NZ519837A - Pharmaceutical compositions comprising a cyclosporin or cyclosporin derivative - Google Patents

Abstract

A pharmaceutical composition comprising a cyclosporin or its derivative dissolved in a solvent-surfactant system, which, when dispersed in water at 37°C, forms an emulsion in which more than 50% of the cyclosporin or its derivative is in droplets of diameter less than 0.45 micron, and wherein the solvent-surfactant system comprises a hydrophilic surfactant, and a lipophillic surfactant, and optionally further comprises a hydrophilic solvent, with the provisos that: i) the amount of cyclosporin or its derivative by weight is greater than 10% of the total of cyclosporin or its derivative, hydrophilic surfactant, lipophillic surfactant and hydrophilic solvent; ii) the composition is free of lipophillic solvent or comprises less than 1 part lipophillic solvent per part cyclosporin or its derivative by weight; iii) if the composition comprises ethanol, the amount of cyclosporin or its derivative by weight is greater than 15% of the total of cyclosporine, hydrophilic surfactant, lipophillic surfactant and hydrophilic solvent; iv) if the composition comprises glycofurol, the amount of glycofurol is less than 1 part per part cyclosporin or its derivative by weight, or alternatively the amount of cyclosporin or its derivative by weight is greater than 19,25% of the total of cyclosporine, hydrophilic surfactant, lipophillic surfactant and hydrophilic solvent; and v) if the composition comprises propylene glycol and does not comprise ethanol, the amount of propylene glycol is less than 1.2 parts per part cyclosporin or its derivative by weight, or alternatively the amount of lipophillic surfactant exceeds 0.55 parts per part cyclosporin or its derivative by weight. Addition to 516269

Description

New Zealand Paient Spedficaiion for Paient Number 519837 FORM 5 NEW ZEALAND S 9 Reg. 19(4) Fee: $250.00 519837 Insert number of Provisional Specification(s) (if any) and date(s) of filing; otherwise leave blank Insert Title of Invention PATENTS ACT 1953 ■ ^ ' ^ - i Number: j ' Date: COMPLETE SPECIFICATION PHARMACEUTICAL COMPOSITIONS COMPRISING A CYCLOSPORIN Insert full name, full street address and nationality of (each) l/WE, BERNARD CHARLES SHERMAN, a Canadian citizen, applicant 0f gQ Q0|0ny R0ad, Willowdale, Ontario M2L 2K1, Canada hereby declare the invention for which l/we pray that a patent may be granted to me/us and the method by which it is to be performed, to be particularly described in and by the following Indicate if following . . . page is numbered Statement.-"1a" .9.96 FORM 5 NEW ZEALAND S.9 Reg. 19(4) Fee: $250.00 PATENTS ACT 1953 Number: Date: COMPLETE SPECIFICATION Insert Title of Invention PHARMACEUTICAL COMPOSITIONS COMPRISING A CYCLOSPORIN Insert number of Provisional Specification(s) (if any) and date(s) of filing; otherwise leave blank Insert full name, full street address and nationality of (each) l/WE, BERNARD CHARLES SHERMAN, a Canadian citizen, applicant 0f qj^ Q0|0ny R0ad) Willowdale, Ontario M2L 2K1, Canada hereby declare the invention for which l/we pray that a patent may be granted to me/us and the method by which it is to be performed, to be particularly described in and by the following Indicate if following . page is numbered Statement.- "1a" 10.9.96 I 2 This invention relates to a modification of the invention described and claimed in New Zealand Patent Specification No. 516269.

TECHNICAL FIELD This invention is directed to pharmaceutical compositions, which facilitate the administration of cyclosporins and their derivatives of cyclosporins, particularly for oral ingestion.

BACKGROUND ART The term "cyclosporin" will be understood to mean any member of the class of nonpolar cyclic oligopeptides with immunosuppressant activity, known as cyclosporins, as defined in the Merck Index, Thirteenth Edition. One such cyclosporin is cyclosporin A, also known as "cyclosporine" and herein referred to as "cyclosporine". Compositions comprising cyclosporine are sold in the united States and elsewhere under the tradenames Sandimmune™ and Neoral™.

A "derivative" of a cyclosporin will be understood to mean any compound with 20 immunosuppressant activity obtained by modification of a cyclosporin. One example is the compound known as ISAtx 247, which is disclosed in Canadian patent 2,298,572 and specifically claimed in claim 6. ™ - trademark 519837 Cyclosporins and their derivatives of cyclosporins are hydrophobic and have low solubility in aqueous media. This makes it difficult to design compositions which exhibit satisfactory absorption into systemic circulation after oral 5 administration.

Cyclosporins and their derivatives of cyclosporins can be dissolved in an organic solvent (e.g. ethanol or propylene glycol), but, if the solvent is water-soluble, when the composition is mixed with gastrointestinal fluid, the 10 cyclosporin or derivative of a cyclosporin will tend to precipitate into particles which are not absorbed.

There are various means disclosed in the prior art for overcoming the tendency to precipitate by use of one or more surfactants.

The first commercially available composition comprising a cyclosporin or derivative of a cyclosporin thereof was an injectable product sold under the tradename Sandimmune™ and comprising, per mL, 50 mg cyclosporine, 650 mg polyoxyl 35 castor oil as a surfactant, with the balance being ethanol as solvent. When this composition is added to water for dilution prior to injectable administration, the composition disperses and the surfactant causes the cyclosporine to be dissolved in a micellar solution, which is sufficiently stable for administration, but from which there may be a small amount of precipitation after some hours. 519837 4 The composition sold as injectable Sandimmune™ is not suitable for chronic oral administration, because its concentration of cyclosporine is only 50 mg per mL, and because the relatively large amount of both the surfactant and 5 the ethanol content gives rise to toxicity concerns.

The prior art also discloses various means of overcoming these problems to enable workable compositions for oral administration.

U.S. patent 4,388,307 discloses compositions comprising cyclosporine in an emulsion preconcentrate that forms an emulsion upon being mixed into water. Commercial products sold under the tradename Sandimmune™ for oral administration are made according to U.S. patent 4,388,307, and, comprise cyclosporine dissolved in a solvent system comprising ethanol, a vegetable oil and a surfactant. Sandimmune™ for oral administration is or was available as both a liquid preconcentrate and liquid-filled soft-gelatin capsules. Although these compositions enable oral administration, they exhibit absorption that is less than the maximum possible and is variable.

U.S. patent 5,741,512 discloses emulsion preconcentrates that are similar to the ones disclosed in U.S. patent 4,888,307 in that they contain, in addition to cyclosporine, a hydrophilic solvent, a lipophilic solvent and a surfactant, but are improved, in that, when added to water, they disperse into droplets of very small size (less than 2000 Angstroms or 0.2 microns), thus leading to 519 8 3 •V* ;i improved absorption. These improved emulsion preconcentrates are referred to as microemulsion preconcentrates. ;5 In the U.S. patent 5,741,512, at Column 8, lines 55 to 60, it is stated that the lipophilic solvent may be any pharmaceutically acceptable solvent which is non-miscible with the hydrophiiic solvent, and devoid or substantially devoid of surfactant function. Thus the lipophilic solvent is limited to components that are lipophilic but not amphiphilic (i.e. not both lipophilic and hydrophiiic). A 10 component that is amphiphilic is considered to be a surfactant component. ;Commercial products made in accordance with the teaching of U.S. patent 5,741,512 are sold under the tradename Neoral™ as both a liquid preconcentrate of concentration 100 mg/mL, and as liquid-filled soft gelatin 15 capsules. ;Neoral™ capsules do enable increased absorption on oral administration relative to Sandimmune™ capsules. However, Neoral™ capsules are still unsatisfactory in the following two respects: ;20 ;1. The concentration of the cyclosporine in the solution contained with the capsules is only about 10 to 12 percent by weight, so that capsules comprising 100 mg of cyclosporine are quite large and difficult to swallow. ;6 ;K 1 Q R 7.7 ;2. The solution contained in the capsules comprises ethanol as a hydrophiiic component. Ethanol is volatile, so that the capsules must be packaged individually in metal pouches. ;5 ;This composition of Neoral™ capsules suggests that the teaching of U.S. patent 5,741,512 may not enable workable compositions (i.e. compositions that are stable and enable high absorption) that have concentration above about 10 to 12 percent and are ethanol free. ;10 ;The prior art discloses three possible approaches to achieving water-dispersible cyclosporine preconcentrates that enable high absorption, comparable to that of Neoral™ products, but that are not within the scope of the claims of U.S. patent 5,741,512. ;15 ;20 ;These approaches are as follows: ;1. Omit the hydrophiiic solvent, so that the composition comprises cyclosporine dissolved in only lipophilic solvent and surfactant. ;2. Omit the lipophilic solvent and use only hydrophiiic solvent and hydrophiiic (i.e. water-soluble) surfactant. There will thus be no component (other than the cyclosporine) that is not water-soluble. ;* 1 Q ft 5 7 7 When such a composition is dispersed in water, what is formed is not an emulsion or microemulsion, but either a micellar solution, or a colloidal dispersion.

Omit the lipophilic solvent, and use only hydrophiiic solvent and one or more surfactants, wherein at least one surfactant is lipophilic (i.e. not water soluble). With appropriately selected solvents and surfactants, such compositions will disperse in water into emulsions or microemulsions, similar to compositions of U.S. patent 5,741,512.

Compositions in accordance with the first of these three approaches are disclosed in U.S. patent 5,858,401; and capsules made according to the teaching of this patent are sold in the U.S. market by Sidmak Laboratories Inc.

These capsules are bioequivalent to Neoral™ capsules; that is to say, the rate and extent of absorption of the cyclosporine upon oral administration is comparable to that of Neoral™. However, the concentration of the cyclosporine in the solution is again only about 10 to 12 percent by weight, so capsules comprising 100 mg of cyclosporine are relatively large and difficult to swallow, as is the case with Neoral™.

Prior art patents which disclose compositions following the second approach, include U.S. patent 5,834,017, and U.S. patent 5,798,333. 51 0 8 A solution made in accordance with the teaching of U.S. patent 5,834,017 has been sold in the United States and elsewhere under the tradename Sang-Cya™. As is the case with Neoral™, the concentration of cyclosporine in 5 Sang-Cya™ solution is again only about 10 to 12 percent by weight, and the solution also comprises ethanol. Hence, it appears that the teaching of U.S. patent 5,834,017 may not enable capsules that are filled with a solution that has concentration substantially above 10 percent by weight or that is ethanol free. Hence, Sang-Cya™ solution does not appear to offer any advantage 10 over Neoral™ products.

Soft gelatin capsules filled with a solution within the scope of the claims of U.S. patent 5,798,333 are sold in the United States by Eon Labs Manufacturing Inc.

The solution in these capsules comprises d-alpha-tocopheryl polyethylene glycol 1000 succinate and polyoxyl 40 hydrogenated castor oil as surfactants, and ethanol as hydrophiiic solvent. As with the other aforementioned marketed products, the concentration of the cyclosporine in the solution in the 20 capsules in only about 10 percent by weight, so that the capsules are again relatively large and difficult to swallow. Also, the ethanol content again requires packaging in metal foil pouches. ™ - trademark 5t 9 o J 9 There are also prior art compositions that follow the third of these three approaches; i.e. that comprise cyclosporine dissolved in a solvent-surfactant system that does not comprise a lipophilic solvent, and comprises a 5 hydrophiiic solvent, and a mixture of surfactants, wherein at least one surfactant is lipophilic.

A composition following this third approach is disclosed in international patent application No. PCT/US96/07155. This patent application discloses compositions comprising cyclosporine dissolved in ethanol as hydrophiiic solvent, d-alpha-tocopheryl polyethylene glycol 1000 succinate as hydrophiiic surfactant, and propylene glycol laurate as lipophilic surfactant. However, when this composition is dispersed in water, it disperses into droplets that are relatively large. It thus does not form a microemulsion and does not enable absorption equivalent to that of Neoral™.

Compositions following the third approach are also disclosed in U.S. patent 6,008,192. These compositions comprise cyclosporine dissolved in a solvent-surfactant system that comprises ethanol and propylene glycol as hydrophiiic 20 solvents, sorbitan monooleate as lipophilic surfactant, and polyoxyl 35 castor oil as hydrophiiic surfactant. However, this patent discloses no example of such a composition that comprises more than 13 percent cyclosporine by weight and none that is ethanol free. Claim 12 specifically limits the 519 8- cyclosporine content to a maximum of 15 percent and the ethanol content to a minimum of 5 percent. A product made in accordance with the teaching of U.S. patent 6,008,192 is sold in the United States by Abbott Laboratories 5 under the tradename Gengraf™. This product is sold as gelatin capsules filled with a solution. Because the concentration of the cyclosporine in the solution is only about 13 percent, the 100 mg strength capsules are large and difficult to swallow. More particularly, the 100mg strength is sold as size 00 two-piece hard gelatin capsules which are filled with a solution, closed and 10 sealed. Also, because ethanol is volatile, the capsules must be individually packaged in metal foil pouches to prevent evaporation of the ethanol.

Compositions following the third approach are also disclosed in South African patent 9,813,596. This patent teaches compositions comprising cyclosporine 15 dissolved in a solvent-surfactant system comprising acetylated monoglycerides along with a hydrophiiic solvent and hydrophiiic surfactant. This patent describes acetylated monoglycerides as being a lipophilic solvent. However, it has surfactant properties. Hence, according to the definition used in U.S. patent 5,741,512, acetylated monoglycerides is a surfactant (i.e. a 20 lipophilic surfactant) rather than a "lipophilic component". Hence, compositions of South African patent 9,813,596 fall within the third approach. However, in every example of this patent, the concentration of cyclosporine is again less than 10 percent by weight.

R 1 Q R v;: vJ g V,' • 11 Compositions following the third approach are also disclosed in U.S. patents 5,945,398, 6,187,747, and 6,008,191 all by the same inventors. These patents teach compositions comprising cyclosporine dissolved in a solvent-5 surfactant system comprising propylene glycol as hydrophiiic solvent, together with at least one lipophilic surfactant and at least one hydrophiiic surfactant. There are only two examples which show a cyclosporine concentration above 10 percent by weight, i.e. examples 5 and 6 in U.S. patent 6,008,191. However, because in both examples there is both a relatively low amount of 10 lipophilic surfactant (only 0.5 or 0.55 part per part cyclosporine by weight) and a relatively high amount of propylene glycol as hydrophiiic solvent (1.2 or 1.285 part per part cyclosporine by weight), it is unlikely that the composition of either example would disperse in water to provide small enough droplets as needed for good absorption. U.S. patent 6,008,191 gives absorption data for 15 only example 10, for which the concentration of cyclosporine by weight is only 10 percent. Moreover, even that data is suspect, as each of the three patents purports to give absorption data for a different composition, and yet the absorption data in the three patents are identical.

Further compositions following the third approach are disclosed in U.S. patent 6,294,192. This patent relates to microemulsion preconcentrates comprising any of a very large number of compounds as the active ingredient, only one of which is cyclosporine. The only example of a microemulsion preconcentrate 519837 12 comprising cyclosporine at above 10 percent by weight is example 57, wherein the amount of cyclosporine is 19.24 percent by weight. However, this example uses glycofurol as hydrophiiic solvent at a level of 1 part per part 5 cyclosporine by weight, but use of glycofurol in compositions for oral use is not permitted by some regulatory agencies worldwide, including the U.S. Food and Drug Administration, because it is not recognized as safe for oral use. Moreover, glycofurol has a boiling point below 100°C. Hence, like ethanol, it is volatile, and capsules comprising glycofurol would have to be packaged in 10 foil pouches to prevent evaporation, as for capsules comprising ethanol.

In light of this prior art, the objective of the present invention is to enable a pharmaceutical composition comprising a cyclosporin or derivative of a cyclosporin thereof dissolved in a solvent-surfactant system that meets the 15 following criteria: 1. The composition will disperse in water to form a fine emulsion or microemulsion so as to enable high absorption upon oral administration; and more particularly, upon dispersion in water at 37°C, all or at least most of the cyclosporin or derivative of a cyclosporin will 20 be in droplets of diameter less than 0.45 micron, and preferably less than 0.22 micron. 2. Every inactive ingredient used in the composition will be one that is safe for oral use.

I ( 51 y u 6 / 13 3. The concentration of the cyclosporin or derivative of a cyclosporin will be above 10 percent by weight, and preferably substantially higher. 4. The composition will be stable against precipitation of the cyclosporin or derivative of a cyclosporin, even on prolonged storage at room temperature.

. The composition will follow the third approach explained in the 10 foregoing. That is to say, it will comprise a cyclosporin or derivative of a cyclosporin dissolved in a solvent-surfactant system that is free or substantially free of lipophilic solvent, and that comprises one or more surfactants, wherein at least one surfactant is lipophilic, and optionally further comprises a hydrophiiic solvent. 6. The composition will preferably be free of ethanol, or any other solvent having a boiling point below 100°C.

DESCRIPTION OF THE INVENTION It has been found that optimal compositions with relatively high concentration of cyclosporin or derivative of a cyclosporin can be achieved by use of surfactants in which the cyclosporin or derivative of a cyclosporin is soluble, and by minimizing or eliminating not only the lipophilic solvent, but also the 0 i a oj / 14 hydrophiiic solvent.

Compositions of the present invention comprise a cyclosporin or derivative of a cyclosporin dissolved in a solvent-surfactant system which further comprises a hydrophiiic surfactant, and a lipophilic surfactant, and wherein the solvent-surfactant system is free or substantially free of lipophilic solvent, and which may optionally also comprise a hydrophiiic solvent, but will preferably be free of hydrophiiic solvent.

With appropriate selection of these ingredients, compositions are produced that have relatively high concentrations of a cyclosporin or derivative of a cyclosporin, that are stable, and that will disperse in water to form fine emulsions or microemulsions. More particularly, upon dispersion in water at 37°C, all or at least most of the cyclosporin or derivative of a cyclosporin will be in droplets of diameter less than 0.45 micron, and more preferably less than 0.22 micron.

The amount of cyclosporin or derivative of a cyclosporin in the compositions 20 of the invention by weight will exceed 10 percent, will preferably exceed 13 percent, will more preferably exceed 15 percent, will even more preferably exceed 20 percent, and will most preferably exceed 25 percent. For this purpose, the weight of the composition will be taken to be the total weight of the cyclosporin or derivative of a cyclosporin, hydrophiiic surfactant, lipophilic 519 637 surfactant and hydrophiiic solvent, if any, and will exclude the weight of additional auxiliary excipients, if any.

For the purposes of this disclosure, the term "lipophilic" when describing a solvent will have the same meaning as used in U.S. patent 5,741,512. That is to say "lipophilic solvent" will mean a pharmaceutical^ acceptable solvent which is devoid or substantially devoid of surfactant function. The compositions of the present invention will be free or substantially free of 10 lipophilic solvent, by which is meant that the amount of lipophilic solvent will be less than 1 part per part cyclosporin or derivative of a cyclosporin by weight, preferably less than 0.5 part per part cyclosporin or derivative of a cyclosporin by weight, and more preferably less than 0.2 part per part cyclosporin or derivative of a cyclosporin by weight. Most preferably, the 15 composition will be entirely free of lipophilic solvent.

The term "hydrophiiic solvent" will mean any solvent, that is water-soluble, and in which the cyclosporin or derivative of a cyclosporin is soluble at a level of at least 1 part cyclosporin or derivative of a cyclosporin per 5 parts solvent 20 by weight at 25°C. The term "water-soluble" is to be understood to mean having a solubility of at least 1 part by weight per 100 parts water at 25°C. Suitable hydrophiiic solvents include for example, mono-alcohols such as ethanol and benzyl alcohol, and propylene glycol. The preferred hydrophiiic solvents are benzyl alcohol and propylene glycol, and most preferred is 51983/ 16 benzyl alcohol. The compositions of the present invention will preferably be free of ethanol or any other solvent with a boiling point of under 100°C.

If the composition comprises ethanol, which is not preferred, then the amount of cyclosporin or derivative of a cyclosporin by weight should exceed 15 percent of the total weight of composition. If the composition comprises propylene glycol but not ethanol, the amount of propylene glycol should be less than 1.2 parts per part cyclosporin or derivative of a cyclosporin by weight, or alternatively the amount of lipophilic surfactant should exceed 0.55 part per part cyclosporin or derivative of a cyclosporin by weight.

If the composition comprises glycofurol as hydrophiiic solvent, which again is not preferred, the amount of glycofurol should be less than 1 part per part cyclosporin or derivative of a cyclosporin by weight, or alternatively the amount of cyclosporin or derivative of a cyclosporin by weight should exceed 19.25 percent of the total weight of the composition.

The term "stable" will be understood to mean stable against significant 20 precipitation of the cyclosporin or derivative of a cyclosporin out of solution at room temperature. A "stable" composition will thus be one in which all or substantially all of the cyclosporin or derivative of a cyclosporin is dissolved in a solvent-surfactant system, and for which there is no precipitation of 17 cyclosporin or derivative of a cyclosporin out of the solution when it is stored at room temperature.

It is necessary that the composition be stable to have a marketable product. The primary or only purpose of including a hydrophiiic solvent in the composition is to add solvent capacity to keep the cyclosporin or derivative of a cyclosporin dissolved. Since one of the objectives of the invention is to achieve high concentration of the cyclosporin or derivative of a cyclosporin, it 10 is preferable to select as lipophilic surfactant and hydrophiiic surfactant compounds that are also good solvents for the cyclosporin or derivative of a cyclosporin, so as to minimize or eliminate the need to add a hydrophiiic solvent. The amount of hydrophiiic solvent in the composition, per part cyclosporin or derivative of a cyclosporin by weight, will preferably be under 1 15 part, more preferably under 0.6 part, and most preferably none.

The term "hydrophiiic surfactant" will include any surfactant that is water-soluble, including, for example: i) Reaction products of natural or hydrogenated vegetable oils and ethylene glycol; i.e. polyoxyethylene glycolated natural or hydrogenated vegetable oils; for example, polyoxyethylene glycolated natural or hydrogenated castor oils. 18 51963'/ ii) Especially suitable are the compounds listed in the United States Pharmacopoeia and National Formulary as polyoxyl 35 castor oil, and polyoxyl 40 hydrogenated castor oil. Most preferred is polyoxyl 35 5 castor oil.

Polyoxyethylene-sorbitan-fatty acid esters; e.g. lauryl, palmityl, stearyl and oleyl esters e.g. of the type known and listed in the United States Pharmacopoeia and National Formulary as polysorbates.

Especially suitable products of this class for use in the compositions of the present invention are polysorbate 20 and polysorbate 80. iv) d-alpha-tocopheryl polyethylene glycol 1000 succinate.

The term "lipophilic surfactant" will include any surfactant that is not water-soluble but is dispersible in water, including for example: a) Trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols. Various forms of trans-esterification product of 20 this class are known and commercially available under the trade name Labrafil™. Especially useful as a component of the compositions of the invention is Labrafil M1944 CS™, a transesterification product of kernel oil and polyethylene glycol.

™ - Trademark 19 51 y ni o / b) Mono-, di- and mono/di-glycerides, especially esterification products of caprylic or capric acid with glycerol. Preferred products of this class are those comprising or consisting mainly or essentially of 5 caprylic/capric acid mono- and di-glycerides, such as are commercially available under the trade name Imwitor™. A particularly suitable product of this class for use in the compositions of the invention is the product Imwitor 742™. c) Soribitan fatty acid esters, such as sorbitan-monolauyl, - monopalmityl -monostearyl, - tristearyl, -monooleyl, and -trioleyl esters. d) Monoglycerides, e.g. glyceryl monooleate and acetylated monoglycerides. It will be understood that acetylated monoglycerides 15 consist of glycerol esterified with fatty acids at one of the three hydroxyl functions, with one or both of the other two hydroxyls replaced by an acetyl moiety. By adjusting the degree of saturation of the monoglycerides and the degree of acetylation, different characteristics are obtained. Fully acetylated monoglycerides prepared from 20 unsaturated monoglycerides are liquids at room temperatures. In this context, the phrase "fully acetylated" is intended to mean having a minimum acetylation of about 96 percent. Fully acetylated monoglycerides are currently available from Eastman Chemical ™ - Trademark 519S? Product Inc. under the designations Myvacet 9-08™ and Myvacet 9-45™. Both are liquids at room temperature, having melting points of 4°C to 12°C. e) Propylene glycol di-fatty acid esters, such as propylene glycol dicaprylate, propylene glycol di-laurate, and propylene glycol caprylic-capric acid diester, known and commercially available under the tradename Miglyol 840™; and propylene glycol mono-fatty acid esters such as propylene glycol monocaprylate and propylene glycol monolaurate. Propylene glycol di-fatty acid esters and mono-fatty acid esters are preferred lipophilic surfactants because they are good solvents for cyclosporins and derivatives of cyclosporins, including in particular cyclosporine, and thus help enable compositions with minimal amounts of hydrophiiic solvent. Propylene glycol mono-fatty esters are especially preferred. Most preferred is propylene glycol monolaurate; for example, the product commercially available under the tradename Lauroglycol 90™, sold by Gattefosse, which has over 90 percent monoester content.

The compositions of the invention will preferably comprise the following quantities of surfactants for each part of cyclosporin or derivative of a cyclosporin by weight: ™-Trademark I 51 21 Hydrophiiic surfactant: from about 0.3 part to about 3.0 parts, and more preferably from about 0.4 part to about 2 parts, and even preferably from about 0.5 part to about 1.5 parts.

Lipophilic surfactant: from about 0.6 part to about 2.5 parts, and more preferably from about 0.8 part to about 2.0 parts.

Compositions in accordance with the invention may also contain other 10 ingredients. For example, the composition may include, in addition to the foregoing, one or more other ingredients that are included as diluents, thickening agents, anti-oxidants, flavouring agents, and so forth.

If it is desired to increase the melting point to ensure that the composition is a 15 solid or semi-solid at room temperature, this may be accomplished by adding a further ingredient with a melting point above room temperature, such as, for example, polyethylene glycol with average molecular weight of above 1000 daltons. Polyethylene glycol with average molecular weights of about 3500 daltons and about 8000 daltons are available under the tradename 20 Carbowax™; i.e. Carbowax™ 3500 and Carbowax™ 8000. Such polyethylene glycols are not considered to be within the scope of "hydrophiiic solvent" as previously defined, because of the low capacity to dissolve cyclosporine.

™- Trademark 51 S h 22 The relative proportion of cyclosporin or derivative of a cyclosporin and other ingredients in the compositions of the invention may, of course, vary considerably, depending on the particular ingredients selected. 5 Determination of workable proportions in accordance with the teaching of this specification in any particular instance will generally be within the capability of persons skilled in the art.

Compositions in accordance with the invention will preferably be in the form of solutions that are filled into capsules, such as gelatin capsules, which may be either soft gelatin capsules or two-piece hard gelatin capsules. Two-piece hard gelatin capsules are preferred. Most preferably, the solution used to fill the capsules will comprise an ingredient such as polyethylene glycol with average molecular weight about 1000 daltons to raise the melting point to above 30°C, and preferably above 40°C. The capsules will be filled with the solution as a liquid at elevated temperature. When the filled capsules are filled and cooled to ambient temperature, the contents will solidify to form a solid or semi-solid, so that the capsules will not have to be sealed to prevent leakage.

Empty two-piece hard gelatin capsules are supplied by numerous manufacturers, including Capsugel™. The Capsugel™ literature shows that ™ - Trademark s 1 y d j 7 23 capsules are available in the following standard sizes (among others), with fill capacity in mL as follows: Size: 00 Pel 0 1 2 Capacity mL: 0.95 0.78 0.68 0.50 0.37 The density of the solutions according to the present invention are about 1.0g per mL, so that the weight in grams of solution that can be put into a capsule 10 of any size is as approximately equal to the volume in mL. The largest capsule of standard size below size 00 is size Oel, which will hold about 0.8g.

It thus can be seen that to fill a capsule of a standard size below size 00 with solution containing 100 mg of a cyclosporin or derivative of a cyclosporin 15 requires that the solution have a cyclosporin or derivative of a cyclosporin concentration of about 100/800 = 12.5 percent by weight, or greater.

Since the present invention enables solutions that produce microemulsions with a cyclosporin or derivative of a cyclosporin concentration well above 10 20 percent by weight, the present invention enables cyclosporin or derivative of a cyclosporin capsules comprising such a solution and having cyclosporin or derivative of a cyclosporin content of about 100mg using capsule sizes smaller than size 00; more particularly, the present invention enables capsules containing such a solution and having cyclosporin or derivative 24 'is»ej of a cyclosporin content of about 100mg, where the capsule has a fill capacity of less than 0.9 mL, less than 0.8 mL, less than 0.7 mL, less than 0.6 mL, less than 0.5 mL, and even less than 0.4 mL.

The invention will be more fully understood by the following examples which are illustrative but not limiting of compositions in accordance with the present invention.

EXAMPLE NO. 1 2 3 4 6 7 8 9 Cyclosporine 100 100 100 100 100 100 100 100 100 Propylene Glycol 160 0 0 0 0 0 0 0 0 Benzyl Alcohol 0 80 60 80 70 50 50 0 0 Polyoxyl 35 Castor Oil 220 220 120 200 200 80 60 100 100 Sorbitan Monooleat Glyceryl Monooleate 160 0 160 0 0 120 0 0 0 0 0 0 0 0 0 0 0 0 Labrafil M1944CS™ 0 0 0 200 0 0 0 0 0 Myvacet 9-45™ 0 0 0 0 120 110 110 0 0 Lauroglycol 90™ 0 0 0 0 0 0 0 150 210 Polyethylene Glycol 8000 0 60 Total 660 580 400 600 510 360 380 360 440 Net fill per capsule, mg 660 580 400 600 510 360 380 360 440 Capsule size used 0 0 1 0 1 2 2 2 1 40 ™- Trademark 519 83 7 For each of the examples, the ingredients in the proportions shown were mixed at elevated temperature (above 60°C) until a clear solution was formed.

Upon cooling to room temperature, the solution of example 3 remained a clear 5 solution.

For all of the other examples, because of the presence of polyethylene glycol 8000, the solutions solidified to form a semi-solid when cooled to room temperature.

When still hot, some of the solution of each of the examples was filled into two-piece hard gelatin capsules of the sizes and with the net fill per capsule as shown. A capsule of each example was dissolved in 1000 mL of water at 37°C. In each case, when the shell dissolved, the contents of the capsule dispersed into a fine emulsion or microemulsion, and most of the cyclosporine was in droplets of diameter less than 0.22 micron, as determined by filtering the emulsion through a 0.22 micron filter and assaying the filtrate for cyclosporine.

It will be understood that compositions similar to those of examples 1-9 may be made using a cyclosporin or derivative of a cyclosporin other than cyclosporine, and in particular using ISAtx 247.

™ - Trademark

Claims (46)

26 519 u o / INDUSTRIAL APPLICABILITY From the foregoing description, it will be apparent that the present invention 5 provides improved compositions for the administration and absorption of a cyclosporin or derivative of a cyclosporin. 20 27 519 u 3 7 WHAT I/WE CLAIM IS:

1. A pharmaceutical composition comprising a cyclosporin or derivative of 5 a cyclosporin dissolved in a solvent-surfactant system, which, when dispersed in water at 37°C, forms an emulsion in which more than 50 percent of the cyclosporin or derivative of a cyclosporin is in droplets of diameter less than 0.45 micron, and wherein the solvent-surfactant system comprises: a hydrophiiic surfactant, and a lipophilic surfactant, 10 and optionally further comprises a hydrophiiic solvent, with the provisos the amount of cyclosporin or derivative of a cyclosporin by weight is greater than 10 percent of the total of cyclosporin or derivative of a cyclosporin, hydrophiiic surfactant, lipophilic surfactant and hydrophiiic solvent; the composition is free of lipophilic solvent or comprises less than 1 part lipophilic solvent per part cyclosporin or derivative of a cyclosporin by weight; if the composition comprises ethanol, the amount of cyclosporin or derivative of a cyclosporin by weight is greater than 15 percent of the total of cyclosporine, hydrophiiic surfactant, lipophilic surfactant and hydrophiiic solvent; that: 15 ii) 20 iii) 25 iv) if the composition comprises glycofurol, the amount of glycofurol is less than 1 part per part cyclosporin or derivative of a cyclosporin by weight, or alternatively the amount of cyclosporin 30 or derivative of a cyclosporin by weight is greater than 19.25 percent of the total of cyclosporine, hydrophiiic surfactant, lipophilic surfactant and hydrophiiic solvent; and 5 I I % W W" 28 v) if the composition comprises propylene glycol and does not comprise ethanol, the amount of propylene glycol is less than 1.2 parts per part cyclosporin or derivative of a cyclosporin by 5 weight, or alternatively the amount of lipophilic surfactant exceeds 0.55 part per part cyclosporin or derivative of a cyclosporin by weight.

2. A composition of claim 1 comprising less than 0.5 part lipophilic solvent 10 per part cyclosporin or derivative of a cyclosporin by weight.

3. A composition of claim 1 comprising less than 0.2 part lipophilic solvent per part cyclosporin or derivative of a cyclosporin by weight. 15

4. A composition of claim 1 that is free of lipophilic solvent.

5. A composition of any of claims 1 to 4 which disperses in water at 37°C to form an emulsion in which more than 50 percent of the cyclosporin or derivative of a cyclosporin is in droplets of diameter less than 0.22 20 micron.

6. A composition of any of claims 1 to 5 that is free of any hydrophiiic solvent having a boiling point under 100°C. 25

7. A composition of any of claims 1 to 6 wherein the amount of cyclosporin or derivative of a cyclosporin by weight is greater than 13 percent of the total of cyclosporin or derivative of a cyclosporin, hydrophiiic surfactant, lipophilic surfactant and hydrophiiic solvent. 29

8. A composition of claim 7 wherein the amount of cyclosporin or derivative of a cyclosporin by weight is greater than 15 percent of the total of cyclosporin or derivative of a cyclosporin, hydrophiiic surfactant, 5 lipophilic surfactant and hydrophiiic solvent.

9. A composition of claim 8 wherein the amount of cyclosporin or derivative of a cyclosporin by weight is greater than 20 percent by weight of the total of cyclosporin or derivative of a cyclosporin, 10 hydrophiiic surfactant, lipophilic surfactant, and hydrophiiic solvent.

10. A composition of claim 9 wherein the amount of cyclosporin or derivative of a cyclosporin by weight is greater than 25 percent by weight of the total of cyclosporin or derivative of a cyclosporin, 15 hydrophiiic surfactant, lipophilic surfactant, and hydrophiiic solvent.

11. A composition of any of claims 1 to 10 that comprises hydrophiiic solvent, wherein the amount of hydrophiiic solvent by weight is less than 1 part per part cyclosporin or derivative of a cyclosporin. 20

12. A composition of claim 11, wherein the amount of hydrophiiic solvent by weight is less than 0.6 part per part cyclosporin or derivative of a cyclosporin. 25

13. A composition of any of claims 1 to 12 that comprises hydrophiiic solvent, wherein the hydrophiiic solvent is selected from a monoalcohol and, propylene glycol.

14. 30 A composition of claim 13 wherein the hydrophiiic solvent is benzyl alcohol. 30 519 85 7

15. A composition of claim 13 wherein the hydrophiiic solvent is propylene glycol. 5 16.

A composition of any of claims 1 to 10 that is free of hydrophiiic solvent.

A composition of any of claims 1 to 16 wherein the lipophilic surfactant is a transesterification product of natural vegetable oil and polyalkylene glycol.

A composition of any of claims 1 to 16 wherein the lipophilic surfactant is selected from mono-, di- and mono/di-glycerides. 17. 10 18. 15 19.

A composition of any of claims 1 to 16, wherein the lipophilic surfactant is a sorbitan fatty acid ester.

A composition of claim 19, wherein the lipophilic surfactant is sorbitan monooleate.

A composition of any of claims 1 to 16, wherein the lipophilic surfactant is a monoglyceride.

22. A composition of any of claims 1 to 16, wherein the lipophilic surfactant 25 is glyceryl monooleate. 20. 20 21.

23. A composition of any of claims 1 to 16, wherein the lipophilic surfactant is acetylated monoglycerides. 30

24. A composition of any of claims 1 to 16, wherein the lipophilic surfactant is a propylene glycol fatty acid ester. 51 u J , 31

25. A composition of claim 24 wherein the lipophilic surfactant is a propylene glycol fatty acid monoester. 5

26. A composition of claim 25 wherein the lipophilic surfactant is propylene glycol monolaurate.

27. A composition of any of claims 1 to 26 wherein the amount of lipophilic surfactant is from 0.6 part to 2.5 parts per part cyclosporin or derivative 10 of a cyclosporin by weight.

28. A composition of claim 27 wherein the amount of lipophilic surfactant is from 0.8 part to 2.0 parts per part cyclosporin or derivative of a cyclosporin by weight. 15

29. A composition of any of claims 1 to 28 wherein the hydrophiiic surfactant is a reaction product of natural or hydrogenated vegetable oil and ethylene glycol. 20

30. A composition of claim 29 wherein the hydrophiiic surfactant is polyoxyl 35 castor oil.

31. A composition of claim 29 wherein the hydrophiiic surfactant is polyoxyl 40 hydrogenated castor oil. 25

32. A composition of any of claims 1 to 28 wherein the hydrophiiic surfactant is a polyoxyethylene-sorbitan fatty acid ester.

33. A composition of any of claims 1 to 28 wherein the hydrophiiic 30 surfactant is d-alpha-tocopheryl polyethylene glycol 1000 succinate. « 51y hj / 32

34. A composition of any of claims 1 to 33, wherein the quantity of hydrophiiic surfactant is from 0.3 part to 3 parts per part cyclosporin or derivative of a cyclosporin by weight. 5

35. A composition of claim 34, wherein the quantity of hydrophiiic surfactant is from 0.4 part to 2 parts per part cyclosporin or derivative of a cyclosporin by weight. 10

36. A composition of claim 35, wherein the quantity of hydrophiiic surfactant is from 0.5 part to 1.5 parts per part cyclosporin or derivative of a cyclosporin by weight.

37. A composition of any of claims 1 to 36 further comprising polyethylene 15 glycol with average molecular weight above 1000 daltons.

38. A composition of any of claims 1 to 37 wherein the cyclosporin or derivative of a cyclosporin is cyclosporine. 20

39. A composition of any of claims 1 to 37 wherein the cyclosporin or derivative of a cyclosporin is ISAyx 247.

40. A capsule containing a composition of any of claims 1 to 39. 25

41. A capsule of claim 40 wherein the content of cyclosporin or derivative of a cyclosporin is about 100mg and the fill capacity of the capsule is less than 0.9 mL.

42. A capsule of claim 41 wherein the fill capacity of the capsule is less 30 than 0.8 mL. 519 b a 33

43. A capsule of claim 42 wherein the fill capacity of the capsule is less than 0.7 mL. 5

44. A capsule of claim 43 wherein the fill capacity of the capsule is less than 0.6 mL. A capsule of claim 44 wherein the fill capacity of the capsule is less than 0.5 mL. A capsule of claim 45 wherein the fill capacity of the capsule is less than 0.4 mL.

45. 10

46. J. D. HARDIE & CO. Patent Attorneys for the Applicant^).