Title:  Emulsion preconcentrate comprising a cyclosporin, propylene carbonate, and glycerides

United States Patent:  6,159,933

Appl. No.:  066712

Pharmaceutical compositions in the form of an emulsion preconcentrate or microemulsion preconcentrate which comprise a cyclosporin as active ingredient, propylene carbonate as hydrophilic solvent, glycerides as lipophilic solvent, and a surfactant.

DETAILED DESCRIPTION OF THE INVENTION

As aforesaid, compositions within the scope of the present invention will comprise a cyclosporin, propylene carbonate, glycerides, and a surfactant.

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 (e.g. C₈ -C₁₀) fatty acids and long chain (e.g. C₁₂ -C₁₈) fatty acids, both unsaturated and saturated.

It will be understood that an unreacted glycerol molecule has three hydroxyl moeities. 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.

This will include, for example, acetylated monoglycerides 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:

i) vegetable oils (which are comprised primarily of fatty acid triglyercides), and extracts therefrom.

ii) any of the mono- or diglycerides approved for pharmaceutical use, including, for example, glyceryl mono-oleate.

iii) a mixed mono-, di-, and triglyceride, which will preferably comprise a mixture of C_12-20 fatty acid mono-, di- and triglycerides.

Preferably these mixed glycerides are predominantly comprised of unsaturated fatty acid residues, in particular C₁₈ 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.

iv) 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 moeities.

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^oC. to 12^oC. Both are well suited for use as lipophilic solvent, but Myvacet 9-45 is especially preferred because of its lower cost.

The preferred glycerides are mixed mono-, di- and tri-glycerides and acetylated monoglycerides. Most preferred is acetylated monoglycerides because of the following advantages:

1. Low cost.

2. They are good solvents for cyclosporins.

3. They are entirely miscible with propylene carbonate.

The fact that a microemulsion preconcentrate can be made using acetylated monoglyceride as lipophilic solvent and propylene carbonate as hydrophilic solvent, despite the fact that they are miscible with each other, is contrary to the teaching of U.S. Pat. No. 5,342,625.

The compositions of the present invention will also include at least one surfactant, by which is meant a compound with both lipophilic and hydrophilic properties, which improves the dispersibility of the composition into an emulsion or microemulsion in water.

Suitable surfactants include those cited in U.S. Pat. No. 5,342,625 and Canadian patent 2072509.

Preferred surfactants are polyoxyethylene glycolated natural or hydrogenated vegetable oils; 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".

It has been surprisingly found that these preferred surfactants act synergistically with other surfactants, so that inclusion of a second surfactant as co-surfactant can reduce the total amount of surfactant needed, without loss of effectiveness in enabling dispersion into an emulsion or microemulsion.

Preferred surfactants for use as co-surfactant are 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-surfactant is polyoxyethylene 20 sorbitan monolaurate, which is also known as polysorbate 20.

Compositions in accordance with the 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 be liquids at ambient temperature or they may be solids prepared, for example, by use of one or more ingredients with melting point above ambient temperature. The ingredients may be blended at a temperature above the melting point and then used to fill capsules while still molten, or cooled to form solids. The solids may be ground into granules or powder for further processing; for example, filling capsules or manufacture of tablets.

If it is desired to increase the melting point to ensure that the composition is a solid at room temperature, this may be accomplished by adding a further ingredient with a relatively high melting point, such as, for example, polyethylene glycol with average molecular weight of above 1000.

Capsules or tablets may be further process by applying coatings thereto.

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, e.g. 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.

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.

Claim 1 of  9 Claims

What is claimed is:

1. A pharmaceutical composition, wherein said composition is an emulsion preconcentrate, comprising a cyclosporin dissolved in a solvent system comprising propylene carbonate, a lipophilic solvent selected from glycerides, and at least one surfactant.

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