FI116120B - A novel process for the preparation of oral pharmaceutical preparations containing cyclosporin - 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

116120

A NEW METHOD FOR THE PHARMACEUTICAL PREPARATION OF ORAL CYCLOSPORIN

PREPARING

ETT NOW FÖRFARANDE FÖR FRAMSTÄLLNING AV PHARMACEUTICAL 5 PREPARAT FÖR ORAL INTAGNING SOM INNEHÄLLER CYKLOSPORIN

The present invention relates to novel processes for the preparation of oral pharmaceutical preparations containing cyclosporin as an active ingredient.

Cyclosporins are a class of peptides whose members are specifically used to suppress the immune system. In addition, cyclosporines are known to have anti-inflammatory and anti-parasitic effects. Thus, the use of cyclosporins is not limited to the suppressors of the immune system, but is directed at all inflammatory diseases, including various autoimmune diseases and other inflammatory conditions, particularly those with autoimmune processes. In particular, the above inflammatory conditions also include arthritis diseases such as rheumatoid arthritis and rheumatic diseases. As an antiparasitic agent, cyclosporins can be used to treat, for example, protozoal infections, for example malaria * f: V: 25.

* j · Cyclosporins are strongly hydrophobic; :; substances that make them difficult to form '. pharmaceutical formulations which could further guarantee an adequate bioavailability. This latter feature is important especially because the cyclosporins have a meaning; essential nephrotoxic (nephrotoxic) side effects. The cyclo: sporine-containing pharmaceutical preparations hitherto proposed are based on 35 alcohol and / or oils or the like * * · I '.! for use with a surfactant.

"· Preparations of this type are known, for example, from DE-OS 2907 460 of 116120. However, the use of such liquid compositions presents a number of drawbacks and difficulties. The use of oils or similar oil-based carriers results in excessive longevity, especially during long-term the alcohol content is necessary to dissolve the active ingredient, as a result of which the patient is constantly consuming alcohol, and as the alcohol evaporates during prolonged use, the desire for such preparations as soft gelatine capsules did not lead to a satisfactory solution as a result of the greater effort involved.

DE-OS 4003 844 proposes a formulation system comprising, in addition to the active ingredient, a fatty acid saccharide monoester and a diluent or carrier, which should be capable of providing solid, semi-solid and liquid preparations containing cyclosporin in such high concentration that . oral administration is possible, and that, for example, * * · bioavailability characteristics are driven by improved performance of the bogies. Thus, these dosage forms contain at least two other components in addition to the active ingredient.

The applicant has now surprisingly found an oral preparation system capable of providing a pharmaceutical preparation of orally administered cyclosporin * · ». ·· *! • Contains only the carrier component in addition to the active substance cyclo • sporine. This component is an alkylene polyether or ester or an arbitrary mixture thereof, wherein the carrier system has an HLB,.,, 35 value of at least 10. The formulations of the present invention achieve a bioavailability of the active ingredient which is at least 3,111,120 comparable to at least the best known formulations containing cyclosporin.

Pharmaceutical formulations of the present invention having a similar high bioavailability can be made more economically, avoid taste-depleting additives and harmful alcohol content, and are also better accepted by patients because of the ingestion of a formulation having the same active ingredient content. , the total weight is lower compared to known formulations.

Accordingly, the present invention relates to a process for the preparation of oral pharmaceutical compositions containing cyclosporin as an active ingredient, comprising: a) cyclosporin as an active ingredient, b) an alkylene polyether or ester or an arbitrary mixture thereof as a binder having an HLB of at least 10; 20 comprising mixing components (a) and (b).

In another embodiment of the invention there is provided a process for the preparation of an oral pharmaceutical preparation comprising mixing a) a cyclospor used as an active ingredient; ; and b) a binder carrier comprising an alkylene polyether or an alkylene polyester; ,, 3 0 alone or in any arbitrary mixture such that the component (b) used has an HLB of at least 10, • '·· provided that (b) is saturated with a:: glycolide glycolide then sucrose monolaurate 35 is not present.

116120 4

Further provided is a process for the preparation of an oral pharmaceutical preparation which comprises mixing (a) cyclo-5 sporine as an active ingredient, (b) a saturated polyglycolized glyceride selected from Gelucir products: Gelucir® 35/10, 44 / 14, 42/12, 50/13, 53/10 and among their alloy mixtures, 10 (c) C2 of low molecular weight mono or polyoxyalkane diol of 2 to 15 carbon atoms, alkylene polyol, alkylene glycol, polyalkylene glycol. A 5-alkyl ether or a partial ether and / or a vegetable oil or a hydrogenated or hydrolysed product of this oil.

In addition, the formulations prepared by the process of the invention may contain other known, conventional and pharmaceutically acceptable additives (d) known in the art for the preparation of oral formulations.

Prepared by the process of the invention. preparations contain from 1 to 50 parts by weight of component V. * (b), corresponding to 0.5 to 20 parts by weight of component (c), by weight, based on the active ingredient. per part by weight of 5 to 10 parts by weight of component (b), respectively 1 to 10 parts by weight of component (c), and in particular 1 part by weight of active ingredient to 5 parts by weight of component (b), respectively part by weight of component (c).

; ·. In the case of component (b), it is suitably a C3.5-alkylene triol, in particular a glycerin, ether or ester. These compounds also include, for example, the interconversion products of this alkylene triol ester and other mono-, di-, or polyols, and the substances described in Chapter II! in the publication DE-OS 40 30 844 entitled "Components C · 5". Particularly preferred are saturated poly-116120 5 glycated glycerides having an HLB value of at least 10. Preferably, saturated, polyglycolized glycerides 5 known under the trade name Gelucire (tradename Gelucire are trademarks of Gattefosse), and in particular Gelucire® 35/10, 42/12, 50/13, 53/10, and arbitrary mixtures thereof, such that the carrier component used has an HLB value of at least 10.

Optional component (c) comprises ethers of the low molecular weight mono-10 or polyoxyalkane diols (C2.12) as well as the partial ethers described in DE-OS 39 30 928, paragraph 1.1. These optional components (c) further include C3.5-15 alkene polyols, C2.4 alkylene glycols, poly (C2.4 alkylene) glycols, and vegetable oils and their hydrogenation and / or hydrolysis products such as castor oil, olive oil, palm oil , coconut oil, corn oil, sesame oil. Component (c) may be present as a single component or as arbitrary mixtures. As preferred examples of component (c) may be mentioned. Nita glycerin, propylene glycol and polyalkylene glycols, having a specific molecular weight of up to and including 600 ·, Transcutol and castor oil and hydrogenation thereof

* · I

25 and products obtained by hydrolysis.

In the case of other useful additives, the usual pharmaceutically acceptable additives are those for oral administration. Examples include va-, ·. 30 blowing agents, thickeners, preservatives, ···, blasting agents, stabilizers, flavors, binders, lubricants and the like. The amount of these additives may be up to 50% of the total composition, but preferably not more than 25%. , ·, 35 and especially up to 10% of the total composition.

• »•» »116120 6

All known, natural and synthetic cyclosporins, including analogs and derivatives thereof, can be used in the preparation of the invention. Examples of such cyclosporins are found, for example, in DE-OS 40 03 844 and DE-OS 40 05 190. Preferably cyclosporin A is used.

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

Oral dosage forms are usually in unit dosage forms and contain about 15 to 200 mg, preferably 50 or 100 mg, of active ingredient per unit dose.

The following examples further illustrate the present invention.

20 Examples, 1. Ingredients Share (ma)

Cyclosporin A 50.0

Gelucir 53/10 300.0 *. * 'Total 350.0 L 2. Cyclosporin A 50.0; Gelucir 44/14 250.0

Propylene Glycol 50..0

Total 350.0 i # i i V 3. Cyclosporin A 50.0 i '··. Gelucir 50/13 250.0

Transcutol 75.0 '.t Total 375.0 4. Cyclosporin A 50.0 116120 7

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 53 / 10.42 / 12,275.0

Transcutol 50.0

Total 375.0 8. Cyclosporin A 50.0

Gelucir 42/12 300.0

Glycerin 25.0

Total 375.0 9. Cyclosporin A 50.0 0 *: Gelucir 50/13 250.0 '! * Castor Oil 75.0 • · k ·

Total 375.0 ti »» · · · i · ·

Preparation: Compositions of Examples 1-9. The compositions of the invention are prepared by melting component (b) by heating to a temperature of at least 60 ° C, and dissolving the active ingredient (a) therein with stirring. Optionally, optional component (c) is added to the melt.

Subsequently, the resulting preparations are filled in, for example, liquid, desired concentrations, hard gelatine capsules of the desired size.

These preparations can also be made into tablets in a known manner. For this purpose, the melts are prepared as described above. These melts are poured and after solidification, they are milled on a sieve-5 machine. Conventional excipients such as lubricating and lubricating agents, disintegrating agents, fillers, flavoring agents and the like are mixed with the granules thus prepared. The finished mixtures are compressed into tablets containing a hopeful amount of cyclosporin. These tablets may likewise be coated with a protective coating.

Bioavailability:

Studies on the bioavailability of the formulations of the invention were conducted in dogs.

A group of six beagle dogs was used for bioavailability studies. Test preparations were administered orally by gavage to non-fed animals. Blood is drawn at specific points in time,. Vena from the saphena vein and blood are collected in the corresponding plastic tubes containing EDTA. Blood samples are stored at -18 ° C to 25 ° C until assay. Cyclosporin is assayed in whole blood by a fluorescence-based polarizing imim M assay (FPIA).

v: The area under the curves showing drug concentration over time (AUC) was calculated according to the trapezoidal rule. The mean AUC * values obtained with the compositions of the invention are shown in the following table side by side with those obtained with commercially available, on the one hand, and, on the other hand; 35 capsules (Sandimmun®), using the same dose and using the same dogs.

116120 9

Examples AUC (0-12h) mg / ml

Ex. 2 9035 ± 2134

Example 3 7859 ± 1512

Example 4 7552 ± 1194

Example 5 8228 ± 857 cyclosporine solution in solution 7990 ± 1320 cyclosporine capsules 8098 ± 1504

As can be seen from the bioavailability tests described above, the cyclosporin used as the active ingredient in the pharmaceutical formulations of the invention can be obtained in an oral form in which the bioavailability is at least equivalent to the formulations known hitherto.

• • * • * * • • • • • • • • • • • • • • • * t * · • • »» *

Claims (12)

116120 A process for the preparation of an oral pharmaceutical preparation, characterized in that the preparation comprises 5 (a) cyclosporin as the active ingredient, and (b) an alkylene polyether or an alkylene polyester used as a binder, either alone or in any arbitrary mixture, b) HLB value of at least 10, prepared by mixing components (a) and (b). The process of claim 1, wherein component (b) is selected from saturated poly-glycolized glycerides. The method of claim 2, wherein component (b) is selected from Gelucir® products: Gelucir® 35/10, 44/14, 42/12, 50/13, 53/10, and any mixture thereof. 4. A process for the preparation of an oral far-20 bulk formulation comprising mixing: (a) cyclosporin as an active ingredient, (b) a binder carrier containing 25 alkylene polyethers or an alkylene polyester, either alone or myself. any arbitrary mixture so that the component (b) used has an HLB * of at least 10, provided that (b) is a saturated polyglycololized glyceride, sucrose monolaurate is not present. A process for the preparation of an oral pharmaceutical preparation comprising: (a) cyclosporin as an active ingredient; (b) a saturated polyglycolized glyceride selected from Gelucir® 35/10, 116120 44 / 14, 42/12, 50/13, 53/10 and their arbitrary mixtures, (c) alkylene polyol, alkylene glycol, polyalkylene glycol, alkyl ether or partial ether of lower monooxyalkanediol or polyoxy-5 alkanediol and / or vegetable oil or hydrogenated thereof or a hydrolysed product, either alone or in arbitrary mixtures. The method of claim 5, wherein components (a), (b) and (c) are present in a weight ratio of 1: 1-50: 0.5-20. The method of claim 5 or 6, wherein components (a), (b) and (c) are present in a weight ratio of 1: 5 to 10: 1 to 10. The method of any one of claims 5 to 7, wherein components (a), (b) and (c) are present in a weight ratio of 1: 5: 1. The method of any one of claims 1 to 8, wherein the preparation is in the form of hard gelatin capsules or tablet. The method of any one of claims 1 to 9, wherein the concentration of cyclosporin is from 20 to 200 mg per unit dose. The method of any one of claims 1 to 10, wherein the concentration of cyclosporin is 50 to 100 mg per unit dose. The process according to any one of claims 1 to 11, wherein the cyclosporin is cyclosporin A.