L-ARGININE ISOXICAMATE

Abstract: The compound L-arginine isoxicamate is disclosed. Pharmaceutical compositions comprising and processes for producing the same are also disclosed. The compound has an improved bioavailability.

Description: L-ARGININE ISOXICAMATE Isoxicam, 4-hydroxy-2-methyl-N-(5-methyl-3 isoxazolyl)-2H-1,2-benzothiazine-3-carboxamide-1, 1-dioxide, is a nonsteroidal anti-inflammatory drug described in U.S. patent 3,787,324. The compound is weakly acidic (pKa about 3.65) and practically insoluble in water and alcohol. Because of the potential for incomplete or inconsistent bioavailability that often accompanies low aqueous solubility, isoxicam has been formulated in capsule dosage forms using drug that has been micronized or precipitated in microcrystalline form. The N-methylglucamine salts of oxicam derivatives have been described in European Published Application No. 0002482 and in U.S. Serial Number 488,922 filed on 27th April 1983. These salts were prepared to enhance the solubility and stability of aqueous solutions of the oxicam derivatives. Water-soluble lysine and arginine salts of piroxicam have been described as especially useful for treating arthritis by parenteral administration in European Published Application No. 0066458. According to the present invention there is provided a compound having the name L-arginine isoxicamate. This is a novel salt of isoxicam and exhibits surprisingly greater bioavailability when administered to mammals. The L-arginine isoxicamate may have a 1:1 stoichiometry. In this case, the compound may be in an anhydrous, crystalline state. According to another aspect of the present invention, there is provided a pharmaceutical composition, suitable for use as an anti inflammatory agent or as an analgesic, which comprises an effective amount of L-arginine isoxicamate in admixture with a pharmaceutically acceptable carrier. Another aspect of the present invention provides a process for preparing L-arginine isoxicamate, which process comprises heating L-arginine and isoxicam together in a solvent. The solvent is preferably aqueous methanol, and the heating is conveniently carried out at the boiling point of the solvent. Isoxicam, its alkali metal, alkaline earth and amine salts, including their method of manufacture and therapeutic properties have been fully described in U.S. Patent 3,787,324. L-arginine isoxicamate may be prepared by heating the suspended reactants, isoxicam and L-arginine, in aqueous methanol at the boiling point of the solvent. L-arginine isoxicamate, when prepared by this method, is an anhydrous, crystalline salt of 1:1 stoichiometry. It is a fine yellow crystalline powder with a water solubility of 19 mg per ml; a saturated solution exhibiting a pH of about 8. & In order to use the compound of the invention, it may be formulated into oral dosage forms such as capsules, tablets, or syrups by blending with an appropriate inert pharmaceutical carrier such as cellulose, lactose, or simple syrup by methods well known to the pharmaceutical art. For injectionable dosage forms, it may be formulated with vehicles such as water. The compound of the invention may also be formulated in topical preparations. The L-arginine salt of isoxicam exhibits greater and more consistent bioavailability when orally administered than other known forms of isoxicam. Thus, for example, when compared to micronized isoxicam, L-arginine isoxicamate affords a significant improvement in bioavailability on oral adminsitration. Isoxicam plasma concentrations and bioavailability parameters in four dogs after a single 100 mg oral dose of the arginine salt or the free acid are shown in Tables 1 and 2, respectively. Reference will now be made, by way of example only, to the accompanying drawings in which: Figure 1 is a line drawing showing the mean plasma time course of four beagle dogs after a single oral dose of 100 mg free acid equivalents of isoxicam; Figure 2 is a line drawing plotting plasma concentrations versus time profile of isoxicam after a single oral dose of 100 mg free acid equivalents to Beagle Dog 120,642; Figure 3 is a line drawing plotting plasma concentrations versus time profile of isoxicam after a single oral dose of 100 mg free acid equivalents to Beagle Dog 117,668; Figure 4 is a lint drawing plotting plasma concentration versus time profile of isoxicam after a single oral dose of 100 mg free acid equivalents to beagle Dog 1930; and Figure 5 is a line drawing plotting plasma concentration versus time profile of isoxicam after a single oral dose of 100 mg free acid equivalents to Beagle Dog 1942. Following a 120 trig (free acid equivalents) per oral dose of the arginine salt of isoxicam a mean peak plasma concentration of 53.9 i 4.0 g/ml was reached at two hours postdose. The range for the individual animals was 51.4 to 63.0 ug/ml with three animals having a peak time of two hours and the final animal at eight hours. These plasma levels were considerably higher when compared to micronized isoxicam. A mean peak plasma concentration of 14.8 + 4.9 bg/ml was observed at four hours postdose for micronized isoxicam. Peak plasma concentrations for individual animals ranged from 9.92 to 19.0 19.0 pg/ml between three and six hours postdose. Mean plasma concentrations proceeded to decline to the last sampling period of 240 hours where 0.82 + 0.3 pg/ml was observed for arginine isoxicamate but were not detectable for micronized isoxicam. Calculated elimination half-lives using a linear regression analysis of the semilogarithmic data are shown in Table 2. Mean half-lives of 36.2 + 7.5 hours and 35.5 + 7.1 hours were found for arginine isoxicamate and micronized isoxicam. Mean Cmax values were dissimilar with a value of 56.2 + 5.6 g/ml observed for arginine isoxicamate and 15.4 + 4.2 g/ml for micronized isoxicam. A graphical presentation of the mean plasma concentration-time Profile is shown in Figure 1. Individual animal data are presented in Figures 2-5. Areas under the plasma concentration versus time curve (AUC0-") were calculated using the trapezoidal rule and extrapolated to infinity with the appropriate elimination rate constants. In every- case, the AUC0 # for arginine isoxicamate was greater than micronized isoxicam. The mean AUCO- for arginine isoxicamate and isoxicam were 2840 + 170 ug.hr.ml1 and 808 + 230 vg.hr.ml¯l, respectively. The relative bioavailability of L-arginine isoxicamate was determined from a comparison of the individual dog AUC0- arginine salt/ AUC0- micronized isoxicam. The relative bioavailability in the four dogs was calculated to be 539, 278, 368, and 313. The mean relative bioavailability (arginine isoxicamate/micronized isoxicam) of arginine isoxicamate was determined to be 374 (t 116)%. These data are summarized in Table 2. TABLE 1 Plasma Levels of isoxicam in Dogs Arginine Salt versus Micronized 100 mg, dog (isoxicamEguivalents) (ug/ml) EMI7.1 <tb> Animals <SEP> Dosed <SEP> with <SEP> Arginine <SEP> Isoxicamate <tb> <SEP> Time <SEP> 1930 <SEP> 1942 <SEP> 117668 <SEP> 120064 <SEP> Mean <SEP> S.D. <SEP> RSD% <tb> Pre-Rx <SEP> N.D. <SEP> N.D. <SEP> N.D. <SEP> N.D. <SEP> ---- <SEP> ---- <SEP> --- <tb> <SEP> 0.5 <SEP> 29.6 <SEP> 7.99 <SEP> 22.8 <SEP> 1.11 <SEP> 15.4 <SEP> 13.1 <SEP> 85.3 <tb> <SEP> 1.0 <SEP> 43.4 <SEP> 28.1 <SEP> 42.6 <SEP> 15.5 <SEP> 32.4 <SEP> 13.3 <SEP> 41.0 <tb> <SEP> 2.0 <SEP> 51.4 <SEP> 58.6 <SEP> ---- <SEP> 51.8 <SEP> 53.9 <SEP> 4.0 <SEP> 7.5 <tb> <SEP> 3.0 <SEP> 1 <SEP> 47.5 <SEP> 1 <SEP> 51.7 <SEP> 1 <SEP> 55.1 <SEP> 1 <SEP> 46.3 <SEP> 1 <SEP> 50.2 <SEP> 1 <SEP> 4.0 <SEP> 1 <SEP> 8.0 <tb> <SEP> 4.0 <SEP> 48.9 <SEP> 53.9 <SEP> 59.3 <SEP> 50.5 <SEP> 53.2 <SEP> 4.6 <SEP> 8.7 <tb> <SEP> 6.0 <SEP> 48.3 <SEP> 50.5 <SEP> 50.2 <SEP> 49.6 <SEP> 49.6 <SEP> 1.0 <SEP> 2.0 <tb> <SEP> 8.0 <SEP> 42.6 <SEP> 42.2 <SEP> 63.0 <SEP> 42.0 <SEP> 47.4 <SEP> 10.4 <SEP> 21.9 <tb> 12.0 <SEP> 37.8 <SEP> 39.4 <SEP> ---- <SEP> ---- <SEP> 38.6 <SEP> 1.1 <SEP> 2.9 <tb> 24.0 <SEP> 32.8 <SEP> 35.6 <SEP> 30.5 <SEP> 31.3 <SEP> 32.6 <SEP> 2.2 <SEP> 6.9 <tb> 32.0 <SEP> 1 <SEP> 25.2 <SEP> 1 <SEP> 25.7 <SEP> 1 <SEP> 29.6 <SEP> 1 <SEP> 34.8 <SEP> 1 <SEP> 28.8 <SEP> 1 <SEP> <SEP> 4.4 <SEP> 1 <SEP> 15.4 <tb> 48.0 <SEP> 1 <SEP> 25.0 <SEP> 1 <SEP> 25.5 <SEP> 1 <SEP> 18.6 <SEP> 1 <SEP> 21.5 <SEP> 1 <SEP> 22.6 <SEP> 1 <SEP> 3.2 <SEP> 1 <SEP> 14.3 <tb> 72.0 <SEP> 1 <SEP> 14.6 <SEP> 1 <SEP> 17.1 <SEP> 1 <SEP> 10.7 <SEP> 1 <SEP> 17.6 <SEP> I <SEP> 15.0 <SEP> 1 <SEP> 3.2 <SEP> 1 <SEP> 21.0 <tb> 96.0 <SEP> i <SEP> 10.2 <SEP> 1 <SEP> 8.96 <SEP> 1 <SEP> 5.10 <SEP> 1 <SEP> 9.39 <SEP> 1 <SEP> 8.41 <SEP> 1 <SEP> 2.3 <SEP> 1 <SEP> 27.0 <tb> 153.0 <SEP> 2.72 <SEP> 2.34 <SEP> 1.27 <SEP> 3.52 <SEP> 2.46 <SEP> 0.9 <SEP> 38.0 <tb> 192.0 <SEP> 1.56 <SEP> 1.26 <SEP> 0.85* <SEP> 2.17* <SEP> 1.46 <SEP> 0.6 <SEP> 37.8 <tb> 240.0 <SEP> 0.89 <SEP> 0.60 <SEP> 0.51 <SEP> 1.26 <SEP> 0.82 <SEP> 0.3 <SEP> 41.5 <tb> EMI7.2 <tb> <SEP> Animals <SEP> Dosed <SEP> with <SEP> Micronized <SEP> Isoxicam <tb> Time <SEP> 1930 <SEP> 1942 <SEP> 117668 <SEP> 120064 <SEP> Mean <SEP> S.D. <SEP> RSD% <tb> Pre-Rx <SEP> N.D. <SEP> N.D. <SEP> N.D. <SEP> N.D. <SEP> ---- <SEP> --- <tb> <SEP> 0.5 <SEP> 2.14 <SEP> 0.27 <SEP> N.D. <SEP> N.D. <SEP> 1.20 <SEP> 1.3 <SEP> 110.0 <tb> <SEP> 1.0 <SEP> 4.07 <SEP> 8.92 <SEP> 1.59 <SEP> 5.10 <SEP> 4.92 <SEP> 3.0 <SEP> 61.9 <tb> <SEP> 2.0 <SEP> 9.39 <SEP> 13.6 <SEP> 9.72 <SEP> 14.3 <SEP> 11.8 <SEP> 2.6 <SEP> 21.8 <tb> <SEP> 3.0 <SEP> 1 <SEP> 9.07 <SEP> 1 <SEP> 17.5 <SEP> 1 <SEP> 14.3 <SEP> 1 <SEP> 17.7 <SEP> 1 <SEP> 14.6 <SEP> 1 <SEP> 4.0 <SEP> 1 <SEP> 27.5 <tb> <SEP> 4.0 <SEP> 1 <SEP> 8.50 <SEP> l <SEP> 19.0 <SEP> I <SEP> 13.3 <SEP> 1 <SEP> 18.5 <SEP> 1 <SEP> 14.8 <SEP> 1 <SEP> 4.9 <SEP> 1 <SEP> 33.3 <tb> <SEP> 6.0 <SEP> 1 <SEP> 9.92 <SEP> 1 <SEP> 18.2 <SEP> 1 <SEP> 12.4 <SEP> 1 <SEP> 16.4 <SEP> I <SEP> 14.2 <SEP> 1 <SEP> 3.8 <SEP> 1 <SEP> 26.4 <tb> <SEP> 8.0 <SEP> 9.91 <SEP> 16.8 <SEP> 11.8 <SEP> 15.6 <SEP> 13.3 <SEP> 3.2 <SEP> 23.8 <tb> <SEP> 12.0 <SEP> ---- <SEP> ---- <SEP> 12.3 <SEP> 15.2 <SEP> 13.8 <SEP> 2.1 <SEP> 14.9 <tb> <SEP> 24.0 <SEP> 7.93 <SEP> 11.8 <SEP> 9.30 <SEP> 12.1 <SEP> 10.3 <SEP> 2.0 <SEP> 19.5 <tb> <SEP> 32.0 <SEP> 5.25 <SEP> 9.38 <SEP> 8.18 <SEP> 9.13 <SEP> 7.98 <SEP> 1.9 <SEP> 23.7 <tb> <SEP> 48.0 <SEP> 4.77 <SEP> 7.92 <SEP> 6.46 <SEP> 7.63 <SEP> 6.70 <SEP> 1.4 <SEP> 21.4 <tb> 72.0 <SEP> 2.72 <SEP> 6.04 <SEP> 3.04 <SEP> 4.60 <SEP> 4.10 <SEP> 1.5 <SEP> 37.4 <tb> 96.0 <SEP> 1.17 <SEP> 3.02 <SEP> 1.80 <SEP> 2.44 <SEP> 2.11 <SEP> 0.8 <SEP> 37.9 <tb> 153.5 <SEP> 0.41 <SEP> 0.94 <SEP> 0.52 <SEP> 0.92 <SEP> 0.70 <SEP> 0.3 <SEP> 39.0 <tb> 192.0 <SEP> 0.22* <SEP> 0.60* <SEP> 0.13 <SEP> 0.66 <SEP> 0.40 <SEP> 0.3 <SEP> 66.2 <tb> 240.0 <SEP> N.D. <SEP> 0.42 <SEP> N.D. <SEP> N.D. <SEP> 0.10 <SEP> 0.2 <SEP> 200.0 <tb> <SEP> fital <tb> Actual time g 193 hours TABLE 2 Bioavailability Parameters for Arginine Isoxicamate and Micronized isoxicamate After Oral Administration of 100 mg (Free Acid Equivalents) to @cagle Dogs EMI8.1 Dog <SEP> AUCO- <SEP> Relative <SEP> Half-Life <SEP> Tmax <SEP> Cmax <tb> Number <SEP> @@xh@xm]-1 <SEP> Bioavailabilty <SEP> (hours) <SEP> (hours) <SEP> ( g/ml) <tb> <SEP> Arginine <SEP> [soxicam <SEP> % <SEP> (Arg <SEP> / <SEP> Isoxicam) <SEP> Arginine <SEP> Isoxicam <SEP> Arginine <SEP> Isoxicam <SEP> Arginine <SEP> Isoxicam <tb> 1930 <SEP> 2910 <SEP> 540 <SEP> 539 <SEP> 38.8 <SEP> 32.6 <SEP> 2 <SEP> 6 <SEP> 51.4 <SEP> 9.92 <tb> 1942 <SEP> 2920 <SEP> 1050 <SEP> 278 <SEP> 34.4 <SEP> 42.4 <SEP> 2 <SEP> 4 <SEP> 58.6 <SEP> 19.0 <tb> 117668 <SEP> 2590 <SEP> 703 <SEP> 368 <SEP> 27.0 <SEP> 26.8 <SEP> 6 <SEP> 3 <SEP> 59.3 <SEP> 14.3 <tb> 120064 <SEP> 2950 <SEP> 941 <SEP> 313 <SEP> 44.8 <SEP> 40.1 <SEP> 2 <SEP> 4 <SEP> 51.8 <SEP> 18.5 <tb> Mean <SEP> 2840 <SEP> 808 <SEP> 374 <SEP> 36.2 <SEP> 35.5 <SEP> 3 <SEP> 4.2 <SEP> 55.3 <SEP> 15.4 <tb> SD <SEP> 170 <SEP> 230 <SEP> 116 <SEP> 7.5 <SEP> 7.1 <SEP> 2 <SEP> 1.3 <SEP> 4.3 <SEP> 4.2 <tb> RSD% <SEP> 6.0 <SEP> 28.5 <SEP> 30.9 <SEP> 20.7 <SEP> 20.1 <SEP> 66.7 <SEP> 29.6 <SEP> 7.7 <SEP> 27.4 <tb> Generally speaking, the L-arginine salt of isoxicam is indicated in conditions such as pain resulting from arthritis, bursitis, and the like. A daily dosage regimen of half the amount of the free acid, i.e., about 0.25 9 to about 1 g in several divided doses is recommended for a mammal weighing about 70 kg body weight to relieve the pain and swelling associated with these conditions. The following Examples are illustrative of the invention. EXAMPLE 1 L-(+)-Arginine, 5.23 g, 0.03 moles, was dissolved in 80 ml of water in a 500 ml round bottom flask. Isoxicam, 10.05 g, 0.03 moles, and 150 ml of methanol were added and the mixture refluxed for two days. The resulting mixture was filtered through a mediumpore sintered glass disc and the filtrate evaporated to dryness. The solid residue was recrystallized from methanol to give 13.2 g (86.4%) of a fine, pale yellow crystalline powder, mp 2200C with decompositon. Analysis calcd. for C20H27N7O7S: C, 47.14; H, 5.34t N, 19.24; S, 6.29. Found; C, 46.845 H, 5.26; N, 19.12, S, 6.45. Solubility: 19 mg per ml in water; pH of saturated solution 8.8. EXAMPLE 2 A tablet is formed from the following ingredients: mq/tablet Arginine isoxicamate, 304 mg equivalent to Isoxicam 200.0 Microcystalline cellulose 80.0 Lactose 16.0 Corn starch 80.0 Hydroxypropyl cellulose 15.0 Calcium stearate 5.0 Hydrate the hydroxypropyl cellulose in about 0.15 ml of water. Blend the arginine isoxicamate, microcrystalline cellulose, lactose, corn starch and mix with the hydroxypropyl cellulose solution to make a moist granulation. Dry granulation at 50 C, add the calcium stearate, mix and blend well. Compress into tablets weighing 500 mg, on a suitable tablet compressing machine. EXAMPLE 3 A two piece hard shell capsule is prepared from the following ingredients: mg/capsule Arginine isoxicamate, 152 mg equivalent to Isoxicam 100.0 Microcystalline cellulose 105.0 Corn starch 100.0 Magnesium stearate 3.0 All the above ingredients are blended together until homogeneous. The resultant mixture is filled into a Number 1 two piece hard gelatin capsule at fill weight of 360 mg, using a conventional capsule filling machine. EXAMPLE 4 A syrup formulation was prepared from the following ingredients: 5 ml dose contains Arginine isoxicamate, 76 mg equivalent to Isoxicam 50.0 mg Sugar, granulated 2.5 g Glucose, liquid 1.1 g Alcohol, USP 0.05 ml Oil of orange 0.5 Lil Peach flavor imitation 0.06 1 Menthol 0.25 mg Water, sufficient quantity to make 5.0 ml Dissolve the arginine isoxicamate in 1.5 ml water, heat to 600C, add and dissolve the sugar with stirring. Add the glucose, mix until clear solution results. Dissolve the oil of orange, peach flavor, and menthol in the alcohol. Add flavor solution to the aqueous drug solution, slowly and with rapid stirring. Filter the syrup until clear and make to final volume with addition of water and mix. EXAMPLE 5 An injectable solution was prepared from the following ingredients: mg/l ml Arginine isoxicamate, 15.2 mg equivalent to Isoxicam 10.0 Water for injection sufficient quantity to make 1.0 ml Dissolve the arginine isoxicamate in the water, check pH (8.7-8.9). Adjust and recheck final volume to 1.0 ml. Sterilize the solution by filtration through a sterile 0.2 tim membrane filter into a sterile receiving vessel. Aseptically fill the desired volume into previously sterilized ampuls or other previously sterilized containers. Close and seal the containers. CLAIMS: for the Contracting States BE, CH, DE, FR, GB, IT, LI, LU, NL, SE) 1. A compound having the name L-arginine isoxicamate. 2. A compound according to Claim 1, and which has 1:1 stoichiometry. 3. A compound according to Claim 2, which is in an anhydrous, crystalline state. 4. A pharmaceutical composition, suitable for use as an anti-inflammatory agent or as an analgesic, comprising an effective amount of a compound as claimed in Claim a, 2 or 3 in admixture with an inert pharmaceutically acceptable carrier. 5. A composition as claimed in Claim 4, in oral dosage form. 6. A process for preparing L-arginine isoxicamate, which process comprises heating L-arginine and isoxicam together in a solvent. 7. A process according to Claim 6, wherein the solvent is aqueous methanol. 8. A process according to Claim 6 or 7, wherein the heating is carried out at the boiling point of the solvent. 9. A process for preparing a pharmaceutical composition, which process comprises admixing an effective amount of a compound as claimed in Claim a, 2 or 3 with an inert pharmaceutically acceptable carrier.

Claims: CLAIMS: for the Contracting State AT 1. A process for preparing a compound having the name L-arginine isoxicarnate, which process comprises heating L-arginine and isoxicam together in a solvent. 2. A process according to Claim 1, wherein the solvent is aqueous methanol. 3. A process according to Claim 1 or 2, wherein the heating is carried out at the boiling point of the solvent. 4. A process according to Claim 1, 2 or 3, for preparing L-arginine isoxicamate having 1:1 stoichiometry. 5. A process according to Claim 4, wherein the L-arginine isoxicamate prepared is in an anhydrous, crystalline state. 6. A process for preparing a pharmaceutical composition which is suitable for use as an anti-inflammatory agent or as an analgesic, which process comprises admixing an effective amount of L-arginine isoxicamate with an inert pharmaceutical carrier. 7. A process according to Claim 6, wherein the composition is in oral dosage form.

Inventors: CHAFETZ, LESTER, HONG, WEN-HAI
Applicants: WARNER-LAMBERT COMPANY
Application year: 1984
Main classification: C07D417
IPC codes: C07D265, A61K31, C07D279, C07D417, A61P29, C07D293, A61P25, C07D241, C07C46