ZA200104828B

ZA200104828B - Cyclosporin solution.

Info

Publication number: ZA200104828B
Application number: ZA200104828A
Authority: ZA
Inventors: Wilfried Fischer
Original assignee: Ratiopharm Gmbh
Priority date: 1998-12-23
Filing date: 2001-06-13
Publication date: 2002-09-13
Also published as: NO20012932D0; HUP0104623A2; CA2355271A1; HK1037140A1; PT1140135E; RU2216342C2; DE59907058D1; ATE249834T1; AU762963B2; DK1140135T3; JP2002533401A; HUP0104623A3; DE19859910C2; EP1140135A1; NO20012932L; CZ20012143A3; DE19859910A1; SK8702001A3; EP1140135B1; ES2203235T3

Description

} C Cyclosporin solution

The present invention relates to a cyclosporin solution.

Cyclosporins are a known group of cyclic undeca- peptides. Cyclosporin A (CgH;11N11012, molecular weight 1202) is used as immunosuppressant pharmaceutical for the treatment of tissue rejection reactions or excessive immunological responses of the body and is commercially available for example as Sandimmun® and

Neoral®. Besides cyclosporin A, a number of additional metabolites are known (cyclosporins B-Z), which show a close relationship to cyclosporin A, both structurally and in some cases also in terms of effect.

The international nonproprietary name of a cyclosporin used for immunosuppression is ciclosporin.

It is additionally known that cyclosporin A has very poor solubility in water. This gives rise to problems in formulating pharmaceutical preparations of cyclosporin A which can be effectively and rapidly absorbed, because rapid and complete or virtually complete absorption of the active ingredient is an indispensible prerequisite for reliable efficacy for the vital indications such as suppression of tissue rejection after organ transplants. Numerous attempts have been made in the prior art to provide cyclosporin A in a formulation which can be absorbed effectively. Because of the great lipophilicity of cyclosporin A, pharmaceutical compositions have been formulated with conventional solid and liquid pharmaceutical carriers, but these often displayed disadvantages, such as inadequate adsorption (Cavanak and Sucker, Formulation of Dosage Forms, Prog. Allergy, 38, 65-72 (1986)), poor tolerability or physical instabilities such as crystallization of the active ingredient. It has also proved to be a disadvantage 40 that the solubility of the active ingredient in the

® -2- ' preparation is often low (about 3%), which means that the amount taken for a daily dose of up to 1 g of cyclosporin A is up to 30 g of the formulation.

The patent DE 29 07 460 discloses, for improving the storage and absorption of cyclosporin A, the use of a carrier composed of a polyalkylene glycol triglyceride, of a fatty acid triglyceride and of a monoglyceride or diglyceride. The formulation is used as oral solution, injection solution or capsule contents. Ethanol can be added to promote solubility. The absorption of such as solution is relatively good, but it has the disadvantage that the blood level may vary greatly and depends on food intake.

An improved formulation is described in DE 39 30 928 as so-called microemulsion preconcentrate, which consists of a hydrophilic phase, a lipophilic phase and an emulsifier. The hydrophilic component may be Cj-s—alkyl or tetrahydrofurfuryl diether or a partial ether of low molecular weight mono- or polyoxyalkanediols or 1,2-propylene glycol. The lipophilic component may be a medium chain-length triglyceride. A polyethoxylated vegetable oil, for example, is provided as emulsifier.

In a comparative absorption study on beagle dogs there was found to be a 49% improvement in absorption compared with the formulation disclosed in

DE 29 07 460.

DE 195 21 974 describes a solution of cyclosporin A in a mixture of an emulsifying vitamin E derivative, another emulsifier, such as a polyoxyethylene vegetable 0il ester and ethanol. The formulation shows a profile of blood levels in beagle dogs comparable to the formulation of DE 39 30 928.

® m3 amorphous cyclosporin A, lower alkanols and polyoxyalkylene emulsifiers as cosolvents.

WO 97/07787 discloses a cyclosporin formulation which comprises an alkanol solvent with 2 to 3 carbon atoms and an emulsifier selected from polyoxyethylene alcohols and fatty acid monoesters of ethoxylated

Cy-¢-polyols.

There continues to be a need for a reasonably priced, well tolerated and stable cyclosporin preparation which, in particular, is easy to produce, is readily miscible with water and forms a stable cyclosporin solution therein, which ensures good absorption of the cyclosporin on oral administration, and which can contain cyclosporin in high concentration.

One object of the present invention is thus to provide a cyclosporin preparation which displays the aforementioned advantages.

It has now been found, surprisingly, that colloidal solutions which are stable in water and which can be diluted with water as desired without precipitation of cyclosporin are formed from a solution of cyclosporin in exclusively water-miscible excipients only in combination with dexpanthenol, an anionic surfactant and a nonionic surfactant or a mixture of nonionic surfactants. Bioavailability investigations have shown good absorption of the active ingredient after oral administration.

The cyclosporin solution according to the invention is able to take up a larger amount of active ingredient per ml of solution than known for cyclosporin formulations in the prior art.

9 - 4 ' The present invention thus relates to a cyclosporin solution comprising dexpanthenol, an anionic surfactant and a nonionic surfactant or a mixture of nonionic surfactants.

Dexpanthenol is the short name for D-{(+)-2,4-dihydroxy-

N- (3-hydroxypropyl)-3,3-dimethylbutyramide.

The preferred cyclosporin is cyclosporin A.

The cyclosporin solution according to the invention may contain the active ingredient plus dexpanthenol, the anionic surfactant and the nonionic surfactant and, where appropriate, other pharmaceutically acceptable excipients in any desired amount as long as the amount of dexpanthenol, of the anionic surfactant and of the nonionic surfactant is sufficient to form a stable cyclosporin solution. The solution preferably comprises 0.2-2 parts by weight of dexpanthenol, 0.2-1 part by weight of anionic surfactant and 0.5-6 parts by weight of nonionic surfactant or a mixture of nonionic surfactants per part by weight of cyclosporin.

The cyclosporin solution according to the invention generally comprises 0.2-2, preferably 0.5-2, for example 0.7-1.3, parts by weight of dexpanthenol, 0.2-1, preferably 0.3-0.7, parts by weight of anionic surfactant and 0.5-6, preferably 3-5, parts by weight of nonionic surfactant or a mixture of nonionic surfactants per part by weight of cyclosporin.

The cyclosporin solution according to the invention may advantageously additionally comprise a diluent. The diluent reduces the viscosity of the solution. This had the advantage that when the solution is used to fill, for example, soft gelatin capsules, after intake of the capsule the contents escape very rapidly from the opening capsule, and thus good absorption of the active ingredient is ensured.

CC @ - 5 -

In the case of an oral solution which is diluted in water before administration so that its viscosity is reduced very greatly it is possible to dispense with addition of diluent.

If the solution according to the invention is to contain a diluent, the content thereof is advantageously 10-40% by weight, in particular about 20% by weight, based on the total weight of the solution. The preferred diluent is ethanol.

The anionic surfactant which can be used for the solution according to the invention is any conventional pharmaceutically acceptable anionic surfactant. It is also possible to use both an anionic surfactant alone or a mixture of two or more anionic surfactants.

Examples of anionic surfactants which can be used according to the invention are alkyl ether sulphates and alkane sulphonates. The preferred anionic surfactant is sodium lauryl sulphate.

The nonionic surfactant which can be used for the solution according to the invention is any conventional, pharmaceutically acceptable nonionic surfactant. It is also possible to use both a nonionic surfactant alone or mixed with other nonionic surfactants, and a mixture of nonionic surfactants is preferred. Examples of nonionic surfactants which can be used according to the invention are glycerol- polyethylene glycol oxystearate (for example Cremophor

RH 40), ethoxylated hydrogenated castor oil and polysorbate 80, a polyoxyethylene (80) sorbitan monooleate which is obtainable under the proprietary name Tween 80. The preferred nonionic surfactants are polysorbate 80 and glyerol-polyethylene glycol oxystearate.

9 - 6 -

A preferred solution according to the invention consists of about 11% by weight of cyclosporin A, about 11% by weight of dexpanthenol, about 5.6% by weight of anionic surfactant, about 55.6% by weight of a mixture of nonionic surfactants, and about 16.8% by weight of diluent, in particular ethanol. This solution is particularly suitable for filling soft gelatin capsules because, owing to its low viscosity, it escapes very rapidly from the opening capsule and ensures good absorption of the active ingredient. Another preferred solution according to the invention consists of about 19-26% by weight of cyclosporin A, about 8-10% by weight of dexpanthenol, about 8-10% by weight of anionic surfactant, about 44-50% by weight of nonionic surfactant and about 12-14% by weight of a diluent.

The combination of dexpanthenol, an anionic surfactant and a nonionic surfactant as solvents for cyclosporin makes available a cyclosporin solution which is readily miscible with water to form a stable aqueous colloidal solution which can be diluted with water as desired without precipitation of cyclosporin. The solution according to the invention is not a microemulsion or microemulsion concentrate and consists exclusively of known pharmaceutical substances. It can be both used to fill capsules and administered in the form of a pleasant-tasting oral solution to the patient.

Compared with the prior art, it was possible owing to the combination of the substances mentioned to dispense with a lipophilic component, which is necessary to form a microemulsion. Completely unexepectedly, dexpanthenol in this case assumes the role of a solubilizer, although it is not a surfactant, resulting in a stable colloidal solution of the cyclosporin in the dissolving medium. The anionic and nonionic surfactants present in the formulation are unable, either alone or in combination, to dissolve the cyclosporin without precipitation.

The surprisingly good dissolving properties of dexpanthenol make it possible to increase the cyclosporin concentration in the solution according to

S the invention compared with the prior art, so that, for example, an increased concentration of active ingredient can be achieved in pharmaceuticals, or the amount of solution to be administered can be reduced.

It is thus possible to produce, for example, smaller capsules which can be taken more easily by the patient.

The present invention thus also relates to an oral pharmaceutical which comprises a cyclosporin solution described above.

Such a pharmaceutical preferably comprises capsules filled with the solution. Soft gelatin capsules are particularly preferred. On examination of the rate of dissolution in media of various pH values as are typical of the gastrointestinal tract, there was found to be substantially pH-independent release of active ingredient from the capsules.

In another embodiment, the pharmaceutical comprising the solution according to the invention is in the form of an oral solution which, besides the cyclosporin solution according to the invention, may contain other conventional, pharmaceutically acceptable additives and, for example, flavourings and colourings and which can be diluted, for example with water, to the required concentration before intake thereof. The cyclosporin solution according to the invention 1s thus also suitable for easy production of a stable aqueous pleasant-tasting oral solution which can easily be administered to the patient.

The necessary cyclosporin levels in the blood are reached very rapidly and reliably after administration of a pharmaceutical according to the invention, and the uniformity of the levels in the blood is greater than after administration of the commercially available product Neoral®.

The described solution can be administered in the form of a diluted aqueous solution for intake or as a single-dose drug form, for example in the form of a capsule. A capsule may contain, for example, a single dose of 100 mg of cyclosporin.

A preferred embodiment of the pharmaceutical according to the invention accordingly comprises soft gelatin capsules which each contain a solution according to the invention composed of about 100 mg of cyclosporin A, about 100 mg of dexpanthenol, about 50 mg of sodium lauryl sulphate, about 100 mg of polysorbate 80, about 400 mg of glycerol-polyethylene glycol oxystearate and about 150 mg of ethanol.

The pharmaceutical according to the invention is particularly suitable for immunosuppression.

The following examples are intended to explain the present invention in detail.

Example 1

This example shows the production of a cyclosporin solution according to the invention and of a pharmaceutical according to the invention in the form of soft gelatin capsules.

Soft gelatin capsules with a filling of the following composition were produced:

surfactant) surfactant) oxystearate (nonionic surfactant)

The cyclosporin A was dissolved in ethanol. Separately from this, sodium lauryl sulphate, dexpanthenol, polysorbate 80 and glycerol polyethylene glycol oxystearate were heated gently to produce a clear solution. The two solutions were mixed homogeneously and then used to fill soft gelatin capsules.

Example 2

An absorption study was carried out on six beagle dogs with the capsules produced in Example 1. Each dog was given a 100 mg cyclosporin A capsule in a crossover test comparing with Neoral® (composition: cyclosporin

A, ethanol, glycerol, corn oil mono-di-tri-glycerides, propylene glycol, macrogol-glycerol hydroxystearate, alpha-tocopherol) and blood samples were taken after 0.5, 1.0, 1.5 and 2.0 hours. The cyclosporin A levels in the samples of blood taken were determined using a commercially available enzyme immunoassay. The following table indicates in each case the means with standard deviations resulting from the curves of levels in the blood.

. ® - 10 -

Table ng/ml ng/ml weorar rest formalation

The example shows that the necessary levels in the blood are reached very rapidly and reliably after administration of the cyclosporin solution according to the invention in the form of a capsule, and the uniformity of the levels in the blood is greater than after administration of the comparison product.

Example 3

A cyclosporin solution of the following composition was produced:

Ingredients

Ciclosporin A 175 mg (about 19.5%)

Dexpanthenol 80 mg (about 8.9%)

Sodium lauryl sulphate 80 mg (about 8.9%) (anionic surfactant)

Polysorbate 80 -

Glycerol-polyethylene glycol stearate 445 mg (about 49.4%)

Diluent 120 mg {about 13.3%)

Total S500 mg

. ® - 11 -

Example 4

A cyclosporin solution of the following composition was produced;

Ingredients

Ciclosporin A 228 mg (about 25.3%)

Dexpanthenol 75 mg (about 8.4%)

Sodium lauryl sulphate (anionic surfactant) 75 mg (about 8.4%)

Polysorbate 80 -

Glycerol-polyethylene glycol stearate 410 mg (about 45.5%)

Diluent 112 mg (about 12.4%)

Total 900 mg

Claims

. ® - 12 - Patent Claims

1. Cyclosporin solution comprising dexpanthenol, an anionic surfactant and a nonionic surfactant or a mixture of nonionic surfactants.

2. Cyclosporin solution according to Claim 1, in which the cyclosporin is cyclosporin A.

3. Cyclosporin solution according to either of the preceding claims, where the solution comprises

0.2-2 parts by weight of dexpanthenol, 0.2-1 part by weight of anionic surfactant and 0.5-6 parts by weight of nonionic surfactant or a mixture of nonionic surfactants per part by weight of cyclosporin. 4, Cyclosporin solution according to any of the preceding claims, which additionally comprises a diluent.

5. Cyclosporin solution according to Claim 4, in which the diluent content is 10-40% by weight based on the total weight of the solution.

6. Cyclosporin solution according to Claim 4 or 5, in which the diluent is ethanol.

7. Cyclosporin solution according to any of the preceding claims, in which the anionic surfactant is sodium lauryl sulphate.

8. Cyclosporin solution according to any of the preceding claims, in which the nonionic surfac- tants are polysorbate 80 and glycerol-polyethylene glycol oxystearate.

9. Cyclosporin solution according to any of Claims 4-8, consisting of about 11% by weight of

. ® - 13 - ) cyclosporin A, about 11% by weight of dex- panthenol, about 5.6% by weight of anionic surfactant, about 55.6% by weight of a mixture of nonionic surfactants and about 16.8% by weight of a diluent, in particular ethanol.

10. Cyclosporin solution according to any of Claims 4-8, consisting of about 19-26% by weight of cyclosporin A, about 8-10% by weight of dex- panthenol, about 8-10% by weight of anionic surfactant, about 44-50% by weight of nonionic surfactant and about 12-14% by weight of a diluent.

11. Oral pharmaceutical comprising a solution accord- ing to any of Claims 1-10.

12. Pharmaceutical according to Claim 11, where the solution is used to fill capsules.

13. Pharmaceutical according to Claim 12, where the capsules are soft gelatin capsules.

14. Pharmaceutical according to Claim 11, where the solution is in the form of an oral solution.

15. Use of a solution according to any of Claims 1-10 for producing a stable aqueous colloidal cyclo- sporin solution.

16. Use of a solution according to any of Claims 1-10 for producing an oral pharmaceutical for immunosuppression.