Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
2000-08-22
2002-07-30
Carr, Deborah D (Department: 1621)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S456000, C424S460000, C424S464000, C424S488000, C424S489000, C424S490000, C424S498000, C424S499000
Reexamination Certificate
active
06426087
ABSTRACT:
This application is a 371 of PCT/EP99/00994 filed Feb. 16,1999.
The invention relates to orally administrable galenic forms comprising one or more active ingredients which are hydrophilic or ionizable in physiological media in combination with one or more excipients. These galenic forms are preferably solid forms such as tablets or gelatin capsules. The galenic compositions of the invention are particularly advantageous in that they allow improved absorption of active ingredients which are hydrophilic and/or ionizable in physiological media, by the transmembrane or paracellular route, because of their particular excipient composition.
The absorption of orally administered active ingredients essentially takes place by the transmembrane or paracellular route at the level of the mucous membranes of the gastrointestinal tract. In the case of active ingredients which are hydrophilic or ionizable in physiological media, the absorption predominantly takes place by the paracellular route. Because of this, the bioavailability of this type of active ingredient is very low, the kinetics of absorption being very slow. Numerous authors have more precisely studied the kinetics of absorption of active ingredients in the form of calcium salts and have observed that the transport of these substances by the paracellular route is very limited: it appears that the calcium salts have the effect of closing again the channels present between the cells which provide for transport by the paracellular route. Reference may be made, for example, to P. Artursson and C. Magnusson, J. Pharm. Sci., 79, 595, 1990 and S. G. Milton and V. P. Knutson, J. Cell. Physiol., 144, 498, 1990.
The use of various excipient systems comprising liquid or amphiphilic compounds such as semisynthetic glycerides for promoting the absorption of active substances has been abundantly illustrated in the art. In this regard, there may be mentioned the following state of the art documents: WO 93/00891, EP 670 166, WO 95/08 983, WO 94/23 733 and WO 96/21 439. All the prior art formulations are intended, however, to improve the bioavailability of lipophilic active substances. Moreover, the formulations provided in the case of tablets, granules or microgranules do not always allow control of the kinetics of release.
This may result in an intense increase in the plasma concentration, which is quite often followed, in the case of compounds having a short half-life, by a rapid decrease in these levels which reach values below the therapeutic threshold. Multiplication of the number of doses is then necessary in order to maintain a therapeutic effect for the medication.
However, control of the absorption of the active ingredients at the level of the gastrointestinal tract will ensure the efficacy of the therapy used. Furthermore, modulation of the release (while preserving an optimized absorption) makes it possible to ensure better therapeutic cover and to improve tolerance and compliance. Thus, it is possible to reduce the number of doses of the medicament and to thereby ensure compliance with the treatment. This is essential in the case of treatment of long-term, or even chronic, disorders or pathologies.
The galenic forms of the invention allow improvement in the absorption of the active ingredients which are hydrophilic and/or ionizable in physiological media, the control of the kinetics of release and the maintenance of the yield of absorption, this being also in the case of solid pharmaceutical forms such as tablets, gelatin capsules or microgranules.
Although the galenic forms of the invention are particularly appropriate for the administration of active substances which are hydrophilic and/or ionizable in physiological media, they are also suitable for the administration of lipophilic substances.
It may also be noted that the pharmaceutical dosage forms of the invention ensure excellent reproducibility of the results, while allowing increased control of the rate of release during the phase of prolonged release of the active ingredient. By using the pharmaceutical dosage forms of the invention, it becomes possible to optimize the availability of the active ingredients in the body taking into account both the tolerance of the subject to the active ingredient and the pharmacokinetic and metabolic profiles of the active ingredient.
The tablets of the invention are moreover advantageous from the point of view of the formulation of the active ingredients since a judicious choice of the excipients leads to tablets with high concentrations of active ingredients.
The invention provides more precisely orally administrable galenic forms comprising an active ingredient which is hydrophilic and/or ionizable in physiological media, an absorption-promoting agent having an HLB (hydrophilic/lipophilic balance value) greater than 8 and one or more pharmaceutically acceptable excipients.
It should be understood that the galenic forms comprising captopril as active ingredient are excluded from the subject of the invention.
According to the invention, the absorption-promoting agent consists of one or more lipid substances chosen from:
polysorbates; ethers of polyoxyethylene and alkyl; esters of polyoxyethylene and fatty acids; fatty acids; fatty alcohols; bile acids and their salts with pharmaceutically acceptable cations; esters of C
1
-C
6
alkanol with fatty acids; esters of polyol with fatty acids, the said polyol comprising from 2 to 6 hydroxyl functional groups; polyglycolysed glycerides.
These lipid substances are of natural or synthetic origin, or alternatively are obtained by semisynthesis. A good number of them are commercially available or are easily prepared from commercial products.
Although the inventors do not intend to be limited to any mechanism of action, it is thought that by acting on the surface tension of biological fluids, these substances act on membrane contacts at the level of the cells of the gastrointestinal mucous membrane. Whatever the case, it is thought that the absorption-promoting agent creates in situ an environment with modified lipophilicity.
The polysorbates are esters of fatty acids of polyethoxylated sorbitan. Polyethoxylated sorbitan offers polyethoxylated sorbitol and polyethoxylated sorbitol anhydrides. The expression “polysorbate” designates both mono- and polyesters of fatty acids. Preferably, the polysorbates used according to the invention are mono-, di- or triesters of saturated or unsaturated fatty acids, in which the fatty acids are preferably C
8
-C
22
, better still C
12
-C
18
. There may be mentioned more particularly monolaurate, monopalmitate, mono- and tristearate, monooleate and monoisostearate.
Preferably, the polysorbates used are the product of the esterification of fatty acids with the copolymer of a molecule of sorbitol or of one of its anhydrides and of 3 to 30 molecules of ethylene oxide.
By way of example, the structural formulae of a monoester and of a triester are given below:
where R is the residue of a fatty acid and x, y, z and w are integers whose sum varies between 3 and 30, preferably between 4 and 20.
Generally, polysorbates will be used whose molecular weight varies between 450 and 2000, better still between 500 and 1900.
Such polysorbates are commercially available, especially under the trade name Tween®.
The ethers of polyoxyethylene and alkyl have the general formula:
CH
3
(CH
2
)×(OCH
2
CH
2
)
y
OH
in which x is an integer between 8 and 22, preferably between 12 and 18, and y is an integer from 10 to 60. Among these compounds, there may be mentioned monocetyl ether of polyethylene glycol, monolauryl ether of polyethylene glycol, monooleyl ether of polyethylene glycol and monostearyl ether of polyethylene glycol. These compounds are commercially available, especially under the trade name Brij®.
The esters of polyoxyethylene and fatty acids are either fatty acid monoesters of the formula:
RCO—(OCH
2
CH
2
)
n
—OH
where R represents the residue of a fatty acid and n the degree of polymerization of the polyethoxylated chain,
or fatty acid diesters of formula:
RCO—(OCH
2
CH
Giet Philippe
Holot Thierry
Michel Dominique
Saslawski Olivier
Carr Deborah D
Merck Patent Gesellschaft mit
Millen White Zelano & Branigan P.C.
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