WO1979000556A1 - Composition containing salicylsalicylic acid and acetaminophen - Google Patents

Abstract

A safe and effective analgesic composition comprises 100 to 1000 mg of salicylsalicylic acid per 100 to 650 mg of acetaminophen.

Description

COMPOSITION CONTAINING SALICYLSALICYLIC ACID AND ACETAMINOPHEN

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a pharmaceutical composition having useful analgesic, antipyretic, antirheumatic and anti-inflammatory properties. This composition may also be compounded, as aspirin and acetaminophen are, with other non-prescription antihistamines, antitussives, sedatives, analeptics, etc., as well as with prescription drugs such as narcotics, barbituates, etc.

2. Description of the Prior Art

There do not appear to be any references in the prior art to the combination of salicylsalicylic acid (hereinafter SSA) and acetaminophen (hereinafter APAP) . However, there are some disclosures of aspirin (acetylsalicylic acid, hereinafter ASA) with APAP.'

For example Cotty et al, U.S. Patent No. 4,049,803 discloses that 10 grains of ASA when combined with 5 to 15 grains of APAP, yields increased blood levels of unhydrolyzed ASA shortly and for extended periods after oral ingestion.

Fujimura et al, U.S. Patent No. 3,284,298 discloses that a Vitamin B,-active substance fortifies or strengthens the analgesic activity of a number of compounds and compositions. Among the analgesics listed are APAP and SSA.

Berger, U.S. Patent No. 2,872,370 discloses a hypnotic composition containing acetophenetidin and salicylamide and suggests the substitution of APAP for acetophenetidii

OMPI However, the substitution of a variety of salicylic acid compounds and derivatives, including ASA, for the salicylamide component is classified as ineffective.

The Abstract of Japanese Patent No. 18,232/66 to Nippon Kayaku Company on October 19, 1966 discloses that a eutectic mixture of acetylsalicylic acid and N-APAP is prepared by heating and melting together the ASA and N-APAP, and that a very suitable eutectic is formed with 53% ASA and 37% N-APAP, and increasing concentration in the blood.

Robertson, U.S. Patent No. 3,431,293 discloses the production of para-N-acetylaminophenol acylsalicylates by several processes including the simple esterification of the appropriate acyl salicylic acid and N-acetyl-p- aminophenol. Only acetylsalicylic acid and its derivativ are disclosed but other lower aliphatic acid groups might be substituted for the acetyl moiety.

Of interest also is Emele, U.S. Patent Numbers 3,063,897 and 3,068,147 which pertain to analgesic compositions containing alkoxybenzamide with a mixture of salicylamide and APAP.

Cherkas , U.S. Patent No. 3,439,089 is of interest in that it relates to medicated hard candies which may include, alternatively, APAP, salicylamides, or ASA.

British Patent No. 1,019,146 issued February 2, 1966 is of interest for its disclosure of a timed release analgesic tablet. Among several analgesic drugs described as being usable in such tablets were APAP and SSA. Mixtures of several drugs are described as being possible for the practice of that invention, but no combination of SSA and APAP is specifically suggested. Examples III and V in the British patent related to the

/"B f manufacture of tablets of acetaminophen and salicylsalicylic acid respectively.

The following sections from Chemical Abstracts may be relevant - 73: 75268J 80: 87539f and 81: T54453r.

SUMMARY OF THE INVENTION

The compositions of this invention comprise from 100 to 1000 mg of SSA per 100 to 625 mg of APAP (the combination hereinafter to be abbreviated as SSA-APAP) . The preferred dosage contains approximately 500 mg SSA and 325 mg APAP.

Like ASA, SSA-APAP is an acetylated salicylate. But SSA-APAP's salicylate factor, SSA, is (1) longer-acting than ASA, (2) a more effective antirheu atic and anti- inflammatory agent than ASA, and (3) gas rically a minimally irritative factor which causes no occult bleeding above placebo values, while ASA has been shown to cause signficantly more irritation, erosion and bleeding in the gastric mucosa. SSA-APAP's acetyl carrying factor, APAP, is also effectively non-irritative and non-bleeding gastrically, while APAP's analgesic action, proven eguipotent to ASA's, is further potentiated by SSA's additional, longer acting analgesic action. APAP's lack of overdosage warning signs is lessened by the presence of SSA which manifests early, more easily reversible, overdosage signals, such as tinnitus. Thus SSA-APAP is safer and more effective than either ASA, APAP alone, or SSA alone.

DETAILED DESCRIPTION OF THE INVENTION

Salicylsalicylic acid (SSA) is also known as salsalate, salysal, diplosal, salicylsalicylate, and salicylosalicylic acid. Chemically it is named in the Merck Index (9th Edition, 1976) referred to as, benzoic acid, 2-hydroxy, 2-carboxyphenyl ester.

SSA was introduced by Boehringer and Soehne in Germany in 1908 and is mentioned by U.S. Patent No. 922,955, issued on May 25, 1909. Under the name Salysal it was listed in the AMA Council on Pharmacy and Chemistry's New and Non-Official Remedies (NNR) from 1937 through 1948. It is presently understood to be sold as an ingredient in four commercial preparations. Two comprise unmixed SSA and are sold to the ethical market only. The remaining two formulations are mixtures with ASA and are sold over- the-counter. Compared to the universally used salicylate ASA, SSA is relatively very little-used. Currently the Merck Index (9th ed., 1976) lists SSA as having the actions and uses of an "analgesic, antipyretic, and antirheumatic". A special review of OTC internal analgesics completed in 1977 by the FDA's Internal Analgesics Panel (IAP) placed SSA in both its Category I recommended for labeling as an analgesic (Federal Registe Vol. 42, No. 131, 7-8-77, Book 2, p. 35443), an antipyret

(p. 35452) and, under a physician's direction, as an anti rheumatic and anti-inflammatory (p. 35468) - and in its Category III: drugs it recommends be further tested.

(p. 35350).

Overall, medical research shows SSA lower than ASA and APAP in analgesic pain relief but superior to ASA and APAP in antirheumatic, anti-inflammatory action and in safety. SSA showed 1/3 the analgesic effect of ASA in tests using the phenylquinone method on mice (Alberg & Larsson, Acta Pharmacol, et Toxicol., 1970, No. 28). The IAP rated SSA's analgesia at 2/3 ASA's (p. 35443). However, P. K. Smith in an unpublished paper in 1952 reported tests showing SSA delivers equal salicylate to the blood from a 30% lower dose than ASA. Alberg and Larsson (above) got over 50% higher anti-inflammatory effect from SSA as compared to ASA in inhibitory effect tests on S-sulphate incorporation in calf rib cartilage.

CHART I The inhibitory effects of salicylates on 35S-sulphate incorporation in calf rib cartilage ____

Experiment Per cent ir lhib ion of 35S incorporation ^±S.E.M. No . ASA (n) SSA (ii) SA __)_

1 47 . 0 * 4 . 2 ( 5 ) 63.2 * 0.8 (5) 31.3 ± 1.8 (4)

2 40 . 0 * 5 . 7 ( 4 ) 66.2 * 1.8 (4) 39.8 ± 3.3 (5)

3 69 . 3 * 4 . 2 ( 4 ) 71.6 * 0.7 (5) 37.3 * 1.5 (5)

4 48 .7 * 2. 3 (5 ) 73.1 * 0.2 (5) . 41.6 * 3.5 (5)

5 39 . 8 * 4 . 6 ( 5) 68.8 * 1.1 (5) 34.4 * 1.4 (5)

6 20 . 4 * 9 . 3 ( 5 ) 76.4 * 1.4 (5) 27.1 * 1.5 (5)

mean * S.E.M. 44.7 * 3.2 (28) 70.0 ± 0.9 (29) 35.4 * 1.3 (29)

The inhibitory effects of ASA, SSA and SA at 6 mM concentration expressed as per cent of mean values for the control groups.

Nordqvist, et al (Nord. Med., 74, 1965) found SSA stayed- in the blood far beyond ASA's 4.7 hr. half-life. Bayles and Tenckhoff (Scientific Ex., Am. Acad. G.P., 1959) showed ASA was unable to maintain overnight effectiveness against the morning ache and stiffness of rheumatism and arthritis. Rubin (Am. J. Med. Sci. , July, 1968) , using a preparation containing 485 mg SSA/160 mg ASA, developed overnight effectiveness against osteoarthritis and the morning blood concentration of salicylate continued to build over several days. CHART II

SERUM SALICYLATE LEVELS IN 17 PATIENTS WITH OSTEOARTHRITIS AFTER ORAL ADMINISTRATION OF A PREPARATION CONTAINING SALICYLSALICYLIC ACID AND ACETYLSALICYLIC ACID FOUR TIMES A DAY FOR EIGHT DAYS

Serum Salicylate (mg./lOO l.)

Zero 2 4 6 8 24 8th Da

Patient Age Sex Vfeight Hour Hours Hours Hours Hours Hours 8am 2

A.A. 66 F 117 0 1.0 6.0 1.0 6.5 7.0 15.0 1

D.A. 54 F 130 0 4.5 8.0 9.5 9.5 8.5 12.5 1

A.B. 75 M - 178 0 0.5 0.5 2.0 1.5 7.0 22.5 2

D.B. 56 F 115 0 5.0 4.0 2.5 11.0 23.5 31.0 1

S.B. 72 F 186 0 1.5 1.0 2.0 3.5 10.5 8.0 1

T.B. 81 F 157 0 2.0 6.0 8.0 7.0 3.5 14.0 1

T.G. 71 F 178 0 3.0 3.5 6.5 8.0 12.0 7.0 1

I.H. 72 F 154 0 3.0 3.5 ^' 8.5 10.0 10.0 2.0

E.I. 70 F 191 0.3 3.0 3.3 6.5 8.5 29.0 1

J.J. 77 F 111 0 4.0 3.5 7.0 11.0 10.5

S.K. 73 F 125 1.0 2.5 3.0 8.0 9.5 1.5 16.0 2

L.K. 61 F 109 0 3.0 2.5 1.5 9.0 19.5 42.0

K.M. 80 F 138 0 1.0 4.0 5.0 2.5 6.5 4.5

S.R. 72 M 150 0 0.5 1.5 2.0 3.5 9.5 4.0

R.S. 80 F 131 0 3.5 5.5 8.0 ^' 9.5 16.0 0.5 2

A.S. 51 F 140 0 5.5 3.5 3.0 3.5 11.5 3.0 1

M.S. 71 F 121 0 2.0 3.5 5.5 4.0 3.5 12.5 1

Mean: 69 147 2.9 3.7 5.3 7.1 10.2 14.5 1

Denson and Thompson (J. Med. Soc. of New Jersey , Vol. 57, 1960) , testing with a very similar preparation, (500 mg SS 150 mg ASA) , noted much less gastric distress than with AS alone as well as increased antirheumatic and anti-inflamma tory overnight effect.

Leonards (J. Lab. & Clin. Med., Dec, 1968), using atomic tracing of occult blood loss, showed SSA "did not produce

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■ A. WIP ^w any bleeding above the control value" determined by placebo, while ASA's loss was 4.8 ml/day compared to the placebo's 0.6 ml/day.

CHART III

Average total blood loss, milliliters per day*

Tablet C

Tablets Tablet A Tablet B (S.S.A. ,+ Tablet D

Subject Weight per day (A.S.A. ,+ (lactose 486 mg. ; (S.S.A. ,+ ' (No.) 840 mg.) placebo) A.S.A. , 602 mg.) 162 mg.)

R.K. 175 5 4.0 0.5 0.9 0.6

R.N. 175 5 13.7 1.2 2.0 1.0

A.T. 159 4 3.2 1.5 1.7 1.6

M.J. 184 5 1.9 0.8 1.6 0.6

P.P. 150 4 3.0 0.5 0.6 0.3

J.M. 230 5 1.6 0.4 0.6 0.3

F.M. 205 5 17.4 0.5 2.1 1.0

M.B. 140 4 2.2 0.3 1.0 0.7

B.E. 120 4 1.1 0.1 0.5 0.3

A.O. 185 5 1.2 0.7 0.6 0.4

J.H. 165 5 3.7 0.8 1.3 0.9

R.J. 160 5 N.T-§ 0.2 N.T.§ 0.2

*Averages ( ±standard error), 4.8 (±5.2), 0.6 (±0.4), 1.2 (±0.5), and 0.7 (±0.4) for A, B, C, and D, respectively. Comparisons:

B vs. A, P 0.05; B vs. C, P 0.01; B vs. D, P 0.10; C vs. D,

P 0.01.

+A.S.A. denotes acetylsalicylic acid.

+S.S.A. denotes salicylsalicylic acid.

§Not tested.

Aberg and Larsson (see above) also reported examination of the gastric mucosa of guinea pigs with SSA and ASA showed SSA caused "no significantly increased. . .irritation", while after ASA the "mucosa became hyperaemic and [the ASA] caused numerous erosions." D. Edmar (Acta Radiologica, Diag. , Vol. 11, 1971) examined human stomach mucosa with an

OMPI - Olympus GT-Va gastrocamera following comparative doses of ASA and SSA with SSA again showing no effects above place while ASA showed "multiple small gastric erosions in all.. subjects" (p. 63) . The IAP noted SSA causes less asthma reaction than ASA (p. 35443). Litchfield (Arch. Pediat. , 55, 1938) reports SSA causes less allergy, and milder salicylism onset than ASA. The NNR (1939, p. 379) stated that SSA is no more toxic generally than ASA. SSA's clinical toxic dose is reported in the 5.5 to 6.6 gram range (Ha zlik, "Actions and Uses of the Salicylates..." 1927, p. 165), while ASA's is 5 to 6 grams (Goodman and Gllman, p. 338). ASA's fatal dose range is 10 to 30 mg (Goodman and Gilman, "The Pharmaceutical Board of Therapeutics", 1975 edition, p. 336). SSA's can be expected to be in the same range.

The second ingredient of this combination, acetaminophen, aside from being abbreviated APAP, is sometimes referred to as paracetamol. It is a metabolite of phenacetin and acetanilid, and is chemically referred to as "n-acetyl- para-aminophenol," formulated C-.H_qN0₂:

The AMA Drug Evaluation Guide, 1977 (p. 346) states APAP is: "...an analgesic and antipyretic, its efficacy is equal to that of aspirin and it has the same uses (ie, treatment of headache, mild to moderate myalgia, arthralgia, fever) . Acetaminophen lacks the anti- inflammatory effect of the salicylates, but it is probably the analgesic-antipyretic of choice as an alternative to aspirin, particularly in patients allergic to aspirin or with a history of peptic ulcer. Unlike aspirin, acetaminophen does not antagonize the effects of uricosuric agents...Acetaminophen produces

fa little or no methemoglobine ia and has not caused hemolytic anemia. It does not cause gastrointestinal bleeding. Although large doses have been reported to potentiate the action of oral anticoagulants, small doses have no effect on prothrombin time. It is not known whether prolonged use of acetaminophen can cause the type of renal injury associated with abuse of analgesic mixtures containing phenacetin. Hepatic necrosis and death have been observed following overdosage; hepatic damage is likely if an adult has taken a single dose of more than 10 g."

The IAP (p. 53335-6) notes: "one of the first symptoms of salicylate intoxification, or overdose, is tinnitus or 'ringing in the ears' ...Unfortunately, acetaminophen has no similar sign of toxicity or 'safety valve' to alert the consumer." Vane "Prostaglandin Synthetase Inhibitors", (Raven Press, 1974) has shown both ASA and APAP have prostaglandin synthetase inhibition (PSI) actions underlying their very similar analgesic and antipyretic effects (p. 9-10) , and he reports another study (p. 233) showing that their shared acetyl factor plays a role in PSI.

Summary of SSA-APAP's Actions, Uses, and Safety Collating all the above information on SSA and APAP, it is now possible to form a summary of how the SSA-APAP combination will be superior in several effects to ASA, APAP, or SSA alone, and to previous combinations of APAP and ASA, and of ASA and SSA. The new combination will be:

(1) a more effective analgesic than ASA, APAP, or SSA alone since, while APAP alone is an equipotent analgesic . to ASA, SSA's additional (if weaker) analgesia will improve APAP's analgesia beyond APAP's own and ASA's, in three ways. First, SSA's strong anti-inflammatory action

(Aberg-Larsson, Rubin, Denson, etc.) will eliminate any dispute about inflammation weakness as a drawback to APAP's analgesia. Second, both SSA's analgesic and anti- inflammatory actions last significantly longer than ASA's or APAP's, (Nordqvist, Rubin, etc.) so the time course o APAP's potentiated analgesia is extended. Third, SSA can deliver these salicylate analgesia effects from a 30% lower dosage than ASA, (P. K. Smith) .

(2) an equipotent antipyretic to ASA, since both APAP and SSA are effective antipyretics (IAP, Merck) . APAP's very similar analgesic and antipyretic action compared to ASA may stem from their sha ed acetyl factors role in prostaglandin inhibition (Vane) .

(3) a more effective anti-inflammatory and anti¬ rheumatic agent than ASA or APAP alone in two ways. Firs SSA is longer lasting than ASA at any dosage level, (Nordqvist) , and at antirheumatic dose levels can build up effective overnight action against morning stiffness within 24 hours (Rubin, Denson, etc.). Second, at any dosage levels, it can deliver 30 to 50% more anti- inflammatory action than ASA (P. K. Smith, Aberg-Larsson)

(4) safer than either ASA or APAP. It will be effective gastrically non-bleeding and non-irritative since both SS (Leonards, Aberg-Larsson, Edmar) and APAP (AMA Drug Eval. are non-bleeding and non-irritative above placebo values. Both SSA and APAP cause less asthma (IAP) and allergy (Litchfield) . APAP's no -symptoms overdose danger will b lessened by SSA's salicylism tinnitus "safety valve" effe (IAP) . SSA has similar toxicity, salicylism, and fatal dose levels to ASA's (Hanzlik, NNR) , but the salicylism onset has been reported as milder than ASA's (Litchfield) Previous APAP-salicylate combinations, in the form of APAP-ASA, have been widely used over the years with excellent safety. Both APAP and SSA have been used separately over many years with an excellent record of safety. Both are FDA approved. -li¬ lt may sometime be advantageous to incorporate with this basic combination other pharmaceutically active ingredients. By way of illustrating these other pharmaceutically active ingredients, the following may be mentioned: other analgesics such as propoxyphene, codeine phosphate, or the like; analeptics such as caffeine, amphetamine or the like; antihistamines such as methapyrilene (or its hydro¬ chloride) , chlorpheniramine maleate or the like; anti- tussives or decongestants such as phenylpropanolamine (or the hydrochloride) , phenyleprine (or the hydrochloride) , or the like; sedatives such as bromural, phenobarbital, chlorpromozine, or the like; muscle relaxants such as mephenesin, chlorzoxazone, or the like; and antispasmodics or local anesthetics such as ethyl amionobenzoate, atropine sulfate, or the like. Additionally, potentiating ingredients may also be added, such as B.. active substances, such as in Fujimara, et al, U.S. Patent No. 3,284,298. However, in the preferred embodiment of this invention, the pharma¬ ceutically active material will consist essentially of the SSA-APAP dosage mixture.

DOSAGE LEVELS

Dosage levels for salicylsalicylate alone typically are between 325 mg to 1000 mg. (Federal Register, p. 35443) . Toxic levels for salicylsalicylate begin somewhere between 5.5 and 6.6 grams per day for an adult (Hanzlik, p. 165). The NNR (1939 p. 379) has stated SSA and ASA are toxically similar. ASA's fatal dose is between 10 and 30 grams per day per adult (Goodman and Gilman, p. 338). SSA's is probably in the same range.

The average dosage for APAP is in the 325 to 600 mg range. (Goodman and Gilman, p. 347) . A recommended maximum dosage level would be in the range of 2.6 to 4 grams per day per adult (AMA Drug Evaluation Guide, 1977, p. 346, and Goodman and Gilman above). Liver damage may

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OMPI occur after a single dose of 10 to 15 grams, and a dose of 25 grams is usually fatal (Goodman and Gilman, p. 345- 346) . In the SSA-APAP combination a dosage level of 325 mg of APAP is sufficient, especially in the presence of SSA's additional analgesia, antipyretic and anti¬ rheumatic actions. Accordingly, an individual capsule or tablet would contain the preferred dosage of the combinat 500 mg of SSA per 325 mg of APAP. A recommended effectiv OTC maximum daily amount of 8-10 tablets will bring total daily consumption to 2.6-3.25 grams of APAP, and 4-5 gram SSA, well within accepted limits. Slightly higher dosage up to full therapeutic doses could also be given under- a physician's advice and supervision for antirheumatic effectiveness.

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Claims

CLAIMS :

1. An analgesic composition, which comprises, as active ingredients, from 100 to 1,000 mg of salicylsalicylic acid per 100 mg to 650 mg of acetaminophen.

2. The composition of Claim 1 comprising approximately

500 mg of salicylsalicylic acid and 325 mg of acetaminophen.

3. A process of making an analgesic composition comprising combining from 100 to 1,000 mg of salicylsalicylic acid with from 100 to 650 mg of acetaminophen.

4. The process of Claim 3, in which approximately 500 mg of salicylsalicylic acid are combined with 325 of acetaminophe .

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