Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-09-19
1998-08-18
MacMillan, Keith D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514434, 514418, 514912, 514814, 514415, 514419, 514414, A61K 3140
Patent
active
057959021
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to pharmaceutical compositions comprising certain 3-substituted 2-oxindole-1-carboxamides and medium chain (C.sub.8 to C.sub.10) fatty acid triglyceride and propylene glycol diesters. These carboxamides are useful as analgesics for use in mammals such as man and in ameliorating or alleviating pain encountered while recovering from surgery or other trauma or in eliminating the symptoms of chronic diseases such as inflammation and pain associated with rheumatoid arthritis and osteoarthritis, as shown in U.S. Pat. Nos. 4,556,672 and 5,047,554. The carboxamides are also useful for treating collagenase mediated disorders and diseases, such as bone resorption disorders, corneal ulceration, periodontal disease, inflammatory diseases, and wounds of the skin and burns in a mammal, as shown in U.S. Pat. No. 5,008,283.
The carboxamides described in formula I are chemically unstable in water. It is known that the rate of hydrolytic degradation may be reduced by protection of labile drugs e.g. sequestration in the hydrophobic core of micelles or formulation in low water activity, non-aqueous solvent-based vehicles i.e. essential oils. In addition to hydrolytic instability the carboxamides are also prone to oxidative degradation in aqueous e.g. water, and non-aqueous e.g. oils, vehicles. Oxidative instability can be reduced in saturated oils by inclusion of antioxidants or by formulation in unsaturated oils which protect the drug by being preferentially oxidized themselves. However, the carboxamides described in formula I are not readily stabilized in oils commonly used in pharmaceutical preparations e.g. sesame oil, peanut oil, safflower oil, cottonseed oil.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical preparation comprising:
(A) at least one triglyceride or propylene glycol diester of fractionated coconut oil fatty acids; and
(B) at least one compound of the formula ##STR1##
where R.sub.1, R.sub.2, and R.sub.3 are each independently hydrogen, fluoro, bromo, or chloro, or a pharmaceutically acceptable salt thereof,
wherein the weight ratio of (A) to (B) ranges from 5.6 to 999.
The pharmaceutical preparation includes 85 to 99% by weight of (A) and 0.1 to 15% by weight of (B).
Preferably, R.sub.1, R.sub.2, and R.sub.3 are each independently fluoro or chloro.
Preferred compounds of formula I include:
5-chloro-2,3-dihydro-2-oxo-3-(2-thienylcarbonyl)-indole-carboxamide;
6-chloro-5-fluoro-2,3-dihydro-2-oxo-3-(2-thienylcarbonyl)-in-dole-carboxami de; and
6-chloro-5-fluoro-2 ,3-dihydro-2-oxo-3-(2-(4-chloro)-thienyl-carbonyl)-indole-carboxamide.
The present invention also includes a method of inhibiting activation of collagenase.
The present invention also includes a method of treating an inflammatory disease.
The present invention also includes a method of eliciting an analgesic response.
DETAILED DESCRIPTION OF THE INVENTION
It has been found that pharmaceutical preparations including the carboxamides of formula I and C.sub.8 to C.sub.10 saturated fatty acid triglycerides and propylene glycol diesters have superior product viability and shelf life. As the result of utilizing such a formulation, the carboxamides are less susceptible to hydrolysis and oxidation which can deteriorate them and ultimately render them ineffective. Stabilization of the carboxamides in these preparations do not require the addition of an antioxidant or other auxiliary stabilizers.
The triglycerides used in the claimed invention are neutral oils which are composed of esters of medium chain (C.sub.8 to C.sub.10) fatty acids, also referred to as fractionated coconut oil. These fatty acids are esterified with either glycerin or propylene glycol and are sold under the name MIGLYOL.RTM. (i.e. MIGLYOL.RTM. 810, MIGLYOL.RTM. 812, and MIGLYOL.RTM. 840). MIGLYOLS are also described as triglycerides of fractionated coconut oil fatty acids or caprylic acid/capric acid triglycerides. Fractionated coconut oil is prepared from the fixed oils obtained from the dried solid part of
REFERENCES:
patent: 4918103 (1990-04-01), Park et al.
Butterfield Garth
Ginsburg Paul H.
MacMillan Keith D.
Pfizer Inc.
Richardson Peter C.
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