Title:  Therapeutic compositions for intranasal administration which include KETOROLAC.RTM.

United States Patent:  6,333,044

Assignee:  Recordati, S.A. Chemical and Pharmaceutical Company (Chiasso, CH)

Filed:  February 1, 1995

Foreign Application Priority Data:  Jul 22, 1991[IT] (MI91A2024)

An analgesic/anti-inflammatory pharmaceutical dosage form which comprises an effective amount of an active ingredient selected from the group consisting of racemic 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, optically active forms thereof and pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable excipient or diluent, said dosage form being an intranasally administrable dosage form.

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, .beta.-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.RTM. 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.RTM., as demonstrated in tests involving rabbits. The predictive value of the rabbit model with respect to bioavailability of nasally administered KETOROLAC.RTM. 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.RTM. 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.RTM.), hydroxypropyl methyl cellulose (METHOCEL.RTM.), hydroxyethyl cellulose (NATROSOL.RTM.), sodium carboxymethyl cellulose (BLANOSE.RTM.), acrylic polymers (CARBOPOL.RTM., POLYCARBOPHIL.RTM.), gum xanthan, gum tragacanth, alginates and agar-agar.

Some of them, such as sodium carboxymethyl cellulose and acrylic polymers, have marked bioadhesive properties and are preferred if bioadhesiveness is desired.

Other formulations suitable for intranasal administration of KETOROLAC.RTM. can be obtained by adding to the aqueous vehicle polymers capable of changing the rheologic behavior of the composition in relation to the temperature. These polymers make it possible to obtain low viscosity solutions at room temperature, which can be applied for instance by nasal spray and which increase in viscosity at body temperature, yielding a viscous fluid which ensures a better and longer contact with the nasal mucous membrane. Polymers of this class include without limitation polyoxyethylene-polyoxypropylene block copolymers (POLOXAMER.RTM.).

In addition to aqueous, oil or gel vehicles, other vehicles which may be used in the compositions according to the invention comprise solvent systems containing ethyl alcohol, isopropyl alcohol, propylene glycol, polyethylene glycol, mixtures thereof or mixtures of one or more of the foregoing with water.

In any case, a pharmaceutically acceptable buffer should be present in order to create optimum pH conditions for both product stability and tolerance (pH range about 4 to about 8; preferably about 5.5 to 7.5). Suitable buffers include without limitation tris (tromethamine) buffer, phosphate buffer, etc.

Other excipients include chemical enhancers such as absorption promoters. These include chelating agents, fatty acids, bile acid salts and other surfactants, fusidic acid, lysophosphatides, cyclic peptide antibiotics, preservatives, carboxylic acids (ascorbic acid, amino acids), glycyrrhetinic acid, o-acylcarnitine. Preferred promoters are diisopropyladipate, POE(9) lauryl alcohol, sodium glycocholate and lysophosphatidyl-choline which proved to be particularly active. Finally, the new compositions according to the invention preferably contain preservatives which ensure the microbiological stability of the active ingredient. Suitable preservatives include without limitation, methyl paraoxybenzoate, propyl paraoxybenzoate, sodium benzoate, benzyl alcohol, benzalkonium chloride and chlorobutanol.

The liquid KETOROLAC.RTM. formulations, preferably in the form of solutions, may be administered in the form of drops or spray, using atomizers equipped with a mechanical valve and possibly including a propellant of a type commercially available, such as butane, N₂, Ar, CO₂, nitrous oxide, propane, dimethyl ether, chlorofluorocarbons (e.g. FREON) etc. Vehicles suitable for spray administration are water, alcohol, glycol and propylene glycol, used alone or in a mixture of two or more.

Generally, illustrative formulations will contain the following ingredients and amounts (weight/volume):

Claim 1 of 51 Claims

What is claimed is:

1. An analgesic/anti-inflammatory pharmaceutical liquid dosage form which comprises a systemically effective amount of an active ingredient selected from the group consisting of racemic 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, optically active forms thereof and pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable excipient or diluent, said dosage form being a non-thermosetting intranasally administrable transmucosally rapidly absorbable dosage form that achieves blood levels in a host effective for analgesic or anti-inflammatory use after intranasal administration.

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