MXPA99004517A - Solid pharmaceutical compositions comprising a cyclosporin and an anionic surfactant - Google Patents

Abstract

A solid pharmaceutical composition for oral administration comprising a cyclosporin and an anionic surfactant, preferably sodium lauryl sulfate.

Description

SOLID PHARMACEUTICAL COMPOSITIONS THAT INCLUDE A CYCLOSPORINE AND AN ANIONIC TENSIONING Field of the Invention The invention relates to solid pharmaceutical compositions for the oral administration of cyclosporins Background of the Invention The term "cyclosporin" as used herein, refers to any member of a class of non-polar polypeptides, as defined in the Merck index, Twelfth Edition. One such cyclosporin is cyclosporin A, also known as "cyclosporin" and hereafter referred to as "cyclosporin", which is known to be therapeutically effective as an immunosuppressant.

Cyclosporins are hydrophobic and have low solubility in aqueous media. This makes it difficult to design pharmaceutical compositions (eg, dosage forms) comprising cyclosporins, which show an absorption REF. 30302 satisfactory within the systemic circulation after oral administration.

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

The methods for overcoming this problem are known in the prior art. The most common approach is to dissolve the 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 the gastrointestinal fluid or other aqueous medium.

Such compositions are called "emulsion preconcentrates" The U.S. patent No. 4388307 describes said compositions. A commercial product that has been sold under the trademark Sandimmune (registered trademark) is manufactured in accordance with U.S. Pat. No. 4388307 and, more specifically, comprises 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 cyclosporine in the composition, since vegetable oil has an inadequate capacity to dissolve cyclosporins.

Sandimmune (registered trademark) is sold in the form of both oral liquid, which is a preconcentrate emulsion for the purpose of being diluted in an aqueous drink before its ingestion, and in a soft gelatin capsule containing the preconcentrate of the emulsion .

The U.S. patent 5342625 describes compositions that are superior in certain aspects to the compositions taught in U.S. Pat. No. 4,388,307. The compositions of U.S. Pat. 5342625 again comprise, cyclosporin, a hydrophilic solvent, a lipophilic solvent (i.e., hydrophobic) and a surfactant. The hydrophilic solvent is either propylene glycol or an alkyl or partial ether or tetrahydrofurfuryl ether of a mono- or poly-oxy-alkanediol of low molecular weight.

The compositions in accordance with U.S. Pat. 5342625, when added to the water, are dispersed in emulsions with droplet size of less than 2000A, which is smaller than those obtained with the compositions of the prior art, thus leading to improved absorption.

Emulsions with drop size of less than 2000 Á, are defined as "microemulsions". Compositions that when added to water, are dispersed in microemulsions are called "microemulsion preconcentrates".

A composition made in accordance with the description of the U.S. patent. 5342625 is now marketed under the trademark Neoral (registered trademark). As is the case with the Sandimmune (registered trademark), Neoral (registered trademark) is available as an oral liquid and soft gelatine capsules.

For both soft gelatin capsules and oral liquid, the microemulsion preconcentrate of Neoral (registered trademark) comprises cyclosporin dissolved in ethanol and propylene glycol as hydrophilic solvents, corn oil glycerides as lipophilic sol vent and oil. of polyoxyl 40 hydrogenated castor as surfactant. It also contains di-α-fatocopherol at a level of about one percent by weight as an antioxidant.

Both the Sandimmune (registered trademark) and the Neoral (registered trademark), in the capsule formulations have certain undesirable characteristics.

Specifically: 1. Both contain ethanol, which is volatile. This means that the capsules must be packaged individually in flexible metal bags to avoid evaporation of the ethanol. 2. The capsules are relatively large and difficult to swallow. This is because the formulations must contain substantial amounts of lipophilic and hydrophilic solvents, which are needed to maintain the cyclosporin and the surfactant in solution. The total weight of the contents of each capsule is about 10 times the weight of the cyclosporin contained therein.

The prior art describes some efforts to overcome these problems, by using formulations containing the cyclosporin and the surfactant, but not the solvent.

Said compositions are of solid form and can be used for tabletting or as a filler for two-piece hard gelatin capsules.

Japanese Patent No. 2536876 to Takada et al., Discloses powdered preparations comprising a cyclosporin dispersed in a solid, non-surfactant carrier together with a surfactant. All the examples of this patent use polyoxyethylene hydrogenated castor oil as a surfactant, which is nonionic. In the examples, the total weight of the compositions is from 5 to 151 times the weight of the cyclosporin, and it seems unlikely that any of the compositions described, particularly those with smaller amounts of inactive ingredients, would give an absorption in humans, equivalent to that of the Sandimmune (registered trademark) or the Neoral (registered trademark).

European Patent Application No. 88305138.5 (Publication No. 0294239) of Kurihara and Murano, discloses solid compositions comprising a cyclosporin blended with an amount of alpha-cyclodextrin or a functional derivative thereof, sufficient to solubilize the cyclosporin in water. However, the amount of alpha-cyclodextrin required is usually several times the amount of cyclosporin by weight, so that this approach seems unable to provide smaller dosage forms than Sandimmune capsules (registered trademark), or the Neoral (registered trademark). Additionally, there is no indication that any of the compositions described will give, upon oral administration, an absorption equivalent to that of Sandimmune (registered trademark) or Neoral (registered trademark).

In Pharmaceutical Research, Vol. 8, No. 4, 1991, pp 518-522, Abdallah and Mayersohn describe a tablet containing cyclosporin 100 mg, mannitol 250 mg, microcrystalline cellulose 200 mg, stearic acid 20 mg and sodium dodecyl sulfate 10 mg. It is established that the tablets provide absorption comparable to that of Sandimmune (registered trademark) in a comparative study of bioavailability in dogs.

However, the relatively large amount of inactive ingredients used excludes tablets or capsules significantly smaller than either Sandimmune (registered trademark) or Neoral (registered trademark), and there is no evidence that such formulation would give an equivalent absorption to that of Sandimmune or Neoral in humans.

In view of the problems with the formulations of the prior art, it is the object of the present invention to allow pharmaceutical compositions containing a cyclosporin (and in particular cyclosporin) with the following properties: 1. They are solid at room temperature and free of volatile solvents. 2. In oral administration, they allow an absorption comparable to that of Sandimmune (registered trademark) or Neoral (commercial brand name). 3. They allow capsules or tablets of smaller size than Sandimmune (registered trademark) or Neoral (registered trademark). That is, they allow compositions wherein the content of the cyclosporin by weight exceeds ten percent and preferably twenty percent of the weight of the composition.

Brief Description of the Invention It has surprisingly been found that the objects of the invention can be achieved by a pharmaceutical composition comprising a cyclosporin in admixture with an anionic surfactant, wherein the amount of anionic surfactant is at least about forty percent of the minimum amount that is it would need to dissolve the cyclosporin in water, using a sufficiently small amount of water, that the concentration of the anionic surfactant in the water would exceed the critical concentration of micelles.

Detailed description of the invention Useful anionic surfactants within the scope of the invention, will include any anionic surfactant which is a solid at normal room temperature (20 ° C to 25 ° C) and of low enough toxicity, which is acceptable for oral administration in a pharmaceutical product. co.

The most commonly used anionic surfactants are those containing carboxylate, sulfonate and sulfate ions.

Preferred anionic surfactants are sodium alkyl sulfates and sulphonates and sodium alkyl aryl sulphonates.

Most preferred is sodium lauryl sulfate (also known as sodium dodecyl sulfate) which is widely used as an emulsifier and solubilizer in pharmaceutical products.

The ability of the anionic surfactants to solubilize the cyclosporins in water is substantially increased when the concentration of the surfactant in water substantially exceeds the critical concentration of micelles.

With the use of sodium lauryl sulfate for example, the critical concentration of micelles is about 0.1% by weight.

At concentrations of sodium lauryl sulfate in water below 0.1%, the amount of cyclosporin to be dissolved will be less than 50% by weight the amount of dissolved sodium lauryl sulfate, but at concentrations of sodium lauryl sulfate in water of 1 % or more, the amount of cyclosporin to be dissolved is approximately equal in weight to the amount of dissolved sodium lauryl sulfate.

As previously mentioned, the compositions within the scope of the invention are compositions wherein the amount of anionic surfactant is at least about forty percent of the minimum amount that would be required to dissolve the cyclosporin in water, using a quantity of water to sufficiently small that the concentration in the anionic surfactant in water would exceed the critical micelle concentration.

Using cyclosporin and sodium lauryl sulfate for example, it follows that compositions within the scope of the invention would be compositions wherein the amount of sodium lauryl sulfate is at least about forty percent by weight of the amount of cyclosporin. The amount of sodium lauryl sulfate will preferably be at least about eighty percent by weight of the amount of cyclosporin.

Due to toxicity concerns, the amount of anionic surfactant should not exceed that which is needed to allow satisfactory absorption of the drug with oral administration.

The amount of anionic surfactant will preferably not exceed about four times the minimum amount that would be required to dissolve the cyclosporin in water, again using a quantity of water small enough that the concentration of the surfactant in the water would exceed the critical concentration of micelles.

It follows, for example, that in the case of compositions comprising cyclosporin and sodium lauryl sulfate, the amount of sodium lauryl sulfate by weight will preferably not exceed four times the amount of cyclosporin. More preferably it will not exceed three times the amount of cyclosporin.

To allow small capsules or tablets, the cyclosporin will preferably comprise at least ten percent and more preferably at least twenty percent of the composition by weight.

Compositions within the scope of the invention can be made by mixing the cyclosporin and the anionic surfactant optionally with other ingredients, in dry form and then processing the powder mixed into the tablets or filling the mixed powder into the two-piece hard gelatin capsules .

However, the effectiveness of the surfactant is increased and the amount necessary to achieve adequate absorption of the medicament is thus lessened if, in the process of making the composition, the cyclosporin and the anionic surfactant are dissolved together (optionally together with other ingredients) in a solvent or a solvent system, and the solvent or solvents are then evaporated to give a dry co-precipitate of the cyclosporin and the anionic surfactant.

The evaporation of the solvent or solvents will preferably be done by spray drying or freeze drying, more preferably by spray drying.

In cases in which the amount of anionic surfactant that is used is sufficient to completely dissolve the cyclosporin in water, water can be used as the sole solvent. If the amount of surfactant is less than that required to completely dissolve the surfactant in the water, then the cyclosporin and the surfactant can be dissolved in a solvent system comprising a mixture of water and an organic solvent, preferably a volatile alcohol such as the methanol.

The invention will be further illustrated by the following examples, which are intended to be illustrative but not limiting of the scope of the invention.

Example 1 50. 0 g of cyclosporin, 55.0 g of sodium lauryl sulfate and 40.0 g of lactose monohydrate were mixed together in dry form.

The mixed powder was filled into capsules of size 2 to a net filling weight of 290 mg per capsule. Each capsule thus contained 100 mg of ciclosporin, 110 mg of sodium lauryl sulfate and 80 mg of lactose monohydrate, Example 2 200. 0 g of cyclosporin, 220.0 g of sodium lauryl sulfate and 160.0 g of mannitol, were dissolved together in 2000.0 g of water. The solution was spray dried. The spray-dried powder was then compacted and then ground into granules. The granules were then filled into capsules of size 2, at a net filling weight of 290 mg per capsule. Each capsule thus contained 100 mg of cyclosporin, 110 mg of sodium lauryl sulfate and 80 mg of mannitol.

Example 3 200. 0 g of cyclosporin, 440.0 g of sodium lauryl sulfate and 160.0 g of mannitol, were dissolved together in 2000.0 g of water. The solution was spray dried.

The spray-dried powder was then compacted and then ground into granules. The granules were then filled into size 1 capsules, at a net filling weight of 400 mg per capsule. Each capsule thus contained 100 mg of cyclosporin, 220 mg of sodium lauryl sulfate and 80 mg of mannitol.

E j us 4 500. 0 g of cyclosporin and 1200.0 g of sodium lauryl sulfate were dissolved together in 5500.0 g of water. The solution was spray dried. The spray-dried powder was then compacted and then ground into granules. The granules were then filled into size 1 capsules at a net filling weight of 340 mg per capsule. Each capsule thus contained 100 mg of ciclosporin and 240 mg of sodium lauryl sulfate.

Example 5 500. 0 g of cyclosporin and 400.0 g of sodium lauryl sulfates were dissolved together in a mixture of water and methanol. The solution was spray dried. The spray-dried powder was then compacted and then ground into granules. The granules were then filled into capsules of size 3, at a net filling weight of 180 mg per capsule. Each capsule thus contained 100 mg of ciclosporin and 80 mg of sodium lauryl sulfate.

Comparative Studies of Bioavailability A comparative study of 3-way bioavailability was carried out in 6 human volunteers, to compare the absorption of the capsules of example 1 and the capsules of example 2 with 100 mg capsules of Sandimmune (registered trademark). After a period of 72 hours after ingestion, the average degree of absorption was determined as 96% of that of Sandimmune (registered trademark) for the capsules of Example 1 and 121% of that of the Sandimmune (registered trademark) for the capsules of example 2.

A comparative study of 3-way bioavailability was carried out in 6 human volunteers, to compare the absorption of the capsules of Example 2 and the capsules of Example 3 with 100 mg capsules of Neoral (registered trademark). After a period of 72 hours from ingestion, the average degree of absorption was determined as 73% of that of Neoral (registered trademark) for the capsules of Example 2 and 92% of that of Neoral (registered trademark ) for the capsules of example 3. It is noted that in relation to this date, the best known method for carrying out the 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 (14)

Claims

1. A solid pharmaceutical osition for oral administration, rising a cyclosporin and an anionic surfactant, characterized in that the amount of anionic surfactant is at least forty percent of the minimum amount that would be required to dissolve the cyclosporin in water, using a sufficient amount of water small that the concentration of the anionic surfactant in the water would exceed the critical concentration of micelles.

2. The osition according to claim 1, characterized in that the anionic surfactant is not more than four times the minimum amount that would be needed to dissolve the cyclosporin in water, using a sufficiently small amount of water, that the concentration of anionic surfactant in water does not would exceed the critical concentration of micelles.

3. The osition according to claim 1 or 2, characterized in that the anionic surfactant is selected from sodium alkyl sulphates, sodium alkyl sulfonates and sodium alkyl aryl sulphonates.

4. The osition according to claim 1 or 2, characterized in that the anionic surfactant is sodium lauryl sulfate.

5. A solid pharmaceutical osition, rising a cyclosporin and sodium lauryl sulfate, characterized in that the amount of sodium lauryl sulfate by weight is from about 40% to about 400% the amount of the cyclosporin.

6. The osition in accordance with the rei indication 5, characterized in that the amount of sodium lauryl sulfate by weight is from about 80% to about 300% of the amount of cyclosporin.

7. The osition according to any of the rei indications 1 to 6, characterized in that the cyclosporin rises more than ten percent of the osition by weight.

8. The osition according to any of claims 1 to 6, characterized in that the cyclosporin rises more than twenty percent of the osition by weight.

9. The osition according to any of claims 1 to 6, characterized in that the cyclosporin is cyclosporin.

10. The osition according to any of claims 1 to 9, characterized in that it is contained within a 2-piece gelatin capsule.

11. The osition according to any of claims 1 to 6, characterized in that it is in the form of a tablet.

12. A process for making a osition as in any of claims 1 to 9, characterized in that it rises the steps of dissolving the cyclosporin and the anionic surfactant in a solvent or a ination of solvents and then evaporating the solvent or the solvents.

13. The process according to claim 12, characterized in that the water is used as a solvent.

14. The process according to claim 12 or 13, characterized in that the evaporation is done by spray drying.