Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-08-02
2002-04-30
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S454000, C549S220000
Reexamination Certificate
active
06380175
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to a method for enhancing the delivery of &Dgr;-9-tetrahydrocannabinol (“THC”) to the brain of a mammal in need of treatment with this drug, by administering water-soluble prodrugs of THC intranasally. More specifically, this invention relates to the enhancement of THC treatment by intranasal administration of water-soluble esters of THC. The invention is particularly useful as an anti-emetic, particulary to treat the nausea associated with anti-cancer chemotherapy.
BACKGROUND
The anti-emetic properties of THC are well-known. The lay press have advocated that marijuana (smoked) be made available for use as an anti-emetic, especially in cancer and AIDS patients who find it to be the only substance that controls their nausea while receiving chemotherapy. Unfortunately, marijuana smoke contains many of the carcinogenic substances that make tobacco smoke dangerous, and the toxicities associated with smoked marijuana are probably as great as those associated with tobacco smoking.
Oral THC is commercially available as the prescription product Marinol® Capsules. However, the oral absorption of THC from Marinol® Capsules is very slow and inefficient. It is estimated that less than half the oral dose of THC is absorbed, and the anti-emetic effects are not seen clinically until the second day after administration has begun. Thus, Marinol® Capsules are not useful unless taken chronically.
On the other hand, THC is rapidly and efficiently absorbed from marijuana smoke. It is likely that this rapid absorption is responsible for its clinical usefulness, i.e., a patient can offset nausea by smoking marijuana after the nausea begins to occur. The absorption of a variety of drugs with a variety of chemical structures from the nasal cavity of humans is known to produce blood concentrations similar to those observed following intravenous administration.
At room temperature, THC exists as a gummy, semisolid mass, which has very poor aqueous solubility. The physical properties of THC cause difficulties in the formulation of dosage forms suitable for human consumption. Certain dosage forms, e.g., injectables, cannot be prepared because of the physical nature of THC. The oral administration of THC is inefficient and highly variable resulting in an on-off therapeutic response and frequent serious side effects. There is a tremendous need for an improved dosage form for THC. Since THC is too insoluble in water, it cannot be administered nasally, transdermally, buccally, or sublingually.
In view of the foregoing, it is apparent that there exists a need in the art for improved methods of delivery of THC for treatment of nausea and prevention of emesis, in particular in connection with anti-cancer chemotherapy.
SUMMARY OF THE INVENTION
Accordingly, since THC is too insoluble in water to be used in conventional intranasal formulations, it is an object of the present invention to provide a method for alleviating nausea comprising intranasal administration of water soluble prodrugs of THC. The prodrug esters of THC described herein are sufficiently water-soluble to allow the formulation of any desired dosage form and are more readily absorbed into the systemic circulation, i.e., are more bioavailable than THC itself.
An intranasal dosage form containing a water-soluble prodrug ester of THC that would rapidly deliver an effective does of THC to the blood following administration would have the same anti-emetic benefits as marijuana smoke but without the toxicities associated with smoke products.
It is a further aspect of this invention to provide a method for administering THC in a manner which significantly enhances plasma levels of THC, and thus its bioavailability, compared to prior art methods.
It is a further aspect of this invention to provide a method for administering THC which provides for enhanced delivery of THC directly to the central nervous system, its intended site of action.
In addition to intranasal dosage forms, the prodrug esters described in the present application also lend themselves to formulation into dosage forms designed to be administered orally, by injection, transdermally, or by any other conceivable routes. In particular, water-soluble derivatives that exist as crystalline solids would lend themselves readily to formulation into oral tablets, capsules, and liquids.
It is a still further aspect of this invention to provide a method for administering THC which minimizes the side-effects associated with conventional THC administration. This object has been achieved in the present invention by the nasal administration of water-soluble esters of THC.
It is a still further aspect of this invention to provide a method for administering THC which is equal or superior to intravenous administration in many respects, including effectiveness, but which avoids many of the problems associated with the intravenous route, including the “on-off effect,” combined with superior ease of administration.
A further aspect of this invention is to provide a pharmaceutical composition suitable for intranasal administration, for treatment of nausea and emesis, particularly associated with anti-cancer chemotherapy. Accordingly, a composition according to the present invention comprises a water-soluble prodrug of THC and a pharmaceutically acceptable carrier therefor.
With the foregoing and other objects, advantages and features of the invention that will become hereinafter apparent, the nature of the invention may be more clearly understood by reference to the following detailed description of the preferred embodiments of the invention and to the appended claims.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION
The present inventors have discovered a novel method for the treatment of nausea and prevention of emesis, by the intranasal administration of a water-soluble prodrug of THC. This method offers significant clinical advantages over the prior art. More specifically, the inventors sought to provide a safe, effective and convenient treatment for nausea and vomiting associated with anti-cancer chemotherapy which comprises the administration of water-soluble prodrugs of THC intranasally, thus avoiding the side-effects associated with oral dosage forms.
A prodrug is a compound formed by chemical modification of a biologically active compound which will liberate the active compound in vivo by enzymatic or hydrolytic cleavage. Advantages of this approach include reduction of general cytotoxicity, better bioavailability of active drug or longer duration of action. Any water soluble prodrug of THC is useful in the practice of this present invention.
The inventors have found that intranasal administration of esters of THC, i.e., prodrugs of THC, are particularly preferred in the practice of the present invention. Intranasal administration of these compounds is as effective as oral or intravenous administration of THC, but may be conveniently and painlessly self-administered by the patient.
Preferred THC esters include alkyl, cycloalkyl, and aryl esters, particularly methyl, butyl, pentyl, cyclohexyl, and benzyl esters, and pharmaceutically acceptable salts thereof.
Pharmaceutically acceptable salts of an acid group or an amino group include, but are not limited to, salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, isothionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-tolylsulfonic acids, and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
In a preferred embodiment, a compound according to the present invention is a THC amine-ester prodrug having, for example, a structure according to Formula (I)
wherein
n=1 to 10; and
R
1
and R
2
are both alkyl, or together are members of a saturated ring.
In an alternative embodiment, a compound according to the present invention is a hemiester THC prodrug having, for example, a structure according to Formula (II):
wherein n 1 to 10.
In another alternative embodi
Dittert Lewis W.
Hussain Anwar A.
Qaisi Ali M.
Traboulsi Ashraf
Burns Doane , Swecker, Mathis LLP
Henley III Raymond
New Millennium Pharmaceutical Research Inc.
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