Patent Document:

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 . colloidal silicon dioxide is used in at least an anti - caking amount , i . e ., an amount such that a firm , difficult to re - suspend cake does not form under normal conditions of transportation and storage . it is possible that re - settling may occur which is easily re - suspended by mild physical agitation ( e . g ., stirring or shaking ). the upper limit for colloidal silicon dioxide is an amount above which , in conjunction with the viscosity agent , causes gelation . the particular grade of colloidal silicon dioxide , so long as it is pharmaceutically acceptable , has not been found to be critical . both the amount of polysorbate and colloidal silicon dioxide are system specific , optimum amounts depending on the drug form ( e . g ., free base versus acid salt ), and the amounts and types of other excipients which may also be used as part of the suspension . generally , the polysorbate will be employed in an amount of from about 0 . 01 to about 2 . 0 by weight % based on the weight of the final suspension , more preferably from about 0 . 05 to about 0 . 30 weight %. the colloidal silicon dioxide will generally be employed in an amount of from 0 . 05 weight % to 2 . 0 weight % based on the weight of the suspension . a suitable viscosity agent ( also referred to in the art as a “ thickening agent ”) is also used as a component of the invention . such viscosity agents function as suspending agents and include , for example , hydrocolloid gums known for such purpose , examples of which include xanthan gum , guar gum , locust bean gum , gum tragacanth , and the like . alternatively , synthetic suspending agents may be used such as sodium carboxymethylcellulose , polyvinylpyrrolidone , hydroxypropylcellulose hydroxypropylmethylcellulose , and the like . the viscosity agent is generally used in an amount of from about 0 . 01 weight % to about 10 weight % based on the weight of the suspension . the amount actually used in a particular formulation is dependent on the exact agent and on other excipients present . ziprasidone free base or an acid addition salt can be used in this invention in any form , including anhydrous or hydrated . the ziprasidone hydrochloride employed herein , including the examples , was ziprasidone hydrochloride monohydrate , and is generally referred to throughout simply as ziprasidone hydrochloride for convenience . the invention is applicable to other ziprasidone acid addition salts as well , such as acetic acid , lactic , succinic , maleic , tartaric , citric , gluconic , ascorbic , benzoic , cinnamic , fumaric , sulfuric , phosphoric , hydrobromic , hydroiodic , sulfamic , sulfonic such as methanesulfonic , benzenesulfonic , and related acids . as previously stated , it is advantageous to include a taste masking agent in the suspension in the specific case of pharmaceutically acceptable ziprasidone acid addition salts . such taste masking agents are alkali metal and alkaline earth metal chlorides including sodium chloride , lithium chloride , potassium chloride , magnesium chloride , and calcium chloride . sodium chloride is preferred . the taste masking agent is generally included in the suspension in a taste - masking amount , generally an amount of about 0 . 5 to about 2 . 0 weight % as sodium chloride based on the weight of the suspension . for other salts , equivalent molar amounts can be calculated . a composition according to the invention is an oral , pre - constituted suspension which contains , as necessary ingredients , ziprasidone free base or a ziprasidone acid addition salt , water , a polysorbate , a viscosity agent , and colloidal silicon dioxide . compositions according to the invention can also contain other conventional pharmaceutically acceptable excipients such as , for example : flavorings , buffers , ph adjusting agents , diluents , colors , preservatives , and sweetening agents . some excipients can serve multiple functions . flavors incorporated in the composition may be chosen from synthetic flavor oils and flavoring aromatics and / or natural oils , extracts from plant leaves , flowers , fruits , and so forth and combinations thereof . these may include cinnamon oil , oil of wintergreen , peppermint oils , clove oil , bay oil , anise oil , eucalyptus , thyme oil , cedar leaf oil , oil of nutmeg , oil of sage , oil of bitter almonds , and cassia oil . also useful as flavors are vanilla , citrus oil , including lemon , orange , grape , lime and grapefruit , and fruit essence , including apple , banana , pear , peach , strawberry , raspberry , cherry , plum , pineapple , apricot , and so forth . the amount of flavoring may depend on a number of factors including the organoleptic effect desired . generally the flavoring will be present in an amount of from about 0 . 01 to about 1 . 0 percent by weight based on the total suspension weight , when a flavor is used . the suspension can be manufactured by conventional pharmaceutical methods , combining the various components using conventional equipment such as an overhead stirrer , usually at about 100 – 500 rpm . many different orders of adding components to the stirrer can be employed . a typical order of mixing in the instant invention , although others are certainly possible , is ( 1 ) adding the water heated to 70 ° c . for any components which require temperatures higher than room temperature ( rt ) as an aid to dissolution ( if no such ingredients are employed , then heating is not required ); ( 2 ) cooling to rt ( about 30 ° c . ); then adding , in the following order ( and assuming each component is employed ), viscosity agent , sweetener , buffer , polysorbate , taste masking agent if employed , ziprasidone , colloidal silicon dioxide , and flavors . the invention is further exemplified and disclosed by the following non - limiting examples : a suspension formulation was prepared by heating 733 . 31 g of water to 70 ° c . followed by adding 1 . 36 g methylparaben and 0 . 17 g propylparaben while stirring at about 200 rpm with an overhead stirrer . after the parabens completely dissolved , the temperature was lowered to about 30 ° c . the following components were then added in order : 2 . 78 g xanthan gum , 333 . 90 g xylitol , 1 . 13 g anhydrous citric acid , 1 . 21 g trisodium citrate dihydrate , 0 . 55 g polysorbate 80 , 11 . 13 g nacl , 11 . 33 g ziprasidone hydrochloride monohydrate having a nominal particle size of 38 μm , 11 . 13 g colloidal silicon dioxide , and 5 . 0 g cherry flavor . the ph was adjusted to 4 . 0 using aqueous sodium hydroxide and hydrochloric acid as needed . this example discloses a process for making a ziprasidone free base suspension . into a 2 liter beaker was weighted 812 . 0 g of water which was stirred using an overhead stirrer at a speed of about 200 rpm . the water was heated to 70 ° c . once the temperature reached 70 ° c ., 1 . 36 g of methylparaben and 0 . 17 g of propylparaben were added . when the parabens were completely dissolved , the temperature was lowered to 40 ° c . to the solution was slowly added 3 . 27 g of a viscosity agent , carbopol ® resin 974p ( union carbide corporation , danbury , conn . ), taking care to avoid big lumps , and increasing the stirring speed as necessary . agitation was maintained until the viscosity agent had completely dispersed and / or dissolved . to the solution was added 218 g of sucrose . after dissolving the sucrose , temperature was lowered to 30 ° c . to the solution was added 2 . 94 g of trisodium citric salt . to the solution was added 0 . 544 g of polysorbate 80 . to the solution was slowly added 11 . 325 g of ziprasidone free base . a 10 % naoh solution was used to adjust the ph of the formulation to 5 . 7 . after the ph had equilibrated , 1 . 09 g of colloidal silicon dioxide ( cab - o - sil ®, cabot corporation ) was added . this example illustrates the results obtained using colloidal silicon dioxide as an anti - caking agent as compared to other agents used for the same purpose . ziprasidone free base suspensions ( nominal ziprasidone particle size of 38 μm ) containing the same components , except for the anti - caking agent , where made as in example 2 , with and without each of the anti - caking agents listed below . each anti - caking agent was added into the formulation in a 60 cc bottle , which was then centrifuged at 2000 rpm for 20 minutes to accelerate settling , and the bottles were then gently rotated at a speed of about one rotation every 2 seconds to resuspend the settled solids . the time required for the formulations to become fully homogeneous ( no solids stuck at the bottom of the bottle by visual inspection ) was recorded . the data support that the time required for the formulations to resuspend is substantially reduced using colloidal silicon dioxide ( csd in the table below ), reducing resuspension time substantially at about 0 . 3 % level . different surfactants were tested for their ability to wet ziprasidone hcl monohydrate in water : sodium lauryl sulfate ( sls ), miglyol ® ( registered trademark of dynamit nobel aktiengesellschaft , germany ) triglyceride ( 810 ), and polysorbate - 80 . in three separate 100 ml volumes of water , each surfactant listed above was added in an amount to make a 1 % solution . miglyol ® was added in excess due to its low solubility . while stirring at 200 rpm with an overhead stirrer , to each of the three surfactant solutions was added 1 . 132 g of ziprasidone was added to each of the three surfactant solutions ( equivalent to 10 mga / ml ). the observed rate of wetting was recorded as follows : 1 ) sls & gt ; 20 min 2 ) miglyol ® triglyceride & gt ; 20 min 3 ) polysorbate - 80 & lt ; 2 min only the polysorbate 80 solution did not show any visible aggregates after mixing overnight . further testing of polysorbate - 80 at different concentrations demonstrated that a concentration as low as 0 . 05 % can significantly decrease drug wetting time .

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