FORM 2THE PATENT ACT 1970(39 of 1970)&The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
2. APPLICANT (S) (a) NAME: WOCKHARDT LIMITED (b)NATIONALITY:(d) ADDRESS: Wockhardt Towers,Bandra-Kurla Complex, Bandra East, Mumbai --400051.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.ATTACHED HEREWITH.

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PHARMACEUTICAL COMPOSITIONS FOR ANALGESIA AND PYREXIA.
Field of the Invention
5 [0001] The present invention relates to a pharmaceutical composition for treatment of pain and that provides a superior analgesic effect. In particular, the composition is useful to treat painful conditions that are accompanied by pyrexia. Anti-inflammatory conditions can be typically accompanied by pyrexia, which is the result of release of pyrogenic substances from the inflamed site, and can lead to a rise in body temperature, i.e., a fever.
10 The pharmaceutical composition includes three drugs. The first drug belongs to a class of centrally acting analgesics, the second drug is an antipyretic agent, and the third drug is an anti-inflammatory agent exerting peripheral analgesia preferably having a different mechanism of action. The pharmaceutical composition has been found to provide superior analgesia as evidenced from animal studies conducted to evaluate the efficacy of the
15 combination composition. The preferred active ingredients include hydrocodone as a centrally acting analgesic agent, acetaminophen as a antipyretic agent and ibuprofen or diclofenac as a peripheral anti-inflammatory agent.
Background of the Invention
20 [0002] Opioid analgesics have been combined with other drugs, including non-opioid analgesic agents, to reduce side effect problems of opioid analgesics, which lower the amount of opioid needed to produce an equivalent degree of analgesia. For example, A. Takemori, Annals New York Acad. Sci., 281,262 (1976) discloses that compositions including combinations of opioid analgesics with drugs other than analgesics exhibit a
25 variety of effects, i.e., sub additive (inhibitory), additive or synergistic. R. Taber et al., J. Pharm. Expt. Thera., 169(1), 29 (1969) disclose that the combination of morphine and methadone, another opioid analgesic, exhibits an additive effect. U.S. Patent. No. 4,571,400 discloses that the combination of dihydrocodeine, an opioid analgesic, and ibuprofen, a non-opioid analgesic, provides a synergistic effect when the components are
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within certain ratios. See also U.S. Patent No. 4,587,252 and U.S. Patent No. 4,569,937, which disclose other ibuprofen opioid combinations. A. Pircio et al., Arch. Int. Pharmacodyn., 235, 116 (1978) report a synergistic analgesic effect with a 1:125 mixture of butorphanol, another opioid analgesic, and acetaminophen, a non-opioid analgesic, 5 whereas a 1:10 mixture did not show any statistical synergism to analgesia.
[0003] Non-opioids such as aspirin and ibuprofen have been used as analgesics, because Ibuprofen, like aspirin, is not subject to the tolerance, addiction and toxicity of the opioid analgesics. However, ibuprofen, aspirin and other nonsteroidal anti-inflammatory drugs (commonly referred to as NSAIDs) are only useful in relieving pain of moderate intensity, 10 whereas opioid analgesics can be used to relieve more intense pain; See, e.g., Woodbury, D. and Fingl, E. in "The Pharmacological Basis of Therapeutics", 5th Ed.; Goodman, L. and Gilman, A., Chapter 15, (1975).
[0004] Combinations of non-opioid analgesics have also been prepared to avoid the side effects associated with opioid analgesics. Some of the combinations are reported to have a
15 benefit of requiring less of each ingredient and producing a synergistic effect. G. Stacher et. al, Int. J. Clin. Pharmacol. Biopharmacy, 17, 250 (1979) report that the combination of non-opioid analgesics, i.e., tolmetin (another NSAID) and acetaminophen, allows for a marked reduction in the amount of tolmetin required to produce analgesia. In addition, U.S. Patent No. 4,260,629 discloses that an orally administered composition of
20 acetaminophen and zomepirac, a non-opioid analgesic, in a particular weight ratio range produces a synergistic effect for relief of pain in mammals. Furthermore, U.S. Patent No. 4,132,788 discloses that 5-aroyl-l-(lower)alkylpyrrole-2-acetic acid derivatives, non-opioid analgesics, when combined with acetaminophen or aspirin exhibit synergistic effect for antiarthritic activity. However, there have been warnings against the daily consumption
25 of non-opioid analgesic mixtures and of the consumption of a single non-opioid analgesic in large amounts or over long periods (see, D. Woodbury and E. Fingl, at page 349). In addition, ibuprofen, aspirin and some other NSAIDs may cause gastrointestinal side effects, if used repeatedly. See, for example, M. J. S. Langman, Am. J. Med. 84 (Suppl. 2A): 15-19, 1988; and P. A. Insel in "The Pharmacological Basis of Therapeutics" 8th Ed.;
30 Gilman, A.G. et al., Chapter 26, pp. 664-668,1990.

[0005] Hydrocodone (7,8-dihydrocodienone) is a centrally acting narcotic analgesic agent with qualitative actions similar to those of codeine. The chemical name for hydrocodone is 4,5-alpha-epoxy-3-methoxy-17-methylmorphinan-6-one. The preparation of hydrocodone and pharmaceutically acceptable acid addition salts thereof are disclosed 5 in, for example, Pfister and Tischler, in U.S. Patent No. 2,715,626, and The Merck Index, (Ninth Edition) Entry No. 4672 (1976).
[0006] Ibuprofen is an anti-inflammatory agent that has been used for the relief of pain in mammals (humans and animals). The chemical name is 2-(4-isobutylphenyl)propionic acid and its pharmaceutically acceptable salts has been described in, for example, U.K. 10 Patent Specification No. 971,700 as alternatives to the use of opioids.
[0007] Ibuprofen is a nonsteroidal anti-inflammatory agent, possesses analgesic and antipyretic activities and has also been recommended for the relief of pain in mammals (humans and animals). Its mode of action is related to prostaglandin synthetase inhibition. The chemical name for Ibuprofen is (±)-2-(p-isobutylphenyl)propionic acid. It has 15 Formula III;

Ibuprofen is commercially available under the trade names of Motrin , Ibu and Ibu-Tab. Ibuprofen is indicated for relief of the signs and symptoms of rheumatoid arthritis and 20 osteoarthritis, mild to moderate pain and treatment of primary dysmenorrhea.
[0008] Acetaminophen, 4'-hydroxyacetanilide, is a non-opiate, non-salicylate analgesic and antipyretic drug. It is a peripherally acting analgesic and is absorbed well orally. It produces analgesia by elevation of the pain threshold and antipyretic through action on the hypothalamic heat-regulating center. The chemical name for Acetaminophen is JV-(4-25 hydroxyphenyl)acetamide. It is commercially available under the trade name of
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TYLENOL® . Acetaminophen provides temporary relief of minor aches and pains with heartburn or acid indigestion and upset stomach associated with these symptoms.
[0009] Combinations of hydrocodone with Ibuprofen are disclosed in U.S. Patent No. 4,587,252. Combinations of hydrocodone with acetaminophen are available in the market
5 under the brandname of Vicodin®.
[0010] U.S. Patent No. 6,284,274 discloses compositions comprising an opiate or non-opiate analgesic using an osmotic release technology.
[0011] U.S. Patent No. 6,221,377 discloses a method of enhancing the analgesic, antiinflammatory and anti-pyretic responses by administering the medicament with a
10 pharmaceutical^ acceptable solution containing nitrous oxide. The presence of nitrous oxide is said to enhance the efficacy of the medicament.
[0012] U.S. Patent No. 6,007,841 discloses the co-administration of the narcotic analgesic with at least one non-toxic N-methyl D aspartate receptor antagonist. The N-methyl D aspartate receptor antagonist may include of drugs such as tramadol, ibuprofen
15 and acetaminophen. However, a feature of the '841 disclosure is the use of N-methyl D aspartate receptor antagonist to provide the effect of a narcotic agonist/antagonist.
[0013] U.S. Patent No. 5,945,416 and U.S. Patent No. 5,998,434 disclose combination compositions of olanzapine with analgesic drugs like ibuprofen, naproxen and others for treatment of pain.
20 [0014] U.S. Patent No. 5,914,129 discloses magnesium containing analgesic compositions, which comprise a magnesium salt, an analgesic agent, and optionally a stimulant.
[0015] U.S. Patent Application No. 2003/0203028 discloses a multiplex drug delivery system comprising at least two immediate release components substantially enveloped by a
25 second extended release component.
[0016] WO 00/29022A1 discloses a composition of a COX-2 inhibitor with a centrally acting narcotic analgesic or an agonist antagonist analgesic or tramadol.
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[0017] WO 06/053012 discloses a pharmaceutical composition comprising an analgesic combination comprising a) an NMDA antagonist or a pharmaceutically acceptable salt thereof, b) a methylxanthine or a pharmaceutically acceptable salt thereof and c) an opiate agonist, partial agonist or agonist/antagonist, or a pharmaceutically acceptable salt thereof.
5 [0018] WO 09850075 discloses a combination composition of a COX-2 inhibitor with a N-methyl D aspartate receptor antagonist and/or a nontoxic substance that block at least one major intracellular consequence of NMDA receptor activation.
[0019] EP Patent No. 0 845 989 Bl discloses a triple composition comprising an analgesic, a skeletal muscle relaxant or sedative and a N-methyl D aspartate receptor 10 antagonist.
[0020] WO 05/107467 discloses a combination of an opioid analgesic, an NSAID and a dopaminergic agent for treating pain or nociception.
[0021] There is a need for a pharmaceutical composition comprising a centrally acting opioid analgesic such as hydrocodone, an antipyretic agent such as acetaminophen and a
15 peripherally acting non-opioid analgesic such as ibuprofen or diclofenac. A pharmaceutical composition including a combination of three active therapeutic ingredients differing in their pharmacological basis of action may be able to alleviate symptoms, in conditions where inflammation leading to pain is accompanied by pyrexia. In addition, the triple combination may offer analgesic control currently unavailable in dual combinations if
20 there is a synergistic effect. This could allow dosing at a lower analgesic level than the combined doses of the individual agents. Lower dosing is advantageous as a decrease of the active ingredients (agents) to the patient can allow a decrease in frequency of dosing over single or dual combinations, which may promote better patient compliance.
25 Summary of the Invention
[0022] The present invention provides to a pharmaceutical composition comprising a centrally acting opioid analgesic agent, an antipyretic agent, and a peripherally acting non-opioid analgesic agent. The compositions of the present invention provide improved analgesia when compared to the individual agents taken alone or in dual combination

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compositions. The compositions of the invention can employ smaller amounts of each ingredient than typically required to provide a similar analgesic response than when the agents are administered alone or when the agents are used as part of a dual combination. By using smaller amounts of the active agents the side effects associated with each agent
5 may be reduced in number and degree. In addition, the pharmaceutical compositions comprising hydrocodone, acetaminophen and ibuprofen have been found to exhibit synergistic analgesic activity at specific ratios. In addition, these combination compositions have been found to be particularly useful in conditions where the treatment of inflammation accompanied by pyrexia is indicated.
10 [0023] The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. The description that follows more particularly exemplifies illustrative embodiments. In several places throughout the application, guidance is
15 provided through lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.
Detailed Description of the Invention
20 [0024] The present invention is directed to compositions comprising hydrocodone, acetaminophen and ibuprofen or diclofenac. Hydrocodone (7,8-dihydrocodienone) is a centrally acting narcotic analgesic agent with qualitative actions similar to those of codeine. The chemical name for hydrocodone is 4,5-alpha-epoxy-3-methoxy-17-methylmorphinan-6-one. As used herein, the term "hydrocorcone" includes the individual
25 stereoisomers, mixtures of stereoisomers, including the racemates, pharmaceutically acceptable salts, solvates, polymorphs and any mixtures thereof.
[0025] The pharmacology of acetaminophen is reported by B. Ameer et al., Ann. Int. Med., 87, 202 (1977). The preparation of acetaminophen is disclosed in U.S. Patent No. 2,998,450, which is incorporated herein by reference.
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[0026] According to the present invention "NSAIDs" are non-opioid analgesics that are non-steroidal drugs, which act as anti-inflammatory, analgesic or anti-pyretic agents. This class of drugs is well known in the art. See for example, Goodman, L. and Gilman, A., supra, in Chapter 26 (1990). These drugs share certain therapeutic actions and side effects.
5 Within this broad class of NSAID drugs are salicylates, such as aspirin; pyrazolone derivatives such as phenylbutazone, onyphenbutazone, antipyrine, aminopyrine, dipyrone and apazone; indomethacin; sulindac; fenamates such as mefenamic, meclofenamic, flufenamic, tolfenamic and etofenamice acids; aryl acetic acid and propionic acid compounds such as 2-(p-isobutylphenyl)propionic acid (generic name, ibuprofen);
10 alphamethyl-4-(2-thienylcarbonyl) benzene acetic acid (generic name, suprofen); 4,5-diphenyl-2-oxazole propionic acid (generic name, oxprozin); rac-6-chloro-alphamethyl-carbazole-2-acetic acid (generic name, carprofen); 2-(3-phenyloxyphenyl)-propionic acid, particularly the calcium salt dihydrate thereof (generic names, fenoprofen and fenoprofen calcium); 2-(6-methoxy-2-naphthyl) propionic acid (generic name, naproxen; the generic
15 name of the sodium salt is naproxen sodium); 4-(l,3-dihydro-l-oxo-2H-isoindol-2-yl)-alpha-methylbenzene acetic acid (generic name, indoprofen); 2-(3-benzoylphenyl)-propionic acid (generic name, ketoprofen); and 2-(2-fluoro-4-biphenylyl) propionic acid (generic name, flurbiprofen) and l-5-(4-methylbenzoyl)-lH-pyrrole-2-acetic acid (generic name, tolmetin). Also included within NSAID drugs are compounds such as sodium 5-(4-
20 chlorobenzoyl)-l,4-dimethyl-lH-pyrrole-2-acetate dihydrate (generic name, zomepirac sodium); 4-hydroxy-2-methyl-N-(2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1 -dio xide (generic name, piroxicam); 2', 4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid (generic name, diflunisal) or l-isopropyl-7-methyl-4-phenyl-2(lH)-quinozolinone (generic name, proquazone), phenylacetic acid derivatives such as diclofenac; etodolac,
25 nabumetone and the like. For the purposes of this invention, para-aminophenol derivatives such as acetaminophen are not considered NSAIDs because of their general lack of antiinflammatory activity. All of the NSAIDs are commercially available materials. A particularly preferred class of NSAIDs for use in the composition of the present invention is the propionic acid derivatives. Within this class of compounds ibuprofen is the most
30 preferred.
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[0027] The normal doses of hydrocodone, acetaminophen and Ibuprofen typically used when given individually as a single ingredient or as a dual combination are from about 2.5 to about 10 mg, about 200 mg to about 750 mg and about 200 to about 800 mg, respectively.
5 [0028] The preferred weight ratio of the agents, hydrocodone to acetaminophen to ibuprofen, is from about 1:175:90 to about 1:200:100, based on the total weight of the agents in the composition. A more preferred the weight ratio of the agents is from about 1:160:80 to about 1:140:80, based on the total weight of the agents in the composition. The most preferred the weight ratio of the agents is from about 1:140:80, based on the total
10 weight of the agents in the composition. Compositions having the weight ratios herein have been found to exhibit a synergistic analgesic effect coupled with superior efficacy in decreasing pyrexia accompanying anti-inflammatory conditions.
[0029] The following experimental examples describe the invention in greater particulars and are intended to be a way of illustrating but not limiting the invention.
15 Example 1

No. Ingredients mg/tab

Part 1 Intragranular
1 Hydrocodone Bitartrate 2.5
2 Acetaminophen 325
3 Starch 17.5
4 Sodium Starch Glycolate 5
5 Povidone - K 30 7.5
6 Sodium Lauryl Sulfate 5
Extragranular
7 Sodium Starch Glycolate 2.5
8 Microcrystalline cellulose 11
9 Talc 5
10 Colloidal Silicon Dioxide 4
11 Magnesium stearate 5

Part 2 Intragranular
12 Ibuprofen 200
13 Lactose Monohydrate 10
14 Microcrystalline cellulose 17.5
15 Croscarmellose sodium 5
16 Povidone - K 30 5

Extragranular
17 Croscarmellose sodium 7.5
18 Colloidal Silicon Dioxide 2.5
19 Magnesium stearate 2.5
Wt. of core tablets 640
20 Opadry 13
Total wt of coated tablet 653
Procedure:
[0030] Part 1: Hydrocodone, acetaminophen, starch and sodium starch glycolate are mixed in a Rapid Mixer Granulator (RMG). The blend is subjected to wet granulation
5 using an aqueous solution of povidone containing sodium lauryl sulphate. The resultant granules are dried, milled and sized. The extragranular material comprising sodium starch glycolate, microcrystalline cellulose, talc, magnesium stearate and colloidal silicon dioxide are sifted and blended with the granules obtained from the intragranular stage.
[0031] Part 2: Ibuprofen, lactose, microcrystalline cellulose and crosscarmellose sodium 10 are mixed in a Rapid Mixer Granulator (RMG). This blend is then subjected to wet granulation using an alcoholic solution of povidone. The resultant granules are dried, milled and sized. The extragranular material comprising crosscarmellose sodium, magnesium stearate and colloidal silicon dioxide are sifted and blended with the granules obtained from the intragranular stage.
15 [0032] Compression and Coating: The granules prepared in Part 1 and Part 2 are mixed together and compressed as a single layered tablets. Alternatively, the granules may be compressed separately to form bilayered tablets. The tablets (both types) are coated with Opadry to obtain a weight gain of approximately 2%.
Example 2
No. Ingredients mg/tab

Part 1 Intragranular
1 Hydrocodone Bitartrate 5
2 Acetaminophen 650
3 Starch 35
4 Sodium Starch Glycolate 10
5 Povidone - K 30 15
6 Sodium Lauryl Sulfate 10

Extragranular
7 Sodium Starch Glycolate 5
8 Microcrystalline cellulose 22
9 Talc 10
10 Colloidal Silicon Dioxide 8
11 Magnesium stearate 10

Part 2 Intragranular
12 Ibuprofen 400
13 Lactose Monohydrate 20
14 Microcrystalline cellulose 35
15 Croscarmellose sodium 10
16 Povidone - K 30 10
Extragranular
17 Croscarmellose sodium 15
18 Colloidal Silicon Dioxide 5
19 Magnesium stearate 5
Wt. of core tablets 1280
20 Opadry 25
Total wt of coated tablet 1305
[0033] The ingredients for Part 1 and Part 2 were blended according to the procedure described in Example 1. The excipients used were similar to those used in Example 1, except the final doses of hydrocodone, acetaminophen, and ibuprofen were 5 mg, 650 mg, 5 and 400 mg, respectively.
[0034] The granules prepared in Part 1 and Part 2 are mixed together and compressed as a single layered tablets. Alternatively, the granules may be compressed separately to form bilayered tablets. The tablets (both types) are coated with Opadry to obtain a weight gain of approximately 2%.
10 Example 3

No. Ingredients mg/tab

Part 1 Intragranular
1 Hydrocodone Bitartrate 7.5
2 Acetaminophen 325
3 Starch 35
4 Sodium Starch Glycolate 10
5 Povidone - K 30 15
6 Sodium Lauryl Sulfate 10

Extragranular
7 Sodium Starch Glycolate 5
8 Microcrystalline cellulose 22
9 Talc 10
10 Colloidal Silicon Dioxide 8
11 Magnesium stearate 10

Part 2 Intragranular
12 Ibuprofen 600
13 Lactose Monohydrate 20
14 Microcrystalline cellulose 35
15 Croscarmellose sodium 10
16 Povidone - K 30 10
Extragranular
17 Croscarmellose sodium 15
18 Colloidal Silicon Dioxide 5
19 Magnesium stearate 5
Wt. of core tablets 1163
20 Opadry 23
Total wt of coated tablet 1186
[0035] The ingredients were blended according to the procedure described in Example 1. The excipients used were similar to the one used in Example 1, except the doses of hydrocodone, acetaminophen, and ibuprofen were 7.5 mg, 325 mg, and 600 mg,
5 respectively.
[0036] The granules prepared in Part 1 and Part 2 are mixed together and compressed as a single layered tablets. Alternatively, the granules may be compressed separately to form bilayered tablets. The tablets (both types) are coated with Opadry to obtain a weight gain of approximately 2%.
10 Example 4

No. Ingredients mg/tab

Part 1 Intragranular
1 Hydrocodone Bitartrate 10
2 Acetaminophen 325
3 Starch 35
4 Sodium Starch Glycolate 10
5 Povidone - K 30 15
6 Sodium Lauryl Sulfate 10

Extragranular
7 Sodium Starch Glycolate 5
8 Microcrystalline cellulose 22
9 Talc 10
10 Colloidal Silicon Dioxide 8
11 Magnesium stearate 10

Part 2 Intragranular
12 Ibuprofen 800
13 Lactose Monohydrate 20
14 Microcrystalline cellulose 35
15 Croscarmellose sodium 10
16 Povidone - K 30 10
Extragranular
17 Croscarmellose sodium 15
18 Colloidal Silicon Dioxide 5
19 Magnesium stearate 5
Wt. of core tablets 1366
20 Opadry 28
Total wt of coated tablet 1394
[0037] The ingredients were blended according to the procedure described in Example 1, except the doses of hydrocodone, acetaminophen, and ibuprofen were 10 mg, 325 mg, and 5 800 mg, respectively.
[0038] Part 1 and Part 2 were prepared as described in Example 1 using the intragranular material and extragranular lubricants with both parts. The mixtures were then co-compressed into a single layered tablet or bi-layered tablet and coated to a weight of about 2% using Opadry.
10 Comparison Example 1: Analgesic Activity
[0039] Male mice (preferably of CD1 strain) are utilized in determining the analgesic effects associated with the compositions of the invention. The mice are all dosed orally with (a) a mixture of hydrocodone bitartarate and acetaminophen (calculated individually in the base form), which is completely dissolved in distilled water, and (b) a mixture of
15 hydrocodone bitartarate and ibuprofen (calculated individually in the base form), which is completely dissolved in distilled water, or in distilled water containing 2% by volume of Tween 80 containing 100% polysorbate 80. An appropriate dosing volume is used.
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[0040] The procedure used to compare the analgesic activity of the different classes of analgesic drugs is disclosed in H. Collier et al., Br. J. Pharmacol., 32, 295 (1968). The data obtained regarding prevention of acetylcholine-induced abdominal constriction in mice from this procedure correlates well with human efficacy.
5 Example 5: Analgesic Activity
[0041] Mice, are intubated with the test doses containing (a) hydrocodone bitartrate with ibuprofen, (b) hydrocodone bitartrate with acetaminophen, (c) hydrocodone bitartrate with acetaminophen with ibuprofen, or (d) a vehicle such as distilled water, or distilled water containing approximately about 2% by volume of Tween 80. The mice were injected
10 intraperitoneally with a challenge dose of acetylcholine bromide. The acetylcholine is completely dissolved in distilled water at a concentration of about 5.0 to 10 mg/kg and injected at a rate of about 0.20 mL/20 g. For scoring purposes an "abdominal constriction" was defined as a contraction of the abdominal musculature accompanied by arching of the back and extension of the limbs. The mice are observed for 10 to 30 minutes for the
15 presence or absence of an abdominal constriction response beginning immediately after receiving the acetylcholine dose, which is about 30 minutes after receiving the oral administration of the test doses. Each mouse is used only once.
[0042] The analysis for synergistic activity with the compositions at each fixed ratio is determined as described by R. J. Tallarida et al, Life Sci., 45, 947 (1989). The procedure
20 requires the determination of the total amount in the mixture that is required to produce a specified level of effect, such as 50% (ED50 mjx), and the corresponding total amount that would be expected to produce the effect under simple additivity (EDsoadd)- Where it is established that EDsomix