SK129895A3 - Cyclosporine-containing pharmaceutical compositions for oral administration - Google Patents

Abstract

New cyclosporine-containing, oral administration pharmaceutical compositions are easy to produce and have a good bioavailability. Besides cyclosporine as active substance, these compositions contain an alkylene polyether or polyester, and may optionally contain an alkylen polyol, an alkylen glycol, a polyalkylene glycol, an alkyl diether or partial ether of a low molecular mono- or polyoxyalkane diol and/or a vegetable oil or its hydrogenated or hydrolysed product.

Description

Novel pharmaceutical preparations containing cyclosporin, administered orally

Technical field

The present invention relates to novel pharmaceutical preparations containing cyclosporin as active ingredient for oral administration.

BACKGROUND OF THE INVENTION

Cyclosporins are a class of peptides that are used primarily as immunosuppressants. It is also known that cyclosporins exhibit anti-inflammatory and anti-parasitic activity. Thus, the use of cyclosporins is not limited to immunosuppressants, but encompasses all inflammatory diseases, including various autoimmune diseases and other inflammatory conditions, in particular inflammatory conditions in which autoimmune processes play a role. In particular, said inflammatory conditions include arthritic diseases e.g. rheumatoid arthritis as well as rheumatoid diseases. As an antiparasitic agent, cyclosporins can be used e.g. in the treatment of protozoa infections.

Cyclosporins are very hydrophobic substances, as a result of which it is difficult to process them in a simple manner into pharmaceutical preparations which would further guarantee excellent bioavailability. The latter aspect is particularly important because cyclosporins exhibit nephrotoxic side effects which are of major importance. The hitherto proposed cyclosporin-containing formulations are based on the use of alcohol and / or oils or similar vehicles in conjunction with a surfactant. Such formulations are e.g. known from DE-OS 2907460. However, the use of such liquid formulations is accompanied by a number of drawbacks and difficulties. The use of oils or oil-based carriers comparable thereto results, in particular in the case of prolonged use in long-term therapy, to affect taste. Since a higher proportion of alcohol is required to dissolve the active substance, patients are permanently administered alcohol and the active substance is excreted when the alcohol is evaporated for prolonged use. Neither the attempt to prepare such formulations in the form of gelatin capsules has provided a satisfactory solution in view of the high costs associated with such a solution.

DE-OS 4003844 proposes a formulation system which, in addition to the active ingredient, contains a saccharide monoester of a fatty acid and a diluent or carrier which can provide solid, semi-solid and liquid formulations containing cyclosporin at a sufficiently high concentration which can be conveniently orally administered and have improved efficacy; for example, in terms of bioavailability properties. These forms of administration contain at least two other ingredients, in addition to the active ingredient.

Surprisingly, a formulation for oral administration has now been found which can be used to offer a cyclosporin-containing pharmaceutical formulation which, in addition to the active ingredient, contains only a carrier component. This component is an alkylene polyether or ester or any mixture thereof, and the carrier system must have an HBL value of at least 10. The formulations of the invention provide the bioavailability of the active ingredient which is comparable to the best known cyclosporin-containing formulations.

Pharmaceutical. The compositions according to the invention can be industrially prepared with comparable good bioavailability, avoiding additives which affect taste as well as disadvantageous alcohol content and thus lead to a better feeling of patient comfort in the sense that the administration form is at the same active ingredient concentration by known preparations reduced in terms of total weight.

SUMMARY OF THE INVENTION

The invention relates to pharmaceutical preparations for oral administration which contain cyclosporin as active ingredient and have the following composition:

(a) cyclosporin as active substance;

(b) an alkylene polyether or ester or any mixture thereof as a carrier, wherein the HLB value is at least 10.

Optionally, the compositions of the invention may contain as an additional component

c) alkylénpolyol, alkylene glycol, polyalkylene glycol, C _2-5 -alkyldi- or partial ether, low molecular weight mono- or polyoxyalkándiolov having 2 to 15 carbon atoms and / or a vegetable oil or a hydrogenated and hydrolysed product.

The preparations according to the invention contain, in parts by weight per part by weight of active substance, 1 to 50 parts by weight (b) or 0.5 to 20 parts by weight (c), preferably per 1 part by weight of active substance 5 to 10 parts by weight (b) or 1 by weight. up to 10 parts by weight (c), and most preferably 1 part by weight of the active substance, 5 parts by weight (b) or 1 part by weight (c).

Component (b) is preferably a C ₃ to C ₅ alkylene triol, especially glycerin, an ether or an ester. They also include eg. reesterification products of alkylene triol ester with other mono-, di- or polyols, as well as those described in DE-OS 4003844 under "Component C" Saturated polyglycolyzed glycerides having an HLB of at least 10 are particularly suitable. They are preferably used under the trade name Gelucire (Gelucire is a trade mark of Gattefossé) known polyglycolyzed glycerides, especially Gelucire ¹¹ 35/10, 44/14, 42/12, 50/13, 53/10 and any mixtures thereof, the HLB value of the carrier components used being at least 10th

The optional component (s) include e.g. diether or partial ether, low molecular weight (C ₂ _i ₂₎ a mono- or polyoxyalkándiolov as described in DE-3,930,928 in the paragraph concerning the components 1.1. The optional component (c) further comprises C ₃ . _5- alkylene polyols, C 2-6 -alkylene glycols, poly-1-alkylene-glycols and vegetable oils, as well as their hydrogenation and / or hydrolysis products, e.g. castor oil, olive oil, palm oil, corn oil, sesame oil. Component (c) may be contained as a single substance or in any mixtures. Preferred examples of components (c) are glycerin, propylene glycol and polyalkylene glycols of molecular weight up to 600, transcutol and castor oil and their hydrogenated and hydrolyzed products.

Other useful ingredients are those commonly used in the oral dosage form field. Examples are release-retarding agents, thickeners, preservatives, stabilizers, flavoring agents, binders, glidants and the like. The proportion of these additives may be up to 50% of the total composition, but is preferably not more than 25% and most preferably not more than 10% of the total composition.

All known natural and synthetic cyclosporins, as well as analogs and derivatives thereof, are suitable for use in the compositions of the invention. Examples of such cyclosporins are found e.g. in DE-OS 4003844 and DE-OS 4005190. Preferably cyclosporin A is used.

Oral dosage forms include, for example, liquids, granules and solid forms such as tablets and capsules, which are known to those skilled in the art and can be made by conventional methods.

Oral dosage forms of the invention are generally in unit dosage form and contain about 20 to 200 mg, preferably 50 to 100 mg, of active ingredient per dosage unit.

The following examples serve to illustrate the invention further.

DETAILED DESCRIPTION OF THE INVENTION

1. Ingredients fraction (mg) cyclosporin A 50.0

Gelucir 53/10 300.0 total 350.0

2. Cyclosporin A 50.0

Gelucir 44/14 250.0 propylene glycol 50.0 total 350.0

3. Cyclosporin A 50.0

Gelucir 50/13 250.0 transcutol 75.0 total 375.0

4. Cyclosporin A 50.0

Gelucir 44/14 250.0 total 300.0

5. Cyclosporin A 50.0

Gelucir 50/13 250.0 propylene glycol 50.0 total 350.0

6. Cyclosporin A 50.0

Gelucir 35/10 250.0 propylene glycol 25.0 total 325.0

7. Cyclosporin A 50.0

Gelucir 50 / 13.42 / 12 275.0 transcutol 50.0 total 375.0

8. Cyclosporin A 50.0

Gelucir 42/12 300.0 glycerine 25.0 total 375.0

9. Cyclosporin A 50.0

Gelucir 50/13 250.0 Castor oil 75.0 Total 375.0

Production: The preparations of Examples 1 to 9 are prepared by melting component (b) by heating, preferably at 60 ° C, and then dissolving the active compound (a) in the melt with stirring. Optionally, optional (c) is added to the melt.

The formulations obtained in liquid form are then filled into, for example, hard gelatin capsules of the desired size at the desired concentration. The formulations can be further processed into tablets in a known manner. For this, a melt is produced as described above. The liquid melt is poured and ground after curing on a screen. The granulate so produced is mixed with conventional excipients such as glidants and lubricants, swelling agents, fillers, flavorings, etc. The finished mixtures are compressed into tablets having the desired cyclosporin content. The tablets may optionally be coated with a protective coating.

bioavailability

Experiments on the bioavailability of the compositions of the invention have been carried out on a dog.

A group of six Beagle dogs was selected to study bioavailability. Administration of the test preparations was carried out orally by means of a sweep probe on fasting animals. The animals were bled at the indicated times from Vena saphena and collected in appropriate EDTA plastic tubes. Blood samples were stored at -18 ° C until analysis. Cyclosporin determination is performed in whole blood by fluorescence-polarization immunoassay (FPIA).

Areas under the curves (AUC), which were constructed by plotting the concentration of drug in the blood over time, were calculated according to the trapezoidal rule. The mean AUC values of the formulations of the invention are shown in the following table as compared to the commercially available Cyclosporin Drinking Solution and Cyclosporin Capsules (Sandimmun ^R ), which were administered in the same manner, at the same doses and to the same dogs.

Example AUC (0-12h) mg / ml Example 2 Example 3 Example 4 Example 5 Cyclosporine Drinking Solution cyclosporin capsules 9035 ± 2134 7859 ± 1512 7552 ± 1194 8228 ± 857 7980 ± 1320 8098 ± 1504

As indicated by the above-mentioned bioavailability experiments, the active ingredient cyclosporin can be provided in the oral form in which the bioavailability is at least the same as in the prior art.

Claims (8)

PATENT CLAIMS A pharmaceutical preparation for oral administration comprising or consisting of a single component (a) cyclosporin as active substance; (b) an alkylene polyether or ester, either alone or any mixture thereof, as a carrier, wherein the HLB value of the components (b) used is at least 10. The pharmaceutical composition of claim 1, further comprising (c) alkylene polyol, alkylene glycol, polyalkylene glycol, alkyldi- or partial ether of low molecular weight mono- or polyoxyalkanedioles and / or vegetable oil, or a hydrogenated or hydrolysed product thereof, either alone or in any mixture. Composition according to claim 1 or 2, characterized in that the individual components (a), (b) or (c) are present in the following weight ratios: 1: 1 - 50: 0.5 - 20, preferably 1: 5 -10: 1 - 10, most preferably 1: 5: 1. Composition according to any one of claims 1 to 3, characterized in that component (b) is selected from saturated polyglycolyzed glycerides. Pharmaceutical preparation according to claim 4, characterized in that component (b) is selected from the group consisting of gelucirenes Gelucire ® 35/10, 44 / 14,42 / 12, 50/13, 53/10 and any mixtures thereof. The pharmaceutical composition of claim 2, wherein the additional component (c) is selected from the group consisting of glycerin, propylene glycol, PEG having a molecular weight of up to about 600, transcutol, and castor oil. Pharmaceutical preparation according to any one of the preceding claims, characterized in that it is in the form of a hard gelatin capsule or in the form of a tablet. Pharmaceutical preparation according to one of the preceding claims, characterized in that it contains the active ingredient in a concentration of 20 to 200 mg, preferably 50 or 100 mg per dosage unit.