the present invention is based upon the discovery of improved pharmaceutical compositions for administering nsaids to patients . in addition to containing one or more nsaids , the compositions include acid inhibitors that are capable of raising the ph of the gi tract of patients . all of the dosage forms are designed for oral delivery and provide for the coordinated release of therapeutic agents , i . e ., for the sequential release of acid inhibitor followed by analgesic . the nsaids used in preparations may be either short or long acting . as used herein , the term “ long acting ” refers to an nsaid having a pharmacokinetic half - life of at least 2 hours , preferably at least 4 hours and more preferably , at least 8 - 14 hours . in general , its duration of action will equal or exceed about 6 - 8 hours . examples of long - acting nsaids are : flurbiprofen with a half - life of about 6 hours ; ketoprofen with a half - life of about 2 to 4 hours ; naproxen or naproxen sodium with half - lives of about 12 to 15 hours and about 12 to 13 hours respectively ; oxaprozin with a half life of about 42 to 50 hours ; etodolac with a half - life of about 7 hours ; indomethacin with a half - life of about 4 to 6 hours ; ketorolac with a half - life of up to about 8 - 9 hours , nabumetone with a half - life of about 22 to 30 hours ; mefenamic acid with a half - life of up to about 4 hours ; and piroxicam with a half - life of about 4 to 6 hours . if an nsaid does not naturally have a half - life sufficient to be long acting , it can , if desired , be made long acting by the way in which it is formulated . for example , nsaids such as acetaminophen and aspirin may be formulated in a manner to increase their half - life or duration of action . methods for making appropriate formulations are well known in the art ( see e . g . remington &# 39 ; s pharmaceutical sciences , 16 th ed ., a . oslo editor , easton , pa . ( 1980 )). it is expected that a skilled pharmacologist may adjust the amount of drug in a pharmaceutical composition or administered to a patient based upon standard techniques well known in the art . nevertheless , the following general guidelines are provided : indomethacin is particularly useful when contained in tablets or capsules in an amount from about 25 to 75 mg . a typical daily oral dosage of indomethacin is three 25 mg doses taken at intervals during the day . however , daily dosages of up to about 150 mg are useful in some patients . aspirin will typically be present in tablets or capsules in an amount of between about 250 mg and 1000 mg . typical daily dosages will be in an amount ranging from 500 mg to about 10 g . however , low dose aspirin present at 20 - 200 mg ( and preferably 40 - 100 mg ) per tablet or capsule may also be used . ibuprofen may be provided in tablets or capsules of 50 , 100 , 200 , 300 , 400 , 600 , or 800 mg . daily doses should not exceed 3200 mg . 200 mg - 800 mg may be particularly useful when given 3 or 4 times daily . flurbiprofen is useful when in tablets at about from 50 to 100 mg . daily doses of about 100 to 500 mg , and particularly from about 200 to 300 mg , are usually effective . ketoprofen is useful when contained in tablets or capsules in an amount of about 25 to 75 mg . daily doses of from 100 to 500 mg and particularly of about 100 to 300 mg are typical as is about 25 to 50 mg every six to eight hours . naproxen is particularly useful when contained in tablets or capsules in an amount of from 250 to 500 mg . for naproxen sodium , tablets of about 275 or about 550 mg are typically used . initial doses of from 100 to 1250 mg , and particularly 350 to 800 mg are also used , with doses of about 550 mg being generally preferred . oxaprozin may be used in tablets or capsules in the range of roughly 200 mg to 1200 mg , with about 600 mg being preferred . daily doses of 1200 mg have been found to be particularly useful and daily doses should not exceed 1800 mg or 26 mg / kg . etodolac is useful when provided in capsules of 200 mg to 300 mg or in tablets of about 400 mg . useful doses for acute pain are 200 - 400 mg every six - eight hours , not to exceed 1200 mg / day . patients weighing less than 60 kg are advised not to exceed doses of 20 mg / kg . doses for other uses are also limited to 1200 mg / day in divided doses , particularly 2 , 3 or 4 times daily . ketorolac is usefully provided in tablets of 1 - 50 mg , with about 10 mg being typical . oral doses of up to 40 mg , and particularly 10 - 30 mg / day have been useful in the alleviation of pain . nabumetone may be provided in tablets or capsules of between 500 mg and 750 mg . daily doses of 1500 - 2000 mg , after an initial dose of 100 mg , are of particular use . mefenamic acid is particularly useful when contained in tablets or capsules of 50 mg to 500 mg , with 250 mg being typical . for acute pain , an initial dosage of 1 - 1000 mg , and particularly about 500 mg , is useful , although other doses may be required for certain patients . lomoxicam is provided in tablets of 4 mg or 8 mg . useful doses for acute pain are 8 mg or 16 mg daily , and for arthritis are 12 mg daily . other nsaids that may be used include : celecoxib , rofecoxib , meloxicam , piroxicam , droxicam , tenoxicam , valdecoxib , parecoxib , etoricoxib , cs - 502 , jte - 522 , l - 745 , 337 , or ns398 . jte - 522 , l - 745 , 337 and ns398 as described , inter alia , in wakatani , et al . ( jpn . j . pharmacol . 78 : 365 - 371 ( 1998 )) and panara , et al . ( br . j . pharmacol . 116 : 2429 - 2434 ( 1995 )). the amount present in a tablet or administered to a patient will depend upon the particular nsaid being used . for example : celecoxib may be administered in a tablet or capsule containing from about 100 mg to about 500 mg or , preferably , from about 100 mg to about 200 mg . piroxicam may be used in tablets or capsules containing from about 10 to 20 mg . rofecoxib will typically be provided in tablets or capsules in an amount of 12 . 5 , 25 or 50 mg . the recommended initial daily dosage for the management of acute pain is 50 mg . meloxicam is provided in tablets of 7 . 5 mg , with a recommended daily dose of 7 . 5 or 15 mg for the management of osteoarthritis . valdecoxib is provided in tablets of 10 or 20 mg , with a recommended daily dose of 10 mg for arthritis or 40 mg for dysmenorrhea . with respect to acid inhibitors , tablets or capsules may contain anywhere from 1 mg to as much as ig . typical amounts for h2 blockers are : cimetidine , 100 to 800 mg / unit dose ; ranitidine , 50 - 300 mg / unit dose ; famotidine , 5 - 100 mg / unit dose ; ebrotidine 400 - 800 mg / unit dose ; pabutidine 40 mg / unit dose ; lafutidine 5 - 20 mg / unit dose ; and nizatidine , 50 - 600 mg / unit dose . proton pump inhibitors will typically be present at about 5 mg to 600 mg per unit dose . for example , the proton pump inhibitor omeprazole should be present in tablets or capsules in an amount from 5 to 50 mg , with about 10 or 20 mg being preferred . other typical amounts are : esomeprazole , 5 - 100 mg , with about 40 mg being preferred ; lansoprazole , 5 - 150 mg ( preferably 5 - 50 mg ), with about 7 . 5 , 15 or 30 mg being most preferred ; pantoprazole , 10 - 200 mg , with about 40 mg being preferred ; and rabeprazole , 5 - 100 mg , with about 20 mg being preferred . the pharmaceutical compositions of the invention include tablets , dragees , liquids and capsules and can be made in accordance with methods that are standard in the art ( see , e . g ., remington &# 39 ; s pharmaceutical sciences , 16 th ed ., a oslo editor , easton , pa . ( 1980 )). drugs and drug combinations will typically be prepared in admixture with conventional excipients . suitable carriers include , but are not limited to : water ; salt solutions ; alcohols ; gum arabic ; vegetable oils ; benzyl alcohols ; polyethylene glycols ; gelatin ; carbohydrates such as lactose , amylose or starch ; magnesium stearate ; talc ; silicic acid ; paraffin ; perfume oil ; fatty acid esters ; hydroxymethylcellulose ; polyvinyl pyrrolidone ; etc . the pharmaceutical preparations can be sterilized and , if desired , mixed with auxiliary agents such as : lubricants , preservatives , disintegrants ; stabilizers ; wetting agents ; emulsifiers ; salts ; buffers ; coloring agents ; flavoring agents ; or aromatic substances . enteric coating layer ( s ) may be applied onto the core or onto the barrier layer of the core using standard coating techniques . the enteric coating materials may be dissolved or dispersed in organic or aqueous solvents and may include one or more of the following materials : methacrylic acid copolymers , shellac , hydroxypropylmethcellulose phthalate , polyvinyl acetate phthalate , hydroxypropylmethylcellulose trimellitate , carboxymethylethyl - cellulose , cellulose acetate phthalate or other suitable enteric coating polymer ( s ). the ph at which the enteric coat will dissolve can be controlled by the polymer or combination of polymers selected and / or ratio of pendant groups . for example , dissolution characteristics of the polymer film can be altered by the ratio of free carboxyl groups to ester groups . enteric coating layers also contain pharmaceutically acceptable plasticizers such as triethyl citrate , dibutyl phthalate , triacetin , polyethylene glycols , polysorbates or other plasticizers . additives such as dispersants , colorants , anti - adhering and anti - foaming agents may also be included . preferably , the combination of an acid inhibitor and an nsaid will be in the form of a bi - or multi - layer tablet . in a bilayer configuration , one portion of the tablet contains the acid inhibitor in the required dose along with appropriate excipients , agents to aid dissolution , lubricants , fillers , etc . the second portion of the tablet will contain the nsaid , preferably naproxen , in the required dose along with other excipients , dissolution agents , lubricants , fillers , etc . in the most preferred embodiment , the nsaid layer is surrounded by a polymeric coating which does not dissolve at a ph of less than 4 . the nsaid may be granulated by methods such as slugging , low - or high - shear granulation , wet granulation , or fluidized - bed granulation . of these processes , slugging generally produces tablets of less hardness and greater friability . low - shear granulation , high - shear granulation , wet granulation and fluidized - bed granulation generally produce harder , less friable tablets . a schematic diagram of a four layer tablet dosage form is shown in fig1 . the first layer contains naproxen sodium distributed throughout a matrix of pharmaceutically acceptable fillers , excipients , binding agents , disintegrants , and lubricants . the second layer is a barrier layer which protects the first layer containing naproxen sodium . the barrier film coat is applied by conventional pan coating technology and the weight of the barrier coat may vary from 1 % to 3 % of the core tablet weight . in particular embodiments , the core naproxen sodium tablet is coated with coating ingredients such as opaspray ® k - 1 - 4210a or opadry ® ys - 1 - 7006 ( colorcon , west point , pa .). polymer film coating ingredients such as hydroxypropylmethylcellulose 2910 and polyethylene glycol 8000 in a coating suspension may also be used . the function of the third layer is to prevent the release of naproxen sodium until the dosage form reaches an environment where the ph is above about 4 or 5 . the enteric coating does not dissolve in areas of the gi tract where the ph may be below about 4 or 5 such as in an unprotected stomach . methacrylic acid copolymers are used as the enteric coating ingredient , triethyl citrate and dibutyl phthalate are plasticizers , and ammonium hydroxide is used to adjust the ph of the dispersion . the coating dissolves only when the local ph is above , for example , 5 . 5 and , as a result , naproxen sodium is released . the outermost layer contains an “ acid inhibitor ” in an effective amount which is released from the dosage form immediately after administration to the patient . the acid inhibitor in the present example is a proton pump inhibitor or , preferably the h2 blocker famotidine , which raises the ph of the gastrointestinal tract to above 4 . the typical effective amount of famotidine in the dosage form will vary from 5 mg to 100 mg . a typical film coating formulation contains opadry clear ® ys - 1 - 7006 which helps in the formation of the film and in uniformly distributing famotidine within the fourth layer without tablets sticking to the coating pan or to each other during application of the film coat . other ingredients may include : plasticizers such as triethyl citrate , dibutyl phthalate , and polyethylene glycol ; anti - adhering agents such as talc ; lubricating ingredients such as magnesium stearate ; and opacifiers such as titanium dioxide . in addition , the ph of the film coating solution can be adjusted to aid in dissolution of the famotidine . the film coating is thin and rapidly releases famotidine for absorption . core tablet ingredients % w / w mg / tablet naproxen sodium , usp 74 . 074 500 . 00 microcrystalline cellulose , nf 17 . 166 115 . 87 ( avicel ph 200 ) povidone ( k29 / 32 ), usp 3 . 450 23 . 29 talc , usp 4 . 350 29 . 36 magnesium stearate , nf 0 . 960 6 . 48 total 100 . 00 675 . 00 fig2 illustrates a three layered dosage form which releases famotidine immediately after ingestion by the patient in order to raise the ph of the gastrointestinal tract to above about 4 . the innermost layer contains naproxen uniformly distributed throughout a matrix of pharmaceutically acceptable excipients . these excipients perform specific functions and may serve as binders , disintegrants , or lubricants . a pharmaceutically acceptable enteric coating surrounds the naproxen core . the function of the enteric coat is to delay the release of naproxen until the dosage form reaches an environment where the ph is above about 4 . the coating does not dissolve in the harshly acidic ph of the unprotected stomach . it contains methacrylic acid copolymers which prevent the release of naproxen in the unprotected stomach . also included are : triethyl citrate , a plasticizer ; simethicone emulsion , an anti - foaming agent ; and sodium hydroxide which is used to adjust the ph of the dispersion . the outermost layer contains an “ acid inhibitor ” in an effective amount which is released from the dosage form immediately after administration to the patient . the acid inhibitor in this example is a proton pump inhibitor or , preferably , the h2 blocker famotidine which raises the ph of the stomach to above 4 . a typical film coating formulation contains opadry clear ® ys - 1 - 7006 which helps in the formation of the film and in uniformly distributing famotidine in the fourth layer without tablets sticking to the coating pan or sticking to each other during application of the film coat . other ingredients are : plasticizers such as polyethylene glycol 8000 ; anti - adhering agents such as talc ; lubricating ingredients such as magnesium stearate ;, and opacifiers such as titanium dioxide . in addition , the ph of the film coating solution can be adjusted to aid in dissolution of the famotidine . the film coating is thin and rapidly releases famotidine for absorption . core tablet ingredients % w / w mg / tablet naproxen , usp 90 . 91 500 . 00 povidone k - 90 , usp 2 . 00 11 . 00 starch , usp 2 . 59 14 . 25 croscarmellose sodium , usp 4 . 00 22 . 00 magnesium stearate , nf 0 . 50 2 . 75 total 100 . 00 550 . 00 purified water , usp qs a trilayer tablet which separates famotidine contained in the film coat from controlled - release naproxen may be used in the present invention . the core tablet of naproxen is formulated using excipients which control the drug release for therapeutic relief from pain and inflammation for 24 hours . fig2 shows an example of an appropriate trilayer tablet . in this particular example , naproxen is mixed with a polymeric material , hydroxypropyl - methylcellulose and granulated with water . the granules are dried , milled , and blended with a lubricant , such as magnesium stearate . they are then compacted into tablets . the controlled - release core tablet of naproxen is film coated with a pharmaceutically acceptable enteric coating . the function of the enteric coat is to delay the release of naproxen until the dosage form reaches an environment where the ph is above about 4 . the coating does not dissolve in the extremely acidic ph of the unprotected stomach . the function of methacrylic acid copolymers is to prevent the release of naproxen until the ph of the stomach rises . triethyl citrate is a plasticizer , simethicone emulsion is a anti - foaming agent , and sodium hydroxide is used to adjust the ph of the dispersion . the outermost layer contains an “ acid inhibitor ” which is released from the dosage form immediately after administration to the patient . the acid inhibitor in the present example is a proton pump inhibitor or , preferably , the h2 blocker famotidine which consistently raises the ph of the stomach to above 4 . the typical effective amount of famotidine in the dosage will vary from 5 mg to 100 mg . a typical film coating formulation contains opadry blue ® ys - 1 - 4215 which is essential for film formation and for the uniform application of famotidine to the core tablet . polymer film coating ingredients , hydroxypropylmethylcellulose or opaspray ® k - 1 - 4210a ( colorcon , west point , pa .) may also be used . other ingredients which help in the formation of the film and in the uniform application of famotidine to the core tablet are : plasticizers such as triethyl citrate and dibutyl phthalate ; anti - adhering agents such as talc ; lubricating ingredients such as magnesium stearate ; and opacifiers such as titanium dioxide . in addition , the ph of the film coating solution can be adjusted to aid in dissolution of the famotidine . the film coating is thin and rapidly releases famotidine for absorption . core tablet ingredients % w / w mg / tablet naproxen , usp 94 . 00 750 hydroxypropyl methylcellulose 5 . 00 39 . 9 2208 , usp ( viscosity 15000 cps ) magnesium stearate , nf 1 . 00 7 . 95 total 100 . 00 797 . 85 a trilayer tablet which separates famotidine contained in the film coat from controlled - release naproxen and famotidine may be used in the present invention . the core tablet of naproxen and famotidine is formulated using excipients which control the drug release for therapeutic relief from pain and inflammation for 24 hours . fig2 is an example of an appropriate trilayer tablet . in this particular example , naproxen and famotidine are mixed with a polymeric material , hydroxypropylmethylcellulose and granulated with water . the granules are dried , milled , and blended with a lubricant , such as magnesium stearate . they are then compacted into tablets . the controlled - release core tablet of naproxen and famotidine is film coated with a pharmaceutically acceptable enteric coating . the function of the enteric coat is to delay the release of naproxen until the dosage form reaches an environment where the ph is above about 4 . the coating does not dissolve in the extremely acidic ph of the unprotected stomach . the function of methacrylic acid copolymers is to prevent the release of naproxen until the ph of the stomach rises . triethyl citrate is a plasticizer , simethicone emulsion is a anti - foaming agent , and sodium hydroxide is used to adjust the ph of the dispersion the outermost later contains an “ acid inhibitor ” which is released from the dosage form immediately after administration to the patient . the acid inhibitor in the present example is a proton pump inhibitor or , preferably , the h2 blocker famotidine which consistently raises the ph of the stomach to above 4 . the typical effective amount of famotidine in the dosage will vary from 5 mg to 100 mg . a typical film coating formulation contains opadry blue ® ys - 1 - 4215 which is essential for film formation and for the uniform application of famotidine to the core tablet . polymer film coating ingredients , hydroxypropylmethylcellulose or opaspray ® k - 1 - 4210a ( colorcon , west point , pa .) may also be used . other ingredients which help in the formation of the film and in the uniform application of famotidine to the core tablet are : plasticizers such as triethyl citrate and dibutyl phthalate ; anti - adhering agents such as talc ; lubricating ingredients such as magnesium stearate ; and opacifiers such as titanium dioxide . in addition , the ph of the film coating solution can be adjusted to aid in dissolution of the famotidine . the film coating is thin and rapidly releases famotidine for absorption . core tablet ingredients % w / w mg / tablet naproxen , usp 88 . 05 500 famotidine , usp 3 . 52 20 . 0 hydroxypropyl methylcellulose 7 . 03 39 . 9 2208 , usp ( viscosity 15000 cps ) magnesium stearate , nf 1 . 40 7 . 95 total 100 . 00 567 . 85 enteric coated naproxen sodium core and pantoprazole immediate release in film coat a schematic diagram of a four layer tablet dosage form is shown in fig1 . the first layer contains naproxen sodium distributed throughout a matrix of pharmaceutically acceptable fillers , excipients , binding agents , disintegrants , and lubricants . the second layer is a barrier layer which protects the first layer containing naproxen sodium . the barrier film coat is applied by conventional pan coating technology and the weight of the barrier coat may vary from 1 % to 3 % of the core tablet weight . in particular embodiments , the core naproxen sodium tablet is coated with coating ingredients such as opaspray ® k - 1 - 4210a or opadry ® ys - 1 - 7006 ( colorcon , west point , pa .). polymer film coating ingredients such as hydroxypropylmethylcellulose 2910 and polyethylene glycol 8000 in a coating suspension may also be used . the third layer is an enteric film coat . it does not dissolve in areas of the gi tract where the ph may be below 4 such as in an unprotected stomach but it dissolves only when the local ph is above about 4 . therefore , the function of the third layer is to prevent the release of naproxen sodium until the dosage form reaches an environment where the ph is above 4 . in this example , hydroxypropylmethylcellulose phthalate is the enteric coating ingredient , cetyl alcohol is a plasticizer and acetone and alcohol are solvents . the fourth layer contains an “ acid inhibitor ” in an effective amount which is released from the dosage form as soon as the film coat dissolves . the acid inhibitor in this example is a proton pump inhibitor , pantoprazole , which raises the ph of the gastrointestinal tract to above 4 . the typical effective amount of pantoprazole in the dosage form may vary from 10 mg to 200 mg . the film coat is applied by conventional pan coating technology and the weight of film coat may vary from 4 % to 8 % of the core tablet weight . other ingredients are , plasticizers such as triethyl citrate , dibutyl phthalate , anti - adhering agents such as talc , lubricating ingredients such as magnesium stearate , opacifiers such as , titanium dioxide , and ammonium hydroxide to adjust the ph of the dispersion . the film coating is thin and rapidly releases pantoprazole for absorption . therefore , pantoprazole releases first and then the core erodes and releases naproxen sodium . core tablet ingredients % w / w mg / tablet naproxen sodium , usp 74 . 075 500 . 00 microcrystalline cellulose , nf 17 . 165 115 . 87 ( avicel ph 200 ) povidone ( k29 / 32 ), usp 3 . 450 23 . 29 talc , usp 4 . 350 29 . 36 magnesium stearate , nf 0 . 960 6 . 48 total 100 . 00 675 . 00 naproxen sodium , 50 % microcrystalline cellulose and povidone are dry mixed and wet granulated in an appropriate granulator with sufficient purified water . the wet granules are dried , milled , and blended with the remaining 50 % microcrystalline cellulose , talc and magnesium stearate . the final granule blend is compressed into tablets . barrier film coating ingredients % w / w opadry ® clear ys - 1 - 7006 5 . 00 purified water , usp 95 . 00 total 100 . 00 opadry clear is added slowly to purified water and mixing is continued until opadry is fully dispersed . the solution is sprayed on to the tablet cores in a conventional coating pan until proper amount of opadry clear is deposited on the tablets . enteric coating ingredients % w / w hydroxypropyl methylcellulose phthalate , nf 5 . 5 cetyl alcohol , nf 0 . 3 acetone , nf 66 . 3 alcohol , usp 27 . 9 total 100 . 00 hydroxypropylmethylcellulose phthalate and cetyl alcohol are dissolved in a mixture of alcohol and acetone . the solution is then sprayed on to the tablet bed in proper coating equipment . a sample of the tablets is tested for gastric resistance and the coating stopped if the tablets pass the test . pantoprazole film coating ingredients % w / w pantoprazole sodium , usp 5 . 00 opadry ® clear ys - 1 - 7006 5 . 00 sodium carbonate , nf 1 . 20 purified water , usp 88 . 80 total 100 . 00 pantoprazole sodium is dissolved in purified water containing sodium carbonate in solution . after thorough mixing , opadry clear is added slowly and mixing is continued until opadry is fully dispersed . the suspension is sprayed on to the tablet cores in a conventional coating pan until the proper amount of pantoprazole sodium is deposited . enteric coated naproxen sodium core and omeprazole immediate release in film coat a schematic diagram of a four layer tablet dosage form is shown in fig1 . the first layer contains naproxen sodium distributed throughout a matrix of pharmaceutically acceptable fillers , excipients , binding agents , disintegrants , and lubricants . the second layer is a barrier layer which protects the first layer containing naproxen sodium . the barrier film coat is applied by conventional pan coating technology and the weight of the barrier coat may vary from 1 % to 3 % of the core tablet weight . in particular embodiments , the core naproxen sodium tablet is coated with coating ingredients such as opaspray ® k - 1 - 4210a or opadry ® ys - 1 - 7006 ( colorcon , west point , pa .). polymer film coating ingredients such as hydroxypropylmethylcellulose 2910 and polyethylene glycol 8000 in a coating suspension may also be used . the third layer is an enteric film coat . it does not dissolve in areas of the gi tract where the ph is below 4 such as in an unprotected stomach but it dissolves only when the local ph is above 4 . therefore , the function of the third layer is to prevent the release of naproxen sodium until the dosage form reaches an environment where the ph is above about 4 . in this example , hydroxypropylmethylcellulose phthalate is the enteric coating ingredient , cetyl alcohol is a plasticizer and acetone and alcohol are solvents . the fourth layer contains an “ acid inhibitor ” in an effective amount which is released from the dosage form as soon as the film coat dissolves . the acid inhibitor in this example is a proton pump inhibitor , omeprazole , which raises the ph of the gastrointestinal tract to above 4 . the typical effective amount of omeprazole in the dosage form may vary from 5 mg to 50 mg . the film coat is applied by conventional pan coating technology and the weight of film coat may vary from 4 % to 8 % of the core tablet weight . other ingredients are , plasticizers such as triethyl citrate , dibutyl phthalate , anti - adhering agents such as talc , lubricating ingredients such as magnesium stearate , opacifiers such as , titanium dioxide , and ammonium hydroxide to adjust the ph of the dispersion . the film coating is thin and rapidly releases omeprazole for absorption . therefore , omeprazole is released first and then the core erodes and releases naproxen sodium . core tablet ingredients % w / w mg / tablet naproxen sodium , usp 74 . 075 500 . 00 microcrystalline cellulose , 17 . 165 115 . 87 nf ( avicel ph 200 ) povidone ( k29 / 32 ), usp 3 . 450 23 . 29 talc , usp 4 . 350 29 . 36 magnesium stearate , nf 0 . 960 6 . 48 total 100 . 00 675 . 00 naproxen sodium , 50 % microcrystalline cellulose and povidone are dry mixed and wet granulated in an appropriate granulator with sufficient purified water . the wet granules are dried , milled , and blended with the remaining 50 % microcrystalline cellulose , talc and magnesium stearate . the final granule blend is compressed into tablets . barrier film coating ingredients % w / w opadry ® clear ys - 1 - 7006 5 . 00 purified water , usp 95 . 00 total 100 . 00 opadry clear is added slowly to purified water and mixing is continued until opadry is fully dispersed . the solution is sprayed on to the tablet cores in a conventional coating pan until the proper amount of opadry clear is deposited on the tablets . enteric coating ingredients % w / w methacrylic acid copolymer , nf 6 . 0 ( eudragit l - 100 - 55 ) triethyl citrate , nf 0 . 6 talc , usp 3 . 0 purified water , usp 5 . 0 isopropyl alcohol , usp 85 . 40 total 100 . 00 methacrylic acid copolymer , triethyl citrate , and talc are dissolved in a mixture of isopropyl alcohol and water . the solution is then sprayed on to the tablet bed in a proper coating equipment . a sample of the tablets is tested for gastric resistance and the coating is stopped if the tablets pass the test . omeprazole film coating ingredients % w / w omeprazole , usp 5 . 00 opadry ® clear ys - 1 - 7006 5 . 00 purified water , usp 10 . 00 isopropyl alcohol , usp 80 . 00 total 100 . 00 omeprazole is dissolved in a purified water and isopropyl alcohol mixture . after thorough mixing , opadry clear is added slowly and mixing is continued until opadry is fully dispersed . the suspension is sprayed on to the tablet cores in a conventional coating pan until proper amount of omeprazole is deposited on the tablets . a coordinated delivery dosage may be used to provide fast release of an acid inhibitor , a proton pump inhibitor , omeprazole which raises the ph of the gastrointestinal tract to above 4 , and the delayed release of a non - steroidal anti - inflammatory drug , naproxen sodium . omeprazole granules modify the ph of the stomach such that the drug readily dissolves and is absorbed in the stomach without significant degradation . the typical effective amount of omeprazole in the dosage form may vary from 5 mg to 50 mg . the release of naproxen sodium is delayed by enteric coating . omeprazole granules contain an alkalizing excipient such as sodium bicarbonate . other soluble alkalizing agents such as potassium bicarbonate , sodium carbonate , sodium . hydroxide , or their combinations may also be used . the alkalizing agent helps solubilize and protect omeprazole from degradation before its absorption . sodium lauryl sulfate helps in the wetting of omeprazole . other surfactants may be used to perform the same function . in the present example , hydroxypropyl methylcellulose helps in granule formation , sodium starch glycolate is a disintegrant , and magnesium stearate is a lubricant . other excipients may also be used to perform these functions . naproxen sodium pellets as shown in fig3 are prepared by the wet massing technique and the conventional extrusion and spheronization process . the excipients used in the formulation are microcrystalline cellulose , and povidone . the pellets after drying and classification are coated with a protective subcoating containing povidone . other coating ingredients may also be used such as opaspray k - 1 - 4210a or opadry ys - 1 - 7006 ( trademarks of colorcon , west point , pa .). polymer film coating ingredients such as hydroxypropylmethylcellulose 2910 and polyethylene glycol 8000 in a subcoating suspension are also alternatives . other ingredients are , plasticizers such as triethyl citrate , dibutyl phthalate , anti - adhering agents such as talc , lubricating ingredients such as magnesium stearate , opacifiers such as , titanium dioxide . the subcoated pellets are enteric coated using enteric coating polymers . in this example , the enteric coating polymer is methacrylic acid copolymer and the plasticizer is dibutyl phthalate which are dissolved in a mixture of acetone and alcohol . the enteric film does not dissolve in the acidic ph but dissolves when the ph in the gut is above about ph 6 and releases naproxen sodium . mmmomeprazole granules % w / w mg / capsule omeprazole , usp 12 . 9 20 . 00 sodium bicarbonate , usp 82 . 40 127 . 72 hydroxypropyl methylcellulose , usp 2 . 00 3 . 10 sodium lauryl sulfate , nf 0 . 20 0 . 31 sodium starch glycolate , nf 2 . 00 3 . 10 magnesium stearate , nf 0 . 50 0 . 77 total 100 100 hydroxypropylmethylcellulose is dissolved in water , then sodium lauryl sulfate is added and the solution is mixed . omeprazole , microcrystalline cellulose , and sodium bicarbonate are dry mixed together and granulated with the granulating solution . the granulation is mixed until proper granule formation is reached . the granulation is then dried , milled , and blended with magnesium stearate . pellet ingredients % w / w mg / tablet naproxen sodium , usp 86 . 80 250 . 00 microcrystalline cellulose , nf 11 . 10 32 . 00 ( avicel ph 200 ) povidone ( k90 ), usp 2 . 10 6 . 00 total 100 . 00 288 . 00 povidone is dissolved in water . naproxen sodium and microcrystalline cellulose are dry mixed and granulated with povidone solution . the wet mass is mixed until proper consistency is reached . the wet mass is then pressed through an extruder and spheronized to form pellets . the pellets are then dried and classified into suitable particle size range . subcoat ingredients % w / w povidone ( k29 - 32 ), usp 10 . 00 alcohol , usp 90 . 00 total 100 . 00 the pellet cores are coated using povidone solution by a conventional coating pan method to a weight gain of 1 - 2 %. enteric coating ingredients % w / w methacrylic acid copolymer , nf 8 . 20 ( eudragit l - 100 ) diethyl phthalate , nf 1 . 70 acetone , nf 33 . 30 isopropyl alcohol , usp 56 . 80 total 100 . 0 eudragit l - 100 is dissolved in isopropanol and acetone and diethyl phthalate is dissolved . the solution is sprayed on the pellet cores using proper film coating equipment . a sample of the pellets is tested for gastric resistance before stopping the coating process . omeprazole fast release granules and naproxen sodium delayed release pellets are blended together and filled into appropriate size capsules to contain 250 mg naproxen sodium and 20 mg omeprazole per capsule . the present example is directed to a coordinated delivery dosage form containing omeprazole and naproxen . the formulation contains 10 mg omeprazole and uses methylcellulose as a binder and croscarmellose sodium as a disintegrant . naproxen pellets as shown in fig3 do not need a subcoating layer and are enteric coated with an aqueous dispersion of methacrylic acid copolymer . optionally , these pellets could be compressed into a core and film coated with an acid inhibitor and thereby form a bilayer tablet . omeprazole granules % w / w mg / capsule omeprazole , usp 6 . 45 10 . 00 sodium bicarbonate , usp 88 . 85 137 . 71 methylcellulose , usp 2 . 00 3 . 10 sodium lauryl sulfate , nf 0 . 20 0 . 31 croscarmellose sodium , nf 2 . 00 3 . 10 magnesium stearate , nf 0 . 50 0 . 78 total 100 100 methylcellulose is dissolved in water , then sodium lauryl sulfate is added to the solution and mixed . omeprazole , microcrystalline cellulose , and sodium bicarbonate are dry mixed together and granulated with the granulating solution . the granulation is mixed until proper granule formation is reached . the granulation is then dried , milled , and blended with magnesium stearate . pellet ingredients % w / w mg / tablet naproxen , usp 76 . 250 . 00 microcrystalline cellulose , nf 21 . 71 . 44 ( avicel ph 200 ) povidone ( k90 ), usp 2 . 6 . 56 total 100 . 328 . 00 povidone is dissolved in water . naproxen and microcrystalline cellulose are dry mixed and granulated with povidone solution . the wet mass is mixed until proper consistency is reached . the wet mass is then pressed through an extruder and spheronized to form pellets . the pellets are then dried and classified into a suitable particle size range . enteric coating ingredients % w / w methacrylic acid copolymer , nf 15 . 60 ( eudragit l30d 30 % dispersion ) talc , usp 7 . 60 triethyl citrate , nf 1 . 60 simethicone emulsion , usp 0 . 20 ( silicone antifoam emulsion se 2 ) purified water , usp 74 . 80 eudragit 30d is dispersed in purified water and simethicone emulsion . talc and triethyl citrate are then dispersed . the suspension is sprayed on the pellet cores using proper film coating equipment . a sample of the pellets is tested for gastric resistance before stopping the coating process . omeprazole fast release granules and naproxen sodium delayed release pellets are blended together and filled into appropriate size capsules to contain 250 mg naproxen and 10 mg omeprazole per capsule . sixty - two subjects were enrolled in a clinical study and randomly assigned to three groups . the following three groups were administered study medication twice daily for five days : ( a ) 550 mg naproxen sodium ( n = 10 ), ( b ) 40 mg famotidine given with 550 mg of naproxen or famotidine followed 90 minutes later by 550 mg naproxen , ( n = 39 ) or ( c ) 20 mg omeprazole followed by 550 mg naproxen sodium ( n = 13 ). gastric ph was measured hourly beginning at the time of dosing of the final daily dose of study medication and for 8 - 10 hours thereafter . subjects had a gastric endoscopy performed at the beginning and on day 5 prior to the morning dose of study medication to identify gastric and duodenal irritation ; no subjects were admitted to the study if gastric irritation was present at the time of initial endoscopy . five patients , three ( 33 %) in the naproxen alone group and two ( 5 %) in the famotidine / naproxen group , presented with gastroduodenal ulcers at the end of the study . in the naproxen alone group , the ph was greater than 4 only 4 % of the time , and in the famotidine / naproxen group the ph was greater than 4 forty - nine percent of the time during the 8 - 10 hours following naproxen sodium dosing . additionally , lanza grade 3 or 4 damage was present in 28 % ( n = 11 ) of the subjects receiving famotidine / naproxen sodium , and present 100 % ( n = 10 ) in the naproxen sodium treatment group . monitoring of gastric acidity on day 5 indicated that patients with lanza scores of greater than 2 had integrated gastric acidity of greater than 100 mmol - hr ./ l . only 20 - 40 % of patients with integrated gastric acidity of less than 100 mmol - hr / l had gastric pathology , whereas all patients with integrated gastric acidity greater than 100 mmol - hr / l had pathology . famotidine and enteric coated naproxen reduce gastroduodenal damage due to nsaid therapy thirty - seven patients were randomized to two groups for a one week study of twice - daily dosing of : 500 mg enteric coated naproxen , and 500 mg enteric coated naproxen preceded by 40 mg famotidine . endoscopies were conducted on all patients prior to first dosing and on the final day of the study . no subjects had evidence of gastroduodenal damage at the beginning of the study ( at first endoscopy ). at the second endoscopy , lanza scores for gastroduodenal damage were assessed for all subjects . 39 % of the subjects in the enteric coated naproxen 500 mg group had grade 3 - 4 gastroduodenal damage . this is lower than the percentage that would be expected for the administration of 500 mg of non - enteric naproxen based upon previous work . nevertheless , subjects administered 500 mg enteric coated naproxen and 40 mg famotidine had an even lower incidence of grade 3 - 4 gastroduodenal damage ( 26 %) than subjects who had previously taken enteric coated naproxen alone which demonstrates the value of combining acid inhibition with enteric coating of nsaid to minimize the gastrointestinal damage . all references cited herein are fully incorporated by reference . having now fully described the invention , it will be understood by those of skill in the art that the invention may be performed within a wide and equivalent range of conditions , parameters and the like , without affecting the spirit or scope of the invention or any embodiment thereof .
the present invention is directed to drug dosage forms that release an agent that raises the ph of a patient &# 39 ; s gastrointestinal tract , followed by a non - steroidal anti - inflammatory drug . the dosage form is designed so that the nsaid is not released until the intragastric ph has been raised to a safe level . the invention also encompasses methods of treating patients by administering this coordinated release , gastroprotective , antiarthritic / analgesic combination unit dosage form to achieve pain and symptom relief with a reduced risk of developing gastrointestinal damage such as ulcers , erosions and hemorrhages .