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US 5,962,017 AGranted
Pharmaceutical compositions comprising cyclosporins
AssigneeNovartis G
InventorsBirgit Hauer, Armin Meinzer, Ulrich Posanski, Friedrich Richter
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AssigneeNovartis G
InventorsBirgit Hauer, Armin Meinzer, Ulrich Posanski, Friedrich Richter
Estimating the term…
Pharmaceutical compositions comprising a cyclosporin, e.g. Ciclosporin or Nva!.sup.2 -Ciclosporin, in "microemulsion pre-concentrate" and microemulsion form. The compositions typically comprise (1.1) a C.sub.1-5 alkyl or tetrahydrofurfuryl di- or partial-ether of a low molecular weight mono- or poly-oxy-alkane diol, e.g. Transcutol or Glycofurol, as hydrophilic component. Compositions are also provided comprising a cyclosporin and (1.1) and, suitably, also a saccharide monoester, e.g. raffinose or saccharose monolaurate. Dosage forms include topical formulations and, in particular, oral dosage forms.
An oil-in water microemulsion composition having particles of less than 2,000 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a propylene glycol hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
An oil-in-water microemulsion composition having an average particle size of less than about 1,500 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a propylene glycol hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
An oil-in water microemulsion composition having particles of less than 2,000 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of an ethanol hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
An oil-in-water microemulsion composition having an average particle size of less than about 1,500 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of an ethanol hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
An oil-in water microemulsion composition having particles of less than 2,000 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant other than the hydrophilic component, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
An oil-in-water microemulsion composition having an average particle size of less than about 1,500 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant other than the hydrophilic component, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
A method of orally administering a composition, said method comprising orally administering to a patient in need of cyclosporin therapy an oil-in water microemulsion composition having particles of less than 2,000 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant other than the hydrophilic component, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
A method of orally administering a composition, said method comprising orally administering to a patient in need of cyclosporin therapy an oil-in-water microemulsion composition having an average particle size of less than about 1,500 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant other than the hydrophilic component, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
A method of reducing the variability of bioavailability levels of cyclosporin A for patients during cyclosporin therapy, said method comprising orally administering an oil-in water microemulsion composition having particles of less than 2,000 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant other than the hydrophilic component, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
A method of reducing the variability of bioavailability levels of cyclosporin A for patients during cyclosporin therapy, said method comprising orally administering an oil-in-water microemulsion composition having an average particle size of less than about 1,500 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant other than the hydrophilic component, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
An oil-in water microemulsion composition having particles of less than 2,000 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component, about 0.5 to about 90% by weight of a hydrophilic surfactant selected from the group consisting of polyoxyethylene glycolated natural vegetable oil, polyoxyethylene glycolated hydrogenated vegetable oil, polyoxyethylene-sorbitan-fatty acid ester and polyoxyethylene fatty acid ester wherein said surfactant is other than said hydrophilic component, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
An oil-in-water microemulsion composition having an average particle size of less than about 1,500 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component, about 0.5 to about 90% by weight of a hydrophilic surfactant selected from the group consisting of polyoxyethylene glycolated natural vegetable oil, polyoxyethylene glycolated hydrogenated vegetable oil, polyoxyethylene-sorbitan-fatty acid ester and polyoxyethylene fatty acid ester wherein said surfactant is other than said hydrophilic component, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
A method of orally administering a pharmaceutical composition, said method comprising orally administering to a patient in need of cyclosporin therapy an oil-in water microemulsion composition having particles of less than 2,000 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component, about 0.5 to about 90% by weight of a hydrophilic surfactant selected from the group consisting of polyoxyethylene glycolated natural vegetable oil, polyoxyethylene glycolated hydrogenated vegetable oil, polyoxyethylene-sorbitan-fatty acid ester and polyoxyethylene fatty acid ester wherein said surfactant is other than said hydrophilic component, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
A method of orally administering a pharmaceutical composition, said method comprising orally administering to a patient in need of cyclosporin therapy an oil-in-water microemulsion composition having an average particle size of less than about 1,500 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component, about 0.5 to about 90% by weight of a hydrophilic surfactant selected from the group consisting of polyoxyethylene glycolated natural vegetable oil, polyoxyethylene glycolated hydrogenated vegetable oil, polyoxyethylene-sorbitan-fatty acid ester and polyoxyethylene fatty acid ester wherein said surfactant is other than said hydrophilic component, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
A method of reducing the variability of bioavailability levels of cyclosporin A for patients during cyclosporin therapy, said method comprising orally administering an oil-in water microemulsion composition having particles of less than 2,000 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component, about 0.5 to about 90% by weight of a hydrophilic surfactant selected from the group consisting of polyoxyethylene glycolated natural vegetable oil, polyoxyethylene glycolated hydrogenated vegetable oil, polyoxyethylene-sorbitan-fatty acid ester and polyoxyethylene fatty acid ester wherein said surfactant is other than said hydrophilic component, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
A method of reducing the variability of bioavailability levels of cyclosporin A for patients during cyclosporin therapy, said method comprising orally administering an oil-in-water microemulsion composition having an average particle size of less than about 1,500 A comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90t by weight of a hydrophilic component, about 0.5 to about 90t by weight of a lipophilic component, about 0.5 to about 90% by weight of a hydrophilic surfactant selected from the group consisting of polyoxyethylene glycolated natural vegetable oil, polyoxyethylene glycolated hydrogenated vegetable oil, polyoxyethylene-sorbitan-fatty acid ester and polyoxyethylene fatty acid ester wherein said surfactant is other than said hydrophilic component, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
A method of orally administering a pharmaceutical composition, said method comprising orally administering to a patient in need of cyclosporin therapy an oil-in water microemulsion composition having particles of less than 2,000 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a propylene glycol hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
A method of orally administering a pharmaceutical composition, said method comprising orally administering to a patient in need of cyclosporin therapy an oil-in-water microemulsion composition having an average particle size of less than about 1,500 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a propylene glycol hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
A method of reducing the variability of bioavailability levels of cyclosporin A for patients during cyclosporin therapy, said method comprising orally administering an oil-in water microemulsion composition having particles of less than 2,000 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a propylene glycol hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
A method of reducing the variability of bioavailability levels of cyclosporin A for patients during cyclosporin therapy, said method comprising orally administering an oil-in-water microemulsion composition having an average particle size of less than about 1,500 .ANG. comprising water, about 5 to about 25% by weight of cyclosporin A, about 0.5 to about 90% by weight of a propylene glycol hydrophilic component, about 0.5 to about 90% by weight of a lipophilic component and about 0.5 to about 90% by weight of a hydrophilic surfactant, all weight percents being based on the total weight of the cyclosporin A, hydrophilic component, lipophilic component and hydrophilic surfactant.
Dependencies are inferred from the claim text.
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Emulsions ; Emulsion preconcentrates; Micelles: microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of…
Filling excipients; Inactive ingredients: organic compounds
Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C: cyclosporins
Nanobiotechnology or nanomedicine
Term ended 19 Sep 2009 (estimated)
USPTO file history isn’t available for this patent, so only indexed dates are shown.
The present invention relates to novel galenic formulations comprising a cyclosporin as active ingredient.
The cyclosporins comprise a class of structurally distinctive, cyclic, poly-N-methylated endecapeptides, commonly possessing pharmacological, in particular immunosuppressive, anti-inflammatory and/or anti-parasitic activity. The first of the cyclosporins to be isolated was the naturally occurring fungal metabolite Ciclosporin or Cyclosporine, also known as cyclosporin A and commercially available under the Registered Trade Mark SANDIMMUN.RTM. or SANDIMMUNE.RTM.. Ciclosporin is the cyclosporin of formula A.
-MeBmt-.alpha.Abu-Sar-MeLeu-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeVal- .vertline. .vertline. .vertline. .vertline. .vertline. 1 2 3 4 5 6 7 8 9 10 11 .vertline. (A) .vertline. .vertline.
FIG. 1 represents a three-way plot for relative concentrations of components (1.1) (e.g. GLYCOFUROL), (2) (e.g. MIGLYOL 812), and (3) (e.g. CREMOPHORE RH40) in compositions according to (A) and comprising ca. 10% cyclosporin by weight. Relative concentration of component (1.1) increases from 0% along the left hand margin of the plot to 100% at the lower right corner, as indicated by the arrow "1.1". Concentration of component (2) increases from 0% at the right hand margin of the plot to 100% at the lower left corner, as indicated by the arrow "2". Relative concentration of component (3) increases from 0% at the baseline of the plot to 100% at the apex, as indicated by the arrow "3". Lines within the plot represent increments of 10%, from 0% at each margin to 100% at the apex opposite. The relative proportion of components (1.1), (2) and (3) will suitably lie within the area A defined by the line a of FIG. 1. More suitably, the relative proportion of components (1.1), (2), and (3) will lie within the area B defined by the line b of FIG. 1.
FIG. 2 represents a three-way plot for relative concentrations of components (1.2), (2) e.g. MIGLYOL 812 and (3) in compositions according to (A) and comprising ca. 10% cyclosporin by weight. In this case (3) comprises an appropriate surfactant/co-surfactant mixture, e.g. in a ratio of 11:1 parts by weight (pbw), for example comprising 11 pbw CREMOPHORE RH40 and 1 pbw Glycerinmonooleate. Relative amounts of components (1.2), (2) and (3) are indicated, as for FIG. 1, by arrows "1.2", "2" and "3" respectively. The relative proportions of components (1.2), (2) and (3) will suitably lie within the area X defined by line x of FIG. 2; more suitably within the area Y defined by line y of FIG. 2; and most suitably within the area Z of FIG. 2 defined by line z.
FIGS. 3 and 4 provide superimposed graphical representations from a trial of whole blood Ciclosporin concentrations recorded for 12 trial participants following single oral administrations of COMPOSITION I (FIG. 3) and COMPOSITION X (FIG. 4), each in an amount providing a Ciclosporin dosage of 150 mg, as determined by specific monoclonal RIA. Blood concentration (in ng/ml) is recorded vertically, and time (in hrs.) horizontally.
The following examples are illustrative of compositions in accordance with the present invention. Examples 1,2,4,5 and 7 illustrate the preparation of compositions in oral unit dosage form, suitable for use, e.g. in the prevention of transplant rejection or for the treatment of autoimmune disease, e.g. any of the autoimmune diseases or conditions hereinbefore described, on administration of from 1 to 5 unit dosages/day. Examples 3 and 6 illustrate the preparation of compositions for topical application, suitable for treatment, e.g. of a topic or contact dermatitis, psoriasis or hair loss, on application at the desired site of therapy, e.g. dermatitidic reaction or psoriatic lesion or to the scalp, at regular intervals, e.g. once, twice or three times per day.
The examples are described with particular reference to Ciclosporin. However, equivalent compositions may be obtained employing any other appropriate cyclosporin. In particular equivalent compositions may in all cases be obtained on replacement of Ciclosporin with Nva!.sup.2 -Ciclosporin in the same amount as indicated for Ciclosporin.
Preparation of oral dosage forms: "microemulsion pre-concentrate" type: