Patent Document:

the invention provides for pharmaceutical compositions in unit dosage form containing dipyridamole , optionally with a corticosteroid . the compositions are useful , for example , for the treatment of immunoinflammatory disorders . several formulations have been prepared and are described in the examples ( example 1 ( variant b ), example 2 ( variant c ), example 3 ( variant d ), example 4 ( variant d0 , example 5 ( variant d2 ), example 6 ( variant e ), and example 7 ( variant f )). the combinations of the invention include a corticosteroid selected from the class of selective glucocorticosteroid receptor agonists ( segras ) including , without limitation , 11 - alpha , 17 - alpha , 21 - trihydroxypregn - 4 - ene - 3 , 20 - dione ; 11 - beta , 16 - alpha , 17 , 21 - tetrahydroxypregn - 4 - ene - 3 , 20 - dione ; 11 - beta , 16 - alpha , 17 , 21 - tetrahydroxypregn - 1 , 4 - diene - 3 , 20 - dione , 11 - beta , 17 - alpha , 21 - trihydroxy - 6 - alpha - methylpregn - 4 - ene - 3 , 20 - dione ; 11 - dehydrocorticosterone ; 11 - deoxycortisol ; 11 - hydroxy - 1 , 4 - androstadiene - 3 , 17 - dione ; 11 - ketotestosterone ; 14 - hydroxyandrost - 4 - ene - 3 , 6 , 17 - trione ; 15 , 17 - dihydroxyprogesterone ; 16 - methylhydrocortisone ; 17 , 21 - dihydroxy - 16 - alpha - methylpregna - 1 , 4 , 9 ( 11 )- triene - 3 , 20 - dione ; 17 - alpha - hydroxypregn - 4 - ene - 3 , 20 - dione ; 17 - alpha - hydroxypregnenolone ; 17 - hydroxy - 16 - beta - methyl - 5 - beta - pregn - 9 ( 11 )- ene - 3 , 20 - dione ; 17 - hydroxy - 4 , 6 , 8 ( 14 )- pregnatriene - 3 , 20 - dione ; 17 - hydroxypregna - 4 , 9 ( 11 )- diene - 3 , 20 - dione ; 18 - hydroxycorticosterone ; 18 - hydroxycortisone ; 18 - oxocortisol ; 21 - acetoxypregnenolone ; 21 - deoxyaldosterone ; 21 - deoxycortisone ; 2 - deoxyecdysone ; 2 - methylcortisone ; 3 - dehydroecdysone ; 4 - pregnene - 17 - alpha , 20 - beta , 21 - triol - 3 , 11 - dione ; 6 , 17 , 20 - trihydroxypregn - 4 - ene - 3 - one ; 6 - alpha - hydroxycortisol ; 6 - alpha - fluoroprednisolone , 6 - alpha - methylprednisolone , 6 - alpha - methylprednisolone 21 - acetate , 6 - alpha - methylprednisolone 21 - hemisuccinate sodium salt , 6 - beta - hydroxycortisol , 6 - alpha , 9 - alpha - difluoroprednisolone 21 - acetate 17 - butyrate , 6 - hydroxycorticosterone ; 6 - hydroxydexamethasone ; 6 - hydroxyprednisolone ; 9 - fluorocortisone ; alclomethasone dipropionate ; aldosterone ; algestone ; alphaderm ; amadinone ; amcinonide ; anagestone ; androstenedione ; anecortave acetate ; beclomethasone ; beclomethasone dipropionate ; betamethasone 17 - valerate ; betamethasone sodium acetate ; betamethasone sodium phosphate ; betamethasone valerate ; bolasterone ; budesonide ; calusterone ; chlormadinone ; chloroprednisone ; chloroprednisone acetate ; cholesterol ; ciclesonide ; clobetasol ; clobetasol propionate ; clobetasone ; clocortolone ; clocortolone pivalate ; clogestone ; cloprednol ; corticosterone ; cortisol ; cortisol acetate ; cortisol butyrate ; cortisol cypionate ; cortisol octanoate ; cortisol sodium phosphate ; cortisol sodium succinate ; cortisol valerate ; cortisone ; cortisone acetate ; cortivazol ; cortodoxone ; daturaolone ; deflazacort , 21 - deoxycortisol , dehydroepiandrosterone ; delmadinone ; deoxycorticosterone ; deprodone ; descinolone ; desonide ; desoximethasone ; dexafen ; dexamethasone ; dexamethasone 21 - acetate ; dexamethasone acetate ; dexamethasone sodium phosphate ; dichlorisone ; diflorasone ; diflorasone diacetate ; diflucortolone ; difluprednate ; dihydroelatericin a ; domoprednate ; doxibetasol ; ecdysone ; ecdysterone ; emoxolone ; endrysone ; enoxolone ; fluazacort ; flucinolone ; flucloronide ; fludrocortisone ; fludrocortisone acetate ; flugestone ; flumethasone ; flumethasone pivalate ; flumoxonide ; flunisolide ; fluocinolone ; fluocinolone acetonide ; fluocinonide ; fluocortin butyl ; 9 - fluorocortisone ; fluocortolone ; fluorohydroxyandrostenedione ; fluorometholone ; fluorometholone acetate ; fluoxymesterone ; fluperolone acetate ; fluprednidene ; fluprednisolone ; flurandrenolide ; fluticasone ; fluticasone propionate ; formebolone ; formestane ; formocortal ; gestonorone ; glyderinine ; halcinonide ; halobetasol propionate ; halometasone ; halopredone ; haloprogesterone ; hydrocortamate ; hydrocortiosone cypionate ; hydrocortisone ; hydrocortisone 21 - butyrate ; hydrocortisone aceponate ; hydrocortisone acetate ; hydrocortisone buteprate ; hydrocortisone butyrate ; hydrocortisone cypionate ; hydrocortisone hemisuccinate ; hydrocortisone probutate ; hydrocortisone sodium phosphate ; hydrocortisone sodium succinate ; hydrocortisone valerate ; hydroxyprogesterone ; inokosterone ; isoflupredone ; isoflupredone acetate ; isoprednidene ; loteprednol etabonate ; meclorisone ; mecortolon ; medrogestone ; medroxyprogesterone ; medrysone ; megestrol ; megestrol acetate ; melengestrol ; meprednisone ; methandrostenolone ; methylprednisolone ; methylprednisolone aceponate ; methylprednisolone acetate ; methylprednisolone hemisuccinate ; methylprednisolone sodium succinate ; methyltestosterone ; metribolone ; mometasone ; mometasone furoate ; mometasone furoate monohydrate ; nisone ; nomegestrol ; norgestomet ; norvinisterone ; oxymesterone ; paramethasone ; paramethasone acetate ; ponasterone ; prednicarbate ; prednisolamate ; prednisolone ; prednisolone 21 - diethylaminoacetate ; prednisolone 21 - hemisuccinate ; prednisolone acetate ; prednisolone farnesylate ; prednisolone hemisuccinate ; prednisolone - 21 ( beta - d - glucuronide ); prednisolone metasulphobenzoate ; prednisolone sodium phosphate ; prednisolone steaglate ; prednisolone tebutate ; prednisolone tetrahydrophthalate ; prednisone ; prednival ; prednylidene ; pregnenolone ; procinonide ; tralonide ; progesterone ; promegestone ; rhapontisterone ; rimexolone ; roxibolone ; rubrosterone ; stizophyllin ; tixocortol ; topterone ; triamcinolone ; triamcinolone acetonide ; triamcinolone acetonide 21 - palmitate ; triamcinolone benetonide ; triamcinolone diacetate ; triamcinolone hexacetonide ; trimegestone ; turkesterone ; and wortmannin . standard recommended dosages for various steroid / disease combinations are provided in table 1 , below . other standard recommended dosages for corticosteroids are provided , e . g ., in the merck manual of diagnosis & amp ; therapy ( 17th ed . m h beers et al ., merck & amp ; co .) and physicians &# 39 ; desk reference 2003 ( 57 th ed . medical economics staff et al ., medical economics co ., 2002 ). in one embodiment , the dosage of corticosteroid administered is a dosage equivalent to a prednisolone dosage , as defined herein . for example , a low dosage of a corticosteroid may be considered as the dosage equivalent to a low dosage of prednisolone . two or more corticosteroids can be administered in the same treatment . equivalent potency in clinical dosing is well known . information relating to equivalent corticosteroid dosing may be found in the british national formulary ( bnf ), 37 march 1999 , the content of which is incorporated herein by reference . the bnf guidelines are included in table 2 below . more specifically , table 2 provides doses of corticosteroids equivalent to 5 mg of prednisolone and equivalent to 1 mg of prednisolone when administered in a manner according to this invention . the invention features unit dosage forms of dipyridamole of between 20 and 400 mg ( e . g ., 20 , 30 , 45 , 90 , 120 , 180 , 360 , or 400 mg ). these dosages can be formulated for controlled release ( e . g ., delayed release and sustained release ) or immediate release using the methods and compositions described herein . the combination of the invention may be optionally administered as a pharmaceutically acceptable salt , such as a non - toxic acid addition salts or metal complexes that are commonly used in the pharmaceutical industry . examples of acid addition salts include organic acids such as acetic , lactic , pamoic , maleic , citric , malic , ascorbic , succinic , benzoic , palmitic , suberic , salicylic , tartaric , methanesulfonic , toluenesulfonic , or trifluoroacetic acids or the like ; polymeric acids such as tannic acid , carboxymethyl cellulose , or the like ; and inorganic acid such as hydrochloric acid , hydrobromic acid , sulfuric acid phosphoric acid , or the like . metal complexes include zinc , iron , and the like . formulations for oral use include tablets containing the active ingredient ( s ) in a mixture with non - toxic pharmaceutically acceptable excipients , preferably an excipient from the gras listing . these excipients may be , for example , inert diluents or fillers ( e . g ., sucrose and sorbitol ), lubricating agents , glidants , and antiadhesives ( e . g ., magnesium stearate , zinc stearate , stearic acid , silicas , hydrogenated vegetable oils , or talc ). formulations for oral use may also be provided in unit dosage form as chewable tablets , tablets , caplets , or capsules ( e . g ., as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent , or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium ). the formulations of the invention include diluents ( e . g ., lactose monohydrate , cellulose , glyceryl monostearate , and / or dibasic calcium phosphate , among others ) and binders ( e . g ., polyvinylpyrrolidone , hypromellose , sucrose , guar gum , and / or starch ). any diluent or binder known in the art can be used in the methods , compositions , and kits of the invention . the formulations of the invention may also include controlled release coatings . such coatings include eudragit rl ®, eudragit rs ®, cellulose derivatives such as ethylcellulose aqueous dispersions ( aquacoat ®, surelease ®), hydroxyethyl cellulose , hydroxypropyl cellulose , hydroxypropyl methylcellulose , polyvinylpyrrolidone , polyvinylpyrrolidone / vinyl acetate copolymer , and opadry ®. the individually or separately formulated agents of the invention can be packaged together , or individually , as a kit . non - limiting examples include kits that contain , e . g ., two pills , a pill and a capsule , a capsule containing multiple bead formulations , etc . additionally , the unit dose kit can contain instructions for preparation and administration of the compositions . the kit may be manufactured as a single use unit dose for one patient , multiple uses for a particular patient ( at a constant dose or in which the individual compounds may vary in potency as therapy progresses ); or the kit may contain multiple doses suitable for administration to multiple patients (“ bulk packaging ”). the kit components may be assembled in cartons , blister packs , bottles , tubes , and the like . kits may also include instructions for administering the pharmaceutical compositions using any indication and / or dosing regimen described herein . further description of kits is provided in the examples . the following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compounds claimed herein are performed , made , and evaluated , and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention . dipyridamole and prednisolone were formulated in bead form and encapsulated in a standard size ‘ 0 ’ capsule . six distinct capsule strengths were manufactured to accommodate the unequal amounts of prednisolone given in the morning and afternoon , and to allow for dose ranging . a dosing regimen including 1 . 8 mg prednisolone + 180 mg dipyridamole administered at 0800 hours followed by 0 . 9 mg prednisolone + 180 mg dipyridamole administered at 1300 hours has been shown to be efficacious in subjects with rheumatoid arthritis ( ra ) and osteoarthritis ( oa ). in this previous study both active ingredients were formulated for immediate release . the strengths are shown in table 3 . the quantitative composition of the capsules is provided in table 4 and table 5 , where the first table gives the quantitative compositions of the three dosage strengths that contain 0 . 9 mg prednisolone with varying amounts of dipyridamole and the second table gives the quantitative compositions of the three dosage strengths that contain 1 . 8 mg prednisolone . the manufacturing process for formulations of the combinations of the invention includes three manufacturing steps followed by packaging : the manufacture of prednisolone beads , the manufacture of dipyridamole beads , and the manufacture of capsules and packaging . the prednisolone beads are manufactured by coating non - pareil seeds with prednisolone . the process is described in greater detail below and is shown schematically in fig1 . pvp ( kollidon 30 ) is dissolved in purified water using a lightnin &# 39 ; mixer , or other similar mixer . prednisolone is then added to the solution of pvp and water and mixed until a uniform suspension is formed . non - pareil seeds of mcc ( celphere cp - 708 ) are charged into the bowl of a fluid bed coater and pre - conditioned to temperature of 40 - 50 ° c . by fluidizing the bed . the prednisolone suspension is sprayed onto the fluidizing pre - conditioned non - pareil seeds at a constant rate of ˜ 100 g / minute ensuring that there is no agglomeration of the beads due to excessive wetting . care is taken to ensure that an appropriate spray rate is maintained so as to prevent spray drying of prednisolone . the product bed temperature is maintained within the range of 40 - 50 ° c . by maintaining the inlet air temperature range of 60 - 70 ° c . upon completion of the spray process , the prednisolone loaded beads are dried to a moisture content of less than 2 %. the dried beads are discharged and screened through a # 20 mesh sieve to remove any agglomerates . the screened beads are stored at room temperature 25 ° c . ( 15 to 30 ° c .) in fiber - board drums double lined with polyethylene bags . the prednisolone beads are analyzed for potency ( assay ) to determine the appropriate fill weight for the manufacture of the capsules . table 6 summarizes the quantitative compositions of prednisolone capsules . the dipyridamole beads are manufactured by extrusion spheronization . the manufacturing process for the dipyridamole beads is described in greater detail below and is shown schematically in fig2 . dipyridamole is screened using an oscillating mill fitted with a # 20 mesh screen and transferred into the bowl of a high shear granulator . mcc , pregelatinized starch and pvp are added to the oscillating mill successively to wash out any remaining dipyridamole . the milled materials are transferred into the bowl of a high shear granulator where they are dry blended for 5 minutes . a moisture sample of the dry blend is taken for information purposes only . the dry dipyridamole mix is then wet granulated using purified water as the granulating agent at a spray rate of 1200 g / minute till a dough is formed . samples are removed for determination of moisture content . the wet mass of the dipyridamole dough is passed through the 0 . 8 mm screen of the extruder and spheronized for about 7 minutes at 800 revolutions per minute ( rpm ) until rounded beads are formed . the wet beads are dried in an oven set at 60 ° c . until the moisture content is less than 1 . 4 %. the dried beads are stored at room temperature 25 ° c . ( 15 - 30 ° c .) in fiber - board drums double lined with polyethylene bags . the final beads are analyzed for potency ( assay ) to determine the appropriate fill weight for capsules . table 7 summarizes the quantitative compositions of dipyridamole capsules . the invention features controlled release dipyridamole ( dp ) beads . examples of such beads include tartaric acid beads coated with dipyridamole ( for example at a ratio of dipyridamole to tartaric acid of 1 : 0 . 8 ). such beads are further coated with a controlled release coating . suitable materials for the release controlling layer include eudragit rl ®, eudragit rs ®, cellulose derivatives such as ethylcellulose aqueous dispersions ( aquacoat ®, surelease ®), hydroxyethyl cellulose , hydroxypropyl cellulose , hydroxypropyl methylcellulose , polyvinylpyrrolidone , polyvinylpyrrolidone / vinyl acetate copolymer , and opadry ®. examples of manufacturing processes for the production of dipyridamole - coated acid beads ( e . g ., tartaric acid beads ) are set forth in the following examples . the capsule manufacturing process is described below and shown schematically in fig6 . the fill weight of each capsule is calculated based upon the percent weight / weight potency values of the prednisolone and dipyridamole beads . the quantity of each type of bead for the desired number of capsules is weighed and added to the bosch gkf 400 encapsulator along with empty capsules . the prednisolone and dipyridamole beads are filled into size “ 0 ” gray / gray capsules . during the encapsulation process , capsules are checked at pre - determined intervals for fill weight variation and proper capsule closure . the machine is adjusted if any deviation is found in the established fill weight . the filled capsules are stored at room temperature conditions of 25 ° c . ( 15 to 30 ° c .) in fiber - board drums double lined with polyethylene bags . the final capsules are tested for identity of the active ingredients , potency of prednisolone and dipyridamole , content uniformity , dissolution , presence and quantities of related substances and bioburden prior to release . dipyridamole / prednisolone capsules are packaged in blister packs using an uhlman packaging machine . bulk capsules are placed on a tray of the uhlman packager to flood feed the blister cavities . the sealing layers are placed over strips containing five capsules each and are heat sealed into place . the sealed strips are inspected at the beginning and end of the process and at 30 minute intervals during the process for proper seals and missed cavities and placed into a labeled holding container if found satisfactory . the holding container is stored in the warehouse for secondary packaging . the following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compounds claimed herein are performed , made , and evaluated , and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention . components used in the manufacture of dipyridamole beads with a controlled release coating of hydroxypropyl methylcellulose phthalate 55 are set forth in tables 8 - 11 ( variant b ). the manufacturing process is depicted schematically in fig3 and described in more detail below . manufacturing begins with the fluid bed coating of cellets , or alternative hthalate seeds , using a coating solution consisting of tartaric acid , pharmacoat 603 , isopropyl alcohol and water . the layering process continues until there is a total of 89 . 1 % w / w of tartaric acid loaded onto the cores . the 89 . 1 % tartaric acid pellets are then coated in the fluid bed with a protective seal coat consisting of kollidon 30 , talc , isopropyl alcohol and water to a level of 20 % weight gain . a dispersion consisting of dipyridamole , kollidon 30 and water is sprayed onto the seal coated tartaric acid cores using the fluid bed . the amount sprayed onto these cores allows for a final ratio of 1 : 0 . 8 ( dipyridamole : tartaric acid ). a coating solution consisting of hydroxypropyl methylcellulose hthalate 55 ( hpmc p - 55 ), triethyl citrate , ethanol and water is sprayed onto the dipyridamole layered pellets . the theoretical weight gain of the modified release coating sprayed onto the dp pellets is 20 %. the coated pellets are then cured in a tray drying oven for 2 hours at 40 ° c . the following is an exemplary protocol for manufacturing the hydroxypropyl methylcellulose hthalate 55 coated beads . dissolve kollidon 30 in isopropyl alcohol using a overhead stirrer under vortex to get a clear solution . disperse dipyridamole ( passed through # 40 sieve ) in the above solution to obtain a homogenous suspension . strain suspension through # 60 sieve . arrange the fluid bed processor with the bottom spray and the wurster column . load the wurster with seal coated tartaric acid beads . spray the suspension of dipyridamole onto the tartaric acid beads using a peristaltic pump at a desired spray rate . ensure that the suspension remains stirring throughout the coating process . coat the tartaric acid bead with the drug suspension . after spraying is complete , dry the drug layered beads in the fluid bed . dissolve hpmc p - 55 in a mixture of ethanol and purified water using an over - head stirrer under vortex stirring . add triethyl citrate and stir the solution for 20 minutes . pass the solution through # 80 sieve and use for coating . arrange the fluid bed processor with the bottom spray and the wurster column . load the wurster with drug loaded beads . spray the polymer solution onto the drug loaded beads using a peristaltic pump at a desired spray rate ensure that the coating solution is stirred throughout the coating process . dry and cure the polymer coated beads for 2 hours . components used in the manufacture of dipyridamole beads with a controlled release coating of of surelease ® and hpmc e5 ( in a ratio of 80 : 20 ) are set forth in tables 12 - 14 ( variant c ). the manufacturing process is depicted schematically in fig4 and described in more detail below . manufacturing begins with the fluid bed coating of cellets using a coating solution consisting of tartaric acid , pharmacoat 603 , isopropyl alcohol and water . the layering process continues until there is a total of 89 . 1 % w / w of tartaric acid loaded onto the cores . the 89 . 1 % tartaric acid pellets are then coated in the fluid bed with a protective seal coat consisting of kollidon 30 , talc , isopropyl alcohol and water to a level of 20 % weight gain . a dispersion consisting of dipyridamole , kollidon 30 and water is sprayed onto the seal coated tartaric acid cores using the fluid bed . the amount sprayed onto these cores allows for a final ratio of 1 : 0 . 8 ( dipyridamole : tartaric acid ). a coating solution consisting of surelease ®: hpmc e5 ( 80 : 20 ), glycerine and water is sprayed onto the dipyridamole layered pellets . the theoretical weight gain of the modified release coating sprayed onto the dp pellets is 15 %. the coated pellets are then dried and cured for 2 hours . dissolve kollidon 30 in isopropyl alcohol using a overhead stirrer under vortex to get a clear solution . disperse dipyridamole ( passed through # 40 sieve ) in the above solution to obtain a homogenous suspension . strain suspension through # 60 sieve . arrange the fluid bed processor with the bottom spray and the wurster column . load the wurster with seal coated tartaric acid beads . spray the suspension of dipyridamole onto the tartaric acid beads using a peristaltic pump at a desired spray rate . ensure that the suspension remains stirring throughout the coating process . after spraying is complete , dry the drug layered beads in the fluid bed . dissolve hpmc e5 in water at 60 - 70 ° c . using an overhead stirrer . cool solution until it attains room temperature and add glycerine while stirring . dilute the solution to the required concentration on surelease by adding water . pass solution through # 80 sieve and use for coating . continue to stir the solution throughout the coating process . dry and cure the coated beads for 2 hours . components used in the manufacture of dipyridamole beads with a controlled release coating of eudragit ® s100 and eudragit ® l100 ( in a ratio of 75 : 25 ) are set forth in tables 15 - 17 ( variant d ). the manufacturing process is depicted schematically in fig5 and described in more detail below . manufacturing begins with the fluid bed coating of cellets using a coating solution consisting of tartaric acid , pharmacoat 603 , isopropyl alcohol and water . the layering process continues until there is a total of 89 . 1 % w / w of tartaric acid loaded onto the cores . the 89 . 1 % tartaric acid pellets are then coated in the fluid bed with a protective seal coat consisting of kollidon 30 , talc , isopropyl alcohol and water to a level of 20 % weight gain . a dispersion consisting of dipyridamole , kollidon 30 and water is sprayed onto the seal coated tartaric acid cores using the fluid bed . the amount sprayed onto these cores allows for a final ratio of 1 : 0 . 8 ( dipyridamole : tartaric acid ). a coating solution consisting of eudragit ® s100 : eudragit ® l100 ( 75 : 25 ), triethyl citrate , talc , isopropyl alcohol and water onto the dipyridamole layered pellets . the theoretical weight gain of the modified release coating sprayed onto the dp pellets is 20 %. the coated pellets are then cured in a tray drying oven for 2 hours at 40 ° c . the following is an exemplary protocol for manufacturing the eudragit ® s100 : eudragit ® l100 ( 75 : 25 ) coated beads . dissolve kollidon 30 in isopropyl alcohol using an overhead stirrer under vortex to get a clear solution . disperse dipyridamole ( passed through # 40 sieve ) in the above solution to obtain a homogenous suspension . strain suspension through # 60 sieve . arrange the fluid bed processor with the bottom spray and the wurster column . load the wurster with seal coated tartaric acid beads . spray the suspension of dipyridamole onto the tartaric acid beads using a peristaltic pump at a desired spray rate . ensure that the suspension remains stirring throughout the coating process . after spraying is complete , dry the beads in the fluid bed . disperse eudragit ® l100 and eudragit ® s100 in ipa using an over - head stirrer . add purified water to suspension and stir to get clear solution . add triethyl citrate and talc to the above solution while stirring . pass the through # 80 sieve and use for coating . continue to stir the solution throughout the coating process . dry and cure the coated beads for 2 hours . components used in the manufacture of dipyridamole beads with a controlled release coating of eudragit ® s100 and eudragit ® l100 ( in a ratio of 75 : 25 ) are set forth in tables 18 - 20 ( variant d1 ). the manufacturing process is described in more detail below . manufacturing begins with the fluid bed coating of cellets using a coating solution consisting of tartaric acid , pharmacoat 603 , isopropyl alcohol and water . the layering process continues until there is a total of 89 . 1 % w / w of tartaric acid loaded onto the cores . the 89 . 1 % tartaric acid pellets are then coated in the fluid bed with a protective seal coat consisting of kollidon 30 , talc , isopropyl alcohol and water to a level of 20 % weight gain . a dispersion consisting of dipyridamole , kollidon 30 and isopropyl alcohol is sprayed onto the seal coated tartaric acid cores using the fluid bed . the amount sprayed onto these cores allows for a final ratio of 1 : 0 . 8 ( dipyridamole : tartaric acid ). a coating solution consisting of eudragit ® s100 : eudragit ® l100 ( 75 : 25 ), triethyl citrate , talc , isopropyl alcohol and water onto the dipyridamole layered pellets . the theoretical weight gain of the modified release coating sprayed onto the dp pellets is 10 %. the coated pellets are then cured in a tray drying oven for 2 hours at 40 ° c . the following is an exemplary protocol for manufacturing the eudragit ® s100 : eudragit ® l100 ( 75 : 25 ) coated beads . dissolve kollidon 30 in isopropyl alcohol using an overhead stirrer under vortex to get a clear solution . disperse dipyridamole in the above solution to obtain a homogenous suspension . strain suspension through # 100 mesh sieve . arrange the fluid bed processor with the bottom spray and the wurster column . load the wurster with seal coated tartaric acid beads . spray the suspension of dipyridamole onto the tartaric acid beads using a peristaltic pump at a desired spray rate . ensure that the suspension remains stirring throughout the coating process . after spraying is complete , dry the beads in the fluid bed . disperse eudragit ® s100 and eudragit ® l100 in water and 90 % of the ipa using an over - head stirrer . add purified water to suspension and stir to get clear solution . add triethyl citrate and mix for at least 15 minutes . in a separate container add water , 10 % of the ipa and talc , then homogenize for 10 minutes to form a dispersion . combine the talc dispersion and eudragit solution and mix for at least 30 minutes prior to coating . continue to stir the coating solution throughout the coating process . dry and cure the coated beads for 2 hours . components used in the manufacture of dipyridamole beads with a controlled release coating of eudragit ® s100 and eudragit ® l100 ( in a ratio of 75 : 25 ) are set forth in tables 21 - 23 ( variant d2 ). the manufacturing process is described in more detail below . manufacturing begins with the fluid bed coating of cellets using a coating solution consisting of tartaric acid , pharmacoat 603 , isopropyl alcohol and water . the layering process continues until there is a total of 89 . 1 % w / w of tartaric acid loaded onto the cores . the 89 . 1 % tartaric acid pellets are then coated in the fluid bed with a protective seal coat consisting of hpmc phthalate ph - 55 , triethyl citrate , isopropyl alcohol and acetone to a level of 15 % weight gain . a dispersion consisting of dipyridamole , kollidon 30 and isopropyl alcohol is sprayed onto the seal coated tartaric acid cores using the fluid bed . the amount sprayed onto these cores allows for a final ratio of 1 : 0 . 8 ( dipyridamole : tartaric acid ). a coating solution consisting of eudragit ® s100 : eudragit ® l100 ( 75 : 25 ), triethyl citrate , talc , isopropyl alcohol and water onto the dipyridamole layered pellets . the theoretical weight gain of the modified release coating sprayed onto the dp pellets is 10 %. the coated pellets are then cured in a tray drying oven for 2 hours at 40 ° c . the following is an exemplary protocol for manufacturing the eudragit ® s100 : eudragit ® l100 ( 75 : 25 ) coated beads . dissolve kollidon 30 in isopropyl alcohol using an overhead stirrer under vortex to get a clear solution . disperse dipyridamole in the above solution to obtain a homogenous suspension . strain suspension through # 100 mesh sieve . arrange the fluid bed processor with the bottom spray and the wurster column . load the wurster with seal coated tartaric acid beads . spray the suspension of dipyridamole onto the tartaric acid beads using a peristaltic pump at a desired spray rate . ensure that the suspension remains stirring throughout the coating process . drying : after spraying is complete , dry the beads in the fluid bed . disperse eudragit ® s100 and eudragit ® l100 in water and 90 % of the ipa using an over - head stirrer . add purified water to suspension and stir to get clear solution . add triethyl citrate and mix for at least 15 minutes . in a separate container add water , 10 % of the ipa and talc , then homogenize for 10 minutes to form a dispersion . combine the talc dispersion and eudragit solution and mix for at least 30 minutes prior to coating . continue to stir the coating solution throughout the coating process . dry and cure the coated beads for 2 hours . components used in the manufacture of prednisolone beads with a controlled release coating of eudragit ® s100 and eudragit ® l100 ( in a ratio of 75 : 25 ) are set forth in tables 24 - 26 ( variant e ). the manufacturing process is described in more detail below . a solution consisting of prednisolone , kollidon 30 and water is sprayed onto cellets using the fluid bed . the amount sprayed onto these cores allows for a final prednisolone amount to be 2 . 0 %. some 2 . 0 % prednisolone pellets are set aside to be used as the ir portion and some will be used for further processing to manufacture the delayed release portion . a solution consisting of kollidon va - 64 , pharmacoat 603 and water is sprayed onto prenisolone coated pellets using the fluid bed . the amount sprayed onto these cores allows for a final prednisolone amount to be 1 . 9 %. the 1 . 9 % prednisolone pellets are then further coated with a delayed release coating . a coating solution consisting of eudragit ® s100 : eudragit ® l100 ( 75 : 25 ), triethyl citrate , talc , isopropyl alcohol and water onto seal coated prednisolone layered pellets . the theoretical weight gain of the modified release coating sprayed onto the dp pellets is 25 %. the coated pellets are then cured in a tray drying oven for 8 hours at 40 ° c . the following is an exemplary protocol for manufacturing the eudragit ® s100 : eudragit ® l100 ( 75 : 25 ) coated beads . dissolve kollidon 30 in water using an overhead stirrer under vortex to get a clear solution . disperse prednisolone in the above solution to obtain a solution . arrange the fluid bed processor with the bottom spray and the wurster column . load the wurster with cellets . spray the prednisolone solution onto the cellets using a peristaltic pump at a desired spray rate . ensure that the solution remains stirring throughout the coating process . drying : after spraying is complete , dry the beads in the fluid bed . dissolve kollidon va - 64 in water and isopropyl alcohol using an overhead stirrer under vortex to get a clear solution . disperse pharmacoat 603 in the above solution and mix until dissolved . arrange the fluid bed processor with the bottom spray and the wurster column . load the wurster with prednisolone coated pellets . spray the seal coat solution onto the prednisolone pellets using a peristaltic pump at a desired spray rate . ensure that the solution remains stirring throughout the coating process . drying : after spraying is complete , dry the beads in the fluid bed . disperse eudragit ® s100 and eudragit ® l100 in water and 90 % of the ipa using an over - head stirrer . add purified water to suspension and stir to get clear solution . add triethyl citrate and mix for at least 15 minutes . in a separate container add water , 10 % of the ipa and talc , then homogenize for 10 minutes to form a dispersion . combine the talc dispersion and eudragit solution and mix for at least 30 minutes prior to coating . continue to stir the coating solution throughout the coating process . dry and cure the coated beads for 8 hours components used in the manufacture of prednisolone beads with a controlled release coating of eudragit ® s100 and eudragit ® l100 ( in a ratio of 75 : 25 ) are set forth in tables 27 - 29 ( variant f ). the manufacturing process is described in more detail below . a solution consisting of prednisolone , kollidon 30 and water is sprayed onto cellets using the fluid bed . the amount sprayed onto these cores allows for a final prednisolone amount to be 2 . 5 %. the 2 . 5 % prednisolone pellets are then further coated in order to contain an immediate release and delayed release functions . a solution consisting of kollidon va - 64 , pharmacoat 603 and water is sprayed onto prenisolone coated pellets using the fluid bed . the amount sprayed onto these cores allows for a final prednisolone amount to be 2 . 4 %. the 2 . 4 % prednisolone pellets are then further coated in order to contain an immediate release and delayed release functions . a coating solution consisting of eudragit ® s100 : eudragit ® l100 ( 75 : 25 ), triethyl citrate , talc , isopropyl alcohol and water onto seal coated prednisolone layered pellets . the theoretical weight gain of the modified release coating sprayed onto the dp pellets is 25 %. the coated pellets are then cured in a tray drying oven for 8 hours at 40 ° c . a solution consisting of prednisolone , kollidon 30 and water is sprayed onto dr coated prednisolone pellets using the fluid bed . the amount sprayed onto these cores allows for a final prednisolone amount to be 5 . 4 % total . the following is an exemplary protocol for manufacturing the eudragit ® s100 : eudragit ® l100 ( 75 : 25 ) coated beads . dissolve kollidon 30 in water using an overhead stirrer under vortex to get a clear solution . disperse prednisolone in the above solution to obtain a solution . arrange the fluid bed processor with the bottom spray and the wurster column . load the wurster with cellets . spray the prednisolone solution onto the cellets using a peristaltic pump at a desired spray rate . ensure that the solution remains stirring throughout the coating process . drying : after spraying is complete , dry the beads in the fluid bed . dissolve kollidon va - 64 in water and isopropyl alcohol using an overhead stirrer under vortex to get a clear solution . disperse pharmacoat 603 in the above solution and mix until dissolved . arrange the fluid bed processor with the bottom spray and the wurster column . load the wurster with prednisolone coated pellets . spray the seal coat solution onto the prednisolone pellets using a peristaltic pump at a desired spray rate . ensure that the solution remains stirring throughout the coating process . drying : after spraying is complete , dry the beads in the fluid bed . disperse eudragit ® s100 and eudragit ® l100 in water and 90 % of the ipa using an over - head stirrer . add purified water to suspension and stir to get clear solution . add triethyl citrate and mix for at least 15 minutes . in a separate container add water , 10 % of the ipa and talc , then homogenize for 10 minutes to form a dispersion . combine the talc dispersion and eudragit solution and mix for at least 30 minutes prior to coating . continue to stir the coating solution throughout the coating process . dry and cure the coated beads for 8 hours fig7 is a graph depiciting the dissolution profiles for variants b , c and d . fig8 is a graph depiciting the dissolution profiles for variants d1 and d2 . fig9 is a graph depiciting the dissolution profiles for variants e and f . all of these are in measured in simulated media as described herein . for the variant b prototype , there is an average release of 20 % dipyridamole in 0 . 1 n hcl within the first two hours . at the two - hour time point there is a media replacement where the prototype is added to a media containing a ph 6 . 8 phosphate buffer with 0 . 25 % sls . during this stage , the dipyridamole is release over time for a period of four hours . for the variant c prototype , there is an average release of 80 % dipyridamole in 0 . 1 n hcl within the first two hours . at the two - hour time point there is a media replacement where the prototype is added to a media containing a ph 5 . 5 acetate buffer with 0 . 25 % sodium lauryl sulfate . during this stage , the dipyridamole is release over time for a period of 22 hours . for the variant d prototype , there is an average release of 39 % dipyridamole in 0 . 1 n hcl within the first two hours . at the two - hour time point there is a media replacement where the prototype is added to a media containing a ph 6 . 8 phosphate buffer with 0 . 25 % sodium lauryl sulfate . during this stage , the dipyridamole is release over time for a period of six hours . we have discovered that headache , a side effect of dipyridamole therapy , can be reduced by reducing the rate of rise to cmax . to minimize the risk of headache the release of dipyridamole from the administered dosage form is modified such that in - vivo absorption rate constant ( ka ) is reduced ( e . g ., to between 0 . 2 to 0 . 90 l / hr ). for the sake of comparison , the absorption rate constant ( ka ) for dipyridamole formulated for immediate release is in the range of 1 . 19 to 1 . 54 l / hr . formulations that can reduce the incidence of headache include , for example , variant d . these conclusions are based upon the results of the clinical studies described below . this trial was an open - label , balanced , randomized , four - treatment , four - sequence , four - period , single - dose crossover comparative oral bioavailability study of immediate release and modified release formulations of dipyridamole 100 mg capsules , manufactured by m / s . rubicon research pvt ltd , mumbai , india for combinatorx in normal , healthy , adult , human subjects after a normal breakfast . t1 : dipyridamole variant a — dipyridamole immediate - release capsules 100 mg ( formula code x ) ( single - dose administration one 100 mg capsule in the morning per treatment period ); t2 : dipyridamole variant b — modified - release capsule ( single - dose administration one 100 mg capsule in the morning per treatment period ); t3 : dipyridamole variant c — modified - release capsule ( single - dose administration one 100 mg capsule in the morning per treatment period ); and t4 : dipyridamole variant d — modified - release capsule ( single - dose administration one 100 mg capsule in the morning per treatment period ). subjects were fasted overnight for at least 10 hours prior to scheduled time for a normal breakfast ( about 500 cal , description provided below ); dosing was done 30 minutes after the start of the breakfast . meals or snacks were provided at 4 , 8 , 12 , 24 , 28 , 32 , 36 and 48 hours after dosing in each period . seventeen blood samples were collected from each subject during each period . the venous blood samples ( 5 ml each ) were withdrawn at pre - dose ( within one and a half hours prior to normal breakfast ) and at times 0 . 25 , 0 . 5 , 0 . 75 , 1 . 0 , 1 . 5 , 2 . 0 , 3 . 0 , 4 . 0 , 6 . 0 , 8 . 0 , 10 . 0 , 12 . 0 , 16 . 0 , 24 . 0 , 36 . 0 and 48 . 0 hours after dosing . plasma samples were analyzed to quantify the concentration of dipyridamole using a validated lc / ms / ms bioanalytical method . pk solutions 2 . 0 ™ noncompartmental pharmacokinetic data analysis software by summit research services was used to estimate ( ka ) values for both ir and modified release dp data , which obeys two - compartment kinetics with first order absorption and elimination ( best described using a triexponential curve fit ). dosing occurred 30 minutes after eating the normal breakfast described below . portion size of food item may vary depending on the amount of water added during cooking all publications , patents , and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference . while the invention has been described in connection with specific embodiments thereof , it will be understood that it is capable of further modifications and this application is intended to cover any variations , uses , or adaptations of the invention following , in general , the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth , and follows in the scope of the claims .

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