Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-10
2003-02-18
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S487000, C540S531000, C540S533000
Reexamination Certificate
active
06521613
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to compositions, components and methods useful in delivering pharmacologically active substances. More particularly, the invention relates to such compounds, compositions and methods for enhancing the penetration or transport of pharmacologically active substances transdermally, that is through the skin, or through a membrane, for example, the cornea and other tissue membranes. The invention also relates to methods of making such compounds.
There continues to be considerable interest in developing pharmaceutical compositions that can be administered topically either for local or systemic benefit. The skin is the largest and most accessible organ of the body, which makes it a particularly attractive target for drug delivery. With regard to systemic uses, the exposed surfaces of the body potentially offer pharmacological advantages, such as avoiding a first pass through the liver, affording greater control over dosage so as to permit the use of drugs having a relatively small therapeutic index, and avoiding side effects otherwise incurred through gastrointestinal delivery.
A principal obstacle to adopting wider use of topical delivery protocols is the barrier to drug penetration presented by external tissues, particularly in the outermost layer of dead keratinized cells. Use of increased dosages in order to overcome the barrier can have unacceptable side effects. A popular approach to penetrating this barrier has been with the use of surface active agents. However, these substances frequently damage the barrier tissue and often show only slight or moderate penetration enhancement. Organic solvents, such as dimethylsulfoxide, dimethylacetamide, and pyrrolidone have also been studied. However, these compounds are often systemically distributed in a short period of time and cause undesirable side effects.
A variety of penetration enhancement vehicles have been proposed over the years. These include amides of heterocyclic amines as described by Mirejovsky et al U.S. Pat. No. 4,743,588, polymers containing heterocyclic groups as described by Choi U.S. Pat. No. 4,246,397, and copolymers of polyvinyl acetate and polyvinyl pyrrolidone as described by Landrau et al U.S. Pat. No. 5,512,293. Permeation enhancers based on the monoalkylethers and alkyl or aryl esters of polyethylene glycol have been proposed, for example, by Lee et al. U.S. Pat. No. 6,004,578.
A further class of compounds studied for their solubilizing properties are the cyclic amides, also referred to as lactams. The lactams are particularly interesting because of the relatively high dipole moment possessed by these compounds. For instance, Login et al U.S. Pat. No. 5,294,644 disclose N-alkyl substituted lactams for use as surfactants. Such compounds can be made by reacting an alkali metal lactamate with an alkyl halide, as disclosed by Poulain U.S. Pat. No. 3,975,377, or by reacting a lactam with ethyleneoxide in the presence of a suitable basic catalyst, as described by Senda et al Japanese Patent 43-26176. N-alkyl substituted lactams, wherein the N-alkyl group contains a hydrolyzable organic acid moiety such as salicylic acid, have been proposed as carriers for biologically active agents by Narayanan et al U.S. Pat. No. 5,206,386. It has been suggested by Copes et al U.S. Pat. No. 3,988,318 that under some conditions, N-alkyl lactams can form complexes with phenols for use as germicides, antiseptic soaps, and emollients. Further, an emulsifier comprising a mixture of an N-alkyl lactam and a non-ionic surfactant, such as a polyethylene glycol alkyl ester, has been proposed by Chuang U.S. Pat. No. 5,280,092.
There continues to be a need to provide compounds, compositions and methods useful to increase the effectiveness of topical administration of pharmaceuticals.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, compositions, and methods for enhancing the transdermal or transmembrane transport of pharmacologically active substances. The invention also provides methods for making the present compounds. In short, the present invention is useful in the topical administration of pharmacologically active substances, and preferably increases or enhances the effectiveness of such topical administration. Advantageously, the present compounds, compositions and methods of use provide local and/or systemic benefits from pharmaceuticals, because of, for example, enhanced dosage control and reduced side effects. The methods of making the present compounds are relatively straightforward and cost effective to practice.
The present compounds contain a N-alkyl lactam moiety, and preferably are highly water soluble. Conventional N-alkyl lactams are not substantially soluble in water. However, the compounds of the present invention include a strongly hydrophilic non-ionic portion or tail bonded to the amide nitrogen atom of the lactam. Representative hydrophilic groups include polyalkyleneoxy chains, such as polyethylene glycol (PEG), which can have a terminal hydroxyl group or a terminal alkyl group.
In one broad aspect of the present invention, compounds are provided having a chemical formula as shown below:
wherein m is an integer in a range of 2 to about 6, n is an integer in a range of 1 to about 8, and R is selected from hydrogen, trimethylsilyl, or lower alkyl, preferably alkyl having 1 to 6 carbon atoms. In one embodiment, m preferably is 3.
In another broad aspect of the present invention, methods for making the present compounds are provided. In one embodiment, methods for making the present compounds in which R is selected from trimethylsilyl and lower alkyl comprise deprotonating a lactam and reacting the deprotonated lactam with a suitable polyalkyleneoxide having or including a leaving group to afford or yield the present compound. Although the polyalkyleneoxide may include any suitable leaving group, in one embodiment the leaving group is tosylate. The present trimethylsilyl (TMS) derivative can be employed as a convenient precursor for making the terminal hydroxyl derivative. For example, the TMS derivative can be hydrolyzed to generate the corresponding compound with a terminal hydroxyl group.
In further broad aspects of the present invention, compositions and methods for enhancing transdermal or transmembrane transport of pharmacologically active substances (medications or drugs) are provided. Such compositions comprise an effective amount of a pharmacologically active substance and at least one compound of the present invention in which R is selected from hydrogen and lower alkyl. The at least one compound is present in an amount effective to enhance the transdermal or transmembrane transport of the active substance in a similar composition without the at least one compound. The at least one compound may be present in any suitable, effective concentration, for example, effective to enhance transdermal and/or transmembrane transport of the active substance. The at least one compound preferably is present in the composition in an amount in a range of about 0.1% to about 50% by weight of the composition. Any suitable pharmacologically active substance or substances may be employed in the present compositions. Such substances preferably are pharmacologically effective when administrated transdermally and/or when administered by being passed through a membrane, for example, a tissue membrane.
Without wishing to be bound by any particular theory of operation, it is believed that the hydrophilic polyalkyleneoxy portion or tail bonded, for example, covalently bonded, to the nitrogen atom of the lactam increases the water solubility of the lactam group. The pharmacologically active substance, which may form one or more stable or transient complexes with the highly polar lactam moiety, in combination with the modified lactam shows enhanced penetration or transdermal or transmembrane transport when compared with a similar composition without the lactam moiety.
In yet another broad aspect of the present invention, methods for administering pharmacologi
Allergan Inc.
Kifle Bruck
Stout, Uxa Buyan & Mullins, LLP
Uxa Frank J.
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