SALTS OF ACETAMINOPHEN

Abstract: Isolated salts of acetaminophen are disclosed. Alkali metal and alkaline-earth metal salts of acetaminophen were formed by reacting the free acid of acetaminophen with the corresponding metal hydroxide and then immediately isolating the resulting salt. These salts have been found to be more water soluble and less bitter in taste than the free acid form of acetaminophen.

Description: SALTS OF ACETAMINOPHEN This is a continuation-in-part of application Serial No. 08/771,176, filed December 20, 1996, which is hereby incorporated by reference. FIELD OF THE INVENTION The present invention relates to salts of acetaminophen and, more particularly, to alkali metal and alkaline-earth metal salts of acetaminophen. BACKGROUND OF THE INVENTION Acetaminophen (APAP) is a well established therapeutic agent having both analgesic and antipyretic activity. Acetaminophen' s relatively poor solubility in water and it's bitter taste, however, make it difficult to formulate into to consumer acceptable oral dosage forms. Most commercially available acetaminophen oral dosage forms incorporate a taste masking coating on the acetaminophen particles or employ flavors and sweeteners to mask the bitter taste of the drug. Other approaches for dealing with the solubility and taste of acetaminophen include the formation of amino acid esters of acetaminophen. 1. M. Kovach in D/.s.v. Abstr. Int. B 1975, 36(2), 734-5 describes the synthesis of p-acetamidophenyl glycinate (APG), α-p-acetamidophenyl aspartate (AAPA) and β-p-acetamidophen l aspartate (BAP A). These esters are reported to have a less bitter taste than acetaminophen. APG-HBr was five times more water soluble than acetaminophen, whereas BAPA-HCl was four times less water soluble than APAP. It is also known that the formation of an appropriate salt of a hydrophobic compound, such as a lipophilic carboxylic acid, will usually improve the aqueous solubility of the compound. Sodium ibuprofen and sodium naproxen are examples of pharmaceutically active lipophilic carboxylic acids which have improved aqueous solubility in their salt form. These salts are typically formed by reacting the carboxylic acid with a strong base, such as sodium hydroxide or potassium hydroxide. USSR Inventor's Certificate No. 629,209, published September 11, 1978, describes a method of preparing bis-[β-(4-acetylaminophenyloxy)ethyl] ether by reacting 4-acetylaminophenol with an alkaline agent, such as potassium hydroxide, in a solution of an organic solvent, such as dimethylformamide, followed by reacting the resulting solution of potassium phenolate with chlorex at the boiling point of the reaction mixture. The resulting ether is reported as being useful for the treatment of animals with helminthic diseases. USSR Inventor's Certificate 1,803,833, published March 23, 1993, describes a method of preparing acetaminophen for fluorescence intensity measurements. The acetaminophen sample was prepared by first dissolving in isopropyl alcohol and then treating with an 8% solution of potassium hydroxide solution and chloroform at a KOHchloroform volume ratio of 3-4. Heating was then carried out for 15-20 minutes at 70-80°C before the measurement of the sample's fluorescence intensity. While both of the of the above-identified USSR Inventor's Certificates report the treatment of acetaminophen with potassium hydroxide, neither document reports the isolation of any potassium salt of acetaminophen. M.S. Yu et al. in US Patent No. 5,360,615 discusses a pharmaceutical carrier system for enhancing the solubility of acidic, basic or amphoteric pharmaceuticals by partial ionization to produce a highly concentrated primarily non-aqueous solution suitable for filling softgels or for two-piece encapsulation or tablet formation. The acetaminophen solution comprised 25-40% (wt.) of acetaminophen, 0.4-1.0 moles of hydroxide ion per mole of acetaminophen and 1-20% (wt.) water in polyethylene glycol. An exemplary concentrated solution of acetaminophen suitable for use as a softgel fill contained 1 equivalent APAP (35% by wt.), 1 equivalent potassium hydroxide, and the balance polyethylene glycol 600. US Patent No. 5,273,759 to D.L. Simmons describes the addition of Mg(OH) 2 in solid form to tablets containing APAP. Both Yu et al. and Simmons fail to report the isolation of any discrete salts of acetaminophen. A need exists for isolated salts of acetaminophen with improved aqueous solubility and taste when compared to the conventional form of acetaminophen. SUMMARY OF THE INVENTION The present invention provides isolated salts of acetaminophen. The isolated salts are preferably the alkali metal and alkaline-earth metal salts of acetaminophen. In a further aspect of the invention the isolated salts have the formula: (CH3CONH i--T y-σ O " )n M^ +)n • xH 2 O, wherein n is 1 or 2, M is alkali metal when n is 1 and M is alkaline-earth metal when n is 2 and x is from 0 to about 10. These salts have been shown to have both improved aqueous solubility and a less bitter taste than the free acid form of acetaminophen. The invention also includes methods of making such salts. Another aspect of the invention relates to the method of administering such salts to mammals in the need of an analgesic and/or antipyretic therapeutic agent. The present invention further relates to orally adminsterable dosage forms containing salts of acetaminophen. BRIEF DESCRIPTION OF DRAWINGS Figure 1 is a plot the results of dissolution tests for tablets containing acetaminophen free acid and the isolated salts of acetaminophen. Figure 2 is a plot of acetaminophen plasma concentrations versus time for the bioequivelency study in dogs described in Example VII. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Prior to the present invention there has been no reported isolation of any discreet salts (phenolates) of APAP. Furthermore, in situ solution characterization of any deprotonated APAP species has not been reported either. As used in the present invention, the "free acid" of acetaminophen means the protonated phenolic form of APAP. The lack of discussion on APAP salts in the scientific literature may oe due in part to the fact that the anionic form of APAP is stable in aqueous solution (pH > 11) for only a short period of time (< 24h). If the salt is not quickly isolated after formation, p-aminophenolate (PAP) can form and result in discoloration of the resulting product. As used in the present invention, isolated salts of acetaminophen refers to salts of p-hydroxyacetanalide which are formed by the deprotonation of the phenolic proton of acetaminophen. The isolated salts are preferably the alkali metal and alkaline-earth metal salts of acetaminophen. In a further aspect of the invention the isolated salts have the formula: wherein n is 1 or 2, M is alkali metal when n is 1 and M is alkaline-earth metal when n is 2 and x is from 0 to about 10. The salts of APAP are prepared via a one step aqueous reaction of APAP with the desired mono or divalent metal hydroxide. Suitable mono or divalent metal hydroxides include sodium hydroxide, calcium hydroxide, lithium hydroxide, potassium hydroxide, magnesium hydroxide and cesium hydroxide. The molar ratio of hydroxide to acetaminophen is about 1 :2 to about 10: 1, preferably about 1:2 to about 1 : 1. The APAP and metal hydroxide are dissolved in water or a mixture of water and a water-miscible organic solvent, such as acetonitrile, methanol, isopropanol, ethanol or tetrahydrofuran. The crude reaction products are then recovered or isolated by precipitation upon the addition of a less polar water miscible reaction mixture. The recovery or isolation should generally be carried out as soon as the reaction product is formed so as to reduce the likelihood of product discoloration due to the formation of PAP. The final product may then be vacuum dried. The APAP salts of the present invention are also amenable to cation exchange reactions. For example, an aqueous slurry or solution of a monovalent metal salt of acetaminophen is contacted with a divalent metal cation whereby the anhydrous, divalent metal salt of acetaminophen is formed via a cation exchange reaction. The salt is then immediately recovered. Specifically, Ci6H 16 N 2 O 4 Ca may be prepared by reacting an aqueous solution of CsH 8 NO 2 Na with 0.5 equivalent of calcium chloride (CaCl 2 ). After vacuum drying above room temperature, the resulting Ci 6 Hi 6 N 2 O 4 Ca was found to be anhydrous. In addition to the anhydrous form, various hydration states of APAP salts can be prepared depending on the reaction conditions. These hydrated salts preferably have less than 10 moles of water per mole of APAP salt, and includes, for example, acetaminophen sodium pentahydrate, acetaminophen sodium hexahydrate, acetaminophen sodium heptahydrate, acetaminophen calcium dihydrate and acetaminophen lithium hexahydrate. The aqueous solubility at 22°C of the APAP salts of the present invention is 490-540, 450-470 and 13 mg/mL for sodium, lithium and calcium, respectively. Accordingly, the sodium, lithium and calcium salts have solubilities equivalent to approximately 260-280, 250-270, and 10 mg/mL, respectively, of APAP free acid. The APAP salts have significantly increased dissolution rates compared to the conventional free acid form of acetaminophen. In 0. IN hydrochloric acid using USP Dissolution Apparatus 2 (paddle speed: 50 rpm) at 37°C, the concentration of acetaminophen at 30 seconds was as follows: APAP Form (Powder) mg/mL of APAP Sodium Salt 0.30 Lithium Salt 0.32 Calcium Salt 0.20 Free Acid (control) 0.02 Figure 1 illustrates the tablet dissolution rates of the salts of the present invention. The sodium, lithium and calcium salts of APAP and the conventional form of APAP were each compressed into tablets and the dissolution rates were evaluated using the conditions described above. The dissolution media was assayed for acetaminophen in the free acid form. Figure 1 shows that the salts of the present invention have significantly higher acetaminophen dissolution rates that the conventional free acid. The calcium and sodium salts of acetaminophen have been observed not to have the bitter properties of the conventional free acid form of acetaminophen. The calcium salt was almost tasteless, while the sodium salt was observed to be somewhat salty. The improved taste properties of the salts of the present invention will allow for acetaminophen oral dosage forms with improved taste to be formulated. The onset of action of acetaminophen is believed to be hastened, relative to the free acid form, with the isolated salts of the present invention. The increase solubility of the salts of the present invention, results in faster peak acetaminophen plasma concentration. This property will potentially provide faster onset of action of the analgesic and/or antipyretic activity of acetaminophen. The acetaminophen salts of the present invention may be administered to a mammal in a therapeutically effective amount, which is an amount that produces the desired therapeutic response upon oral administration, and can be readily determined by one skilled in the art. In determining such amounts, the particular compound being admin- istered, the bioavailability characteristics of the compound, the dose regime, the age and weight of the patient, and other factors must be considered. A typical unit dose orally administered to a human would range from about 80-1000 mg (APAP free acid basis) . The acetaminophen salts of the present invention are generally administered orally in a solid dosage form. Suitable solid preparations include as swallowable, chewable or fast dissolving tablets, pills, capsules, caplets, powders, wafers, sachets, gelatin coated tablets and granules. In preparing solid dosage forms, the salt of acetaminophen can be mixed with conventional solid fillers or carriers, such as corn starch, talc, calcium phosphate, calcium sulphate, calcium stearate, magnesium stearate, stearic acid, sorbitol, microcrystalline cellulose, mannitol, gelatin, natural or synthetic gums, such as carboxymethylcellulose, methylcellulose, alginate, dextran, acacia gum, karaya gum, locust bean gum and other conventional carriers. Additionally, other recipients such as diluents, binders, lubricants, disintegrants, colors and flavoring agents may be employed. The dosage form can also be film coated. Conventional methods can be used for preparing the solid dosage forms of the present invention. Suitable techniques are described in Remington's Pharmaceutical Sciences, 18th Ed., Chapter 89 (1990) which is hereby incorporated by reference. The following example illustrates a specific embodiment of the present invention. This invention, however, is not confined to the specific limitations set forth in this example but rather to the scope of the appended claims. Unless otherwise stated, the percentages and ratios given below are by weight. EXAMPLE I This Example discloses the preparation of acetaminophen sodium (C 8 H 8 NO 2 Na » 6H 2 O ). 30 mL IN NaOH solution (0.030 mol) were added to a stirred suspension of 4.53 g (0.033 mol) acetaminophen in 25 mL water. After all solids dissolved, 200 mL acetonitrile was added while the solution was rapidly stirred. The resulting white precipitate (9.15 g, 99% yield as the 6-hydrate) was collected on a frit, washed with tetrahydrofuran (THF) and dried at room temperature. 1H NMR (DMF d 7 ) δ 9.4 (s, 1H, NH), 7.1 (m, 2H, Ar-H), 6.3 (m, 2H, Ar-H), 1.96 (s, 3H, CO-CH 3 ); IR (cm "1 , KBr) 3421 (broad, OH), 1635 (sharp, CO), 1594 (sharp), 1534 (sharp), 1500 (sharp), 1279 (sharp) ; Combustion analysis calculated for C 8 H 8 NO 2 Na » 6H 2 O: C 34.16, H 7.12, N 4.98; found C 34.05, H 6.96, N 5.00; Water content calculated for C 8 H 8 NO 2 Na»6H 2 O: 38%, Found: 38% (Karl Fischer); FAB mass spectral analysis m/e calculated for C 8 H 8 NO 2 Na«6H 2 0: 173, found 174 (M + 1). The aqueous solubility at 22°C was 493 mg/mL. EXAMPLE II This Example discloses the preparation of acetaminophen sodium (C 8 H 8 NO 2 Na « 7H 2 O). 80g (2.00 mol) NaOH was dissolved in 400 mL water and added dropwise to a flask charged with 302g (2.00 mol) APAP dissolved in 2100 mL t-propanol, at 50°C with stirring. The solution was cooled to room temperature, whereupon an off- white precipitate formed. The solids were filtered, washed with three 200 mL portions of -propanol, and dried under a vacuum (500g, 84 % as the 7-hydrate). The 1H NMR and IR spectra were identical to that of C 8 H 8 NO 2 Na*6H 2 O. Combustion analysis calculated for C 8 H 8 NO 2 Na » 7H 2 O: C 32.1 1 H 7.41 N 4.68; Found: C 31.99, H 7.38, N 4.31; Water content calculated for C 8 H 8 NO 2 Na«7H 2 O: 42.1%; Found 42.7% (Karl Fischer). The aqueous solubility at 22°C was 541 mg/mL. EXAMPLE III This Example discloses the preparation of acetaminophen calcium (C 16 H 16 N 2 O 4 Ca-2H 2 O). 5g (0.033 mol) APAP and 1.22g (0.016 mol) Ca(OH) 2 were suspended in 200 mL water and the mixture was stirred for 4h, whereupon all solids went into solution. The solution was frozen in a bath of liquid nitrogen and lyophilized, leaving a light microcrystalline off-white solid (5.44g, 100% crude yield based on the hydrate X 2). 1H NMR (DMF d 7 ) δ 9.39 (s, 1H, NH), 7.15 (m, 4H, Ar), 6.80 (m, 4H, Ar), 2.10 (s, 6H, CO-CH 3 ). IR 3287 (broad, OH), 1648 (sharp, NH), 1594, 1541, 1500, 1279 (sharp) Combustion analysis calculated for Cι 6 H ]6 N 2 O 4 Ca « 2H 2 O: C 51.05, H 5.36, N 7.45; 9.6, Found: C 51.21, H 5.21, N 7.63. Water content calculated (Karl Fischer) for Cι 6 H 16 N 2 O 4 Ca » 2H 2 O: 9.6%, Found: 9.8%. The aqueous solubility at 22°C was 13 mg/mL. EXAMPLE IV This Example discloses the preparation of acetaminophen lithium (C 8 H 8 NO 2 Li«6H 2 O). 5g (0.033 mol) APAP was dissolved in 30 mL i-propanol/THF (1 :3, degassed with argon). This solution was added rapidly to a flask charged with 1.38g (0.033 mol) LiOH dissolved in 20 mL water (argon degassed). The colorless solution was stored at 0° C for 16 h, whereupon white crystals formed. The crystals were filtered under argon, washed with THF and dried under a vacuum for 16 h (4.25g, 6 hydrate). 1H NMR (DMF-d 7 ) δ Η NMR (DMF d 7 ) d 9.39 (s, IH, NH), 7.15 (m, 4H, Ar), 6.80 (m, 4H, Ar), 2.10 (s, 6H, CO-CH 3 ); IR 3568 (sharp), 3402, 3243 (broad), 1672, 1618 (sharp NH), 1533, 1501, 1407, 1267, 1174 (sharp). Combustion analysis calculated for C 8 H 8 NO 2 Li « 6H 2 O: C 36.23, H 7.60, N 5.28; Found: C 36.67, H 7.68, N 5.23; Water content calculated (Karl Fischer) for C 8 H 8 NO 2 Li»6H 2 O: 40.1%, Found: 38.4%. The aqueous solubility at 22°C was 455 mg/mL. EXAMPLE V This Example discloses an alternative preparation of acetaminophen lithium (C 8 H 8 NO 2 Li«6H 2 O). Acetaminophen (15. lg; 0.1 mol), water, 90 mL and lithium hydroxide 1 N (100 mL, 0.1 mol) were placed in a 2 L beaker. After the solution became clear, acetonitrile (1500 mL) was added. The resulting white solids were filtered, washed with THF (ca. 500 mL) and dried at ambient leaving a dry white solid (23.0 g, 87% based on C 8 H 8 NO 2 Li»6H 2 O). 1H NMR (DMF-d 7 ) δ 2.0 (s,3H, CO-CH3), 6.5 (m, 2H, Ar-H), 7.2 (m, 2H, Ar-H), 9.3 (s, IH, AC-NH-Ar), 2.0 (s,3H, CO-CH3), 6.5 (m, 2H, Ar-H), 7.2 (m, 2H, Ar-H), 9.3 (s,lH, AC-NH-Ar). IR 3568 (sharp), 3402, 3243 (broad), 1672, 1618 (sharp NH), 1533, 1501, 1407, 1267, 1174 (sharp). Combustion analysis calculated for C 8 H 8 NO 2 Li » 6H 2 O: C 36.23, H 7.60, N 5.28; Found: C 36.56, H 7.56, N 5.05. Water content calculated (Karl Fischer) for C 8 H 8 NO 2 Li«6H 2 O: 40.1%, Found: 40.0%. The aqueous solubility at 22°C was 472 mg/mL. EXAMPLE VI This Example discloses the preparation of an anhydrous acetaminophen calcium (C 16 H. 6 N 2 O Ca). Acetaminophen (90.6g, 0.60 mol) was suspended in 135 mL water and a solution containing sodium hydroxide (24. Og, 0.6 mol) and 36mL water was added at 18-26°C over 30 min. To the resulting NaAPAP-slurry, a solution containing calcium chloride (CaCl ) (44. lg, 0.3 mol) and 54 mL water was added at 20-25°C over 30 min. at room temperature. The reaction mixture was then heated to 60°C within 60 min. Immediately after reaching 60°C, the slurry was cooled to 20°C within 60 min. and stirred at 20°C for 30 min. The resulting Cι 0 Hι 6 N 2 O 4 Ca (79g, 78%) was filtered off, washed with t-propyl alcohol (75 mL) and dried overnight at 80°C under vacuum. Η NMR (D 2 O) δ 7.01 (d,8,4H), 6.57 (d,8,4H), 2.06 (s, 6H, CO-CH 3 ). IR ^m "1 ): 1651 (sharp, NH), 1506, 1276, 854 (sharp). Combustion analysis calculated for Cι 6 Hι 6 N 2 O 4 Ca: C 55.65, H 4.7, N 8.23; Found: C 55.80, H 4.53, N 8.13. EXAMPLE VII A study was conducted in dogs to determine the bioavailability of acetaminophen sodium. The free acid form of acetaminophen was used as the control. Compressed cylindrical pellets having the following composition were prepared: Acetaminophen Sodium - compressed neat (no excipients). Control - 150 mg APAP, 30 mg microcrystalline cellulose, and 30 mg dextrates. Eight male purebred beagles having a body weight at initial dosing of approximately 9 to 14 kg were used in the study. The dogs were fed PMI® Certified Canine Diet Meal No. 5007 and water, both ab libitum. The dogs were fasted overnight for approximately 12 hours prior to dosing and food was returned 4 hours after dosing. The dogs were divided into two groups and each group was dosed with either acetaminophen sodium or the control (free acid APAP) pellets. A single dose equivalent to 300 mg of acetaminophen free acid was administered via an oral gavage using a stomach tube. Each dose was followed by 20 mL of water. After a period of one week, the each group was dosed again, but with the other form of acetaminophen. Twelve blood samples were collected form each dog on each dosing day (1 prior to dosing and 11 thereafter). The plasma was separated and tested for acetaminophen. The following summarizes the pharmacokinetic measurements for acetaminophen: Parameter APAP Sodium Control AUC (ug-hr/mL) 31.4 ± 5.7 27.4 ± 6.1 C max (ug/mL) 23.6 ± 4.2 19.4 ± 6.9 T max (hr) 0.27 ± 0.1 0.60 ± 0.3 AUC = areas under the plasma concentration-time curve to the last quantifiable concentration. C max = peak plasma concentration. Tmax = peak time. Figure 2 is a plot of the acetaminophen plasma concentration-time curve. This Figure demonstrates that the acetaminophen salt of the present invention is absorbed faster than the free acid acetaminophen control. The faster T max for the acetaminophen salt suggests faster onset of action of the analgesic and antipyretic activities relative to the free acid control. Various modifications can be made from the above-described embodiments without departing from the spirit and scope of the present invention.

Claims: WHAT IS CLAIMED IS: 1. An isolated salt of acetaminophen. 2. The salt of claim 1 wherein the salt is an alkali metal or alkaline-earth metal salt. 3. The salt of claim 2 wherein the alkali metal is selected from the group consisting of lithium, sodium, potassium and cesium. 4. The salt of claim 2 wherein the alkaline-earth metal is selected from the group consisting of calcium and magnesium. 5. The salt of claim 2 in a hydrated form. 6. The salt of claim 2 in an anhydrous form. 7. The salt of claim 6 wherein the alkaline-earth metal is calcium. 8. A solid orally adminsterable dosage form comprising the salt of claim 2. 9. A method of treating a mammal in need of an analgesic or antipyretic agent, comprising the oral administration of a therapeutically effective amount of an isolated salt of acetaminophen. 10. The method of claim 9 wherein the salt is an alkali metal or alkaline-earth metal salt. 11. The method of claim 10 wherein the alkali metal is selected from the group consisting of lithium, sodium, cesium and potassium. 12. The method of claim 10 wherein the alkaline-earth metal is selected from the group consisting of calcium and magnesium. 13. The method of claim 10 wherein the salt is in a hydrated form. 14. The method of claim 10 wherein the salt is in an anhydrous form. 15. The method of claim 14 where in the alkaline-earth metal is calcium. 16. A method of eliciting an onset hastened analgesic or antipyretic response in a mammal, comprising the oral administration of an isolated salt of acetaminophen. 17. The method of claim 16 wherein the salt is an alkali metal or alkaline-earth metal salt. 18. The method of claim 17 wherein the alkali metal is selected from the group consisting of lithium, sodium, cesium and potassium. 19. The method of claim 17 wherein the alkaline-earth metal is selected from the group consisting of calcium and magnesium. 20. The method of claim 17 wherein the salt is in a hydrated form. 21. The method of claim 17 wherein the salt is in an anhydrous form. 22. The method of claim 21 wherein the alkaline-earth metal is calcium. 23. The isolated compound: (CHjCONH- y-O-)« M (+) "* xH2θ, wherein n is 1 or 2, M is alkali metal when n is 1 and M is alkaline-earth metal when n is 2 and x is from 0 to about 10. 24. The compound of claim 23 wherein the alkali metal is selected from the group consisting of sodium, potassium, cesium and lithium. 25. The compound of claim 23 wherein the alkaline-earth metal is selected from the group consisting of calcium and magnesium. 26. The compound of claim 23 in a hydrated form. 27. The compound of claim 23 in an anhydrous form. 28. The compound of claim 27 wherein the alkaline-earth metal is calcium. 29. A method of preparing an isolated salt of acetaminophen, comprising: reacting acetaminophen with a mono or divalent metal hydroxide in the presence of a solvent to form a reaction mixture and immediately recovering the resulting salt from the reaction mixture. 30. The method of claim 29 wherein the solvent is water or a water-mi scible organic liquid. 31. The method of claim 29 wherein the salt is recovered by crystallization with a water-miscible solvent. 32. The method of claim 29 wherein the salt is recovered by lyophilization. 33. A method of preparing an anhydrous, isolated salt of acetaminophen, comprising: contacting a monovalent metal salt of acetaminophen with a divalent metal cation whereby a divalent metal salt of acetaminophen is formed via a cation exchange reaction and immediately recovering the resulting anhydrous, divalent metal salt of acetaminophen. 34. The method of claim 33 wherein an aqueous solution or slurry of said monovalent metal salt of acetaminophen is contacted with said divalent metal cation and the resulting anhydrous salt is recovered by vacuum drying. 35. The method of claim 33 wherein the anhydrous salt is Ci6Hι 6 N 2 O 4 Ca. 36. The method of claim 35 wherein said anhydrous salt is formed by a cation exchange reaction between acetaminophen sodium and calcium chloride.

Inventors: HIGGINS JOHN D III, NADIG DAVID, OHANNESIAN LENA A, REY MAX, HIGGINS, JOHN, D., III, NADIG, DAVID, OHANNESIAN, LENA, A., REY, MAX
Applicants: MCNEIL PPC INC, MCNEIL-PPC, INC.
Application year: 1997
Main classification: A61K
IPC codes: A61K31, A61P29, C07C231, C07C233