thus , the invention relates to pharmaceutical compositions or extended release formulations for use in the treatment of individuals possessing a functional cyp 2d6 gene with an active agent metabolized by cyp 2d6 and the methods of treating such individuals comprising parenterally administering , e . g ., injecting , the active agent in a first extended release formulation in a first administration . the invention further relates to a method for preventing adverse drug reactions in individuals possessing a functional cyp 2d6 gene with an active agent metabolized by cyp 2d6 comprising parenterally administering , e . g ., injecting , the active agent in a first extended release formulation in a first administration . the active agent for use in the inventions can be any active agent that is metabolized by cyp 2d6 and includes drugs , medicaments , diagnostic agents , neutraceuticals , etc . preferred active agents include those that are active in the central nervous system ( or cns ), such as those requiring transport across the blood brain barrier and for treating individuals under psychiatric treatment . examples of such drugs include antispychotics , antidepressants , serotonin reuptake inhibitors , neuroleptics , and opioids . particularly preferred active agents include risperidone , aripiprazole , timolol , thioridazine , tramadol , propranolol , propafenone , perphenazine , oxycodone , debrisoquine , nortriptyline , paroxetine , trazodone , venlafaxine , alprenonol , minaprine , bufuralol , encainide , fluovoxamine , lidocaine , methoxyamphetamine , morphine , doxepin , ondansetron , amphetamine , flecainide , perhexiline , amitriptyline , bisoprolol , chlorpromazine , clomipramine , clozapine , codeine , cyclobenzaprine , desipramine , dexfenfluramine , fenfluramine , donepezil , mexiletine , fluphenazine , fluoxetine , haloperidol , hydrocodone , imipramine , maprotiline , meperidine , methadone , methamphetamine , metoprolol , dextromethorphan , s - metoprolol , carvediol , phenacetin , phenformin , quanoxan , sparteine , tamoxifen , selegine , sertraline , citalopram , amoxapine , desipramine , amitriptyline , trimipramine , protriptyline , phenelzine , tranylcypromine , l - deprenyl , moclobemide , nefazodone , mirtazipine , bupropion , dextroamphetamine , pemoline , methylphenidate , mianserine , mirtazepine , perphanize , zuclopenthixol , dextromethorphan , debrisonide , olanzapine and analogs thereof . preferred active agents are risperidone , aripiprazole , and analogs thereof . similar drugs are described in u . s . pat . nos . 4 , 804 , 663 ; 5 , 006 , 528 and 4 , 734 , 416 , for example . the active agent is preferably administered subcutaneously or intramuscularly , e . g ., by injection or implantation , in an extended release formulation . in one embodiment , the extended release formulation releases the active agent over a period of at least about 7 days , preferably at least about 14 days , alternatively for at least 2 , 3 or 4 weeks . in one embodiment , the formulations can be administered as a single or sole dose . however , the invention is particularly beneficial for those individuals that require constant or chronic therapy , such as those that receive repeated doses over several weeks or months or more . in such dosing regimens , the method can comprise a first administration of a first extended release formulation and a second administration of a second extended release formulation . the second formulation can be the same , substantially the same or different as the first and can include the same active agent or a different active agent . for example , the second formulation can be administered at about 7 days , or more , such as at least about 14 days , or at least about 17 days , after the first administration , where the first administration results in the release of agent for a period of 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 days , or more . the term “ therapeutically effective amount ” is further meant to define an amount resulting in the improvement of any parameters or clinical symptoms . the actual dose may vary with each patient and does not necessarily indicate a total elimination of all disease symptoms . as used herein , the term “ individual ”, “ subject ” or “ patient ” refers to a warm blooded animal , including but not limited to humans , such as a mammal which is afflicted with a particular disease state . a therapeutically effective amount of the compound used in the treatment described herein can be determined by the attending diagnostician , as one skilled in the art , by the use of conventional techniques and by observing results obtained under analogous circumstances . in determining the therapeutically effective dose , a number of factors are considered by the attending diagnostician , including , but not limited to : the species of mammal ; its size , age , and general health ; the specific disease involved ; the degree of or involvement or the severity of the disease ; the response of the individual patient ; the particular compound administered ; the mode of administration ; the bioavailability characteristic of the preparation administered ; the dose regimen selected ; the use of concomitant medication ; and other relevant circumstances . preferred amounts according to the mode of administration are able to be determined by one skilled in the art . pharmaceutical compositions can be manufactured utilizing techniques known in the art . typically the therapeutically effective amount of the compound will be admixed with a pharmaceutically acceptable carrier . the compositions of the present invention may be administered parenterally , such as by injection . preferred methods of administration include intramuscular and subcutaneous administration , e . g . by injection , for example . for injection , the compounds may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a suspension . viscous injectable carriers are preferred , having for example , a viscosity of at least 20 cp at 20 ° c . in other embodiments , the fluid phase of the suspension has a viscosity at 20 ° c . of at least about 30 cp , 40 cp , 50 cp , and 60 cp . the composition may also comprise a viscosity enhancing agent , a density enhancing agent , a tonicity enhancing agent , and / or a wetting agent . illustrative pharmaceutical carriers also include water , aqueous methylcellulose solution , saline , dextrose solutions , fructose solutions , ethanol , or oils of animal , vegetative , or synthetic origin . the pharmaceutical carrier may also contain preservatives , and buffers as are known in the art . in another embodiment , the formulation can be surgically implanted . such formulations can include any of the well - known biodegradable and bioerodible carriers , such as polylactides and poly - lactide - co - glycolides and collagen formulations . such materials may be in the form of solid implants , sponges , and the like . in any event , for local use of the materials , the active ingredients usually are present in the carrier or excipient in a weight ratio of from about 1 : 1000 to 1 : 20 , 000 , but are not limited to ratios within this range . preferably , the compounds are in an extended release formulation . extended ( also referred to as sustained or controlled ) release preparations may be achieved through the use of polymers ( preferably poly - lactide or poly - lactide - co - glycolide polymers ) to entrap or encapsulate the active agent described herein . extended release formulations can be made by spray drying polymer - drug mixtures , emulsion - based technologies , coacervation based technologies , film casting , extrusion based technologies and other processes to manufacture polymer - drug microparticles possessing an extended release profile . examples of suitable extended release technologies that can be used to incorporate the drugs described herein include , without limitation , the medisorb ® technology , as described in , for example , u . s . pat . no . 6 , 264 , 987 to wright , u . s . pat . no . 5 , 654 , 008 and / or u . s . pat . no . 5 , 792 , 477 , for example ; the prolease ® technology , as described , for example in u . s . pat . no . 6 , 358 , 443 to herbert ; the technologies described by southern research institute , as described for example in u . s . pat . nos . 5 , 407 , 609 and 6 , 306 , 425 ; and “ method of preparing sustained release microparticles ,” u . s . application no . 60 / 441 , 946 , filed jan . 23 , 2003 , and the technologies described by alza corp ., including the alzamer ® depot injection technology . the contents of these patents are incorporated herein by reference in their entirety . in one preferred embodiment , the agent is present in the extended release device or formulation in an amount of at least about 5 % by weight , preferably at least about 10 % by weight , more preferably at least about 30 % by weight of the total weight of the device , or formulation . also contemplated is the entrapment of the active agent in microparticles prepared , for example , by coacervation techniques or by interfacial polymerization ( for example , hydroxymethylcellulose or gelatine - microcapsules and poly -( methylmethacrylate ) microcapsules , respectively ), in colloidal drug delivery systems ( for example , liposomes , albumin , microparticles , microemulsions , nanoparticles , and nanocapsules ), or in macroemulsions . when the composition is to be used as an injectable material , including but not limited to needle - less injection , it can be formulated into a conventional injectable carrier . suitable carriers include biocompatible and pharmaceutically acceptable solutions . the individuals who can be beneficially treated by the described methods include those individuals who possess a functional cyp 2d6 gene , such as um and ems , as described above . in one embodiment , the individual possesses a homozygous cyp 2d6 gene . in another embodiment , the individual possesses a heterozygous gene . profiling patients for the cyp alleles is described in u . s . patent application publication us 2003 / 0072710 . thus , the individual can , optionally , be profiled to ascertain whether or not he / she possesses a functional cyp 2d6 gene . in another embodiment , the individual &# 39 ; s profile can be ascertained or estimated by other parameters , such as race or heredity . thus , it is not essential to phenotype the individual prior to the practicing the methods described herein . preferred individuals include those who are at particularly high risk for cyp 2d6 drug - drug interactions . thus in one embodiment , the individual is one who is receiving a cyp 2d6 inhibitor , such as doxorubicin , amiodarone , chorpheniramine , cimetidine , clomipramine , terbinafine , cocaine , desipramine , celecoxib , thioridazine , sertraline , celecoxib , ritonavir , ranitidine , quinidine , propafenone , fluphenazine , nalofentrine , moclobemido , mibefradil , methadone , levomepromazine , haloperidol , fluoxetine , paroxetine , propafenone , perphenazine , glaucine , brompheniramine , promethazine , pyrilamine , doxylamine , diphenhydramine , phenyltoloxamine , triprolodine and chloropheniramine and analogs thereof . see u . s . pat . no . 6 , 124 , 282 , which is incorporated herein by reference . alternatively , the method includes preventing cyp 2d6 drug - drug interactions in individuals at risk thereof comprising administering the formulations described herein . microparticles comprising risperidone were prepared at the 20 - kilogram scale . the 20 kg process ( 8 kg of active agent and 12 kg of polymer ) provides a theoretical drug loading of the microparticles of 40 % ( 8 kg / 20 kg × 100 %). the polymer solution was prepared by dissolving 12 . 0 kg of medisorb 7525 dl polymer ( alkermes , inc ., blue ash , ohio ) in 60 kg of ethyl acetate ( emd chemicals , gibbstown , n . j .). the polymer was added to the solvent at 25 degree c . in a stainless steel reactor . the temperature of the tank was raised to 37 degree c . to facilitate dissolution . the vessel was agitated for at least 16 hours to dissolve the polymer . once dissolved , the solution temperature was reduced to 25 ° c . the drug solution was prepared by dissolving 8 . 0 kg of risperidone base ( janssen pharmaceutica , beerse , belgium ) in 25 . 3 kg of benzyl alcohol ( spectrum chemicals , new brunswick , n . j .) at 25 ° c . in a stainless steel reactor . the organic phase was prepared by adding the drug solution to the polymer solution at 25 ° c . in a stainless steel reactor and mixing for at least 15 minutes . the continuous or aqueous phase was prepared by dissolving 6 . 0 kg of polyvinyl alcohol ( pva ) ( dupont , wilmington , del .) in 594 . 0 kg hot (& gt ; 60 degree c .) water for injection ( wfi ) in a stainless steel vessel to form a 1 % solution . the vessel was agitated for at least 6 hours to dissolve the pva . once the pva was dissolved , the temperature was reduced to 25 ° c . and 42 . 0 kg of ethyl acetate ( emd chemicals , gibbstown , n . j .) was added , and mixed for at least 30 minutes to dissolve the ethyl acetate . the two phases are combined using a static mixer , such as a ½ ″ kenics static mixer available from chemineer , inc ., north andover , mass . a total flow rate of 20 kg / min generally provides microparticle size distributions with a mass median diameter ( mmd ) in the range of about 80 - 90 microns . the ratio of continuous phase to discontinuous phase is 4 . 5 : 1 ( v / v ). the quench liquid is 2 . 5 % solution of ethyl acetate and water - for - injection ( wfi ) at 5 - 10 ° c . the volume of the quench liquid is 0 . 25 l per gram of batch size . the quench step is carried out for a time period greater than about 6 hours , with stirring of the microparticles in the quench tank . after completion of the quench step , the microparticles are transferred to the collecting , de - watering , and drying device . the microparticles are rinsed using a chilled ( approximately 5 ° c .) 300 kg of a 25 % ethanol solution . the microparticles are then subjected to substantially complete intermediate drying . the microparticles are dried using vacuum and a dry nitrogen bleed . to avoid agglomeration , the temperature is maintained at less than 15 ° c . by chilling the dryer jacket and the feed nitrogen . dryness is monitored by an absolute humidity probe , available from vaisala , inc ., woburn , mass ., in the vacuum line of the drying device . the substantially complete intermediate drying can be performed by drying under vacuum with a gas bleed or sweep ( air , nitrogen or other dry gas ) for a period in the range of approximately 16 - 48 hours . the microparticles are then re - slurried in a re - slurry tank using a 25 % ethanol solution ( extraction medium ) maintained at a temperature lower than the tg of the microparticles . the temperature in the re - slurry tank is preferably in the range of 9 ° c . or less . the microparticles are then transferred back to the quench tank for washing for a time period of at least 6 hours with another extraction medium ( 25 % ethanol solution ) that is maintained at a temperature higher than the tg of the microparticles . the tg of the microparticles is about 18 ° c . ( about room temperature ), and the temperature of the extraction medium in the quench tank is greater than about 18 ° c ., preferably 25 ° +/− 1 ° c . the microparticles are transferred back to the collecting , de - watering , and drying device for de - watering and final drying . the final drying step is carried out in a manner similar to that described above for the intermediate drying step , but the temperature is warmed to greater than about 20 ° c . but below 40 ° c . drying continues for a time period greater than about 16 hours . injectable microparticles comprising polymer and drug can be prepared using an efficient and facile single solvent process . plg polymer and salt can be co - dissolved in a single solvent ; ( 2 ) the solvent removed by vacuum drying or sublimation to form a polymer / drug matrix ; ( 3 ) the matrix milled to produce a powder ; ( 4 ) the resulting powder compacted to form a compressed matrix ; and ( 5 ) the compressed matrix milled to form a dense , injectable microparticle formulation . specifically , the drug loading can be about 30 % or more ( w / w ) of the final weight of the microparticle composition . solvents , for example , methylene chloride , acetone , dimethylsulfoxide ( dmso ), acetonitrile , and ethyl acetate are suitable for use . lactide : glycolide ratio ; intrinsic viscosity ; end group ; solvent a 30 % ( w / w ) 50 : 50 ; 0 . 75 dl / g ; acid end group ; ch 2 cl 2 b 30 % ( w / w ) 75 : 25 ; 0 . 60 dl / g ; lauryl ester end group ; ch 2 cl 2 c 25 30 % ( w / w ) 50 : 50 ; 0 . 61 dl / g ; lauryl ester end group ; ch 2 cl 2 the drug / polymer / solvent mixtures can be poured into either a polytetrafluoroethylene flat mold ( approximately 1 inch × 1 inch × ½ inch deep ) or a 3 inch diameter jar to form a film , for example . the films can be dried either in an fts dura - dry lyophilizer ( kinetic systems , inc ., santa clara , calif .) or in a vacuum oven . films dried under various conditions including variation of maximum vacuum , ambient pressure , elevated temperature , ambient temperature , and drying time can be made . the films can be milled using a 24 - tooth retsch ultra centrifugal mill ( retsch , inc ., newtown , pa .) operating at 14 , 000 rpm . the collection pan is filled with liquid nitrogen prior to milling . the resulting powder , collected from the collection pan , is a flowable product that aids subsequent compaction steps . a portion of the powders produced by milling the films can be retained for analysis at this point . these powders can be retained for comparison with the powders made by the subsequent compacting and re - milling of the film powders described below . a portion of the milled powders can be compacted using a carver model c press ( carver , inc ., wabash , ind .) and either about ¼ inch or about ½ inch cylindrical dies . about 50 to about 300 milligrams of milled powder is filled into the dies and compacted at a machine setting of about 5000 pounds for about 30 seconds at room temperature to form pellets . the compacted matrix is subsequently milled using a 24 - tooth retsch ultra centrifugal mill ( retsch , inc ., newtown , pa .) operating at 14 , 000 rpm . the collection pan is filled with liquid nitrogen prior to milling . the final powder was collected from the collection pan and placed into vials for analysis . the sustained release compositions described herein can also be prepared by any of emulsion , coacervation , and cryogenic microencapsulation techniques . the general process associated with each technique is described below . the coacervation process , also referred to herein as a water - oil - oil ( w / o / o ) process , requires formation of a water - in - oil emulsion with aqueous drug and organic polymer solutions . oil , typically silicone oil , is then added to the water - in - oil emulsion to induce phase separation and to precipitate the polymer . the embryonic microparticles are then quenched in a solvent that removes the oil and polymer solvent . drug is encapsulated in plg polymer using a water - oil - oil ( w / o / o ) emulsion system . the initial embryonic microparticles were formed in a w / o / o inner emulsion step after which they are subjected to coacervation and hardening steps . the microparticles are collected , dried and filled into vials . further details of each step in the complete process are set forth below . a water - in - oil emulsion is created using sonication . the water phase of the emulsion contains dissolved drug and any optional excipients in water . the plg phase contains polymer dissolved in methylene chloride . coacervation is induced by adding silicone oil at a controlled rate to the inner emulsion with agitation , forming embryonic microparticles . the embryonic microparticles formed are relatively soft and require hardening . the embryonic microparticles are added to a heptane / ethanol solvent mixture with gentle agitation . the solvent mixture hardens the embryonic microparticles . after hardening for about one hour at about 3 ° c ., the solvent mixture is decanted and pure heptane is added at 3 ° c . and mixed for about one hour . after the hardening step , the microparticles are transferred and collected on a fine mesh pore - plate inside a drying chamber . a final heptane rinse of the hardening vessel is performed . the microparticles are dried with nitrogen gas over a four - day period with temperature ramping from about 3 ° c . to about 38 ° c . in general , plg is dissolved in methylene chloride . the inner water phase is prepared by dissolving the drug and excipients in water or an aqueous buffer . the aqueous solution is then injected into the polymer solution while probe sonicating . the resultant water / oil emulsion is then added to an emulsion reactor . silicone oil ( 350 centistokes ) is slowly added to the reactor via peristaltic pump with stirring at about 1000 rpm . the mixture is then added to n - heptane . after stirring for about two hours , the microparticles are isolated by filtration and vacuum dried overnight . the emulsion process is also referred to as a water - oil - water ( w / o / w ) process . briefly , an aqueous solution of drug is dispersed in a polymer solution which is then emulsified in an outer aqueous phase ( e . g ., pva ). the microparticles are then hardened in an aqueous quench . in a typical experiment , plg ( 1 . 96 g ) is dissolved in methylene chloride ( 22 . 5 g ) and drug is dissolved in water ( 20 mg drug in 1 . 75 g water ). the drug solution is then drawn up in a syringe and injected into the polymer solution while it is probe sonicated . the resultant w / o emulsion is then quickly added to an emulsion reactor containing 125 g aqueous 5 % polyvinyl alcohol ( pva ). the stir rate of the reactor is set to about 800 rpm . the mixture is stirred for about 1 . 5 minutes and then added to a water quench ( 2 . 8 l at 10 ° c .). after about two hours in the quench , the hardened microparticles are isolated by filtration and vacuum dried overnight . the cryogenic process used atomization to form droplets of polymer solution containing drug . embryonic microparticles are then frozen in liquid nitrogen and the polymer solvent is removed through a subsequent ethanol extraction technique . the cryogenic processing to produce microparticles includes two steps : ( 1 ) the production of a lyophilizate or dried drug substance ; and ( 2 ) microencapsulation of the lyophilizate using a low - temperature , non - aqueous technique . lyophilizates are formulated by atomizing a mixture of drug and excipient using a two - fluid nozzle , freezing the atomized droplets and drying the frozen droplets using lyophilization . it is understood that any suitable methods of drying known in the art can be employed . specifically , frozen droplets are dried for about 7 days at a primary drying condition of − 26 ° c . shelf and 96 mtorr chamber pressure followed by secondary drying for an additional 3 days at about 20 ° c . and 0 mtorr . drug containing microparticles can be produced with the cryogenic , non - aqueous process . drug is suspended in an organic solution consisting of plg dissolved in methylene chloride . this suspension is sonicated for about 4 minutes on ice , and then the suspension is atomized using a sonication nozzle and frozen by contacting with liquid nitrogen layered over a bed of frozen ethanol . the sample is warmed to − 80 ° c . in order to allow microparticle hardening and extraction of solvent . the microparticles are then filtered and dried . solid drug can also be encapsulated using modified versions of the emulsion and coacervation processes described above . these modified processes are referred to solid / oil / water ( s / o / w ) and solid / oil / oil ( s / o / o ). for example , solid drug is suspended in methylene chloride containing plg and sonicated for about four minutes on ice . subsequent processing is conducted in a manner analogous to either the w / o / o or w / o / w methods . examples of specific plg polymers suitable for use are listed below . all of the polymers employed in the following examples are set forth in the list and all listed polymers were purchased from alkermes , inc . and can be described as follows : polymer 2a : poly ( lactide - co - glycolide ); 50 : 50 lactide : glycolide ratio ; 12 . 3 kd mol . wt . ; iv = 0 . 15 ( dl / g ). polymer 2a - 1 : poly ( lactide - co - glycolide ); 65 : 35 lactide : glycolide ratio ; 16 kd mol . wt . ; iv = 0 . 19 ( dl / g ). polymer 2 . 5a : poly ( lactide - co - glycolide ); 50 : 50 lactide : glycolide ratio ; 25 kd mol . wt . ; iv = 0 . 24 ( dl / g ). polymer 3a : poly ( lactide - co - glycolide ); 50 : 50 lactide : glycolide ratio ; 47 kd mol . wt . ; iv = 0 . 38 ( dl / g ). polymer 3 . 5a : poly ( lactide - co - glycolide ); 50 : 50 lactide : glycolide ratio ; mol . wt ., not determined ; iv = 0 . 42 ( dl / g ). polymer 4a : poly ( lactide - co - glycolide ); 50 : 50 lactide : glycolide ratio ; mol . wt . 45 - 64 kd ; iv = 0 . 45 - 0 . 47 ( dl / g ). polymer 4a - 1 : poly ( lactide - co - glycolide ); 65 : 35 lactide : glycolide ratio ; mol . wt . 53 kd ; iv = 0 . 43 ( dl / g ). modifications and variations of the invention will be obvious to those skilled in the art from the foregoing detailed description of the invention . such modifications and variations are intended to come within the scope of the appended claims . all patents , patent application publications and articles cited herein are incorporated by reference in their entirety .
the present invention relates , in part , to the discovery that injectable extended release formulations possess an unexpected advantage in treating patients classified as cyp 2d6 um and / or em . this advantage is particularly beneficial where the metabolite is increasingly water soluble , as compared to the parent drug , and / or possesses a decreased mobility across the blood brain barrier . thus , the invention relates to a method for treating individuals possessing a functional cyp 2d6 gene with an active agent metabolized by cyp 2d6 comprising injecting the active agent in a first extended release formulation in a first administration , and the formulations for use in such methods . the invention further includes a method for preventing adverse drug reactions in individuals possessing a functional cyp 2d6 gene with an active agent metabolized by cyp 2d6 comprising injecting the active agent in a first extended release formulation in a first administration .