Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1995-02-01
2001-12-25
Dudash, Diana (Department: 1619)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C514S947000, C514S413000
Reexamination Certificate
active
06333044
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to therapeutic compositions with analgesic and anti-inflammatory activity, suitable for intranasal administration, which include KETOROLAC® or its pharmaceutically acceptable salts as the active ingredient.
This invention also relates to a therapeutic method which provides for the administration of KETOROLAC® or its salts by the intranasal route.
BACKGROUND OF THE INVENTION
KETOROLAC® or 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, the formula of which is:
has been known for several years (U.S. Pat. No. 4,089,969) and is used in human therapy as an analgesic and an anti-inflammatory.
Both the racemic form and each of the dextro and levo isomers of this compound are known. Many pharmaceutically acceptable salts, the most commonly used of which is the tromethamine(2-amino-2-hydroxymethyl-1,3-propanediol) salt, are also known. Hereinafter, the name KETOROLAC® shall encompass individually or collectively the racemic mixture or either optically active compound and shall encompass the free acid as well as the tromethamine salt or any other pharmaceutically acceptable salt of any one of the foregoing.
Ample literature is available on KETOROLAC® (for instance, “KETOROLAC®—A review of its pharmacodynamic and pharmacokinetic properties and its therapeutic potential”,
Drugs
39(1): 86-109, 1990. It is described as a drug with considerably higher analgesic and anti-inflammatory activity than many other non-steroid anti-inflammatory drugs. Most significantly, it has higher analgesic activity than morphine, without the well-known side effects of the latter.
In the several pharmacological and clinical trials involving KETOROLAC® that have been conducted, this drug was administered both by the oral route and by injection (in turn, both intravenous and intramuscular). Regardless of the administration route, KETOROLAC® proved active and was found comparatively more active than the better known non-steroid drugs with analgesic and anti-inflammatory activity. However, about 10% of the patients treated (20 doses of 30 mg each administered over five days) by the intramuscular route suffered from one or more undesirable side effects such as somnolence, local (injection site) pain, sweating, nausea, headache, dizziness, vomiting, pruritus, and vasodilation.
The incidence of side effects was even higher (around 32%) in the patients treated with KETOROLAC® by the oral route for a few days. In the case of oral administration, gastrointestinal disorders (nausea, g.i. pain, dyspepsia, diarrhea, flatulence, g.i. fullness, vomiting) were noted in up to 50% of the patients in addition to side effects incident to i.m. administration.
Intravenous administration is inconvenient and is limited to the treatment of acute conditions.
On the whole, the data available to date clearly describe a drug which is very active, but still unsatisfactory from the point of view of convenience of administration and/or side effects.
SUMMARY OF THE INVENTION
We have now found that it is possible to prepare Analgesic/anti-inflammatory formulations containing KETOROLAC® as an active ingredient, which are suitable for intranasal administration and that KETOROLAC® so administered is rapidly and thoroughly absorbed, giving therapeutic effects equivalent to those obtained by the intravenous route (acute treatments) or the intramuscular or oral routes (extended or chronic treatments), without inducing severe side effects. Most important, any possibility of gastrointestinal disorders is excluded, while disorders caused by CNS stimulation are considerably reduced both in incidence (e.g. number of patients affected) and intensity.
Another aspect of the present invention is directed to a therapeutic method for the treatment of inflammatory processes and for the therapy of pain of a traumatic or pathologic origin, which method comprises administering by the intranasal route an analgesic/anti-inflammatory amount of KETOROLAC® along with an absorption promoter and pharmaceutically acceptable diluents and/or excipients.
The new method provides for the intranasal administration of KETOROLAC® doses ranging between 0.5 and 40 mg, preferably between 5 and 30 mg, and is particularly effective in acute therapies, where a very rapid systemic delivery is required especially one not accompanied by the drawbacks of i.v. delivery (hospitalization, cost, etc.).
DETAILED DESCRIPTION OF THE INVENTION
All cited patents and literature are incorporated by reference in their entirety.
Although nasal administration to mammals (especially humans) of certain therapeutic agents is known, it is not to be presumed that all therapeutic agents can be effectively administered by this route. To the contrary, many therapeutic agents cannot be nasally administered. At present, the molecules which have proved suitable for this route of administration are still very few and consist essentially of only small peptide or hormone molecules (such as calcitonin, cerulean, &bgr;-endorphin, glucagon, horseradish peroxidase, B-interferon, oxytocin and insulin) in special formulations. The ability of drug molecules to be absorbed by the nasal mucous membranes is utterly unpredictable, as is the ability of intranasal formulations to avoid irritation of the mucous nasal membranes. In fact, mucous membrane irritation caused by the drug and/or excipient is the most common reason for which intranasal administration has not gained wider acceptance.
The new compositions according to the invention include the active ingredient in quantities ranging from 0.5 to 40 mg per dose, preferably 5 to 30 mg per dose, diluted in excipients such as humectants, isotoning agents, antioxidants, buffers and preservatives. A calcium chelating agent is also preferably included.
The intranasal formulations of the invention contain KETOROLAC® concentrations ranging from 5 to 20%, preferably about 15% weight/volume. Of course, the selection of the particular excipients depends on the desired formulation dosage form, i.e. on whether a solution to be used in drops or as a spray (aerosol) is desired or a suspension, ointment or gel to be applied in the nasal cavity are desired. In any case, the invention make it possible to have single-dose dosage forms, which ensure application of an optimum quantity of drug.
Administration of the present intranasal formulations provides very good absolute bioavailability of KETOROLAC®, as demonstrated in tests involving rabbits. The predictive value of the rabbit model with respect to bioavailability of nasally administered KETOROLAC® in humans is art-recognized (Mroszczak, E. J. et al.,
Drug Metab. Dispos.,
15:618-626, 1987, especially Tables 1 and 3). According to the results of the rabbit tests set forth below it is extrapolated that in humans intranasal administration of a composition according to the invention in amounts ranging between 0.5 mg/kg/day and 4 mg/kg/day will generate plasma levels of KETOROLAC® within the range of 0.3-5 mg/liter of plasma.
Suitable vehicles for the formulations according to the invention include aqueous solutions containing an appropriate isotoning agent selected among those commonly used in pharmaceutics. Substances used for this purpose are, for instance, sodium chloride and glucose. The quantity of isotoning agent should impart to the vehicle (taking into account the osmotic effect of the active ingredient), an osmotic pressure similar to that of biological fluids, i.e. generally from about 150 to about 850 milliOsmoles (mOsm) preferably from about 270 to about 330 mOsm.
However, it is known that nasal mucous membranes are also capable of tolerating slightly hypertonic solutions. Should a suspension or gel be desired instead of a solution, appropriate oily or gel vehicles may be used or one or more polymeric materials may be included, which desirably should be capable of conferring bioadhesive characteristics to the vehicle.
Several polymers are used in pharmaceutics for the preparation of a gel; the following can be mentioned as nonlimiting examples: hydroxypropyl cellulose (KLUCEL®
Bilato Ettore
Bottoni Giuseppe
Santus Giancarlo
Darby & Darby
Dudash Diana
Ostrup Clinton
Recordati S.A. Chemical and Pharmaceutical Company
LandOfFree
Therapeutic compositions for intranasal administration which... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Therapeutic compositions for intranasal administration which..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Therapeutic compositions for intranasal administration which... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2579927