CN101896160A - Cyclosporin compositions - Google Patents
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- CN101896160A CN101896160A CN2007800345683A CN200780034568A CN101896160A CN 101896160 A CN101896160 A CN 101896160A CN 2007800345683 A CN2007800345683 A CN 2007800345683A CN 200780034568 A CN200780034568 A CN 200780034568A CN 101896160 A CN101896160 A CN 101896160A
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Abstract
Herein disclosed is the Therapeutic Method relevant, compositions and medicament with cyclosporin.
Description
Related application
The application is based on following provisional application, and foundation 35 U.S.C. § 120 require the priority of following provisional application: the series number of submitting on July 25th, 2006 is 60/820,239 U.S. Provisional Application; The series number of submitting on October 17th, 2006 is 60/829,796 U.S. Provisional Application; The series number of submitting on October 17th, 2006 is 60/829,808 U.S. Provisional Application; The series number of submitting on January 5th, 2007 is 60/883,525 U.S. Provisional Application; The series number of submitting on May 7th, 2007 is 60/916,352 U.S. Provisional Application; And the series number of December in 2006 submission on the 11st is 60/869,459 U.S. Provisional Application; This wherein each part provisional application is all included the application in full by quoting.
Background technology
Relevant can be subjected to the unusual mammal of this class to bring discomfort unusual usually with lacrimal gland function or with shedding tears to chance.
Description of drawings
Fig. 1 is with instil average (± SD) cornea cyclosporin A concentration (semilog) to the bilateral eye of New Zealand white rabbit of a kind of single part in three kind of 0.05% cyclosporin A preparation.
Fig. 2 is with instil average (± SD) conjunctiva cyclosporin A concentration (semilog) to the bilateral eye of New Zealand white rabbit of a kind of single part in three kind of 0.05% cyclosporin A preparation.
Fig. 3 is with instil average (± SD) sclera cyclosporin A concentration (semilog) to the bilateral eye of New Zealand white rabbit of a kind of single part in three kind of 0.05% cyclosporin A preparation.
Fig. 4 is with instil average (± SD) margo palpebrae cyclosporin A concentration (semilog) to the bilateral eye of New Zealand white rabbit of a kind of single part in three kind of 0.05% cyclosporin A preparation
Fig. 5 is with instil average (± SD) nasolacrimal duct cyclosporin A concentration (semilog) to the bilateral eye of New Zealand white rabbit of a kind of single part in three kind of 0.05% cyclosporin A preparation.
The specific embodiment
Herein disclosed is a kind of compositions, it contain concentration between about 0.0001% (w/v) to cyclosporin A below about 0.05% (w/v).
We are surprised to find that can prepare the concentration with therapeutic effect is the compositions of the following cyclosporin A of about 0.05% (w/v).
In one embodiment, give that with compositions disclosed herein it is had required mammiferous eyes, to strengthen or to recover lachrymal gland and shed tears.
In another embodiment, give that with compositions disclosed herein it is had required mammiferous eyes, produce with the tear that increases in the adacrya eyes.
In another embodiment, give that with compositions disclosed herein it is had required mammiferous eyes, with the treatment keratoconjunctivitis sicca.
In another embodiment, give that with compositions disclosed herein it is had required mammiferous eyes, with the treatment xerophthalmia.
Cyclosporin A
Cyclosporin A is to have inhibitive ability of immunity, structure cyclic peptide as implied above.Known it also have other title, comprise Cyclosporin A, cyclosporin A, ciclosporin and ciclosporin A.
Therapeutic Method
An embodiment is a kind of method for the treatment of xerophthalmia, and comprising to it has required mammal between 0.0001% (w/v) to the compositions topical administration of cyclosporin A below about 0.05% (w/v) with containing concentration.
Treatment generally includes the 10-50 μ L described mammal of drop topical administration of compositions disclosed herein or people's eye or eyes.To every day administration of human or mammal fix on really in those of ordinary skills' the limit of power with the number of drops that effective mitigation is provided.
In one embodiment, described compositions gives 1 to 4 time every day.
In another embodiment, described compositions gave twice in one day.
In another embodiment, described compositions only gave once in one day.
In another embodiment, when described compositions was only given once to reach three months in one day, eye burn damage can appear in the patient less than 14%.
In another embodiment, when described compositions was only given once to reach three months in one day, eye burn damage can appear in the patient less than 10%.
In another embodiment, when described compositions was only given once to reach three months in one day, eye burn damage can appear in the patient less than 8%.
Disclosure for the application, " treatment ", " treatment " or " therapy " all refer to chemical compound, compositions, the reagent with therapeutic activity or medicine are used for diagnosis, healing, alleviation, treatment, prevent disease or other bad diseases, perhaps are used to influence structure or any function of the health of people or other animals.
Compositions
The concentration of cyclosporin A is about below 0.05%.This is intended to show that it is by name that this concentration is lower than the trade mark that is purchased
0.05% cyclosporin A emulsion in concentration.
In another embodiment, the concentration of cyclosporin A is that about 0.005% (w/v) is to about 0.04% (w/v).
In another embodiment, the concentration of cyclosporin A is that about 0.02% (w/v) is to about 0.04% (w/v).
In another embodiment, the concentration of cyclosporin A is about 0.005% (w/v).
In another embodiment, the concentration of cyclosporin A is about 0.015% (w/v).
In another embodiment, the concentration of cyclosporin A is about 0.02% (w/v).
In another embodiment, the concentration of cyclosporin A is about 0.03% (w/v).
In another embodiment, the concentration of cyclosporin A is about 0.04% (w/v).
Preparation can eye usefulness liquid, can be thereby make with its topical administration eyes.Comfort level should be up to the degree that can realize, but preparation Consideration (as medicine stability, bioavailability etc.) may force comfort level can not reach the most desirable sometimes.Under comfort level can not maximized situation, should prepare liquid, thereby make and tolerated by the patient when this liquid topical ophthalmic uses.In addition, liquid that can eye usefulness both can be wrapped up and be used for single and use, and prevented repeatedly contaminated between the operating period thereby also can contain antiseptic.
With regard to ocular administration, use normal saline solution to prepare solution or medicament usually as main carrier.Ophthalmic solution is maintained at comfortable pH by suitable buffer system usually.Described preparation also can contain conventional pharmaceutically acceptable antiseptic, stabilizing agent and surfactant.
Can use various buffer agent and the means that are used to adjust pH, as long as resulting preparation can eye usefulness.Therefore, buffer agent includes but not limited to acetate buffer, citrate buffer agent, phosphate buffer and borate buffer.Also can use bronsted lowry acids and bases bronsted lowry to adjust the pH of these preparations as required.
In another embodiment, described compositions contains antiseptic.
The antiseptic that can be used for pharmaceutical composition disclosed herein includes but not limited to:
Cationic antiseptic, for example
Quaternary ammonium compounds, comprise benzalkonium chloride, polyquad etc.;
Antiseptic based on guanidine, comprise PHMB, chlorhexidine etc.;
Chlorobutanol
Mercurial antiseptic, for example thimerosal, phenylmercuric acetate and phenylmercuric nitrate; With
The oxidation antiseptic, for example stable oxygen chlorine complex (as
).
In another embodiment, described compositions contains surfactant.
Surfactant can be used for helping in excipient dissolving or activating agent, the dispersive composition solid or liquid, increase humidity, change the drop size, perhaps based on multiple other purpose purposes.Useful surfactant comprises but is not limited to the surfactant of following classification: alcohols; The oxidation amine; The block polymer class; The alcohol of carboxylation or alkylphenol polyoxyethylene class; Carboxylic acids/fatty acid; The ethoxylation alcohols; The ethoxylated alkyl phenols class; Ethoxylation aryl phenols; The ethoxylated fatty acid class; Ethoxylated fat esters or oils (animal oil and vegetable oil); The fat esters; The fatty acid methyl ester ethoxylate class; Glyceride type; The ethylene glycol esters; Derivant based on lanoline; Lecithin and lecithin derivant; Lignin and lignin derivative; The methyl ester class; Monoglyceride and derivant; Polyethylene Glycol; Polymeric surfactant; Propoxyl group and ethoxylated fatty acid, alcohols or alkylbenzene phenols; Based on proteic surfactant; Sarcosine derivative; The anhydrosorbitol derivant; Sucrose and glucose esters and derivant.
Particularly, can use alcohol ethoxylate surfactant.
Alcohol ethoxylate surfactant is for having-O (CH
2CH
2O)
nThe surfactant of-OH part, wherein n is at least about 1.
In one embodiment, n is about 1 to about 10000.
In another embodiment, n is 1 to about 1000.
In another embodiment, n is about 1 to about 500.
Some ethoxylates contain an ethoxylate part.In other words, single ethoxylate chain is all arranged on each molecule.
Example with surfactant of ethoxylate part includes but not limited to:
Wherein alcohol has the ethyoxyl alcohols of single hydroxyl unit; The alkylphenol polyoxyethylene class; The ethoxylated fatty acid class; The fatty acid methyl ester ethoxylate class; Polyethylene Glycol etc.
Ethoxylate can contain more than one ethyoxyl part.In other words, several different pieces of molecule can be connected with the ethyoxyl part.Example includes but not limited to: block polymer; Ethoxylation oils; The anhydrosorbitol derivant; Sucrose and glucose ethoxylate; Or the like.
Block polymer: these are the polymer with structure A-B-A ', and wherein A and A ' are the Polyethylene Chain of one or more ethylene units, and B is the polypropylene chains of one or more propylene units.Usually, but also nonessential, the much the same length of A and A '.
In one embodiment, A and A ' contain and have an appointment 2 to about 200 ethylene units.
In another embodiment, A and A ' contain and have an appointment 5 to about 100 ethylene units.
In another embodiment, A and A ' contain and have an appointment 7 to about 15 ethylene units.
In another embodiment, A and A ' contain and have an appointment 7, about 8 or about 12 ethylene units.
In another embodiment, B contains and has an appointment 25 to about 100 propylene units.
In another embodiment, B contains and has an appointment 30 to about 55 propylene units.
In another embodiment, B contains and has an appointment 30, about 34 or about 54 propylene units.
In another embodiment, molecular weight is about 1000 to about 20000.
In another embodiment, molecular weight is about 2000 to about 10000.
In another embodiment, molecular weight is about 2500, about 3000, about 3800 or about 8400.
These include but not limited to:
Poloxalene: wherein A has about 12 ethylene oxide units, and B has about 34 propylene oxide units, and A ' has about 12 ethylene oxide units, and mean molecule quantity is about 3000.
Poloxamer 182: wherein A has about 8 ethylene oxide units, and B has about 30 propylene oxide units, and A ' has about 8 ethylene oxide units, and mean molecule quantity is about 2500.
Poloxamer 188: wherein A has about 75 ethylene oxide units, and B has about 30 propylene oxide units, and A ' has about 75 ethylene oxide units, and mean molecule quantity is about 8400.
Poloxamer 331: wherein A has about 7 ethylene oxide units, and B has about 54 propylene oxide units, and A ' has about 7 ethylene oxide units, and mean molecule quantity is about 3800;
The ethoxylation alcohols
These include but not limited to:
Have about 6 ethoxylates to the linear alcohols of about 20 carbon atoms.
In one embodiment, linear alcohols has about 10 to about 16 carbon atoms.
In another embodiment, n is about 1 to about 100.
In another embodiment, n is about 1 to about 50.
In another embodiment, n is about 5 to about 50 ethylene oxide units.
In another embodiment, n is about 1 to about 20 ethylene oxide units.
In another embodiment, n is about 30 to about 50 ethylene oxide units.
The ethoxylated alkyl phenols class
These are by the alkylbenzene phenols of ethoxylation, and promptly phenol OH is partly replaced by ethoxylation.
These include but not limited to:
Octyl phenol polyoxyethylene ether, i.e. C
8H
17Ph (OCH
2CH
2O)
nH.
Nonyl phenol polyoxyethylene ether, i.e. C
9H
19Ph (OCH
2CH
2O)
nH.
Wherein n is the alkylphenol of about 1 to about 100 following formula.
Wherein n is the alkylphenol of about 1 to about 50 following formula.
Wherein n is this phenol of alkyl of about 9 to about 15 following formula.
1.5 moles of polyoxyethylene ether of octyl phenol (being n average out to about 1.5); 5 moles of polyoxyethylene ether of octyl phenol; 7 moles of polyoxyethylene ether of octyl phenol; 9 moles of polyoxyethylene ether of octyl phenol; 12 moles of polyoxyethylene ether of octyl phenol; 40 moles of polyoxyethylene ether of octyl phenol; 1.5 moles of polyoxyethylene ether of nonyl phenol; 4 moles of polyoxyethylene ether of nonyl phenol; 6 moles of polyoxyethylene ether of nonyl phenol; 9 moles of polyoxyethylene ether of nonyl phenol; 10 moles of polyoxyethylene ether of nonyl phenol; 10.5 moles of polyoxyethylene ether of nonyl phenol; 12 moles of polyoxyethylene ether of nonyl phenol; 15 moles of polyoxyethylene ether of nonyl phenol; 15 moles of polyoxyethylene ether of nonyl phenol; 30 moles of polyoxyethylene ether of nonyl phenol; With 40 moles of polyoxyethylene ether of nonyl phenol;
The ethoxylated fatty acid class
These include but not limited to:
The esterified ethoxylate that forms following material:
Monoesters class, i.e. RCO
2(CH
2CH
2O)
nOH, wherein RCO
2H is a fatty acid; Perhaps
Two esters, i.e. RCO
2(CH
2CH
2O)
nC (=O) R.
Fatty acid includes but not limited to:
The saturated fat acids, they do not have the C=C part, comprise myristic acid, Palmic acid, stearic acid, arachidic acid, mountain acid, lignoceric acid.
Unsaturated fatty acids, comprise following:
The monounsaturated fatty acid class, they have a C=C group, for example palmitoleic acid, oleic acid and nervonic acid;
Two unsaturated fatty acids, they have two C=C groups, for example linoleic acids;
Three unsaturated fatty acids, they have three C=C groups, for example alpha-linolenic acid and gamma-Linolenic acid;
Four unsaturated fatty acids, they have four C=C groups, for example arachidonic acids;
Five unsaturated fatty acids, they have five C=C groups, for example eicosapentaenoic acid.
Also can use following:
Lauric acid; 14 carbon fatty acids are myristic acid for example; 16 carbon fatty acids are Palmic acid and palmitoleic acid for example; 18 carbon fatty acids are stearic acid, oleic acid, linoleic acid, alpha-linolenic acid and gamma-Linolenic acid for example; 20 carbon fatty acids are eicosapentaenoic acid for example; 22 carbon fatty acids are arachidic acid for example; With for example lignoceric acid and the nervonic acid of 24 carbon fatty acids.
In one embodiment, n is about 2 to about 100.
In another embodiment, n is about 5 to about 50.
In another embodiment, n is about 30 to 50.
Ethoxylated fat esters or oils (animal oil and vegetable oil).
These materials are oxirane and fatty ester or the oily product that obtains that reacts.When using fatty oil, product is the mixture of ethoxylate etc. of ethoxylate, monoglyceride and the diglyceride of the ethoxylate that is present in the fatty acid in the oil, glycerol.
Concrete example includes but not limited to:
The ethoxylate of following oils: Oleum Anisi Stellati, Oleum Ricini, Oleum Caryophylli, cassia oil, Oleum Cinnamomi; Almond oil, Semen Maydis oil (Corn oil), Oleum Arachidis hypogaeae semen (Arachis oil), Oleum Gossypii semen, safflower oil, Semen Maydis oil (Maize oil), Semen Lini oil, Oleum Brassicae campestris, soybean oil, olive oil, caraway oil, oil of rosemary, Oleum Arachidis hypogaeae semen (Peanut oil), Oleum menthae, Oleum Helianthi, Eucalyptus oil and Oleum sesami; Fructus Coriandri oil, Essential lavender oil, citronella oil, juniper oil, Fructus Citri Limoniae oil, orange peel oil, sage oil, Semen Myristicae oil, tea tree oil, Oleum Cocois, tallow and Adeps Sus domestica;
In one embodiment, every mole of oily triglyceride uses 1 to about 50 moles oxirane.
In another embodiment, every mole of oily triglyceride uses about 30 to about 40 moles oxirane.
Oxirane can be RCO with formula also
2The fatty acid ester reaction of R ' forms RCO
2(CH
2CH
2O)
nR '.Therefore, formula is RCO
2(CH
2CH
2O)
nThe surfactant of R ' also among considering, RCO wherein
2H is a fatty acid, and R ' is for having the alkyl of 1-6 carbon.
An embodiment is a fatty acid methyl ester ethoxylate, and wherein R ' is a methyl.
In another embodiment, RCO
2H is a lauric acid; 14 carbon fatty acids are myristic acid for example; 16 carbon fatty acids are Palmic acid and palmitoleic acid for example; 18 carbon fatty acids are stearic acid, oleic acid, linoleic acid, alpha-linolenic acid and gamma-Linolenic acid for example; 20 carbon fatty acids are eicosapentaenoic acid for example; 22 carbon fatty acids are arachidic acid for example; Perhaps for example lignoceric acid and nervonic acid of 24 carbon fatty acids.
Polyethylene GlycolBe ethoxylate unsubstituted or that finish with oxygen at two ends, i.e. HO (CH
2CH
2O)
nH,
The anhydrosorbitol derivant:
These materials are the chain of one or more ethoxylation ethoxylation sorbates titled with fatty acid.For example, polyoxyethylene sorbitan monoleate has an oleic acid medicated cap, shown in following structural formula.
These chemical compounds are named as anhydrosorbitol polyoxyethylene (w+x+y+z) ether list (or two or three) fatty acid ester (POE (w+x+y+z) sorbitan mono (or di-or tri-) fatty acid).
For example, polyoxyethylene sorbitan monoleate is anhydrosorbitol polyoxyethylene (20) ether monoleate (POE (20) sorbitan monooleate).
Therefore, the number in the bracket is the sum of ethylene oxide unit in the molecule, and the end is the number and the capping acid of sour medicated cap.
These include but not limited to:
Wherein ethylene oxide unit adds up to 3 to 30 anhydrosorbitol derivant;
Wherein ethylene oxide unit adds up to 4,5 or 20 anhydrosorbitol derivant;
Wherein capping acid is lauric acid, Palmic acid, stearic acid or oleic anhydrosorbitol derivant;
The anhydrosorbitol derivant can be anhydrosorbitol polyoxyethylene ether monolaurate;
Anhydrosorbitol polyoxyethylene ether dilaurate;
Anhydrosorbitol polyoxyethylene ether trilaurin;
Anhydrosorbitol polyoxyethylene ether monopalmitate;
Anhydrosorbitol polyoxyethylene ether dipalmitate;
Anhydrosorbitol polyoxyethylene ether tripalmitate;
Anhydrosorbitol polyoxyethylene ether monostearate;
Anhydrosorbitol polyoxyethylene ether distearate;
Anhydrosorbitol polyoxyethylene ether tristearate;
Anhydrosorbitol polyoxyethylene ether monoleate;
Anhydrosorbitol polyoxyethylene ether dioleate;
Or anhydrosorbitol polyoxyethylene ether trioleate;
Instantiation comprises:
Anhydrosorbitol polyoxyethylene (20) ether monolaurate; Anhydrosorbitol polyoxyethylene (4) ether monolaurate; Anhydrosorbitol polyoxyethylene (20) ether monopalmitate; Polyoxyethylene (20) ether monostearate; Anhydrosorbitol polyoxyethylene (20) ether monostearate; Anhydrosorbitol polyoxyethylene (4) ether monostearate; Anhydrosorbitol polyoxyethylene (20) ether tristearate; Anhydrosorbitol polyoxyethylene (20) ether monoleate; Anhydrosorbitol polyoxyethylene (20) ether 15 monoleates; Anhydrosorbitol polyoxyethylene (5) ether 10 monoleates; Anhydrosorbitol polyoxyethylene (20) ether trioleate; And
Sucrose and glucose ester and derivant:
Although a lot of surfactants based on sucrose and glucose are arranged, still have some sucrose and glucose ester
AndDerivant is similar to above-described sorbate derivant.In other words, one, several or whole hydroxylic moiety of sugar is by ethoxylation, and the chain of one or more ethoxylation is by titled with carboxylic acid.Other sucrose and glucose ester be only by ethoxylation, but do not have the carboxylic acid of capping.Other sucrose and glucose ester can be by ethoxylations and titled with the alkyl group by forming with alcohol reaction.Other sucrose and glucose ester can be the ester or the ether of following sugar: this sugar has hydrophobic chain, and other position that should sugar exists ethoxylate to replace.
Various useful carriers can be used in the ophthalmic preparation disclosed herein.These carriers include but not limited to polyvinyl alcohol, polyvidone, hydroxypropyl emthylcellulose, poloxamer, carboxymethyl cellulose, hydroxyethyl-cellulose and acrylate (as
).
Tonicity contributor can add as required or when appropriate.They include but not limited to salt, especially sodium chloride, potassium chloride, and mannitol and glycerol, what perhaps any other was suitable can the eye tonicity contributor.
Under similar situation, can the eye usefulness antioxidant include but not limited to sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
Other vehicle group that can be included in the ophthalmic preparation are divided into chelating agen.A kind of useful chelating agents is a disodiumedetate, but other chelating agen also can replace it or coupling with it.
Compositions can be aqueous solution or emulsion or some other acceptable liquid forms.For emulsion, can use one or more oil to form this emulsion, and will need one or more surfactants in some cases.Suitable oil includes but not limited to Oleum Anisi Stellati, Oleum Ricini, Oleum Caryophylli, cassia oil, Oleum Cinnamomi, almond oil, Semen Maydis oil (corn oil), Oleum Arachidis hypogaeae semen (arachis oil), Oleum Gossypii semen, safflower oil, Semen Maydis oil (Maize oil), Semen Lini oil, Oleum Brassicae campestris, soybean oil, olive oil, caraway oil, oil of rosemary, Oleum Arachidis hypogaeae semen (peanut oil), Oleum menthae, Oleum Helianthi, Eucalyptus oil, Semen Sesami wet goods.
In one embodiment, described compositions is an aqueous solution.
In another embodiment, described compositions does not contain ethanol.
In another embodiment, described compositions does not contain hyaluronic acid.
In another embodiment, described compositions does not contain vitamin E TPGS.
In another embodiment, described compositions does not contain cyclodextrin A.
In another embodiment, described compositions does not contain cyclodextrin.
Compositions P, A, B and C prepare according to following steps.
1. measure to about 90% pure water of a batch and place in the suitable beaker or container.
2. begin to mix this water with strong mixer (Rotosolver), to obtain strong eddy current.
3. the sodium carboxymethyl cellulose that will weigh in advance adds in this strong eddy current.Continue strong the mixing at least 1 hour.
4. agitator is transferred to than low velocity.
5. add and polyoxyethylene sorbitan monoleate that dissolving is weighed in advance.
6. add and glycerol that dissolving is weighed in advance.
7. add and mannitol that dissolving is weighed in advance.
8. add and Sodium Citrate, usp, Dihydrate Powder that dissolving is weighed in advance.
9. add and boric acid that dissolving is weighed in advance.
10. add and ten water sodium borate that dissolving is weighed in advance.
11. the potassium chloride that adding and dissolving are weighed in advance.
12. check pH, and adjust where necessary.Target pH is 7.5+/-0.1.
13. the Purite that adding and dissolving are weighed in advance.
14. add the pure water of sufficient quantity, to reach final batch volume.This will obtain final placebo preparation (P).
The step of preparation 0.03% (A), 0.04% (B), 0.05% (C)
15. measure the placebo (9815X) that satisfies the required exact amount of batch requirement, and place the medium bottle that contains magnetic stir bar.
16. the cyclosporin that adding and dissolving are weighed in advance.Stir at a slow speed, avoid bubbling.Usually need spend the night to mix and dissolve this cyclosporin fully.
Mix after the end 17. spend the night, extract this Cyclosporin A solution by Millipore Milligard prefilter and PallSuporlife sterilizing filter, and collect this filtrate with sterile manner.
18. then this bacteria-free filtrate is assigned in the multiple dose drop bottle that is suitable for a usefulness with sterile manner.
19. cyclosporin sample, pH, osmolality, viscosity, Purite, sterility and the antimicrobial efficacy of reply end-product are test.
20. end-product answers room temperature to preserve and lucifuge.
Embodiment 2
Prepare following preparation.Prepare D and E with standard method known in the art.The preparation of F is identical with the preparation of A-C mentioned above, and different is to replace sodium carboxymethyl cellulose with Pemulen TR-2, and does not add citrate and borate buffer solution.
| D | E | F | |
| Emulsion | Emulsion | Solution | |
| Cyclosporin A | 0.05 | 0.05 | 0.05 |
| Oleum Ricini | 1.25 | 0.30 | N/A |
| Myrj 52, NF | N/A | 0.30 | N/A |
| Polyoxyethylene sorbitan monoleate | 1.00 | 0.30 | 1.00 |
| Glycerol | 2.20 | 1.00 | 1.00 |
| Mannitol | N/A | 2.00 | 2.00 |
| Pemulen?TR-2 | 0.05 | 0.10 | 0.10 |
| Sodium hydroxide (1N) | PH regulator | PH regulator | PH regulator |
| Pure water | QS | QS | QS |
| pH | pH＝7.4 | 7.39 | 7.35 |
Bioavailability
This paper compositions open and that use provides the cyclosporin A of treatment effective dose as mammal.Yet although have no intention to limit to by any way scope of the present invention, the concentration of cyclosporin A can significantly be lower than usually and treats those relevant concentration of valid density in the described compositions.For example, a kind of commercialization preparation---Allergan Inc sells
---be 0.05% cyclosporin A Oleum Ricini emulsion.Current other composition concentrations of developing are 0.1% or higher.
This paper has reported the pharmacokinetic data of experiment in the rabbit body.But, it is believed that rabbit experiment is for comprising human useful bioavailability model for other interior mammals.Therefore, although the bioavailability parameter is disclosed in claims and characterizes, but they should be interpreted as only is processing at rabbit, and should be interpreted as: be considered for processing to other mammals especially people equally by the compositions that bioavailability characterized and defined in rabbit.
In one embodiment, AA compares with compositions, and the cornea that described compositions is behaved provides more cyclosporin A.
In another embodiment, BB compares with compositions, and the cornea that described compositions is behaved provides more cyclosporin A.
In another embodiment, CC compares with compositions, and the cornea that described compositions is behaved provides more cyclosporin A.
In one embodiment, DD compares with compositions, and the cornea that described compositions is behaved provides more cyclosporin A.
In another embodiment, EE compares with compositions, and the cornea that described compositions is behaved provides more cyclosporin A.
In another embodiment, F compares with composition F, and the cornea that described compositions is behaved provides more cyclosporin A.
In one embodiment, GG compares with compositions, and the cornea that described compositions is behaved provides more cyclosporin A.
In another embodiment, HH compares with compositions, and the cornea that described compositions is behaved provides more cyclosporin A.
In another embodiment, I compares with composition I, and the cornea that described compositions is behaved provides more cyclosporin A.
In another embodiment, JJ compares with compositions, and the cornea that described compositions is behaved provides more cyclosporin A.
In another embodiment, KK compares with compositions, and the cornea that described compositions is behaved provides more cyclosporin A.
In another embodiment, LL compares with compositions, and the cornea that described compositions is behaved provides more cyclosporin A.
In another embodiment, MM compares with compositions, and the cornea that described compositions is behaved provides more cyclosporin A.
In one embodiment, AA compares with compositions, and the conjunctiva that described compositions is behaved provides more cyclosporin A.
In another embodiment, BB compares with compositions, and the conjunctiva that described compositions is behaved provides more cyclosporin A.
In another embodiment, CC compares with compositions, and the conjunctiva that described compositions is behaved provides more cyclosporin A.
In one embodiment, DD compares with compositions, and the conjunctiva that described compositions is behaved provides more cyclosporin A.
In another embodiment, EE compares with compositions, and the conjunctiva that described compositions is behaved provides more cyclosporin A.
In another embodiment, F compares with composition F, and the conjunctiva that described compositions is behaved provides more cyclosporin A.
In one embodiment, GG compares with compositions, and the conjunctiva that described compositions is behaved provides more cyclosporin A.
In another embodiment, HH compares with compositions, and the conjunctiva that described compositions is behaved provides more cyclosporin A.
In another embodiment, I compares with composition I, and the conjunctiva that described compositions is behaved provides more cyclosporin A.
In another embodiment, JJ compares with compositions, and the conjunctiva that described compositions is behaved provides more cyclosporin A.
In another embodiment, KK compares with compositions, and the conjunctiva that described compositions is behaved provides more cyclosporin A.
In another embodiment, LL compares with compositions, and the conjunctiva that described compositions is behaved provides more cyclosporin A.
In another embodiment, MM compares with compositions, and the conjunctiva that described compositions is behaved provides more cyclosporin A.
In another embodiment, the described compositions of the one 35 μ L of every eyes of topical administration female New Zealand white rabbits is after described topical 30 minutes the time, for the cornea of this rabbit provides cornea at least about 500ng cyclosporin A/this rabbit of gram.
In another embodiment, the described compositions of the one 35 μ L of every eyes of topical administration female New Zealand white rabbits is after described topical 30 minutes the time, for the cornea of this rabbit provides cornea at least about 1000ng cyclosporin A/this rabbit of gram.
In another embodiment, the described compositions of the one 35 μ L of every eyes of topical administration female New Zealand white rabbits is after described topical 30 minutes the time, for the cornea of this rabbit provides cornea at least about 1400ng cyclosporin A/this rabbit of gram.
In another embodiment, the described compositions of the one 35 μ L of every eyes of topical administration female New Zealand white rabbits is after described topical 30 minutes the time, for the cornea of this rabbit provides cornea at least about 2000ng cyclosporin A/this rabbit of gram.
In another embodiment, the described compositions of the one 35 μ L of every eyes of topical administration female New Zealand white rabbits is after described topical 30 minutes the time, for the cornea of this rabbit provides cornea at least about 2400ng cyclosporin A/this rabbit of gram.
In another embodiment, the described compositions of the one 35 μ L of every eyes of topical administration female New Zealand white rabbits is after described topical during 24 hours, for the cornea of this rabbit provides cornea at least about 17000ng cyclosporin A/this rabbit of gram.
In another embodiment, described compositions is to contain 0.005% aqueous solution to about 0.04% cyclosporin A, the described compositions of the one 35 μ L of every eyes of the female new zealand rabbit of topical administration wherein, for the cornea of this rabbit provides at least about 17000ng cyclosporin A/gram cornea, this can measure by the following method:
With each every the eye only in 15 female New Zealand white rabbits test subject of described compositions topical administration; And
After giving described experimenter about 0.5 hour, about 2 hours, about 6 hours, about 12 hours and about 24 hours, measure the amount of cyclosporin A in three experimenters' the cornea;
Wherein the amount of cyclosporin A is only measured once in every experimenter's the cornea.
In another embodiment, the described compositions that gives every eyes of new zealand rabbit provides at least about 30000ng cyclosporin A/gram cornea for the cornea of described rabbit.
In another embodiment, the described compositions that gives every eyes of new zealand rabbit provides at least about 45000ng cyclosporin A/gram cornea for the cornea of described rabbit.
In another embodiment, the described compositions that gives every eyes of new zealand rabbit provides at least about 95000ng cyclosporin A/gram cornea for the cornea of described rabbit.
In another embodiment, the described compositions that gives every eyes of new zealand rabbit provides at least about 155000ng cyclosporin A/gram cornea for the cornea of described rabbit.
In another embodiment, the described compositions of the one 35 μ L of every eyes of topical administration female New Zealand white rabbits, after described topical in 24 hours time period, for the conjunctiva of this rabbit provides conjunctiva at least about 6000ng cyclosporin A/this rabbit of gram.
In another embodiment, described compositions is to contain 0.005% aqueous solution to about 0.04% cyclosporin A, the described compositions of the one 35 μ L of every eyes of topical administration new zealand rabbit wherein, for the conjunctiva of this rabbit provides at least about 6000ng cyclosporin A/gram conjunctiva, this can measure by the following method:
With each every the eye only in 15 female New Zealand white rabbits test subject of described compositions topical administration; And
After giving described experimenter about 0.5 hour, about 2 hours, about 6 hours, about 12 hours and about 24 hours, measure the amount of cyclosporin A in three experimenters' the conjunctiva;
Wherein the amount of cyclosporin A is only measured once in every experimenter's the conjunctiva.
In another embodiment, the described compositions that gives every eyes of new zealand rabbit provides at least about 5000ng cyclosporin A/gram conjunctiva for the conjunctiva of described rabbit.
In another embodiment, the described compositions that gives every eyes of new zealand rabbit provides at least about 7000ng cyclosporin A/gram conjunctiva for the conjunctiva of described rabbit.
In another embodiment, the described compositions that gives every eyes of new zealand rabbit provides at least about 10000ng cyclosporin A/gram conjunctiva for the conjunctiva of described rabbit.
In another embodiment, the described compositions that gives every eyes of new zealand rabbit provides at least about 17000ng cyclosporin A/gram conjunctiva for the conjunctiva of described rabbit.
In another embodiment, for every day twice described compositions by its eyes 35 microlitre drop forms of topical administration reach for 12 months the people, the blood levels of its cyclosporin A is below the 0.1mg/mL.
Every eyes with the 35 μ L aliquot topical administration female New Zealand white rabbits (n=3 rabbit/time point) of one of three kinds of test formulation.After administration 0.5,2,6,12,24,48 and 144 hour, collect cornea, conjunctiva, sclera, margo palpebrae, nasolacrimal duct and blood sample.The sample that to collect from untried rabbit (n=2) as administration before sample.Quantitative scope in the blood is 0.2-40ng/mL, and in cornea and the conjunctiva is 0.1-200ng, and in margo palpebrae and the nasolacrimal duct is 0.1-100ng, and in sclera and the lachrymal gland is 0.1-20ng.
The pharmacokinetic parameter of cyclosporin A is summarised in the following table 1 in the part tissue of eye after the single eye instils one of three kind of 0.05% cyclosporin A preparation:
Table 1
| Tissue/substrate | Composition F | Compositions E | Compositions D |
| C max AUC 0-t t 1/2 (ng/g) (ng·hr/g) (hr) | C max AUC 0-t t 1/2 (ng/g) (ng·hr/g) (hr) | C max AUC 0-t t 1/2 (ng/g) (ng·hr/g) (hr) | |
| Cornea and conjunctiva sclera margo palpebrae nasolacrimal duct blood | 4050 163000 41.34460 18100 11.3545 6110 29.73120 38300 42.5195 2190 NC2.21 NC NC | ?1100 76200 41.7?2560 11600 5.57?136 2840 24.8?2020 42200 38.1?74.4 1190 NC?0.441 NC NC | ?536 29300 49.8?694 5290 4.55?53.0 1040 18.7?2450 27700 24.4?72.0 279 NC?BLQ BLQ NC |
NC=can't calculate
BLQ=is lower than quantitative limit
In a word, after the single eye instils 0.05% cyclosporin A preparation, when using composition F, observe the highest cyclosporin A ocular tissue exposure level, secondly be compositions E, be compositions D once more.
Material
Tester
Above-mentioned compositions D, E and F are used for these experiments.
Chemicals, reagent and supplier
Every other chemicals is SILVER REAGENT or higher level.
Animal
Species, strain, sex, age, build, source and discriminating
The female New Zealand white rabbits of heavy 1.8-2.6kg available from Charles River (St.Constant, Quebec, Canada).Permanent ear tag is used for differentiating animal.
Reason
Similarity between rabbit and people's the eye anatomy makes rabbit become extraordinary animal model.
Animal feeding
All animals all are housed in the Experimental Establishment that the environment of being furnished with the time control fluorescent lamp system is controlled, and this time control fluorescent lamp system provides the illumination/12 hour lucifuge phase 12 hours every days.Room temperature maintains 61 to 72 °F, and relative humidity is between 30 to 70%.Airflow range is for per hour taking a breath 10-30 time.Temperature, humidity and air-flow are by the 4.0th edition monitoring of Edstrom Watchdog system.
For these animals provide standardized rabbit high fibre diet.Provide meals authentication and analysis by selling the merchant.Analysis outside those that do not carry out that manufacturer provided are analyzed.Unrestrictedly provide by inverse osmosis and handle the drinking water that purification obtains.Just any pollutant that may disturb this research to carry out are regularly analyzed water.
By manufacturer animal feed is analyzed.
Animal environment adapts to
, every day animal is observed between the laundering period in Allergan Inc with regard to any variation of general health situation or behavior.Before beginning one's study, with rabbit quarantine at least five days.All animals all show as health before studying and during the research.
Sacrifice of animal and disposal
By will be at least the 1mL pentobarbital sodium be expelled to the edge ear vein and make animal euthanasia.
Research design and test procedure
Research design
Table 1 research design
| Animal species and strain | New Zealand white rabbit |
| Sex | Female |
| Number | 3 preceding 2 rabbits of rabbit/time point administration (bioanalysis contrast) |
| Body weight | 1.8-2.8kg |
| Dosage regimen | The topical ophthalmic administration, single-dose, bilateral |
| The administration volume | 35μL |
| Test article | The preparation that contains 0.05%AGN 192371 (cyclosporin A) |
| Time point | After the administration 0.5,2,6,12,24,48 and 144 hour |
| Tissue/substrate | Cornea, conjunctiva, sclera, nasolacrimal duct, margo palpebrae and blood |
| Analytical method | LC-MS/MS |
| Analytic target | AGN 192371 (cyclosporin A) |
| Quantitative scope | Blood: 0.5-40ng/mL cornea: 0.1-200ng conjunctiva: 0.1-200ng margo palpebrae: 0.1-100ng nasolacrimal duct: 0.1-100ng sclera: 0.1-20ng |
The administration of single bilateral, 3 rabbits of each time point (6 eyes and 3 blood samples).Two animals of the 4th group do not have administration, contrast used as bioanalysis.Before the administration, 65 animals are weighed and it is divided into four seminar.Research design provides in table 1.These four seminar provide in following table 2:
Table 2
| Group is inferior | Handle | Dosage (μ L) | | n | |
| 1 | Composition F | 35 | The administration of single bilateral | Each time point 3F (21F altogether) | |
| 2 | Compositions E | 35 | The administration of single bilateral | Each time point 3F (21F altogether) | |
| 3 | Compositions D | 35 | The administration of single bilateral | Each time point 3F (21F altogether) | |
| 4 | There is not administration | -- | -- | Two F (2F altogether) |
The number of animals that n=is every group
F=is female
Check before handling
Before studying, every animal is checked UP.Use standardized data collection form, note before administration and immediately overall observed result after the dosing eyes.
Random packet
Before the administration, 65 animals are weighed and be divided into four seminar at random.
Dosing step:
At the 0th hour of research, animal is carried out single administration by the instillation of bilateral eye.Before facing administration, check eyes anyly unusually for example infect, blood-shot eye illness or inpairment of vision.Only use the animal that does not have eyesight abnormality.Palpebra inferior is pulled away from eyes lightly.Use Gilson precision pipette, 35 μ L administration solution are instilled in the following conjunctival cul-de-sac of every eyes.Note administration time.Make eyes closed about 5 seconds lightly, be uniformly distributed in the eyes to guarantee medicine.After the administration eye is totally observed.Just stimulate indication that animal (comprising by the eyes of administration) is carried out subjective assessment.The record observed result.
Mortality rate/sickness rate
During studying, observe mortality rate/sickness rate of animal.
Body weight
The previous day animal is weighed in administration, carry out random packet subsequently.
Blood collection before the postmortem
Before euthanasia/postmortem, gather blood from every rabbit.By the intravenous injection amount is that ketamine/xylazine mixture (87mg/mL ketamine, 13mg/mL xylazine) of 0.1mL/kg comes anesthetized animal.Gather blood by cardiac puncture.Nearly 5mL blood is collected into 10mL grey violet lid (K
3EDTA) in the test tube.Blood sample is kept at-15 ℃ or about below-15 ℃ approximately, until carry out bioanalysis.
Euthanasia
After blood collection, be purchased euthanasia solution by intravenous injection and make animal euthanasia.
Postmortem and ocular tissue collect
When postmortem, collect the eye sample from eyes, when being fit to it is stained with dried, weigh and place the independently silanization bottle of appropriate flags.Eyes are all used LENS
Flushing, purpose are the residual surface preparations that flush away remains in the eye surface.
Conjunctiva
The conjunctiva up and down of every eyes is taken out and put together, note weight, place each independently to have the glass 13x100 silanization test tube of screw lid, and be put on ice immediately.Sample is kept at-15 ℃ of pacts or is lower than-15 ℃ approximately, until carry out bioanalysis.
Cornea
Take out whole cornea from every eyes; Note weight, place each independently to have the glass 13x100 silanization test tube of screw lid, and be put on ice immediately.Sample is kept at below-15 ℃ or-15 ℃, until carry out bioanalysis.
Sclera
Take out sclera from every eyes; Note weight, place each independently to have the glass 13x100 silanization test tube of screw lid, and be put on ice immediately.Sample is kept at below-15 ℃ or-15 ℃, until carry out bioanalysis.
Nasolacrimal duct
Taking-up contains the tissue of the nasolacrimal duct that links to each other with every eyes; Note weight, place glass 13x100 silanization test tube, and be put on ice immediately with screw lid.Sample is kept at below-15 ℃ or-15 ℃, until carry out bioanalysis.
Margo palpebrae
Take out margo palpebrae from every eyes; Note weight, place each independently to have the glass 13x100 silanization test tube of screw lid, and be put on ice immediately.Sample is kept at below-15 ℃ or-15 ℃, until carry out bioanalysis.
Sample is preserved
Blood sample and part tissue of eye sample are kept at below-15 ℃ or-15 ℃, until carry out bioanalysis.
Bioanalysis
Use following method to come the concentration in part tissue of eye and the blood is carried out quantitatively.
Extract the part tissue of eye sample by spending the night to flood with 2.0mL methanol down at 4 ℃.At room temperature flood for the second time subsequently and vibrated about one hour with 2.0mL methanol.From 4mL organic extract (whole 4mL of lachrymal gland sample are all analyzed) altogether, take out the 1mL aliquot, and mark (CsG of 20 μ L 500ng/mL) in adding.With the methanolic extract evaporate to dryness, and be dissolved in 50: 50 acetonitriles with 200 μ L: the 2mM ammonium acetate in the water/0.4% formic acid is heavy molten, is used for LC MS/MS and analyzes.The bioanalytical method that is used to analyze blood sample relates to that (10 μ L 500ng/mL) add in the 0.5mL aliquot of the Sanguis Leporis seu oryctolagi that K3EDTA handles with interior mark CsG.
After under 37 ℃, blood sample being hatched 30 minutes, with 0.1N HCL (2mL) acidify sample.Methyl tertiary butyl ether(MTBE) (4mL) is added to each sample and mixed 15 minutes.Take out organic layer and make its alkalization by adding 0.1N NaOH (2mL).With organic extract from water layer separate, evaporate to dryness and be dissolved in 50: 50 acetonitriles with 200 μ L: the 2mM ammonium acetate the water/0.4% formic acid is heavy molten, is used for LC MS/MS analysis.Use PE Sciex API 3000 mass spectrographs (Applied Biosystems, Foster City, CA), the automatic sampling instrument (Carrboro of Leap, NC) and HPLC pump (ShimadzuScientific Instruments, Columbia, MD), analyze the aliquot (50 μ L) of described heavy molten sample by LC-MS/MS.On Keystone BDS C8 post (3 μ m, 2.1x50mm, 65 ℃), carry out reversed-phase HPLC, solution gradient eluting (2mM ammonium acetate/0.4% formic acid that 2mM ammonium acetate/0.4% formic acid that A=is water-soluble and B=are dissolved in acetonitrile), flow velocity is 0.3mL/min.Employed precursor-product ion was to being during MRM analyzed: CSA's
And the m/z of IS (cyclosporin G)
The bulk analysis time is 5 minutes, and the retention time of CsA and CsG was respectively about 1.82 and 1.86 minutes.
Date processing
Data collection
● comprehensive examination of eyes before and after handling
● body weight: 1 day randomization of pro-
● the administration record
● mortality rate/sickness rate
● blood sample: before the postmortem
● ocular tissue's sample: after the postmortem
Data computation and outlier analysis
Except that the data of being missed because of reasonable grounds, all data all are used for calculating in the initial data.
Pharmacokinetics is analyzed
Thermo Electron Watson
TM(Philadelphia, PA) and
(Redmond Washington) is used for pharmacokinetics and calculates Excel.Use known non-split-run calculate following pharmacokinetic parameter (referring to Tang-Lui, et.Al.PharmaceuticalResearch, Vol 5, No.4,1988,238-241).Under possible situation, for example meansigma methods and standard deviation are described pharmacokinetic data to use descriptive statistics.Area under the Cot curve (AUC) value is registered as compound AUC, and under possible situation, be registered as meansigma methods ± standard error (SEM).
The numerical value and the numeral that are lower than quantitative limit round off
Be lower than quantitative limit (BLQ) if be used for the concentration value over half of calculating mean value, then be represented as statistically and can't calculate (NC).If half or numerical value over half are quantifiable, then any BLQ numerical value replaces by numerical value " 0 ", and comes calculating mean value and standard deviation (SD) thereof by these superseded numerical value.Calculate the meansigma methods and the standard error of the mean of each sampling time point in each processed group.Smaller or equal to 2 o'clock, only list meansigma methods at sample number.All meansigma methodss all are recorded to 3 position effective digitals, and the decimal place that standard deviation records is identical with its meansigma methods separately.
Scheme changes
о is before time point was collected ocular tissue's sample in 6 hours, without Lens
The flushing eyes come any residual surface preparation that remains in the eye surface of flush away.Because this medicine usually can be by eye surface fast Absorption, it is very little to think that therefore this change is studied resulting result's influence for this.In addition, the rabbit during 6 hours should be able to play the effect of any residual surface preparation of removing nictation equally.
The о initialism
| ACN | Acetonitrile | LLOQ | Lower limit of quantitation |
| ALQ | Be higher than quantitative limit | M | Male |
| AUC | Blood plasma or blood substance area under the concentration-time curve | N、n、No.、no. | Number |
| AUC Extrap | But blood plasma that put |
N/A, N.A. or n/a | Inapplicable |
| BID | Twice of every day | N/C, N.C., NC or n/c | Can't calculate |
| BLQ | Be lower than quantitative limit | NR | The report of coming to nothing/do not have |
| BMS | Bioanalysis type mass spectrography | NS | There is not sample |
| CFR | Code of Federal Regulations | NZW | New Zealand white rabbit |
| C0 or C 0 | The extrapolation blood plasma of |
OD | Right eye |
| Cmax or C max | Maximum drug level | OU | Eyes |
| CONC | Concentration | PKDM | Pharmacokinetics and drug metabolism |
| DG | The day (Day of Gestation) of pregnancy | PO | Oral |
| DSE | The drug safety assessment | QID | Four times a day |
| EDTA(K 3) | Ethylenediaminetetraacetic acid potassium | QNS | Quantity not sufficient |
| F | Female | SD, S.D. or sd | Standard deviation |
| GD | Conceived day (Gestation Day) | SE | Standard error |
| FDA | FDA Food and Drug Administration | Sec | Second |
| GLP | GLP | SMP | Sample |
| IC | Intracardiac | T1/2 or T 1/2 | Drug half-life |
| IS | The sample deficiency of collecting | TA | Triamcinolone acetonide |
| IM | Intramuscular | TID | Every day three times |
| IU | Iu | TK | Toxicokinetics |
| IV | Intravenous | Tmax or T max | Observe C maxThe time time |
| IVT | In the vitreous body | U | Unit |
| LC-MS/MS | The liquid chromatograph tandem mass spectrometry | ULOQ | Upper limit of quantification |
Annotate: be not that all initialisms of listing all can appear in this report.
Result and discussion
Cornea
Mean concentration and pharmacokinetic parameter are summarised in table 3 and 4.After single bilateral eye gave one of three kind of 0.05% cyclosporin A preparation of rabbit, the concentration-time curve of cyclosporin A was shown in Fig. 1 in the cornea.
Table 3 behind local one of the three kind of 0.05% cyclosporin A preparation that instil of the bilateral eye single of New Zealand white rabbit, the average cornea concentration of cyclosporin A.
Meansigma methods is represented the meansigma methods of n=6
aBe used to calculate t
1/2The concentration time point
Table 4 behind local one of the three kind of 0.05% cyclosporin A preparation that instil of the bilateral eye single of New Zealand white rabbit, the pharmacokinetic parameter of cyclosporin A in cornea.
| Parameter | Composition F | Compositions E | Compositions D |
| C max(ng/g) | 4050±1220 | 1100±190 | 536±138 |
| T max(hr) | 0.500 | 2.00 | 6.00 |
| AUC 0-t(ng·hr/g) a | 163000±7000 | 76200±3300 | 29300±2000 |
| AUC 0-24(ng·hr/g) | 59000 | 22100 | 9450 |
| t 1/2(hr) | 41.3 | 42.2 | 49.8 |
| MRT(hr) | 50.3 | 56.5 | 61.6 |
a0-144 hour AUC interval is used to the calculating of these three kinds of preparations.
Composition F
After single bilateral eye instillation composition F, cyclosporin A is quickly absorbed in the cornea, cornea peak concentration (C
Max) be 4050 ± 1220ng/g, appear at after the administration 0.500 hour.Area under the concentration-time curve (AUC to last detection time of point
0-t) value is 163000 ± 7000nghr/g, and AUC
0-24Numerical value is 59000nghr/g.Final half-life (t
1/2) be 41.3 hours, mean residence time (MRT) is 50.3 hours.
Compositions E
Behind single bilateral eye instillation compositions E, cyclosporin A is absorbed in the cornea, C
MaxValue is 1100 ± 190ng/g, appears at after the administration 2.00 hours.AUC
0-tValue is 76200 ± 3300nghr/g, and AUC
0-24Value is 22100nghr/g.Final t
1/2Be 41.7 hours, MRT is 56.5 hours.
Compositions D
Behind single bilateral eye instillation compositions D, cyclosporin A is absorbed in the cornea, C
MaxValue is 536 ± 138ng/g, appears at after the administration 6.00 hours.AUC
0-tValue is 29300 ± 2000nghr/g, and AUC
0-24Value is 9450nghr/g.Final t
1/2Be 49.8 hours, MRT is 61.6 hours.
Conjunctiva
Mean concentration and pharmacokinetic parameter are summarised in table 5 and 6.After single bilateral eye gave one of three kind of 0.05% cyclosporin A preparation of rabbit, the concentration-time curve of cyclosporin A was shown in Fig. 2 in the conjunctiva.
Table 5 behind local one of the three kind of 0.05% cyclosporin A preparation that instil of the bilateral eye single of New Zealand white rabbit, the average conjunctiva concentration of cyclosporin A.
Meansigma methods is represented the meansigma methods of n=6
BLQ=is lower than quantitative limit
aBe used to calculate t
1/2The concentration time point
Table 6 behind local one of the three kind of 0.05% cyclosporin A preparation that instil of the bilateral eye single of New Zealand white rabbit, the pharmacokinetic parameter of cyclosporin A in conjunctiva.
| Parameter | Composition F | Compositions E | Compositions D |
| C max(ng/g) | 4460±650 | 2560±1070 | 694±410 |
| T max(hr) | 0.500 | 0.500 | 0.500 |
| AUC 0-t(ng·hr/g) | 18100±800 a | 11600±700 b | 5290±480 b |
| AUC 0-24(ng·hr/g) | 17100 | 11600 | 5290 |
| t 1/2(hr) | 11.3 | 5.57 | 4.55 |
| MRT(hr) | 7.37 | 5.93 | 6.07 |
a0-48 hour AUC interval is used for calculating
b0-24 hour AUC interval is used for calculating
Composition F
After single bilateral eye instillation composition F, cyclosporin A is quickly absorbed in the conjunctiva, C
MaxValue is 4460 ± 650ng/g, appears at after the administration 0.500 hour.AUC
0-tValue is 18100 ± 800nghr/g, and AUC
0-24Value is 17100nghr/g.Final t
1/2Be 11.3 hours, MRT is 7.37 hours.
Compositions E
Behind single bilateral eye instillation compositions E, cyclosporin A is quickly absorbed in the conjunctiva, C
MaxValue is 2560 ± 1070ng/g, appears at after the administration 0.500 hour.AUC
0-tValue is 11600 ± 700nghr/g.Final t
1/2Be 5.57 hours, MRT is 5.93 hours.
Compositions D
Behind single bilateral eye instillation compositions D, cyclosporin A is quickly absorbed in the conjunctiva, C
MaxValue is 694 ± 410ng/g, appears at after the administration 0.500 hour.AUC
0-tValue is 5290 ± 480nghr/g.Final t
1/2Be 4.55 hours, MRT is 6.07 hours.
Sclera
Mean concentration and pharmacokinetic parameter are summarised in table 7 and 8.After single bilateral eye gave one of three kind of 0.05% cyclosporin A preparation of rabbit, the concentration-time curve of cyclosporin A was shown in Fig. 3 in the sclera.
Table 7 behind local one of the three kind of 0.05% cyclosporin A preparation that instil of the bilateral eye single of New Zealand white rabbit, the average sclera concentration of cyclosporin A.
Meansigma methods is represented the meansigma methods of n=6
BLQ=is lower than quantitative limit
aBe used to calculate t
1/2The concentration time point
Table 8 behind local one of the three kind of 0.05% cyclosporin A preparation that instil of the bilateral eye single of New Zealand white rabbit, the pharmacokinetic parameter of cyclosporin A in sclera.
| Parameter | Composition F | Compositions E | Compositions D |
| C max(ng/g) | 545±98 | 136±43 | 53.0±10.9 |
| T max(hr) | 0.500 | 0.500 | 6.00 |
| AUC 0-t(ng·hr/g) | 6110±260 a | 2840±150 a | 1040±50 b |
| AUC 0-24(ng·hr/g) | 3900 | 1560 | 792 |
| t 1/2(hr) | 29.7 | 24.8 | 18.7 |
| MRT(hr) | 25.3 | 26.9 | 23.8 |
a0-144 hour AUC interval is used for calculating
b0-48 hour AUC interval is used for calculating
Composition F
After single bilateral eye instillation composition F, cyclosporin A is quickly absorbed in the sclera, C
MaxValue is 545 ± 98ng/g, appears at after the administration 0.500 hour.AUC
0-tValue is 6110 ± 260nghr/g, and AUC
0-24Value is 3900nghr/g.Final t
1/2Be 29.7 hours, MRT is 25.3 hours.
Compositions E
Behind single bilateral eye instillation compositions E, cyclosporin A is quickly absorbed in the sclera, C
MaxValue is 136 ± 43ng/g, appears at after the administration 0.500 hour.AUC
0-tValue is 2840 ± 150nghr/g, and AUC
0-24Value is 1560nghr/g.Final t
1/2Be 24.8 hours, MRT is 26.7 hours.
Compositions D
Behind single bilateral eye instillation compositions D, cyclosporin A is absorbed in the sclera, C
MaxValue is 53.0 ± 10.9ng/g, appears at after the administration 6.00 hours.AUC
0-tValue is 1040 ± 50nghr/g, and AUC
0-24Value is 792nghr/g.Final t
1/2Be 18.7 hours, MRT is 23.8 hours.
Margo palpebrae
Mean concentration and pharmacokinetic parameter are summarised in table 9 and 10.After single bilateral eye gave one of three kind of 0.05% cyclosporin A preparation of rabbit, the concentration-time curve of cyclosporin A was shown in Fig. 4 in the margo palpebrae.
Table 9 behind local one of the three kind of 0.05% cyclosporin A preparation that instil of the bilateral eye single of New Zealand white rabbit, the average margo palpebrae concentration of cyclosporin A.
Meansigma methods is represented the meansigma methods of n=6
aBe used to calculate t
1/2The concentration time point
Table 10 behind local one of the three kind of 0.05% cyclosporin A preparation that instil of the bilateral eye single of New Zealand white rabbit, the pharmacokinetic parameter of cyclosporin A in margo palpebrae.
| Parameter | Composition F | Compositions E | Compositions D |
| C max(ng/g) | 3120±1040 | 2020±980 | 2450±970 |
| T max(hr) | 0.500 | 0.500 | 2.00 |
| AUC 0-t (ng·hr/g) a | 38300±5300 | 42200±10800 | 27700±3300 |
| AUC 0-24 (ng·hr/g) | 19900 | 17600 | 18000 |
| t 1/2(hr) | 42.5 | 38.2 | 24.4 |
| MRT(hr) | 40.5 | 38.4 | 21.9 |
a0-144 hour AUC interval is used for the calculating of these three kinds of preparations
Composition F
After single bilateral eye instillation composition F, cyclosporin A is quickly absorbed in the margo palpebrae, C
MaxValue is 3120 ± 1040ng/g, appears at after the administration 0.500 hour.AUC
0-tValue is 38300 ± 5300nghr/g, and AUC
0-24Value is 19900nghr/g.Final t
1/2Be 42.5 hours, MRT is 40.5 hours.
Compositions E
Behind single bilateral eye instillation compositions E, cyclosporin A is quickly absorbed in the margo palpebrae, C
MaxValue is 2020 ± 980ng/g, appears at after the administration 0.500 hour.AUC
0-tValue is 42200 ± 10800nghr/g, and AUC
0-24Value is 17600nghr/g.Final t
1/2Be 38.1 hours, MRT is 38.4 hours.
Compositions D
Behind single bilateral eye instillation compositions D, cyclosporin A is absorbed in the margo palpebrae, C
MaxValue is 2450 ± 970ng/g, appears at after the administration 2.00 hours.AUC
0-tValue is 27700 ± 3300nghr/g, and AUC
0-24Value is 18000nghr/g.Final t
1/2Be 24.4 hours, MRT is 21.9 hours.
Nasolacrimal duct
Mean concentration and pharmacokinetic parameter are summarised in table 11 and 12.After single bilateral eye gave one of three kind of 0.05% cyclosporin A preparation of rabbit, the concentration-time curve of cyclosporin A was shown in Fig. 5 in the nasolacrimal duct.
Table 11 behind local one of the three kind of 0.05% cyclosporin A preparation that instil of the bilateral eye single of New Zealand white rabbit, the average nasolacrimal duct concentration of cyclosporin A.
Meansigma methods is represented the meansigma methods of n=6
BLQ=is lower than quantitative limit
Table 12 behind local one of the three kind of 0.05% cyclosporin A preparation that instil of the bilateral eye single of New Zealand white rabbit, the pharmacokinetic parameter of cyclosporin A in nasolacrimal duct.
| Parameter | Composition F | Compositions E | Compositions D |
| C max(ng/g) | 195±201 | 74.4±20.9 | 72.0±91.7 |
| T max(hr) | 0.500 | 0.500 | 0.500 |
| AUC 0-t(ng·hr/g) | 2190±350 a | 1190±212 b | 279±39 c |
| AUC 0-12(ng·hr/g) | 478±86 | 465±106 | 279±39 |
| t 1/2(hr) | NC | NC | NC |
| MRT(hr) d | 17.6 | 24.7 | 12.1 |
NC=can't calculate
a0-144 hour AUC interval is used for calculating
b0-48 hour AUC interval is used for calculating
c0-12 hour AUC interval is used for calculating
d0-12 hour interval is used for calculating
Composition F
After single bilateral eye instillation composition F, cyclosporin A is entered fast and is absorbed subsequently in the nasolacrimal duct tissue, C
MaxValue is 195 ± 201ng/g, appears at after the administration 0.500 hour.AUC
0-tValue is 2190 ± 350nghr/g, and AUC
0-12Value is 478 ± 86nghr/g.MRT is 17.6 hours.
Compositions E
Behind single bilateral eye instillation compositions E, cyclosporin A is entered fast and is absorbed subsequently in the nasolacrimal duct tissue, C
MaxValue is 74.4 ± 20.9ng/g, appears at after the administration 0.500 hour.AUC
0-tValue is 1190 ± 210nghr/g, and AUC
0-12Value is 465 ± 106nghr/g.MRT is 24.7 hours.
Compositions D
Behind single bilateral eye instillation compositions D, cyclosporin A is entered fast and is absorbed subsequently in the nasolacrimal duct tissue, C
MaxValue is 72.0 ± 91.7ng/g, appears at after the administration 0.500 hour.AUC
0-tValue is 279 ± 39nghr/g.MRT is 12.1 hours.
Blood
The mean concentration of cyclosporin A is summarised in table 13 in the blood.
Table 13 behind local one of the three kind of 0.05% cyclosporin A preparation that instil of the bilateral eye single of New Zealand white rabbit, the average blood concentration of cyclosporin A.
Meansigma methods is expressed as the meansigma methods of n=3
BLQ=is lower than quantitative limit
Composition F
After the single bilateral eye instillation composition F, in blood, detected cyclosporin A concentration in 0.5 and 2 hour after the administration and be respectively 2.21 ± 0.33ng/mL and 0.463 ± 0.021ng/mL.At all subsequently time points, the cyclosporin A level all is lower than quantitative limit.
Compositions E
Behind the single bilateral eye instillation compositions E, detecting cyclosporin A concentration in 0.5 hour in blood after the administration is 0.441 ± 0.126ng/mL.At all subsequently time points, the cyclosporin A level all is lower than quantitative limit.
Compositions D
Behind the single bilateral eye instillation compositions D, at all time points, the cyclosporin A level all is lower than quantitative limit.
Give rabbit with composition F and the cyclosporin A of top level can be sent usually and pass ocular tissue, when comparing with compositions D, the area under curve (AUC) of observing concentration-time curve has on average increased by 5 times.When comparing, give rabbit with compositions E and make AUC on average increase by 2 times with compositions D.In this research, after giving New Zealand white rabbit with compositions D viewed pharmacokinetics analysis with before the report data very identical.
In general, final half-life of the actual measurement of composition F and mean residence time are the longest, secondly are compositions E, are compositions D once more.Therefore, except the AUC of the AUC that reported cornea, conjunctiva, sclera and margo palpebrae to 24 hour and nasolacrimal duct to 12 hour, but also reported the AUC value of putting to last detection time, so that one day is assessed to the levels of drugs that is reached in a medicine is afterwards between same zone.Generally speaking, comparing AUC
0-tThe viewed trend comparison AUC that coexists during value
0-24Or AUC
0-12The time viewed trend consistent.
In a word, when medicine is made into the composition F aqueous solution, having observed the highest cyclosporin A ocular tissue exposure level after the single eye instils 0.05% cyclosporin A preparation, secondly is compositions E, is compositions D once more.Blood substance is also observed corresponding trend in exposing.
Limit the scope of the invention although have no intention, but think that these pharmacokinetics result shows: the concentration remarkable low cyclosporin A of known concentration before can be used in the topical ophthalmic compositions, and still can obtain to treat the cyclosporin A of effective dose.
Pharmacokinetics research 2
Following preparation of compositions mode is similar to compositions D, E and F's.
| Preparation | Compositions G | Compositions H | Compositions D |
| Composition | Aqueous solution | Aqueous solution | Emulsion |
| Cyclosporin A | 0.020 | 0.030 | 0.050 |
| Purite | 0.01％ (100ppm) | 0.01％ (100ppm) | 0.0％ (0ppm) |
| Polyoxyethylene sorbitan monoleate | 1.0 | 1.0 | 1.0 |
| Glycerol | 1.0 | 1.0 | 2.2 |
| Mannitol | 0.5 | 0.5 | N/A |
| Sodium carboxymethyl cellulose (CMC)-7LFPH | 0.5 | 0.5 | N/A |
| Sodium Citrate, usp, Dihydrate Powder | 0.4 | 0.4 | N/A |
| Boric acid | 0.25 | 0.25 | N/A |
| Ten water sodium borate | 0.41 | 0.41 | N/A |
| Potassium chloride | 0.14 | 0.14 | N/A |
| Oleum Ricini | N/A | N/A | 1.25 |
| Pemulen?TR-2 | N/A | N/A | 0.05 |
| Sodium hydroxide | N/A | N/A | pH7.4 |
| Pure water | QS | QS | N/A |
Use the analytical method similar to carry out pharmacokinetics research to those analytical methods of having described.Parameter is as follows:
Test formulation: G, H and D
Animal species/strain: New Zealand white rabbit
Sex: female
Number: 2 rabbit/time points (2 blank rabbits)
Route of administration: topical ophthalmic
Dosage regimen: bilateral, QD (aqueous solution)/BID (compositions D)-5 day
Administration volume: 35 μ L
Time point: the 1st day and the 5th day-0.5,2,6,12,24hr after the administration
Analytical method: LC-MS/MS
Analytic target: cyclosporin A
Data analysis: C
Max, AUC
0-24, standardized AUC dosage
The results are shown in the following form in cornea, tear and the blood.
The bioavailability of Cyclosporin A in table 14. cornea.
The bioavailability of Cyclosporin A in table 15. blood.
N=2 rabbit/time point
BLQ-is lower than detectability (0.2ng/mL)
The bioavailability of Cyclosporin A in table 16. tear.
Standard composition
These compositionss (AA-MM) are considered as the standard of comparison product, to characterize compositions disclosed herein by special.
Following compositions is intended to expression and those are at Kanai et.al., TransplantationProceedings, Vol 21, No 1 (February), and those identical compositionss of disclosed compositions among the 1989:3150-3152 (including it in this paper) by quoting:
Compositions AA: the solution of forming by 0.025% cyclosporin A, 40mg/mL α cyclodextrin and water;
Compositions BB: the solution of forming by 0.009% cyclosporin A, 20mg/mL α cyclodextrin and water; With
Compositions CC: the solution of forming by 0.003% cyclosporin A, 10mg/mL α cyclodextrin and water.
Following compositions be intended to the expression with those at Cheeks et.al., Current Eye Research, Vol 11, No 7 (1992), those identical compositionss of disclosed compositions among the 641-649 (including it in this paper by quoting):
Compositions DD: the α cyclodextrin solution that contains the 40mg/mL of 0.025% Cyclosporin A.
Following compositions be intended to the expression with those at Tamilvanan, Stp Pharma SciNov-Dec; 11 (6): those identical compositionss of disclosed compositions among the 421-426 (including it in this paper by quoting), different is the concentration difference of cyclosporin A.
Compositions EE: by cyclosporin A (0.05w/w%), Oleum Ricini (2.5w/w%), stearmide (0.12w/w%), alpha-tocopherol (0.01w/w%), benzalkonium chloride (0.01w/w%) be up to the emulsion that the water of 100w/w% is formed.
Following compositions is intended to expression and those identical compositionss of the disclosed sample C-E of U.S. Patent No. 5,051,402 (the 7th hurdle).Its whole disclosure is included this paper in by quoting.
The sodium chloride of the cyclosporin A of composition F F:0.25mL/mL, the alpha-cyclodextrin of 40mg/mL and 7.79mg/mL;
The sodium chloride of the cyclosporin A of compositions GG:0.10mL/mL, the alpha-cyclodextrin of 20mg/mL and 8.40mg/mL; And
The sodium chloride of the cyclosporin A of compositions HH:0.05mL/mL, the alpha-cyclodextrin of 10mg/mL and 8.70mg/mL.
Following compositions is intended to expression and Abdulrizak, Stp Pharma Sci Nov-Dec; 11 (6): 427-432 (including this paper in by the quoting) compositions that disclosed compositions is identical, different is the concentration difference of cyclosporin A.
Composition I I: the emulsion of forming by cyclosporin A (0.05w/w%), Oleum Ricini (2.5w/w%), poloxamer 188 (0.425w/w%), glycerol (2.25w/w%), Lipoid E-80 (0.5w/w%), stearmide (0.12w/w%), tocopherol (0.01w/w%), benzalkonium chloride (0.01w/w%) and water.
Following compositions is intended to expression and Kuwano Mitsuaki et al.Pharm Res 2002Aug; 19 (1): the compositions that the disclosed compositions of 108-111 is identical.
Compositions JJ: by cyclosporin A (0.0865%), ethanol (0.1%), MYS-40 (2%), HPMC (0.3w/v%), sodium dihydrogen phosphate (0.2w/v%) and EDTA disodium (0.01%w/v%), be used for Zhang Du is adjusted to the sodium chloride of 287mOsm and the solution that water is formed.
Compositions KK is intended to be illustrated in the table 1 of US20010041671 (including this paper in by quoting) with the disclosed compositions of preparation 1 form.Compositions LL be in US20010041671 with the disclosed compositions of preparation 3 forms, the concentration of different is Cyclosporin A reduces.
Compositions KK: cyclosporin A (0.02%), hyaluronate sodium (0.05%), Tween 80 (0.05%), Na
2HPO
412H
2O (0.08%), Sorbitol (5.46%) are mended pure water to 100mL, pH 7.0-7.4, and mosm/L=295-305.
Compositions LL: cyclosporin A (0.2%), hyaluronate sodium (0.10%), Tween 80 (5.00%), Na
2HPO
412H
2O (0.08%), Sorbitol (5.16%) are mended pure water to 100mL, pH 7.0-7.4, and mosm/L=295-305.
Following compositions is intended to be illustrated in US 5,951, the embodiment 2 disclosed compositionss of 971 (including this paper in by quoting).
Compositions MM: cyclosporin A (0.025g), polyoxyl-40-stearate (0.5g), hydroxypropyl emthylcellulose (0.2g), butylated hydroxytoluene (0.0005g), ethanol (0.1g), sodium chloride (0.73g), sodium dihydrogen phosphate (0.2g), edetate sodium (0.1g) are used for and will transfer the sodium hydroxide of pH to 6.0 and moisturizing to 100mL.
In another embodiment, after topical ophthalmic gives a present composition or compositions AA 30 minutes, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions AA provided many, the drop of wherein said compositions is identical with the droplet size of compositions AA.
In another embodiment, after topical ophthalmic gives a present composition or compositions BB 30 minutes, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions BB provided many, the drop of wherein said compositions is identical with the droplet size of compositions BB.
In another embodiment, after topical ophthalmic gives a present composition or compositions CC 30 minutes, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions CC provided many, the drop of wherein said compositions is identical with the droplet size of compositions CC.
In another embodiment, after topical ophthalmic gives a present composition or compositions DD 30 minutes, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions DD provided many, the drop of wherein said compositions is identical with the droplet size of compositions DD.
In another embodiment, after topical ophthalmic gives a present composition or compositions EE 30 minutes, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions EE provided many, the drop of wherein said compositions is identical with the droplet size of compositions EE.
In another embodiment, after topical ophthalmic gives a present composition or composition F F 30 minutes, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than composition F F provided many, the drop of wherein said compositions is identical with the droplet size of composition F F.
In another embodiment, after topical ophthalmic gives a present composition or compositions GG 30 minutes, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions GG provided many, the drop of wherein said compositions is identical with the droplet size of compositions GG.
In another embodiment, after topical ophthalmic gives a present composition or compositions HH 30 minutes, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions HH provided many, the drop of wherein said compositions is identical with the droplet size of compositions HH.
In another embodiment, after topical ophthalmic gives a present composition or composition I I 30 minutes, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than composition I I provided many, the drop of wherein said compositions is identical with the droplet size of composition I I.
In another embodiment, after topical ophthalmic gives a present composition or compositions JJ 30 minutes, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions JJ provided many, the drop of wherein said compositions is identical with the droplet size of compositions JJ.
In another embodiment, after topical ophthalmic gives a present composition or compositions KK 30 minutes, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions KK provided many, the drop of wherein said compositions is identical with the droplet size of compositions KK.
In another embodiment, after topical ophthalmic gives a present composition or compositions LL 30 minutes, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions LL provided many, the drop of wherein said compositions is identical with the droplet size of compositions LL.
In another embodiment, after topical ophthalmic gives a present composition or compositions MM 30 minutes, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions MM provided many, the drop of wherein said compositions is identical with the droplet size of compositions MM.
In another embodiment, after topical ophthalmic gives a present composition or compositions AA 30 minutes, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions AA provided many, the drop of wherein said compositions is identical with the droplet size of compositions AA.
In another embodiment, after topical ophthalmic gives a present composition or compositions BB 30 minutes, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions BB provided many, the drop of wherein said compositions is identical with the droplet size of compositions BB.
In another embodiment, after topical ophthalmic gives a present composition or compositions CC 30 minutes, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions CC provided many, the drop of wherein said compositions is identical with the droplet size of compositions CC.
In another embodiment, after topical ophthalmic gives a present composition or compositions DD 30 minutes, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions DD provided many, the drop of wherein said compositions is identical with the droplet size of compositions DD.
In another embodiment, after topical ophthalmic gives a present composition or compositions EE 30 minutes, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions EE provided many, the drop of wherein said compositions is identical with the droplet size of compositions EE.
In another embodiment, after topical ophthalmic gives a present composition or composition F F 30 minutes, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than composition F F provided many, the drop of wherein said compositions is identical with the droplet size of composition F F.
In another embodiment, after topical ophthalmic gives a present composition or compositions GG 30 minutes, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions GG provided many, the drop of wherein said compositions is identical with the droplet size of compositions GG.
In another embodiment, after topical ophthalmic gives a present composition or compositions HH 30 minutes, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions HH provided many, the drop of wherein said compositions is identical with the droplet size of compositions HH.
In another embodiment, after topical ophthalmic gives a present composition or composition I I 30 minutes, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than composition I I provided many, the drop of wherein said compositions is identical with the droplet size of composition I I.
In another embodiment, after topical ophthalmic gives a present composition or compositions JJ 30 minutes, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions JJ provided many, the drop of wherein said compositions is identical with the droplet size of compositions JJ.
In another embodiment, after topical ophthalmic gives a present composition or compositions KK 30 minutes, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions KK provided many, the drop of wherein said compositions is identical with the droplet size of compositions KK.
In another embodiment, after topical ophthalmic gives a present composition or compositions LL 30 minutes, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions LL provided many, the drop of wherein said compositions is identical with the droplet size of compositions LL.
In another embodiment, after topical ophthalmic gives a present composition or compositions MM 30 minutes, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions MM provided many, the drop of wherein said compositions is identical with the droplet size of compositions MM.
The comparison of two kinds of compositionss in the human or animal can give eyes by the compositions that will require to protect and give modes such as another eyes with second kind of compositions to carry out.
In another embodiment, after topical ophthalmic gives a present composition or compositions AA during 24 hours, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions AA provided many, the drop of wherein said compositions is identical with the droplet size of compositions AA.
In another embodiment, after topical ophthalmic gives a present composition or compositions BB during 24 hours, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions BB provided many, the drop of wherein said compositions is identical with the droplet size of compositions BB.
In another embodiment, after topical ophthalmic gives a present composition or compositions CC during 24 hours, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions CC provided many, the drop of wherein said compositions is identical with the droplet size of compositions CC.
In another embodiment, after topical ophthalmic gives a present composition or compositions DD during 24 hours, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions DD provided many, the drop of wherein said compositions is identical with the droplet size of compositions DD.
In another embodiment, after topical ophthalmic gives a present composition or compositions EE during 24 hours, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions EE provided many, the drop of wherein said compositions is identical with the droplet size of compositions EE.
In another embodiment, after topical ophthalmic gives a present composition or composition F F during 24 hours, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than composition F F provided many, the drop of wherein said compositions is identical with the droplet size of composition F F.
In another embodiment, after topical ophthalmic gives a present composition or compositions GG during 24 hours, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions GG provided many, the drop of wherein said compositions is identical with the droplet size of compositions GG.
In another embodiment, after topical ophthalmic gives a present composition or compositions HH during 24 hours, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions HH provided many, the drop of wherein said compositions is identical with the droplet size of compositions HH.
In another embodiment, after topical ophthalmic gives a present composition or composition I I during 24 hours, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than composition I I provided many, the drop of wherein said compositions is identical with the droplet size of composition I I.
In another embodiment, after topical ophthalmic gives a present composition or compositions JJ during 24 hours, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions JJ provided many, the drop of wherein said compositions is identical with the droplet size of compositions JJ.
In another embodiment, after topical ophthalmic gives a present composition or compositions KK during 24 hours, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions KK provided many, the drop of wherein said compositions is identical with the droplet size of compositions KK.
In another embodiment, after topical ophthalmic gives a present composition or compositions LL during 24 hours, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions LL provided many, the drop of wherein said compositions is identical with the droplet size of compositions LL.
In another embodiment, after topical ophthalmic gives a present composition or compositions MM during 24 hours, the cyclosporin A that described compositions provides for the cornea of female New Zealand white rabbits than compositions MM provided many, the drop of wherein said compositions is identical with the droplet size of compositions MM.
In another embodiment, after topical ophthalmic gives a present composition or compositions AA during 24 hours, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions AA provided many, the drop of wherein said compositions is identical with the droplet size of compositions AA.
In another embodiment, after topical ophthalmic gives a present composition or compositions BB during 24 hours, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions BB provided many, the drop of wherein said compositions is identical with the droplet size of compositions BB.
In another embodiment, after topical ophthalmic gives a present composition or compositions CC during 24 hours, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions CC provided many, the drop of wherein said compositions is identical with the droplet size of compositions CC.
In another embodiment, after topical ophthalmic gives a present composition or compositions DD during 24 hours, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions DD provided many, the drop of wherein said compositions is identical with the droplet size of compositions DD.
In another embodiment, after topical ophthalmic gives a present composition or compositions EE during 24 hours, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions EE provided many, the drop of wherein said compositions is identical with the droplet size of compositions EE.
In another embodiment, after topical ophthalmic gives a present composition or composition F F during 24 hours, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than composition F F provided many, the drop of wherein said compositions is identical with the droplet size of composition F F.
In another embodiment, after topical ophthalmic gives a present composition or compositions GG during 24 hours, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions GG provided many, the drop of wherein said compositions is identical with the droplet size of compositions GG.
In another embodiment, after topical ophthalmic gives a present composition or compositions HH during 24 hours, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions HH provided many, the drop of wherein said compositions is identical with the droplet size of compositions HH.
In another embodiment, after topical ophthalmic gives a present composition or composition I I during 24 hours, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than composition I I provided many, the drop of wherein said compositions is identical with the droplet size of composition I I.
In another embodiment, after topical ophthalmic gives a present composition or compositions JJ during 24 hours, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions JJ provided many, the drop of wherein said compositions is identical with the droplet size of compositions JJ.
In another embodiment, after topical ophthalmic gives a present composition or compositions KK during 24 hours, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions KK provided many, the drop of wherein said compositions is identical with the droplet size of compositions KK.
In another embodiment, after topical ophthalmic gives a present composition or compositions LL during 24 hours, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions LL provided many, the drop of wherein said compositions is identical with the droplet size of compositions LL.
In another embodiment, after topical ophthalmic gives a present composition or compositions MM during 24 hours, the cyclosporin A that described compositions provides for the conjunctiva of female New Zealand white rabbits than compositions MM provided many, the drop of wherein said compositions is identical with the droplet size of compositions MM.
In one embodiment, the described compositions of the one 35 μ L of every eyes of topical administration female New Zealand white rabbits wherein is behind described topical 30 minutes the time, for the cornea of this rabbit provides cornea at least about 500ng cyclosporin A/this rabbit of gram.
In another embodiment, the described compositions of the one 35 μ L of every eyes of topical administration female New Zealand white rabbits is behind described topical 30 minutes the time, for the cornea of this rabbit provides cornea at least about 2000ng cyclosporin A/this rabbit of gram.
In another embodiment, the described compositions of the one 35 μ L of every eyes of topical administration female New Zealand white rabbits is behind described topical 30 minutes the time, for the cornea of this rabbit provides cornea at least about 2400ng cyclosporin A/this rabbit of gram.
In another embodiment, the described compositions of the one 35 μ L of every eyes of topical administration female New Zealand white rabbits is during behind the described topical 24 hours, for the cornea of this rabbit provides cornea at least about 17000ng cyclosporin A/this rabbit of gram.
In another embodiment, the described compositions of the one 35 μ L of every eyes of topical administration female New Zealand white rabbits is during behind the described topical 24 hours, for the conjunctiva of this rabbit provides conjunctiva at least about 3300ng cyclosporin A/this rabbit of gram.
In another embodiment, described compositions is to contain 0.005% aqueous solution to about 0.04% cyclosporin A, the described compositions of the one 35 μ L of every eyes of topical administration new zealand rabbit wherein, for the cornea of this rabbit provides cyclosporin A/gram cornea at least about 17000ng, this records by following steps:
With each every the eye only in 15 female New Zealand white rabbits test subject of described compositions topical administration, and
The amount of cyclosporin A in three experimenters' the cornea is measured in about 0.5 hour, about 2 hours, about 6 hours, about 12 hours and about 24 hours after giving described experimenter, wherein only to the measurement amount of cyclosporin A in every experimenter's the cornea once.
In another embodiment, described compositions is to contain 0.005% aqueous solution to about 0.04% cyclosporin A, the described compositions of the one 35 μ L of every eyes of topical administration new zealand rabbit wherein, for the conjunctiva of this rabbit provides cyclosporin A/gram conjunctiva at least about 17000ng, this records by following steps:
With each every the eye only in 15 female New Zealand white rabbits test subject of described compositions topical administration, and
The amount of cyclosporin A in three experimenters' the conjunctiva is measured in about 0.5 hour, about 2 hours, about 6 hours, about 12 hours and about 24 hours after giving described experimenter, wherein only to the measurement amount of cyclosporin A in every experimenter's the conjunctiva once.
As mentioned above, except that rabbit, these compositionss also are suitable for other mammals, comprise the people.Therefore, claims or other places by the rabbit body in any compositions of characterizing of bioavailability all be considered for people or another kind of mammal.Come the definitions section compound should not be interpreted as and to use the Therapeutic Method of said composition to be confined to be used for rabbit by the bioavailability in rabbit, and the treatment of adopting said composition should be interpreted as comprising to people and other mammiferous treatments.
More than describe to describe in detail and can be used to implement concrete grammar and the compositions that the present invention and representative are considered to best mode.But, it is evident that for those of ordinary skills other compositionss with required materia medica character can prepare in a similar manner.Therefore, no matter appear at above in have how in detail, should not be interpreted as restriction to its entire scope; Or rather, scope of the present invention only is limited by the legal explanation to claim.
Claims (39)
1. compositions, containing concentration is that about 0.0001% (w/v) is to the cyclosporin A that is lower than about 0.05% (w/v).
2. the compositions of claim 1 is aqueous solution.
3. the concentration of claim 1, wherein the concentration of cyclosporin A is that about 0.02% (w/v) is to about 0.04% (w/v).
4. the compositions of claim 2, wherein the concentration of cyclosporin A is that about 0.02% (w/v) is to about 0.04% (w/v).
5. the compositions of claim 2 does not contain ethanol.
6. the compositions of claim 2 does not contain hyaluronic acid.
7. the compositions of claim 2 does not contain cyclodextrin A.
8. the compositions of claim 6 does not contain cyclodextrin.
9. the compositions of claim 8 does not contain ethanol.
10. the compositions of claim 9 does not contain vitamin E TPGS.
11. the compositions of claim 9 does not contain hyaluronic acid.
12. the compositions of claim 1, the described compositions of the one 35 μ L of every eyes of topical administration female New Zealand white rabbits wherein is after described topical 30 minutes the time, for the cornea of this rabbit provides cornea at least about 500ng cyclosporin A/this rabbit of gram.
13. the compositions of claim 1, the described compositions of the one 35 μ L of every eyes of topical administration female New Zealand white rabbits wherein is after described topical 30 minutes the time, for the cornea of this rabbit provides cornea at least about 1000ng cyclosporin A/this rabbit of gram.
14. the compositions of claim 1, the described compositions of the one 35 μ L of every eyes of topical administration female New Zealand white rabbits wherein is after described topical 30 minutes the time, for the cornea of this rabbit provides cornea at least about 1400ng cyclosporin A/this rabbit of gram.
15. the compositions of claim 1, the described compositions of the one 35 μ L of every eyes of topical administration female New Zealand white rabbits wherein, after described topical during 24 hours, for the cornea of this rabbit provides cornea at least about 17000nghr cyclosporin A/this rabbit of gram.
16. the compositions of claim 2, the described compositions of the one 35 μ L of every eyes of topical administration female New Zealand white rabbits wherein, during behind the described topical 24 hours, for the conjunctiva of this rabbit provides conjunctiva at least about 3300nghr cyclosporin A/this rabbit of gram.
17. the compositions of claim 2, wherein said compositions is for containing the aqueous solution of 0.005% (w/v) to about 0.04% (w/v) cyclosporin A, the described compositions of the one 35 μ L of every eyes of topical administration new zealand rabbit wherein, for the cornea of this rabbit provides cyclosporin A/gram cornea at least about 17000nghr, this records by following steps:
With each every the eye only in 15 female New Zealand white rabbits test subject of described compositions topical administration; And
After giving described experimenter about 0.5 hour, about 2 hours, about 6 hours, about 12 hours and about 24 hours, measure the amount of cyclosporin A in three experimenters' the cornea;
Wherein only once to the measurement amount of cyclosporin A in every experimenter's the cornea.
18. the compositions of claim 2, wherein said compositions is for containing the aqueous solution of 0.005% (w/v) to about 0.04% (w/v) cyclosporin A, the described compositions of the one 35 μ L of every eyes of topical administration new zealand rabbit wherein, for the conjunctiva of this rabbit provides at least about 6000ng cyclosporin A/gram conjunctiva, this measures by the following method:
With each every the eye only in 15 female New Zealand white rabbits test subject of described compositions topical administration; And
After giving described experimenter about 0.5 hour, about 2 hours, about 6 hours, about 12 hours and about 24 hours, measure the amount of cyclosporin A in three experimenters' the conjunctiva;
Wherein the amount of cyclosporin A is only measured once in every experimenter's the conjunctiva.
19. the compositions of claim 1 also contains surfactant.
20. the compositions of claim 1 also contains antiseptic.
21. a method comprises that compositions topical administration with claim 1 has required mammiferous eyes to strengthen or recovers lachrymal gland and shed tears to this.
22. the tear that the method for claim 21, wherein said method have increased in the adacrya eyes produces.
23. the method for claim 21, wherein said method is effectively treated keratoconjunctivitis sicca.
24. the method for claim 21, wherein said method is effectively treated xerophthalmia.
25. the method for claim 21, wherein said mammal are patient, and when described compositions was only given once to reach three months in one day, wherein burn or twinge can occur less than 10% patient.
26. the method for claim 21, wherein said mammal are patient, and when described compositions was only given once to reach three months in one day, wherein eye burn damage can occur less than 10% patient.
27. the method for claim 21, wherein said compositions only gave once in one day.
28. an aqueous solution, containing concentration is the cyclosporin A of 0.01% (w/v) to 0.019% (w/v).
29. the compositions of claim 28, wherein the concentration of cyclosporin A is about 0.015% (w/v).
30. an aqueous solution, containing concentration is that 0.01% (w/v) is to the water more than the cyclosporin A and 95% (w/w) of 0.02% (w/v).
31. an aqueous solution, containing concentration is the cyclosporin A of 0.01% (w/v) to 0.02% (w/v), and does not contain the hyaluronate sodium that concentration is 0.05% (w/v).
32. the aqueous solution of claim 31 does not contain hyaluronate sodium.
33. an aqueous solution, containing concentration is the cyclosporin A of 0.01% (w/v) to 0.02% (w/v), and does not contain the polyoxyethylene sorbitan monoleate that concentration is 0.05 (w/v).
34. the aqueous solution of claim 31 contains 0.1% to 1% polyoxyethylene sorbitan monoleate.
35. test kit with container, this container fills that to contain concentration be the aqueous solution of 0.005% (w/v) to the cyclosporin A of 0.03% (w/v), the wherein said container eye drop of can providing and delivering, and wherein said compositions was preserved two months in described container at least.
36. a compositions, containing concentration is the cyclosporin A of 0.01% (w/v) to 0.02% (w/v), and antiseptic.
37. the compositions of claim 36, the concentration of wherein said cyclosporin A are about 0.015% (w/v).
38. the compositions of claim 2, the concentration of wherein said cyclosporin A are about 0.04% (w/v).
39. the compositions of claim 2, the concentration of wherein said cyclosporin A are about 0.005% (w/v).
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US82980806P | 2006-10-17 | 2006-10-17 | |
| US82979606P | 2006-10-17 | 2006-10-17 | |
| US60/829,808 | 2006-10-17 | ||
| US60/829,796 | 2006-10-17 | ||
| PCT/US2007/074079 WO2008014200A2 (en) | 2006-07-25 | 2007-07-23 | Cyclosporin compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101896160A true CN101896160A (en) | 2010-11-24 |
Family
ID=43105063
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2007800345683A Pending CN101896160A (en) | 2006-10-17 | 2007-07-23 | Cyclosporin compositions |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101896160A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104114152A (en) * | 2011-12-07 | 2014-10-22 | 阿勒根公司 | Efficient lipid delivery to human tear film using a salt-sensitive emulsion system |
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|---|---|---|---|---|
| US5051402A (en) * | 1987-06-04 | 1991-09-24 | Sankyo Company, Limited | Pharmaceutical composition containing cyclosporin in admixture with α- |
| CN1084079A (en) * | 1992-05-13 | 1994-03-23 | 山道士药品株式会社 | Ophthalmic composition |
| CN1317342A (en) * | 2000-04-07 | 2001-10-17 | 梅迪多姆实验室股份有限公司 | Eye preparation |
-
2007
- 2007-07-23 CN CN2007800345683A patent/CN101896160A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5051402A (en) * | 1987-06-04 | 1991-09-24 | Sankyo Company, Limited | Pharmaceutical composition containing cyclosporin in admixture with α- |
| CN1084079A (en) * | 1992-05-13 | 1994-03-23 | 山道士药品株式会社 | Ophthalmic composition |
| CN1317342A (en) * | 2000-04-07 | 2001-10-17 | 梅迪多姆实验室股份有限公司 | Eye preparation |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104114152A (en) * | 2011-12-07 | 2014-10-22 | 阿勒根公司 | Efficient lipid delivery to human tear film using a salt-sensitive emulsion system |
| CN108969482A (en) * | 2011-12-07 | 2018-12-11 | 阿勒根公司 | Effective lipid delivery is carried out to people's tear film with the quick property emulsion system of salt |
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