MXPA98003393A - Preconcentrated emulsion comprising a cyclosporine and monoglycerid acetyl - Google Patents

Abstract

The present invention relates to pharmaceutical compositions in the form of an emulsion preconcentrate or microemulsion preconcentrate, which comprise a cyclosporin as an active ingredient, acetylated monoglyceride as a hydrophilic solvent, a surfactant, and optionally a hydrophilic solvent.

Description

PRECONCENTRATED EMULSION COMPRISING A CYCLOSPORINE AND ACCEPTED MONOGLYCERIDATE TECHNICAL FIELD The invention is directed to pharmaceutical compositions, which facilitate the administration of cyclosporins.

BACKGROUND OF THE INVENTION The term "solvent system" used herein refers to a carrier, in which an active drug (ie, a cyclosporin) is dissolved. The solvent system can be a single solvent or a mixture of ingredients included as solvents, surfactants, diluents, or for other purposes.

The term "cyclosporin" used herein refers to any member of a class of non-polar polypeptides, as defined in the Merck Index, Twelfth Edition. Such cyclosporin is cyclosporin A, also known as "cyclosporin" and hereinafter referred to as "cyclosporin", it is known that it is therapeutically active as an immunosuppressant. REF: 27421 Cyclosporins are hydrophobic and have low solubility in aqueous medium. This makes it difficult to make pharmaceutical compositions (ie, dosage forms) comprising cyclosporins, which exhibit satisfactory absorption in systematic circulation after oral administration, or absorption in the target tissue in topical administration.

The cyclosporin can be dissolved in an organic solvent (for example ethanol or propylene glycol), but if the solvent is miscible in water, when the composition is mixed with gastrointestinal fluid or other aqueous medium, cyclosporin will precipitate.

Methods for overcoming this problem are now known in the prior art. The most common approach is to dissolve cyclosporin in a solvent system comprising at least one lipophilic (hydrophobic) solvent and a surfactant, so that the composition is dispersed in an emulsion when mixed with gastrointestinal fluid or other aqueous medium.

Such compositions are called "emulsion preconcentrates".

The U.S. patent No. 4388307 describes such compositions. A commercial product that has been registered under the trademark "Sandimmune" is made according to the U.S. patent. No. 4,388,307, and, more specifically, comprises a cyclosporin dissolved in a solvent system comprising ethanol as a hydrophilic solvent, a vegetable oil as a lipophilic solvent, and a surfactant. Ethanol is required to dissolve cyclosporin in the composition since vegetable oil has inadequate ability 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. In addition, the use of ethanol has disadvantages, since ethanol is volatile, and Sandimmune capsules must be individually packaged in metal bags to prevent the evaporation of ethanol.

The U.S. patent 5342625 describes compositions that are superior in certain respects to the compositions taught in the above reference. The compositions of the U.S. patent 5342625 also comprise, in addition to cyclosporin, a hydrophilic solvent, a lipophilic (i.e., hydrophobic) solvent and a surfactant. On the other hand, the hydrophilic solvent is an alcohol and more particularly a polyol, which consists of either a propylene glycol or a pharmaceutically acceptable alkyl or tetrahydrofurfuryl di- or partial-ether of a mono- or poly-oxy-alkanediol. of low molecular weight. This reference teaches that only the lipophilic solvent that is not miscible with the selected hydrophilic solvent is suitable for the purpose of this invention.

It is also disclosed that the compositions according to U.S. Pat. 5342625, when added to water, are dispersed in emulsions with droplet size of less than 2000 Á, which is smaller than that obtained with the prior art compositions, therefore leading to improved absorption.

Emulsions with droplet size of less than 2000 Á are defined as "microemulsions". The compositions which, in addition to water, are dispersed in microemulsions are called "microemulsion preconcentrates".

The application of UK Patent No. 2 270 842 published March 30, 1994 relates to pharmaceutical compositions comprising a 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; (ii) a lipophilic solvent; Y (iii) an ester surfactant of polyoxyethylene sorbitan fatty acid.

Canadian Patent 2072509 discloses microemulsion preconcentrates comprising a cyclosporin dissolved in a carrier, which comprises: (i) a hydrophilic solvent, propylene glycol, either alone or with lower alkanols, for example ethanol; (ii) as a lipophilic solvent a mono-, di-, and mixed triglyceride; Y (iii) a surfactant.

On the other hand, 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 US Patent 5342625, but is limited to propylene glycol as a hydrophilic solvent and a mono-, di-, and triglyceride mixed as a lipophilic solvent.

A composition made according to the description of Canadian Patent 2072509 is now registered under the trademark "Neoral", in the form of both an oral liquid, which is a microemulsion preconcentrate intended to be diluted in an aqueous beverage before the ingestion, and a soft gelatin capsule containing the microemulsion preconcentrate.

For both the soft gelatin capsules and the oral liquid, the labeling indicates that the "Neoral" emulsion preconcentrate comprises a cyclosporin dissolved in ethanol and propylene glycol as a hydrophilic solvent, corn oil glycerides as a lipophilic (hydrophobic) solvent, and 40 polyoxyl hydrogenated castor as a surfactant. It also contains di-alpha-tocopherol at a level of about one percent by weight as an antioxidant.

Although Canadian patent 2072509 includes some examples without ethanol, the use of ethanol in the commercial "Neoral" product indicates that the compositions without ethanol either are not found to give adequate stability or are not found to give adequate absorption with ingestion.

While Neoral allows improved absorption relative to Sandimmune, it still has certain undesirable properties. Specifically: 1. Ethanol is volatile, so that soft gelatin capsules have to be individually packaged in metal bags to prevent the evaporation of ethanol. 2. The ethanol contributes to an undesirable taste of the microemulsion preconcentrate, so that, even after dilution in a sweetened beverage, there is still some unpleasant taste. 3. The lipophilic solvent, which is mono-, di-, and mixed triglycerides, is relatively expensive.

Several publications of the prior art further describe improvements achieved by selecting different lipophilic and / or hydrophilic solvents.

International Publication No. WO94 / 25068 discloses improved compositions in the form of microemulsion preconcentrates, in which the main solvent for cyclosporin is an alcohol, which is selected from alcohols having a boiling point above 100 ° C. and a solubility in water below 10 g per 100 g at 20 ° C. Because such alcohols are good solvents for cyclosporin, they eliminate the need for ethanol. Preferred alcohols, within the scope of the disclosure of WO94 / 25068, are saturated alkyl alcohols having 8 to 14 carbon atoms per molecule, including the alcohols of 1-octyl, 2-octyl, 1-decyl, 1 -dodecyl and 1-tetradecyl. 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 Publication No. 280689 discloses improved microemulsion pre-concentrates, 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 the hydrophilic solvent are again not intermiscible. While these compositions exhibit improved properties over the prior art, such lipophilic solvents are relatively expensive.

In view of the difficulties with the compositions of the prior art, it is an objective within the invention to allow compositions with the advantages of those described in US Patent 5342625 and Canadian Patent 2072509, which comprise a lipophilic solvent which is economical and which it is also a relatively good solvent for cyclosporins, as well as reduces the cost of the composition and also reduces or eliminates the need for ethanol in the composition.

BRIEF DESCRIPTION OF THE INVENTION It has been unexpectedly found that such advantages can be achieved and overcome the drawbacks of the prior art when acetylated monoglycerides are used as the solvent. The acetylated monoglycerides are inexpensive and exhibit ideal properties for use as a lipophilic (hydrophobic) solvent in the emulsion preconcentrates with cyclosporin.

Therefore the present invention provides a pharmaceutical composition in the form of an emulsion preconcentrate comprising a cyclosporin dissolved in a solvent system comprising acetylated monoglycerides, and a surfactant.

In a further embodiment, such a pharmaceutical composition is in the form of a microemulsion preconcentrate.

DETAILED DESCRIPTION OF THE INVENTION As mentioned above, an essential component of an emulsion preconcentrate is a lipophilic solvent, and it has been found that the function of the acetylated monoglycerides is surprisingly good as a lipophilic solvent in the emulsion preconcentrates with cyclosporin.

It will be understood that acetylated monoglycerides consist of glycerol esterified with fatty acids in one of the three hydroxyl functions, with the other two hydroxyl substituted by acetyl parts.

Acetylated monoglycerides are registered in the United States under the trademark "Myvacet" by Eastman Chemical Products Inc. They are made by reacting fats with glycerol and triacetin.

Due to the adjustment of the degree of saturation of the monoglyceride and the degree of acetylation, different characteristics are obtained.

The acetylated monoglycerides completely prepared from the unsaturated monoglycerides are liquid at room temperature. In this context, the "fully acetylated" phase is intended to mean that they have a minimum acetylation of about 96%.

Fully acetylated monoglycerides are currently available from Eastman Chemical Product Inc. under the designations Myvacet 9-80 and Myvacet 9-45. For Myvacet 9-08, the source of fat is hydrogenated coconut oil. For Myvacet 9-45, the fat source is partially hydrogenated soybean oil.

The Myvacet 9-08 and Myvacet 9-45 are both liquid at room temperature, boiling from 4 ° C to 12 ° C. Both are well suited for use as a lipophilic solvent, but Mivacet 9-45 is especially preferred because of its low cost.

Compared to other ingredients used in the prior art as a lipophilic solvent, these acetylated monoglycerides offer the following advantages: 1. Low cost. 2. They are good solvents for cyclosporins, therefore they reduce the amount of lipophilic solvent required and / or reduce the need for a hydrophilic cosolvent to maintain cyclosporin in a stable solution. 3. they are easily inter-dissolved with preferred hydrophilic cosolvents. For example, they are completely miscible with propylene carbonate. 4. They become easily dispersible in emulsions or microemulsions with the inclusion of an appropriate surfactant.

Due to the aforementioned properties, the acceptable emulsion preconcentrates or microemulsion preconcentrates can be made using only the active drug (ie, a cyclosporin), acetylated monoglycerides, and a surfactant.

However, also preferred compositions will comprise a hydrophilic solvent (ie, a solvent having a solubility of at least 1 g per 100 g in water at 20 ° C) as a cosolvent. This is because the appropriate hydrophilic solvents are more efficient than the acetylated monoglycerides as solvents for cyclosporin. The inclusion of an appropriate hydrophilic solvent can therefore reduce the total amount of solvent needed, thereby increasing the feasible concentration of cyclosporin in the composition.

Suitable hydrophilic solvents include, for example, ethanol, propylene glycol, propylene carbonate, benzyl alcohol, and polyethylene glycol having an average molecular weight of less than about 1000.

It is preferable to avoid the use of ethanol due to its volatility. The preferred hydrophilic solvents are propylene glycol and propylene carbonate. Propylene carbonate is more preferred due to its complete miscibility with the acetylated monoglycerides.

The fact that a microemulsion preconcentrate can be made using an acetylated monoglyceride as a lipophilic solvent and propylene carbonate as a hydrophilic solvent, despite the fact that they are miscible with one another, is contrary to the teaching of U.S. Pat. 5342625.

Also the compositions of the present invention will include at least one surfactant, by which means a compound with both lipophilic and hydrophilic properties, which improve the dispersibility of the composition in an emulsion or microemulsion in water.

Suitable surfactants include those cited in U.S. Pat. 5342625 and Canadian patent 2072509.

Preferred surfactants are natural glycolated polyoxyethylene or hydrogenated vegetable oils; for example, natural glycolated polyoxyethylene or hydrogenated castor oil. Particularly preferred is the surfactant designated in United States Pharmacopoeia and the National Formulary as Oil Polyoxyl 40 Hydrogenated Ricino, which is available under the trademark of "Cremofor RH40".

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

Preferred surfactants for use as co-surfactants are polyoxyethylene sorbitan fatty acid esters; for example the esters of mono- and trilauril, palmityl, stearyl and oleyl; for example products of the type known as polysorbates and available under the trademark "Tween". In particular, polyoxyethylene sorbitan 20 monolaurate, which is also known as polysorbate 20, is preferred as a cosurfactant.

Also the compositions according to the invention may contain other ingredients.

For example, the composition may include, in addition to the aforesaid, one or more other ingredients that are included as diluents, thickening agents, antioxidants, flavoring agents, and so forth.

The compositions according to the invention may be liquid at room temperature or may be prepared solids, for example, by use of one or more ingredients with a boiling point above room temperature. The ingredients can be mixed at a temperature above the boiling point and then used to fill capsules while they are still melted, or cooled to form solids. The solids can be made into granules or powder for further processing; for example, filling capsules or manufacturing tablets.

If it is desired to increase the boiling point to ensure that the composition is a solid at room temperature, this can be done by adding an additional ingredient with a relatively high boiling point, such as, for example, polyethylene glycol with average molecular weight above 1000 The capsules or tablets can also be processed by applying coatings to them.

The compositions according to the invention may comprise dosage forms for direct administration as emulsion preconcentrates or microemulsion preconcentrates. For example, an emulsion preconcentrate or microemulsion preconcentrate can be used directly as a liquid for oral ingestion, parenteral use, or topical application or can be encapsulated in 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. Therefore, where oral administration is practiced, the emulsions or microemulsions obtained, for example by eluting a preconcentrate with water or other aqueous medium (for example, a sweet preparation or flavor for drinking), can be used as beverage formulations. Similarly, where topical administration is intended, compositions comprising an emulsion preconcentrate, a thickening agent, and water will provide an aqueous emulsion in the form of gel, paste, cream or the like.

The compositions according to the present invention, the emulsion preconcentrates, microemulsion pre-concentrates, emulsions, or microemulsions, can be employed for administration in any appropriate manner and form; for example orally, parenterally, topically, or rectally.

The relative proportion of cyclosporin and other ingredients in the compositions of the invention, from source, will vary considerably depending on the particular type of composition concerned; for example, if this is a preconcentrate emulsion, preconcentrate microemulsion, emulsion, or microemulsion, the route of administration, and so on. The relative proportions will also vary depending on the particular ingredients employed and the desired physical characteristics of the composition; for example in the case of a composition for topical use, if this is a free flowing liquid or a paste. The determination of the proportions that can be worked on in any particular example will generally be within the ability of persons skilled in the art.

The invention will be more fully understood by the following examples, which are illustrated but are not limiting of the compositions according to the present invention.

EXAMPLES In the following example, the ingredients are weighed in a test tube in the proportions shown, the test tubes and contents are heated to 100 ° C in a water bath, and then the test tubes are shaken until the contents of the test tubes are stirred. Each tube are inter-dissolved to form a clear solution.

Example A Ciclosporin 1 0 Myvacet 9-45 6. 0 Cremophor RH40 3. 7 10.7 Then transfer 1 g of the resulting emulsion preconcentrate to another test tube, add about 20 ml of water, and shake the test tube. The preconcentrate is dispersed to form an emulsion.

In each of the following examples, the ingredients are weighed in a test tube in the proportions shown, the test tubes and contents are heated to 100 ° C in a water bath, and then the test tubes are shaken until The contents of each tube are inter-dissolved to form a clear solution.

Then 1 g of the resulting emulsion preconcentrate is transferred into each test tube, approximately 20 ml of hot water (37 ° C) are added, and the test tube is shaken to disperse the gram of the composition in the water to form a emulsion or microemulsion. Then the resulting emulsions or microemulsions are compared for clarity by measuring the transmittance of light through a 1 cm cell at 600 nm. A higher transmittance indicates a smaller droplet size and therefore a fine emulsion or microemulsion.

Example No.

Ciclosporin 1.0 1.0 1.0 1.0 Myvacet 9-45 2.7 2.5 2.3 2.1 Propylene glycol 1.6 1.6 1.6 1.6 Crep-ophor RH40 3.6 3.6 3.6 3.6 Polysorbate 20 1.8 2.0 2.2 2.4 Total: 10.7 10.7 10.7 10.7 Permit of Transmittance 87.3 89.3 91.4 91.4 at 600 nm Example No.

Ciclosporin 1.0 1.0 1.0 1.0 Myvacet 9-45 2.7 2.5 2.3 2.1 Propylene carbonate 1.6 1.6 1.6 1.6 Cremophor RH 0 3.6 3.6 3.6 3.6 Polysorbate 20 1.8 2.0 2.2 2.4 Total 10.7 10.7 10.7 10.7 Percent transmittance 87.5 89.4 91.6 91.4 at 600 nm As previously mentioned, the transmittance is that of an emulsion or microemulsion made by dispersing 1 g of the composition in about 20 ml of hot water (37 ° C).

In each case, the density of the pre-concentrate is approximately 1.0 g / ml, so that each mL of the pre-concentrate contains approximately 100 mg of cyclosporin.

As a basis of comparison, 1 g of the registered product, Neoral Oral Solution, is similarly dispersed in approximately 20 ml of hot water (37 ° C) and transmittance through a 1 cm cell at 600 nm that is It measures 83.9%. The compositions of all the examples 1 to 8, therefore all give higher transmittance than the Neoral, which indicates that the microemulsions are at least as fine as those obtained with the Neoral.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (11)

1. A pharmaceutical composition in the form of an emulsion preconcentrate, characterized in that it comprises a cyclosporin dissolved in a solvent system comprising acetylated monoglycerides, and a surfactant.

2. A composition according to claim 1, characterized in that it is in the form of an emulsion preconcentrate.

3. A composition according to claim 1 or 2, characterized in that the acetylated monoglyceride is an acetylated monoglyceride completely prepared from the unsaturated monoglyceride.

4. A composition according to claim 1 or 3, characterized in that it also comprises a hydrophilic solvent.

5. A composition according to claim 4, characterized in that the hydrophilic solvent is selected from ethanol, propylene glycol, propylene carbonate, and polyethylene glycol having an average molecular weight of less than about 1000.

6. A composition according to claim 4, characterized in that the hydrophilic solvent is miscible with the acetylated monoglycerides.

7. A composition according to claim 4, characterized in that the hydrophilic solvent is propylene carbonate.

8. A composition according to claim 1 or 7, characterized in that the surfactant is a natural glycol polyethylene or hydrogenated vegetable oil.

9. A composition according to claim 8, characterized in that the surfactant is polyoxyl hydrogenated castor oil 40.

10. A composition according to claim 1 or 8, characterized in that the surfactant is an ester of polyoxyethylene sorbitan fatty acid.

11. A composition according to claims 1 to 7, characterized in that it comprises 2 surfactants, one of which is a natural glycolated polyoxyethylene or hydrogenated vegetable oil and the second is an ester of polyoxyethylene sorbitan-fatty acid.