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Ziprasidone suspensionRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Preparations Characterized By Special Physical Form, Tablets, Lozenges, Or PillsZiprasidone suspension description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070134323, Ziprasidone suspension. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] This invention relates to an oral suspension comprising ziprasidone free base or a pharmaceutically acceptable ziprasidone acid addition salt, a polysorbate, colloidal silicon dioxide, a viscosity agent, and water. In a more specific aspect, the invention relates to such a suspension which is taste masked. The invention further relates to a method of treating a psychosis with such a formulation. BACKGROUND OF THE INVENTION [0002] Ziprasidone is a known compound having the structure: [0003] It is disclosed in U.S. Pat. Nos. 4,831,031 and 5,312,925, both of which are herein incorporated by reference in their entirety, has utility as a neuroleptic, and is thus useful, inter alia, as an antipsychotic. It is typically administered orally as the hydrochloride acid addition salt, ziprasidone hydrochloride monohydrate. The hydrochloride salt is advantageous in that it is a high permeability drug, a factor which favorably affects bioavailability. The hydrochloride salt, as well as other ziprasidone acid addition salts, does, however, possess relatively poor aqueous solubility, a factor which unfavorably affects bioavailability. [0004] Difficult to wet pharmaceutically acceptable compounds can be problematic in the pharmaceutical arts from a formulations perspective. For example, ziprasidone hydrochloride, in addition to having low solubility, is difficult to wet with an aqueous medium, and thereby presents special problems from the standpoint of trying to form an aqueous suspension. In the discussion which follows, ziprasidone hydrochloride is discussed as an exemplary member of the mass composed of ziprasidone free base and ziprasidone acid addition salts which are difficult to wet. The invention is not to be taken as being limited to ziprasidone hydrochloride, however. [0005] Owing to difficulties in wetting ziprasidone acid addition salts such as ziprasidone hydrochloride, the material is difficult to adequately suspend in an aqueous medium without having to resort to using long periods of high shear mixing. An ordinary laboratory homogenizer generally does not wet ziprasidone hydrochloride without being run for a very long time. Long blending periods almost inevitably lead to foaming and still yield poor results with drug aggregates still being visibly present, entrained in the foam. Thus, ziprasidone hydrochloride tends to float on the surface of water and other aqueous media and can be induced to form a suspension only with physical measures (high shear mixing for long times) that are considered extreme. [0006] An alternative mixing procedure comprises first adding only a small amount of water to the ziprasidone salt, followed by grinding to wet the bulk drug substance. This wets the mass sufficiently so that it can be suspended in water. This procedure is still disadvantageous however in that it is difficult to scale up. Moreover, once ziprasidone hydrochloride has been induced to form an aqueous suspension in this fashion, an additional challenge is the prevention or retarding of rapid re-settling, which occurs relatively quickly with ziprasidone hydrochloride, generally within an hour or so, depending on the particle size. Settling can be particularly problematic for a pharmaceutical suspension since the suspension must be adequately re-suspended to ensure that an adequate dosage is administered to the patient. [0007] One approach to improving the anti-settling properties of a suspension is to use a viscosity agent such as any of the natural gums or cellulosics, such as hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC) to increase viscosity, and thereby retard the rate of re-settling of wetted particles in the suspension. Such an approach has been found to be problematic in the case of ziprasidone hydrochloride since, once a viscosity agent has been added, when the ziprasidone hydrochloride eventually settles, it tends to form a thin cake which sits on the bottom and can be very difficult to break up and to re-suspend. Such caking is facilitated by temperature fluctuations and by vibrations such as those which occur during normal handling and transportation. [0008] Further, in the specific case of ziprasidone acid addition salts, such salts generally exhibit a very bitter taste, the degree of bitterness increasing with increasing solubility of the particular salt. Sugars, with or without the presence of other sweetening and/or flavoring agents, are generally insufficient to mask the bitter taste. Adjusting the pH to form the less soluble, hence less bitter, free base, is an option for decreasing bitterness. However, such adjustment can lead to changes in particle size if very careful and continuous control is not maintained. Substantial changes in particle size can, in turn, undesirably lead to changes in bioavailability. [0009] Thus, a suspension comprising ziprasidone free base or ziprasidone hydrochloride (or other pharmaceutically acceptable ziprasidone addition salt) which maintains an improved shelf life (i.e., which maintains a longer period of suspension prior to re-settling) and which is easily re-suspendible would represent a valuable addition to the formulations arts. In the particular case of a suspension of a ziprasidone acid addition salt, a suspension with improved taste would be a further valuable addition. SUMMARY OF THE INVENTION [0010] It has now been determined that dry components comprising ziprasidone free base or a difficult to wet pharmaceutically acceptable ziprasidone acid addition salt, a polysorbate, a viscosity agent, and colloidal silica easily form a good suspension in aqueous media. Thus one aspect of the invention is a composition of matter which is a suspension comprising ziprasidone free base or a difficult to wet pharmaceutically acceptable ziprasidone acid addition salt, water, a polysorbate, a viscosity agent, and colloidal silicon dioxide. By "difficult to wet" it is meant a pharmaceutically acceptable salt of ziprasidone that does not readily form a suspension in water when mixed by ordinary means such as a laboratory blender which has been run at normal speed for ten minutes. Such salts do not, by themselves, form a "good suspension", as defined below, in water. [0011] Again, it is noted ziprasidone hydrochloride is used herein to exemplify the invention, although it is to be understood that the use of an example is not to be considered as limiting. [0012] The particle size of the ziprasidone hydrochloride particles is not considered particularly important in terms of ability to be wetted, although the mean particle size is generally below or equal to 85 .mu.m. [0013] Pre-constituted suspensions according to the invention exhibit good suspension and can be remixed upon settling. By "good suspension" it is meant (1) that in a suspension according to the invention there is no visible settling for greater than 24 hours at room temperature (RT, usually 25.degree. C.) preferably for greater than one week and (2) that when visible settling does occur, resuspension is easily effected by simple physical mixing such as gentle manual stirring or moderate manual shaking, high shear mixing not being required. [0014] The invention is surprising in that polysorbates are the only wetting agents among a range of wetting agents that were tested which yielded positive results. Other wetting agents such as sodium lauryl sulfate caused foaming before adequate wetting could be obtained. Such foaming was problematic in that, although some particles appeared to wet, other salt particles became entrained in the foam, and still other salt particles sat as a dry mass atop the water, with the result that a homogeneous suspension did not form. Thus, polysorbates are useful as agents in the instant invention that allowed complete wetting below the level at which they foam. [0015] The term "polysorbate" is employed for its art-recognized meaning, i.e., polyoxyethylene sorbitan fatty acid esters as disclosed and defined in the Handbook Of Pharmaceutical Excipients, edited by Ainley Wade and Paul Weller, The Pharmaceutical Press, London, 1994. Useful polysorbates include polysorbate 20, 21, 40, 60, 61, 65, 80, 81, 85, and 120. Polysorbate 80 is preferred. [0016] The colloidal silicon dioxide useful herein is of the type known in the art (e.g., of the type available commercially as CAB-O-SIL.RTM., registered trademark of Cabot Corporation, Boston, Mass.) and, while not wishing to be bound by any particular theory or mechanism, is believed to function as an anti-caking agent. That is, even though some re-settling may occur in a suspension according to the invention, the re-settled material does not cake, meaning that, even though a viscosity agent is present, resettled material does not form a firm mass that is difficult to break up and re-disperse in the presence of colloidal silicon dioxide. In the presence of colloidal silicon dioxide, anti-caking properties are effected such that re-suspension can be effected by simple physical mixing, as previously described. Thus the advantage of the invention is that the combination of a polysorbate and colloidal silicon dioxide achieves good wetting together with facile re-suspendability in the event settling occurs. [0017] In a more specific aspect of the invention, there is provided an aqueous suspension of ziprasidone comprising a ziprasidone acid addition salt suspended in an aqueous pharmaceutically acceptable carrier which contains an alkali metal (e.g., sodium, lithium, or potassium) chloride or an alkaline earth metal (e.g. magnesium or calcium) chloride. It has been determined that these salts are very effective as taste masking agents. While not wishing to be bound by theory or statements of mechanism, it is believed that such salts reduce the solubility, and thereby the dissolved amount and/or concentration, of ziprasidone salt in the suspension. Reduced concentration of dissolved ziprasidone is not a disadvantage in a suspension dosage form, however, and in the instant invention is advantageous since suspended ziprasidone is more chemically stable than dissolved ziprasidone, thereby improving chemical stability, as well as taste. [0018] The invention further provides a method of treating a psychosis, comprising administering to a patient in need of such treatment an effective amount of a suspension comprising ziprasidone free base or a pharmaceutically acceptable ziprasidone acid addition salt, a polysorbate, a viscosity agent, colloidal silicon dioxide, and water, said suspension being otherwise disclosed and described herein. [0019] Ziprasidone hydrochloride can be used in any active crystalline or amorphous form, although crystalline ziprasidone hydrochloride monohydrate is preferred. DETAILED DESCRIPTION [0020] In general, the polysorbate is used in an amount which is at least sufficient to effect complete wetting, i.e., meaning that drug is easily dispersed within a reasonable amount of time. The amount of polysorbate employed should not, as an upper limit, equal or exceed the amount which causes foaming. Continue reading about Ziprasidone suspension... Full patent description for Ziprasidone suspension Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Ziprasidone suspension patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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