preferably 0.1-1wt%, by the gross weight meter of ophthalmic preparation.
When " second active component " of the present invention is azole compounds, its concentration is preferably 0.05～40 μm, and preferably 0.5
～10 μm.Above-mentioned azole compounds are selected from econazole, isoconazole, Bifonazole, clotrimazole, Aripiprazole, Ketoconazole, fluorine health
Azoles, phenylimidazole, miconazole, SSF109, Triadimenol, Tebuconazole, propiconazole or a combination thereof.
Glucocorticoid compound in the present invention is selected from the group: dexamethasone, hydrocortisone or a combination thereof.
Antibiotic in the present invention is selected from the group: tobramycin, gentamycin sulfate, chlortetracycline, chloromycetin or its group
Close.
Polyol
As used herein, term " polyol " refers to the compound in molecule with two or more hydroxyls.This
A person of good sense is it was unexpectedly observed that when being applied in combination described polyol with lanosterol class compound, be on the one hand used for carrying
High lanosterol class compound dissolubility in aqueous, on the other hand will not produce unfavorable shadow to lanosterol class compound
Ring.Additionally, also contributing to the first active component holdup time within the eye, and then improve the cataractous treatment for the treatment of further
Effect.
Described polyol preferably has the skeleton that carbon, hydrogen and hetero atom (as n) are constituted, and active group base
In basis or entirely hydroxyl.
In another preference, described polyol includes alcohols polyol (units as many in c2-c10
Alcohol) and cyclodextrin and cyclodextrin derivative.
In another preference, described polyol is selected from the group: propylene glycol, glycerol, Polyethylene Glycol, modification
Or unmodified cyclodextrin and its derivant, or a combination thereof.
In another preference, described polyol is HP-β-CD.
The dissolubility that described polyol can be used alone for improving lanosterol class compound, also can be with it
His drug regimen is used along, thus improving the degree of absorption to active component for the human body, strengthens drug effect.
The consumption of polyol can change according to dosage form, usage and type of compounds, in the present invention,
Consumption (or content) in lanosterol class compound water solution for the polyol is generally 0.1-50wt%, e.g., at this
The propylene glycol of 1-15wt% in invention, can be used, or the cyclodextrin of 20-50wt%.
Other pharmaceutically acceptable carriers
In the present invention, in addition to polyol, it is pharmaceutically acceptable that described ophthalmic preparation also can contain other
Carrier, representational from including but not limited to: surfactant, thickening agent, osmotic pressure regulator, buffer agent, preservative,
Chelating agen, slow releasing agent.
Surfactant
In the present invention, surfactant is selected from anion surfactant, cationic surfactant, non-ionic surface
Activating agent, chaotropic type (chaotropic) surfactant or a combination thereof.Wherein nonionic surfactant is selected from: tween, department
Disk, fatty glyceride, polyoxyethylene, Pluronic F68, or a combination thereof.General surfactant
Consumption (or content) is 0-2wt%, more preferably 0.1-1wt%.
Thickening agent
Thickening agent can be used for improving thing system viscosity, makes thing system keep uniformly stable suspended state or milkiness state.This
Invention, by adding appropriate thickening agent, increases medicine in the holdup time of eye, thus increasing eye for effective ingredient Pilus Caprae seu Oviss
The absorption of phytosterin compound.
In the present invention, thickening agent preferably shitosan, hydroxypropyl methyl cellulose (hpmc), methylcellulose (mc), and
Polyvidone (pvp), gelatin, sodium carboxymethyl cellulose (cmc-na) etc..
Typically, the consumption (or content) of thickening agent is 0～6wt%, preferably 0.1-5wt%.
Additionally, the ophthalmic preparation of the present invention also can contain extra pharmaceutically acceptable carrier, including (but not
It is limited to): osmotic pressure regulator, buffer agent, preservative, chelating agen, slow releasing agent.
For example, it is suitably added a certain amount of chelating agen, such as edta, the stability of preparation can be increased.Generally, chelating agen is dense
Degree scope is 0～0.05wt%.
Species and consumption typically for extra pharmaceutically acceptable carrier are not particularly limited, as long as not affecting
The dissolving of active component or therapeutic activity.
Generally, the total content of these other pharmaceutically acceptable carriers is 0.1-80wt%, preferably 1-50wt%.
The preparation of ophthalmic preparation
Ophthalmic preparation of the present invention can use conventional equipment and method, the drug component being provided according to the inventive method and joining
Ratio is prepared.Including following several method:
Method 1: by (a) pharmaceutically acceptable carrier；(b) as the lanosterol class compound of the first active component
Mixed, thus forming the ophthalmic preparation of the present invention.
Method 2: by (a) pharmaceutically acceptable carrier；(b) as the lanosterol class compound of the first active component
(c) the second active component described in is mixed, thus forming the ophthalmic preparation of the present invention.
Method 3:
I () will be scattered in polyhydroxy as the lanosterol class compound of the first active component and the second optional active component
In based compound, form the first dispersion；
(ii) described first dispersion is mixed with the carrying out of remaining pharmaceutically acceptable carrier, thus forming this
Bright ophthalmic preparation.
It is also possible to first be mixed remaining pharmaceutically acceptable carrier in step (i i), form the second solution
Or second dispersion, then described first dispersion is mixed with described second solution or the second dispersion, thus forming this
Bright ophthalmic preparation.
For eye drop, can according in above-mentioned 3 kinds of methods, any one is prepared, adjust ph, and sterilization filling in
In suitable container.
The aqueous solution for dosing eyes prepared according to the method, can be used for local and is administered to eye.
Purposes
The ophthalmic preparation of the present invention can be used for preventing or treat people or non-human mammal cataract.Representational cataract
It is selected from: senile cataract, congenital cataract, traumatic cataract and complicated cataract.
The usage of described preparation and consumption do not have certain limitations, the situation according to patient and cataractous species and
Adjustment, above-mentioned adjustment can by those skilled in the art by the symptom of patient combine state of the art and known often
Knowledge draws.
Main advantages of the present invention are:
1) can easily be administered, better tolerance, and the holdup time within the eye is long directly to ocular administration, there is preferable treatment
Effect.
2) drug component is stable, even if long-time placement is not easy to go bad, storage is convenient, is especially suitable for making commercially available medicine
Product.
3) medicine is little to Ocular irritation, and patient compliance is good.
4) significantly improve the concentration (bringing up to 5～250mm or higher) of active component, make concentration reach clinical eye
Medication requirements.
5) treatment cataract need not be performed the operation or glass intracavitary administration medicine.
6) the second active component azole compounds selecting list molecule for fda approved, so the discovery of this purposes can
To rapidly enter clinical phase experiment, be conducive to shortening the research and development time and reduce R ＆ D Cost.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than restriction the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally according to conventional strip
Part, such as sambrook et al., molecular cloning: laboratory manual (new york:cold spring harbor
Laboratory press, 1989) condition described in, or according to the condition proposed by manufacturer.Unless otherwise indicated, no
Then percentage ratio and number are calculated by weight.
Embodiment 1
Prepare solution of eyedrop according to document (zhao, chen et al.2015) formula, in no glass chamber drug administration by injection simultaneously
Under the premise of, evaluate and use merely lanosterol eye drop to cataractous therapeutic effect in Canis familiaris L. eye.25mm lanosterol eye drop
Containing 12.5 grams of lanosterol (tokyo chemical industry, japan), 200 milliliters of medical ethanols and 1.1 grams
(edta)2Na and 0.55 gram of benzalkonium chloride, whole solution tri-distilled water is prepared and is surely dissolved in 1.1 liters.In the solution preparing
Portion can clearly be seen that the lanosterol granule not being completely dissolved.
Early, middle and late three administrations daily of above-mentioned 25mm lanosterol eye drop, dosing interval at least 5 hours.Administration object
It is that a variety of causes causes cataractous Canis familiaris L., the cataract participating in test suffers from eye totally 7, and administering mode is the direct Deca of eye, protects
Card medicine instills ophthalmic completely.Every trouble eye administration one every time accepting treatment, about 50 microlitres, successive administration 12 weeks, all 7
Example cataract suffers from the asymptomatic mitigation of eye or remission sign.
Embodiment 2
Eye drop of the present invention is homogeneous, non-suspended, white liquid, complete aqueous phase, and cosolvent is cyclodextrin, preferably hydroxypropyl
Group-beta-cyclodextrin, the concentration of lanosterol is 25mm, has no the white particle insoluble in aqueous phase inside whole eye drop.
Eye drip formula of liquid:
Note: can be by physics dissolution means such as conventional ultrasonic, heating in preparation process.
Administering mode:
Early, middle and late three administrations daily of said medicine preparation, dosing interval at least 5 hours.Administration object is a variety of causes
Cause cataractous Canis familiaris L., administering mode is the direct Deca of eye it is ensured that medicine instills ophthalmic completely.Every dog accepting treatment is every
Side is suffered from eye and is administered one every time, about 50 microlitres, successive administration 8 weeks.Statin quasi-molecule must not be taken during administration simultaneously.
Evaluation index:
Using slit lamp observation len's opacity, typically lenticular opacity can be divided into the 0- phase.
0 phase-crystalline lenses are transparent；
Phase-crystalline lenses peripheral cortical is dispersed in tiny cavity；
Phase-crystalline lenses peripheral cortical circlewise intensive medium cavity；
Phase-other partial cortical lamellar is muddy；
Phase-nucleus lentis and core week cortex muddiness；
Phase-crystalline lenses are completely muddy.
Therapeutic effect:
Cataract therapy effect is as shown in Figure 1 it was demonstrated that the curing cataract eye drop according to present invention preparation can be no
Need to perform the operation or the injection of eye glass chamber, the administering mode only being dripped by eye, cure cataract completely.Especially for traumatic
Cataract, administration can be cured for 2 weeks completely.The whole no any Canis familiaris L. of the course for the treatment of has discomfort or anaphylaxiss.
Comparative example 1
Solution character according to document (zhao, chen et al.2015) formula:
White or milky suspension or emulsion, inside contains 20% about ethanol, and the concentration of lanosterol is 25mm,
The entirely internal visible small in a large number white particle insoluble in aqueous phase of eye drop.
Comparative example 2
Method, with embodiment 2, only difference is that: with 25-HYDROXY CHOLESTEROL (5mm) (25-
Hydroxycholesterol) replace lanosterol, without any azole compounds, and dosage is every other day Canis familiaris L. to be carried out
Eye drip, eye 1 every time is suffered from every side, and Canis familiaris L. quantity is 8.
Successive administration is observed after 6 weeks and is suffered from eye and pass judgment on, and all cataract suffer from the asymptomatic mitigation of eye or remission sign.
Above-described embodiment shows, the addition of polyol, can effectively improve insoluble drug lanosterol class
Dissolubility in water for the compound, reaches the requirement of dosing eyes.And the addition of suitable thickening agent, then can increase preparation steady
Qualitative, and promote the absorption of medicine during dosing eyes, improve administering effect.The ophthalmic preparations zest that the present invention provides is little, tool
There is good therapeutic effect, be especially suitable for preventing or treat people or non-human mammal cataract.
The all documents referring in the present invention are all incorporated as reference in this application, independent just as each document
It is incorporated as with reference to like that.In addition, it is to be understood that after the above-mentioned teachings having read the present invention, those skilled in the art can
To make various changes or modifications to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited
Enclose.
Claims (11)
1. the ophthalmic preparation that a kind of non-wound (non-invasive) is administered is it is characterised in that described ophthalmic preparation includes: (a) medicine
Acceptable carrier on, and (b) is as the lanosterol class compound of the first active component；
Wherein, in described ophthalmic preparation, the concentration of lanosterol class compound is 5～250mm.
2. preparation ophthalmically acceptable as claimed in claim 1 is it is characterised in that described ophthalmic preparation is selected from the group: eye drop, breast
Agent, gel, spongaion, sustained-release micro-spheres, intraocular slow-released plant piece, eye slow-release medicine-membrane.
3. ophthalmic preparation as claimed in claim 1 is it is characterised in that described ophthalmic preparation also includes: (c) second activity becomes
Point, the second wherein said active component is selected from the group: azole compounds, glucocorticoidss compound, antibiotic or its group
Close.
4. preparation as claimed in claim 1 is it is characterised in that described pharmaceutically acceptable carrier is non-stimulated to eyes
Property.
5. preparation as claimed in claim 1 is it is characterised in that described ophthalmic preparation contains: polyol, optional table
Face activating agent and optional thickening agent,
Wherein, by the gross weight meter of described ophthalmic preparation,
The content of polyol is 0.1-50wt%；
The content of surfactant is 0-2wt%；
The content of thickening agent is 0-6wt%.
6. preparation as claimed in claim 1 is it is characterised in that described ophthalmic preparation ph value is 5.5～8.5, preferably 6.0～
8.0, more preferably 6.5-7.5.
7. preparation as claimed in claim 1 is it is characterised in that described ophthalmic preparation is the aqueous solution for dosing eyes.
8. ophthalmic preparation as claimed in claim 1 is it is characterised in that described ophthalmic preparation contains following component:
10～50mm lanosterol class compound；
0.05～40 μm of azole compounds；
The polyol of 0.1-50wt%, preferably propylene glycol or beta cyclodextrin；
0-1wt% solubilizing agent, preferably Polysorbate；
0.2-0.4wt% thickening agent, preferably shitosan；
0-0.5wt% preservative, preferred antibiotics；
With the water of surplus,
And described ophthalmic preparation ph value about 6.5-7.5, and osmotic pressure is 240～510mosm.
9. a kind of preparation method of ophthalmic preparation as claimed in claim 1 is it is characterised in that comprise the following steps:
(1) by (a) pharmaceutically acceptable carrier；(b) the lanosterol class compound as the first active component is mixed
Close, thus forming the ophthalmic preparation described in claim 1.
10. ophthalmic preparation as claimed in claim 1 purposes it is characterised in that described ophthalmic preparation be used for preparation prevention or
Treatment people or the cataractous medicine of non-human mammal.
A kind of 11. preventions or the cataractous method for the treatment of are it is characterised in that give the non-invasively administration right of eyes of the object needing
Require the ophthalmic preparation described in 1.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610720166.XA CN106344587A (en) | 2016-08-24 | 2016-08-24 | Lanosterol compound preparation for eyes |
| PCT/CN2017/098661 WO2018036522A1 (en) | 2016-08-24 | 2017-08-23 | Lanosterol compound ophthalmic preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610720166.XA CN106344587A (en) | 2016-08-24 | 2016-08-24 | Lanosterol compound preparation for eyes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106344587A true CN106344587A (en) | 2017-01-25 |
Family
ID=57844945
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610720166.XA Pending CN106344587A (en) | 2016-08-24 | 2016-08-24 | Lanosterol compound preparation for eyes |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN106344587A (en) |
| WO (1) | WO2018036522A1 (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018036522A1 (en) * | 2016-08-24 | 2018-03-01 | 上海毕傲图生物科技有限公司 | Lanosterol compound ophthalmic preparation |
| CN109021051A (en) * | 2017-06-12 | 2018-12-18 | 盛世泰科生物医药技术(苏州)有限公司 | Crystal form of tetracyclic triterpenoid and application thereof |
| CN109985071A (en) * | 2017-12-29 | 2019-07-09 | 上海蓝木化工有限公司 | The new application of Inonotus obliquus extract |
| CN109985052A (en) * | 2017-12-29 | 2019-07-09 | 上海蓝木化工有限公司 | The new application of triterpene compound |
| WO2020177714A1 (en) * | 2019-03-04 | 2020-09-10 | 中山大学中山眼科中心 | Composition of lanosterol prodrug compound, preparation method therefor and use thereof |
| CN113413415A (en) * | 2021-06-30 | 2021-09-21 | 东莞博盛生物科技有限公司 | Lanosterol eye drops and preparation method thereof |
| WO2023012754A1 (en) | 2021-08-06 | 2023-02-09 | Foodvica, S.A. De C.V. | Ophthalmic composition for the treatment of visual disorders |
| WO2023030430A1 (en) * | 2021-09-03 | 2023-03-09 | 成都瑞沐生物医药科技有限公司 | Ophthalmic formulation for preventing and/or treating cataracts by eye drop administration |
| WO2023143452A1 (en) * | 2022-01-28 | 2023-08-03 | 广州润尔眼科生物科技有限公司 | Application of steroidal compound in prevention and/or treatment of cataracts |
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| CN113143862A (en) * | 2021-06-23 | 2021-07-23 | 顾凌雯 | Dimethyl fumarate eye drops, preparation method thereof and application of dimethyl fumarate eye drops as fungal keratitis treatment medicine |
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| WO2016029197A1 (en) * | 2014-08-22 | 2016-02-25 | Kang Zhang | Compositions and methods to treat and/or prevent vision disorders of the lens of the eye |
| WO2016029199A1 (en) * | 2014-08-22 | 2016-02-25 | Kang Zhang | Compositions and methods to treat vision disorders |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018036522A1 (en) * | 2016-08-24 | 2018-03-01 | 上海毕傲图生物科技有限公司 | Lanosterol compound ophthalmic preparation |
| CN109021051A (en) * | 2017-06-12 | 2018-12-18 | 盛世泰科生物医药技术(苏州)有限公司 | Crystal form of tetracyclic triterpenoid and application thereof |
| CN109985071A (en) * | 2017-12-29 | 2019-07-09 | 上海蓝木化工有限公司 | The new application of Inonotus obliquus extract |
| CN109985052A (en) * | 2017-12-29 | 2019-07-09 | 上海蓝木化工有限公司 | The new application of triterpene compound |
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| CN113413415A (en) * | 2021-06-30 | 2021-09-21 | 东莞博盛生物科技有限公司 | Lanosterol eye drops and preparation method thereof |
| WO2023012754A1 (en) | 2021-08-06 | 2023-02-09 | Foodvica, S.A. De C.V. | Ophthalmic composition for the treatment of visual disorders |
| WO2023030430A1 (en) * | 2021-09-03 | 2023-03-09 | 成都瑞沐生物医药科技有限公司 | Ophthalmic formulation for preventing and/or treating cataracts by eye drop administration |
| WO2023143452A1 (en) * | 2022-01-28 | 2023-08-03 | 广州润尔眼科生物科技有限公司 | Application of steroidal compound in prevention and/or treatment of cataracts |
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| Publication number | Publication date |
|---|---|
| WO2018036522A1 (en) | 2018-03-01 |
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