Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-12-10
2001-09-18
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06291527
ABSTRACT:
This application is of PCT/IB 99/00626, filed Apr. 9, 1999.
This invention refers to the use of soluble Ketoprofen salts with amino acids for administration through the injectable, transdermal/mucosal and oral routes. These new compounds in addition to increasing the solubility of the active substance, are also able to increase the speed of absorption and the tolerability of the anti-inflammatory drug, as well as increasing the capacity to localize themselves in the inflammed sites in a preferential manner, particularly in inflammed joints and cartilaginous structures.
Ketoprofen is one of the most active non-steroidal anti-inflammatory drugs and, within its class of products (propionic acid derivatives), is the one with the most rapid anti-inflammatory and analgesic activity. Ketoprofen's anti-inflammatory action is exerted through various mechanisms:
a)inhibition of prostaglandin synthesis;
b)counteraction of pro-inflammatory peptide activity (e.g. bradykinin);
c)stabilization of cellular and liposomial membranes;
d)platelet anti-aggregating activity;
Ketoprofen is indicated for the treatment of rheumatoid arthritis, ankylosing spondylitis, acute gout, osteoarthrosis in various locations, sciatic pain, radiculitis, myalgia, bursitis, tendonitis, tendosynovitis, synovitis, capsulitis, very severe bruises, sprains, dislocations, muscular dilaceration, phlebitis, superficial thrombophlebitis, lymphangitis, painful inflammatory dental, ENT, and urinary tract affections and in pneumology. Injectable Ketoprofen (i.m. and i.v.) is especially indicated for the symptomatic treatment of acute pain due to inflammation of the muscular-skeletal apparatus. Topical Ketoprofen is indicated for the treatment of myalgia, muscular dilacerations, bruises, sprains, dislocations, muscular dilaceration, phlebitis, superficial thrombophlebitis, lymhangitis.
The pharmacological tests performed with Ketoprofen have demonstrated the substance's excellent tolerability and lack of acute and chronic toxicity following local application. In fact, dermal application of high quantities over extended intact and abraded surface areas in experimental animals did not induce any local or general harm, even after long term treatment. Ketoprofen, vehicled in suitable excipients and applied to the skin, is absorbed gradually. It has a half-life of 1.6 to 1.9 hours. Peak concentration following intramuscular administration is reached within 30 min.; peak mean value is 10.4 mcg/ml.
Ketoprofen's pharmacokinetic behaviour in synovial fluid is particularly interesting; and in view of the fact that this subject is the strategic part of this patent it, therefore, requires brief mention. In medical practice it has been noted that there is a limited correlation between clinical response of patients treated with anti-inflammatories and the dose administered, as well as the consequent plasma levels. This phenomenon can be correlated with the fact that the plasma concentrations are not a suitable measure of drug concentration in the joints, which are the site of the inflammatory reaction.
It is, therefore, useful to evaluate the active substance concentration in synovial fluid after oral, transdermal or intramuscular administration of a NSAID. Netter et al. (Netter P. et all.,
Clin. Pharmacol. Ther
., 42: 555-561, 7987) investigated Ketoprofen levels in plasma and synovial fluid in 37 patients (23 males and 14 females) by taking samples at various intervals between 15 minutes and 15 hours after intramuscular administration of 100 mg.
The results obtained demonstrate that Ketoprofen penetrates promptly into the joints, in view of the significant concentrations that are detectable even 15 minutes after administration.
The maximum serum concentration is reached after 30 minutes (6.5 &mgr;g/ml); whilst equilibrium, i.e.: when serum and synovial concentrations are equivalent, is reached after 3.5 hours (1.3 &mgr;g/ml). After 8 to 15 hours from intramuscular administration of 100 mg Ketoprofen concentrations in synovial fluid are treble those observable in serum. The AUC of the free Ketoprofen fraction in serum is 127 hr*ng*ml
−1
, whilst in synovial fluid it is 119 hr*ng*ml
−1
. Mean resident time in the joints was about three times longer than that observed in serum.
Ballerini et al. (Ballerini R. et all.,
Int. J. Clin. Pharm. Res VI
: 69-72, 1986) also investigated the concentrations of Ketoprofen in the joints and in circulation. They administered a Ketoprofen gel to 6 patients who were to undergo a knee operation and in whom it was possible to determine the presence of the active substance in the intraarticular adipose tissue, in the capsular tissue and in synovial fluid. The gel was applied once a day for three days; the operations were performed 12 hours after the last administration. Ketoprofen was detectable from the 2nd hour (6.3 ng/ml) and reached peak concentration after six hours (18.2 ng/l) with values that remained constant for 12 hours. In synovial fluid mean values after 12 hours were 1.31 mcg/g, whilst in intraarticular adipose tissue they were 4.70 mcg/g and in the capsular tissue 2.36 mcg/g. The data obtained show a greater active substance concentration in the joint than in systemic circulation indicating a direct transdermal diffusion in the joint without direct involvement of circulatory flow, in which the active principle is present only due to local diffusion.
Kohler et al. (Kohler G. et all.,
Sem. Hop. Par
., 48: 3210-3213, 1983) investigated 16 patients affected by rheumatoid polyarthritis or deforming arthrosis subjected to surgical procedures. The patients were treated with Ketoprofen 100 mg administered i.m. approximately 3 hours before the operation.
The mean values observed were 0.85 &mgr;g/g in synovial fluid, 0.32 &mgr;g/g in the synovial membrane, 0.25 &mgr;g/g in bone, 0.26 &mgr;g/g in muscle, 0.28 &mgr;g/g in fat, and 1.39 &mgr;g/g in blood.
Finally Kennedy (Kennedy A.C.
Sem. Hop. Par
., 48: 3206-3209, 1983) investigated Ketoprofen levels in the synovial fluid of patients affected by rheumatoid arthritis, by treating 6 subjects with 100 mg and 5 subjects with 50 mg, administered orally. The resulting concentrations demonstrated that in synovial fluid, after administration of Ketoprofen 50 mg, the peak (0.91 &mgr;g/ml) appears approximately two hours after the plasma peak; whilst with a 100 mg dose synovial concentrations remained practically stable for a period of 3 to 6 hours after treatment.
It is, therefore, possible to conclude that, following treatment through various routes of administration, the intraarticular Ketoprofen concentrations reach peak levels later with respect to those observable in serum and plasma, but remain at higher levels than the latter for a longer period after treatment and always with higher values compared to those present in circulatory flow.
Ketoprofen is mainly excreted with urine (>50% in the form of metabolites) and only a minimal percentage is eliminated with the feces (1%).
Toxicity studies have demonstrated Ketoprofen's low toxicity and high therapeutical ratio. The oral LD
50
in the rat is 165 mg/kg; whilst in the mouse, for various routes of administration, it is between 365 and 662 mg/kg.
Ketoprofen, 3-Benzoyl-&agr;-methylbenzeneacetic acid, C
16
H
14
O
3
; mol wt 254,29 is practically insoluble in water, in acid solutions, and soluble in alkaline solutions. This substance's solubility in water can be modified when the molecule is salified with inorganic or organic bases.
The use of Ketoprofen salts has always attracted substantial interest because of the evident improvements obtainable with regard to bioavailability, tolerability and compliance (use of more suitable and specific pharmaceutical presentations).
Numerous developments and patents have been obtained in this field; for example it is possible to mention the use of K sodium salt, Arginine, Lysine and Methylglucamine salt for use in soft gelatin capsules(PCT/FR91/00273).
Another patent (PCT/US94/09581) describes the composition of anti-inflammatories s
Errekappa Euroterapici S.p.A.
Jarvis William R. A.
Ladas & Parry
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