WO1993011767A1

WO1993011767A1 - Transdermal delivery of (e)-1,2,5,6-tetrahydro-1-methyl-3-pyridine-carboxaldehyde-o-methyloxine hcl and related compounds in the treatment of cognitive disorders and for analgesia

Info

Publication number: WO1993011767A1
Application number: PCT/US1992/009990
Authority: WO
Inventors: Majid Mahjour; Zhara Rashidbaigi; Galen Radebaugh
Original assignee: Warner Lambert Co LLC
Current assignee: Warner Lambert Co LLC
Priority date: 1991-12-18
Filing date: 1992-11-18
Publication date: 1993-06-24
Anticipated expiration: 1994-06-18
Also published as: AU3142793A; MX9207389A; PT101138A; ZA929784B

Abstract

Transdermal formulations containing O-substituted-1,2,5,6-tetrahydro-3-pyridine oximes or O-substituted-1,2,3,6-tetrahydro-4-pyridine oximes are disclosed. Methods of treating cognitive disorders and affecting analgesia using the transdermal formulations are also disclosed.

Description

TRANSDERMAL DELIVERY OF (E)-l,2,5,6-TETRAHYDR0-l-METHYL-3-PYRIDINE- CARBOXALDEHYDE-O-METHYLOXINE HCL AND RELATED COMPOUNDS IN THE TREATME OF COGNITIVE DISORDERS AND FOR ANALGESIA

The present invention is directed to transdermal delivery of 0-substituted-l,2,5,6-tetrahydro-3-pyridine oximes or O-substituted-1,2,3,6-tetrahydro-4-pyridine oximes (TOM compounds) and their pharmaceutically acceptable bases and salts.

TOM compounds are useful in treating disorders of cognition, memory loss, Huntington's Chorea, tardive dys inesia, senile dimensia, Alzheimer's Disease and the like. TOM compounds are also useful analgesics. The us of TOM compounds in oral and injectable dosage forms is disclosed in commonly-assigned U.S. Patent Nos. 4,710,50 and 4,786,648. The disclosure each of these patents is incorporated by reference herein. While oral and parenteral formulations are effective, alternative means of delivering therapeutic amounts of these biologically active compounds have been sought, particularly, via the transdermal route.

Transdermal drug delivery is a diffusion process whereby a therapeutic agent travels from a reservoir int and through the skin of a mammal. Transdermal delivery offers several advantages over other routes of administration. For example, transdermal administration avoids the gastrointestinal disturbances associated with the oral administration of some medications. Transderma administration also substantially avoids the "first pass" effect of liver metabolism, thus reducing the amount of active required to achieve the desired therapeutic result. In addition, most transdermal systems are designed to deliver an active over extended periods of time, and, therefore, remove the need to take several daily doses of a medicine. This effect enhances patient compliance with therapeutic regimens. The very nature of cognitive disorders dictates that compliance with treatment regimens involving self- administration of multiple oral doses can hardly be assured. In the institutional setting, multiple parenteral administrations are not only uncomfortable for the patient but also require substantial expenditure of skilled nursing time.-

TOM compounds, however, pose particular problems when included in transdermal type delivery systems. TOM compounds tend to be rather volatile and there is concern about whether transdermal systems can contain, maintain during storage, and deliver sufficient amounts of a TOM compound.

Accordingly, in view of the foregoing, it would be advantageous to be able to effectively deliver TOM compounds transdermally. This route of administration would offer a useful alternative when the oral and parenteral routes are unavailable or impractical. Transdermal systems delivering TOM compounds over an extended time would also be advantageous in the treatment of cognitive disorders to assure that proper dosage levels were maintained in both self administration and institutional settings.

It is, therefore, an object of the present invention to provide transdermal delivery systems for TOM compounds.

It is a further object of the present invention to provide methods of treatment by transdermally administering TOM compounds. SϋMMARY OF THE INVENTION

The present invention includes a transdermal delivery system for delivering effective amounts of 0- substituted-1,2,5,6-tetrahydro-3-pyridine oximes, 0- substituted-l,2,3,6-tetrahydro-4-pyridine oximes, their pharmaceutically acceptable bases, acid addition salts and mixtures thereof. In a preferred embodiment, the delivery system includes (E)-1,2,5,6-tetrahydro-l-methyl 3-pyridine-carboxaldehyde-0-methyloxime monohydrochloride. The effective amounts of TOM compounds range from about 0.001 mg. to about 100 mg. pe kg. of body weight per day and preferably from about 0.001 mg. to about 1 mg. per kg. of body weight per day.

Transdermal delivery systems containing the TOM compounds may be of the reservoir-type or, preferably, the adhesive matrix-type where the TOM compound is dispersed in a matrix formed with an acrylic polymer adhesive.

In further embodiments, there are provided methods of treating cognitive disorders and, separately, affecting analgesia. The methods include transdermal administration of effective amounts of TOM compounds to achieve the treatment goal.

As a result of the present invention, effective amounts of TOM compounds can be delivered transdermally. The transdermal systems provide a useful and advantageou alternative route of administration. Moreover, the transdermal devices of tit* present invention need not contain permeation enhancers to deliver TOM compounds. Although permeation enhancers are useful adjuncts in man transdermal systems in assisting the penetration of the active through the skin, the enhancers are known to caus local irritation. Permeation enhancers can also negatively effect the predictability of release of some therapeutic agents.

When the TOM compounds are included in the preferred adhesive matrix-type transdermal delivery system, the adhesive matrix environment has been found to surprisingly exert a stabilizing effect on the inherently volatile TOM compounds.

For a better understanding of the present invention, together with other and further objects, reference is made to the following description, and its scope will be pointed out in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The transdermal delivery systems of the present invention effectively deliver TOM compounds and their related pharmaceutically acceptable analogs. The invention is based in part on the fact that the human skin is essentially a semi-permeable membrane-type barrier and that certain chemical compounds can cross the barrier and then be assimilated into the blood stream. It has been discovered that TOM compounds can be effectively delivered using this route.

The TOM compounds included in the present invention are selected from the 0-substituted-l,2,5,6-tetrahydro-3- pyridine oximes or 0-substituted-l,2,3,6-tetrahydro-4- pyridine oximes, their pharmaceutically acceptable bases and salts. In a preferred embodiment, the compound included in the transdermal delivery system is (E)- 1,2,5,6-tetrahydro-l-methyl-3-pyridine-carboxaldehyde-O- methyloxime monohydrochloride. Illustrative TOM compounds, their methods of preparation and dosages are disclosed and commonly assigned U.S. Patent Nos. 4,786,648 and 4,710,508, the disclosures of which are incorporated herein by reference.

The transdermal delivery systems prepared in accordance with the present invention include an effective amount of one or more TOM compounds. By the term "effective amount", it is understood that such an amount is sufficient to provide the desired result, that is, treatment of cognitive disorders and/or affecting analgesia. In this regard, transdermal delivery systems include an amount of from about 0.001 mg. to about 100 mg. per kg. of body weight per day of one or more TOM compounds. In a preferred embodiment, the transdermal delivery system delivers the TOM compound(s) in amounts of from about 0.001 mg. to about 1 mg. per kg. of body weight per day.

The transdermal delivery systems of the present invention, in the broadest sense, are diffusion delivery devices. As such, the devices contain at least one reservoir from which an active ingredient may diffuse. Generally, the devices allow an active to be stored for suitable periods without loss of potency and permit transdermal diffusion of the active through a selectively permeable membrane that is placed in contact with the skin.

In a preferred embodiment, the transdermal delivery system of the present invention includes one or more TOM compounds dispersed in an adhesive matrix-type transdermal system. Such adhesive matrix systems have been found to afford additional stability for volatile actives. The adhesive matrix includes an acrylic polymer adhesive, the TOM compound and a stabilizer that is laminated onto an inert impermeable film backing.

The acrylic polymer adhesive included in the matrix can be selected from one of several related types. Preferably, the adhesive is a vinyl acetate-ethylene acrylate polymer commercially known as Flexcryl^®, manufactured by Air Products, Inc. of Allentown, PA. This hydrous emulsion contains the polymer in ratios of from about 30% to about 60% solids. The adhesive, in turn, makes up from about 70% to about 99% and preferably from about 90 to about 97% of the adhesive-TOM compound matrix. Other suitable acrylate polymer adhesives are available as organic solvents and include, for example, ethyl hexyl acrylate, butyl acrylate and ethyl acrylate such as those available from National Starch, Inc. of Bridgewater, New Jersey and the 3M Company of Minneapolis, Minnesota.

The adhesive matrix includes from about 0.1 to about 30% by weight of the TOM compound. Preferably, the compound is present in an amount of from about 0.5 to about 5.0% by weight, and most preferably in an amount of about 3.0% by weight of the combined adhesive matrix.

Stabilizing agents such as butylated hydroxytoluene may also be included in the transdermal delivery system of the present invention. Such stabilizing agents may be present in amounts of from about 0.05 to 0.2% w/w of the final mixture. Other suitable stabilizing agents useful in the practice of the present invention are ascorbyl palmitate and ferrous oxide. Auxiliary acid stabilizers such as short chain fatty acids, (8-22 carbons) , such as linoleic acid, L-tartaric acid, hydrochloric acid or salicylic acid may be added to the TOM compound/acrylate adhesive matrix in amounts of from about 0.1% to about 10% w/w to further stabilize the TOM compound.

An emulsion thickener may be included to firm up the TOM-acrylate matrix which, upon addition of water or organic solvent, becomes quite viscous. Suitable thickeners are polyvinyl pyrrolidone, hydroxyethylcellulose, hyroxypropylmethylcellulose and mixtures thereof. Such thickeners can be present in amounts of from about 0.5 to about 5.0% w/w of the adhesive matrix composition along with an additional solvent such as water, in amounts of from about 3.0 to about 7.0% w/w and/or ethyl alcohol (USP) in amounts of from about 3.0 to about 6.0% w/w to incorporate the stabilizers and emulsion thickener. Gelling agents such as silicone dioxide may also be used in amount of from about 0.1 to about 10% by weight. Neither the acid stabilizer nor the emulsion thickener are required components in the delivery system of the present invention, but, the presence of one requires the presenc of the other.

The present invention also includes a method of preparing a transdermal delivery system for delivering one or more TOM compounds. The method includes preparin an adhesive matrix which includes combining an acrylic polymer adhesive, one or more TOM compounds and a stabilizer. The resulting adhesive emulsion or organic adhesive solvent mixture is laminated onto the inert impermeable film backing such as aluminum polyester or aluminum polyethylene polyvinyl acetate. Heat is applie to the adhesive matrix laminate to evaporate any solvent contained therein. Finally, a removable release liner i laminated over the exposed surface of the dried adhesive matrix.

Preferably, any auxiliary acid stabilizer, the emulsion thickener and primary stabilizer are first dissolved in the water and/or ethyl alcohol (USP) respectively, and later added to the vinyl acetate- ethylene acrylate polymer to create a wet adhesive mixture. The TOM compound is incorporated and uniformly dispersed throughout the polymer by stirring, agitation and the like. The resulting matrix is spread over an inert impermeable backing, such as aluminum polyester or aluminum polyethylene polyvinyl acetate, such as that available from the 3M Company of Minneapolis, Minnesota, and dried at a temperatures ranging from about 45 to about 55^βC to remove any excess water and alcohol until the surface is firm, dry and tacky. In order to prevent oxidation of the TOM compound during storage, as well as prevent or limit reactions with other elements, an impermeable inert silicone or fluorocarbon-coated release layer can be laminated over the dry TOM compound-polymer matrix. In use, the release layer is peeled off just prior to the patch being applied to the skin.

Although the transdermal delivery system of the present invention is preferably included as part of an affixable membrane or patch, alternative delivery devices, such as films, swabs, creams, gels, ointments and like, are also contemplated.

EXAMPLEB

The following Examples serve to provide further appreciation of the invention but are not meant in any way to restrict the effective scope of the invention.

EXAMPLE 1

In this Example, a transdermal delivery system containing the TOM compound (E)-1,2,5,6-tetrahydro-l- methyl-3-pyridine-carboxaldehyde-0-methyloxime monohydrochloride is prepared according to the formula set forth below.

TABLE 1

INGREDIENT WEIGHT PART

TOM compound 0.2-3

Vinyl acetate-ethylene acrylate adhesive 98.7-95.9 Butylated hyroxytoluene 0.1

Ethyl alcohol (USP) l.o

The TOM compound is homogeneously blended with the vinyl acetate-ethylene acrylate adhesive. Separately, the butylated hyroxytoluene is dissolved in the ethyl alcohol and combined with the TOM/acrylate adhesive matrix. The resultant viscous adhesive matrix is spread on an impermeable aluminum polyester film backing. The coated sheet is dried at a temperature of about 45-55°C until firm yet sticky and a silicone-based release liner is laminated over the exposed TOM-acrylate polymer matrix. The laminated TOM-acrylate sheet is cut into patches having about an inch diameter and packaged into moisture and oxygen impermeable packaging material.

Upon need, the patches are removed from the package material, the silicone-based release layer is peeled away and the exposed TOM-acrylate surface is placed onto the skin where the TOM compound is delivered over a 24 hour period.

EXAMPLE 2

A transdermal system containing the TOM compound (E)-1,2,5,6-tetrahydro-l-methyl-3-pyridine- carboxaldehyde-O-methyloxime monohydrochloride is prepared according to the formula set forth below.

TABLE 2

INGREDIENT

TOM compound Butyl acrylate solution Butylated hydroxytoluene Ethyl alcohol (USP) Polyvinyl pyrrolidone linoleic acid Water

The TOM compound is blended with the butyacrylate solution until the active is uniformly dispersed throughout the solution. Separately, butylated hydroxytoluene and linoleic acid is dissolved in ethyl alcohol and thereafter the polyvinyl pyrrolidone is added as a matrix thickening agent. The PVP-butylated hydroxytoluene-alcohol-linoleic acid mixture is then added to and thoroughly mixed with the TOM-acrylate adhesive. Once blended, the aqueous acid solution is added to the adhesive matrix and mixed. The formulation is then spread on an aluminum polyester backing, dried as set forth in Example 1 and laminated with a silicone- based release liner. The TOM compound patches are thereafter cut into circular patches and packaged as set forth above. EXAMPLES 3 - 6

In these Examples, .in vitro permeation studies of the TOM compound (E)-1,2,5,6-tetrahydro-l-methyl-3- pyridine-carboxaldehyde-O-methyloxime in both the monohydrochloride and base form were undertaken. In each of the Examples below,. 10% w/w solutions of the respective TOM compound were prepared and the permeation of the compound across full thickness human skin was recorded (N=l) .

As can be seen from Table 3 above, TOM compounds traverse human skin barriers. Further, sufficient amounts of TOM compounds traverse the semi-permeable membrane without permeation enhancers. Table 3 also shows that TOM compounds are deliverable through the skin from both aqueous and non-aqueous vehicles as well as in the hydrochloride and base forms.

Example 3 demonstrates that the hydrochloride form of the TOM compound in an aqueous vehicle has a relatively low level of permeation rate. Thus, transdermal systems containing a TOM compound in the hydrochloride form and dispersed in an aqueous vehicle would deliver relatively low levels of the drug over a one day period. In contrast thereto, in Example 4, the base form of the TOM compound also in a water vehicle was found to have an over 120 times greater average flux value, given the same 10% w/w solution.

Examples 5 and 6 demonstrate the ability of TOM compounds to traverse human skin from non-aqueous vehicles. In Example 5, the base form TOM compound was placed in a mineral oil vehicle and delivered 13080 μg/cm over a 24 hour period, (545 μg/cm²/h of TOM x 24 hours) . In Example 6, the base form of the drug demonstrated adequate flux from a triacetin vehicle. The delivery approximated the delivery pattern observed with the hydrochloride form shown in Example 3.

The foregoing in vitro permeation studies show that TOM compounds can be successfully delivered transdermally in a variety of forms such as hydrochloride salts and bases and from a variety of vehicles. The skilled artisan therefore has the option of both the form of the drug and vehicle to achieve a desired flux rate.

While there have been described what are presently believed to be the preferred embodiments of the invention, those skilled in the art will realize that changes and modifications may be made thereto without departing from the spirit of the invention, and it is intended to claim all such changes and modifications as fall within the true scope of the invention.

Claims

WHAT IS CLAIMED IS;

1. A transdermal delivery system, comprising: a compound selected from the group consisting of 0-substituted-l,2,5,6-tetrahydro-3-pyridine oximes, 0- substituted-1,2,3,6-tetrahydro-4-pyridine oximes, their pharmaceutically acceptable bases, acid addition salts and mixtures thereof.

2. The delivery system of Claim 1, wherein said compound is (E)-1,2,5,6-tetrahydro-l-methyl-3-pyridine- carboxaldehyde-O-methyloxime monohydrochloride.

3. The delivery system of Claim l, wherein said compound is present in an amount of from about 0.001 mg. to about 100 mg. per kg. body weight per day.

4. The delivery system of Claim 3, wherein said compound is present in an amount of from about 0.001 mg. to about 1 mg. per kg. body weight per day.

5. The delivery system of Claim 1, wherein said compound is dispersed in an adhesive matrix.

6. The delivery system of Claim 5, wherein said adhesive matrix comprises an acrylic polymer adhesive.

7. The delivery system of Claim 6, wherein said acrylic polymer adhesive is selected from the group consisting of vinyl acetate-ethylene acrylate, ethyl hexyl acrylate, butyl acrylate, ethyl acrylate and mixtures thereof.

8. The transdermal delivery system of claim 7, further comprising a stabilizer present in an amount of from about 0.05 to about 0.2% by weight of said adhesive matrix formulation.

9. The transdermal delivery system of Claim 8, wherein said stabilizer is selected from the group consisting of butylated hydroxytoluene, ascorbyl palmitate, ferrous oxide and mixtures thereof.

10. The transdermal delivery system of Claim 9, wherein said compound is present in an amount of from about 0.1 to about 30% by weight of said adhesive matrix.

11. The transdermal delivery system of Claim 10, wherein said compound is present in an amount of from about 0.5 to about 5.0% by weight of said adhesive matrix.

12. The transdermal delivery system of Claim 10, wherein said compound is present in an amount of about 3.0% by weight of said adhesive matrix.

13. The transdermal delivery system of Claim 12, wherein said acrylic polymer adhesive is present in an amount of from about 70 to about 99% by weight of said adhesive matrix.

14. The transdermal delivery system of Claim 13, wherein said acrylic polymer adhesive is present in an amount of from about 90 to about 97% by weight of said adhesive matrix.

15. A method of preparing a transdermal delivery system for delivering a compound selected from the group consisting of 0-substituted-l,2,5,6-tetrahydro-3-pyridine oximes, 0-substituted-l,2,3,6-tetrahydro-4-pyridine oximes, their pharmaceutically acceptable bases, acid addition salts and mixtures thereof, comprising: a) providing an adhesive matrix comprising of an acrylic polymer adhesive, said compound and a stabilizer; b) laminating said adhesive matrix onto an inert impermeable film backing; c) heating said adhesive matrix laminate at a sufficient temperature and time to evaporate any solvent

5 contained therein; and d) laminating a removable release liner over the exposed surface of the dried adhesive matrix.

16. The method of Claim 15, wherein said acrylic polymer adhesive is selected from the group consisting of

10 vinyl acetate-ethylene acrylate, ethyl hexyl acrylate, butyl acrylate, ethyl acrylate and mixtures thereof.

17. The method of Claim 16, wherein said compound is present in an amount of from about 0.1 to about 30% by weight of said adhesive matrix.

I⁵ 18. The method of Claim 17, wherein said compound is present in an amount of from 0.5 to about 5.0% by weight of said adhesive matrix.

19. The method of Claim 17, wherein said compound is present in an amount of about 3.0% by weight of said

²⁰ adhesive matrix.

20. The method of Claim 19, wherein said stabilizer is present in an amount of from about 0.05 to about 2.0% by weight of said adhesive matrix.

21. The method of Claim 20, wherein said stabilizer 5 is selected from the group consisting of butylated hydroxytoluene, ascorbyl palmitate, ferrous oxide, and mixtures thereof.

22. A method of treating cognitive disorders, comprising: 0 transdermally administering an effective amount of a compound selected from the group consisting of 0- substituted-l,2,5,6-tetrahydro-3-pyridine oximes, 0- substituted-1,2,3,6-tetrahydro-4-pyridine oximes, their pharmaceutically acceptable bases, acid addition salts f and mixtures thereof.

23. The method of Claim 22, wherein said compound is (E)-1,2,5,6-tetrahydro-l-methyl-3-pyridine- carboxaldehyde-O-methyloxime monohydrochloride.

24. The method of Claim 22, wherein said compound is present in an amount of from about 0.001 mg. to about 100 mg. per kg. body weight per day.

25. The method of Claim 24, wherein said compound is present in an amount of from about 0.001 mg. to about 1 mg. per kg. body weight per day.

26 m. A method of effecting analgesia, comprising: transdermally administering an effective amount of a compound selected from the group consisting of 0- substituted-l,2,5,6-tetrahydro-3-pyridine oximes, 0- substituted-1,2,3,6-tetrahydro-4-pyridine oximes, their pharmaceutically acceptable bases, acid addition salts and mixtures thereof.

27. The method of Claim 26, wherein said compound is (E)-1,2,5,6-tetrahydro-l-methyl-3-pyridine- carboxaldehyde-0-methyloxime monohydrochloride.

28. The method of Claim 27, wherein said compound is present in an amount of from about 0.001 mg. to about 100 mg. per kg. body weight per day.

29. The method of Claim 28, wherein said compound is present in an amount of from about 0.001 mg. to about 1 mg. per kg. body weight per day.