Transdermal formulations

Details Transdermal formulations Transdermal formulations

1994-03-15

1997-03-18

Phelan, D. Gabrielle

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Web, sheet or filament bases; compositions of bandages; or...

424448, 514947, A61F 1300

Patent

active

056120567

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to prophylactic and therapeutic formulations having improved skin penetration efficacy, being particularly useful in the delivery of acetylcholinesterase (AchE) inhibitors of the carbamate base type, more particularly of the physostigmine type.
The carbamates pyridostigmine and physostigmine are non-competitive inhibitors of acetylcholinesterase but have the property of dissociating from that enzyme such that after a relatively short period, eg. about 15 minutes, significant reactivated esterase activity is achieved. This effect is in stark contrast to that of organophosphate nerve gents, such as sarin and tabun, which chemically alter the esterase active site, permanently destroying esterase activity and thus the cholinergic systems concerned.
It has been found that a prophylactic dose of such carbamates can be used to protect a proportion of a subject's acetylcholinesterase against interaction with organophosphates (OPs) by virtue of their ability to block the enzyme active site. While a treated subject may lose consiousness or suffer other symptoms when challenged with organophosphate it is found that the proportion of esterase protected by the physostigmine can be sufficient to prevent death, as and when it is released from blockade by the carbamate dissociating from it.
Obviously, for long term anticholinesterase protection or other long term reversable inhibition treatments a sustained release formulation would be required. An oral sustained release formulation would reduce the frequency of administration while providing a convenient dosage method which requires no special equipment. So far no satisfactory formulation has emerged to achieve this modest aim.
The carbamate in current use as a nerve agent prophylaxis is pyridostigmine and it is used in tablet form. Pyridostigmine does not cross the blood brain barrier and consequently provides no central nervous protection. The same chemical property which prevents pyridostigmine from entering the brain, its positive charge, will prevent it from penetrating the skin. Physostigmine however, carries no charge and is an ideal candidate for transdermal delivery. However physostigmine has a short plasma half life and a narrow therapeutic index which necessitates the use of a sustained release formulation.
While it is known to administer physostigmine by injection an attractive alternative route for administering protective doses is the transdermal route using a patch bearing a suitable transdermal delivery composition. A known such physostigmine delivery composition is disclosed by GB 2163347 A and comprises a 50% wt.:vol. mix of physostigmine with propionic acid. Recent work to find a treatment for Alzheimers disease (Christie et al; Br. J. Psychiatry, 138 46-50 (1981)) has identified such transdermal formulations which deliver physostigmine at therapeutically useful doses and a further recent study (Pardo et al; J. Pharm. Sci. 79 p573-578 (1990)) has shown that the thermodynamic activity of physostigmine, which drives the diffusion of drug into the skin, is highest from a binary vehicle of isopropyl myristate and isopropyl alcohol (9:1; vol./vol.).
These composition may be used to treat a variety of cholinergic nervous system disorders but when applied to the dosage requirements of organophosphate (OP) poisoning it is found that inconveniently large patch sizes are necessary. Furthermore, the large Mounts of physostigmine that must be provided on such patch may prove fatal should the wearer suffer a skin lesion, such as a penetrating wound, at the site of the patch.
The present invention provides improved compositions which enable increased amounts of basic compounds to be delivered transdermally per unit compound in the patch. Most beneficially the compositions are applied to delivery of basic compounds of non-ionic form, ie. those not committed to being ionised by way of, eg. quaternarised nitrogen groups. Thus use of the present compositions allows a reduction in the amount of compound required in a patch with the accompany

REFERENCES:
patent: 4294852 (1981-10-01), Wildnauer
patent: 5350581 (1994-09-01), Kochinke
patent: 5352457 (1994-10-01), Jenkins
patent: 5391375 (1995-02-01), Hille
J. of Pharmaceutical Sciences/ 409 vol. 77, No. 5, May 1988 Kadir "Penetration of Adenosine into Excised Human Skin from Binary Vehicles: The Enhancement Factor".

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