Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1999-07-16
2002-04-02
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S452000, C424S456000, C424S463000, C424S469000, C424S480000
Reexamination Certificate
active
06365180
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pharmaceutically elegant compositions for oral administration, and methods of using such compositions for enhancing the rate and degree of absorption of the pharmaceutically active component of such compositions, and for minimizing gastric irritation induced or caused by ingestion of such pharmaceutically active components. The pharmaceutically active component of compositions of the present invention include at least one pharmaceutically active agent having at least one acid moiety, preferably a carboxylic acid moiety, especially of the class of agents known as non-steroidal anti-inflammatory drugs (NSAIDs) which is soluble in acid at a ratio of about 30 to 1 (acid to solute) to about 10,000 to 1 (acid to solute).
BACKGROUND OF THE INVENTION
Within the pharmaceutical art, the formulation of pharmaceutically active compounds into usable dosage forms, in which the absorption of the active ingredient is optimized and the extent of controllable side effects is minimized, is challenging to pharmaceutical formulation scientists and, frequently, unpredictable. In particular, pharmaceutical formulations for pharmaceutical agents having at least one acid moiety, preferably a carboxylic acid moiety, and which is soluble in acid at a ratio of about 30 to 1 (acid to solute) to about 10,000 to 1 [acid to solute; sparingly soluble to practically insoluble or insoluble (see, e.g., Sokoloski, T. D.,
Remington's Pharmaceutical Sciences
, 16:208; 1990)] are generally known in the art to have less-than-optimum absorption and, in some instances, to cause otherwise controllable side effects upon administration to mammals. Representatives of these compounds include, for example, pharmaceutical agents well known in the art as non-steroidal anti-inflammatory drugs (NSAIDs), acetylcholinesterace (“ACE”) inhibitors represented by the “pril” family, HMG-COA reductase inhibitors represented by the “statin” family, histamine H
1
-receptor antagonists such as, for example, fexofenadine, inhibitors of gastric acid secretion such as omeprazole, mast cell stabilizing agents, antihyperlipidemia agents, penicillins, antiacne agents, cephalosporins, including, for example, &bgr;-lactams, salicylates, and a multitude of individual pharmaceutical agents.
For example, U.S. Pat. No. 4,880,835 describes the preparation of oral liquid compositions of calcium sulindac using a pharmaceutical vehicle comprised of a glycol, a polyol, and an optional alcohol. The patent further describes the well recognized problem of absorption of pharmaceutical agents, as described above, particularly NSAIDs, from the gut.
K. Chan, et al.,
Pharma Research
, 7:1027 (1990) demonstrated that sodium diclofenac (an NSAID) was more orally bioavailable from an enteric coated tablet than from an aqueous solution. This is contrary to the expectation of the art and confirms the fact that a problem in the art exists. U.S. Pat. No. 4,704,405 also describes the problem of absorption of the above-described compounds, particularly NSAIDs such a sulindac, from the gastrointestinal tract.
N. M. Najib, et al.,
International Journal of Pharmaceutics
, 45:139 (1988) have reported that ibuprofen-polyvinylpyrrolidone may form a weak acid-weak base type of complex in a solid state or in solution. This reference does not report any studies of the media or excipients used in the present invention.
U.K. Patent No. 2,059,768 describes the formation of more soluble derivatives of NSAIDs with the TRIS group of compounds.
Furthermore, U.S. Pat. No. 5,183,829 describes the preparation of NSAID formulations which appeared, in part, to improve adsorption of the pharmaceutically active agent while having positive effect on the aforementioned gastric side effects caused by NSAIDs. The patent describes a glycol-polyol media which can not be effectively used with soft gelatin capsules. More particularly, it was discovered that the polyols, and the concentration of polyols taught therein, caused the soft gelatin capsules to become tacky and adhere to adjacent soft capsules. This problem renders the pharmaceutical formulation taught in the '829 patent unviable when used in soft gelatin capsules.
Accordingly, the pharmaceutical formulations of the present invention represent a solution to the problems which result from formulations of the '829 patent as well as an advancement in the art of formulating pharmaceutically active substances into more elegant medicaments.
SUMMARY OF THE INVENTION
This invention relates to improved oral compositions which are useful as oral, liquid medicaments which can also be used to fill soft capsules or solidified, as taught here, to be used in hard capsules, particularly soft gelatin capsules and hard gelatin capsules, respectively, comprising
one or more pharmaceutically active agents wherein said pharmaceutically active agent is selected from the group consisting of said agents wherein at least one of said agents having at least one acid moiety, and
at least one of said agents having at least one ester group or other chemically active moiety in which the terminal moiety to said ester group or other chemically active moiety is hydrolyzed or otherwise removed in situ or in vivo forming at least one acid moiety; and wherein said pharmaceutically active agent is soluble in acid at a ratio of about 3:1 (acid to solute) to about 10,000:1 (acid to solute) or a pharmaceutically acceptable salt thereof (hereinafter, the “Active Ingredient”);
at least one dispersing agent; and
at least one solubilizing agent; and, optionally,
at least one surfactant; and, further optionally,
at least one plasticizing agent.
The present invention further relates to the use of the compositions of the present invention for improving adsorption of the Active Ingredients and for minimizing the controllable side effects induced by such Active Ingredients, particularly the NSAIDs, where appropriate. Also provided are methods of using the compositions of the present invention wherein said composition comprises as an Active Ingredient at least one NSAID and, optionally a motility and/or antinausea agent, for the treatment of paroxysmal headaches, particularly migraine headaches.
DETAILED DESCRIPTION OF THE INVENTION
One aspect of the present invention provides compositions which are useful as oral, liquid medicaments which can also be used to fill soft capsules or solidified, as taught herein, to be used in hard capsules, particularly soft gelatin capsules and hard gelatin capsules, respectively, comprising
one or more pharmaceutically active agents wherein said pharmaceutically active agent is selected from the group consisting of said agents wherein at least one of said agents having at least one acid moiety, and
at least one of said agents having at least one ester group or other chemically active moiety in which the terminal moiety to said ester group or other chemically active moiety is hydrolyzed or otherwise removed in situ or in vivo forming at least one acid moiety; and wherein said pharmaceutically active agent is soluble in acid at a ratio of about 3:1 (acid to solute) to about 10,000:1 (acid to solute) or a pharmaceutically acceptable salt thereof (hereinafter, the “Active Ingredient”);
at least one dispersing agent; and
at least one solubilizing agent; and, optionally,
at least one surfactant; and, further optionally,
at least one plasticizing agent.
The Active Ingredients used in the present compositions are well known in the pharmaceutical art, are prepared via methods well known in the chemical and pharmaceutical arts, and include, for example, pharmaceutically active compounds as described above having at least one acid moiety wherein such acid moiety is, most preferably, a carboxylic acid. Other acid moieties are well known to one of ordinary skill in the art. Representative Active Ingredients include, for example, non-steroidal, anti-inflammatory drugs (NSAIDs) which are exemplified by the aralkylcarboxylic acids such as, for example, diclofenac, fenoprofen, flurbiprofen, ibu
Clark Christy M.
Desai Ashok J.
Meyer Glenn A.
Sancilio Frederick D.
Trespidi Laura A.
Fontana, Esq. Steven A.
Page Thurman K.
Tran S.
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