The term "solvent system" as used herein refers to a carrier in which an active drug (i.e. a cyclosporin) is dissolved. The solvent system may be a single solvent or a mixture of ingredients included as solvents, surfactants, diluents, or for other purposes.
The term "cyclosporin" as used herein refers to any member of a class of nonpolar polypeptides, as defined in the Merck Index, Twelfth Edition. One such cyclosporin is cyclosporin A, also known as "cyclosporine" and hereinafter referred to as "cyclosporine", known to be therapeutically active as an immunosuppressant.
Cyclosporins are hydrophobic and have low solubility in aqueous media. This makes it difficult to design pharmaceutical compositions (i.e. dosage forms) comprising cyclosporins which exhibit satisfactory absorption into systemic circulation after oral administration, or absorption into the target tissue upon topical administration.
The cyclosporin can be dissolved in an organic solvent (e.g. ethanol or propylene glycol), but if the solvent is water-miscible, when the composition is mixed with gastrointestinal fluid or other aqueous medium, the cyclosporin will precipitate.
Methods of overcoming this problem are now known in the prior art. The most common approach is to dissolve the cyclosporin in a solvent system that comprises at least one lipophilic (hydrophobic) solvent and a surfactant, so that the composition disperses into an emulsion when mixed into gastrointestinal fluid or other aqueous medium.
Such compositions are called "emulsion preconcentrates".
U.S. Pat. No. 4,388,307 discloses such compositions. A commercial product that has been sold under the trademark "Sandimmune" is made according to U.S. Pat. No. 4,388,307, and, more specifically, comprises cyclosporine dissolved in a solvent system comprising ethanol as hydrophilic solvent, a vegetable oil as lipophilic solvent, and a surfactant. The ethanol is required to dissolve the cyclosporin in the composition as the vegetable oil has inadequate capacity to dissolve cyclosporins. While this composition is superior to previously known compositions, it still exhibits absorption that is less than the maximum possible and is variable. Moreover, the use of ethanol has disadvantages, as ethanol is volatile, and Sandimmune capsules must be individually packaged in metallic pouches to avoid evaporation of the ethanol.
U.S. Pat. No. 5,342,625 discloses compositions that are superior in certain respects to the compositions taught in the prior reference. The compositions of U.S. Pat. No. 5,342,625 also comprise, in addition to the cyclosporin, a hydrophilic solvent, a lipophilic (i.e. hydrophobic) solvent and a surfactant. Again, the hydrophilic solvent is an alcohol and more particularly a polyol which consists of either propylene glycol or a pharmaceutically acceptable alkyl or tetrahydrofurfuryl di- or partial-ether of a low molecular weight mono- or poly-oxy-alkanediol. This reference teaches that only lipophilic solvent that is not miscible with the selected hydrophilic solvent is suitable for the purpose of this invention.
It is also disclosed that compositions according to U.S. Pat. No. 5,342,625, when added to water, disperse into emulsions with droplet size of less than 2000,.ANG., which is smaller than obtained with prior art compositions, thus leading to improved absorption.
Emulsions with droplet size of less than 2000 .ANG. are defined as "microemulsions". Compositions that, upon addition to water, disperse into microemulsions are called "microemulsion preconcentrates".
UK Patent Application No. 2 270 842 published Mar. 30, 1994 relates to pharmaceutical compositions comprising cyclosporin in a carrier medium; the carrier comprises:
(i) a hydrophilic organic solvent in the form of a polyol and/or a lower alkanol such as propylene glycol and ethanol; PA1 (ii) a lipophilic solvent; and PA1 (iii) a polyoxyethylene-sorbitan-fatty acid ester surfactant. PA1 (i) as hydrophilic solvent, propylene glycol, either alone or with other lower alkanols e.g. ethanol; PA1 (ii) as lipophilic solvent a mixed mono-, di- and tri-glyceride; and PA1 (iii) a surfactant. PA1 1. Ethanol is volatile, so that the soft gelatin capsules have to be packaged individually in metallic pouches to prevent evaporation of the ethanol. PA1 2. Ethanol contributes to an undesirable taste of the microemulsion preconcentrate, so that, even after dilution into a sweetened drink, there is still a somewhat unpleasant taste. PA1 3. The lipophilic solvent, which is mixed mono- di- and tri-glycerides, is relatively expensive. PA1 1. Low cost. PA1 2. They are good solvents for cyclosporins, thus reducing the amount of lipophilic solvent required and/or reducing the need for a hydrophilic co-solvent to maintain the cyclosporin in a stable solution. PA1 3. They are readily inter-dissolved with preferred hydrophilic co-solvents. For example, they are entirely miscible with propylene carbonate. PA1 4. They become readily dispersible into emulsions or microemulsions upon inclusion of a suitable surfactant.
Canadian Patent 2072509 discloses microemulsion preconcentrates comprising a cyclosporin dissolved in a carrier which comprises:
Again the hydrophilic solvent and the lipophilic solvent are not intermiscible.
The compositions of Canadian Patent 2072509 appear to be within the scope of claim 1 of U.S. Pat. No. 5,342,625, but limited to propylene glycol as hydrophilic solvent and a mixed mono-, di-, and tri-glyceride as lipophilic solvent.
A composition made according to the disclosure of Canadian patent 2072509 is now marketed under the trademark "Neoral", in the form of both an oral liquid which is a microemulsion preconcentrate intended to be diluted into an aqueous drink before ingestion, and a soft gelatin capsule containing the microemulsion preconcentrate.
For both the soft gelatin capsules and the oral liquid, the labelling indicates that the "Neoral" emulsion preconcentrate comprises cyclosporine dissolved in ethanol and propylene glycol as hydrophilic solvents, corn oil glycerides as lipophilic (hydrophobic) solvent, and polyoxyl 40 hydrogenated castor oil as surfactant. It also contains dl-alpha-tocopherol at a level of about one percent by weight as antioxidant. Although Canadian patent 2072509 includes some examples without ethanol, the use of ethanol in the commercial "Neoral" product indicates that compositions without ethanol either were not found to give adequate stability or were not found to give adequate absorption upon ingestion.
While Neoral does enable improved absorption relative to Sandimmune, it still has certain undesirable properties. Specifically:
Several prior art publications disclose further improvements achieved by selecting different lipophilic and/or hydrophilic solvents.
International Publication Number W094/25068 discloses improved compositions in the form of microemulsion preconcentrates in which the principal solvent for the cyclosporin is an alcohol which is selected from alcohols having a boiling point above 100.degree. C. and a solubility in water of under 10 g per 100 g at 20.degree. C. Because such alcohols are good solvents for cyclosporine, they eliminate the need for ethanol. Preferred alcohols, within the scope of the disclosure of W094/25068, are saturated alkyl alcohols having 8 to 14 carbon atoms per molecule, including 1-octyl, 2-octyl, 1-decyl, 1-dodecyl and 1-tetradecyl alcohols. However, a problem with such compositions is that the selected alcohols are more toxic than other lipophilic solvents generally used in the art.
New Zealand Patent Application No. 280689 discloses improved microemulsion preconcentrates in which a cyclosporin is dissolved in a solvent system comprising a lipophilic (hydrophobic solvent), a hydrophilic solvent and a surfactant, wherein the lipophilic solvent is selected from tocol, tocopherols and tocotrienols, and derivatives thereof, including specifically Vitamin E. The lipophilic solvent and hydrophilic solvent again are not intermiscible. While these compositions exhibit improved properties over the prior art, such lipophilic solvents are relatively expensive.
In light of the difficulties with prior art compositions, it is an object of the within invention to enable compositions with the advantages of those disclosed in U.S. Pat. No. 5,342,625 and Canadian Patent 2072509, which comprise a lipophilic solvent that is inexpensive and that is also a relatively good solvent for cyclosporins, so as reduce the cost of the composition and also reduce or eliminate the need for ethanol in the composition.