United States Patent: 6,106,860
Inventors: Stuchlik; Milan (Opava, CZ); Andrysek; Tomas (Opava, CZ); Jegorov; Alexandr (Ceske Budejovice, CZ); Husek; Ales (Opava, CZ); Matha; Vladimir (Ceske Budejovice, CZ); Stuchlik; Josef (Hrabyne, CZ); Benesova; Kvetoslava (Opava, CZ)Assignee: Galena AS (Opava, CZ)
Appl. No.: 230695Filed: June 1, 1999
Provided are therapeutic compositions which provide high bioavailability of the active ingredients from the group of cyclosporin, at the same time permitting concentrations in dosage forms higher than 10%.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
It should be understood for the purposes of this
description that a "carrier" means a pharmaceutic adjuvant in
which the active substance is dissolved or dispersed in an absorbable
form. When required the carrier can also contain further excipients such
as antioxidants, taste correcting agents and the like.
The formulations according to this invention can be liquid at the ambient
temperature or can be prepared as solids with the use of carriers having a
melting point above ambient temperature. The ingredients of the carrier
can be mixed together with the active substance at temperatures above the
melting point before cooling to a temperature suitable for grinding to
powdery granules for further treatment, eg for filling into bipartite
capsules or sachets for dispersing as required. The liquid formulations,
due to their viscous character, may be employed especially for filling
into bipartite capsules. The capsules can then be treated, eg with an
acid-resistant coating, for use in treatment of auto-immune diseases of
the intestinal tract.
The partial esters of polygylcerol with fatty acids used as components of
the carrier may have the general formula
HO--CH2 --CHOH--CH2 (O--CH2 --CHOH--CH2)x
--O--CH2 --CHOH--CH2 --OH
wherein x=0 to 13. Preferred partial esters are characterised by the
following data:
______________________________________
Number of OH hydroxyl
mol.weight
groups value
______________________________________
diglycerol 166 4 1352
triglycerol
240 5 1169
tetraglycerol
314 6 1071
pentaglycerol
388 7 1012
hexaglycerol
462 8 970
heptaglycerol
536 9 941
octaglycerol
610 10 920
nonaglycerol
684 11 903
decaglycerol
758 12 880
pentadecaglycerol
1228 17 846
______________________________________
Fatty acids suitable for esterification of polyglycerol include, pure non-branched saturated and unsaturated fatty acids as well as mixtures of fatty acids obtained by hydrolysis from natural fats and oils. The acids may also be substituted, for example 1,2-hydroxyoleic acid, or branched, for example isostearic acid.
Partial esters of polyglycerols with the C8 to C22 fatty acids are generally prepared either by esterification of polyglycerols with corresponding saturated or unsaturated acids or by trans-esterification of vegetable oils with polyglycerols. Each individual partial ester of polyglycerols may be characterised by its saponification number.
The degree of polymerisation may be indicated by the hydroxyl value. Products which are especially suitable as component (i) of the carrier include:
______________________________________
diglyceryl monooleate
NIKKO .RTM. DGMO-90
triglyceryl monooleate
DANISCO TS-T 122
tetraglyceryl monostearate
NIKKO .RTM. Tetraglyn 1-S
tetraglyceryl monooleate
NIKKO .RTM. Tetraglyn 1-0
decaglyceryl trioleate
NIKKO .RTM. Decaglyn 3-0
decaglyceryl tristearate
NIKKO .RTM. Decaglyn 3-S
decaglyceryl pentaoleate
NIKKO .RTM. Decaglyn 5-0
______________________________________
Preferred compounds which may be used a s component (ii) of the carrier include:
______________________________________
hexaglyceryl monolaurate
NIKKO .RTM. Hexaglyn 1-L
hexaglyceryl monococoate
--
hexaglyceryl monomyristate
NIKKO .RTM. Hexaglyn 1-M
decaglyceryl monolaurate
NIKKO .RTM. Decaglyn 1-L
decaglyceryl monomyristate
NIKKO .RTM. Decaglyn 1-M
______________________________________
Preferred components (i) of the carrier are lipophilic fat-like substances (pseudo-lipids). They have very low toxicity. The acceptable daily dose (ADI) for the polyglycerols was determined by FAO/WHO in 1975 as 25 mg/kg body weight. That is ten times greater than the acceptable dose for fatty acid microesters, which are suggested as a carrier for cyclosporin formulations in GB patent 2230440. Components (i) of the carrier include partial esters of long chain fatty acids. They dissolve the active substances well and are needed for absorption of cyclosporins from the gastrointestinal tract by the mechanism of formation of mixed micelles, in which bile acids are involved.
Preferred components (ii) include medium to long chain fatty acids. They may have an amphiphilic character, but retain their ability to dissolve cyclosporins. These acids may effect the surface tension of the mixed carrier and facilitate dispersion of the resulting combination in water. Even with a great excess of water these acids may form a physically stable dispersion having an average particle size below 2 .mu.m. This is a preferred condition for uniform absorption of the active substance. The products of hydrolysis of partial esters of medium long fatty acids with glycerols are absorbed by another mechanism even in the absence of bile acids. That is especially advantageous in some diseases with reduced release of bile.
The whole group of the especially preferred partial esters of fatty acids with polyglycerols, useful as the carriers of the active substance, is characterised by one or more of the following criteria:
______________________________________
acid number max. 6
fatty acid Na salts content
max. 2% (as Na stearate)
heavy metal content
max. 10 ppm
water content max. 2%
total ash max 1%
iodine number 50-110 (unsaturated acid
esters)
max. 3 (saturated acid
esters)
saponification number
100-180
______________________________________
Polyglyceryl esters of fatty acids are physiologically more acceptable. adjuvants in comparison with polyoxyethylated tensides, which are commonly used in commercially available ciclosporin compositions. They do not contain any residues of ethylene oxide monomer or its conversion products such as 1,4-dioxane.
Claim 1 of 9 Claims
1. A pharmaceutical composition for internal use,
comprising:
10% to 25% by weight of a cyclosporin; and
a carrier comprising,
(i) one or more partial esters of C16 to C22 fatty
acids with a glycerol derivative selected from the group consisting of
diglycerol to decaglycerol and,
(ii) one or more partial esters of C8 to C16 fatty
acids with a glvcerol derivative selected from the group consisting of
pentaglycerol to pentadecaglycerol in mutual weight ratios (i):(ii) of 1:1
to 1:5.
____________________________________________
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