CA1325973C - Cyclosporin-containing pharmaceutical composition - Google Patents
Cyclosporin-containing pharmaceutical compositionInfo
- Publication number
- CA1325973C CA1325973C CA000568734A CA568734A CA1325973C CA 1325973 C CA1325973 C CA 1325973C CA 000568734 A CA000568734 A CA 000568734A CA 568734 A CA568734 A CA 568734A CA 1325973 C CA1325973 C CA 1325973C
- Authority
- CA
- Canada
- Prior art keywords
- cyclodextrin
- alpha
- cyclosporin
- derivative
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Abstract
ABSTRACT OF THE DISCLOSURE
Cyclosporins are useful immunosuppressive, anti-fungal and antiphlogistic agents which are relatively insoluble in water and aqueous fluids (including body fluids). They may be rendered more soluble by the concomitant administration of .alpha.-cyclodextrin, either separately but essentially simultaneously or, preferably, in admixture.
Cyclosporins are useful immunosuppressive, anti-fungal and antiphlogistic agents which are relatively insoluble in water and aqueous fluids (including body fluids). They may be rendered more soluble by the concomitant administration of .alpha.-cyclodextrin, either separately but essentially simultaneously or, preferably, in admixture.
Description
1325g73 M&C FOLIO: 56522 WANGDOC: 0959H
CYCLOSPORIN-CONTAINING PHARMACEUTICAL COMPOSITION
Backaround To The Invention The present invention relates to a novel pharmaceutical composition wherein at least one cycloseorin is the active ingredient and i~ accompanied by a solubilising agent which is a-cyclodextrin and/or a derivative thereof.
The cyclosporins are a homologous group of bio}ogically active oligopeptides, which are metabolites produced by certain fungi imperfecti. Cyclosporin A is the best known member of this group, but cyclosporins B to I have also so far been identified, and the commercially available product may contain a mixture of several individual cyclosporins. They all share a cyclic peptide structure consisting of 11 amino acid residues with a total molecular weight of about 1,200, but with differer.t substituents or configuration of some of the amino acids, For convenience, the term "cyclosporin" (in the ~
singular and without further qualification) will be used ~ -hereinafter to designate the cyclosporin component in the composition of the present invention. However, it should be understood that, as used with reference to the invention, this term is intended to include any individual member of the cyclosporin group, as well as mixtures of two or more such individual cyclosporins whether in the form of commercially available mixtures or otherwise. - ~-.
:
... . . . ... . . . .. . . , . , . . ~ . .. . .. . ...
' ~ ' ', ' . ' -..... ... : .. ~ ~ . . , -, . .. ...... .
132~973 Cyclospocin has immunosuppressive, antifungal and antiphlogistic activities, but has so far been primarily used therapeutically for its immunosuppressive activity. In its therapeutic use as an immuno-suppressive, it is currently used either orally or by injection. However, since the solubility of cyclosporin in water is extremely low (e.g 20 ~g/ml to 30 ~g/ml for cyclosporin A), both types of formulation are prepared as an oily solution containing ethanol. Even so, the bioavailability of its oral preparations i5 extremely low, generally below 30% [X. Takada et al, Drug Delivery System 1, No. 1, 1-7 (1986)]. Thi is believed to be due to the separation of cyclosporin a3 a solid immediately after it comes into cont-act with water, e.g. in the mouth or in the gut. Injectable preparations of cyclosporin formed as an oily solution containing ethanol have first to be diluted with physiological saline before intravenous administration. -In the case of intravenous administration, however, it is clearly not merely undesirable but highly dangerous for cyclosporin to separate out on contact with water.
Accordingly, a surface active agent, such as a polyoxyethylated castor oil, is added as a solubilizer to injectable preparations in order to prevent the cyclosporin from separating out. However, the addition of surface active agents, such as polyoxyethylated castor oil, to injectable preparations can give rise to safety problems.
Cyclosporin is effective in the treatment of the ocular symptoms of Behçet's Syndrome. If it is administered orally for the treatment of these symptomg and relies upon systemic circulation to reach the eyes, the side effects of the drug may cause various adver~e reactions, such as hypertrichosis or renal dysfunction.
However, if oily pceparations containing cyclosporin are applied directly to the eyes, irritation or a clouded . : . , ......... - , , .... , , : ., ,, .... . - .
3 132~973 visual field may result. Hence, cyclosporin i6, in practice, of little practical use in the treatment of the ocular symptoms of BehSet's Syndrome, for which it would otherwise be well suited. Moreover, if it were possible to prepare a formulation suitable for topical application to the eyes, it would be expected to have -various other uses in addition to the treatment of the ocular symptoms of Behçet's Syndrome. For example, from its pha~macological mode of action, it is thought that it could be useful during keratoplasty, a well as in the treatment of herpetic keratitis and spring catarrh.
One way of overcoming this problem would be to dissolve sufficient cyclosporin in an aqueous solvent system so as to reach an effective concentration for treatment. Such a solvent system should not contain any additive, such as a surface active agent, which could -give rise to safety problems. If this could be -achieved, the cyclosporin would already be in an aqueous solution and its contact with bodily fluids would merely constitute dilution, so that it would not immediately separate out when contacted with the water of such fluids. However, so far it has been very difficult to make any such preparation because cyclosporin has an extremely low solubility in water and has a cyclic structure with a molecular weight significantly greater than 1,000, with the result that insufficient can be dissolved to be effective for the desired treatment.
For instance, Table 1 shows the solubility of cyclosporin A in various Xind~ of solvents, from which it can be seen that the solubility pattern seems quite unique.
- , - . ,,, . . - . - , . , :
132~973 ~
Solvent Solubility parame~ers Solubility of cyclosporin A
[mg/ml]
~d ~p ~h ~ethanol 7.4 6.0 10.9>1000 Ethanol 7.7 4.3 9.5>1000 Acetonitrile 7.5 8.8 3.0>1000 Ethyl acetate 7.4 2.6 4.5 >1000 Benzene 8.9 0.5 1.0400 -~
Tetrahydrofuran 8.2 2.8 3.9 400 Acetone 7.6 5.1 3.4100 Propylene glycol 8.2 4.6 11.4100 Isopropanol 7.7 3.0 8.0 50 Cyclohexane 8.2 0.0 0.0 Z0 Hexane 7.2 0.0 0.0< 10 : :
Water 6.0 15.3 16.7< 1 In the above Table, ~d, ~p and ~h are measure~
of dispersion force, polarity and hydrogen bonding, respectively.
In view of these solubility properties, it has, in -the past, been considered not merely difficult but practically impossible to prepare a pharmaceutical composition containing cyclosporin dissolved in an aqueous medium.
We have now surprisingly found that this long-felt want can be met by incorporating -cyclodextrin into the pharmaceutical preparation.
:
: ' ' 132~973 Brief SummarY of Invention Thus, in accordance with the present invention, there is provided, as a new composition of matter, a pharmaceutical composition comprising at least one cyclosporin in admixture with an amount of ~-cyclodextrin or a functional derivative thereof sufficient to solubilise the cyclosporin in water.
In a further aspect of the present invention, there is provided a method of suppressing the mammalian immune system by administering to a mammal an effective amount of at least one cyclosporin in association with sufficient a-cyclodextrin or a functional derivative thereof to solubilise said cyclosporin.
Detailed DescriPtion of the Invention As currently commercially available, cyclosporin is supplied as a mixture in which the principal ingredient i8 cyclosporin A and which also contains significant, but much smaller, quantities of the other cyclosporins, specifically cyclosporins B, C, D and G. However, as already explained, the present invention can be applied either to a pure cyclosporin (whether cyclosporin A or another member of the cyclosporin group) or to a mixture of individual cyclosporins, such as the above-mentioned commercial mixture.
The discovory on which the present invention i8 ~-~
based has several ~urprising features which could not -have been anticipated on the basis of conventional thinking. Thus, although it is already known that the cyclodextrin vil1 for~ inclusion compound~ with other compounds and v~ll thereby increase the solubility of these la~ter compounds, this formation of inclusion compounds has bsen limited to situations in which the .
, . . - . . .
hydrophobic cavity (which is several Angstrom units, i.e. several tenths of a nanometer, in diameter) can accommodate the guest compound. No example has been found of a cyclodextrin forming a clathrate in a case, such as the present, where the guest compound is not particularly hydrophobic in its solubility characteristics, has a molecular weight as large as 1,200, and has a cyclic structure.
We have, moreover, found that whereas ~-cyclodextrin or y-cyclodextrin can increase the solubility of cyclosporin by perhaps about twice, a-cyclodextrin can increase the solubility of cyclosporin by several orders of magnitude. Since a-cyclodextrin has the smallest diameter cavity among these three cyclodextrins and the cyclosporins are relatively large compounds, this is most unexpected.
Both of these factors indicate very strongly that the solubilising effect achieved by a-cyclodextrin is not based simply (or, perhaps, at all) on the formation of a conventional cyclodextrin inclusion compound.
. .
Apart from a-cyclodextrin itself, we have found that the increase in solubility achieved with a-cyclodextrin is also achieved with a variety of derivative~ of a-cyclodextrin, provided that the e~sential structure and si2e of the a-cyclodextrin molecule are retained. Also, of course, since the composition is intended for therapeutic use, the solubilising compounds used must be physiologically tolerable. Examples of a-cyclodextrin derivatives which may be used include:
pharmaceutically acceptable esters in which some or all of the hydroxy groups in the glucose units have bçen acylated; there is no particular limitation upon the nature of the acyl units, providsd that the resulting 1 ~25973 7 :
compounds are pharmaceutically acceptable and any acyl ~ -groups, whether they be derived from carboxylic, sulLonic or other physiologically tolerable acids may be employed; preferred examples of such groups include:
groups derived from carboxylic acids, such as acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, eivalic acid, fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid or maleic acid; groups derived from organic sulfonic acids, such as the lower alkylsulfonic acids (e,g, methanesulfonic acid, trifluocomethanesulphonic acid or ethanesulfonic acid) and arylsulfonic acids (e.q. benzenesulfonic acid ~-or P-toluenesulfonic acid); and groups derived from amino acids, such as glutamic acid or aspargic acid;
, , ether derivatives of a-cyclodextrin, particularly ~ ~
those in which the ether moiety is an alkyl groUp having ~.. - .
from 1 to 4 carbon atoms~
. . .:.: .
aminoalkylated derivatives of a-cyclodextrin, :
particularly those in which the alkyl group has from 1 to 4 carbon atoms, for example aminomethyl-a-cyclo-dextrin or aminoethyl-a-cyclodextrin~
:-: ~;.,'~
sulfur-containing derivatives, particularly those formed with sulfur-containing acids such as a-cyclodextrin sulfate; :: .
. -, ,: .
carboxyalkylated derivatives of a-cyclodextrin, - :
particularly those in which the alkyl group has from 1 .:
to 4 carbon atoms, such as carboxymethyl-a-cyclo-dextrin, carboxyethyl-a-cyclodextrin or carboxy- ~
propyl-a-cyclodextrin; -derivatives in which a monosaccharide or disaccharide has been condensed with one of the hydroxy group~ of the -~
a-cyclodextrin molecule, for example tho~e derived 8 ~325973 from malto~e, glucose, fructose, galactose, sucrose or lactose; and polymers containing a-cyclodextrin in the main chain or pendant from the main chain, for example those disclosed in ~Cyclodextrins and their inclusion complexes" by J. Szejtli (Akademiai ~iado, Budapest, -- -;
1982).
. .
There is no particula~ limit on the quantity of a-cyclodextrin which may be employed in order to achieve a ~olubilising effect and any amount of a-cyclodextrin will achieve some degree of solubilisation. In general, all other factors being equal, it would seem that, the higher the proportion of a-cyclodextrin, the greater the solubilising effect.
We normally prefer a proportion of cyclosporin to a-cyclodextrin or derivativeg thereof of from 1: 0 .5 to 1 : 1000, a ratio of from 1 : 1 to 1 : 200 by weight being more preferred.
The intended final use of the compo6ition of the invention will dictate its physical form. For example, for oral preparations, the composition may be ~ -administered as an aqueous solution or as a solid preparation, such as powders, granules, capsule6 or tablets. For injection or as eye drops, the composition is employed as a solution, which may be supplied to the end user as a powder for making up with, e.g. water for injections or another suitable aqueous medium, or it may be suppiied to the end user as a solution. All such formulations may be prepared by methods which are ~ se ~ -well known in the pharmaceutical art.
For example. at its simplest, the composition of the invention may comprise the cyclosporin and the a-cyclodextrin or derivati~e thereof as a mixture of 1325973 ~ ~
powders. This mixture may be administered as such (normally orally), or may be kept a~ a powdery mixture until the point of use, at which time it is made up with water or another aqueous medium. Alternatively, the composition of the invention may be provided as a solution in water. In order to allow cyclo6porin to be employed at a higher concentration than would otherwise be possible, it may be desirable to use an a-cyclodextrin derivative having a water-solubility greater than that of a-cyclodextrin itself. ~
Alternatively, a water-miscible solvent capable of ;-dissolving the cyclosporin may be added, for example a ;~-simple alcohol such as ethanol, or a glycol 6uch as ~ -propylene glycol or polyethylene glycol.
:: ' In addition, if required, there may be added the -various additives commonly used in this field, such as pH adjustors, osmotic pressure regulators, antiseptics, urface active agents, flavours and masking agents, or any two or more thereof.
Where the composition of the invention is provided as a powdery mixture, this may be prepared by mixing the cyclosporin with the a-cyclodextrin and/or derivative thereof (and aiso any additiveg used) in powder form. -~
Another method of providing a solid comeosition is by ` -mixing the said ingredients in powder form, moistening --the mixture with water or an aqueous solution of a water-miscible solvent, and then allowing the resulting pasty mixture to dry at ambient or under forced air circulation. Alternatively, a solution of the said ingr~dients in water or in an aqueou6 solution of a wateE-miscible solvent may be subjected to spray-drying or freeze-drying, which permits of easy sterilization and al~o gives a more uniform composition.
1325973 :
The composition of the invention may also be provided in the form of a solution, which may be either a solution prepared as above or a solution prepared by dissolving the spray-dried or freeze-dried eowder in water or an aqueous solution of a water-miscible solvent. Where the composition of the invention is provided as a solution, we ~refer that the concentration of a-cyclodextrin should be from 10 to 130 mg/ml, more preferably f;om 20 to 130 mg/ml, and that the concentration of cyclosporin should be from 0.1 to 2.0 mg/ml, more preferably from 0.2 to 1.5 mg/ml.
~' Although the cyclosporin and the a-cyclodextrin should be administered at essentially the same time in order to achieve the benefits of the present invention, it is not necessary that they be administered in admixture, especially where they are to be administered orally. In such a case, it is possible to administer the two components separately, provided that they are administered essentially simultaheously.
The invention is further described with reference to the following examples, Compa~ative Example~ and Experiments. The cyclosporin u~ed in all of these was su~plied by Sandoz Ltd. and pharmaceutical preparations thereof are co~meccially available from Sandoz Ltd.
under the trade name "Sandimmune".
-' 0, 150, 300 or 500 mg of a-cyclodextrin were added to 4 separate portions each of 10 mg of cyclosporin, and 2,000 mg of a-cyclodextrin were added to a 50 m~
por~ion of cyclosporin. 10 ml of water was then added to each o~ tho re~ulting mixture~, and each mixture was stirred for about 15 hours at 25C. At the end of this time, each miYture was filtered through a millipore fil~er and the quantity of cyclosporin in each filtrate ~ -.,. -. -.~ , 132~973 ` ~
11 .. ~
was determined by HPLC (high pressure liquid chromatography). The solubilities were found to be 25, -~
70, 145, 300 and 1,900 ~g/ml, respectively.
"~ ' E~AMPLE 2 .. . . .
100 mg of cycloseorin and 10 g of a-cyclodextrin -were dissolved in 50 ml of water. The solution was ;:-stirred for 2 hours at ambient temperature and then filtered through a millipore filter. The filtrate was frozen using a freezing mixture of dry ice and ethanol, which caused it to freeze-dry under reduced pressure. -~
The powder obtained was then added to a volume of water - ~
equivalent to the volume of the filtrate obtained as ^~ -described above, where it dis~olved immediately to give ~ :
a transparent aqueous solution.
COMæARATIVE EXAMPLE I
0, 100, 200, 300, 500 or 1,000 mg of ::
~-cyclodextrin were added to separate 10 mg portions ~ -of cyclosporin. 10 ml of water was then added to each of the resulting mixtures, and each mixture was stirred ~;~
for about 15 hours at 25C and then filtered through a -millipore filter. The amount of cyclosporin in each filtrate wa~ determined by HPLC. The solubilities were found to be 25, 32, 43, 46, 45 and 44 ~g/ml, -respectively.
COMP~RATIVE EXAMPLE 2 0, 1,000, 2.000, 3,000, 5,000 or 10,000 mg of y-cyclodextrin were added to separate 10 mg portions of cyclosporin. 10 ml of water was then added to each of the resultinq mixtures, and each mixture was stirred for about 15 hours at 25C and then filtered through a millipore filter. The amount of cyclooporin in each ,'~- ' 132~973 . :
filtrate was determined by HPLC. The solubilities were found to be 28, 42, 62, 89, 80 and 75 ~g/ml, respectively.
Sample A.
0.75 mg/ml of cyclosporin, 80 mg/ml of a-cyclodextrin and 6.57 mg/ml of sodium chlocide were dissolved in distilled water for injections. To the ` `~
solution was added a trace of a 0.01 N aqueous solution of sodium hydroxide sufficient to raise its pH to about ~ -7, after which the solution was filtered through a 0.22 ~m filter. The cyclosporin concentration, relative osmotic pressure (against a physiological saline solution) and pH of the resulting solution (which was named "Sample A") were 0.75 mg/ml, 1.05 and 6.B5, respectively.
Sam~le B
. ~
Peanut oil was heated to 40 - 50C, and 10 mg/ml of cyclosporin was dissolved in the hot oil. The solution was then cooled to ambient temperature.
' :' Ocular Test ,., ' 0.05 ml of either Sample A or Sample B was dropped into the right eye of a male Japanese white rabbit.
This operation was carried out a total of 10 times at intervals oE 30 minutes. 30 minutes after the last application, the cornea was excised. In order to ensure that the sample obtained was free from cy~losporin absorbed onto its surface, the corneal epithelium was removed at the same time.
This experiment was performed on three 6eparate ~-rabbits with each of Samples A and B, and the re~ults were averaged. The average of the recults from Samples A were 10,400 ng/ml, whilst the average of the re~ults from Samples B was 5,400 ng/ml. The cyclosporin in the corneal parenchyma samples was analysed quantitatively . ~
using a radio-immunoassay kit p~oduced by Sandoz Ltd. ~ -Although the cyclosporin concentration in solution in Sample A was less than one tenth of that in Sample B ;
(0.75 mg/ml, against 10 mg/ml), the results shown above indicate that Sample A exhibited better tissue transfer, showing a bioavailability more than 20 times that of Sample B. `
EXPERIMENT 2 ;-Samples C, D and E
0.25 mg/ml of cyclosporin, 40 mg/ml of ~-cyclodextrin and 7.79 mg/ml of sodium chloride (Sample C), or 0.10 mg/ml of cyclosporin, 20 mg/ml of a-cyclodextrin and 8.40 mg/ml of sodium chloride (Sample D) or 0.05 mg/ml of cyclosporin, 10 mg/ml of a-cyclodextrin, and 8.70 mg/ml of sodium chloride (Sample E) were dissolved in distilled water for injections. A trace of a 0.01 N aqueous solution of sodium hydroxide was then added to each of these solutions to raise its pH ~o a value in the approximate region of 7, after which the solutions were filtered through a 0.22 ~m filter. The cyclosporin concentrations, relative osmotic pres6ures (against physiological saline) and pH of the solutions were respectively as follows~
:', ' Sample C: C.25 mg/ml, 1.04, 6.30;
Sample D: 0.09 mg/ml, 1.92, 6.86;
Sample E: 0.03 mg/ml. 1.02, 6.58.
14 132~973 ocular Effects : .
0.05 ml of each of Samples A, C, D or E was applied in a single administration to the right eye of a male Japanese white rabbit. This adminis~ration was repeated a further 3 times (making 4 administrations in total) at intervals of 2 hours. 30 minutes after the last application, the cornea was excised as described in Experiment 1 and the cyclosporin levels in the corneal parenchyma were determined, also as in Experiment 1, averaging the results from 3 corneal samples. The results achieved were as follows: .
A: 4900 ng/ml;
C: 4100 ng/ml;
D: 2200 ng/ml;
E: 1300 ng/ml.
The cyclosporin levels in the uvea were alsd determined and were found to be as ollows:
` : ' ` ` ..
A: 970 ng/ml;
C: 780 ng/ml:
D: 830 ng/ml;
E: 760 ng/ml, This demonstrates that cyclosporin was successfully transferred into the ocular tissues. The level iQ ~he corneal parenchyma is important iQ relation to its use in keratoplasty, whilst that iQ the uvea is important in i-the treatment of Behcet's Syndrome.
, ,~ .
CYCLOSPORIN-CONTAINING PHARMACEUTICAL COMPOSITION
Backaround To The Invention The present invention relates to a novel pharmaceutical composition wherein at least one cycloseorin is the active ingredient and i~ accompanied by a solubilising agent which is a-cyclodextrin and/or a derivative thereof.
The cyclosporins are a homologous group of bio}ogically active oligopeptides, which are metabolites produced by certain fungi imperfecti. Cyclosporin A is the best known member of this group, but cyclosporins B to I have also so far been identified, and the commercially available product may contain a mixture of several individual cyclosporins. They all share a cyclic peptide structure consisting of 11 amino acid residues with a total molecular weight of about 1,200, but with differer.t substituents or configuration of some of the amino acids, For convenience, the term "cyclosporin" (in the ~
singular and without further qualification) will be used ~ -hereinafter to designate the cyclosporin component in the composition of the present invention. However, it should be understood that, as used with reference to the invention, this term is intended to include any individual member of the cyclosporin group, as well as mixtures of two or more such individual cyclosporins whether in the form of commercially available mixtures or otherwise. - ~-.
:
... . . . ... . . . .. . . , . , . . ~ . .. . .. . ...
' ~ ' ', ' . ' -..... ... : .. ~ ~ . . , -, . .. ...... .
132~973 Cyclospocin has immunosuppressive, antifungal and antiphlogistic activities, but has so far been primarily used therapeutically for its immunosuppressive activity. In its therapeutic use as an immuno-suppressive, it is currently used either orally or by injection. However, since the solubility of cyclosporin in water is extremely low (e.g 20 ~g/ml to 30 ~g/ml for cyclosporin A), both types of formulation are prepared as an oily solution containing ethanol. Even so, the bioavailability of its oral preparations i5 extremely low, generally below 30% [X. Takada et al, Drug Delivery System 1, No. 1, 1-7 (1986)]. Thi is believed to be due to the separation of cyclosporin a3 a solid immediately after it comes into cont-act with water, e.g. in the mouth or in the gut. Injectable preparations of cyclosporin formed as an oily solution containing ethanol have first to be diluted with physiological saline before intravenous administration. -In the case of intravenous administration, however, it is clearly not merely undesirable but highly dangerous for cyclosporin to separate out on contact with water.
Accordingly, a surface active agent, such as a polyoxyethylated castor oil, is added as a solubilizer to injectable preparations in order to prevent the cyclosporin from separating out. However, the addition of surface active agents, such as polyoxyethylated castor oil, to injectable preparations can give rise to safety problems.
Cyclosporin is effective in the treatment of the ocular symptoms of Behçet's Syndrome. If it is administered orally for the treatment of these symptomg and relies upon systemic circulation to reach the eyes, the side effects of the drug may cause various adver~e reactions, such as hypertrichosis or renal dysfunction.
However, if oily pceparations containing cyclosporin are applied directly to the eyes, irritation or a clouded . : . , ......... - , , .... , , : ., ,, .... . - .
3 132~973 visual field may result. Hence, cyclosporin i6, in practice, of little practical use in the treatment of the ocular symptoms of BehSet's Syndrome, for which it would otherwise be well suited. Moreover, if it were possible to prepare a formulation suitable for topical application to the eyes, it would be expected to have -various other uses in addition to the treatment of the ocular symptoms of Behçet's Syndrome. For example, from its pha~macological mode of action, it is thought that it could be useful during keratoplasty, a well as in the treatment of herpetic keratitis and spring catarrh.
One way of overcoming this problem would be to dissolve sufficient cyclosporin in an aqueous solvent system so as to reach an effective concentration for treatment. Such a solvent system should not contain any additive, such as a surface active agent, which could -give rise to safety problems. If this could be -achieved, the cyclosporin would already be in an aqueous solution and its contact with bodily fluids would merely constitute dilution, so that it would not immediately separate out when contacted with the water of such fluids. However, so far it has been very difficult to make any such preparation because cyclosporin has an extremely low solubility in water and has a cyclic structure with a molecular weight significantly greater than 1,000, with the result that insufficient can be dissolved to be effective for the desired treatment.
For instance, Table 1 shows the solubility of cyclosporin A in various Xind~ of solvents, from which it can be seen that the solubility pattern seems quite unique.
- , - . ,,, . . - . - , . , :
132~973 ~
Solvent Solubility parame~ers Solubility of cyclosporin A
[mg/ml]
~d ~p ~h ~ethanol 7.4 6.0 10.9>1000 Ethanol 7.7 4.3 9.5>1000 Acetonitrile 7.5 8.8 3.0>1000 Ethyl acetate 7.4 2.6 4.5 >1000 Benzene 8.9 0.5 1.0400 -~
Tetrahydrofuran 8.2 2.8 3.9 400 Acetone 7.6 5.1 3.4100 Propylene glycol 8.2 4.6 11.4100 Isopropanol 7.7 3.0 8.0 50 Cyclohexane 8.2 0.0 0.0 Z0 Hexane 7.2 0.0 0.0< 10 : :
Water 6.0 15.3 16.7< 1 In the above Table, ~d, ~p and ~h are measure~
of dispersion force, polarity and hydrogen bonding, respectively.
In view of these solubility properties, it has, in -the past, been considered not merely difficult but practically impossible to prepare a pharmaceutical composition containing cyclosporin dissolved in an aqueous medium.
We have now surprisingly found that this long-felt want can be met by incorporating -cyclodextrin into the pharmaceutical preparation.
:
: ' ' 132~973 Brief SummarY of Invention Thus, in accordance with the present invention, there is provided, as a new composition of matter, a pharmaceutical composition comprising at least one cyclosporin in admixture with an amount of ~-cyclodextrin or a functional derivative thereof sufficient to solubilise the cyclosporin in water.
In a further aspect of the present invention, there is provided a method of suppressing the mammalian immune system by administering to a mammal an effective amount of at least one cyclosporin in association with sufficient a-cyclodextrin or a functional derivative thereof to solubilise said cyclosporin.
Detailed DescriPtion of the Invention As currently commercially available, cyclosporin is supplied as a mixture in which the principal ingredient i8 cyclosporin A and which also contains significant, but much smaller, quantities of the other cyclosporins, specifically cyclosporins B, C, D and G. However, as already explained, the present invention can be applied either to a pure cyclosporin (whether cyclosporin A or another member of the cyclosporin group) or to a mixture of individual cyclosporins, such as the above-mentioned commercial mixture.
The discovory on which the present invention i8 ~-~
based has several ~urprising features which could not -have been anticipated on the basis of conventional thinking. Thus, although it is already known that the cyclodextrin vil1 for~ inclusion compound~ with other compounds and v~ll thereby increase the solubility of these la~ter compounds, this formation of inclusion compounds has bsen limited to situations in which the .
, . . - . . .
hydrophobic cavity (which is several Angstrom units, i.e. several tenths of a nanometer, in diameter) can accommodate the guest compound. No example has been found of a cyclodextrin forming a clathrate in a case, such as the present, where the guest compound is not particularly hydrophobic in its solubility characteristics, has a molecular weight as large as 1,200, and has a cyclic structure.
We have, moreover, found that whereas ~-cyclodextrin or y-cyclodextrin can increase the solubility of cyclosporin by perhaps about twice, a-cyclodextrin can increase the solubility of cyclosporin by several orders of magnitude. Since a-cyclodextrin has the smallest diameter cavity among these three cyclodextrins and the cyclosporins are relatively large compounds, this is most unexpected.
Both of these factors indicate very strongly that the solubilising effect achieved by a-cyclodextrin is not based simply (or, perhaps, at all) on the formation of a conventional cyclodextrin inclusion compound.
. .
Apart from a-cyclodextrin itself, we have found that the increase in solubility achieved with a-cyclodextrin is also achieved with a variety of derivative~ of a-cyclodextrin, provided that the e~sential structure and si2e of the a-cyclodextrin molecule are retained. Also, of course, since the composition is intended for therapeutic use, the solubilising compounds used must be physiologically tolerable. Examples of a-cyclodextrin derivatives which may be used include:
pharmaceutically acceptable esters in which some or all of the hydroxy groups in the glucose units have bçen acylated; there is no particular limitation upon the nature of the acyl units, providsd that the resulting 1 ~25973 7 :
compounds are pharmaceutically acceptable and any acyl ~ -groups, whether they be derived from carboxylic, sulLonic or other physiologically tolerable acids may be employed; preferred examples of such groups include:
groups derived from carboxylic acids, such as acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, eivalic acid, fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid or maleic acid; groups derived from organic sulfonic acids, such as the lower alkylsulfonic acids (e,g, methanesulfonic acid, trifluocomethanesulphonic acid or ethanesulfonic acid) and arylsulfonic acids (e.q. benzenesulfonic acid ~-or P-toluenesulfonic acid); and groups derived from amino acids, such as glutamic acid or aspargic acid;
, , ether derivatives of a-cyclodextrin, particularly ~ ~
those in which the ether moiety is an alkyl groUp having ~.. - .
from 1 to 4 carbon atoms~
. . .:.: .
aminoalkylated derivatives of a-cyclodextrin, :
particularly those in which the alkyl group has from 1 to 4 carbon atoms, for example aminomethyl-a-cyclo-dextrin or aminoethyl-a-cyclodextrin~
:-: ~;.,'~
sulfur-containing derivatives, particularly those formed with sulfur-containing acids such as a-cyclodextrin sulfate; :: .
. -, ,: .
carboxyalkylated derivatives of a-cyclodextrin, - :
particularly those in which the alkyl group has from 1 .:
to 4 carbon atoms, such as carboxymethyl-a-cyclo-dextrin, carboxyethyl-a-cyclodextrin or carboxy- ~
propyl-a-cyclodextrin; -derivatives in which a monosaccharide or disaccharide has been condensed with one of the hydroxy group~ of the -~
a-cyclodextrin molecule, for example tho~e derived 8 ~325973 from malto~e, glucose, fructose, galactose, sucrose or lactose; and polymers containing a-cyclodextrin in the main chain or pendant from the main chain, for example those disclosed in ~Cyclodextrins and their inclusion complexes" by J. Szejtli (Akademiai ~iado, Budapest, -- -;
1982).
. .
There is no particula~ limit on the quantity of a-cyclodextrin which may be employed in order to achieve a ~olubilising effect and any amount of a-cyclodextrin will achieve some degree of solubilisation. In general, all other factors being equal, it would seem that, the higher the proportion of a-cyclodextrin, the greater the solubilising effect.
We normally prefer a proportion of cyclosporin to a-cyclodextrin or derivativeg thereof of from 1: 0 .5 to 1 : 1000, a ratio of from 1 : 1 to 1 : 200 by weight being more preferred.
The intended final use of the compo6ition of the invention will dictate its physical form. For example, for oral preparations, the composition may be ~ -administered as an aqueous solution or as a solid preparation, such as powders, granules, capsule6 or tablets. For injection or as eye drops, the composition is employed as a solution, which may be supplied to the end user as a powder for making up with, e.g. water for injections or another suitable aqueous medium, or it may be suppiied to the end user as a solution. All such formulations may be prepared by methods which are ~ se ~ -well known in the pharmaceutical art.
For example. at its simplest, the composition of the invention may comprise the cyclosporin and the a-cyclodextrin or derivati~e thereof as a mixture of 1325973 ~ ~
powders. This mixture may be administered as such (normally orally), or may be kept a~ a powdery mixture until the point of use, at which time it is made up with water or another aqueous medium. Alternatively, the composition of the invention may be provided as a solution in water. In order to allow cyclo6porin to be employed at a higher concentration than would otherwise be possible, it may be desirable to use an a-cyclodextrin derivative having a water-solubility greater than that of a-cyclodextrin itself. ~
Alternatively, a water-miscible solvent capable of ;-dissolving the cyclosporin may be added, for example a ;~-simple alcohol such as ethanol, or a glycol 6uch as ~ -propylene glycol or polyethylene glycol.
:: ' In addition, if required, there may be added the -various additives commonly used in this field, such as pH adjustors, osmotic pressure regulators, antiseptics, urface active agents, flavours and masking agents, or any two or more thereof.
Where the composition of the invention is provided as a powdery mixture, this may be prepared by mixing the cyclosporin with the a-cyclodextrin and/or derivative thereof (and aiso any additiveg used) in powder form. -~
Another method of providing a solid comeosition is by ` -mixing the said ingredients in powder form, moistening --the mixture with water or an aqueous solution of a water-miscible solvent, and then allowing the resulting pasty mixture to dry at ambient or under forced air circulation. Alternatively, a solution of the said ingr~dients in water or in an aqueou6 solution of a wateE-miscible solvent may be subjected to spray-drying or freeze-drying, which permits of easy sterilization and al~o gives a more uniform composition.
1325973 :
The composition of the invention may also be provided in the form of a solution, which may be either a solution prepared as above or a solution prepared by dissolving the spray-dried or freeze-dried eowder in water or an aqueous solution of a water-miscible solvent. Where the composition of the invention is provided as a solution, we ~refer that the concentration of a-cyclodextrin should be from 10 to 130 mg/ml, more preferably f;om 20 to 130 mg/ml, and that the concentration of cyclosporin should be from 0.1 to 2.0 mg/ml, more preferably from 0.2 to 1.5 mg/ml.
~' Although the cyclosporin and the a-cyclodextrin should be administered at essentially the same time in order to achieve the benefits of the present invention, it is not necessary that they be administered in admixture, especially where they are to be administered orally. In such a case, it is possible to administer the two components separately, provided that they are administered essentially simultaheously.
The invention is further described with reference to the following examples, Compa~ative Example~ and Experiments. The cyclosporin u~ed in all of these was su~plied by Sandoz Ltd. and pharmaceutical preparations thereof are co~meccially available from Sandoz Ltd.
under the trade name "Sandimmune".
-' 0, 150, 300 or 500 mg of a-cyclodextrin were added to 4 separate portions each of 10 mg of cyclosporin, and 2,000 mg of a-cyclodextrin were added to a 50 m~
por~ion of cyclosporin. 10 ml of water was then added to each o~ tho re~ulting mixture~, and each mixture was stirred for about 15 hours at 25C. At the end of this time, each miYture was filtered through a millipore fil~er and the quantity of cyclosporin in each filtrate ~ -.,. -. -.~ , 132~973 ` ~
11 .. ~
was determined by HPLC (high pressure liquid chromatography). The solubilities were found to be 25, -~
70, 145, 300 and 1,900 ~g/ml, respectively.
"~ ' E~AMPLE 2 .. . . .
100 mg of cycloseorin and 10 g of a-cyclodextrin -were dissolved in 50 ml of water. The solution was ;:-stirred for 2 hours at ambient temperature and then filtered through a millipore filter. The filtrate was frozen using a freezing mixture of dry ice and ethanol, which caused it to freeze-dry under reduced pressure. -~
The powder obtained was then added to a volume of water - ~
equivalent to the volume of the filtrate obtained as ^~ -described above, where it dis~olved immediately to give ~ :
a transparent aqueous solution.
COMæARATIVE EXAMPLE I
0, 100, 200, 300, 500 or 1,000 mg of ::
~-cyclodextrin were added to separate 10 mg portions ~ -of cyclosporin. 10 ml of water was then added to each of the resulting mixtures, and each mixture was stirred ~;~
for about 15 hours at 25C and then filtered through a -millipore filter. The amount of cyclosporin in each filtrate wa~ determined by HPLC. The solubilities were found to be 25, 32, 43, 46, 45 and 44 ~g/ml, -respectively.
COMP~RATIVE EXAMPLE 2 0, 1,000, 2.000, 3,000, 5,000 or 10,000 mg of y-cyclodextrin were added to separate 10 mg portions of cyclosporin. 10 ml of water was then added to each of the resultinq mixtures, and each mixture was stirred for about 15 hours at 25C and then filtered through a millipore filter. The amount of cyclooporin in each ,'~- ' 132~973 . :
filtrate was determined by HPLC. The solubilities were found to be 28, 42, 62, 89, 80 and 75 ~g/ml, respectively.
Sample A.
0.75 mg/ml of cyclosporin, 80 mg/ml of a-cyclodextrin and 6.57 mg/ml of sodium chlocide were dissolved in distilled water for injections. To the ` `~
solution was added a trace of a 0.01 N aqueous solution of sodium hydroxide sufficient to raise its pH to about ~ -7, after which the solution was filtered through a 0.22 ~m filter. The cyclosporin concentration, relative osmotic pressure (against a physiological saline solution) and pH of the resulting solution (which was named "Sample A") were 0.75 mg/ml, 1.05 and 6.B5, respectively.
Sam~le B
. ~
Peanut oil was heated to 40 - 50C, and 10 mg/ml of cyclosporin was dissolved in the hot oil. The solution was then cooled to ambient temperature.
' :' Ocular Test ,., ' 0.05 ml of either Sample A or Sample B was dropped into the right eye of a male Japanese white rabbit.
This operation was carried out a total of 10 times at intervals oE 30 minutes. 30 minutes after the last application, the cornea was excised. In order to ensure that the sample obtained was free from cy~losporin absorbed onto its surface, the corneal epithelium was removed at the same time.
This experiment was performed on three 6eparate ~-rabbits with each of Samples A and B, and the re~ults were averaged. The average of the recults from Samples A were 10,400 ng/ml, whilst the average of the re~ults from Samples B was 5,400 ng/ml. The cyclosporin in the corneal parenchyma samples was analysed quantitatively . ~
using a radio-immunoassay kit p~oduced by Sandoz Ltd. ~ -Although the cyclosporin concentration in solution in Sample A was less than one tenth of that in Sample B ;
(0.75 mg/ml, against 10 mg/ml), the results shown above indicate that Sample A exhibited better tissue transfer, showing a bioavailability more than 20 times that of Sample B. `
EXPERIMENT 2 ;-Samples C, D and E
0.25 mg/ml of cyclosporin, 40 mg/ml of ~-cyclodextrin and 7.79 mg/ml of sodium chloride (Sample C), or 0.10 mg/ml of cyclosporin, 20 mg/ml of a-cyclodextrin and 8.40 mg/ml of sodium chloride (Sample D) or 0.05 mg/ml of cyclosporin, 10 mg/ml of a-cyclodextrin, and 8.70 mg/ml of sodium chloride (Sample E) were dissolved in distilled water for injections. A trace of a 0.01 N aqueous solution of sodium hydroxide was then added to each of these solutions to raise its pH ~o a value in the approximate region of 7, after which the solutions were filtered through a 0.22 ~m filter. The cyclosporin concentrations, relative osmotic pres6ures (against physiological saline) and pH of the solutions were respectively as follows~
:', ' Sample C: C.25 mg/ml, 1.04, 6.30;
Sample D: 0.09 mg/ml, 1.92, 6.86;
Sample E: 0.03 mg/ml. 1.02, 6.58.
14 132~973 ocular Effects : .
0.05 ml of each of Samples A, C, D or E was applied in a single administration to the right eye of a male Japanese white rabbit. This adminis~ration was repeated a further 3 times (making 4 administrations in total) at intervals of 2 hours. 30 minutes after the last application, the cornea was excised as described in Experiment 1 and the cyclosporin levels in the corneal parenchyma were determined, also as in Experiment 1, averaging the results from 3 corneal samples. The results achieved were as follows: .
A: 4900 ng/ml;
C: 4100 ng/ml;
D: 2200 ng/ml;
E: 1300 ng/ml.
The cyclosporin levels in the uvea were alsd determined and were found to be as ollows:
` : ' ` ` ..
A: 970 ng/ml;
C: 780 ng/ml:
D: 830 ng/ml;
E: 760 ng/ml, This demonstrates that cyclosporin was successfully transferred into the ocular tissues. The level iQ ~he corneal parenchyma is important iQ relation to its use in keratoplasty, whilst that iQ the uvea is important in i-the treatment of Behcet's Syndrome.
, ,~ .
Claims (24)
1. A pharmaceutical composition comprising at least one cyclosporin in admixture with an amount of .alpha.-cyclodextrin or a functional derivative thereof sufficient to solubilise the cyclosporin in water.
2. The composition of Claim 1, wherein the weight ratio of said cyclosporin to said .alpha.-cyclodextrin or derivative thereof is from 1 : 0.5 to 1 : 1000.
3. The composition of Claim 1, wherein the weight ratio of said cyclosporin to said .alpha.-cyclodextrin or derivative thereof is from 1 : 1 to 1 : 200.
4. A pharmaceutical composition comprising at least one cyclosporin in admixture with an amount of .alpha.-cyclodextrin sufficient to solubilise the cyclosporin in water.
5. The composition of Claim 4, wherein the weight ratio of said cyclosporin to said .alpha.-cyclodextrin is from 1 : 0.5 to 1 : 1000.
6. The composition of Claim 4, wherein the weight ratio of said cyclosporin to said .alpha.-cyclodextrin is from 1 : 1 to 1 : 200.
7. The composition of Claim 1, wherein the .alpha.-cyclodextrin derivative is selected from the group consisting of .alpha.-cyclodextrin esters, .alpha.-cyclodextrin ethers, aminoalkylated derivatives of a-cyclodextrin, salts of .alpha.-cyclodextrin with sulfur-containing acids, carboxyalkylated derivatives of .alpha.-cyclodextrin, addition compounds of .alpha.-cyclodextrin with a monosaccharide or with a disaccharide, polymers containing .alpha.-cyclodextrin in their main chain and polymers containing .alpha.-cyclodextrin pendant on their main chain.
8. The composition of Claim 1, wherein the .alpha.-cyclodextrin derivative is selected from the group consisting of acetylated .alpha.-cyclodextrin, methylated .alpha.-cyclodextrin, aminoethyl-.alpha.-cyclodextrin, .alpha.-cyclodextrin sulfate and maltosylated .alpha.-cyclodextrin.
9. A pharmaceutical composition comprising at least one cyclosporin and .alpha.-cyclodextrin or a functional derivative thereof dissolved in water, the amount of .alpha.-cyclodextrin or said functional derivative thereof being sufficient to solubilise the cyclosporin in the water.
10. The composition of Claim 9, wherein the weight ratio of said cyclosporin to said .alpha.-cyclodextrin or derivative thereof is from 1:0.5 to 1:1000.
11. The composition of Claim 9, wherein the weight ratio of said cyclosporin to said .alpha.-cyclodextrin or derivative thereof is from 1:1 to 1:200.
12. The use of an effective amount of at least one cyclosporin in association with sufficient .alpha.-cyclodextrin or a functional derivative thereof to solubilise said cyclosporin for suppressing the mammalian immune system.
13. The use according to Claim 12, wherein said cyclosporin and said .alpha.-cyclodextrin or derivative thereof are administered in admixture.
14. The use according to Claim 12, wherein said cyclosporin and said .alpha.-cyclodextrin or derivative thereof are administered separately but effectively simultaneously.
15. The use according to Claim 12, wherein the .alpha.-cyclodextrin derivative is selected from the group consisting of .alpha.-cyclodextrin esters, .alpha.-cyclodextrin ethers, aminoalkylated derivatives of .alpha.-cyclodextrin, salts of .alpha.-cyclodextrin with sulfur-containing acids, carboxyalkylated derivatives of .alpha.-cyclodextrin, addition compounds of .alpha.-cyclodextrin with a monosaccharide or with a disaccharide, polymers containing .alpha.-cyclodextrin in their main chain and polymers containing .alpha.-cyclodextrin pendant on their main chain.
16. The use according to Claim 12, wherein the .alpha.-cyclodextrin derivative is selected from the group consisting of acetylated .alpha.-cyclodextrin, methylated
17
18 .alpha.-cyclodextrin, aminoethyl-.alpha.-cyclodextrin, .alpha.-cyclodextrin sulfate and maltosylated .alpha.-cyclodextrin.
17. The use according to Claim 12, wherein the weight ratio of said cyclosporin to said .alpha.-cyclodextrin or derivative thereof is from 1:0.5 to 1:1000.
18. The use according to Claim 12, wherein the weight ratio of said cyclosporin to said .alpha.-cyclodextrin or derivative thereof i8 from 1:1 to 1:200.
17. The use according to Claim 12, wherein the weight ratio of said cyclosporin to said .alpha.-cyclodextrin or derivative thereof is from 1:0.5 to 1:1000.
18. The use according to Claim 12, wherein the weight ratio of said cyclosporin to said .alpha.-cyclodextrin or derivative thereof i8 from 1:1 to 1:200.
19. The use of an effective amount of at least one cyclosporin in association with .alpha.-cyclodextrin, the weight ratio of said cyclosporin to said .alpha.-cyclodextrin being from 1:0.5 to 1:1000.
20. The method of Claim l9, wherein the weight ratio of said cyclosporin to said .alpha.-cyclodextrin is from 1:1 to 1:200 for suppressing the mammalian immune system.
21. A pharmaceutical composition comprising (a) cyolosporin A or a mixture of cyclosporin A with at least one other cyclosporin in admixture with (b) an amount of .alpha.-cyclodextrin or a functional derivative thereof sufficient to solubilise said cyclosporin in water.
18a
18a
22. A pharmaceutical composition comprising (a) cyclosporin A or a mixture of cyclosporin A with at least one other cyclosporin in admixture with (b) an amount of .alpha.-cyclodextrin sufficient to solubilise said cyclosporin in water.
23. The use of an effective amount of (a) cyclosporin A or a mixture of cyclosporin A with at least one other cyclosporin in association with (b) sufficient .alpha.-cyclodextrin or a functional derivative thereof to solubilise said cyclosporin for suppressing the mammalian immune system.
24. The use of an effective amount of (a) cyclosporin A or a mixture of cyclosporin A with at least one other cyclosporin in association with (b) sufficient .alpha.-cyclodextrin to solubilise said cyclosporin for suppressing the mammalian immune system.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62-140703 | 1987-06-04 | ||
| JP14070387 | 1987-06-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1325973C true CA1325973C (en) | 1994-01-11 |
Family
ID=15274767
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000568734A Expired - Lifetime CA1325973C (en) | 1987-06-04 | 1988-06-06 | Cyclosporin-containing pharmaceutical composition |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US5051402A (en) |
| EP (1) | EP0294239B1 (en) |
| JP (1) | JP2577049B2 (en) |
| AT (1) | ATE72629T1 (en) |
| AU (1) | AU607506B2 (en) |
| CA (1) | CA1325973C (en) |
| DE (1) | DE3868438D1 (en) |
| ES (1) | ES2033429T3 (en) |
| GR (1) | GR3004199T3 (en) |
| HK (1) | HK28097A (en) |
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| US7745400B2 (en) * | 2005-10-14 | 2010-06-29 | Gregg Feinerman | Prevention and treatment of ocular side effects with a cyclosporin |
| US9839667B2 (en) | 2005-10-14 | 2017-12-12 | Allergan, Inc. | Prevention and treatment of ocular side effects with a cyclosporin |
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| DE102006051512A1 (en) | 2005-12-06 | 2007-06-14 | Pari GmbH Spezialisten für effektive Inhalation | Pharmaceutical drug compositions with cyclosporin |
| FI118537B (en) * | 2006-03-08 | 2007-12-14 | Kuopion Yliopisto | Procedure for increasing cyclodextrin complexation |
| US9561178B2 (en) * | 2006-07-25 | 2017-02-07 | Allergan, Inc. | Cyclosporin compositions |
| US20080146497A1 (en) * | 2006-07-25 | 2008-06-19 | Graham Richard S | Cyclosporin Compositions |
| AU2016203191B2 (en) * | 2006-07-25 | 2018-03-01 | Allergan, Inc. | Cyclosporin compositions |
| CN101896160A (en) * | 2006-10-17 | 2010-11-24 | 阿勒根公司 | Cyclosporin compositions |
| MX2010003364A (en) | 2007-10-08 | 2010-07-06 | Lux Biosciences Inc | Ophthalmic compositions comprising calcineurin inhibitors or mtor inhibitors. |
| US20100016219A1 (en) * | 2008-07-19 | 2010-01-21 | Jerry Zhang | Ophthalmic compositions containing solubilized cyclosporin |
| MX338355B (en) | 2009-06-09 | 2016-04-13 | Aurinia Pharmaceuticals Inc | Topical drug delivery systems for ophthalmic use. |
| ES2780182T3 (en) * | 2011-06-29 | 2020-08-24 | Allergan Inc | Macrogol 15-hydroxystearate formulations |
| MA50637A (en) * | 2015-05-29 | 2020-08-05 | Oculis Ehf | CYCLOSPORIN A / CYCLODEXTRIN NANOPARTICLE FORMATION |
| CN105997863B (en) * | 2016-07-21 | 2018-09-04 | 河南省眼科研究所 | CSA Eye-drop and preparation method thereof |
| US20190224275A1 (en) | 2017-05-12 | 2019-07-25 | Aurinia Pharmaceuticals Inc. | Protocol for treatment of lupus nephritis |
| CN112724200B (en) * | 2019-10-28 | 2022-09-27 | 上海云泽生物科技有限公司 | Stable cyclosporine A diluent and application thereof |
| WO2022098122A1 (en) | 2020-11-09 | 2022-05-12 | 주식회사 스카이테라퓨틱스 | Solid cyclosporin a and dispersion composition comprising same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4117118A (en) * | 1976-04-09 | 1978-09-26 | Sandoz Ltd. | Organic compounds |
| SE445174B (en) * | 1978-03-07 | 1986-06-09 | Sandoz Ag | PHARMACEUTICAL COMPOSITION CONTAINING A CYCLOSPORIN AND A HEALING SUBSTANCE |
| PH19156A (en) * | 1982-02-01 | 1986-01-15 | Sandoz Ltd | Dihydrocyclosporin d in the treatment of multiple sclerosis |
| EP0094157B1 (en) * | 1982-04-30 | 1987-07-29 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition and its use |
| DE3346123A1 (en) * | 1983-12-21 | 1985-06-27 | Janssen Pharmaceutica, N.V., Beerse | PHARMACEUTICAL PREPARATIONS OF SUBSTANCES MEDICAL OR UNSTABLE IN WATER AND METHOD FOR THE PRODUCTION THEREOF |
| DE3580717D1 (en) * | 1984-08-02 | 1991-01-10 | Sandoz Ag | PHARMACEUTICAL APPLICATION OF (NVA) 2-CYCLOSPORINE. |
-
1988
- 1988-06-02 JP JP63136250A patent/JP2577049B2/en not_active Expired - Lifetime
- 1988-06-03 AU AU17386/88A patent/AU607506B2/en not_active Expired
- 1988-06-06 ES ES198888305138T patent/ES2033429T3/en not_active Expired - Lifetime
- 1988-06-06 EP EP88305138A patent/EP0294239B1/en not_active Expired - Lifetime
- 1988-06-06 AT AT88305138T patent/ATE72629T1/en not_active IP Right Cessation
- 1988-06-06 DE DE8888305138T patent/DE3868438D1/en not_active Expired - Lifetime
- 1988-06-06 CA CA000568734A patent/CA1325973C/en not_active Expired - Lifetime
-
1990
- 1990-09-21 US US07/587,580 patent/US5051402A/en not_active Expired - Lifetime
-
1992
- 1992-03-31 GR GR920400570T patent/GR3004199T3/el unknown
-
1997
- 1997-03-06 HK HK28097A patent/HK28097A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AU607506B2 (en) | 1991-03-07 |
| ATE72629T1 (en) | 1992-03-15 |
| US5051402A (en) | 1991-09-24 |
| AU1738688A (en) | 1988-12-22 |
| ES2033429T3 (en) | 1993-03-16 |
| EP0294239A1 (en) | 1988-12-07 |
| HK28097A (en) | 1997-03-06 |
| JP2577049B2 (en) | 1997-01-29 |
| GR3004199T3 (en) | 1993-03-31 |
| DE3868438D1 (en) | 1992-03-26 |
| EP0294239B1 (en) | 1992-02-19 |
| JPS6485921A (en) | 1989-03-30 |
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