AU1549499A - Onset-hastended/enhanced analgesia - Google Patents

Description

P/01/009 28/5/91 Regulation 3.2

AUSTRALIA

Patents Act 1990 TRUE COPY COMPLETE SPECIFICATION STANDARD PATENT We certify that the following forty one (41) pages are a true and correct copy of the description and claims of the original complete specification in respect of an invention entitled ONSET-HASTENED/ENHANCED ANALGESIA Name of Applicant: STERLING DRUG, INC Signature (Note: An exact copy of the material attached to Form 10 must be attached to this form) 0 Title of the Invention ONSET-HASTENED/ENHANCED ANALGESIA Field of the Invention The present invention relates to the use of ibuprofen to elicit an onset-hastened and enhanced analgesic response in a human or other mammal suffering from pain, and to certain pharmaceutical compositions comprising unit dosage effective amounts ofS(+) ibuprofen.

Background of the Invention Ibuprofen, or 2-(p-isobutylphenyl)propionic acid, has the structural formula

H

3 C

CH

3

CH-CH

2

-CH-COOH

H

3

C

The compound is well-known as a non-steroidal anti-inflammatory drug having analgesic and antipyretic activity. Ibuprofen is currently marketed by prescription in the United States generically, as well as under tradenames such as Motrin which is available in 400, 600 and 800 mg tablets for oral administration. Ibuprofen has recently also become available in this country in non-prescription strength (200 mg) under a variety of tradenames, including Advil and Nuprin as well as in generic form. For the treatment of mild to moderate pain, 400 mg level 4 to 6 hours, not to exceed 3200 mg daily, is generally recommended for Motrin The lower dose over-the-counter products are generally recommended for minor aches and pains, to be used orally at the 200 to 400 mg level, every 4 to 6 hours, not to exceed 1 2 00mng daily unless directed by a physician. Sec also Physician's Desk Reference, 40th edition, 19S6, publisher Edward R. Barnhart, Medical Economics Company, Inc., Oradell, NJ 07649, pp. 1854-1855 and 1S97.

0 As is apparent from its chemical nomenclature, ibuprofen is a racemic mixture. It is only the racemic mixture which has in fact ever been marketed. There have, however, been some studies of the individual and isomers reported in the literature.

These generally reflect that the isomer is rapidly converted to the enantiomer, which is the active form of ibuprofen.

Adams et al, Curr. Med. Res. Opin., 3, 552 (1975) and J. Pharm. Pharmacol., 28, 256-257 (1976), reported that in vivo anti-inflammatory and analgesic tests in guinea pigs, rats and mice comparing the dextro levo and racemic mixture forms of ibuprofen showed the three forms to be very similar in potency. (The in vivo tests were conducted in an acetylcholine-induced writhing test in the mouse, in a pain threshold technique test using the yeast-inflamed paw of the rat and using ultraviolet erythema in the guinea pig.) In vitro, however, it was found that nearly all of the activity resided in the dextrorotatory form. The authors concluded that the in vitro results suggested that the dextro form was the active one, but that in vivo the levo form was converted to the dextro form so that there was little difference in pharmacological activity. This was also seen to be an explanation for earlier observations [Adams et al, J. Pharm. Sci., 56, 1686 (1967) and Mills et al, Xenobiotica, 3, 589-598 (19733] that ibuprofen's urinary metabolites in man were found to be dextrorotatory. Thus, it has been recognized for over a decade that the isomer is the active form.

Wechter et al, Biochem. Biophys. Res. Commun., 61, 833-837 (1974) reported the results of tests in healthy human subjects designed to determine the stereochemistry involved in ibuprofen's metabolism and the relative stereochemical relationships between ibuprofen's optical isomers and its metabolic products. They found there was a facile epimerization of ibuprofen's isomer to the isomer and concluded that this accounted for the essential bioequivalence of the and isomers.

Related observations were reported by Vangiessen et al, J. Pharm. Sci., Vol 64, No. 5, 798-801 (May 1975), who found that after oral administration of the racemic mixture to human volunteers, the predominant enantiomer in the peripheral circulation and excreted in the urine was of the d-configuration. Vangiessen et al estimated that the plasma drug disappearance half-lives for the d-and 1-isomers were 3.34 and 2.01 hours, respectively.

-3- SThe concentration ratio of d to 1 increased progressively with time from 1.17 at one hour to 2.65 at eight hours. However, these estimates are compromised by the small sample size the fact that normal subjects were used, and the extremely large standard deviations from the mean at the earliest (one-hour) post-dosing time point. Interpretation of the results of this study is further compromised because was not administered alone so that no comparisons with the racemate are possible.

Subsequently, Kaiser et al., J. Pharm. Sci., Vol. 65, No. 2, 269-273 (February 1976) reported on characterization of enantiomeric compositions of ibuprofen's major urinary metabolites after oral administration of the racemic mixture and the individual and isomers to healthy human subjects. It was found that only the enantiomer of the intact drug was inverted to its optical antipode, Hutt et al, J. Pharm. Pharmacol., 35, 693-704 (1983), reviewed the earlier work on the metabolic chiral inversion of 2-arylpropionic acids, including ibuprofen, which they indicate was the first substituted 2-arylpropionic acid conclusively shown to undergo the inversion as well as the most studied member of the group. The authors again noted that Adams et al (1976) found no significant difference in in vivo activity among the and isomers and the racemic mixture in three different animal models, but very large differences in vitro between the and isomers, ascribing this discrepancy to the virtually quantitative conversion of the to the active isomer in vivo. Hutt et al indicated similar properties for fenoprofen. The enantiomers of fenoprofen were reported to be of equal potency in animal test systems.

In the same paper, Hutt et al reported that, in contrast, for several other 2-arylpropionic acids, the inactive isomer was not converted in vivo to the active isomer as readily as ibuprofen and fenoprofen, although the conversion seemed to occur to some extent over time. Naproxen, they noted, has been the only compound marketed as the enantiomer to date. And in the case of indoprofen, the enantiomer was found to be about 20 times less pharmacologically active in rats and mice in vivo than the isomer.

Hutt et al concluded: It is likely that benefits will be obtained from the use of the S(+)enantiomer of 2-arylpropionates as drugs as opposed to the racemates. This is only -4found at present in the case of naproxen. In cases of rapid inversion, the inactive isomer serves merely as a prodrug for the active S(+)-antipode. Where inversion is slow, the enantiomer is an unnecessary impurity in the active form. Use of the S(+)-enantiomer would permit reduction of the dose given, remove variability in rate and extent of inversion as a source of variability in therapeutic response and would reduce any toxicity arising from non-stereo-specific mechanisms.

Thus, in cases of rapid inversion, such as ibuprofen and fenoprofen, where substantially equivalent in vivo responses have been reported for the individual enantiomers and the racemic drug, Hutt et al suggested that no benefits would be obtained from the use of the isomer because the inactive isomer merely acts as a prodrug for the active form. Contrariwise, in cases where chiral inversion is slow, e.g. naproxen and indoprofen, 1the use of the enantiomer is desirable for several reasons enumerated by Hutt et al.

Indeed, naproxen has been reported to be marketed as the d-isomer for one of the reasons given by Hutt et al, i.e. to reduce side effects (Allison et al, "Naproxen," Chapter 9 in Anti-inflammatory and Anti-Rheumatic Drugs, eds. Rainsford and Path, CRC Press Inc., Boca Raton, Florida, 1985, p. 172).

Another general report on earlier work has been provided by Hutt et al in Clinical Pharmacokinetics, 9, 371-373 (1984). In this article on the importance of stereochemical considerations in the clinical pharmacokinetics of 2-arylpropionic acids, the authors tabulated relative potencies of the enantiomers of a number of 2-arylpropionic acids in vivo and in vitro. The in vitro results showed the S isomer in each case to be the active species. In vivo, however, the results were not consistent across the entire class.

Thus, the results for naproxen and indoprofen demonstrate the S isomer to be much more active in vivo, indicating a relatively slow inversion of the inactive R isomer to the active S isomer; the results for fenoprofen and ibuprofen, on the other hand, demonstrate the inactive R and the active S isomers to be approximately equally effective in viv, indicating a rapid inversion of R isomer to S isomer.

The medicinal chemistry of 2-arylpropionic acids and other NSAIDs (non-steroidal anti-inflammatory drugs) has been reviewed by Shen in Anqewandte Chemie o International Edition, Vol. 11, No. 6, 460-472 (1972) and in "Nonsteroidal anti-inflammatory Agents," Chapter 62 in Burger's Medicinal Chemistry, 4th edition, part III, Wiley Interscience, New York (1981), pp. 1205-1271. In the latter publication, Shen notes that ibuprofen is used as a racemic mixture because the two optical isomers are equally potent in the UV erythema assay, a commonly used anti-inflammatory model.

Lee et al, Br. J. Clin. Pharmac. 19: 669-674 (1985), administered racemic ibuprofen and each of the enantiomers separately to four healthy human males, then studied stereoselective disposition. They estimated that about 63% of the dose of was inverted to the enantiomer over a 14 hour period. Lee et al noted that the kinetics of the and enantiomers were changed when the respective optical antipode was concurrently administered. The authors speculated that this alteration reflected an interaction between the and forms at the binding sites for plasma protein. An ibuprofen plasma level time 1profile for a single subject is shown graphically in the paper and might suggest that there was minimal conversion in the early hours of the study, but the authors did not appear to attach any significance to this. Lee et al indicated that the half-life of after administering the racemate was 2.5 hours, whereas the half-life of after administering was 1.7 hours.

The authors recognized the limitations of their work, for reasons including the small number of subjects studied, and an assumption that the clearance of is unchanged between administrations of and They also cautioned that it is quite likely that the fraction of that is inverted to varies from individual to individual.

Cox et al, J. Pharmacol. Exp. Ther., Vol. 232, No. 3, 636-643 (1985), carried out liver perfusion experiments to study the role of the liver in the clearance of the stereoisomers of ibuprofen in normal and disease states. Experiments were conducted with normal and fatty rat liver. Results showed that when liver is fatty, clearance of the isomer is affected and preferential hepatic distribution is eliminated. However, the effects were predicted to have only minimal impact on total ibuprofen plasma levels following racemic ibuprofen dosing.

Cox et al, abstract in Amer. Soc. Clin. Pharmacol. Ther., February 1987, 200 (abstract PIIL-7) described a three way crossover study in which single doses of ibuprofen solution were given orally to twelve healthy human males. The doses given were 800 mg of -6racemic ibuprofen, 400 mg of ibuprofen and 400 mg of ibuprofen. Based on area under-the-curve measures, significant chiral inversion was observed for but not for Elimination of was inhibited as plasma concentration of R:S increased. The extent of inversion, based on urinary data, was the same for the racemate and the isomer, with a mean of.66. Again, the authors gave no information as to what occurred in the first two hours. The statement on reduced clearance of in the racemate is consistent with the finding of increased length of half-life after administering the racemate found by Lee et al.

Laska et al, Clin. Pharmacol. Ther., Vol. 40, No. 1, 1-7 (July 1986), reported that administration of racemic ibuprofen to patients with moderate to severe pain subsequent to third molar extraction gave correlations between pain intensity ratings and serum levels of ibuprofen. Correlations were found between contemporaneous serum levels and measures of 15 pain intensity improvement, supporting the proposition that increased ibuprofen serum levels lead to increased analgesia, particularly in the first few hours after dosing. However, the authors did not correlate analgesia with either isomer of ibuprofen; the possibility of critical differences between free and bound ibuprofen and between the and isomers was not addressed.

In summary, the current state of the art recognizes that, in mammals, the form is the active enantiomer of ibuprofen. The art further recognizes that there is a significant, relatively rapid conversion in vivo of to with little if any conversion of to Furthermore, in the only animal experiments on efficacy reported in the literature, it was noted that there were no significant differences in potency between the racemate and the enantiomers. This is attributed to the rapidity of the chiral inversion. This would suggest there would be no benefit to be derived from the use of ibuprofen for analgesia. Indeed, use of alone would appear to reduce the half-life of the active drug.

The prior art, moreover, is conspicuously silent in respect to any onset-hastened/enhanced alleviation of mammalian pain utilizing whatever form of the ibuprofen drug species.

SUMMARY OF THE INVENTION Surprisingly, the present inventors now find that ibuprofen can be advantageously administered to mammals suffering from pain, especially humans, to not only elicit a more potent analgesic response but also to evoke such response more rapidly than possible by administrating of the same dose of ibuprofen in its racemic form.

This is particularly surprising in light of the art's failures to attribute any significative difference in activity in vivo for ibuprofen versus the racemic mixture, a failure which the present inventors brand as resulting from the lack of telling observations of the pain level or amount of relief at meaningful time points sufficiently soon after dosing in an appropriate analgesic model.

In one aspect, the present invention thus provides a method of hastening the onset of analgesia in a mammal, said method comprising administering to a mammal in need of such treatment an effective onset-hastening analgesic amount of ibuprofen substantially free of ibuprofen.

In another aspect, the present invention provides a method of eliciting an enhanced analgesic response in a mammal, particularly shortly after dosing, said method comprising administering to a mammal in need of such treatment an effective analgesia enhancing amount of ibuprofen substantially free of ibuprofen.

In yet another aspect, the present invention provides a pharmaceutical composition of matter for use in eliciting an onset hastened and enhanced analgesic response in mammals, especially humans, said composition comprising an effective analgesic unit dosage amount of ibuprofen substantially free of ibuprofen. Typically, ibuprofen is associated with a nontoxic pharmaceutically acceptable inert carrier or diluent therefor.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows a plot of overall relative potencies as a product of the Slope Ratio and Log Concentration-Effect Potencies.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION The term "ibuprofen" or"racemic ibuprofen" as used herein is intended to encompass not only 2-(p-isobutylphenyl)propionic acid itself but also any pharmaceutically acceptable salt thereof, q. ibuprofen aluminium.

7a The term ibuprofen" as used herein is intended to encompass not only the dextrorotatory or isomer of 2-(p-isobutylphenyl)propionic acid but also any pharmaceutically acceptable, analgesically effective salt thereof. The expression "substantially free of ibuprofen" as used in conjunction with the term ibuprofen" means that the ibuprofen is sufficiently free of ibuprofen [which is the levorotatory Sform or isomer of2-(p-isobutylphenyl)- propionic acid or salt thereof] to exert the desired onset-hastened and enhanced analgesic effect. Practically speaking, this means that the active ingredient should contain at least 90% by weight ibuprofen and 10% or less by weight ibuprofen. Preferably, the weight ratio of ibuprofen to ibuprofen is greater than 20:1, more preferably greater than 97:3. Most preferably the ibuprofen is 99 or more by weight free of ibuprofen, the weight ratio of S to R is approximately equal to or greater than 99:1.

Where specific amounts of ibuprofen are set forth below, it should be understood that, unless otherwise specified, the amounts are given in mg of the acid, not of a salt. Moreover, unless otherwise specified, for simplicity's sake the amounts given represent total ibuprofen content, most of which is in the form. For example, "400 mg ibuprofen" means 400 mg total ibuprofen at least 90% of which is in the form, prefera- 1bly at least 95%, more preferably at least 97% and most preferably 99% or more.

ibuprofen, in accord with the present invention, produces the following unexpected results: the analgesic effect of ibuprofen on the mammal is brought on more quickly than by use of the same dose of racemic ibuprofen; and a greater analgesic response is elicited in the early hours than is elicited by the same dose of racemic ibuprofen.

These unexpected results can be achieved in the treatment of pain responsive to an NSAID (non-steroidal anti-inflammatory drug) and specifically pain associated with inflammation. This includes postpartum and postoperative pain, dental pain, headache pain, dysmenorrhea, pain of musculoskeletal origin and pain and discomfort associated with respiratory infections such as colds and flu.

For patients suffering from such pain, who require treatment at a particular dose of racemic ibuprofen, the time from administration of medication to the onset of effective relief is clearly of paramount importance. The present inventors' discovery that ibuprofen, when used in place of racemic ibuprofen at the same dose, substantially shortens the onset time substantially hastens the onset) of analgesia is therefore very significant. It is likewise quite unexpected. Moreover, in patients suffering from -9- 0inflammatory or degenerative joint disease, e.g. rheumatoid arthritis, osteoarthritis, gout or acute musculo-skeletal disease, the substantial shortening of analgesic onset is extremely important; pain is an important component of these disease states and more rapid relief from pain is of substantial psychological benefit. The ibuprofen will, of course, over time provide relief from other aspects of inflammatory disease as well, including, e.g. morning stiffness.

In a group responsive to a given dose of the racemate, it is believed that onset time for analgesia can be reached, on the average, about one-third sooner when ibuprofen is used rather than when racemic ibuprofen is administered, depending on the dose level and the severity of the pain, but particularly at the low end (100-400 mg) of the analgesic dosage range and for patients with moderate pain.

Insofar as concerns enhanced analgesia, more pronounced analgesia is obtained when ibuprofen is used at the same dose level as racemic ibuprofen, especially during the first few hours.

The precise amount of ibuprofen for use in accord with the present invention will vary depending, for example, on the size and kind of the mammal and the condition for which the drug is administered. For use in humans, the analgesically effective amount of ibuprofen will typically be from about 100 to 600 mg, although greater amounts 1000 mg) may be employed if needed for pain relief and if tolerated by the patient. The daily dose in humans preferably will not exceed 3200 mg ibuprofen, although greater amounts could be employed if tolerated by the patient. Preferred unit dosage compositions for use in the treatment of mild to moderate pain having an inflammatory component contain 50, 100, 200, 400, 600 or 800 mg ibuprofen.

While the compositions for use in the invention are preferably for oral use, they may also be formulated for and administered by other routes which are known for administering non-narcotic analgesics/nonsteroidal anti-inflammatory drugs, e.g. as suppositories or parenteral solutions, or as topical formulations such as ointments, gels, creams, lotions, solutions, impregnated bandages or other topical delivery devices, and so forth. Also, it should be noted that the preferred human dosage levels indicated above are for use in adults; pediatric compositions would contain proportionately less of the active ingredient.

The compositions for use herein are very conveniently administered to mammals by any route of administration suitable for racemic ibuprofen, e.g. oral, rectal, topical or parenteral. Preferably ibuprofen is formulated with any suitable nontoxic pharmaceutically acceptable inert carrier material. Such carrier materials are well known to those skilled in the art of pharmaceutical formulations. For those not skilled in the art, reference is made to the text entitled Remington's Pharmaceutical Sciences, 17th edition, 1985, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, Pennsylvania 18042. In a typical preparation for oral administration, e.g. tablet, capsule or caplet, ibuprofen in an effective analgesic amount and substantially free of ibuprofen, is combined with any oral nontoxic pharmaceutically acceptable inert carrier such as lactose, starch (pharmaceutical grade), dicalcium phosphate, calcium sulfate, kaolin, mannitol and powdered sugar.

1Additionally, when required, suitable binders, lubricants, disintegrating agents and coloring agents can also be included. Typical binders include starch, gelatin, sugars such as sucrose, molasses and lactose, natural and synthetic gums such as acacia, sodium alginate, extract of Irish moss, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyethylene glycol, ethylcellulose and waxes. Typical lubricants for use in these dosage forms can include, without limitation, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine and polyethylene glycol. Suitable disintegrators can include, without limitation, starch, methylcellulose, agar, bentonite, cellulose, wood products, alginic acid, guar gum, citrus pulp, carboxymethylcellulose and sodium lauryl sulfate. If desired, a conventional pharmaceutically acceptable dye can be incorporated into the dosage unit form, any of the standard FD&C dyes. Sweetening and flavoring agents and preservatives can also be included, particularly when a liquid dosage form is formulated, e.g. an elixir, suspension or syrup. Also, when the dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills or capsules may be casted with shellac and/or sugar. Such compositions should preferably contain at least 0.1% of ibuprofen; generally, ibuprofen will be from about 2% to about 60% of the weight of the unit. Typical unit dosage forms for oral -11- 0 administration will contain about 50 to 1000 mg, preferably 100 to 800 mg, most preferably 100 to 600 mg, ibuprofen, if formulated for immediate release, as is preferred. If the composition is intended for sustained release, much larger amounts of the active ingredient would of course be incorporated into an individual unit; in such case, at least 50, and preferably up to 600 or 800 mg of the total amount of ibuprofen, should be formulated for immediate release so as to obtain the desired degree of enhanced analgesia and hastened onset.

A typical tablet for oral administration may contain, in addition to the selected amount of ibuprofen, the following combination of inactive ingredients/carrier materials: acacia, acetylated monoglycerides, beeswax, calcium sulfate, colloidal silicon dioxide, dimethicone, iron oxide, lecithin, pharmaceutical glaze, povidone, sodium benzoate, sodium carboxymethylcollulose, starch, stearic acid, sucrose and titanium dioxide; or carnauba wax, cornstarch, D&C Yellow No. 10, FD&C Yellow No. 6, hydroxypropylmethylcellulose, propylene glycol, silicon dioxide, stearic acid and titanium dioxide.

Moreover, the compositions for use in obtaining enhanced analgesia and hastened onset in accord with the present invention may, in addition to the selected dose of 20 ibuprofen, also contain other active ingredients and/or enhancing agents. Thus, for example, ibuprofen may be combined with such ingredients and agents as have been described for combination with racemic ibuprofen, e.g. caffeine or other xanthine derivative, a narcotic analgesic (with or without caffeine), a skeletal muscle relaxant, an antihistamine, decongestant, cough suppressant and/or expectorant. See, for example, Sunshine et al United States Patent No. 4,420,483, issued December 13, 1983; Sunshine et al United States Patent No. 4,464,376, issued August 7, 1984; Sunshine et al United States Patent No. 4,479,956, issued October 30, 1984; Sunshine et al United States Patent No. 4,552,899, issued November 12, 1985; Sunshine et al United States Patent No. 4,558,051, issued December 1985; Sunshine et al United States Patent No. 4,585,783, issued April 29, 1986; and Sunshine et al United States Patent No. 4,619,934, issued October 28, 1986; and Sunshine et al pending United States Patent Application Serial No. 815,502, filed January 2, 1986.

The enhanced analgesic effect and hastened onset obtained by use of 12o ibuprofen in comparison with racemic ibuprofen can be evaluated in animal and human studies such as those described below.

For example, to establish the efficacy of the compositions of this invention in humans, patients with moderate to severe pain requiring an oral analgesic/anti-inflammatory agent, can be administered ibuprofen or racemic ibuprofen. Typical pain models include dysmenorrhea, post-operative pain, post-partum pain and dental extraction pain.

Either a crossover design or a completely randomized design can be used. To determine analgesic efficacy, an observer interviews the patients as to their level of pain at subsequent periods of time. Patients are asked to subjectively estimate the time at which the medication begins to provide significant relief. Patients may be given a stopwatch to help estimate onset more accurately. Appropriate statistical methods, including survival analysis, can be used to show that the enantiomer has shorter onset and is more efficacious (Laska, Gormely, Sunshine, Belleville, Rantor, Forrest, Siegel, C. and Meisner, "A Bioassay Computer Program for Analgesic Clinical Trials, Clin. Pharmacol. Ther. 8:658, 1967; Cox, "Regression Models and Life Tables," Journal Royal Statistical Society, Series B, Volume 34:187-202, 1972).

ibuprofen for use in the method and compositions of the present 2 invention can be prepared by a variety of methods, such as by resolution of racemic ibuprofen.

Resolution of racemic ibuprofen has been described in the literature. Kaiser et al, J. Pharm. Sci., Vol. 65, No. 2, 269-273 (February 1976) added -methylbenzylamine dropwise, with stirring, to a cooled solution of racemic ibuprofen in ether. The solid -methylbenzylamine salt of ibuprofen thus obtained was removed by filtration, recrystallized first from isopropanol and then from methanol, acidified with 3N aqueous sulfuric acid, extracted with ether and washed with water and saline solution. The ether extract was evaporated to dryness and the resultant white solid was recrystallized from ethanol to give ibuprofen, m.p. 50-52 [ac]D 57 with 95% optical purity as determined by GLC analysis as the a-methylbenzylamide derivative. Cox et al, L Pharmacol. Exp. Ther., Vol. 232, No. 3, 636-643 (March 1985), using Kaiser et al's method, were able to obtain an ibuprofen preparation which was 99% S isomer and 1% R isomer 13 o Generally speaking, the isomer can be separated from racemic ibuprofen by preparing a salt ofibuprofen with an alkaloid or similar resolving agent such as cinchonidine, then separating the products by fractional crystallization from a solvent in which the dextrorotatory isomer is least soluble. The d-salt can then be acid cleaved to yield ibuprofen. Compare, for example, Alvarez United States Patent No. 3,637,767, issued January 25, 1972, which relates to resolution ofnaproxen and related compounds.

When ibuprofen is to be employed in the form ofa pharmaceutically acceptable, analgesically active salt thereof, such salt may be conveniently prepared by direct salification ofS(+) ibuprofen. Compare Armitage et al United States Patent No. 4,501,727, issued February 26, 19S5, which describes the N-methyl-D-glucamine salt of flurbiprofen.

Such a salt may not only be used in oral or rectal compositions, but, if sufficiently soluble in water, may be useful in the preparation of aqueous solutions of ibuprofen for parental injection Example 1 Antiphenvlquinone Writhing Test This test is a standard procedure for detecting and comparing analgesic activity and generally correlates well with human efficacy.

Mice are first dosed with the medications studied. The medications used are two dose levels ofS(+) ibuprofen and two dose levels of racemic ibuprofen. The mice are then challenged with phenyl-p-benzoquinone given intraperitoneally and observed for the characteristic stretch-writhing syndrome. Lack of writhing constitutes a positive response.

The degree of analgesic protection can be calculated on the basis of suppression of writhing relative to control animals run the same day. Time response data are also obtained.

Observations are made early enough post-dosing to detect differences in onset. The test is a modification from the methods ot'Sigmund et al and Blumberg et al (Sigmund, Cadmus.

and Lu, Proc. Soc. Exp. Biol. and Med. 95. 729-731 1 957; Blumberg, et al. Proc.

Soc. E\n. Biol. and Med. I IS. 763-766. 1965).

-14- Example 2 The Inflamed Rat Paw Test: Pressure Induced Stimuli The method ofRandall-Selitto, modified according to Winter et al, is used to ascertain the escape response threshold resulting from the application of increasing pressure to the yeast inflamed left hind paw. Drug treatment is given. The medications studied are two dose levels of ibuprofen and two dose levels of racemic ibuprofen. A constantly increasing force is applied to the paw and the "flight reaction" is observed and recorded at several points in time (Randall, and Selitto, Arch. Int. Pharmacodyn., II, 409419, 1957; Winter, and Lars, J. Pharmacol. Exp. Therap. 148, 373-379, 1965). Observations are made early enough post-dosing to detect differences in onset.

Example 3 STUDY OF THE ANALGESIC EFFICACY OF IBUPROFEN AND RACEMIC IBUPROFEN IN HUMANS A study comparing the analgesic efficacy of ibuprofen to ibuprofen racemate and placebo in post-operative dental pain was carried out in San Juan, Puerto Rico.

The study utilized a single center, randomized, double-blind, single-dose, parallel group comparative design. Randomization of patients to treatments was stratified by baseline pain intensity to ensure balance among the groups.

The purpose of the study was to evaluate the analgesic safety and efficacy of four dose levels of film-coated ibuprofen caplets (S80, S200, S320, S400) as compared to three dose levels of racemic ibuprofen caplets (1100, 1200, 1400) and placebo caplets in post-operative dental pain. Pharmacodynamic pharmacokinetic PK/PD and bioassay analyses were utilized to assess the relative performance of the treatments. The sample size was chosen to allow a broad range of doses to be studied and to be modeled in the PK/PD and bioassay analyses. The sample size of 25 subjects per treatment group was not anticipated to be able to statistically distinguish pairwise differences between doses and treatments because the statistical power to do so is too low.

Study Design A single oral administration of one of 4 dose levels of ibuprofen and 3 dose levels of racemic ibuprofen and placebo was given to patients with moderate to severe post-operative pain following extraction of impacted third molars. All patients fasted for eight hours prior to dosing and for two hours post-dosing. Pain intensity and pain relief were assessed at 15, 30 and 45 minutes, and at 1, 2, 3, 4, 5 and 6 hours after dosing or until a further analgesic was required within 6 hours. Both ordinal and visual analog scales (VAS) were used. Blood samples were taken prior to dosing, at 10, 20, 30 and 45 minutes and at 1, 1.5, 2, 2.5, 3, 4, 5, 6, and 8 hours post-dosing. Patients who did not achieve adequate pain relief were free to use rescue analgesic medication. Those who used rescue medication two hours after baseline or later received Vicodin and no further assessments were carried out.

Those who used rescue medication prior to two hours after baseline received a single dose of either 400 mg racemic ibuprofen or 400 mg of ibuprofen in a double-blind randomized fashion and had blood samples drawn at 15, 30 and 45 minutes, and at 1, 1.5, 2, 2.5, 3, 4, 5, 6 hours post-dosing. The blood samples were centrifuged and the plasma separated, frozen, and later assayed for determination of and racemic ibuprofen plasma concentrations by high performance liquid chromatography (HPLC).

Efficacy Parameters The principal measures of efficacy were pain intensity pain relief (PAR), pain intensity difference from baseline (PID), weighted sum of PID (SPID), percent SPID and weighted sum of pain relief (TOTPAR). Pain Intensity (PI) and Pain Relief (PAR) were assessed using the following ordinal scales. For PI, 0 none, 1 mild, 2 moderate and 3 severe. For PAR, 0 no relief(0%), 1 a little relief(25%), 2 some relief(50%), 3 a lot of relief 4 complete relief(100%).

The VAS pain intensity measure utilized a 100 mm horizontal line with "None" at the left margin at 0 mm) and "Worst Possible Pain" at the right margin at 100 mm). The VAS relief assessment utilized a 100 mm horizontal line with "No Relief' at the left margin and "Complete Relief' at the right margin. Separate forms were used for each assessment and patients did not refer to forms completed earlier.

-16- Pain intensity difference (PID), for both ordinal and VAS scores were computed by subtracting the pain intensity score at each time point from the baseline intensity score. Weighted sum of PID (SPID) and weighted sum of pain relief (TOTPAR) is an estimate of the area under the curves of the respective effect measure.

These scales are commonly used in analgesic trials and are described in such publications as Max MB, Portenoy RK Laska EM, The Design of Analgesic Clinical Trials, Raven Press New York 1991, which is incorporated herein by reference.

Methods of Analysis Several methods were used to analyze the data. The first method, a pharmacodynamic analysis, examines the relationship between treatments/doses in terms of efficacy measures. The second method examines the pharmacokinetics of the treatments, relating dose to serum concentration. The third method, a pharmacokinetic/pharmacodynamic analysis is used to estimate the probabilities of achieving various scores on the efficacy measure PAR as a function of the dose and treatment administered. Finally, a bioassay analysis, relates dose to serum concentration and serum concentration to efficacy to determine the relative potency of S ibuprofen to racemic ibuprofen. In each case, the presentation of the results emphasizes findings for the early time points in the study in order to describe the hastened onset achieved by the administration of ibuprofen compared to racemic ibuprofen.

Pharmacodvnamic Analysis Efficacy measures at each time point were compared to evaluate differences among the treatments using a one way analysis of variance (ANOVA). Whenever ANOVA identified a group difference at the p<0.5 level of significance, pairwise differences between treatments were assessed using Fisher's least significant difference (LSD) test. Missing values related to early terminations because patients utilized rescue medication were imputed to be the greater of pain intensity at time of remedication or the initial pain level, and the resulting value was extrapolated for the remainder of the 6 hours. Pain relief values were imputed to be "none" for the remainder of the 6 hours.

17- Pharmacokinetic Analysis Each of the individual isomer curves was subjected to a non-linear curvefitting method to estimate standard PK parameters which indicate the rate and extent of absorption. Areas under the curve to infinity (AUCI) in mcg*hr/ml as well as maximally attained plasma concentrations, CpMAX in mcg/ml, and their associated times, TMAX in hours, were determined.

PK/PD Analysis Data obtained on serum concentrations of ibuprofen and on pain relief were analyzed using a nonlinear mixed effects model of the relationship of dose to ibuprofen concentration, and via a logistic model, to the probability of pain relief. These are used to obtain to expected concentration for each dose of the treatments and the probability that PAR is 3, 4, or greater or equal to 3 for racemic and ibuprofen.

A biexponential model was used to describe the pharmacokinetics of plasma ibuprofen concentrations as follows: e -e Cij D i a i -bi(t-lt e-(1) c ai -b in which C;j is the predicted value of the ibuprofen plasma concentration for the ih individual at time, tii, relative to the dose, Di,. The values b, and ci and t,,gi are other parameters for the i' individual where ai a,i if the drug is ibuprofen, and if the 2 drug is racemic ibuprofen. The values bi, c, and tlagi were similarly defined.

Interindividual variability was modeled as ki (2) in which Pki is the estimate of the k' pharmacokinetic parameter for the i" individual, Pk is the expected value of the k' h pharmacokinetic parameter in the population, and rk i is the random effect of the parameter for the individual. Inter-individual variability of ibuprofen and the racemate were assumed to derive from different populations.

Intraindividual variability was modeled as 18- 0 In Cs, ln(Cs, ei (3) in which Csi is thef h measured plasma concentration of the ith individual.

If an individual received a second dose of ibuprofen at time t, his/her plasma concentrations were modeled as C. C, C, (4) in which C, represents the concentration attributable to the initial ibuprofen dose and C 2 represents the concentration attributable to the second ibuprofen dose. The concentrations post-remedication were used for pharmacokinetic (but not pharmacodynamic) modeling.

The probability of a particular PAR score was modeled as a logistic distribution. The Cumulative Distribution Function (CDF) of PAR has the form logit(CDF(PAR)) g(l, t, Ceg, O, r), where I indexes the specific PAR score, t is time, and Ce is the/j' effect site concentration for the i' individual. The elements 1, t and Cey are associated with the parameter vector 0.

The elements of interindividual variability are associated with the normally distributed vector rl assumed to have mean zero and covariance matrix Q. Thus, the cumulative probability F t, Ceij; 0, Tq) Pr(T..cei)(i"' subject having jth PR score less than 1; 0, q) exp(g t, Ceij; 1)) 1, 2, 3, 4, 1 exp(g r, Cey; 8, T)) for which Pr(ocei,)(i th subject having jth PR score less than 0; 0, TI) 0, and Pr( 5 ,r.c,)(iz h subject having jh PR score less than 5; 0, i) 1.

Thus, the probability that thej observation in the individual will be a specific PAR score of 1, 1, 2, 3, 4, is f 1, Cei) Pr(+ 1 ,tCei,) Pr(1.t,Ce,) (6) 19- 0 From equation we have 4 Ceij g t, Ceij; 0, 1) 9.m lm(1) 1 5 (t)-e 5 e 6

C

m=1 Ceij +Ce 50 (7) which the effect site concentration for the i'h individual having thej' PR score is Di"a e-a Cej ci (b a)(ko, a) e e (a i bi)(k, b) (ai keo)(bi ko,) (8) In equation b, c i and are the individual estimates from the pharmacokinetic model [equation D, is the dose, and kog is the estimate of the individual effect site 1rate constant. Interindividual variability in the parameter was modeled by the form shown Ce, in equation In equation the component 0, called the "intensity of effect Ce, Ceso site concentration," is the contribution of serum concentration to the logit. Here Ce 5 o is defined as: for all four levels of ibuprofen Ces 08, for 400 mg racemic buprofen; and for the two lower levels of racemic ibuprofen; (9.1) or f07, for all four levels of ibuprofen Ceso 08, for three levels of racemic buprofen.

(9.2) The five indicator functions in equation are defined to be 1 1 2 m-1 0, otherwise for m 1, 2, 3, 4; and I 0St 0.5 0 otherwise.

(11) The likelihood function of the data can be written as follows: Likelihood f- f Tr; 1, t, Cei,) (12) where the product is over all i and j. Estimates of 0, r and Q were obtained using the method of approximate Maximum Likelihood. The estimates of the parameters were obtained using the computer program NON-MEM, in which -2log(Likelihood) is minimized using a quasi- Newton method (ZXMIN of ISML). Confidence intervals for the model parameters were obtained by standard methods based on the usual asymptotic estimate of the covariance matrix of the estimators.

The model assumes that the pharmacodynamic effect of ibuprofen adds to and is independent of the average placebo effect and that the placebo effect does not differ among individuals. When D 1, 2, 3, 4, the density function of the outcome for placebo is estimated by exp(go(l+1, t; 0o)) exp(go(l, t; 0o)) plcbo exp(go(+l, t; 00)) 1 exp(g 0 t; 00)) (13) in which -21 0 4 go(l, t; 6 0 em1,(1) +15(tr)-5 m=l (14) The vector 00 is contained within 0, and and I(t) are defined in equations (10) and (11).

In this model the probability of having a specific PAR score due to the placebo effect is a constant prior to 0.5 hours, and another constant thereafter.

The probability of having a specific PAR score that is greater than or equal to 1, 1, 2, 3, 4, is 4 Pr(the typical subject having jt PR score I) f t, Cej) h=in which Ce. is the expected value of the j' concentration at the effect site. Finally, the expected PAR score can be estimated from the equation E(L; t, Cej) f r, Ce), i=0 (16) and its variance is 4 VAR(L; r, Cei) [I E(L; t, Ce)] 2 f r, Ce,), =-0 (17) where L stands for the random variable corresponding to the PAR score. EpIaebo and VARp,,cebo can be estimated using equations (16) and (17) substitutingfp,, abo(, t) for(f, t, Ce In simple terms, the model assumes that E(L; t, Cej) Eplacebo Eibuprofen (18.1) and VAR(L; r, Cej) VARplacebo VARibuprofen (19.1) -22o Therefore, the mean PAR score which is attributable to ibuprofen can be estimated from Eibuprofen E(L; t, Cej) Eplacebo (18.2) and the variance can be estimated from VARibuprofen VAR(L; t, Cej) VARplacebo (19.2) Bioassay Analysis In order to obtain an estimate of the equivalent dose of racemate and ibuprofen, a series ofbioassay analyses were performed separately at each observation time.

These were a Slope Ratio Assay in which the dose of ibuprofen and of ibuprofen are related to the resulting serum concentrations of ibuprofen; a Serum Concentration- Effect Assay or Log Concentration Effect Assay in which the serum concentration of ibuprofen is related to the analgesic response and a Dose Effect Relationship in which the results of the slope ratio assay and the results of the Serum Concentraton-Effect Assay are combined to obtain the relationship between the dose of and racemic ibuprofen, and the analgesic response. These were used to obtain the relative potency of the two treatments at each time point and overall. The overall estimates were based on the summary efficacy measures SPID and %SPID, and the area under the serum concentration curve was used as the independent variable in the slope ratio assay, and as the dependent variable in the serum concentration effect assay.

The mathematical details of these three analyses are as follows: Slope Ratio Assay. To relate dose administered to serum levels, a linear model at each time point was assumed. In this model I Du Ca (t)Du where Du is the dose administered at t 0 for u 1, which indicates racemic ibuprofen or 2 which indicates ibuprofen. Here as above, E stands for expected value.

Let r(t) be the relative potency of the dose of to racemic ibuprofen that produces equal serum concentration at time t. That is, if dose D| of racemic ibuprofen and -23o dose D 2 of produce equal concentrations at time t then Di r(t) D 2 Since at time t Eic(t) E 2 C(t) 0 ai(t) Di -a2(t) D 2 Qa(t) a 2

D

2 it follows that r(t) a 2 ac(t). Also, for the same dose D, El(c(t) I D) E 2 I r(t) D r(t)E 2 I D).

Serum Concentration Effect Assay. To relate analgesic response to serum concentration of ibuprofen, a log linear model at each time point was assumed. Thus, Eu PID(t) Yu P log c, Let p(t) be the relative potency of the concentration after receiving racemic ibuprofen to the concentration after receiving ibuprofen that produces equal PID scores at time t. That is, ifcl(t) of racemic ibuprofen and c2(t) of ibuprofen produce equal PID scores at time t then p(t) cl(t). Therefore, since at time t El (PID(t)) E 2 (PID(t)) 0 Y1 P log cl(t) (Y2 P log C 2 (Yi 72) p (log cl(t) log p(t) cl(t)), it follows that log (Yi Y2) 3.

Also, E2 (PID(t) I c El (PID(t) Ip(t)c(t)).

Dose Response Relationship. The relative potency, between dose and PID score at time t may be obtained by combining the relationship between dose and serum and between serum and effect. At time t, if the two treatments produce equal PID scores, then E2 (PID(t) I D 2 El (PID(t) I DI) Y2 P log a 2

D

2 71 P log ai(t) D, Y 3 log ac(t) R(t)D 2 Yl 3 log a 2 p(t)D 2 Subtracting the last two equations and solving for R yields R(t) p(t) ca2(t)/ ac(t) p(t)r(t), so that the relative potency at t is the product of the potencies obtained in the slope ratio and concentration effect assays.

Solubility analysis With the exception of the ibuprofen component, other components of the and racemic caplet formulations were made to be identical or at least comparable. To Sdetermine whether solubility plays a role in the onset of analgesic action of racemic 351.

-24- 0compared to ibuprofen, the dissolution profiles of the caplets were compared using the USP dissolution test. The caplets were put into a test buffer and the percent dissolved was measured at 5, 10, 15, 20 and 30 minutes thereafter.

Results Patient Information A total of 203 patients, 69 males and 134 females, entered the study. The 69 males ranged in age from 16-37 years (mean 21.8 years) and in weight from 117-318 pounds (mean 168.8 pounds). The females ranged in age from 16-42 years (mean 21.5 years) and in weight from 80-254 pounds (mean 139.0 pounds). There were 26 patients in the S400 treatment group, 25 patients in each of the S80, S200, 1100, 1400 and placebo groups and 27 patients in the 1200 group. No patients were excluded from the efficacy analysis.

Pharmacodynamic Analysis: The seven active treatments were significantly superior to placebo for most of the time points for ordinal and VAS PR and PID as shown in Tables 1-4.

Table 1 Mean Pain Intensity Difference (Ordinal), Sample Sizes and Fisher's LSD Comparison' (vertically) of Pairwise Comparisons Between the Different Treatment Groups At Each of the Observation Times (minutes) After Dosing TREATMENT 15 30 45 60 120 180 240 300 360 80 25 25 25 25 24 22 19 17 13 0.24 ABC 1.00 BC 1.48 BC 1.64 BC 1.88 C 1.72 C 1.32 C 1.28 B 1.08 BC 200 25 25 25 25 23 21 20 17 15 0.44 A B 1.00 BC 1.44 BC 1.80 BC 2.24 BC 1.96 BC 1.36 C 1.16 BC 1.16 BC 320 25 25 25 25 24 23 23 23 23 0.48 A I.08 AB 1.75 AB 2.08 AB 2.20 BC 2.20 ABC 2.00 AS 1.72 AB 1.24 BC S(+)400 26 26 26 26 26 26 25 25 22 0.38 AS :.42 A 1.96 A 2.27 A 2.69 A 2.69 A 2.54 A 2.23 A 1.92 A lu 100 25 25 25 25 25 24 23 20 18 0.28 ABC C.84 BC 1.32 BC 1.72 BC 2.00 BC 1.84 BC 1.84 BC 1.68 AB 1.52 A3 [bu 200 27 27 27 27 27 26 25 24 23 0.19 BC :.00 BC 1.63 ABC 1.96 ABC 2.33 AS 2.30 AB 2.11 AB 2.11 A 1.93 A Thu 400 25 25 25 25 24 24 23 21 19 0.04 C C.64 C 1.28 C 1.60 C 2.20 BC 2.32 AB 2.24 AB 2.04 A 1.64 AB Placebo 25 25 25 25 15 9 a 8 a 0.08 C C.16 0 0.48 D 0.44 D 0.40 D 0.56 0 0.56 D 0.64 C 0.64 C p-value 0.013 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.001 1 Same letter indicates absence of significant difference (p<0.05 level of significance) Table 2 Mean Pain Intensity Difference (VAS), Sample Sizes and Fisher's LSD Comparison' (vertically) of Pairwise Comparisons Between the Different Treatment Groups At Each of the Observation Times (minutes) After Dosing TREATMENT 15 30 45 60 120 180 240 300 360 80 25 25 25 25 24 22 19 17 13 11.0 AsB 34.6 BC 50.8 AS 60.7 AS 64.7 B 57.4 C 44.5 C 40.0 C 34.6 CD 200 25 25 25 25 23 21 20 17 15.8 A 34.8 BC 48.0 B 62.1 AS 70.9 B 65.3 BC 52.7 BC 43.0 BC 41.4 BC 320 25 25 25 25 24 23 23 23 16.4 A 41.5 AB 58.6 AS 66.1 As 74.6 AS 70.0 ABC 67.1 AB 60.3 AS 41.7 SC S(+)400 26 26 26 26 26 26 25 25 22 14.8 A 48.2 A 63.7 A 71.5 A 84.3 A 83.2 A 78.9 A 73.2 A 62.3 A Thu 100 25 25 25 25 25 24 23 20 18 9.5 AB 31.5 BC 49.5 AB 62.8 AS 70.8 B 68.2 ABC 63.4 AB 58.4 ABC 52.1 ABC ru 200 27 27 27 27 27 26 25 24 23 9.1 AS 36.7 ABC 54. 9 AS 65.6 AB 74.8 AB 73.8 AB 68.5 AB 67.7 A 60.1 AB thu 400 25 25 25 25 24 24 23 21 19 5.8 a 25.5 C 44.6 B 56.4 8 72.0 AS 76.2 AB 69.3 AB 65.1 A 56.4 AS Placebo 25 25 25 25 15 9 8 8 8 2.6 B 4.6 0 13.9 C 15.0 C 10.5 C 13.6 D 15.5 D 16.9 D 17.9 D p-value 0.025 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 1 Same letter indicates absence of significant difference (p<0.05 level of significance) -26- Table 3 Mean Pain Relief (Ordinal), Sample Sizes and Fisher's LSD Comparison' (vertically) of Pairwise Comparisons Between the Different Treatment Groups At Each of the Observation Times (minutes) After Dosing TREATMNT 15 30 45 60 120 180 240 300 360 80 25 25 25 25 24 22 19 17 13 0.64 ABC 1.76 ABC 2.44 ABC 2.68 BC 2.8 C 2.68 C 2.12 D 1.88 C 1.64 CD 200 25 25 25 25 23 21 20 17 0.72 ABC 1.84 ABC 2.52 ABC 2.88 ABC 3.32 ABC 2.92 BC 2.32 C. 2.00 BC 1.92 BC S(+)320 25 25 25 25 24. 23 23 23 1.00 A 2.04 AB 2.00 As 3.20 AB 3.28 BC 3.24 ABC 3.04 ABC 2.76 AB 2.00 ABC 400 26 26 26 26 26 26 25 25 22 0.88 AB 2.31 A 2.96 A 3.35 A 3.81 A 3.81 A 3.58 A 3.31 A 2.85 A Ibu 100 25 25 25 25 25 24 23 20 18 0.64 ABC 1.56 BC 2.32 BC 2.76 BC 3.04 BC 2.88 BC 2.84 BCD 2.56 ABC 2.32 ABC lbu 200 27 27 27 27 27 26 25 24 23 0.56 BCD 1.93 ABC 2.67 ABC 3.04 ABC 3.44 AS 3.41 AB 3.15 AB 3.07 A 2.85 A Tbu 400 25 25 25 25 24 24 23 21 19 0.32 CD 1.40 C 2.20 C 2.52 C 3.28 BC 3.40 A3 3.28 AB 3.00 A 2.52 AB Placebo 25 25 25 25 15 9 8 8 8 0.20 D 0.40 D 0.80 D 0.96 D 0.80 D 0.84 D 0.92 E 0.96 D 0.96 C p-value 0.006 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 1 Same letter indicates absence of significant difference (p<0.05 level of significance) Table 4 Mean Pain Relief (VAS), Sample Sizes and Fisher's LSD Comparison' (vertically) of Pairwise Comparisons Between the Different Treatment Groups At Each of the Observation Times (minutes) After Dosing TrRATMENT 15 30 45 60 120 180 240 300 360 80 25 25 25 25 24 22 19 17 13 13.1 ABC 42.4 ABC 61.4 ABC 71.6 AS 77.0 C 69.8 C 54.8 C 48.2 C 42.8 BC S(+)200 25 25 25 25 23 21 20 17 15.7 AB 45.4 ABC 63.6 ABC 75.8 AB 86.4 ABC 77.7 BC 63.9 BC 54.1 BC 51.8 AS 320 25 25 25 25 24 23, 23 23 19.8 A 51.4 A3 72.5 AB 80.2 AB 87.7 ABC 84.1 ABC 80.0 AS 74.8 AS 52.5 AS 400 26 26 26 26 26 26 25 25 22 19.7 A 56.2 A 75.8 A 83.9 A 97.8 A 97.0 A 91.9 A 85.8 A 74.1 A Ibu 100 25 25 25 25 25 24 23 20 18 11.9 ABC 36.0 BC 58.7 BC 72.6 AB 79.6 BC 78.0 BC 73.0 ABC 67.8 ABC 62.6 AB Tbu 200 27 27 27 27 27 26 25 24 23 10.6 ABC 47.7 AB 67.5 ABC 79.5 AB 90.7 AB 88.8 A3 82.0 AS 80.4 A 72.7 A Thu 400 25 25 25 25 24 24 23 21 19 6.3 BC 31.1 C 54.4 C 66.1 a 84.2 BC 90.0 AB 83.3 A 78.4 A 68.7 A Placebo 25 25 25 25 15 9 8 8 8 3.6 C 8.2 D 17.3 D 19.7 C 16.8 D 21.8 D 23.6 C 25.2 0 24.3 C p-value 0.021 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 1 Same letter indicates absence of significant difference (p<0.05 level of significance) There was a reversal of the rank order of the mean efficacy between the 4001 and 2001 doses.

These differences were not statistically significant and with small sample size not unexpected. The treatments showed their superiority to placebo beginning at -27minutes while the racemic ibuprofen treatments did not show superiority over placebo until minutes. Pairwise and racemic ibuprofen treatment comparisons resulted in the higher dose levels of demonstrating superiority over racemic ibuprofen starting from minutes and lasting through 1 hour. 4001 and 2001 tended to be significantly more effective than 200S and 80S at the 4th, 5th and 6th hours.

Generally, the PD analysis showed that all seven treatments were significantly superior to placebo, 320S and 400S had the fastest onset of analgesic action, and 400S and 2001 had the longest duration's of analgesic activity.

Pharmacokinetic Analysis: The mean AUCI ibuprofen concentration levels and CpMax together with their standard deviations are given in Table Table MEAN AREA AND CpMAX VALUES OF IBUPROFEN IN PLASMA AUCI (mcg*hr/ml) CpMax (mcg/mL) Dose n Mean (StDev) Mean (StDev) 25 20.56 7.32) 8.54 2.45) 200S 24 42.04 (13.43) 18.26 5.49) 320S 24 72.61 (18.91) 29.49 8.57) 400S 25 94.47 (26.04) 41.11 (11.94) 100I 22 17.26 7.50) 4.78 1.47) 2001 23 34.91 (11.06) 9.59( 3.11) 4001 24 66.81 (19.06) 17.96 6.05) The mean TMAX values for doses are: 1.06 for 80S, 1.14 for 200S, 1.30 for 320S, and 1.33 for 400S. The mean ibuprofen TMAX values for racemic ibuprofen doses were 1.41 for 100I, 1.86 for 2001, and 1.96 for 400I.

The mean AUCI racemic ibuprofen concentration levels and CpMax together with then standard deviations for the 1100, 1200 and 1400 doses are shown in Table 6.

-28- Table 6 MEAN AREA AND CpMAX VALUES OF IBUPROFEN IN PLASMA AUCI (mcg*hr/ml) CpMax (mcg/mL) Dose n Mean (StDev) Mean (StDev) 100I 24 16.91 5.22) 6.06 (1.83) 2001 23 31.13( 7.69) 11.66 (2.84) 4001 23 59.39 (17.94) 23.40 (7.16) The corresponding TMAX values were 1.43 for 1001, 1.62 for 200, and 1.79 for 4001.

The results demonstrated an apparent linear dose proportionality for AUCIs, CpMAXs, and TMAXs for both ibuprofen and racemic ibuprofen.

PK/PD analysis The hastened onset of compared to racemic ibuprofen at the same dose may be seen by examining the results of the analysis at 0.25, 0.5 and 0.75 hours.

Table 7 displays the expected effect site concentration (Ce) and the expected PAR by time and dose computed under models 9.1 and 9.2. These data are summarized for placebo, 200S(+), 2001, 400S(+) and 4001 at 0.25, 0.5, and 0.75 hours.

-29- Table 7 Expected Effect Site Concentration and Expected PAR Time Drug (hours) Model 9.1 Ce E(L Model 9.2 e E(L) 0.25 Placebo 200S(+) 2001 400S(+) 4001 0.00 0.35 0.09 0.36 0.14 .7 .92 .78 1.13 .79 0.00 0.35 0.09 0.36 0.13 .69 .92 .77 1.14 .86 Placebo 200S(+) 2001 400S(+) 4001 0.00 2.43 .85 3.97 1.09 0.7 1.86 1.51 2.41 1.56 0.00 2.44 .88 3.97 1.01 .69 1.86 1.51 2.38 2.01 Placebo 200S(+) 2001 400S(+) 4001 0.00 4.83 1.97 9.20 2.68 1.19 2.93 2.71 3.31 2.76 0.00 4.86 2.04 9.21 2.45 1.21 2.94 2.72 3.21 3.13 It can be seen that there are higher concentrations of at 0.25, 0.5 and 0.75 hours achieved by administering the isomer than by administering the racemate.

Table 8 displays the probability of observing a PAR of 3, of 4 and of 3 or 4, for placebo, 200S(+), 2001, 400S(+) and 4001 at 0.25, 0.5, and 0.75 hours computed under Model 9.1. Table 9 displays the same values computed under Model 9.2.

Table 8 Probability of PAR 3. 4 and 3 or 4. Comouted under Model 9.1 4 and 3 or 4. ComDuted under Model 9.1 Time Drug Prob, PAR =3 ProbPAR =4 Prob PAR t3 (hours) Placebo 200S(+) 200R 400S(+) 400R Placebo 200S(+) 200R 400S(+) 400R Placebo 200S(+) 200R 400S(+) 400R .046 .071 .062 .072 .056 .046 .237 .202 .313 .131 .110 .432 .4 .41 .358 .006 .01 .009 .011 .008 .006 .052 .046 .092 .025 .017 .243 .23 .395 .133 .053 .081 .072 .084 .064 .053 .29 .248 .405 .156 .127 .674 .633 .805 .491 -31 Table 9 4 and 3 or 4. Comouted under Model 9.2 Probability of PAR 3.

4 an 31TTI or 4. Co otdude oe Time (hours) Drug Prob PAR=3 Prob PAR=4 Prob PAR >3 Placebo 200S(+) 2001 400S(+) 4001 Placebo 200S(+) 2001 400S(+) 4001 Placebo 200S(+) 2001 400S(+) 4001 .045 .071 .054 .102 .063 .045 .259 .172 .405 .301 .114 .482 .473 .416 .459 .007 .011 .008 .016 .009 .007 .052 .03 .117 .065 .018 .28 .2 .46 .370 .052 .082 .061 .118 .072 .052 .311 .201 .522 .366 .132 .763 .673 .875 .829 It can be seen that under both models, there is a greater likelihood of having substantial pain relief at 0.25 and 0.5 hours for those on the isomer in comparison to those on the racemate.

There is a diminution of the differential effect between treatments by 0.75 hours.

Bioassay Analysis Slope ratio assay: Serum concentration versus dose. Table 10 displays, for and for racemic ibuprofen, the slope, ca(t), of the regression line that relates the expected 3 sem concentration ofS(+) to the dose administered at baseline.

serum concentration of to the dose administered at baseline.

-32- Table Slope Ratio Assay Serum Concentration As A Function Of Dose Time Slope* Standard Error Relative Lower Upper (min) Racemate Racemate MSE Little g Potency Conf Conf Limit Limit .019 .006 .0022 .0026 35.2 .689 3.03 1.56 17.96 .054 .017 .0033 .0040 83.7 .213 3.10 2.08 5.81 .067 .025 .0031 .0038 75.1 .086 2.66 2.02 3.80 .075 .028 .0029 .0035 65.9 .063 2.72 2.14 3.66 120 .053 .031 .0019 .0023 26.2 .021 1.70 1.45 2.01 180 .032 .028 .0013 .0016 12.7 .013 1.16 1.01 1.33 240 .022 .019 .0014 .0017 14.0 .030 1.12 .91 1.40 300 .013 .015 .0008 .0010 4.7 .019 .91 .76 1.09 360 .009 .011 .0006 .0008 2.5 .019 .82 .67 .99 AUCI .242 .174 .0068 .0084 279.6 .009 1.39 1.25 1.55 *Slope of and the racemate significantly 0 (regression test, p. Also exhibited are the p values of the test of the null hypothesis that the slope a(t) 0. For each time point, the relative potency, the factor by which the dose of must be multiplied to obtain a dose of ibuprofen that would produce the same expected serum concentration, is displayed. For both and racemic ibuprofen, at all time points and for AUCI the slopes of the regression lines were significantly different from zero. The slopes of the regression lines for patients receiving increase until 60 minutes and decrease thereafter whereas the slopes of the regression lines for those patients receiving ibuprofen increase until 120 minutes and decrease thereafter. In the first half hour was more than three times as potent as ibuprofen. Thereafter, the relative potency of to racemic ibuprofen decreased but remained above one with confidence limits that did not embrace one until 180 minutes.

At 300 and 360 minutes the relative potency estimates were below one but were not significantly different from one. By 360 minutes was only 0.817 as potent as ibuprofen.

The relative potency based on AUCI was 1.39 indicating that overall was more potent than ibuprofen. This overall relative potency was significantly different from one.

Serum Effect Assay:Log Serum versus PID, Mean Log Serum, Mean PID and Relative Potency. Table 11 displays the mean log serum and mean PID for and ibuprofen, and the relative potency for all assessment points, and for SPID and %SPID.

-33- Table 11 The Relationship of PID to Log Serum Mean Log Serum. Mean PID Relative Potency Time Mean log Sequence Mean PID Relative Lower Upper Conf (minutes) Racemate Racemate Potency Conf Limit Limit 15 .581 .222 .524 .306 2.100 .3835 59.1120 1.005 .600 1.222 1.017 .735 .3578 1.8823 1.061 .747 1.660 1.500 .718 .3999 1.4203 1.149 .756 1.949 1.829 .533 .3127 .9759 120 1.032 .766 2.365 2.222 .792 .4519 1.5959 180 .828 .689 2.371 2.264 .919 .5662 1.5827 240 .652 .575 2.145 2.303 .586 .2722 1.0740 300 .532 .495 2.072 2.368 .401 .0842 .8195 360 .401 .439 2.053 2.311 not estimable SPID 1.749 1.530 12.996 12.718 .731 .3303 1.9253 %SPID 1.749 1.530 76.439 74.061 .811 .4027 2.0196 The relative potency represents the factor by which the serum level produced by racemic ibuprofen would have to be multiplied in order to produce the same clinical effect as that produced by ibuprofen. Analyses of variance indicated that at 60 and 300 minutes, there was a significant difference in mean PID scores between and racemic ibuprofen.

For all time points except for 360 minutes, there was a significant linear regression. There 20 was no evidence that the assumption of parallelism was violated at any assessment point. A test of the assumption of linearity was not rejected at any time point with the exception of 180 minutes.

The confidence intervals for the relative potency for the most part encompassed one and over time, the trend of the relative potencies is decreasing. At minutes, the relative potency was well above one, indicating that higher concentrations of ibuprofen compared to were required to obtain the same clinical response. However, the confidence interval covered one. Thereafter, the relative potency was less than one, although, except at 60 and 300 minutes, it did not significantly differ from one. Overall, in terms of SPID and SPID, the relative potency was 0.73 and 0.81 but these were not significantly different from one.

Dose Effect Assay:. Product of Potencies.Table 12 displays the product of the relative potencies obtained from the analysis of PID versus log serum and from the slope -34- 0 ratio assay of serum versus dose, for each assessment point, and for SPID and SPID.

Table 12 Product Potency Time (Minutes) 120 180 240 300 360

SPID

%SPID

Relative Potency PID vs Log Serum 2.100 .735 .718 .533 .792 .919 .586 .401 not estimable .731 .811 Relative Potency: Slope Ratio Assay 3.030 3.140 2.655 2.720 1.695 1.156 1.122 .907 .817 1.387 1.387 Product Potency: PID vs Dose 6.363 2.281 1.906 1.450 1.342 1.062 0.657 0.364 1.014 1.125 The resulting relative potency represents the factor by which the dose of must be multiplied to obtain the dose ofibuprofen that produces the same clinical effect. Figure 1 depicts the plot of these relative potencies over time.

The relative potencies are well above one until 120 minutes, about one at 180 minutes and thereafter are less than one. The relative potency of SPID is approximately one and of %SPID is slightly greater than one. Thus, equal doses of and racemic ibuprofen produce approximately the same overall effect, but compared to racemic ibuprofen, is more potent earlier and less potent later.

Solubility analysis: Tables 13 and 14 respectively show dissolution profiles of 200 mg caplets form Lot DMGIS 9157 (Table 13) and of 200 mg racemic ibuprofen caplets from Lot DMGIR 9153 (Table 14) at 5, 10, 15, 20 and 30 minutes.

Table 13 Ibuprofen Dissolution Profile Lot DMGIS 9157 Vessel Number dissolved 5 min 1 76 2 83 3 87 4 81 74 6 78 7 79 8 84 9 73 75 11 80 12 82 %Dissolved 10 min 96 100 104 104 98 102 98 100 100 104 100 100 Dissolved 15 min 98 101 105 105 101 103 100 102 103 106 103 102 Dissolved 20 min 98 101 105 105 101 102 100 102 103 105 102 102 Dissolved min 98 102 105 105 101 102 101 102 103 105 102 102 Mean 79 100 102 102 102 RSD 5.4 2.5 2.2 2.1 Minimum 73 96 98 98 98 Maximum 87 104 106 105 105 -36- Table 14 Ibuprofen Dissolution Profile Ibuprofen Caplet. 200 mg (Racemate) Lot DMGIR 9153 Dissolved Dissolved Dissolved Dissolved Dissolved Vessel Number 5 min 10 mi 15 min 20 min 30 mi 1 48 89 100 100 101' 2 61 94 99 98 99 3 44 95 102 103 103 4 46 98 101 102 102 51 96 100 100 100 6 56 98 101 101 101 Mean 49 95 100 101 101 RSD 8.7 3.4 1.4 1.5 Minimum 43.8 89.3 98.6 98.4 98.7 Maximum 55.8 98.3 102.4 102.6 103.1 Although there was a significant difference in the mean amount of ibuprofen versus racemic ibuprofen dissolved at the 5 minute time point (79% versus 49%, compare Table 13 to Table 14), the two released approximately the same mean amount of drug by the 10 minute time point (100% versus The difference in solubility at minutes is of no clinical consequence considering that gastric emptying profiles have a halflife of about 10-15 minutes for a solution, the volumes of fluid in the fasting stomach are much less than the 900 ml used in the test, and the half-life for absorption in vivo is much longer than a 5 minute difference in an in vitro dissolution test.

Summary and Discussion of Example 3 The results of the PD analysis of this study demonstrate that ibuprofen and racemic ibuprofen are significantly more effective than placebo and that ibuprofen has a faster onset of effect.

Based on the PK analysis, higher concentrations of are obtained from ibuprofen than from racemic ibuprofen at 0.25, 0.5 and 0.75 hours. Based on the bioassay analysis, in order for racemic ibuprofen to yield the same serum concentration at 15 minutes as is produced by a dose that is three times higher than the dose of -37o ibuprofen is required. Not until 180 minutes are and racemic ibuprofen equipotent and thereafter less ibuprofen is required. Overall, however, based on AUCI, a dose of ibuprofen that is 1.4 times greater than the dose of is required to produce equal serum concentrations.

The PK/PD analysis indicates that the expected values of PARs at early times after dosing are higher for those receiving than for those receiving the same amount of racemic ibuprofen.

The bioassay analysis demonstrated that higher serum levels result in higher PID scores for both racemic and ibuprofen. After 15 minutes, racemic ibuprofen requires less serum concentration of than is required by ibuprofen in order to achieve the same PID score. Integrated over the entire time interval of the study, as measured by SPID, racemic ibuprofen requires only about three quarters as much serum concentration as is required by ibuprofen to achieve the same clinical effects.

The bioassay analysis indicates that is more potent than racemic ibuprofen until 180 minutes and less potent thereafter. Initially it is 6.4 times as potent, which is reflected in a more rapid onset for Thus, at the same doses, ibuprofen achieves faster onset of effect than does racemic ibuprofen. Averaged overall, based on SPID and SPID, as they relate to the total serum concentration (AUCI) the two treatments are equipotent.

From the foregoing description, one of ordinary skill in the art can easily ascertain the essential characteristics of the instant invention, and without departing from the spirit and scope thereof, can make various changes and/or modifications of the invention to adapt it to various usages and conditions. As such, these changes and/or modifications are properly, equitably and intended to be within the full range of equivalence of the following claims.

Claims (32)

1. The method of eliciting an onset-hastened and enhanced analgesic response in a human mammal suffering from pain comprising administering to said human mammal a unit dosage onset-hastening/enhancing analgesically effective amount of the ibuprofen enantiomer, and said enantiomer being substantially free of its ibuprofen antipode.

2. A method according to claim 1, wherein the weight ratio of ibuprofen to ibuprofen is greater than 9:1.

3. A method according to claim 2, wherein the weight ratio of ibuprofen to ibuprofen is greater than 20:1.

4. A method according to claim 3, wherein the weight ratio of ibuprofen to ibuprofen is greater than 97:3. A method according to claim 4, wherein the weight ratio of ibuprofen to ibuprofen is approximately equal to or greater than 99:1.

6. A method according to claim 1, comprising administering to said human mammal from 50 to 1000 mg ibuprofen.

7. A method according to claim 1, comprising administering to said human mammal from 100 to 800 mg ibuprofen.

8. A method according to claim 1, comprising administering to said human mammal from 100 to 600 mg ibuprofen.

9. A method according to claim 2, comprising administering to said human mammal from 50 to 1000 mg ibuprofen. A method according to claim 2, comprising administering to said human mammal from 100 to 800 mg ibuprofen.

11. A method according to claim 2, comprising administering to said human mammal from 100 to 600 mg ibuprofen.

12. A method according to claim 3, comprising administering to said human mammal from 50 to 1000 mg ibuprofen.

13. A method according to claim 3, comprising administering to said human mammal from 100 to 800 mg ibuprofen. -39-

14. A method according to claim 3, comprising administering to said human mammal from 100 to 600 mg ibuprofen. A method according to claim 4, comprising administering to said human mammal from

16. human mammal from

17. human mammal from

18. human mammal from

19. human mammal from human mammal from

21. 50 to 1000 mg ibuprofen. A method according to claim 4, comprising administering to said 100 to 800 mg ibuprofen. A method according to claim 4, comprising administering to said 100 to 600 mg ibuprofen. A method according to claim 5, comprising administering to said 50 to 1000 mg ibuprofen. A method according to claim 5, comprising administering to said 100 to 800 mg ibuprofen. A method according to claim 5, comprising administering to said 100 to 600 mg ibuprofen. A method according to claim 1, wherein said human mammal is suffering from postoperative pain.

22. A method according to claim suffering from postpartum pain.

23. A method according to claim suffering from dental pain.

24. A method according to claim suffering from dysmenorrhea. A method according to claim 1, wherein said human mammal is 1, wherein said human mammal is 1, wherein said human mammal is 1, wherein said human mammal is suffering from headache pain.

26. A method according to claim 1, wherein said human mammal is suffering from musculoskeletal pain.

27. A method according to claim 1, wherein said human mammal is suffering from pain or discomfort associated with a respiratory infection.

28. A method according to claim I, wherein said human mammal is suffering from pain or discomfort associated with a cold or flu.

29. A method according to claim 1, wherein said human mammal is suffering from pain associated with inflammatory or degenerative joint disease. suffering from suffering from suffering from suffering from administered to administered to A method according to claim 1, wherein said human mammal is pain associated with rheumatoid arthritis.

31. A method according to claim 1, wherein said human mammal is pain associated with osteoarthritis.

32. A method according to claim 1, wherein said human mammal is pain associated with gout.

33. A method according to claim 1, wherein said human mammal is pain associated with morning stiffness.

34. A method according to claim 1, wherein the ibuprofen is or said human mammal. A method according to claim 1, wherein the ibuprofen is re Ssaid human mammal. ally ctally

36. A method according to claim 1, wherein the enantiomer is topically administered to said human mammal.

37. A pharmaceutical composition of matter when used in the method of any one of claims 1 to 36 adapted to elicit an onset-hastened and enhanced analgesic response in a human mammal in pain, said composition comprising a solid-state unit dosage onset-hastening/enhancing analgesically effective amount of the ibuprofen enantiomer, said enantiomer being substantially free of its antipode, and a nontoxic pharmaceutically acceptable carrier or diluent therefor.

38. The pharmaceutical composition of matter according to claim 37, adapted for oral administration.

39. The pharmaceutical composition of matter according to claim 38, formulated as a tablet, caplet, pill or capsule. DATED THIS 8th day of February, 1999 STERLING DRUG, INC. WATERMARK PATENT TRADEMARK ATTORNEYS 2nd Floor, 290 Burwood Road, HAWTHORN. VICTORIA. 3122.