US 20100015184Al (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0015184 A1 Tue] (43) Pub. Date: Jan. 21, 2010

(54) METHODS OF MAKING PHARMACEUTICAL Publication Classi?cation COMPONENTS FOR CUSTOMIZED DRUG PRODUCTS (51) Int. Cl. A61K 9/00 (2006.01) (76) Inventor: Stephen M_ Tue], Columbia, SC (52) US. Cl...... 424/400 (Us) (57) ABSTRACT Correspondence Address: Methods and systems for developing and manufacturing STIPKALA LLC componentized drug product precursor modules that can be 5401 NETHERBY LANE, SUITE 102-A simply assembled to create customized drug products are NORTH CHARLESTON, SC 29420 (US) disclosed. Each module contains components of a ?nal drug product (e.g., active pharmaceutical ingredients, nutritional (21) App1_ NO_; 12/518,311 ingredients, and/or excipients) in a ?xed mixture selected to maximize desired pharmaceutical characteristics (e.g., stabil (22) PCT Filed: Dec_ 13, 2007 ity, manufacturing ef?ciency) and minimize cost. The mod ules can be extensively tested for quality and assembled (86) PCT NO _ PCT M52007 I025 43 0 immediately, or at a later time, in multiple combinations to " customize the ?nal drug product characteristics (e.g., mul § 371 (6X1), tiple active ingredients, doses, ?avor, viscosity, etc.) to meet (2)’ (4) Date: Jun 9, 2009 individual patient/consumer needs and/or preferences While assuring high quality. Permitted combinations may be main . . tained in a database to enable networked dru roduct selec Related U's'Apphcatlon Data tion, prescribing, and ordering. Each resulgnrg customized (60) Provisional application No, 60/874,554, ?led on Dec, drug product dose can be labeled to facilitate compliance and 13, 2006. reduce the number of drug products administered per day. Patent Application Publication Jan. 21, 2010 Sheet 1 0f 7 US 2010/0015184 A1 Figure 1 API module dose selection

Search public clinical, medical, and health literature, especially pediatric, geriatric, and metabolic disease areas

De?ned minimum and maximum License or create additional doses, minimum escalation proprietary dose knowledge interval dose

Convert, as necessary, relative doses to absolute doses

Minimum dose is N0 Analysis of clinical use, market ultiple of escalation interv demand, and total dosing range or viceversa V Select greatest common factor or smaller of minimum dose and escalation interval Minimum dose No is greater than escalation interval Select minimum dose Yes as API module close Select escalation interval as API module close I

Broad total dosing range Develop one API module dose

Market and manufacturing analysis » Develop two API module doses Patent Application Publication Jan. 21, 2010 Sheet 2 0f 7 US 2010/0015184 A1

Figure 2 API module excipient selection

N Liquid formulation 0

Available public Available public or proprietary data on API or proprietary data on granul solubility formulation License/create additional formulation knowledge

Add solubilizers, Develop simplified antioxidants, pH modi?ers coated granules; only if absolutely necessary 1 binder i i sustained release characteristics Avoid flavors, sweeteners, colors, or viscosity agents ‘ i Minimize granule size Use aseptic process to avoid antiseptics/preservatives l Minimize liquid volume L i, Goal is minimum number of excipients Patent Application Publication Jan. 21, 2010 Sheet 3 0f 7 US 2010/0015184 A1

Figure 3 Excipient module component selection

Liquid formulation N Yes

N ‘ Taste-masking module 0 Compare volumes of solid dose API Yes module portfolio with Select portfolio of sweet and non- total vom‘mes °f_?na| — sweet ?avors; add sweeteners, other formulat'on opt'ons taste-masking agents as needed ‘ Select limited No number of target Colorant module volumes for ‘filler’ Yes modules _ Develop limited number of color com- ' ‘ ponents with maximum compatibility se|ect physica| components of modules Viscosity module No Yes Develop limited number of viscosity agents with maximum compatibility

Develop limited number of preservative modules with maximum compatibility l Goal is minimum number of excipient modules with maximum flexibility of combinations Patent Application Publication Jan. 21, 2010 Sheet 4 0f 7 US 2010/0015184 A1

Figure 4 Module portfolio management

Potential new API module

No Dose/concentration inside range of existing Yes modules Select dose sqect ——> (see Fig 1) —> exclpients Assess analytical, (see F'Q- 2) formulation, and manufacturing issues

Need for No new excipient module(s Potential new excipient module components alters need for __|

1 Select excipient > module components (see Fig. 3)

No Additional opportunities to use module Change in Y components creates new Reassess market, opportunities business factors l GolNoGo decision Patent Application Publication Jan. 21, 2010 Sheet 5 0f 7 US 2010/0015184 A1

Figure 5 Module selection for final assembly

Select ?rst API module type i Select number of API modules Select next API to provide a'dose based on module type ‘ users physical and clinical measures, age, species/breed, A or other characteristics

Additional API Liquid N0 needed formulation Yes

_ Select compatible Select ?nal Compatible taste-masking product form and AP' module module(s) size, e.g., capsule available + Select compatible V colorant, viscosity, Select number and/or preservative of excipient modules as needed (filler) modules

All needed , modules available Fon/vard need for additional modules to R&D Assemble into ?nal product or package for later assembly Patent Application Publication Jan. 21, 2010 Sheet 6 of7 US 2010/0015184 A1

Figure 6 Final assembly options

API Excipient module module portfolio portfolio

Packaged modules

Modules for ?nal product Delayed Consumer assembly assembly lm mediate assembly Yes

Manual or Manual or automated process automated process l Patent Application Publication Jan. 21, 2010 Sheet 7 of7 US 2010/0015184 A1

Figure 7 Quality control and ordering processes

Public chemical, pharma ceutical, medical, and veterinary information Module design and development Batch manufacturing : ’¥ *b License/create of modules proprietary information Quality and stability testing l Module assembly ‘ Permitted combinations database/ordering application V t Packaging/shipping 4 Internet A A

'’ \ . Physician, veterinarian, or other health professional US 2010/0015184 A1 Jan. 21,2010

METHODS OF MAKING PHARMACEUTICAL [0007] In some embodiments, the present invention COMPONENTS FOR CUSTOMIZED DRUG includes a method and system for developing and manufac PRODUCTS turing componentiZed drug product precursor modules that can be simply assembled to create customiZed drug products. CROSS REFERENCE TO RELATED Some precursor modules of the present system contain tWo or APPLICATIONS more components of a ?nal drug product in a ?xed mixture selected to maximiZe desired pharmaceutical characteristics [0001] This application claims bene?t of priority under and minimize cost. The modules are divided into tWo classes: PCT Chapter I, Article 8, and 35 U.S.C. § 119(e) of US. 1) modules containing an active pharmaceutical ingredient or Provisional Application No. 60/874,554, entitled “Method of speci?c nutritional ingredient (hereafter called API), and 2) Making Pharmaceutical Components for Assembly of Cus modules containing only excipients. tomiZed Drug Products,” ?led on Dec. 13, 2006, Which is incorporated herein by reference. [0008] The modules can be extensively tested for quality and assembled in multiple predetermined combinations, cus tomiZing the ?nal drug product characteristics to meet TECHNICAL FIELD patient/consumer needs and/or preferences While assuring [0002] This invention relates to methods and systems for high quality. Permitted combinations can be maintained in an developing and manufacturing componentiZed drug product Internet-linkable computer database to enable netWorked precursor modules that can be assembled to create custom drug product selection, prescribing, and ordering. The result iZed drug products. ing customiZed drug product can facilitate compliance and reduce the number of drug products administered per day. BACKGROUND ART [0009] Some embodiments of the present invention provide an API module, comprising: at least one excipient in a ?rst [0003] Pharmaceutical products for use in humans or ani ?xed amount, and at least one active pharmaceutical ingredi mals are produced primarily in tWo Ways. High volume or ent in a second ?xed amount of at least a dose escalation high priced drugs are manufactured under very tightly con interval or a fraction thereof. In other embodiments, the sec trolled conditions With detailed speci?cations, quality test ond ?xed amount can be greater than the dose escalation ing, and documentation. Because of the high cost and com interval. In still other embodiments, the second ?xed amount plexity of this type of pharmaceutical manufacturing, loW can be less than a dose of the at least one active pharmaceu volume, highly specialiZed drugs are produced in a cottage tical ingredient. Additional embodiments provide the second industry of compounding pharmacies. These pharmacies mix ?xed amount being less than the minimum dose of the at least various active ingredients and excipients into an often unique one active pharmaceutical ingredient. In yet other embodi product based on a doctor’s prescription. The speci?cations, ments, methods for making at least one API module are quality testing, and documentation are often minimal or non provided. Such methods comprise, in some embodiments, existent. Fully testing these products for quality can be cost isolating a ?rst ?xed amount of a ?rstAPI, combining the ?rst prohibitive because of the small volume. Patients are often ?xed amount of the ?rst API With a second ?xed amount of at forced to choose betWeen the assurance of high quality and least one ?rst excipient, to form the at least one API module. the ?exibility of customiZed products. When patients are unable to obtain high quality customiZed drug products they [0010] Further embodiments provide an excipient module, often demonstrate loWer compliance With the prescribed regi comprising: at least one ?rst excipient in a ?rst ?xed amount; and at least one second excipient in a second ?xed amount; men and can suffer health consequences. Wherein the at least one ?rst excipient and the at least one [0004] Processes of preparation and manufacturing of spe second excipient are compatible With at least one active phar ci?c active ingredients, including the use of speci?c excipi maceutical ingredient. In some embodiments, the sum of the ents in the formulation, are known. These cover only a frac ?rst ?xed amount and the second ?xed amount is su?icient to tion, hoWever, of the millions of possible combinations of form at least one ?nal drug product comprising the at least one active and inactive ingredients Which can address special active pharmaceutical ingredient. In other embodiments, the needs of patient groups. Various compounding machines at least one ?rst excipient and the at least one second excipient related to this area are also knoWn, but these merely automate are compatible With tWo or more active pharmaceutical ingre the traditional process of mixing bulk actives With a series of dients. excipients according to a recipe. They do little to address the quality issues inherent in the compounding of medications. [0011] Still further embodiments provide a ?nal drug prod uct, made by a process comprising: combining at least one [0005] Accordingly, there exists a need for a method and system for developing and manufacturing componentiZed API module comprising at least one active pharmaceutical drug product precursor modules that can be simply assembled ingredient, and at least one excipient module, to make the to create customiZed drug products. ?nal drug product; Wherein the at least one active pharma ceutical ingredient is present in the ?nal drug product in an amount effective for treating at least one disease, at least one DISCLOSURE OF THE INVENTION disorder, at least one condition, or a combination thereof, in at [0006] The folloWing presents a simpli?ed summary of the least one human or animal patient in need thereof. invention in order to provide a basic understanding of some [0012] Yet other embodiments provide a method for manu aspects of the invention. This summary is not an extensive facturing a ?nal drug product, comprising: selecting a ?rst overvieW of the invention. It is not intended to identify key or API module comprising at least one ?rst active pharmaceu critical elements of the invention or to delineate the scope of tical ingredient and at least one ?rst excipient; determining a the invention. Its sole purpose is to present concepts of the number of the ?rst API module; choosing a ?rst excipient invention in a simpli?ed form as a prelude to the more module comprising at least one second excipient; determin detailed description that is presented later. ing a number of the ?rst excipient module; and combining the US 2010/0015184 A1 Jan. 21,2010

number of the ?rst API module and the number of the ?rst nents implementable in a system operable to manufacture at excipient module to manufacture the ?nal drug product. least one ?nal drug product, at least one ?nal drug package, or [0013] Some embodiments of the present invention further both, comprising: a computer-executable component for pro comprise: selecting a second API module comprising at least viding one or more of compatibility information, dose infor one second active pharmaceutical ingredient and at least one mation, and dose escalation interval information for at least third excipient; determining a number of the second API one API module in the API module portfolio. Other embodi module; optionally choosing a second excipient module com ments provide such computer-readable medium as a separate prising at least one fourth excipient, and determining a num embodiment. ber of the second excipient module; and combining the num [0019] Further embodiments provide an excipient module ber of the second API module and optionally the number of portfolio, comprising a plurality of different excipient mod the second excipient module With the number of the ?rst API ules. Such embodiments optionally include one or more com module and the number of the ?rst excipient module to manu puter-executable components for providing compatibility facture the ?nal drug product. information for one or more excipient module in the excipient [0014] Some embodiments of the present invention provide module portfolio. Other embodiments provide such com methods of manufacturing at least one ?nal drug product, at puter-readable medium as a separate embodiment. least one ?nal drug package, or both, implemented by com [0020] Other embodiments provide methods for develop puter-executable instructions stored on one or more com ing anAPI module portfolio. Still other embodiments provide puter-readable media. methods for developing an excipient module portfolio. [0015] Still other embodiments provide a ?nal drug pack [0021] Other features and advantages of the present inven age, comprising: at least one API module, Which comprises at tion Will be apparent to those skilled in the art from a careful least one ?rst excipient, and at least one active pharmaceutical reading of the entire application, including the Modes for ingredient; and at least one excipient module, Which com Carrying Out the Invention presented beloW and accompa prises at least one second excipient; Wherein the at least one nied by the draWings. second excipient is compatible With the at least one active pharmaceutical ingredient; Wherein the at least one active BRIEF DESCRIPTION OF DRAWINGS pharmaceutical ingredient is present in the ?nal drug package [0022] FIG. 1 shoWs a process for selection of an API in an amount effective for treating at least one disease, at least module dose according to one embodiment of the present one disorder, at least one condition, or a combination thereof, invention; in at least one human or animal patient in need thereof; and [0023] FIG. 2 shoWs a process for minimiZing the number Wherein the at least one API module and the at least one of excipients in an API module according to one embodiment excipient module are adapted to form a ?nal drug product. of the present invention; [0016] Some embodiments provide a system for manufac [0024] FIG. 3 shoWs a process for developing a portfolio of, turing at least one ?nal drug product, at least one ?nal drug and selecting the components in, modules not containing an package, or both, comprising: at least one API module port API according to one embodiment of the present invention; folio comprising a plurality of different API modules; and at [0025] FIG. 4 shoWs a process for managing the portfolio of least one excipient module portfolio comprising a plurality of modules according to one embodiment of the present inven different excipient modules; Wherein the at least one API tion; module portfolio and the at least one excipient module port [0026] FIG. 5 shoWs a process for selecting modules for folio are operatively connected to manufacture the at least one ?nal drug assembly according to one embodiment of the ?nal drug product, the at least one ?nal drug package, orboth. present invention; Other embodiments further comprise one or more means for [0027] FIG. 6 shoWs a process including alternative steps storing compatibility information for each API module and for assembling modules for the ?nal drug product according each excipient module. to one embodiment of the present invention; [0017] Additional embodiments provide a computer-read [0028] FIG. 7 shoWs a method for controlling quality, able medium having computer executable components including assessing compatibility and permissible combina implementable in a system operable to manufacture at least tions of modules, and ordering processes according to one one ?nal drug product, at least one ?nal drug package, or embodiment of the present invention. both, comprising: a computer-executable component for pro viding one or more of compatibility information, dose infor MODES FOR CARRYING OUT THE INVENTION mation, and dose escalation interval information for at least one API module in an API module portfolio; and a computer [0029] “API module” indicates an isolated ?rst ?xed executable component for providing compatibility informa amount of at least one active pharmaceutical ingredient tion for at least one excipient module in an excipient module together With a second ?xed amount of at least one excipient. portfolio. In some embodiments, compatibility information In certain embodiments, the at least one excipient is compat for anAPI module indicates compatibility With one or more of ible With the at least one API. The API module may be other APIs, other API modules, excipients, and excipient enclosed in any suitable container, for example, so that the modules. In still other embodiments, compatibility informa module may be stored for a period of time before being tion for an excipient module indicates compatibility With one combined With one or more other modules to form a ?nal drug or more of APIs, API modules, other excipients, and other product. Suitable containers include, but are not limited to, excipient modules. vials, ampules, capsules, pipettes, packets such as foil pack [0018] Still other embodiments provide an API module ets, bubble packets, and the like; and those containers may be portfolio, comprising a plurality of different API modules. Water soluble, soluble in another solvent, insoluble, biode Such embodiments optionally include a computer-readable gradable, edible, recyclable, reusable, steriliZable, dispos medium having one or more computer executable compo able, or combinations thereof. Such containers can be made US 2010/0015184 A1 Jan. 21,2010

of any suitable material, such as, for example, glass, metal, excipient in a second ?xed amount effective to carry, solubi ceramic, polymer, paper, cardboard, and combinations liZe, suspend, bind, and/or stabiliZe the ?rst excipient in the thereof. In some embodiments, anAPI module is not enclosed ?rst ?xed amount. Excipient modules may contain tWo or in a container; in such embodiments, theAPI module could be more excipients for any suitable purpose in any suitable in the form of a pill, pellet, froZen pellet, single granule, or the amounts. In some embodiments, those suitable amounts do like. The ?rst ?xed amount of the at least one API in an API not exceed amounts needed to form the maximum dose of an module is any suitable amount, and is knoWn or is determin API, or the maximum safe amount of anAPI in administrable able. In some embodiments, the ?rst ?xed amount is equal to form. In other embodiments, those suitable amounts are frac the dose escalation interval for the API, the minimum dose for tions of the amounts su?icient to carry, solubiliZe, suspend, the API, or both When those amounts are equal. In other bind, and/ or stabiliZe a dose of anAPI, and/or impart at least one characteristic to a ?nal drug product. Those suitable embodiments, the ?rst ?xed amount is a fraction of the dose escalation interval or the minimum dose. In still other amounts can be chosen from amounts suitable for a minimum embodiments, the ?rst ?xed amount is an amount other than dose of an API, a dose escalation interval for an API, or a the dose escalation interval, the minimum dose, or a fraction fraction of either of the foregoing, in some embodiments. thereof. For example, the ?rst ?xed amount could be a mul [0031] “API module portfolio” refers to a plurality of dif tiple of the minimum dose or the dose escalation interval, or ferent API modules. In some embodiments, information it could be any other suitable amount. In some embodiments, about one or more API modules is available for the API the ?rst ?xed amount does not exceed the maximum dose of module portfolio. Such information includes any suitable the API. In other embodiments, the ?rst ?xed amount does not information, and may comprise one or more of identity, exceed the maximum safe amount of the API. In still other amount, co-API compatibility, excipient compatibility, co embodiments, the ?rst ?xed amount does not exceed about medication compatibility (for APIs administered separately), 80%, about 50%, about 25%, or about 10% of the minimum allergy and adverse drug reaction information, minimum dose of the API. The second ?xed amount of the at least one dose, dose escalation interval, dosing schedule, and maxi excipient is any suitable amount. In some embodiments, the mum dose for each API in each API module. second ?xed amount is an amount suf?cient to carry, solubi [0032] “Excipient module portfolio” indicates a plurality liZe, suspend, bind, and/or stabiliZe the ?rst ?xed amount of of different excipient modules. In some embodiments, infor the at least one API, and/or impart at least one characteristic mation about one or more excipient modules is available for to a ?nal drug product. In still other embodiments, an API the excipient module portfolio. Such information includes module optionally contains at least one second API in a third any suitable information, and may comprise one or more of ?xed amount. In further embodiments, an API module con identity, amount, API compatibility, co-excipient compatibil tains at least one second excipient in a fourth ?xed amount. ity, allergy information, minimum effective excipient The concept of the ?xed amount alloWs for degradation of a amounts, maximum recommended excipient amounts, dos given ingredient that may occur over time in some embodi age form information, timed-release information, and the like ments. for each excipient in each excipient module in the portfolio. [0030] “Excipient module” indicates an isolated ?rst ?xed [0033] “Final drug package” means a collection of one or amount of at least one excipient. The ?rst ?xed amount can be more API modules and one or more excipient modules su?i any suitable amount. In some embodiments, the ?rst ?xed cient to formulate a ?nal drug product. In some embodiments, amount is knoWn or is determinable. In other embodiments, a ?nal drug package is adapted to be provided to a treating the ?rst ?xed amount is a su?icient amount, that is, an amount medical professional and/or a patient so the professional or suf?cient to carry, solubiliZe, suspend, bind, and/or stabiliZe a patient can formulate the ?nal drug product. In further given amount of at least one API and/or at least one other embodiments, a ?nal drug package is su?icient to formulate a excipient, and/or impart at least one characteristic to a ?nal single dose. In still further embodiments, a ?nal drug package drug product. The excipient module can comprise a container, is suf?cient to independently formulate more than one single in some embodiments, such as those containers described for dose. For example, a ?nal drug package in some embodi API modules. In other embodiments, an excipient module ments contains enough modules and optionally instructions comprises a ?rst ?xed amount of a ?rst excipient, and a to formulate a month’s Worth of daily single doses. A ?nal second ?xed amount of a second excipient. The ?rst ?xed drug package, in certain embodiments, is not in a form amount and the second ?xed amount are, independently, any intended for administration directly to the patient. suitable amounts. In some embodiments, the ?rst ?xed [0034] “Final drug product” means, in some embodiments, amount and the second ?xed amount together are su?icient to a combination of the contents of at least one API module and carry, solubiliZe, suspend, bind, and/or stabiliZe a given at least one excipient module in a form that can be adminis amount of anAPI, and/or impart at least one characteristic to tered to a human or animal patient. In some embodiments, a a ?nal drug product. In other embodiments, the ?rst ?xed ?nal drug product contains one dose of at least one API, and amount and the second ?xed amount together are su?icient to a suf?cient amount of at least one excipient. In other embodi carry, solubiliZe, suspend, bind, and/or stabiliZe various ments, a ?nal drug product comprises the contents of at least amounts of more than one API, and/or impart at least one one API module and tWo or more alike or different excipient characteristic to a ?nal drug product. In still other embodi modules. In still other embodiments, a ?nal drug product ments, the ?rst ?xed amount is su?icient to carry, solubiliZe, comprises the contents of tWo or more alike or different API suspend, bind, and/or stabiliZe a given amount of a ?rst API, modules and tWo or more alike or different excipient mod While the second ?xed amount is su?icient to carry, solubi ules. liZe, suspend, bind, and/or stabiliZe another given amount of [0035] In those embodiments in Which “the excipients are a secondAPI. In still other embodiments, an excipient module the same or different,” that means, for example, that a ?rst comprises a ?rst excipient in a ?rst ?xed amount effective to excipient can be the same as, or different from, a second impart a characteristic to a ?nal drug product, and a second excipient. If there are more than tWo excipients, any one US 2010/0015184 A1 Jan. 21,2010

excipient may be the same as or different from any other grams per kilogram or square meter respectively. In these excipient. For example, a ?rst excipient may be the same as a cases, the dose recommendation must be converted into an second excipient, both of Which differ from a third excipient. absolute measure by evaluating the applicable characteristic Alternatively, all three excipients in the previous example can of the patient population using the particular API. For differ from each other. The amount of any excipient in one example, anAPI given to adolescents for hormonal regulation module is independent of Whether the excipient is the same as during puberty is unlikely to be used in a patient Weighing less or different from any other excipient in another module. than 30 kg. If the relative minimum dose is 8 mg/kg and the [0036] “Combining the number” of modules refers to com dose escalation interval is 2 mg/kg, then the absolute mini bining the contents of the modules, Which are present in any mum dose Would be 240 mg and the dose escalation interval suitable number, in any suitable manner. The modules could Would be 60 mg. An API With identical relative dose recom be mixed together, and their biodegradable or edible contain mendations (8 mg/kg and 2 mg/kg respectively) that is used ers are mixed in With the contents of the modules, in some for life support in premature infants (Who can Weight only embodiments. In other embodiments, the contents of the hundreds of grams) Would have much smaller absolute dose modules are removed from the containers and mixed together. recommendations at 4 mg and 1 mg for the minimum and In certain embodiments, the contents of the modules are escalation interval respectively. In some embodiments, a quantitatively transferred for mixing. In still other embodi “dose” is an amount of an API effective for treating at least ments, the contents of some modules could be added to the one disease, at least one disorder, at least one condition, or a contents of other modules, in the containers of those other combination thereof. In other embodiments, a “dose” is an modules. established amount of an API, such as, for example, a recom [0037] “Manufacture” can indicate any suitable steps for mended daily alloWance. making an article. Manufacturing can take place in a factory, [0041] Once absolute minimum and maximum dose, and in a specially-adapted apparatus such as a kiosk, a portable minimum dose escalation interval are established, the dose of kit, and a machine, and in a patient’s home. For example, a the API Within the module is selected. In some embodiments, patient can manufacture a ?nal drug product from a ?nal drug the minimum dose is either equal to, or is a Whole number package by combining a number of alike or different API multiple of, the dose escalation interval, e.g., for a dose esca modules and a number of alike or different excipient modules lation interval of 5 mg, the minimum dose is usually 5 mg, or to form the ?nal drug product. 10 mg, or 15 mg, etc. Also, in some cases, the minimum [0038] The present invention provides, in some embodi escalation interval is less than the minimum dose and all ments, a method and system for developing and manufactur generally prescribed doses Will be a Whole number multiple ing componentiZed drug product precursor modules. The of the dose escalation interval. Thus, in some API modules, modules are divided into tWo classes: 1) modules containing the dose in a single module is equal to the minimum dose an active pharmaceutical ingredient or speci?c nutritional escalation interval. ingredient (API), and 2) modules containing only excipients. [0042] In the event that the dose escalation interval is The development process differs for each class. greater than the minimum recommended dose, the minimum recommended dose may be selected for the dose Within the Modules Containing an API API module if the dose escalation interval is a Whole number [0039] Some issues that govern the development of mod multiple of that minimum dose (e. g., for a minimum dose of ules that contain an API include selecting the dose and mini 10 mg, and a dose escalation interval of 20 mg, or 30 mg, etc.). miZing the number of excipients. FIG. 1 illustrates and sum [0043] Another potential circumstance is Where the mini mariZes the process of selecting the dose of an API in the mum dose is not a Whole number multiple of the dose esca module, in one embodiment of the invention. One possible lation interval, e.g., a minimum dose of 5 mg With a dose step in determining the dose of anAPI module is to assess the escalation interval of 2 mg. In this case a judgment must be range of doses prescribed and/or used for that particular API. made Whether to use the greatest common factor of the mini Drug formularies and FDA records may provide information mum dose and escalation interval (e.g., 1 mg in the previous on currently manufactured APIs, in some embodiments. In example), or to proceed With the smaller of the minimum dose other embodiments, recommended minimum and maximum and escalation interval (2 mg in the previous example) and doses, and minimum dose escalation intervals, can be deter force prescribing clinicians and/or consumers to choose mined through a detailed assessment of the clinical, medical, betWeen a dose someWhat higher or loWer than the recom and health literature by methods knoWn in the art. Searches mended minimum (e.g., 4 mg or 6 mg in the previous need not be limited to speci?c diseases, conditions, or indi example), or to choose another amount. This decision may cations, but may include all potential uses, both regulatory rely on a broad analysis of clinical usage (e.g., physicians approved and unapproved. Searches for minimum dose and may prefer the someWhat loWer minimum dose), market dose escalation interval may focus on literature discussing demand (e.g., the percentage of patients actually using the pediatric, geriatric, and metabolic disease (e.g., hepatic insuf minimum dose may be insigni?cant; in the previous example ?ciency) because these populations are often more fragile and every patient may be receiving 10 mg or above), and total require greater accuracy in dosing. In cases Where the public dosing range (i.e., smaller modular dose is more practical for literature is insu?icient, it may be necessary to license or a narroW total range, as Will be discussed beloW). otherWise obtain existing proprietary knoWledge or to create [0044] Another API dose selection decision is Whether to proprietary knoWledge through clinical trial methods knoWn develop an additional dose module, such as, for example, an in the art. API module having a higher dose of the API. In drugs With a [0040] Dose recommendations are often given in terms broad total range (maximum dose minus minimum dose), the relative to patient characteristics, especially in pediatric maximum dose can be a very large multiple of the minimum patients, e.g., a dose may be relative to the patient’s Weight or dose or escalation interval. This can require a large number of body surface area and recommended as a number of milli API modules, e.g., a drug With a minimum dose/escalation US 2010/0015184 A1 Jan. 21,2010

interval of 5 mg, yielding anAPI module dose of 5 mg, Would lites, stereoisomers, enantiomers, diastereomers, salts, sol require 100 modules to reach a maximum dose of 500 mg. For vates, hydrates, complexes, polymorphs, crystals, co-crys some embodiments, a large number of API modules may be tals, and other chemical- and physical derivatives of considered inconvenient. In these cases one or more higher pharmacologically-active substances. dose modules can be developed. The exact dose multiple of [0048] Moreover, it is understood that some substances the initial module may depend on market and manufacturing may be considered active, and may also ?nd use as an excipi analysis, but a 10x multiple is a useful default option for some ent. For example, certain antibiotics could be useful as APIs embodiments. in some embodiments of the present invention, While they [0045] FIG. 2 summarizes the process of minimizing the also could ?nduse as preservative excipients in other embodi number of excipients in an API module, in one embodiment. ments of the present invention. Indeed, some ingredients After the dose of an API module has been selected, the next could function simultaneously as both APIs and excipients. step can be to choose one or more additional components to For further examples, alcohol and mineral oil can be used as carry and stabilize the active ingredient Within the module. APIs or as excipients. One of ordinary skill in the art Will For some embodiments such as solid formulations, this may appreciate that describing a substance as a member of one be a relatively straightforward process of encapsulating very class (e. g., API) does not preclude using that substance in the small amounts of the API, With or Without a binder, in a other class (e. g., excipient), and vice versa. Water-soluble coating, With or Without sustained release char [0049] Active pharmaceutical ingredients suitable for API acteristics, using methods knoWn in the art to create granules modules include, but are not limited to, analgesics and muscle such as those used to ?ll capsules. The granule size may be relaxants, anesthetics and surgical adjuvants, antibiotics, minimized to permit the greatest number of potential combi antidiabetic agents, antifungal agents, antihistamines, anti nations during ?nal assembly of the ?nal drug product. in?ammatory agents, antimicrobial agents, antiparasitic [0046] For some embodiments comprising liquid formula agents, antivirals, biological and cellular agents, bone disease tions, the process may start With the selection of a solvent or agents, botanicals, cardiovascular agents, dermatologic suspending agent to create a liquid. A liquid formulation may agents, diuretics, gastrointestinal agents, hematologic and be in any suitable form, such as solution, suspension, slurry, oncologic agents, hormones, minerals, neuromodulators, or the like. Some liquid formulation API modules of the nutraceuticals, obstetric and fertility agents, opthalmologic present invention provide formulary simplicity. In certain agents, proteins, enzymes and enzyme inhibitors, respiratory embodiments, an API module has only an active ingredient agents, rheumatologic agents, steroids, urological agents, and a solvent; Whenever possible additional excipients may vitamins, and other agents. be avoided. Antioxidants, acidi?ers, alkalinizers, and buffers [0050] Suitable analgesics and muscle relaxants include, may be required, but for an API module, no ?avors, sWeeten but are not limited to, acetaminophen, alfentanil, almotriptan, ers or taste-masking agents, colors, or viscosity agents are aspirin, bromfenac, buprenorphine, butalbital, butorphanol, needed in some embodiments. Preservatives and antiseptics carisoprodol, chlorzoxazone, codeine, cyclobenzaprine, dan are permitted, but can be avoided by using an aseptic manu trolene, dihydrocodeine, dihydroergotamine, eletriptan, facturing process. Minimizing the number of excipients may ergotamine, fentanyl, frovatriptan, hydrocodone, hydromor simplify analytic method development and manufacturing phone, levorphanol, meclofenamate, meprobamate, meperi development and expense, and likely promotes a more stable dine, metaxalone, methadone, methocarbamol, morphine, formulation. Based on these and/or other considerations, the nabilone, nalbuphine, naratriptan, pentazocine, formula is developed by methods knoWn in the art. The vol orphenadrine, oxycodone, oxymorphone, propoxyphene, ume of liquid can be minimized to permit the greatest number remifentanil, rizatriptan, sufentanil, sumatriptan, tramadol, of potential combinations during assembly of the ?nal drug ziconotide, and zolmitriptan. product. [0051] Suitable anesthetics and surgical adjuvants include, [0047] APIs may be chosen from any suitable active phar but are not limited to, articaine, atracurium, benzocaine, bupi maceutical ingredient. As used herein, “active pharmaceuti vacaine, chloroprocaine, cisatracurium, des?urane, dexme cal ingredient” refers very broadly to any substance that may detomidine, dibucaine, en?urane, etomidate, glycopyrrolate, have pharmaceutical, nutritional, nutraceutical, or other iso?urane, ketamine, lidocaine, mepivacaine, metaraminol, activity in a human or animal body. Such substances need not methohexital, midazolam, pancuronium, prilocalne, require formal government approval, such as FDA approval. procaine, proparacaine, propofol, rocuronium, ropivacaine, Substances that can be sold as dietary supplements, such as sevo?urane, succinylcholine, tetracaine, and vecuronium. vitamins, minerals, botanicals, and the like are speci?cally [0052] Suitable antibiotics include, but are not limited to, included Within the scope of APIs. In some embodiments, an acetohydroxamic acid, amikacin, aminosalicylic acid, amox active pharmaceutical ingredient is any component of a ?nal icillin, ampicillin, azithromycin, aztreonam, bacitracin, bleo drug product intended to furnish pharmacological activity or mycin, capreomycin, carbenicillin, cefaclor, cefadroxil, cefa other direct effect in the diagnosis, cure, mitigation, treat zolin, cefdinir, cefditoren, cefepime, ce?xime, cefoperazone, ment, or prevention of disease, or to affect the structure or any cefotaxime, cefotetan, cefoxitin, cefpodoxime, cefprozil, function of the body of humans or other animals. Active ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, pharmaceutical ingredients include those components of the cefuroxime, cephalexin, chloramphenicol, cipro?oxacin, ?nal drug product that may undergo chemical change during clarithromycin, clindamycin, cloxacillin, colistin, cyclos the manufacture of the ?nal drug product and be present in the erine, dapsone, daptomycin, demeclocycline, dicloxacillin, ?nal drug product in a modi?ed form intended to fumish the doripenem, doxycycline, ertapenem, erythromycin, etham speci?ed activity or effect. In some embodiments, active butol, ethionamide, fosfomycin, gemi?oxacin, gentamicin, pharmaceutical ingredients include sub stances that affect the gramicidin, imipenem, isoniazid, kanamycin, levo?oxacin, general health and/or aging of one or more body systems. lincomycin, linezolid, lome?oxacin, mafenide, meropenem, Active pharmaceutical ingredients include prodrugs, metabo methenamine, minocycline, moxi?oxacin, mupirocin, nafcil US 2010/0015184 A1 Jan. 21,2010

lin, nalidixic acid, neomycin, nitrofurantoin, nitrofuraZone, [0061] Suitable bone disease agents include, but are not nor?oxacin, o?oxacin, oxacillin, oxytetracycline, penicillin, limited to, alendronate, calcitonin, etidronate, ibandronate, piperacillin, polymyxin B, pyraZinamide, retapamulin, pamidronate, raloxifene, risedronate, tiludronate, and Zoledr rifabutin, rifampin, rifapentin, rifaximin, spectinomycin, onate. streptomycin, sulbactam, sulfacetamide, sulfadiaZine, sul [0062] Suitable botanicals include, but are not limited to, famethoxaZole, sulfanilamide, sul?soxaZole, telithromycin, agrimony, alfalfa, algae (red, broWn, and green), aloe vera, tetracycline, ticarcillin, tigecycline, tobramycin, trimethop anise, apple, ashWagandha, astragalus, barberry, barley, basil, rim, and vancomycin. bilberry, blackberry, black cohosh, black currant, black haW, [0053] Suitable antidiabetic agents include, but are not lim black Walnut, bloodroot, boneset, borage, bosWellia, broom, ited to, acarbose, acetohexamide, chlorpropamide, exenatide, brussel sprouts, bugleWeed, burdock, butcher’s broom, cab glimepiride, glipiZide, glyburide, insulin, levocamitine, mef bage, calendula, camphor, cantaloupe, capsicum, caraWay, formin, miglitol, nateglinide, pioglitaZone, pramlintide, repa cardamom, cascara sagrada, catnip, cat’s claW, cayenne, cel glinide, rosiglitaZone, sitagliptin, thiaZolidinedione, tolaZa ery, chamomile, chaste berry, chicory, Chinese cucumber, mide, and tolbutamide. choke cherry, cinnamon, cleavers, cloves, cocoa, coltsfoot, [0054] Suitable antifungal agents include, but are not lim comfrey, coriander, cramp bark, cranberry, dandelion, devil’s ited to, amphotericin B, anidulafungin, butena?ne, butocona claW, dill, dong quai, echinacea, elder, eucalyptus, evening Zole, caspofungin, ciclopirox, clioquinol, clotrimaZole, primrose, fennel, fenugreek, feverfeW, ?ax, ?g, garlic, gen econaZole, ?uconaZole, ?ucytosine, griseofulvin, itracona tian, ginger, ginkgo, ginseng, goldenrod, goldenseal, gotu Zole, ketoconaZole, metronidaZole, micafungin, miconaZole, kola, grape seed, grapefruit, guarana, guggul, haWthom, nafti?ne, natamycin, nystatin, oxiconaZole, posaconaZole, hops, horehound, horse chestnut, horseradish, horsetail, hys sertaconaZole, sulconaZole, terbina?ne, terconaZole, tiocona sop, Iceland moss, ipecac, jasmine, jojoba, kava, kelp, kom Zole, and voriconaZole. bucha mushroom, lady’s mantle, lavender, legumes, lemon, [0055] Suitable antihistamines include, but are not limited lemonbalm, licorice, lime, lovage, mango, marijuana, marsh to, acrivastine, antaZoline, aZelastine, bromaZine, bromphe malloW, meadoWsWeet, milk thistle, mint, motherWort, mul niramine, carbinoxamine, cetiriZine, chlorpheniramine, lein, mustard, myrrh, nettle, oak, oat bran, olive, onion, clemastine, cromolyn, cyproheptadine, desloratadine, dex orange, oregano, papaya, parsley, passion?oWer, pear, pep brompheniramine, dexchlorpheniramine, dimenhydrinate, permint, pineapple, plum, pomegranate, poppy, pumpkin diphenhydramine, doxylamine, emedastine, epinastine, etha seed, raspberry (red and black), red clover, red rice yeast, nolamine, fexofenadine, hydroxyzine, ketotifen, levocetiriz rose, rosemary, saf?oWer, sage, St. John’s Wort, savory, saW ine, loratadine, mecliZine, olopatadine, pheniramine, promet palmetto, seneca root, senna, sesame, slippery elm, soapWort, haZine, and triprolidine. star anise, straWberry, tea tree, thyme, tomato, turmeric, uva ursi, valerian, vervain, White WilloW, Wild yam, Wintergreen, [0056] Suitable anti-in?ammatory agents include, but are Witch haZel, yarroW, yelloW dock, and the extracts of any of not limited to, amlexanox, celecoxib, clofaZimine, the foregoing. diclofenac, di?unisal, dimethyl sulfoxide, etodolac, fenopro fen, ?urbiprofen, hydrocortisone, ibuprofen, indomethacin, [0063] Suitable cardiovascular agents include, but are not ketoprofen, ketorolac, mefenamic acid, meloxicam, nabume limited to, acebutolol, aliskiren, ambrisentan, amiodarone, tone, naproxen, nepafenac, oxaproZin, piroxicam, sulindac, amlodipine, aprotinin, atenolol, atorvastatin, benaZepril, tolmetin, and tromethamine. betaxolol, bisoprolol, bosentan, bretylium, candesartan, cap topril, carteolol, carvedilol, cilostaZol, clo?brate, clonidine, [0057] Suitable antimicrobial agents include, but are not clopidogrel, diaZoxide, digoxin, diltiaZem, dipyridamole, limited to, benZalkonium, benZethonium, chlorhexidine, disopyramide, dobutamine, dofetilide, doxaZosin, enalapril, chloroxylenol, hexachlorophene, malathion, resorcinol, enalaprilat, epinephrine, eplerenone, epoprostenol, eprosar thimerosal, triclocarban, and triclosan. tan, epti?batide, esmolol, eZetimibe, felodipine, feno?brate, [0058] Suitable antiparasitic agents include, but are not fenoldopam, ?ecainide, ?uvastatin, fosinopril, gem?broZil, limited to, albendaZole, atovaquone, chloroquine, diatriZoate, guanabenZ, guanfacine, hydralaZine, ibutilide, iloprost, e?ornithine, hydroxychloroquine, iodoquinol, ivermectin, inamrinone, irbesartan, isoetharine, isoproterenol, isosor lindane, mebendaZole, me?oquine, metronidaZole, nitaZox bide, isradipine, labetalol, levobunolol, lisinopril, losartan, anide, paromomycin, pentamidine, permethrin, piperonyl lovastatin, mecamylamine, methyclothiaZide, methyldopa, butoxide, praZiquantel, primaquine, proguanil, metoprolol, metyrosine, mexiletine, midodrine, milrinone, pyrimethamine, and tinidaZole. minoxidil, moexipril, nadolol, naphaZoline, nesiritide, nicar [0059] Suitable antivirals include, but are not limited to, dipine, nifedipine, nimodipine, nisoldipine, nitroglycerin, abacavir, acyclovir, adefovir, amantadine, amprenavir, ataZa norepinephrine, olmesartan, penbutolol, pentoxifylline, per navir, cidofovir, darunavir, delavirdine, didanosine, indopril, phenoxybenZamine, phentolamine, pindolol, pra docosanol, efavirenZ, emtricitabine, enfuvirtide, entecavir, Zosin, pravastatin, procainamide, propafenone, propranolol, famciclovir, fosamprenavir, foscarnet, ganciclovir, idoxuri quinapril, quinidine, ramipril, ranolaZine, rescinnamine, dine, indinavir, lamivudine, lopinavir, maraviroc, nel?navir, reserpine, rosuvastatin, sildena?l, simvastatin, sotalol, tad nevirapine, oseltamivir, penciclovir, raltegravir, ribavirin, ala?l, telmisartan, tetrahydroZoline, ticlopidine, tiro?ban, rimantadine, ritonavir, saquinavir, stavudine, telbivudine, trandolapril, trepostinil, valsartan, vardena?l, verapamil, and tenofovir, thiabendaZole, tipranavir, tri?uridine, valaciclovir, xylometaZoline. valganciclovir, Zalcitabine, Zanamivir, and Zidovudine. [0064] Suitable dermatologic agents include, but are not [0060] Suitable biological and cellular agents include, but limited to, acitretin, adapalene, alitretinoin, allantoin, alpha are not limited to, antibodies, antigens, bacteria, cell frag hydroxy acid, anthralin, avobenZone, aZelaic acid, bento ments, DNA, molds, phages, polynucleotides, polypeptides, quatam, benZoyl peroxide, calcipotriene, clobetasol, crotami RNA, stem cells, viruses, Whole cells, and yeasts. ton, desonide, desoximetasone, dioxybenZone, ecamsule, US 2010/0015184 A1 Jan. 21,2010

?uocinonide, ?urandrenolide, halcinonide, hydroquinone, sodium, sulfur, Zinc, and the Various salts thereof, including isotretinoin, mequinol, methoxsalen, methyl aminolevuli metal salts, halide salts, organic acid salts, alkoxide salts, nate, monobenZone, octinoxate, octocrylene, oXybenZone, carboxylate salts, ammonium salts, and the like. pimecrolimus, pramoxine, prednicarbate, sinecatechins, taZ [0070] Suitable neuromodulators include, but are not lim arotene, titanium dioxide, tretinoin, and Zinc oxide. ited to, acamprosate, acetylcholine, alpraZolam, [0065] Suitable diuretics include, but are not limited to, ambenonium, amitriptyline, amoxapine, amphetamine, apo acetaZolamide, amiloride, bendro?umethiaZide, bumetanide, morphine, aripipraZole, armoda?nil, atomoxetine, baclofen, chlorothiaZide, chlorthalidone, ethacrynate, furosemide, benZphetamine, benZtropine, biperiden, bromocriptine, hydrochlorothiaZide, hydro?umethiaZide, indapamide, met bupropion, buspirone, butabarbital, cabergoline, caffeine, haZolamide, metolaZone, polythiaZide, spironolactone, carbamaZepine, carbidopa, cevimeline, chlordiaZepoXide, torsemide, and triamterene. chlorpromaZine, citalopram, clomipramine, clonaZepam, [0066] Suitable gastrointestinal agents include, but are not limited to, alosetron, aluminum hydroxide, aprepitant, bal cloraZepate, cloZapine, desipramine, dextromethorphan, salaZide, bisacodyl, bismuth subsalicylate, cholestyramine, dexmethylphenidate, dextroamphetamine, diaZepam, dieth cimetidine, colesevelam, colestipol, dicyclomine, difenoxin, ylpropion, divalproex, donepeZil, doxepin, droperidol, dulox diphenoxylate, dronabinol, esomepraZole, famotidine, lactu etine, edrophonium, ergoloid, escitalopram, estaZolam, lose, lansopraZole, loperamide, lubiprostone, mepenZolate, esZopiclone, ethosuximide, ethotoin, felbamate, ?umaZenil, mesalamine, methscopolamine, metoclopramide, misopros ?uoxetine, ?uphenaZine, ?uraZepam, fo sphenytoin, gabapen tol, niZatadine, olsalaZine, omepraZole, ondansetron, orlistat, tin, galantamine, haloperidol, imipramine, isocarboxaZid, pantopraZole, rabepraZole, ranitidine, scopolamine, simethi lamotrigine, levetiracetam, levodopa, lisdexamfetamine, cone, sincalide, sucralfate, sulfasalaZine, trimethobenZa lithium, loraZepam, loxapine, maprotiline, memantine, mep mide, and ursodiol. robamate, methamphetamine, methsuximide, methylpheni [0067] Suitable hematologic and oncologic agents include, date, mirtaZapine, moda?nil, molindone, nalmefene, nalox but are not limited to, altretamine, amifostine, aminoglute one, naltrexone, nefaZodone, nortriptyline, olanZapine, thimide, aminolevulinic acid, anagrelide, anastroZole, arga oXaZepam, oXcarbaZepine, paliperidone, paroxetine, pento troban, aZacytidine, bexarotene, bicalutamide, bivalirudin, barbital, perphenaZine, phendimetraZine, phenelZine, phe borteZomib, busulfan, capecitabine, carboplatin, carmustine, nobarbital, phentermine, phenyloin, pimoZide, pralidoxime, cetrorelix, chlorambucil, cisplatin, cladribine, clofarabine, pramipexole, pregabalin, primidone, prochlorperaZine, pro cyclophosphamide, cyclosporine, cytarabine, dacarbaZine, cyclidine, protriptyline, pyridostigmine, quaZepam, quetiap dactinomycin, dalfopristin, dalteparin, dasatinib, daunorubi ine, ramelteon, rasagline, riluZole, risperidone, rivastigmine, cin, decitabine, deferasirox, deferoxamine, desirudin, dexra ropinirole, rotigotine, secobarbital, selegiline, sertraline, ZoXane, docetaxel, dolasetron, doxorubicin, enoxaparin, epi sibutramine, tacrine, temaZepam, thioridaZine, thiothixene, rubicin, erlotinib, estramustine, etoposide, exemestane, tiagabine, tiZanidine, topiramate, tranylcypromine, traZ ?oxuridine, ?udarabine, ?uorouracil, ?utamide, fonda odone, triaZolam, tri?uoperaZine, trihexyphenidyl, tri parinux, fulvestrant, ge?tinib, gemcitabine, gemtuZumab, methadione, trimipramine, Valproate, Varenicline, venlafax granisetron, heparin, hydroxyurea, idarubicin, ifosfamide, ine, Zaleplon, Ziprasidone, Zolpidem, and Zonisamide. imatinib, imiquimod, irinotecan, ixabepilone, lapatinib, lena [0071] Suitable nutraceuticals include, but are not limited lidomide, lepirudin, letroZole, leucovorin, mechlorethamine, to, 5-hydroxytryptophan, acidophilus, alpha-linolenic acid, megestrol, melphalan, mercaptopurine, mesna, methotrexate, bee pollen, benecol, beta-carotene, beta glucan, breWer’s mitomycin, mitotane, mitoxantrone, mycophenolate, nelara yeast, bromelain, carnitine, catalase, catechins, chalcones, bine, nilotinib, nilutamide, oxaliplatin, paclitaxel, pal chlorophyll, cholestin, choline, chondroitin, coenZyme Q10, onosetron, pemetrexed, pentostatin, plicamycin, podo?lox, creatine, dehydroepiandrosterone (DHEA), daidZein, dim procarbaZine, protamine, quinupristin, sirolimus, sorafenib, ethyl sulfoxide (DMSO), docosahexanoic acid, eicosapen streptoZotocin, sunitinib, tacrolimus, tamoxifen, temoZolo taenoic acid, ?avonoids, genistein, glucomannan, glu mide, temsirolimus, teniposide, thalidomide, thioguanine, cosamine, glutamine, glycosides, hesperidin, iso?avones, thiotepa, tinZaparin, topotecan, toremifene, tranexamic acid, L-arginine, lactoferrin, lecithin, linoleic acid, lipoic acid, urokinase, Valrubicin, Vinblastine, Vincristine, Vinorelbine, malvin, melatonin, methylsulfonylmethane (MSM), narin Vorinostat, and Warfarin. gin, palmitate, para-aminobenZoic acid, phenylalanine, phos [0068] Suitable hormones include, but are not limited to, phatidylserine, phytoestrogens, polyphenols, psyllium, chorionic gonadotropin, conivaptan, corticorelin, corticotro proanthocyanidins, pycnogenol, quercetin, resveratrol, rutin, pin, cosyntropin, danaZol, desmopressin, desogestrel, doxer S-adenosylmethionine, sesamol, shark cartilage, silymarin, calciferol, drospirenone, estradiol, estrogen, estrone, estropi soy protein, spirulina, ubiquinol, Vinpocetine, and xanthine. pate, ethynodiol, etonogestrel, follitropin, glucagon, [0072] Suitable obstetric and fertility agents include, but goserelin, histrelin, lanreotide, leuprolide, levonorgestrel, are not limited to, carboprost, choriogonadotropin, clo levothyroxine, liothyronine, lomustine, lutropin, mecaser mifene, dinoprostone, ganirelix, menotropin, methylergono min, medroxyprogesterone, mestranol, methimaZole, nafare Vine, mifepristone, and ritodrine. lin, norelgestromin, norethindrone, norgestimate, norgestrel, [0073] Suitable opthalmologic agents include, but are not octreotide, oxytocin, paricalcitol, pegvisomant, progester limited to, apraclonidine, atropine, bimatoprost, brimonidine, one, secretin, sermorelin, somatotropin, teriparatide, thy brinZolamide, carbachol, cyclopentolate, dipivefrin, dorZola rotropin, triptorelin, and urofollitropin. mide, echothiophate, ?uorescein, gati?oxacin, homatropine, [0069] Suitable minerals include, but are not limited to, hyaluronidase, hydroxyamphetamine, hydroxypropyl cellu boron, bromine, calcium, chloride, chromium, cobalt, copper, lose, latanoprost, lodoxamide, loteprednol, metipranolol, ?uoride, iodine, iron, lithium, magnesium, manganese, naphaZoline, pegaptanib, pemirolast, pilocarpine, rimex molybdenum, phosphorus, potassium, rubidium, selenium, olone, timolol, tropicamide, travoprost, and Vertepor?n. US 2010/0015184 A1 Jan. 21,2010

[0074] Suitable proteins, enzymes and enzyme inhibitors may be complex. To add value, such an excipient-only mod include, but are not limited to, adenosine, albumin, algluc ule may be useful for more than one ?nal product; otherWise erase, aminocaproic acid, antigens, arginine, cilastatin, cla it Would be simpler to use standard large-volume manufac vulanate, cysteamine, cysteine, disulfuram, entacapone, turing or compounding techniques, for some embodiments. fomepizole, glutamate, glutathione, glycine, glatiramer, imi Components of excipient modules may be selected for versa glucerase, metyrapone, miglustat, nitisinone, pegademase, tility in combination With the portfolio ofAPI modules, and as propylthiouracil, protein fragments, sacrosidase, tazobactam, the number and type of API modules changes, the portfolio of tolcapone, viruses. polynucleotides, excipient modules canbe optimized. Some excipient modules [0075] Suitable respiratory agents include, but are not lim fall into these classes: ?llers used in combination With solid ited to, acetylcysteine, albuterol, aminophylline, arformot dose API modules; and liquid carriers used in combination erol tartrate, benzonatate, beractant, budesonide, calfactant, With liquid dose API modules, Which may contain one or ciclesonide, doxapram, dyphylline, formoterol, guaifenesin, more ?avors, sWeeteners and other taste-masking agents, col ipratropium, levalbuterol, levonordefrin, menthol, metaprot ors, viscosity agents, preservatives, and antiseptics. erenol, methacholine, montelukast, nedocromil, oxtriphyl [0082] Ingredients of excipient modules include any suit line, oxymetazoline, phenylephrine, pirbuterol, poractant, able ingredients. Such ingredients include, but are not limited pseudoephedrine, salmeterol, terbutaline, theophylline, to, colorants, ?avors, sWeeteners and other taste-masking tiotropium, za?rlukast, and zileuton. agents, fragrances, and other ingredients used to modify char [0076] Suitable rheumatologic agents include, but are not acteristics of the product, including solvents and solutions, limited to, allopurinol, aurano?n, azathioprine, colchicine, diluents, binders, ?llers, disintegrants, lubricants, emulsi? le?unomide, penicillamine, probenecid, quinine, and sul?n ers, carriers, suspensions and suspending agents, elixirs, pyrazone. acidi?ers, alkalinizers and buffers, solubilizers, surfactants, [0077] Suitable steroids include, but are not limited to, clarifying, gelling and/or thickening agents, viscosity alclometasone, amcinonide, beclomethasone, betametha enhancers, coatings, antioxidants, chelating agents, stabiliz sone, clocortolone, cortisone, dexamethasone, di?orasone, ers, sustained release agents, antiseptics, preservatives, and ?udrocortisone, ?unisolide, ?uocinolone, ?uorometholone, multifunction agents. ?uoxymesterone, ?uticasone, halobetasol, methylpredniso [0083] Suitable colorants include, but are not limited to, lone, methyltestosterone, mometasone, nandrolone, oxan dyes and inks approved for use in drugs and cosmetics drolone, oxymetholone, prednisolone, prednisone, testolac (D&C), dyes and inks approved for used in food, drugs and tone, testosterone, and triamcinolone. cosmetics (FD&C), branded dyes, inks, and coatings, other [0078] Suitable urological agents include, but are not lim dyes, and other inks. ited to, alfuzosin, alprostadil, bethanechol, darifenacin, [0084] Suitable D&C approved colorants include, but are dutasteride, ?nasteride, ?avoxate, oxybutynin, pentosan not limited to, D&C Black #1, Blue #1, 2, and 6, Green #1, 4, polysulfate, propantheline, solifenacin, tamsulosin, tera and 5, Orange #3, Red#3, 4, 5, 6, 7, 19, 21, 22, 27, 28, 30, 33, zosin, tiopronin, tolterodine, and trospium. 36, 39, and 40, Violet #2, andYelloW #5, 6, and 10, including [0079] Suitable vitamins include, but are not limited to, lakes. alpha-tocopherol (vitamin E), ascorbic acid (vitamin C), [0085] Suitable FD&C approved colorants include, but are biotin (vitamin B7), cholecalciferol and calcitriol (vitamin not limited to, FD&C Blue #1, 2, 10, 40, Green #1 and 3, D3), cyanocobalamin and hydroxocobalamin (vitamin B12), Orange #2, Red #1, 2, 3, 4, 7, 19, 27, 28, 30, 33, and 40, Violet ergocalciferol (vitamin D2), folic acid (vitamin B9), inositol #1, andYelloW #1, 3, 5, 6, and 10, including lakes. (vitamin B8), menaquinone (vitamin K2), mendione (vitamin [0086] Suitable branded colorants include, but are not lim K3), niacin and nicotinic acid (vitamin B3), pantothenic acid ited to, BLUE TEK PRINT SB-6008 and SB-6029; and pantethine (vitamin B5), phylloquinone (vitamin K), CHROMA-TERIC Deb-5037-Ore, T3000-We, and YelloW pyridoxine (vitamin B6), retinol, retinoids, and carotenoids T3277-Ye; CHROMA-TONE PDDB-8906-W and PDDB (vitamin A), ribo?avin (vitamin B2), and thiamine (vitamin 8746-Or; CHROMACOTE T 2700GN, T 2716Y, and T B l). 2956Y; COATERIC YPA-6-7430 White and YPA-6-7089 [0080] Suitable other agents include, but are not limited to, White; DIOLACK 00f32892 Yellow; DRI KLEAR; DRI alcohol, aminohippurate, cinacalcet, citrate, dextrose, dimer KLEAR 042; DRI KLEAR LV 609527; DRY FLO; DRY caprol, edetate, ferumoxides, ferumoxsil, ?udeoxyglucose, CLEAR LV; DURO-TAK 80-1196, 87-2070, 87-2194, gadobenate, gadodiamide, gadopentetate, gadoteridol, 87-2287, 87-2296, 87-2888, 87-2979, and 280-2516; gadoversetamide, gallium, glycerin, icodextrin, indocyanine, FLEXOGRAPHIC Pink; PHARMACOAT 606; Red and iodipamide, iodixanol, iohexyl, iopamidol, iopromide, White COTOLENE-P; SPECTRABLEND Csl-15764 iothalamate, ioversol, ioxaglate, kaolin, lactate, lanolin, lan (Blue); SPECTRASPRAY Blue 50726; WHITE TEK PRINT thanum, mineral oil, pentetate, per?utren, por?mer, petrola SB-007p. tum, samarium, sevelamer, strontium, succimer, technetium, [0087] Additional branded colorants and coatings include, thallous chloride, and trientine. but are not limited to, OPACOAT Na2203, Na4108 Blue, Modules not Containing an API Na4711 Lavender, Na7013 Clear; OPACODE A-10450 Black, A-10509 Black, Ns-78-10013-N, Ns-78-17502 Gray, [0081] FIG. 3 summarizes the process of developing a port Ns-78-17821, Ns-78-8000 Black, Ns-78-8001, Nsp-78 folio of, and selecting the components in, modules not con 17734 Black, S-1-13001 Orange, S-1-15034-Fd Red, S-1 taining an API, for one embodiment of the present invention. 15038 Red, S-1-16507, S-1-1666 Red, S-1-1666-M Red, S-1 Whereas the key issues that govern the development of pre 1681 Red, S-1-17706 Black, S-1-17711 Black, S-1-17734 cursor modules that contain an API can be relatively straight Black, S-1-17749 Black, S-1-17762 Black, S-1-17797 Black, forward, the key issues that govern the development of pre S-1-18025 White, S-1-26514 BroWn, S-1-3110 Green, S-1 cursor modules (especially liquids) that do not contain anAPI 3171 Green, S-1-4124 Blue, S-1-4157, S-1-4159 Black, S-1

US 2010/0015184 A1 Jan. 21,2010

5-1727 Red, 5-2028 Yellow, 5-2042 Yellow, 5-2086 Yellow, 1-4700 Purple, 1-4710, 1-4739 Lavender, 1-4812 Lavender, 5-2312 Yellow, 5-2328 Orange, 5-2371 Orange, 5-2394 1-4845 Purple, 1-6275 Orange, 1-6300, 1-6312 Yellow, Orange, 5-2450 Orange, 5-2451 Orange, 5-2644 Beige, 1-6318 Yellow, 1-6320 Yellow, 1-6357 Yellow, 1-6370g Yel 5-2646 Beige, 5-3140 Green, 5-3171 Green, 5-3193 Green, low, 1-6378g Yellow, 1-6381 Yellow, 1-6382g Yellow, 5-3296 Green, 5-4129 Blue, 5-4270 Blue, 5-4287 Blue, 1-7000e White, 1-7002 White, 1-7003 White, 1-7003hWhite, 5-4295 Blue, 5-6233 Light Orange, 5-6301 Yellow, 5-6308, 1-7006 Clear, 1-7022 Off-White, 1-7027 White, 1-7040 5-7058 White, 5-7068 White, 5-7072 White, 5-7411 Purple, White, 1-7052 White, 1-7059 White, 1-7060 White, 1-7086 5-7524 Grey, 5-8050 Black, 5-9006 Brown, and 5-9020 White, 1-7191 Brown, 1-7444g White, 1-7449 White, 1-7472 Brown. Clear, 1-7507 Grey, 1-7552 Grey, 1-7700 White, 1-7706g White, 1-8325 Beige, 1-8343g Beige, 1-8345g Beige, 1-8608 [0092] Also, OPADRY Yellow; OPADRY YPS-7-2127; Orange, 1-8619 Orange, 1-89193 Clear, 1-9011 Brown, OPADRYYS-1-003 White, 1-10010 Purple, 1-10291 Laven 1-9012 Brown, 1 r1418 Pink, 1 r-7006 Clear, 2-10657 Blue, der, 1-10523a Blue, 1-10525 Blue, 1-10533a, 1-10542a Blue, 2-19071a Clear, 2-19114a Clear, 22-16576 Brown, 22-18119 1-10547a Blue, 1-10563 Blue, 1-10613a Blue, 1-10618, White, 2-7013 Clear, 2-7063 White, 3-7011 Clear, 3-7031 1-10629, 1-10654a Blue, 1-10682 Blue, 1-10690a Blue, Clear, 3-7413 Clear, 5-12575Yellow, 5-12576Yellow, 5-1260 1-10699 Blue, 1-10745 Blue, 1-10748a Light Blue, 1-10755 Pink, 5-1296 Pink, 5-17266 Tan, 5-18068 White, 5-18074 Blue, 1-10783a Blue, 1-11000 Pink, 1-11051 Green, 1-11060 White, 5-2085 Yellow, 5-2370 Orange, 5-3116 Green, 5-4277 Green, 1-1107 Green, 1-11075a Green, 1-11113 Green, Blue, 5-4278 Blue, 5-7017, 5-7042 Clear, 5-7068, and 5-7099 1-11171 Green, 1-11234 Green, 1-11305 Green, 1-11369 White. Green, 1-1246 Pink, 1-1252 Pink, 1-12524a Yellow, 1-12525aYellow,1-12526aYellow, 1-12529Yellow, 1-12541 [0093] Also, OPAGLOS GS 2-0300 and 2-0310; OPAG Yellow, 1-1256-AYellow, 1-12573 Yellow, 1-12581 Yellow, LOS S 0750; OPALUXAS 1406 Pink, 1475 Pink, 1537 Pink, 1-1262 Pink, 1-12625Yellow, 1-12702aYellow, 1-12732Yel 1589 Pink, 2006 Yellow, 2007 Yellow, 2052 Yellow, 2062 low, 1-1277 Pink, 1-12789 Yellow, 1-12826 Yellow, 1-1283 Yellow, 2086 Chartreuse, 2094, 2167 Yellow, 2236, 2269 Pink, 1-12844Yellow, 1-12847Yellow, 1-1298 Pink, 1-13013 Yellow, 2324 Orange, 2336 Orange, 2395 Peach, 2413, 2433 Peach, 1-13065a Orange, 1-13119 Orange, 1-13121 Yellow, Orange, 2490 Coral, 2498 Orange, 2553 Orange, 2612, 2613 1-13148a Orange, 1-13214 Orange, 1-13269 Orange, Tan, 2620-B Tan, 2676 Salmon Jasper Red, 2754, 2768, 2787 1-13271 Orange, 1-13555 Orange, 1-13591a Orange, Butterscotch, 3140 Green, 3287, 3288 Green, 3308 Green, 1-13664a Orange, 1-13673a Orange, 1-13675a Orange, 3348-C Green, 3376, 3381, 3389 Green, 3391 Green, 3942 1-14012 Pink, 1-14129 Pink, 1-14130 Pink, 1-1418 Pink, Maroon, 4025, 4151 Blue, 4188 Blue, 4193 Blue, 4208-A 1-1441g, 1-1448g Pink, 1-14518a Pink, 1-14519a Pink, Blue, 4258 Blue, 4270 Blue, 4800 Lavender, 4854 Lavender, 1-14532 Pink, 1-1454 Pink, 1-14555a Pink, 1-14559 Pink, 4855 Purple, 4891, 5034 Red, 5107, 5162 Green, 5178 Green, 1-1456g Pink, 1-14587a Pink, 1-14593a Pink, 1-14595 Pink, 5203 Green, 5212 Green, 7000-B, 7000-P White, 7001, 7535 1-14608a, 1-14643a Pink, 1-14725 Pink, 1-14756a Pink, Gray, 8010-A Black, 8050-L Black, 9010 Brown, 9030 1-14779a Pink, 1-15050 Red, 1-1510 Pink, 1-1528 Pink, Brown, and 9050 Brown. 1-1543 Pink, 1-15585a Red, 1-16002 Maroon, 1-16518a [0094] Also, OPALUX Blue and Green; Opaque Blue 100, Brown, 1-17169a, 1-17180a Beige, 1-17181a Beige, Blue 147, Blue 605, Brown 85 Bf, Green 1664, Green 97, 1-17192a,1-17209 Beige, 1-17220, 1-17222a Tan, 1-17235a Green/Flesh, Maroon 6 Dar, Pink 0439, White 001, White Peach, 1-1724 Red, 1-17274a Beige, 1-17277a Beige, 002, White 535, White 536, White 538, and White 8. 1-17307a Butterscotch, 1-17505a Gray, 1-17506a Gray, [0095] Also, OPASPRAY 3-1700, 3-1810, 3-1820, 3-1830, 1-1751g Red, 1-1755 Gray, 1-18005 White, 1-18022 White, lm-176, K-1-1230 Pink, K-1-1243, K-1-1254, K-1-1279, 1-18027 White, 1-18027a White, 1-18028 White, 1-18097a K-1-1289 Pink, K-1-14016 Pink, K-1-1413 Pink, K-1-1414 White, 1-1811 Red, 1-18111 White, 1-18130aWhite, 1-1814 Pink, K-1-1432, K-1-1437, K-1-1455 Pink, K-1-1526 Pink, Red, 1-18177a White, 1-18202a White, 1-18229 White, K-1-1563 Pink, K-1-1573 Lavender, K-1-1574, K-1-1584, 1-1846 Red, 1-1847 Red, 1-1891 Red, 1-19025-A Clear, K-1-1719 Red, K-1-2004 Yellow, K-1-2013 Yellow, 1-2007 Yellow, 1-2013 Yellow, 1-2053 Yellow, 1-2063 Yel K-1-2043 Yellow, K-1-2182 Yellow, K-1-2186 Yellow, K-l low, 1-2074 Yellow, 1-2083 Yellow, 1-2115 Yellow, 1-2122 2216-A Yellow, K-1-2227 Yellow, K-1-2228 Yellow, K-1 Yellow, 1-2134 Yellow, 1-2135 Yellow, 1-2136 Yellow, 2239, K-1 -2240 Yellow, K-1-2256Yellow, K-1-2275 Yellow, 1-2141 Yellow, 1-2152 Yellow, 1-2167 Yellow, 1-2181 Yel K-1-2300 Peach, K-1-2301 Peach, K-1-2303 Orange, K-1 low, 1-2184 Gold, 1-2186 Yellow, 1-2192 Yellow, 1-2305 2304 Orange, K-1-2314 Orange, K-1-2327 Orange, Orange, 1-2308 Dark Orange, 1-2344 Yellow, 1-2383 K-1-2330 Orange, K-1-2335 Orange, K-1-2406 Orange, Orange, 1-2398 Orange, 1-2449 Orange, 1-2455 Red, K-1-2410 Orange, K-1-2417 Orange, K-1-2430, K-1-2441 1-2465, 1-2487 Orange, 1-2522 Orange, 1-2526 Orange, Orange, K-1-2471 Orange, K-1-2473, K-1-2492, K-1-2531, 1-2527 Orange, 1-2534, 1-2546 Orange, 1-2548 Orange, K-1-2533 Orange, K-1-2554, K-1-2568 Orange, K-1-2570 1-2549 Orange, 1-2558 Orange, 1-2563 Orange, 1-2564, Orange, K-1-2588 Orange, K-1-2614 Beige, K-1-2621 1-2578 Orange, 1-2596 Orange, 1-2604 Beige, 1-2612 Beige, Brown, K-1-2626 Orange, K-1-2656 Beige, K-1-2670 Tan, 1-2619, 1-2621 Rust, 1-2623 Brown, 12630 Yellow, 1-2635 K-1-2674 Beige, K-1-2685, K-1-2711, K-1-2723 Butter Tan, 1-2660 Salmon, 1-2665 Beige, 1-2669 Rust, 1-2671 scotch, K-1-2837, K-1-3000, K-1-3142 Green, K-1-3144 Beige, 1-3105 Green, 1-3130 Green, 1-3134 Green, 1-3146 Green, K-1-3147, K-1-3148 Green, K-1-3156, K-1-3173 Green, 1-3147, 1-3166 Green, 1-3256 Green, 1-3288 Green, Green, K-1-3178 Green, K-1-3197 Green, K-1-3202 Green, 1-4014 Blue, 1-4018 Blue, 1-4112 Blue, 1-4137 Blue, K-1-3209 Green, K-1-3220 Green, K-1-3227, K-1-3300-A 1-4215, 1-4216, 1-4221 Blue, 1-4228 Blue, 1-4229 Blue, Green, K-1-3300-C Green, K-1-4108 Blue, K-1-4119, K-1 1-4234 Blue, 1-4235 Blue, 1-4236 Blue, 1-4240 Blue, 1-4241 4122 Blue, K-1-4136 Blue, K-1-4205 Blue, K-1-4210-A, Blue, 1-4245 Blue, 1-4249 Blue, 1-4251 Blue, 1-4254, K-1-4213 Blue, K-1-4214, K-1-4227, K-1-4234 Blue, K-1 1-4255, 1-4256 Blue, 1-4282 Blue, 1-4298 Blue, 14644 Pink, 4235 Blue, K-1-4728, K-1-4731 Purple, K-1-4743 Lavender, US 2010/0015184 A1 Jan. 21,2010

K-1-4786, K-1-5024 Red, K-1-7000 White, K-1-70008 46971; Creme de Menthe 14677; Creme de Vanilla 28156; White, K-1-7000b, K-1-7076, K-1-9027 Brown, K-1-9039-L Curacao 50.397A; and Custard 52.940/A FIR. Brown, K-1-9060 Red, K-1-9080 Brown, K-1-9112 Brown, [0099] Also, DF-119, DF-1530, and E-472; Enhancer L-2113, L-3305 Green, L-3306 Green, L-7000 White, M-1 F-5397A and F-9843; FIG. 827118; FritZsche 21028-D, 2042, M-1-3459 B Orange, M-1-4395b Blue, M-1-7111-B, 46215, 73959, 75021, and 78087; Fruit 01-10428 and M-1-711b White, M-1-7120 White, M-1-8429 Yellow, and 84.6422;FruitGum912;FruitMint75588;Fruit Punch#716, Wd-1270 Pink; OPATINTAd-25000 Red, Dd-13009 Orange, #28140, and 14761 FM; Grape 59.145/APO5.51, 59.266/ Dd-14000 Pink, Dd-1800 White, and Dd-18000 White. APO5.51, 6175, 054158, 486939, 501040A, 13403873, IFF [0096] Suitable other dyes include, but are not limited to, 13549478, PFC 8439, PFC-9711, and PFC-9924; Guarana Beige P-1437; Black LB-260, 442, 636, 1171, and 9972; FMC-15417; IFF FP 69 F; Kiwi S-718; Lemon 812 and Black Oxide; Blue LB-332, 781, and 1245; Blue Lakolene; FMC-10471; Lemon Mint 862.547; Lemon Mint FritZsche Brown LB-292, 464, 1685, 1792, and 56069; Burnt Umber; 54369; Lemon Spray V3938-1 N1; Mandarin 15228-71; Caramel 105; Caramel Acid Proof 100; Carmine 09349; Cas Maque Tree 377(BUSH); Mask RBT-NV-7759; Masking ing 27-75; Emerald Green LB-9207; Ferric Oxide Brown, 35321; Menthol Mint PFC-9926; Mint 287, 51296 TP0551, Green, Orange, Pink, Red, Red-Brown, and Yellow; Gray and SN027513; Mixed Fruit PFC-9970; and NNS DZ-03226. #2982; Green70363; Green LB-265, 279, 333, 482, 555, 603, [0100] Also, Orange #7679, 9/79J839, 57.458/AP05.51, 820, 883, 1174, 1236, 1441, 1594, 1616, 1644, 3323, and 739K (PB82), 13334, 74016-71, 249792, 607217, G-10431, 9583; Green PB-1543 and 1766; Green PMS-579; Green P-5614, and PFW-730016U; Orange Banana WL-18093; PR-1333 and 1339; Lavender LB-1356 and 1603; Mint Orange Pineapple FV-43; Peach 10457, 302789, and Green; Ochre 3506; Orange 54172; Orange LB-452, 715, 13503584; Peach Mint FritZsche 106109; Peach Pineapple 1387, 1439, and 3810; Peach LB-1576; Pink; Purple LB-562, FMC 14258; Peppermint 104, 517, 894.143, K373, PFC 588, 639, 694, and 1902; Red LB-6053-R and 9570; Red 9927, and WL-6167; Peppermint Stick FMC 16170; Pine PB-1595; Salmon LB-1668; Swedish Orange #2191; Tan apple 182661, N-2566, and N-2766; Pineapple-Coconut, Pri PB-1388; Tetrarome Orange; Turquoise LB-1430; White mary Taste Modi?er # 29275; Punch 610962U and WL-7126; TC-1032; Wild Cherry 7598; Yellow LB-104, 111, 1577, Raspberry 954, 954K (BK77), 998, 1840, 8456, 21028D, 1637, 1769, and 9706; Yellow PB-1345 and 1381; Yellow 28106, 50776, 65934, 262085, A11693, D9599, DY-04447, WD-2014; Yellow #70362; and Yellow Ochre. F-1784, F-1840, F-6887-S, and PFC-8407; and Root Beer [0097] Suitable other inks include, but are not limited to, 180339. Black 2271, A-10464, A-10527, FGE-1386, GG-606, S-1 [0101] Also, Strawberry 052311 AP0551, 133.5655, 17.36. 8100-Hv, SW-9007, SW-9008, SW-9009, and SW-9010; 8509, 17C56217, 52.311AP, 5210(FD&D), 52312/AP, 5951, Blue and Yellow Imprint GG-823; Blue Black A-10463, and 9843, 14953, 55058, 523121A, DY-04359, F-5665, F-5930 A-9371; Blue S-1-10551 and S-1-4118; Dark Yellow and A, FN-13819, PFC-9626, and WL-16650; Strawberry Yellow Imprint GG-824; Edible Black, Blue, Brown, Gray, Guarana 586.997/APO5.51; Sweet 24052 and 604978; Sweet Orange, Pink, Red, Red A-8032, and White; Fine Black Tone 28837 and AM 918.005; Sweetness Enhancer 5401 B; 2202c and 2212; Green A-10454 and A-10629; Orange and Tangerine FritZsche 51465; TM 313298; TPF 135 and TPF Yellow Imprint GG-822; Pink Imprinting SB-1003; Red 5-1 143; Tropical Blend FV-50; Tropical Fruit Punch 1591 and 9034 and A-8032; Red and Aqua Imprinting GG-827; Red N&A 50432; Tutti Frutti 0002028, 24093FM, 51.880/AP05. and Caramel Imprinting Gg-825; Red Imprinting Gg-826; 51, P-5400, and WL-18481; Vanilla 323453, 33869, 501441 S-1-7085; Thinner; and White 21-K, A-8154, S-1-7075, and AP2004, F-6257, P-1160, PFC-8541, and PFC-9772; Wild SB-0007p. Cherry 29653, 695047U, K-321, NV-101-1489, PFC-14783, [0098] Suitable ?avors, sweeteners, and taste-masking and WL-1093; Wintergreen PFC-8421, Yellow Plum Lemon agents include, but are not limited to, Anise 29653; Apple 39K 020, High Fructose Corn Syrup; and Flavors #18317, Watermelon PFC 9887; Apricot 23067 and 24829; Apricot 57000 IU, 57820/A, 89-186, and 89-259, and other sweeten Peach; Banana 15223, 501013 AP0551, 71507, 74546, FMC ers and taste-masking agents. 23406, and SA84; BBA-47769; Berry Citrus Blend 8409, [0102] Suitable branded ?avors include, but are not limited 9621, and 9756; Bitter Mask 9885; Bitterness Modi?er to, AROMALOK 182608 and 262453; Banana 15555, 36734, and 367343; Black Cherry 501027 AP0551; DURAROME 860.095 TD09.91; C&K Mixed FruitA13688; Blood Orange 51 .226T and SA; Bubble Gum 15864, 175303, Cheri Beri PCD-5580, PFC-8573, PFC-8580, and PFC-8573; 3266P, and MC-4938; Buttermint 24020; Butterscotch Cherry DURAROME 860.097 TD10.91; Cherry E.P. Modi 61005-U and F-1785; Candied Sugar 510155U; Cherry ?ed 151; Cherry FONA 825.662; Cherry H&R PHARMA 57.679/A, 213, 349, 594 SD, 825.476WC, 842, 1566, 3321, 004; Cherry WIXON 3566; FELTON 6-R-9; FLORA 8513, 11539, 11929, 104613, 107026, 181612, 231494, SYNTH; Fruit Tak 20008; Grape FIRMENICH 587.444 and 338614, 500910U, 590271A, 598384, A-22872, DP300684, 597.303/C; Grape GIVAUDAN 433160; Grape MANHE EP-3699, F-232, FI-8568, FMC 22872, FMC 8513, IFF IMER 522463; Grape MICRON ZD-3876; Grape Nector 13530912, L-1233, N-2755, NV-1489, PFC-9768, R-6556, PFC-8599; HAVERSTROO ZD 49284; Lemon GIVAUDAN WL-1093, WL-18022, and WL-4658; Cherry Berry F-1194; 74940-74; MAGNASWEET 100, 110, 135, 180, and 185; Cherry Blend 770; Cherry Burgundy 11650; Cherry Cream MCP Lemon DURAMONE 4409A; MCP Lime DURA 14850; Cherry Maraschino S-3531, Cherry Mint 5073A; MONE 6419; Menthol VERALOCK; Orange GIVAUDAN Cherry Pistachio PFC-8450; Cherry Vanilla Compound 74388-74; Orange WONF 608352; Orbit Serene 20340; Pep A77487; Cherry-Anise PFC-9758; Chloroform 103589; permint SEELOCK 34907; PERLAROM Strawberry; Phar Chocolate P727; Coconut 41 and F-3893; Coconut Toasted maceutical 182608; PHARMASWEET 10772900; 1323PG; Cola FMC 15740; Cotton Candy 30-92-0011 and PLUSWEET; PROSWEET 604, 694, and K; Raspberry F-9967; Cough Syrup 819, 110257, and 134681; Cream AROME PFC-9908; Raspberry POLAK 5000064; EP-17688; Cream Soda; Creamy Vanilla 16345; Creme Refrachessment FD-8027D; RHODIA PHARMACEUTI US 2010/0015184 A1 Jan. 21,2010

CAL #RE 451; Strawberry MICROSEAL; Strawberry TRU hydroxide, lactate, phosphate, pyrophosphate, salicylate, SlL WINDSOR 237303; TETRAROME; Tutti Frutti PER stearate, sulfate, sulfate dihydrate, and sulfate hemihydrate, MASEAL 77919-31; Vanilla BECK C7984; VERALOCK and other calcium compounds. Bubble Gum; and Wild Cherry GIVAUDAN F-1813. [0111] Also, caldiamide sodium; calteridol calcium; can [0103] Suitable fragrances include, but are not limited to, delilla Wax; canola oil; caprylic triglyceride; capsicum oleo Essence Bouquet 9200, FritZbro Orange, Lemon, and resin; captan; and caramel. Orange; Fragrance 3949-5, 520a, 6.007, 91-122, 9128-Y, 93498g, Balsam Pine #5124, Bouquet 10328, CHEMOD [0112] Also, carbomer 934, 934p, 940, 941, 974, 974p, ERM 6401-B and 6411, Cream #73457, Cs-28197, Felton 980, 981, and 1342; carbon; carbon black; carbon dioxide; 066m, FlRMENlCH 47373, GIVAUDAN Ess 9090/lc, carboxy Vinyl copolymer; carboxymethyl starch; carboxym H-6540, Herbal 10396, Nj-1085, P 0Fl-147, Pa 52805, PERA ethylamylopectin sodium; carboxymethylcellulose; carboxy DERM D, Rbd-9819, SHAW Mudge U-7776, Tf 044078, polymethylene; cardamom; carmine; carmine 50; carnauba UNGERER Honeysuckle K 2771, and UNGERER N5195; Wax; carrageenan; cassia oil; castor oil; cedar leaf oil; cel and Perfume 25677, Bouquet, E-1991, Gd 5604, TANA 90/42 lacefate; cellulose; cellulose acetate; cellulose acetate ot-320s Scba, and W-1952-1. and ca-398-10; cellulose microcrystalline; cellulosic poly mers; cerasynt-se; and ceresin. [0104] Suitable other excipients include, but are not limited to, 1,1,1-trichloroethane; 1,1,2,2-tetra?uoroethane; 1,2,6 [0113] Also, ceteareth-12, 15, and 30; cetearyl alcohol and hexanetriol; 1,2-dimyri stoyl-sn-glycero-3 -(phospho-s-(1 octanoate; ceteth-2, 10, 20 and 23; cetrimonium chloride; glycerol)); 1,2-dioleoyl-sn-glycero-3-phosphocholine; 1,2 cetyl alcohol, esters, and palmitate; cetylpyridinium chloride; dipalmitoyl-sn-glycero-3-(phospho-rac-(1-glycerol)); 1,2 chartreus colored spheres; chemoderm 6401b; cherry; chlo distearoyl-sn-glycero -3 -(phospho-rac-(1-glycerol)); 1,3 - robutanol; chlorobutanol hemihydrate; chlorocresol; chloro dimethylol-5,5-dimethyl-hydantoin; form; chloroxylenol; cholesterol; choleth; cinnamaldehyde; 1-aminocyclohexanecarboxylic acid, c-11; 1-methyl-2-pyr cinnamon; citric acid; citric acid monohydrate; clove oil; rolidinone; 1 -o-tolylbiguanide; 2-amino-2-methyl- 1 -pro cocamide diethanolamine and ether sulfate; cocamine oxide; panol; 2-ethylhexyl salicylate; and 2-naptholene sulfonate coco betaine; cocoa bean and butter; cocoglycerides; sodium salt. cocomonoethanolamide; coconut oil; coffee; collagen; com [0105] Also, acacia; acesulfame potassium; acetic acid; pressible sugar; copovidone; coriander oil; corn glycerides; acetic anhydride; acetone; acetone sodium bisul?te; corn oil; corn oil peg-6 esters; corn syrup; cottonseed oil; acetophenone; acetylated monoglycerides; acetylcysteine; cream base; creatine; creatinine; cresol; croscarmellose acetyltributyl citrate; acetyltryptophan; acrylates copolymer; sodium; crospovidone; crystal gum; cupric sulfate; cutina; acrylic acid; activated charcoal; adipic acid; AEROTEX resin cyclamic acid; cyclomethicone; cysteine; and cysteine hydro 3730; agar; air; alanine; albumin; alcohol; alfadex; alginic chloride. acid; alkyl ammonium sulfonic acid betaine; alkyl aryl [0114] Also, dehydroacetic acid; dehymuls e; denatonium sodium sulfonate; allantoin; almond oil; alpha-terpineol; benZoate; deoxycholic acid; dextran; dextran 40; dextrates; alpha-tocopherol; and althea. dextrin; dextrose; diacetylated monoglycerides; diatoma [0106] Also, aluminum acetate, chlorhydroxy allantoinate, ceous earth; diatriZoic acid; diaZolidinylurea; dibutyl phtha diacetate, hydroxide monostearate, oxide, polyester, potas late; dibutyl sebacate; dichlorobenZyl alcohol; dichlorodif sium sulfate, silicate, silicate pentahydrate, starch octenyl luoromethane; dichloro?uoromethane; succinate, stearate, and sulfate, and other aluminum com dichlorotetra?uoroethane; diethanolamine; diethyl phthalate pounds. and sebacate; diethylene glycol monoethyl ether; diglycol [0107] Also, ALZAMER-39 and 50; AMBERLlTE; stearate; dihydroxyaluminum glycinate; dihydroxyalumi AMERCHOL c and cab; ammonia; and ammonio methacry num sodium carbonate; diisopropanolamine; diisopropyl adi late copolymer. pate; diisopropyl dimerate; and diisopropylbenZothiaZyl-2 [0108] Also, ammonium acetate, calcium alginate, chlo sulfenamide. ride, glycyrrhiZate, hydroxide, lauryl sulfate, nonoxynol 4 [0115] Also, dimethicone 350, 360, copolyol, and mdx4 sulfate, phosphate, and sulfate, and other ammonium com 4210; dimethyl dioctadecylammonium bentonite, isosorbide, pounds. phthalate, siloxane, and sulfoxide; dimyristoyl lecithin; dio [0109] Also, ammonyx; amphoteric-2; amphoteric-9; amyl ctylphthalate; dipropylene glycol; disodium cocoamphodiac acetate; anethole; anidrisorb 85/70; anise; anoxid sbn; anti etate, edisylate, laureth sulfosuccinate, lauryl sulfosuccinate, foam; antipyrine; apricot kernel oil peg-6 esters; aquacel 126; and sulfosalicylate; disofenin; diVinylbenZene styrene aquacoat; aquaphor; arginine; arlacel; arlatone 289; ascorbic copolymer; docosanol; docusate sodium; and dusting poW acid; ascorbyl palmitate; aspartame; aspartic acid; attapulg der. ite; balsam; barium sulfate; b-cyclodextrin sulfobutyl ether [0116] Also, edamine; edetate calcium disodium, diso sodium; beesWax; beheneth-10; bentonite; benZaldehyde; dium, and sodium; egg yolk phosphatides; eiderdoWn soap; benZalkonium chloride; benZenesulfonic acid solution; ben entsulfon; epilactose; erythorbic acid; ethanolamine hydro Zethonium chloride; benZododecinium bromide; benZoic chloride; ether; ethyl acetate, hexanediol, maltol, oleate, and acid; benZoin; benZyl alcohol, benZoate, and chloride; beta Vanillin; ethylcellulose; ethylene; ethylene glycol; ethylene dex; beta-naphthol; betose; bibapcitide; bismuth subcarbon glycol monoethyl ether; ethylene Vinyl acetate copolymer; ate and subgallate; boric acid; brocrinat; butane; butyl alco ethylenediamine dihydrochloride; ethylene-propylene hol, ester, and stearate; butylated hydroxyanisole and copolymer; ethylparaben; eucalyptol; and eucalyptus oil. hydroxytoluene; butylene glycol; butylparaben; c20-40 [0117] Also, EUDRAGIT E 100, L 100, L 100-55, L 30 D, pareth-24; and caffeine. 130D-55, NE 30 D, NE 40 D, RL 100, RL 12.5, RL 30 D, RS [0110] Also, calcium acetate, alginate, ascorbate, carbon 100, RS 12.5, RS 30 D, and S 100, and other EUDRAGIT ate, carrageenan, chloride, citrate, cyclamate, gluceptate, products.