Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-07-24
2003-04-08
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S452000, C424S456000, C424S464000, C424S465000, C424S466000
Reexamination Certificate
active
06544551
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to new solid pharmaceutical compositions containing hexedecylphosphocholine (miltefosine) for oral administration for the treatment of leishmaniasis. These compositions have suitable flowability for processing into forms such as tablets and have a purity suitable for oral administration for treatment of leishmaniasis. Other aspects of the invention include compositions comprising the new solid pharmaceutical miltefosine composition, an antiemeticum, and/or an antidiarrhoeal product; methods of, and dosage schemes for oral administration of said pharmaceutical composition in the treatment of leishmaniasis; and processes for the manufacture of solid pharmaceutical compositions containing miltefosine.
2. Background of the Invention
Leishmaniasis is a name for a group of tropical diseases which are caused by flagellates of the genus Leishmania. Leishmaniasis is transmitted by various blood-sucking insects. The manifestations of leishmaniasis may be visceral (e.g. kala-azar), mucocutaneous (e.g American leishmaniasis) or cutaneous (e.g Aleppo boil or diffuse cutaneous leishmaniasis). The incubation period for leishmaniasis is weeks or months. A very high mortality rate is observed in untreated cases, particular in instances of kala-azar and American leishmaniasis.
Leishmania is a parasitic disease which is often encountered in geographical areas with extreme tropical climates and where medical care is complicated by inadequate modes of transport. Medications and methods for treating leishmaniasis must take into account these harsh environmental conditions and constraints.
Prior to the present invention there was no medicament available for oral therapy of leishmaniasis. Prior art therapies for leishmaniasis required intravenous (i.v.) injection of agents such as pentavalent antimony compounds (e.g. sodium stibogluconate) and aromatic diamidines. However, such methods cause severe side-effects due to the high toxicity of the prior art medications. Further, i.v. administration of such medications increases the risk of infection compared to medications which are administered orally or topically. Additionally, the prior art methods are inconvenient, particularly in tropical countries without adequate transportation, adequate hospital care facilities or adequate medical resources.
The usability of milefosine for oral and topical treatment of leishmaniasishas been described by Eibl et al. in German unexamined patent application no. P 41 32 344, filed Sep. 27, 1991. However, miltefosine is difficult to handle due to its poor flowability, its hygroscopicity and its ability to become electrostatically charged.
One reason miltefosine has poor flowability is because of its high hygroscopicity. The incorporation of water molecules into miltefosine may result in an increase in weight of up to 30%, melting point depression, or in agglomeration and agglutination of the crystals. Miltefosine which contains water exhibits insufficient workability to be further processed into solid pharmaceutical compositions, such as tablets, capsules or sachets. Flowability is desirable and one of the essential prerequisites for manufacturing solid pharmaceutical compositions on an industrial scale, however, the flowability of water-containing miltefosine is particularly insufficient for these purposes.
While miltefosine may be obtained in dry or anhydrous form as crystalline plates with a definite melting point of above 200° C., this form has the undesirable characteristic of becoming electrostatically charged. Anhydrous miltefosine exhibits inadequate flowability for processing into a solid pharmaceutical composition due to its significant tendency for electrostatic charging, particularly when stirred in dry state. Moreover, electrostatic charging raises significant safety concerns due to the risks of both explosion during processing or handling. Electrostatic charging may also cause damage to electronic parts in machinery which dry miltefosine comes into contact during its handling and processing.
Prior art attempts to overcome these problems have been unsatisfactory because they rely on processes which use highly volatile and toxic halogenated hydrocarbons that can introduce undesirable contaminants into the final products. For example, Eibl et al. attempt to overcome the aforementioned problems in the preparation of solid pharmaceutical compositions containing miltefosine by means of a process which uses halogenated hydrocarbons. Eibl et al. suggest coating miltefosine onto the surface of silicon dioxide particles by making a suspension of 1 part by weight of silicon dioxide in a solution containing 1 part by weight of miltefosine and evaporating to dryness. While under laboratory conditions, the resulting solid dispersion exhibits sufficient flowability to be filled into capsules, the process as described by Eibl et al. requires the use of non-inflammable solvents which are highly volatile. The solvents used must be non-inflammable due to the danger of electrostatic charging. For all practical purposes, there are only two solvents available in the state of the art which meet these requirements, namely methylene chloride and chloroform. Both of these solvents are halogenated hydrocarbons and are classified as toxic and cancerogenic compounds, particularly chloroform. Halogenated hydrocarbons when ingested accumulate or are enriched in the fat tissues of animals and are only slowly metabolized. Therefore, solid pharmaceutical compositions containing miltefosine produced by the process of Eibl et al. which require the use of solvents like chloroform or methylene chloride suffer from the risk of contamination with these toxic compounds. Such compositions face a lengthy and costly regulatory process and may be denied regulatory approval for use in humans or in animals forming part of the food chain. Such risks discourage scaling up the prior art processes for industrial use.
Accordingly, there is a long-felt need for a solid pharmaceutical composition containing miltefosine having suitable flowability and purity, and which does not suffer from the health, regulatory and commercial risks associated with miltefosine produced by prior art processes.
BRIEF SUMMARY OF THE INVENTION
The present invention provides novel methods for manufacturing, processing or providing hexedecylphosphocholine (miltefosine) in a solid form having suitable flowability and purity for production of pharmaceutical compositions which do not suffer from the risks associated with miltefosine produced by prior art processes. These solid compositions are suitable and convenient for oral administration of miltefosine in the treatment of leishmaniasis. These compositions may be compound in a variety of forms and may contain other active ingredients such as an antiemeticum and/or an antidiarrhoeal product. Novel methods of treatment and dosage schemes using these new orally administered miltefosine compositions also form important aspects of the invention.
DETAILED DESCRIPTION OF THE INVENTION.
As noted above, prior art miltefosine products suffer from a number of problems. Surprisingly and unexpectedly, it has now been found that the aforementioned problems can be solved by simple physical mixing of miltefosine (HPC); at least one flowability-controlling agent and/or lubricant such as those selected from the group consisting of highly dispersed silicon dioxide, talc, magnesium stearate and mixtures thereof; and at least one filler, such as fillers selected from the group consisting of lactose, microcrystalline cellulose and mixtures thereof.
The subject matter of the present invention is new and non-obvious over the prior art since it is not necessary to use carrier particles or granulating solvents to.obtain a solid miltefosine-containing pharmaceutical composition with sufficient flowability. The present invention uses simple physical blending of miltefosine, a flowability-controlling agent and/or lubricant, and at least one filler, to provide a solid pharmaceut
Engel Juergen
Hilgard Peter
Klenner Thomas
Milsmann Eckhard
Sarlikiotis Werner
Bennett Rachel M.
Page Thurman K.
Zentaris AG
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