Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-12
2001-10-23
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S895000
Reexamination Certificate
active
06306896
ABSTRACT:
The present invention relates to a pharmaceutically active composition which contains a substance active against malaria parasites and has a high activity against multiresistant lines of
Plasmodium falciparum
. The present invention relates in particular to an acceptable form of artemisinin and/or a derivative of artemisinin, for example arteether, artemether, artemisin or artesunate, especially artesunate, for rectal administration. Artesunate is a water-soluble derivative of artemisinin. Artemisinin (qinghaosu) is obtained from the leaves of the shrub
Artemisia annua
and is a naturally occurring sesquiterpene lactone with an endo peroxide group. Because of the low water solubility of the natural substance artemisinin, attempts have been made to convert it to a variety of synthetic derivatives in order to improve the pharmaceutical availability. One such derivative is artesunate. Artemisinin and artesunate are efficient active substances in the treatment of malaria. Artemisinin preparations are currently the substances which act most rapidly against malaria parasites. In particular, they show a high activity against multiresistant lines of
Plasmodium falciparum
. Also, when administered to humans, only a few side effects and no significant toxicity have been observed, although neurotoxicity has occurred in animals. Nevertheless, relatively little has hitherto been disclosed about the pharmacogenetics of artemisinin and artesunate, which may be connected with the complicated analytical methods needed to quantify these drugs in the blood.
In the body, both artemisinin and artesunate are converted to dihydroartemisinin (DHA, artesol), which is the actual schizonticidal active substance. Artemisinin and artesunate can therefore be regarded as prodrugs for dihydroartemisinin.
Artesunate corresponds to the compound dihydroartemisinin hemisuccinate and its salts, especially its sodium salt. Dihydroartemisinin has the chemical name 3&agr;,12&agr;-epoxy-3,4,5,5a&agr;,6,7,8a&agr;,9,10,12&bgr;,12a-dodecahydro-10-hydroxy-3&bgr;,6&agr;,9&bgr;-trimethylpyrano[4,3-j]-1,2-benzodioxepine. Dihydroartemisinin is also known by the name dihydroqinghaosu. Artesunate, or dihydroartemisinin hemisuccinate, can be prepared for example by converting dihydroartemisinin to dihydroartemisinin hemisuccinate by means of acylation. Arteether, artemether and artemisin are known per se.
Artemisinin, artesunate, dihydroartemisinin and derivatives thereof are manufactured especially in China and Vietnam and are marketed for example in tablet form. In severe cases of malaria (possibly cerebral) caused by
Plasmodium falciparum
, the patients are often unconscious and an oral treatment is not possible. The parenteral administration of quinine, for example, is only permitted in hospitals. In such cases artesunate in a rectal form of administration can save lives throughout the world and in practically any situation. A further advantage of the rectal form is administration to children, where oral use is often complicated by swallowing problems. Rectal forms of artesunate can also be administered successfully for other types of malaria, e.g. VIVAX.
Approximately one million children die of malaria every year in Africa. Although tablets and injectable solutions (as a powder preparation) are already commercially available, suppositories are not. This is principally connected with the fact that artesunate is unstable in conventional suppository formulations, especially at elevated temperature. Numerous areas, for example subtropical and tropical regions, often have an exceptionally warm climate and hence also above-average temperatures. Furthermore, by their very nature, suppositories are generally unstable at elevated outside temperatures since they are intended to melt at approx. 37° C.
The object of the present invention is to find a rectal pharmaceutical form containing artemisinin and/or a derivative of artemisinin, for example arteether, artemether, artemisin and/or artesunate, especially artesunate, as the active substance, this form having an adequate stability of the active substance for the appropriate storage period and containing a sufficient amount of active substance to allow reliable control of the Plasmodium pathogens in the blood. Examples of rectal forms are suppositories, rectal foams, enemas or rectal capsules. The term artesunate will be used predominantly hereafter to represent artemisinin and its derivatives.
The conventional prerequisite for the production of rectal capsules is the presence in every case of surface-active substances, especially wetting agents (surfactants), but also emulsifiers and optionally washing-active substances, in order to assure an adequate bioavailability of the active substance by improving the distribution in the rectum. However, studies have shown that such artesunate formulations have a high degree of instability even after a short storage period.
Surface-active substances are subdivided according to their hydrophilic-lipophilic balance, i.e. by means of their HLB values, into antifoams (HLB values of 1-3), emulsifiers (HLB values of 4-6 and 8-18), wetting agents (HLB values of 7-9), washing-active substances (HLB values of 13-15) and solubilizers (HLB values of 10-18). The boundaries between these effects overlap partially and are fluid. Depending on the composition in which it is present, a compound may exhibit its assigned effect inadequately, if at all, despite its HLB value, or it may act for example both as an emulsifier and as a wetting agent. Compounds referred to as antifoams, emulsifiers, wetting agents, washing-active substances and solubilizers are known per se.
It has now been found, surprisingly, that a composition which is substantially free of compounds with an HLB value in the range 7-9.9, and which contains the active substance artemisinin and/or a derivative of artemisinin, especially artesunate, in an excipient which is inert towards the active substance, not only gives a medicinally stable formulation which satisfies the requisite criteria in respect of the chemical stability of the active substance, but also has an active substance bioavailability which is within the internationally recognized limits applied to comparative bioavailability.
In terms of the present invention, the expression “substantially free of compounds with an HLB value in the range 7-9.9” means that any compound present with an HLB value in the range 7-9.9, preferably a compound with an HLB value in the range 7-9, has a concentration in the composition of at most 10 percent by weight, preferably at most 5 percent by weight and particularly preferably at most 2 percent by weight, based on the weight of the pharmaceutically active substance. It is usually preferred that no compound with an HLB value in the range 7-9.9, preferably no compound with an HLB value in the range 7-9, be present in the composition.
The present invention is defined in the claims. In particular, the invention relates to a pharmaceutically active composition which contains a substance active against malaria parasites and has a high activity against multiresistant lines of
Plasmodium falciparum
, characterized in that this composition contains a pharmaceutically effective amount of the active substance artemisinin and/or a derivative of artemisinin in an excipient which is inert towards the active substance, and the excipient is substantially free of compounds with an HLB value in the range 7-9.9, preferably in the range 7-9.
The expression “artemisinin and derivatives of artemisinin” is to be understood as meaning especially arteether, artemether, artemisin and/or artesunate, preferably artesunate.
The present invention further relates to the use of the composition according to the invention for the production of pharmaceutical forms for rectal administration. Such forms for rectal administration are preferably suppositories, rectal foams, enemas and rectal capsules.
The present invention further relates to rectal forms, preferably suppositories, rectal foams, enemas or rectal capsules, p
Hoffmann & Baron , LLP
Mepha AG
Weddington Kevin E.
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