SK283442B6 - Pharmaceutical composition 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

Technical field

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

BACKGROUND OF THE INVENTION

Cyclosporins are a class of peptides that are used primarily as immunosuppressants. It is also known that cyclosporins have 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, particularly inflammatory conditions in which autoimmune processes play a role. In particular, said inflammatory conditions include such 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 infections caused by protozoa, such as malaria.

Cyclosporins are very hydrophobic substances, making it difficult to process them in a simple manner into pharmaceutical preparations that would guarantee sufficient bioavailability. The latter aspect is particularly important because cyclosporins have nephrotoxic side effects which are of major importance. The proposed cyclosporin-containing compositions hitherto proposed are based on the use of alcohol and / or oils or similar carriers 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 ingredient, the patient is continuously administered alcohol and the active ingredient precipitates when alcohol is used 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 which, in addition to the active ingredient, comprises a saccharide monoester of a fatty acid and a diluent or carrier which can be used to prepare 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 characteristics. These forms 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 prepare 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.

The pharmaceutical compositions of the present invention can be industrially formulated with comparable good bioavailability, avoiding ingredients that affect taste as well as disadvantageous alcohol content and thus result in a better feeling of patient comfort in that the total weight of the administration form is at the same active ingredient concentration. compared to known formulations reduced.

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) alkylene polyol, alkylene glycol, polyalkylene glycol, C ₂₅ -alkyldi- or partial ether of low molecular weight mono- or polyoxyalkanediols having 2 to 15 carbon atoms and / or vegetable oil, or a hydrogenated or hydrolysed product thereof.

The compositions of the invention may further comprise conventional pharmaceutically acceptable excipients (d) known in the art for the manufacture of preparations for oral administration.

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 of active substance, 5 to 10 parts by weight (b), 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 e.g. re-esterification products of alkylene triolester with other mono-, di- or polyols, as well as the compounds described in DE-OS 4003844 in the section "Component C". Saturated polyglycolized glycerides having an HLB value of at least 10 are particularly suitable. Saturated polyglycolized glycerides known under the trade name Gelucire (Gelucire trade name Gattefossé), in particular Gelucire ^R 35/10, 44/14, 42/12, are preferably used. 50/13, 53/10 and any mixtures thereof, wherein the HLB value of the carrier components used is at least 10.

The optional component (c) comprises e.g. diether or partial ether of low molecular weight (C _2nd | ₂₎ 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 . ₄ -alkylénglykoly, poly _{(C2. 4} -alkylénjglykoly and vegetable oils, and their hydrogenation and / or hydrolysis products, e.g. castor oil, olive oil, palm oil, corn oil, sesame oil. Component (c) can be included Preferred examples of components (c) are glycerin, propylene glycol and polyalkylene glycols of molecular weight up to 600, transeutol and castor oil, and their hydrogenated and hydrolyzed products.

Other suitable ingredients are pharmaceutically acceptable ingredients commonly used in the oral dosage form field. Examples are release controlling 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 described 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 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 further illustrate the invention.

DETAILED DESCRIPTION OF THE INVENTION

ingredients percentage (mg) 1. cyclosporin A 50.0 Gelucir 53/10 300.0 pretty 350.0 2. cyclosporin A 50.0 Gelucir 44/14 250.0 propylene glycol 50.0 pretty 350.0 3. cyclosporin A 50.0 Gelucir 50/13 250.0 transeutol 75.0 pretty 375.0 4. cyclosporin A 50.0 Gelucir 44/14 250.0 pretty 300.0 5. Cyclosporin A 50.0 Gelucir 50/13 250.0 propylene glycol 50.0 pretty 350.0 6. Cyclosporin A 50.0 Gelucir 35/10 250.0 propylene glycol 25.0 pretty 325.0 7. cyclosporin A 50.0 Gelucir 50 / 13.42 / 12 275.0 transeutol 50.0 pretty 375.0 8. Cyclosporin A 50.0 Gelucir 42/12 300.0 glycerin 25.0 pretty 375.0 9. Cyclosporin A 50.0 Gelucir 50/13 250.0 castor oil 75.0 pretty 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 ingredient (a) in the melt while 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, 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 were 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 specified times from the saphenous vein 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 blood concentration of the drug 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 Drink Solution and Cyclosporin Capsules (Sandimmun ^R ), which were administered in the same manner, at the same doses and to the same dogs.

Example Example 2 Example 3 Example 4 Example 5 Cyclosporin Solution for Drinking Cyclosporin Capsules

AUC (0-12h) mg / ml

9035 + 2134

78591 1512

7552 ± 1194

8228 1,857

7980 + 1320

8098 + 1504

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

Claims (12)

PATENT CLAIMS What is claimed is: 1. A pharmaceutical composition for oral administration comprising (a) cyclosporin as active substance; and b) an alkylene polyether or ester either alone or in any desired mixture as carrier, wherein the HLB value of component (b) used is at least 10, and when (b) is a saturated polyglycolized glyceride, no sucrose monolaurate is present. 2. A pharmaceutical preparation for oral administration comprising (a) cyclosporin as active substance; and (b) a carrier consisting of an alkylene polyether or ester, either alone or in any desired mixture, as a carrier, wherein the HLB value of component (b) used is at least 10, and when (b) the saturated polyglycolized glyceride is absent monolaurate sucrose. 3. A pharmaceutical preparation for oral administration comprising (a) cyclosporin as active substance; (b) an alkylene polyether or ester either alone or in any desired mixture as a carrier, wherein the HLB value of component (b) used is at least 10; and c) alkylene polyol, alkylene glycol, polyalkylene glycol, alkyldial or a partial ether of a low molecular weight mono- or polyoxyalkanediol of 2 to 15 carbon atoms and / or a vegetable oil or a hydrogenated or hydrolysed product thereof, either alone or in any mixtures. Composition according to one of the preceding claims, characterized in that components (a), (b) or (c) are present in the following weight ratios: 1: 1-50: 0.5-20, preferably 1: 5- 10: 1-10, especially 1: 5: 1. Composition according to any one of the preceding claims, characterized in that component (b) is selected from saturated polyglycolized glycerides. Pharmaceutical preparation according to claim 5, characterized in that component (b) is selected from the group consisting of (I) saturated polyglycolized glycerides containing caprylic, capric, lauric, myristic, palmitic and stearic acids, wherein the HLB value is approximately 10 (Gelucir ® 35/10 or Gelucir® 53/10), (II) saturated polyglycolized glycerides containing caprylic, capric, lauric, myristic, palmitic and stearic acids, with an HLB value of approximately 14 (Gelucir® 44/14), (III) saturated polyglycolized glycerides containing caprylic, capric, lauric, myristic, palmitic and stearic, with an HLB value of approximately 12 (Gelucir® 42/12), (IV) saturated polyglycolized glycerides containing caprylic, capric, lauric, myristic, palmitic and stearic acid, wherein the HLB value is about 13 (Gelucir® 50/13), (V) and any mixtures thereof. Pharmaceutical preparation according to one of claims 3 to 6, characterized in that the additional component (c) is selected from the group consisting of glycerin, propylene glycol, polyethylene glycol 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. Pharmaceutical preparation according to any one of the preceding claims, characterized in that it is in the form of a tablet. Pharmaceutical preparation according to any one of the preceding claims, characterized in that the concentration of active substance is 20 to 200 mg per dosage unit. Pharmaceutical preparation according to any one of the preceding claims, characterized in that the concentration of active substance is 50 to 100 mg per dosage unit. Pharmaceutical preparation according to any one of the preceding claims, characterized in that the cyclosporin is Cyclosporin A.