CA2178686A1 - Oral formulations of s(+)-etodolac - Google Patents

Abstract

This invention discloses organoleptically acceptable formulations containing S(+)1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, preferably with an acidic component, also known as S(+)etodolic acid or S(+)etodolac.

Description

OR~-, FORMU-,ATIONS OF S(+)-F.TODO-,AC

This invention relates to novel formulations of etodolac, also known as etodolacacid. More particularly, this invention relates to organoleptically acceptable oral 5 formulations ~1tili~ing S(+)- etodolac. For the purposes of this description, organoleptically acceptable compounds, m~t~ri~l~ and form~ ti~ ns are those which can contact the taste receptors of the recipients mouth and which are generally acceptable to the senses of the recipient, particularly the sense of taste. More particularly, the organoleptically acceptable formulations of this invention are those in which the S(+)-10 etodolac colll~nelll does not have the unpleasant, bitter taste normally associated witha racemic mixture of etodolac.

~ckyround of the Tnvention Etodolac is a nonsteroidal ~ntiinfl~"~ r),y drug (NSAID) that exhibits anti-infl~."..-~t~?ly, analgesic, and antipyretic activities in animal models. Like that of other NSAIDs, the mechanism of etodolac is not completely understood, but is believed to be ty1 with an inhibition of prost~gl~n-lin biosynthesis. Etodolac is presently .n~.l..ot~l by Wyeth-Ayerst Laboratories in the form of Lodine~ tablets and capsules, which utilize a racemic mixture of etodolac.

U.S. Patent No. 3,939,178 (Demerson et al.) teaches and claims certain pyrano[3,4-B]indoles and thiopyrano[3,4-B]indoles which include the (+) 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-B]indole-l-acetic acid ingredient of Lodine~ tablets and capsules.

U.S. Patent No. 4,710,511 (Wooley) discloses a method of using etodolac compositions for inhibiting joint ankylosis for the Ll~alllæll~ of arthritides. U.S. Patent No. 4,742,076 teaches a method of using such compounds for lowering rheumatoid factor blood level. U.S. Patent No. 4,966,768 (Michelucci et al.) describes a sustained release form of etodolac having as essçnti~l components etodolac, hydroxypropylmethylcellulose, ethylcellulose and a release rate modifying agent such as dibasic sodium phosphate, the hydroxypropylmethylcellulose having a hydroxypropoxyl content of about 7.0% to 8.6% by weight.

Demerson et al. disclose in the Journal of Medicinal Chemistry, 1983, Vol. 26, No 12, pp. 1778-1780, that bioch~mir~l and ph~rm~ological tests showed that virtually all of the effects of etodolac are due to the S(+) enantiomer.
s PCT application WO 93/17680 teaches methods and compositions lltili7ing optically pure R(-) etodolac for the LlcaLll~nl of pain. WO 93/17680 in~ t~s that the optically pure R(-) etodolac substantially reduces certain pul~lLcd adverse effects associated with the a lministration of the racemic llfi~llllC of etodolac.
Because of its unpleasant, bitter taste, etodolac has not, without some form of coating or taste-masking, been fully utilized in many formulations which would allow the etodolac to contact the recipient's taste buds. It is, therefore, ~i~nifi~:~nt that this invention provides organoleptically acceptable formulations cc.~ -g uncoated and15 llnm~k~l etodolac as an active ingredient. It is also signifi~nt that the production of the formulations of this invention do not require the additional form~ tion steps of coating the etodolac ingredient or incorporating taste m~C~ing ingredients into the formulations.

Descri~tion of the ~nvention Etodolac is a pyranocarboxylic acid chemically design~ted as (+) 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, also known as etodolic acid, which has the structural formula:

,~,~ N ~ ~CH2COOH
~ ~J

and is ~ Lly m~rketed as a racemic mixture in Lodine~) etodol~c tablets and capsules by Wyeth-Ayerst Laboratories, Division of ~ ..;c~ll Home Products Corporation, 2 1 7 ~ 6 ~ 6 AHP-94179 ..~

P.O. Box 8299, Philadelphia, PA 19101. Etodolac is a non-steroidal anti-infl~ ol~ drug (NSAID) that exhibits anti-infl~ l-..y, analgesic and antipyreticactivities, which are well documented in the art. FtoW ~ can be prepared by methods known in the art, such as those described in U.S. Patent No. 3,939,178 (Demerson et S al.), which is incorporated herein by reference. The r~<em~t~s of etodolac may also be resolved by methods known in the art. For instance, they may be resolved by the cryst~lli7~tion of diastereomeric salts with (+)-cinchonine to afford (+)-etodolac of al)plv~ at~ly 100% enantiomeric purity in an overall yield of 81%, with recovery of the (+)-cinchonine, as described in U.S. Patent No. 4,520,203 (Abraham et al.).
It has been discovered that the d~ rolatc,ly or S(+) form of etodolac, S(+) 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, which may also be referred to herein as the ~;U~OIllt;l of etodolac or the etodolac eutomer, does not contain the unpleasant, bitter taste of the racemic etodolac. It is, therefore, now understood and 15 considered as within the scope of this invention that the use of the S(+) stereoisomer of etodolac substantially free of its R(-) form, preferably free of its R(-) form, enables one to create a wide variety of etodolac formulations which are pharmaceutically andorganoleptically acceptable for oral ~lmini~tration.

Not only does this knowledge provide those skilled in the art the ability to create organoleptically ~ccept~l le etodolac f(lrm~ tions, it does so without the need for the additional steps of coating or taste m~ing the etodolac. In many cases, the technique for coating ph~rm~eutical m~tçri~l~ is imperfect, leaving a portion of the compound in question ~ces.cible to the taste buds. Likewise, in formulations where chewing is likely to occur, the grinding action of the teeth can puncture coated particles in the form~ ti~n to release some of the unpleasant tasting m~tçri~l By starting with an acceptable tasting base ingredient, the form~ tions of this invention elimin:~t~ the chance of an unexpected release of unpleasant m~tçri~l~ This improvement not only improves the m~rkot~hility and reduces production costs of such formulations, it can also improve the recipient's compliance with a prescribed dosage regimen.

In view of this knowledge, the present invention comprises organoleptically ~cept~hle oral forml-l~ti~ ns comprising, alone or in conjunction with other organoleptically and pharmaceutically acceptable components, the S(+) stereoisomer of etodolac substanti~lly free of its R(-) form, preferably free of its R(-) form. These oral formulations include those orally a~lmini~terable formulations in which active ingredients and other cc~ pol-ents of the form-llation may normally be presented to the taste and or smell receptors of the recipient. Such f~ rmlllations include, but are not S limited to, organoleptically acceptable etodolac liquid dispersions, suspensions, emulsions, syrups, colloids, sachets, tablets, including chewable, buccal and sublingual tablets, powders or granular compositions, effervescent formulations,cachets, troches or lozenges, pastes, foams, dentifrices and gels. Because of the use of NSAIDs in veterinary medicine, formulations which are organoleptically acceptable to 10 anim~l~, particularly cc,lllpallion animals such as cats and dogs, can be produced within the scope of this invention.

In its simplest form, this invention comprises an organoleptically ~cep~ble etodolac formulation which comprises the etodolac eutomer, alone. This compound 15 may be taken alone for the relief described in the art for etodolac. The ~U~Cn~ of etodolac may also be taken with water, fruit juices, soft drinks, milk or other liquids or beverages being used to assist in the oral a-lministration of the drug. Other simplified a~lmini~trations can include the a~lmini~tration of the ~U~C~Illc;l to food, which may then be consumed in the normal fashion. These food-related or drink-related routes of20 ~lmini~tration may be pl~;relled by any llulll~r of recipients, particularly children.

It is pl~,rell~d that the form~llati~ ns of this invention col-lai~ g the etodolac ~u~oll~r also contain an acidic component of sufficient amount to m~intain the pH of the formlllation below 7, preferably between 2 and 6. Pharma~e~1tically acceptable acids 25 for use in these formulations include, but are not limited to, commonly used food acids such as citric acid, t~aric acid, malic acid, fumaric acid, lactic acid, adipic acid, ascorbic acid, aspartic acid, erythorbic acid, ghltami~ acid, and succinic acid.
The etodolac eutomer-con~illing compositions of this invention may be used in 30 the manner and for the dosages suggested for the Lodine(~ tablets and capsules presently on the market. It will be understood by those skilled in the art that etodolac, like other NSAIDs, may exhibit a variation in response from individual to individual.
Therefore, the recommended initial therapeutic dose should be one which is likely to be effective for the majority of recipients, with the dosage being adjusted th.,.
according to the beneficial and adverse effects observed by the recipient.

Etodolac a.l..lil~ lion in healthy, young to middle-aged adults has shown S ~yml)t~ relief for acute pain lasting 5 to 6 hours following single etodolac doses of 400 mg and relief lasting 4 to 5 hours following 200 mg doses. Formulations of this invention include dosage of the etodolac eulom~ from as low as 10 mg or lower to as high as 1,000 mg or more. A recom,..r~-~led etodolac dosage for the form~ ons ofthis invention would be an initial 200 - 400 mg dose, followed every 6 to 8 hours by doses of 50 mg to 400 mg, preferably 200 mg to 400 mg. For relief of the ~ymplollls of osteoarthritis, a starting dose of 800 to 1200 mg/day in divided doses may berequired. These divided doses may be 400 mg t.i.d. or b.i.d. or 300 mg q.i.d. or t.i.d.
As with other NSAIDs, the lowest dose and longest dosing interval which alleviates symptoms is recommended. The reco.. ~ d total daily dose of etodolac using thecolll~o~ilions described and claimed herein is 600 to 1200 mg/day given in divided doses, such as 400 mg t.i.d. or b.i.d., 300 mg q.i.d., t.i.d. or b.i.d., or 200 mg q.i.d.
or t.i.d. It will be understood that, despite the amount of etodolac t;UI~lllC;l listed in the ex~rnrles that follow, the formulations below may be created with any dose of the etodolac eulo~ described above.
While the etodolac ~ululll~ of this invention does not impart an undesirable taste to form~ tions in which it is used, the form~ 3tions described herein may include ~weetenillg or flavoring agents to increase the overall flavor, taste and desirability of the formulation. Such ~weelening agents may include all ph~rm~reutir~lly acc~lc 25 ~weelelling agents including, but not limited to, molasses, glycine, corn syrup, sugars, such as sucrose, glucose, fructose and confectioner's sugar, sorbitol, saccharin, saccharose, saccharin sodium, saccharin calcium, a~ ;ulle (available under the Nutrasweet~) trademark, Nutrasweet Company, Deerfield, Illinois), stevioiside, neohesperidyl dihydrochalcone, glycyrrhiza, perillaldehyde, xylitol, dextrose, m~nnil-)l 30 and lactose.

The formulations herein may also include ph~lllaceutically acceptable excipients, fillers, diluents, lubricants, disintegrants, suspending or stabilizing agents, and binding agents including, but not limited to, magnesium stearate, sodium lauryl sulfate, microcrystalline cellulose, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, m~nnitol, sodium chloride, talc, dry starch (e.g. corn, potato or tapioca starch) and powdered sugar.

In a simple form, the formulations of this invention would include powdered or granular dosage form~ tions cont~ining the etodolac ~u~ læl. For instance, the t;u~ æl can be taken orally, by itself, in a powdered or granular form. The recipient may wish to place such a powdered or granular fr~rm~ tion into his mouth and wash it 10 down by ~lrinking a liquid or eating a solid food. Because of the relatively small volume of S(+) etodolac found in the dosages described herein, it may be preferable to include in the powdered or granular dosage form one or more organoleptically acceptable powdered ph~rm~reuti~l components. These may be compounds with additional pharrnaceutical activities or fillers, sweeteners, etc. as described herein. It 15 will be understood that any dosage of etodolac eu~on~ can be a-lmini~tored in this way, with the volume of additional components being limited only to the amount found acceptable to a recipient.
With the use of this S(+) ~;u~ullæl of etodolac, organoleptically acceptable oral 20 liquid etodolac dosage forms can be fi~rmlll~te l and lltili7yl Such liquid formulations may be created with a water base.

These oral liquids may include any oral liquid form~ tions utili7ing the eul~llæof etodolac, including the mere incol~l~ion of the desired dose of etodolac t;ululll~,l 25 into a normally consumed amount of beverages and drinks including for example, but not limited to, carbonated or non-carbonated water, fruit juices, coffee, tea, soft drinks and milk. Because of the relatively small volume occupied by a single dose of the etodolac eu~ome~, it may be preferable to incorporate the eutomer into a small, manageable amount of one or more ph~rm~euti~lly elegant and organoleptically 30 acceptable materials, such as those described herein.

In one type of pler~llc;d oral liquid of this invention, the oral liquid comprises from about 0.8% to about 4% etodolac eu~ r weight by volume of the total composition, about 0.1% to about 2% weight by volume of the total composition of 2 1 7 86~6 AHP-94179 suspension stabilizing agents, about 20% to about 70% by weight of the total composition of one or more flavoring agents, about 30% to about 70% weight by volume of the total composition of water, with the composition conlaining a ~hal.,.a~e~lir~lly and organoleptically acceptable food acid, such as citric acid or 5 phosphoric acid, in an amount of 0.1 % to about 2% weight by volume. Preferably the suspending agents include xanthan gum, microcrystalline cellulose, sodium ca~ y~ hylcelluloseand poly~olbale 80. Examples 1 and 2, below, describe how two such formulations may be produced.
Fxam~le 1 Percent Grams Per ~redient Wt/Vol. 15 ,iters Xantha~ Gum 0.15 22.5 Microcrystalline Cellulose 0.75 112.5 Sodium Benzoate, NF 0.25 37.5 Citric Acid, Monohydrate, USP 0.95 142.5 Sucrose, NF 50 00 7500 0 Corn Syrup 20.00 3000.00 Etodolac, Eutomer 2.0 300.0 Sodium Carboxymethylcellulose, USP0.10 15.0 Polysorbate 80, NF 0.30 45 0 RedFDC40Color 0.15 2.25 Disodium Fdet~te, USP 0.05 7.5 Ar~ficial Lime Flavor Oil 0.16 24.0 Phosphoric Acid q.s. to pH 3.0-3.5 q.s. to pH 3.0-3.5 Purified Water, USP q.s. to 100 mL q.s. to 15000 mL

A first portion of this oral liquid form~ tion may be prepared by first placing the Sorbitol solution and glycerin portions into a j;lc~et~A kettle equipped with a stirrer.
Then the sodium carboxymethyl cellulose component is sprinkled onto the solution and mixed for 10 minutes until it becomes col~ letcly wet. The mixture should then be 35 heated to about 70 C and mixed until the gum is comrl~t~ y hydrated, followed by cooling of the llli~lUle to 45 C and addition of the polysorbate 80 component. Mixing 21786~6 AHP-94179 is con~in-le~l while cooling the mixture to 30 C. The etodolac, eu~ r is sprinkled slowly into the mixture and mixing continued for 15 minutes.

A second portion is then created by placing the required amount of water into a S container equipped with a propeller-type mixer and adding slowly and hydrating the x~nth~n gum by mixing with a high shear for al)p~ a~ly 25 minutes. This should be followed by placing into a separate mixing vessel, equipped with a propeller type mixer, a (luanlily of water equivalent to about 30% to 40% by volume of the total batch (4500 to 6000 mL). The microcrystalline cellulose may then be sprinlded onto the10 water and mixed at m~ lm shear for about 30 min~1tes to completely disperse the cellulose.

The required amount of the xanthan gum solution from the first portion, above, is added to the cellulose suspension with mixing for about 15 minutes or until a15 uniform suspension is obtained. This is followed by slow addition of the sucrose with mixing for about 15 minutes, or until no sucrose particles are observed. Coloring agents, such as the Red FDC 40 Color mentioned above, may be added and mixed until dispersed throughout the Imi~lUlC;.

This is followed by addition of the slurry from the first portion, above, and slowly mixing for about 15 minlltes The sodium benzoate, disodium edetate and citric acid and flavoring are then added and mixed for about S minutes after each addition.
The phosphoric acid cc~ onent is added with mixing until the formlll:~tion reaches a pH from about 3.0 to about 3.5. The final f(~rmlll~tion should be balanced with water and mixed until the form.ll~tion is homogenous.

F~n~le 2 Another example of an oral liquid fonnlll~tion ~tili7ing S(+) 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, the eulc~llæl of etodolac, is the following:

Percent Grams Per In~redier~t W~ht/Vol. 15 I,iters Xanthan Gum 0.15 22.5 Microcrystalline Cellulose 0.75 112.5 Sodium Benzoate, NF 0.25 37.5 CitricAcidHydrous, USP 0.95 142.5 Sucrose, NF 50.00 7500.0 Glycerin, USP 10.00 1500.00 Sorbitol Solution, USP 10.00 1500.00 Etodolac Eutomer 2.0 300.0 Sodium Carboxymethylcellulose, USP 0.10 15.0 Polysorbate 80, NF 0.30 45.0 Red FDC 40 Color 0.15 2.25 Disodium Edetate, USP 0.05 7.5 Artificial Lemon Flavor Oil 0.16 24.0 Hydrochloric Acid q.s. to pH 2.5-3.5 q.s. to pH 2.5-3.5 Purified Water, USP q.s. to 100 mL q.s. to 15000 rnL

This ~lc~al~Lion may be prepared by m~ lnng the sorbitol solution and glycerin into a jacketed kettle equipped with a stirrer. Into this solution is sprinkled the sodium carboxymethylcellulose, which is mixed for 10 minutes or until all of theparticles are completely wet. The reslll~ing mixture is then heated to about 70 C and mixed until the gum is completely hydrated, after which the mixture is cooled to 45 C
and the Polysorbate 80 is added. Mixing is then continued while the mixture is cooled to 30 C. The etodolac euLoll~el is then added slowly into the mixture and mixing is continued for l5 minules to produce what is referred to below as the etodolac slurry.

A second solution, which may be referred to as the xanthan gum solution, is prcpalcd first in the form of a 1% by weight xanthan gum solution in water. The n gum should be added slowly to the water and mixed at high shear for a~pl~ aLcly 25 minutes. Into a separate mixing vessel equipped with a mixer is placed a volume of water equivalent to 30% to 40% weight by volume of the total batch (45aO to 6000 ml). The microcrystalline cellulose is then sprinkled onto the water and mixed at m.-Aium shear for 30 minutes or until the microcrystalline cellulose is 2 ~ 7 8 6 8 6 AHP-94179 completely suspended. The required amount of ~nth~n gum solution is then added to the microcryst~lline cellulose suspension with mixing for 15 minutes or until a uniro suspension is obtained.

S The sucrose is then added slowly to the second solution with mixing for 15 min~ltes or until no sucrose particles are observed. The coloring agents may then be added. The required amount of the etodolac slurry is then added slowly and mixed for 15 minutes. The sodium benzoate, disodium edetate and cit~ic acid are then seq~lçnti~lly added and mixed for S minutes following each addition. The hydrochloric acid coml)ollellt is added with mixing until the formulation reaches a pH from about 2.5 to about 3.5. The rem~intler of the water is then added with mixing until the formulation is homogenous.
Fxam~le 3 Chewable Tablets Con~ai~ lg the F.todol~ Eutomer:
Chewable tablets conlaining the etodolac ~uLom~l and falling within the scope ofthis invention will be understood to include those chewable tablet formulations known in the art to be ph~"-~elltically and organoleptically acceptable. These formulations will include those having a) etodolac eulolll~l in the dosage amounts described herein;
b) from about S mg to about 400 mg, preferably from about 10 mg to about 200 mg, of a solid acidifier colllpollent, such as the food acid components described herein; and c) from about 50 mg to about 5 g, preferably from about 100 mg to about 1 g, of a ph~. "-~e~ltic~lly and organoleptically acceptable excipient, such as dextrates,maltodextrins, lactose, modified food starches, ~11l.";~.ll"~ stearate, chewing gum base, and comp~rt~hle food grade sugars, as well as other materials suitable as filler and carrier agents. Optionally, these chewable tablet formulations may contain up to about 100 mg of a ph~,.~ellti~lly acceptable glidants or lubricants. An example of such a chewable tablet is provided below:

Input For 1000 ~n~redier ts Tablet T~blet~
Etodolac Eutomer 200 mg 0.200 kg Citric Acid, USP 0.020 kg Manitol, USP 0.532 kg Polyethylene Glycol, 8000, NF, Powdered 0.144 kg Flavor-Spea~ t, Aromalok, 180235, Fritzsche 0.00480 kg Aluminum Stearate, USP 0.00580 kg TheoreticalTabletWeight = 916.6 mg MAnufActuring Procedure For Etodolac Eutomer Chew Tablets:

15 Precaution: - All operations must be carried out at a relative humidity not excee~ling 30 and at a temperature not exceeding 27C (80F).

Chewable tablets of this fi rmlllAtion may be prepared by first blending the Etodolac Eutomer, Sorbitol, Citric Acid Polyethylene Glycol 9000, and Spearmint 20 Flavor in a blender for about 10 minutes. This is followed by passing this newly formed blend through a mill using a #14 screen, medium speed, knives forward. Then add the Al~ llm Stearate to the mixture and blend for about one (1) minute. Thisblended mixture should then be compressed into tablets of the correct weight using a 5/8" flat, round, beveled edge punch and die set.
The organoleptically acceptable etodolac ~ul~ln~ form--lAtions of this inventionalso include effervescing or foaming formulations. These formulations include any ~h~ A~ ;rAl composition which utilizes the etodolac eutomer in an effervescing formulation, particularly those containing an effervescing or foaming combination of an 30 organoleptically acceptable acid, such as a food grade acid, and a carbonate.PLa.--.A~e~1ticAlly acceptable acids for use in these fi)rmlllAtions include, but are not limited to, citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, ascorbic acid, aspartic acid, erythorbic acid, ~llltAmic acid, and succinic acid. Glycine may also be used as part of the acidic cc,lllponent, if desired, but it is most pler~lled that glycine not 35 comprise the majority of the acidic component. It is most pl~r~ d that the acidic com~onent of these effervescent form~ ions exceed that of the carbonate component to create an effervescent solution with a pH below 7, more preferably below 6.

The carbonates may include any effervescing or foaming carbonate which is 5 ph~rm~euh~lly and organoleptically acceptable, including, but not l~mited to, sodium bica,l~nat~, potassium carbonate, sodium carbonate, calcium calbollale, alnll~..-ulll carbonate, magnesium call,onate, and the like. It is understood that the acidic and carbonate colllponents of these formulations may comprise one or more of the acceptable acids or carbonates.
In the broadest sense, the effervescent or foaming formulations of this invention comprise the active etodolac en~Qm~r plus any active all~unL~ of the acid and carbonate colll~nents. Preferably, the portions of these three colll~onents comprise a) the desired amount of the etodolac ~ulolll~l, b) from about 0.1% to about 50% by weight 15 of the acid component and c) from about 0.1% to 50% by weight of the carbonate component.

For instance, a single dose of this drug may comprise a) 10-1,000 mg of etodolac eu~ , b) 0.5 - 8 g citric acid, or an equivalent amount of one or more of 20 the other acceptable acids described herein, and c) 0.5 - 8 g of sodium bicarbonate, or an equivalent amount of one or more of the ~rcept~le carbonates described herein. It will be understood by those skilled in the art that the components of these form~ hons may be varied depending upon the required dosage of the drug, the desired amount of effervescence or foaming to be created, as well as the pH of the liquid into which the 25 formlll~hon will be added.

It is also understood that, in addition to these three components, the effervescent or foaming formulations of this invention may include any additional ph~rm~euhr~lly and organoleptically acceptable com~nents, including, but not limited 30 to, fillers, flavoring agents, coloring agents, sweetening agents, binders, pharmaceutically acceptable odor enhancing agents, perfumes, etc. These formulations may also include other ph~rm~reutically active agents, such as analgesics, ~ntihi~ es, antacids, anti-gas agents, etc. Examples of effervescent or foaming formulations within the scope of this invention include the following:

2l 7~686 Effervescing Powders Co"liii~-illg the Etodolac F~ltom~r One hundred dose batches of an effervescing or foaming powder of this invention S can be made by mixing together any of the following combinations, with or without ~ lition~l components:

F,Y~nU~Ie 4 a) 1,000 to 100,000 mg etodolac eutomer b) 110 g tartaric acid c) 100 g sodium bicarbonate F,Y~l~le 5 a) 1,000 to 100,000 mg etodolac eutomer b) 150 g malic acid c) 150 g fumaric acid lS d) 100 grams calcium carbonate e) 180 grams m~g-~si ulll carbonate e) 100 g fructose F,Y~l~le 6 a) 1,000 to 100,000 mg etodolac eutomer b) 250 g citric acid c) 125 g potassium carbonate d) 100 g ammonium carbonate F,Y~nU~Ie 7 a) 1,000 to 100,000 mg etodolac eutomer b) 10 g citric acid c) 10 g sodium bicarbonate d) 40 g sucrose e) 10 g sorbitol f) 10 g ,.I~ ilQl g) 10 g hydroxypropyl cellulose h) S g carbo~ymelllyl cellulose F~mDle 8 Effervescent Tablets Co/.~ g the Etodolac Eutomer:
To make five hundred 200 mg effervescent tablets:

~m I~rediellt Amo--nt Per T~blet 1 Etodolac eutomer, micronized 100 g 200 mg 2 Sodium Bicarbonate 386 g 3 Tartaric Acid 164 g 4 CitricAcid 250 g Polyethylene Glycol 6000 100 g Theoretical Tablet Weight 2.0 G

Manufacturing Procedure:

20 Precautions: After Step #1 all processes to be accomplished in an envi~ ællt which does not exceed 30% relative humidity and 27C.
1. ~ry Items 1, 2, 3, and 4 at from 80C to 105C for from 1 hour to 4 hours.
2. Blend Items 1, 2, 3 and 4 to make a homogeneous powder.
3. Pass the blend from Step #2 through a 60 mesh sieve.
4. Pass Item #5, through a 60 mesh sieve.

5. Add the screened Item #5 to the blend from Step #3 and blend to onlyjust distribute.

6. Compress using a flat, beveled edge, 5/8", punch and die to a 2.0 g tablet weight.
Directions for Use:
Place the desired dose, 200 mg per tablet, into a liquid, such as about three fluid ounces of water, and wait for the tablet to completely disintegrate.

F,xPn~le 9 Effervescent Granules with the Etodolac Eutomer:

To make 500 sachets or packets of effervescent granules, use the ingredients of Example No. 8 replacing Item No. 5 with dry orange flavor powder (from Virginia Dare, Brooklyn, NY 11232) and replacing Step No. 6 of Example 8 with the following two steps:

Step No. 6: Place the powder obtained from procedure Step No. 5 in a fluidized bed tower and when the powder is suspended with air, add enough water mist to create granules approaching 10 mesh in size.

Step No. 7: Add heat to dry the granules and remove to a not greater than 25% relative h~lmi(lity area to package in hermetic packets at 2.0 g each.

These effervescent granules may be orally ~rlmini~t~red after merely adding the desired number of packets of granules to water and waiting until all granules disintegrate.
Rapidly Disintegrating Solid Dosage Forms Another form in which the organoleptically acceptable compositions of this invention may take are the rapidly dissolving or disintegrating dosage formnl~tions, such as those described in U.S. Patent No. 4,371,516, the disclosure of which isinccn~ol~led herein by reference. These dosing forms are preferably soluble solid forms which are designed to break down in a matter of seconds upon contact with liquids, such as water or the saliva of the recipients mouth. These formulationspreferably ~ int~grate within 10 seconds of contact with liquids. Such formulations are especi~lly useful for ~rlmini~t~ring medicines to pediatric or geri~tric patients or others who may not be receptive to the heahl~ellt and who may attempt to spit out the m~icine or hide a non~ integrating form in their mouth until it can be thrown away later.

While the process for making rapidly disintegrating dosage forms which are useful with this invention are described in detail in U.S. Patents Nos. 4,371,516 (Gregory et al.) and 4,305,502 (Gregory et al.), the following examples demonstrate the production of rapidly disintegrating dosage forms col.~il~ing pl~relled dosage S ranges of the etodolac eul~llæi.
F~n~le 10 75 individual 50 mg rapidly disintegrating doses of the etodolac eulollh~l can be 10 pl~alGd in the following manner:

a) A hydrolyzed gelatin solution is prepared by dissolving 30.0 grarns of gelatin B.P. in 1,000 ml of purified water with the aid of heat and constant stirring.
The reslllhng gelatin solution is then autoclaved at 121C and 15 p.s.i. for one hour.
15 The gelatin solution is then allowed to cool to room ~ ture.

b) An ~ ,.." mold co~ 75 cylin-lri~l depressions, each depression being about 0.5 cm in ~ ter and 1 cm deep, is cooled to about -192C in liquid nitrogen contained in a stainless steel tray. 100 g of the etodolac eul~mel, 20 g of 20benzoic acid, 0.25 g of F.D.C. Yellow No. S Coloring Agent, and 0.5 g of Nordaspray dried orange flavor are mixed with the gelatin solution and mixed continually while 1/2 ml of the mixture is added to each depression by a hypodermic syringe. The contents of the depressions are allowed to freeze. Then the mold is placed at room tUl~ under a vacuum of 0.3 mm Hg overnight. The freeze dried fonn~ tions, 25each co~ i.-g 50 mg of the etodolac eu~c~llæl, are then removed from the mold and stored under airtight conditions. Each formulation will dissolve in a matter of a few seconds when taken orally or added to a liquid.

It will be understood by those skilled in the art that the techniques described 30above can be used to forrnlll~te rapidly ~ integrating dosage forms of this invention cont~ining a variety of individual dosages of etodolac eutomer. These solutions may also include a variety of flavoring agents, sweetening agents, coloring agents, etc. to make the solutions more appealing to various recipients. In addition, other carrier m~teri~l~ may be used in exchange for the partially hydrolyzed gelatin. These include, but are not limited to, polysaccharides, such as hydrolyzed dextran, ~lgin:~t~s (e.g.
sodium ~lgin~te), and dextrin, or mix~ eS thereof with each other or with other carrier m~tt-ri~l~, including acacia, polyvinyl alcohol or polyvinylpyrrolidine.

For the production of these rapidly ~ integrating formulations, it is pl`~r~
that the etodolac euloll~l utilized be in the form of a micl~ni;~ed powder to elimin~te the potential for the ~l-;e~,on of a gritty texture as the fi~rm~ tion ~ integrates in the recipient's mouth. Most preferably, the etodolac eu~ol~er is in the form of a mi~ ~ized powder comprising particles of 50 microns or less. It will be understood by those skilled in the art that these formulations, by the nature of their design, will ~ integrate if subjected to moisture or physical h~n-lling or concussion. Therefore, it is understood that these formulations should be h~ncllefl with care and pa~g~1 in containers which minimi7~ the risk of their ~lelllatule disintegration, such as the p~c~ging described in U.S. Patent No. 4,305,502.
The following examples 11 through 14 list combinations of etodolac ~ o~
and other components which may be added to 1,000 ml of the gelatin solution, or other applu~liate carrier m:~t~ri~l~, in the manner described above.

F~mDle 11 10 mg etodolac ~ulolller/dose a) 20 g etodolac eulcm b) 30 g fructose c) 10 g benzoic acid F~mDle 12 100 mg etodolac ~ulc.lllel/dose a) 200 g etodolac eul~n~l b) 0.25 g F.D.C. Yellow No. 5 Coloring Agent c) 0.5 g Norda spray dried orange flavor d) 25 gsucrose e) 20 g benzoic acid F~PmDIe 13 200 mg etodolac eu~ el/dose s a) 400 g etodolac ~u~oll~r b) 0.25 g F.D.C. Yellow No. 5 Coloring Agent c) 10 g fructose d) 15 g sucrose e) 40 g benzoic acid F~PmDIe 14 400 mg etodolac eutomer/dose - without hydrolyzed gelatin a) 533.33 g etodolac eutomer b) 17 g sodium alginate c) 35 g Dextran d) 15 g aspartame e) distilled water to 1000 ml f) 50 g benzoic acid This formulation of Example 14, not col-lAil-il-g the hydrolyzed gelatin of the previous examples, may be produced in depressions on a 220 x 330 mm p.v.c. sheetco~ -g 150 cylin-lri-~l depressions, each depression being about 0.7 cm deep andabout 1.4 cm in diameter, which has been cooled with solid carbon dioxide. The forrnlllAtion may be produced by suspending the etodolac t;u~OIll~[ in the watercon~ g the sodium Algin~te, Dextran and as~ e listed above with the use of ultrasonic vibrations. 0.75 ml of the suspension can then be placed into each of the p.v.c. sheet's depressions, where they can be freeæ dried to complete the rapidly disintegrating solid formulation.

li'Y~n~le 15 1 g etodolac euL~ /dose-without hydrolyzed gelatin S a) 1,333.33 g etodolac eu~ lle b) 20 g polyvinylalcohol c) 20 g polyvinylpyrrolidine d) 30 g sucrose e) 0.2 g Tween 80 f) ~ ;tille~l water - qs to 1000 ml g) 50 g benzoic acid Another example of a rapidly (li~int~grating solid formulation may be produced with the components listed above and the carbon dioxide cooled p.v.c. sheet described 15 in the previous example. This may be done by adding the polyvinylalcohol to about 500 ml of hot distilled water, which is then allowed to cool. The polyvinylpyrrolidine, sucrose and Tween 80 can then be added and the mixture shaken to dissolve all of the solids. The etodolac eutomer is added and dispersed with ultrasonic vibration. This mixture should then be brought to the final volume of 1000 ~ by the ~l(litit)n of 20 distilled water. 0.75 ml of this solution may then be added to each depression for freeze d~ying to the final solid form~ tion.

Buccal Formulations Buccal formulation co~.l;.il~in~ the etodolac eutomer of this invention may be produced by the steps and ph~ ellti~l components set forth in U.S. Patent No.
4,764,378 (Keith et al.), the contents of which are incorporated herein by reference. It is most preferred that these buccal f~ tions have incorporated therein an acidiccomponent, such as a micronized solid food acid. Such a food acid may comprise from about 0.1-2.0% of the weight of the final buccal formulation, though more acid may be added if desired.

F,YP~Ie 16 ~ o7en~f~ or Troche Formulations S Lozenge or troche formulations, which may also be lc;r~llc;d to as pastilles, con'~ g the etodolac eu~ el may also be prepared for any dosage described hereinby methods known in the art. For instance, such lozenges may be prepared by molding and subsequently drying by evaporation a concentrated syrup co,~ -i.-g the etodolac el~o.--f ~, with thickening agents such as acacia or tr~g;lc~nth gums added, if necessary.
This type of lozenge is often referred to as a candy mass lozenge or troche. Using the following ingredients and technique, candy mass lozenges can be made for any dosage of etodolac t;u~nlæl described herein. Described below is a form~ tion useful for producing lozenges cont~ining 100 mg of etodolac eutomer.

Ingredient Amount Sucrose 6,000 g Cream of Tartar 30.0 g (optional) Corn Syrup 4,000 g Citric Acid (fine 100 mg/4 g powder through 100 mesh) Etodolac Eutomer 100 mg/ 4 g These loænges can be produced by adding the sucrose, cream of tartar 25 (optional) and corn syrup listed above to a stock pot with mixing, followed by boiling to dissolve the sucrose and cream of tartar. These components should be removed from the heat when a stiff boil is achieved, which will occur at about 290F, and about 30~o of the original volume is lost to evaporation. These components should be mixed until the mass cools to a~plv~imaLely 280F. At this point the citric acid and etoclo 30 eulomer should be added to the mass with mixing to create a homogenous dispersion.
When the batch cools to about 190F the mass can be rolled into a rope or u lllmn~r shape and cut into 4 g pieces. These pieces may then be placed on a mesh to cool to ambient If;~ ulcs.

A more readily rli~integrating lozenge or troche form may be made using 9200 g of co~ ,ssible sugar, such as Dipac g) brand compressible sugar (Domino Sugar Co., New York, NY), and the amounts of cream of tartar (optional), citric acid and etodolac c;uloll~l (or other plc;r~lled dose of the etodolac eu~ollæl) described above. These 5 coml,ol-el-ts may be homogeneously mixed and co~ )~ssed into loænges of the desired size, such as the 4 g size described above.

In lieu of compressible sugar, an equivalent amount of sucrose or lactose may be thoroughly mixed with a suitable binding agent, such as about 525 g of sodium10 ~lgin~te, and a ph~rm~re~ltir~lly suitable gr~n~ ting fluid to create a wet mass. This wet mass may be passed through a gr~mll~ting mill and compl~3sed into lozenges of the desired size.

Dentifrice Compositions Drntifrire compositions known in the art may have S(+) etodolac, preferably with an additional acidic component, inco~porated therein for use in the prevention or reduction of bone loss and/or for promoting regrowth of bone previously lost. It will be understood that dçntifrices herein are intended to include any dental form.ll~tions that 20 may be used in the ~ llent and ll~il~nal~ce of teeth and mouth tissues. Theseinclude, but are not limited to pastes, gels, powders, granular compositions, liquids, etc. An example of a toothpaste within the scope of this invention can be produced by slowly adding the non-aqueous components listed below to water, followed by conventional mixing with a roller mill.

2 1 78 6~ 6 AHP-94179 FY~n~le 1 7 Colllpol-ent % Composition S(+) Etodolac 1%
S ~ si--~-l Ah-.-~ Silicate 1%
Citric Acid 1%
Dicalcium Phosphate 46%
Mint or other flavor 4%
Sodium carboxymethylcellulose 0.5%
Sodium Lauryl Sulfate 2%
Water 44.5%

The organoleptically acceptable dentim~es within the scope of this invention may include any of the known dentim~e formulations, preferably with an existing or 15 added acidic com~llent. Paste formulations of this type may contain, for example, by weight from 10-50% of an abrasive system, 0.5-10% thickeners, 10-80% humectant, 0.1-1% sweetener, 0.05-2% flavoring agents, 0.001-0.02% coloring agents, 1-7.5%
surfactant, 0.1-0.8% antimicrobial preservatives, and 0.01-5% acidifiers.

Abrasive components of these formulations can include calcium pyrophosphate, hydrated silica, insoluble sodium metaphosphate, organic polymers, ~hlmin~ trihydrate, dicalcium phosphate dihydrate, dicalcium phosphate anhydrous and calcium carbonate.
Thickeners can include silica aerogel, pyrogenic silica, silica precipitates, carboxymethylcellulose, carboxy vinyl polymers, xanthan gum and carrageenan.
Hl~ of use include sorbitols, glycerine and polyethylene glycols. Useful sweeteners include saccharin, xylitol, cyclamate, a~ e and th~llm~tin Flavoring agents can be modified according to taste and market acceptability, but include ~p~ lt, spearrnint, winl~r~l~en, cinnamon, and anise flavors, as well as essential oils. Any FDA approved coloring agents may be chosen for incorporation into suchdental formulations. Surfactants may include sodium lauryl.clllfate, sodium laurylsarcosinate, pluronics, tweens, sodium cocomonoglyceride sulfonate, sodiumdodecylbenzene sulfonate, and dioctylsodium sulfosuccinate. Antimicrobial agents and preservatives for use in this art include parahydroxybenzoates, sorbic acid and benzoic acid. Acid components for these forms include the food acids described herein, including lactic acid, citric acid, phosphoric acid and tartaric acid.

An example of such a dentifrice can be formed from the following ingredients.
s F,Y~Ie 18 Ingredient Function Weight Percentage FtQdQl~ Flltomsr Active Ingredient 2.0%
Silica xerogel Abrasive 14.0%
Silicaaerogel Thi~ .ner 7 5%
Sodium Carboxymethylcellulose Thickener 1.0%
Sorbitol Hllm~ct~nt 60%
Saccharin Sweetener 0.2%
Sodium monofluorophosphate Fluoride Source 0.76%
Sodium lauryl sulfate Surfactant 5%
(29% Solution) Tutti Fruitti Flavor Flavoring Agent 1%
(Virginia Dare, AK 27) Equal Parts Ethylparaben, Antimicrobial Preservatives 0.4%
Me~lyllJ~aben and Propylparaben FDC BlueNo. 1 ColoringAgent 1%
Phosphoric Acid Acidifier q.s. to pH 5.0-5.2 Water,demineralized Vehicle q.s. to 100%
To minimi7P any possibility of demintq,ralization of tooth structure, it is suggested that the pH of this fnrmlll~ti~n not be lower than about 5Ø Sodium monofluorophosphate is an a~lv~flate fluoride source for use within this desired pH
range.
Chewing Gum Formul~tions Another organoleptically acceptable formlll~tion within the scope of this invention are chewing gum types of formulations. It will be understood that these 35 types of formulations can be created by incorporating the etodolac ~ulollær, most 2 ~ 7 8 6 8 6 AHP-94179 preferably along with a suitable acidic component, into any of the organoleptically accel~labl~ chewing gum bases. An example of a chewing gum fonn~ tion of this invention can be made with the components seen below in Example 19.

Fy~n~le 19 Function in Amt. per Amt. per Ingredient Formulation 3g Unit 3 kg batch Etodolac Eutomer, micronized Active Ingredient 0.010 g 10 g Chicle Gum Base 1.000 g 1000 g Glycerol ester of Gum Base 0.200 g 200 g hydrogenated rosin Sucrose, fine powder Sweetener 1.600 g 1600 g BalsamTolu Acidifier 0.187 g 187 g Ci.-n~.lo/- Oil Flavoring Agent 0.003 g 3 g The components listed above can be combined into a chewing gum formulation by warming the gum base ingredients to a softened stage, followed by separate addition steps for the acidifier, sweetener, etodolac eulolller and flavoring agent, with kneading 20 to produce a homogenous mixture following each addition. The final homogenouschewing gum form~ tion can then be rolled out with a sizing machine and cut into 3 g pieces using finely powdered sucrose to facilitate handling, followed by standard wl~ping and packaging. It is understood that other chewing gum formulations may be utilized within the scope of this invention and that the components of the form~ tion 25 described above may be replaced with equivalent amounts of other functionaL
components, including those described herein for use with other formulations.

Ve~ r Formulations It is also understood that the use of organoleptically acceptable formulations is illl~Ol~t in veterinary applications. While this is true for any ",i..""l~l which a veterinary specialist may recommend the use of an NSAID, it is particularly true in the case of comp~niQn ~nim~l~, such as dogs and cats, where owners and handlers app~ciate the relative ease of ~rlmini~tering readily accepted oral dosage fi~rm~ ti~>ns, 35 as opposed to those which must be a~lmini~tered with animal restraint techniques.

V~lu~al~ form~ tions of this invention include any of the solid or liquid dosage forms mentioned above which may also be given to ~nim~l~ These fi~ tions may be incc.l~ ted into an animal's food or drink or given as a sep~l~S phS ~ s;ul;c~l entity. If given sel)~alely, it is l~colllll~ led that the formlll~tion contain an ingredient, preferably a taste ingredient, which is no~nally found appealing to the animal in question. For example, with cats and dogs a flavor base component of liver digest, seafood digest, poultry digest, desiccated liver, soya flour, sugar, cod liver oil, soy bean meal, fish meal, bone meal, yeast, wheat germ meal, fish meal or other 10 known food bases or a combination thereof may be used. Such ingredients may be used as flavoring agents in the formulations listed above or they may be used as fillers in place of other m~t~ described herein. It will be understood that the ~lcel,~ges of ingredients in animal-oriented oral f~rmlll~tions of this invention will be detormin~ d in large part by the size of the animal and the siæ of the desired formulation. For 15 in~t~nce, a relatively small chewable tablet may consist of a mixed and compressed combination of the following:

F.y~n~le 20 Ingredient Weight Percentage Etodolac Eutomer 60%
Flavor Base Component 15-25%
Microcrystalline Cellulose 10-20%
Povidone K29-32 2-6%
Alulnillum Stearate 1-2%
Lactic Acid 0.1-2.0%

To create a larger solid f~rm~ ti~n co~ -g a desirable dosage of the etodolac eulolll~,r, the amounts of the components may be increased as desired, such as with the 30 following form~ tion:

Fy~n~le 21 Ingredient Weight Percent~e Etodolac Eutomer 15%
Flavor Base Component 35-45%
Dibasic Calcium Phosphate 15-25%
Microcrystalline Cellulose 15-25%
Povidone K29-32 2-6%
Stearate 1-2%
It would be most preferred that these form~ tions also contain an acidic cc lllpollent, such as a solid food acid. For instance, a food acid such as cit~ic or malic acid can comprise from 1-5% of the weight of the fonnulation, though the amount of acidic colll~onenl may be raised if desired. Another chewable solid form~ tion which 15 may be useful for animal ~-lmini~tration would be the following:

FY~n~le 22 Ingredient mg/tablet Etodolac Eutomer 5-500 Whey, Dry Sweet 2,000 Liver, De~i~c~ted 210 Yeast, Dried 50 .~ll,."i.lll"~ Stearate, NF 50 Citric Acid 30 FxamDIe 23 Another chewable tablet form~ tion for use with companion animals can be produced with the following con~ollenls and methods. While this example shows the production of 200 mg tablets cont~ining the etodolac eutomer, it will be understood that any dosage required can be formnl~ted in this type of formulation.

Ingredients Amount/Tablet Amount/l~000 Tablet Batch Fto~1O1~c Eutomer 200 mg 200 g Sodium Starch Gycolate, 600 mg 600 g NF (SSG) Spray DriedU.S.P. Lactose4441 mg 441 g Decir~t~ Liver 252 mg 252 g Dried Yeast 62 mg 62 g ,~lll.. ,i~"l.ll Stearate 45 mg 45 g Fumaric Acid 100 mg 100 g Chewable tablets of this formulation can be produced by blending the etodolac eul<ml~r, sodium starch glycolate, spray dried lactose, fumaric acid, desirc~ted liver and dried yeast in a suitable mixer until uni~~ . Then 2/3 of the quantity of ~ ."i~
stearate can be added to a portion, such as a~plu~ ately 10%, of the mixture of 15 ingredients just described with mixing until uniform. The rem~ining mass of the ingredients can then be added with sufficient mixing to distribute the aluminum stearate-cont~ining mass. This blended mixture may then be slugged mYlillm hard and sizedthrough a rotary granulator using a #10 screen. The rem~infl~r of alll.--il)l,,,, stearate can then be added to the gr~n~ ted mixture with mixing. The final tablets of this 20 form~ tion can be compressed into tablet form, such as by using a 11/16" flat face punch at a hardness of from 12 to 15 SCU. Tablets of this type may be either given whole or broken into smaller sections for lower dosage deliver.

Based upon the disclosure herein, those skilled in the art will be able to utilize 25 S(+) etodolac to create a variety of organoleptically acceptable oral formulations within the scope of this invention.

Claims (11)

1. An organoleptically acceptable oral pharmaceutical composition comprising the S(+)1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid substantially free of R(-) 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid and an acidic component.

2. The organoleptically acceptable oral pharmaceutical composition of Claim 1 in which the acidic component comprises citric acid, tartaric acid, malic acid, fumaric acid, lactic acid, adipic acid, ascorbic acid, aspartic acid, erythorbic acid, glutamic acid, and succinic acid, or mixtures thereof.

3. The organoleptically acceptable pharmaceutical composition of Claim 1 further comprising an organoleptically acceptable pharmaceutical carrier.

4. An organoleptically acceptable pharmaceutical composition of Claim 3 which is contained within a powdered or granular formulation.

5. An organoleptically acceptable pharmaceutical composition of Claim 3 which is contained within a liquid formulation.

6. An organoleptically acceptable pharmaceutical composition of Claim 3 which is contained within a chewable tablet formulation.

7. An organoleptically acceptable pharmaceutical composition of Claim 3 which is contained within an effervescent formulation.

8. An organoleptically acceptable pharmaceutical composition of Claim 3 which is contained within a lozenge formulation.

9. An organoleptically acceptable pharmaceutical composition of Claim 3 which is contained within a rapidly disintegrating solid dosage formulation.

10. An organoleptically acceptable pharmaceutical composition of Claim 3 which comprises a chewable veterinary formulation.

11. An organoleptically acceptable pharmaceutical composition of Claim 3 which comprises a chewing gum formulation.