New Zealand Paient Spedficaiion for Paient Number 329929
New Zealand No 329929 International No PCT/
TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION
Priority dates 09 03 1998
Complete Specification Filed 09 03 1998
Classification (6) A61K38/13
Publication date 28 October 1999
Journal No 1445
no drawings
NEW ZEALAND PATENTS ACT 1953
COMPLETE SPECIFICATION
Title of Invention
Emulsion preconcentrates comprising a cyclosporin and glycerides
Name, address and nationality of applicant(s) as in international application form
BERNARD CHARLES SHERMAN, a Canadian citizen of 50 Old Colony Road, Willowdale, Ontario M2L 2K1, Canada
TECHNICAL FIELD
The invention is directed to pharmaceutical compositions which facilitate the administration of cyclosporins
BACKGROUND ART
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 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 patent 4388307 discloses such compositions A commercial product that 5 has been sold under the trademark "Sandimmune" is made according to U S patent 4388307, 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 cyclosporine in the compositions 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 patent 5342625 discloses compositions that are superior in certain respects to the compositions taught in U S patent 4388307 The compositions of U S patent 5342625 comprise (in addition to the cyclosporin, a lipophilic solvent and surfactant) a hydrophilic solvent which is of either propylene glycol or an alkyl or ^ tetrahydrofurfuryl di- or partial-ether of a low molecular weight mono- or poly-oxy-alkanediol
It is also disclosed that compositions according to U S patent 5342625, when added to water, disperse into emulsions with droplet size of less than 2000 , which is smaller than obtained with prior art compositions, thus leading to improved absorption
Emulsions with droplet size of less than 2000 are defined as "microemulsions" Compositions that, upon addition to water, disperse into microemulsions are called "microemulsion preconcentrates"
Canadian Patent 2072509 discloses microemulsion preconcentrates comprising a cyclosporin dissolved in a carrier which comprises
(i) as hydrophilic solvent propylene glycol, either alone or with other lower alkanols e g ethanol,
(11) as lipophilic solvent a mixed mono-, di- and tri-glyceride, and
(m) a surfactant
The compositions taught by Canadian Patent 2072509 appear to be within the scope of Claim 1 of US Patent 5342625, 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 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, ethanol is volatile, so that the compositions have to be specially packaged to prevent evaporation of the ethanol
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 C and a solubility in water of under 10 g per 100 g at 20 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 they 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 solvent, a hydrophilic solvent and a surfactant, wherein the lipophilic solvent is selected from tocol, tocopherols and tocotnenols, and derivatives thereof, including specifically Vitamin E
New Zealand Patent Application No 280689 further discloses use of propylene carbonate as hydrophilic solvent
6
Preferred compositions within the scope of New Zealand Patent application No 280689 comprise both a lipophilic solvent selected from tocol, tocopherols and tocotnenols and derivatives thereof, including specifically Vitamin E While these compositions exhibit improved properties over the prior art, the disclosed lipophilic solvent such as Vitamin E are relatively expensive
New Zealand Patent Application No 314701 provides a pharmaceutical composition in the form of a microemulsion preconcentrate comprising a
1 0
' cyclosporin dissolved in a solvent system comprising propylene carbonate as hydrophilic solvent, a lipophilic solvent selected from glycerides, and at least one surfactant Such compositions overcome some problem of the prior art However, propylene carbonate is not an ingredient presently approved by the United States Food and Drug Administration ("FDA") for oral ingestion
Accordingly, it is the object of the present invention to enable a microemulsion preconcentrate comprising a cyclosporin, which has all the following properties
1 It contains, as inactive ingredients, only ingredients approved by the FDA for pharmaceuticals for oral administration
2 It does not contain ethanol or any other volatile solvent
3 It is stable against precipitation of the cyclosporin
SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical composition in the form of an emulsion preconcentrate or microemulsion preconcentrate comprising a cyclosporin dissolved in a solvent system which is free of ethanol and comprises
1
A lipophilic solvent selected from glycerides
7
2 Propylene glycol or polyethylene glycol as hydrophilic solvent
3 Polyoxyethylcne glycolated natural or hydrogenated vegetable oil, as surfactant, and
4 A co-surfactant selected from polyoxyethylene-sorbitan-fatty acid esters
The composition will optimally and preferably also cornpnse benzyl alcohol as hydrophilic co-solvent
DETAILED DESCRIPTION OF THE INVENTION
As aforesaid, compositions within the scope of the present invention will comprise a lipophilic solvent selected from glycerides For purposes of the within specification and claims, the term "glycerides" is to be understood to include mono-, di-, and tri-esters of glycerol with fatty acids, and mixtures thereof "Fatty acids" will be understood to include both medium chain (eg Cg - C-jO) fatty acids and long chain (eg C-|2 - C-]8) fatty acids, both unsaturated and saturated
It will be understood that an unreacted glycerol molecule has three hydroxyl moieties Monoglyceride will have two unreacted hydroxyls, diglycerides will have one, and triglycerides will have none
Hence, mono- and di-glycerides formed by glycerol and fatty acids are capable of further esterification at the remaining one or two hydroxyls
For the purposes of the within specification and claims, the term "glycerides" is to be understood to include compounds formed by further esterification of fatty acid mono- and di-glycerides with acids other than fatty acids
8
This will include, for example, acetylated monoglycendes which are formed by reacting fats with glycerol and triacetin
^ Glycerides useable within the scope of the invention will thus include, but not be limited to, the following vegetable oils (which are comprised primarily of fatty acid triglycerides), and extracts therefrom any of the mono- or diglycerides approved for pharmaceutical use, including, for example, glyceryl mono-oleate in) a mixed mono-, di-, and triglyceride, which will preferably comprise a mixture of C-|2-20 acic' mono-, di - and triglycerides
Preferably these mixed glycerides are predominantly comprised of unsaturated fatty acid residues, in particular C-jq unsaturated fatty acid residues such as linolenic, linoleic and oleic acid residues
The mixed mono-, di-, and tri-glycerides are preferably predominantly comprised of mono- and di-glycerides
The mixed mono-, di-, and tri-glycerides may be prepared by admixing individual mono-, di, and tri-glycerides in appropriate relative proportions Conveniently, however, the mixed glycerides comprise transesterification products of vegetable oils, for example almond oil, ground nut oil, olive oil, peach oil, palm oil, soybean oil, corn oil, sunflower oil or safflower oil, with glycerol Preferably the vegetable oil is corn oil Also, mixtures of the oils may be transesterified with glycerol
The transesterification products are generally obtained by heating the selected vegetable oil with glycerol to effect transesterification or
glycerolysis This may be carried out at high temperature in the presence of an appropriate catalyst, under an inert atmosphere and with continuous agitation In addition to the mono-, di- and tri-glyceride components, the transesterification products also generally comprise minor amounts of free glycerol
Transesterification products of corn oil and glycerol provide particularly suitable mixed mono-, di-, and tri-glycerides An example of a suitable mixed glyceride product is the transesterification product commercially available under the trade name MAISINE (available from the company Etablissements Gattefosse, of 36 Chemin de Genas, P O Box 603, 69804 Saint-Priest, Cedex (France)) This product is comprised predominantly of linoleic and oleic acid mono-, di- and tri-glycerides together with minor amounts of palmitic and stearic acid mono-, di- and tri-glycerides
Acetylated monoglycerides which consist of glycerol esterified with fatty acids at one of the three hydroxyl functions, with the other two hydroxyls replaced by an acetyl moieties
Acetylated monoglycerides are sold in the United States under the tradename "Myvacet" by Eastman Chemical Products Inc They are made by reacting fats with glycerine and triacetin
By adjusting the degree of saturation of the monoglyceride and the degree of acetylation, different characteristics are obtained
Fully acetylated monoglycerides prepared from unsaturated monoglycerides are liquids at room temperature In this context, the phrase "fully acetylated" is intended to mean having a minimum acetylation of about 96%
Fully acetylated monoglycerides are currently available from Eastman Chemical Products Inc under the designations Myvacet 9-08 and Myvacet 9-45 For Myvacet 9-08, the fat source is hydrogenated coconut oil For Myvacet 9-45 the fat source is partially hydrogenated soybean oil
Myvacet 9-08 and Myvacet 9-45 are both liquids at room temperature, having melting points of 4 C to 12 C Both are well suited for use as lipophilic solvent, but Myvacet 9-45 is especially preferred because of its
1 n
1 u lower cost
The preferred glycerides are mixed mono-, di- and tri-glycerides and acetylated monoglycerides because of the advantages of low cost and being good solvents for cyclosporins
As aforesaid, compositions with the scope of the present invention will further comprise as hydrophilic solvent, either propylene glycol or polyethylene glycol When polyethylene glycol is used, it will preferably have a mean molecular weight of less than 1000 More preferably the mean molecular weight will be
9f)
^ from about 400 to about 200, even more preferably from about 300 to about 200, and most preferably it will be about 200
As aforesaid, the composition will optimally and preferably also contain benzyl alcohol as hydrophilic co-solvent
As aforesaid, compositions within the scope of the present invention will further comprise, as surfactant, a polyoxyethylene glycolated natural or hydrogenated vegetable oil, for example, polyoxyethylene glycolated natural or hydrogenated castor oil Particularly preferred is the surfactant designated in the United States Pharmacopoeia and National Formulary as Polyoxyl 40 Hydrogenated Castor Oil, which is available under the tradename "Cremophor RH40"
11
The stability of the composition and the dispersibility in water can be improved by including in the composition a co-surfactant Preferred co-surfactants are selected from polyoxyethylene-sorbitan-fatty acid esters, e g mono- and tri-lauryl, palmityl, stearyl and oleyl esters, e g products of the type Known as polysorbates and available under the tradename "Tween" Especially preferred as co-s« irfactant are polyoxyethylene (20) sorbitan monolaurate, which is also known as poiyporbate 20, and polyoxyethylene (20) sorbitan monooleate, which is also known as polysorbate 80
Compositions in accordance with the present invention may also contain other ingredients
For example, the composition may include, in addition to the foregoing, one or more other ingredients that are included as diluents, thickening agents, antioxidants, flavouring agents, and so forth
Compositions in accordance with the invention may comprise dosage forms for direct administration as emulsion preconcentrates or microemulsion preconcentrates For example, an emulsion preconcentrate or microemulsion preconcentrate may be directly used as liquid for oral ingestion, parenteral use, or topical application, or it may be encapsulated into gelatin capsules for oral ingestion
However, the present invention also provides pharmaceutical compositions in which the emulsion preconcentrate or microemulsion preconcentrate is further processed into an emulsion or a microemulsion Thus, where oral administration is practised, emulsions or microemulsions obtained, eg by diluting a preconcentrate with water or other aqueous medium (for example, a sweetened or flavoured preparation for drinking), may be employed as formulations for drinking Similarly, where topical application is intended, compositions comprising an emulsion preconcentrate, a thickening agent, and water will provide an aqueous emulsion in gel, paste, cream or like form
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Compositions in accordance with the present invention, whether emulsion preconcentrates, microemulsion preconcentrates, emulsions, or microemulsions, may be employed for administration in any appropriate manner and form, e g orally, parenterally, topically, or rectally
The relative proportion of the cyclosporin and other ingredients in the compositions of the invention will, of course, vary considerably depending on the particular type of composition concerned, e g whether it is an emulsion preconcentrate, microemulsion preconcentrate, emulsion, or microemulsion, the route of administration, and so forth The relative proportions will also vary depending on the particular ingredients employed and the desired physical characteristics of the composition, e g in the case of a composition for topical use, whether this is to be a free flowing liquid or a paste Determination of workable proportions in any particular instance will generally be within the capability of persons skilled in the art
The invention will be more fully understood from the following examples, which are illustrative but not limiting of compositions in accordance with the present invention
EXAMPLES
In each of the following examples, the ingredients were weighed into a test tube in the proportions shown, the test tubes and contents were warmed to 100 C in a water bath, and then the test tubes were shaken until the contents of each tube were interdissolved to form a clear solution
Then 1 g from the resulting emulsion preconcentrate in each test tube was transferred to another test tube, about 20 ml of warm (37 C) water was added, and the test tube was shaken to disperse the 1 g of the composition in the water to form an emulsion or microemulsion The resultant emulsions or microemulsions were then compared for clarity by measuring the light
I
13
transmittance through a 1 cm cell at 600 nm A higher transmittance indicates a smaller droplet size and hence, a fir.er emulsion or microemulsion
Example No
JL
_2_
_3_
Cyclosporine
1 0
1 0
1 0
Maisine
2 1
2 1
23
Propylene Glycol
2 9
26
0
Pokethylene Glycol 200
0
0
24
Benzyl Alcohol
0
03
04
Cremophor RH40
3 6
36
Polysorbate 80
1 0
1 0
1 0
Total
106
6
6
Percent Transmittance at 600 nm
82 8
87 1
80 2
Example No
4_
5_
_6_
Cyclosporine
1 0
1 0
1 0
Myvacet 9-45
1 8
24
24
Propylene Glycol
23
0
Polyethylene Glycol 200
0
0
23
Benzyl Alcohol
04
04
04
Cremophor RH40
36
3 5
Polysorbate 80
1 0
1 0
1 0
Total
107
107
6
Percent Transmittance at 600 nm
90 0
87 1
84 9