WO1992022530A1

WO1992022530A1 - Ketobemidone prodrugs

Info

Publication number: WO1992022530A1
Application number: PCT/DK1992/000184
Authority: WO
Inventors: Hans Bundgaard; Lona Louring Christrup; Ann Fullerton; Laila Bach Hansen
Original assignee: H. Lundbeck A/S
Priority date: 1991-06-13
Filing date: 1992-06-12
Publication date: 1992-12-23
Also published as: DK113091D0; AU1984992A; IE921890A1

Abstract

The invention relates to a composition for topical delivery of ketobemidone. The composition comprises an effective amount of a ketobemidone prodrug in association with a topical pharmaceutical carrier which gives solutions, suspensions, ointments, lotions, creams, gels, pastes, jellies, sprays and aerosols and/or together with a medical device. The invention also relates to the use of the ketobemidone prodrugs for the manufacture of a topical medicament for relieving pain or tranquilizing a mammal.

Description

KETOBEMIDONE PRODRUGS

BACKGROUND OF THE INVENTION

Field of the Invention

This invention relates to a class of prodrug derivatives of ketobemidone useful in effecting transdermal delivery of ketobemidone to the systemic circulation of a mammal.

For purposes of this specification, the term "prodrug" denotes a derivative of ketobemidone which, when administered topically to warm-blooded animals, e.g. humans, is converted into the proven drug, i.e. ketobemidone.

Description of the Prior Art

Ketobemidone is a well known drug and it is a generally known and an accepted practice to administer ketobemidone to control chronic pain. Ketobemidone plays an important role in the control of pain associated with chronic diseases, especially the chronic pain of cancer, and acute pain, especially the acute pain experienced post-operatively. However, such prior art uses of ketobemidone are subject to some problems. In addition to the obvious problems associated with potential abuse and addiction, the oral and parenteral administration of ketobemidone for pain control frequently involve variations in the pharmacodynamics of the drug over each dosing interval. Furthermore, ketobemidone has a short duration of action and is inefficient- ly and variably absorbed orally due to first-pass metabolism in the intestine and liver (Bondesson et al.-Eur.J.CIin. Pharmacol. 17 (1980) 45-50).

Transdermal administration may be a promising approach to overcome many of the drawbacks associated with the parenteral, rectal or oral route of administration. A prerequisite for the development of a transdermal delivery system of ketobemidone is, however, that the drug is capable of penetrating the skin at a sufficiently high rate and is not metabolized during the percutaneous absorption. Ketobemidone shows, unfortunately, a limited skin permeability which makes it unsuited for transdermal delivery.

From the prior art the O-ethoxycarbonyl derivative of ketobemidone is known. Said derivative was prepared for use in a method for determination of the concentration of ketobemidone and norketobemidone in plasma (Bondesson et al., Biomedical Mass Spectrometry,1983, 10 , 283-286). No mention or indication of pharmacologi¬ cal activity of said derivative is given.

It has now surprisingly been found that it is feasible to achieve transdermal delivery of ketobemidone by the prodrug approach, certain prodrug derivatives of ketobemi¬ done penetrating the skin properly and at the same time being cleaved enzymatical- ly to ketobemidone in a proper way.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel compositions comprising a compound represented by the following general Formula I

wherein R1 is a group

R⁴

\

R OO--CC-- ,, RR - j-OOCCHH₂₂-- , RR^J* 1--QC-- oorr

in which R2 is C1-20 alkyl, C2-20 alkenyl, aryl, cycloalkyl, adamantyl, cycloalkenyl, arylalkyl or -alkenyl, cycloalkylalkyl or -alkenyl, adamantyl, or cycloalkenylalkyl or - alkenyl;

R3, R4 and R⁵ are each independently hydrogen or as R2; or a non-toxic pharmaceutically acceptable acid addition salt thereof.

Any alkyl or alkenyl group present may be substituted or unsubstituted, and straight- chain or branched.

Cycloalkyl, and cycloalkenyl may be substituted or unsubstituted and comprise 3-8 carbon atoms in the ring and cycloalkyl- and cycloalkenylalkyl and -alkenyl groups designate alkyl or alkenyl substituted with such groups and containing until 20 carbon atoms.

Aryl means optionally substituted phenyl or a heteroaromatic group containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and arylalkyi or -alkenyl designate alkyl or alkenyl substituted with such aryl group and containing 4-13 carbonatoms.

Examples of suitable straight-chain alkyl groups in Formula I include methyl, ethyl propyl, butyl, hexyl, heptyl, octyl, dodecyl, palmityl and the like groups.

Examples of suitable branched-chain alkyl groups include isopropyl, sec-butyl, t- butyl, 2-methylbutyl, 2-pentyl, 3-pentyl and the like groups.

Examples of suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

Examples of suitable alkenyl groups include vinyl (ethenyl), 1 -propenyl, i-butenyl, pentenyl, hexenyl, n-decenyl and c-pentenyl and the like groups.

The groups may be substituted, generally with 1 or 2 substituents, wherein the substituents are independently selected from halogen, hydroxy, alkoxy, amino, mono-and dialkylamino, nitro, carboxyl, alkoxycarbonyl and cyano groups. Examples of suitable aryl groups comprise phenyl and heteroaromatic groups such as pyridinyl, thienyl and imidazolyl.

Examples of arylalkyi groups are benzyl, phenethyl and phenylpropyl groups wherein the phenyl moiety may be substituted. When substituted, the aryl group or the aryl moiety of the arylalkyi group may contain independently, from 1 to 3 alkyl, hydroxy, alkoxy, halogen, amino, mono- and dialkylamino, nitro, carboxyl, alkoxycar-. bonyl and cyano groups.

As used herein, the expression halogen is meant in the conventional sense to include F, Cl, Br, and I.

The term "non-toxic pharmaceutically acceptable acid addition salts" as used herein generally includes the non-toxic addition salts of compounds of Formula I, formed with non-toxic inorganic or organic acids. For example, the salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, nitric, phosphoric and the like; and the salts with organic acids such as acetic, propionic, succinic, fumaric, maleic, tartaric, citric, glycolic, lactic, stearic, malic, pamoic, ascorbic, phenylacetic, benzoic, glutamic, salicylic, sulfanilic, methanesul- fonic, and the like.

Preferably the composition of the invention is a topical composition for transdermal delivery comprising a compound of formula I in association with a topical pharma- ceutical carrier which gives a solution, suspension, oinment, lotion, cream, gel, paste, jellie, spray or aerosol. The composition may be incorporated in a medical device for transdermal administering .

The composition of the invention may also contain a non-toxic additive acting as a skin penetration enhancer. In another embodyment of the invention the composition is a topical dosage form consisting af a matrix type or reservoir type patch system containing a compound as defined in Formula I and optionally in combination with a penetration enhancing delivery device/process such as iontophoresis. Reservoir type patch system and iontophoresis are both well known systems for transdermal delivery.

The composition according to the invention may also be combined with an additio¬ nal drug delivery device such as patches, gauze or compresses.

The absorption enhancers used may be of any type such as fatty acids, fatty acid esters and fatty alcohols as well as any type of pharmaceutical additive commonly used for topical or dermal preparations and/or delivery systems such as trans¬ dermal patches.

In another aspect the invention relates to the use of the prodrugs of Formula I for the manufacture of a topical medicament for transdermal delivery and useful in relieving pain or tranquilizing a mammal.

In a further aspect the present invention provides the novel ketobemidone prodrugs having the general formula I as defined above with the proviso that Ri may not be an ethoxycarbonyl group.

When applied to mammalian skin, the composition according to the present invention induces and maintains analgesia by administering through an area of intact skin a ketobemidone prodrug of the Formula I at an analgetically effective rate and continuing the administration of said material at said rate for an extended period of time at least sufficient to induce analgesia. Thereby the present invention provide an improved method of treating and controlling acute and/or chronic pain.

By administering transdermally a ketobemidone prodrug of Formula I according to the present invention, the fluxes of the compounds and compositions through mammalian skin tissue are established as being sufficient in magnitude to be practical for direct transdermal applications, producing time-sustained dosage rates consistent for pain suppression and tranquilizing effects over prolonged periods of time.

The ketobemidone prodrug derivatives of the present invention show a higher lipid solubility or lipophilicity and a lower melting point than the active parent drug while still having a proper water affinity and have been found to be more able to pene¬ trate the skin of a human or non-human animal and surprisingly they are capable of reverting to the active ketobemidone during or following the transport through the skin. These characteristics make the derivatives useful for transdermal delivery of ketobemidone.

DETAILED DESCRIPTION OF THE INVENTION

Among the compounds of the invention represented by the general Formula I, preferred compounds are those wherein Ri is one of the following groups: formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, isobutyryl, octanoyl, methoxyacetyl, ethoxyacetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxy- carbonyl, iso-butoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, and imidazo- lylcarbonyl.

Preparation of Compounds of Formula I

The compounds of Formula I can be prepared by a variety of synthetic routes commonly used for the preparation of esters, and carbamates. One method comprises reacting ketobemidone or a ketobemidone salt, e.g. ketobemidone- hydrochloride, with an acylating agent selected from

, R3CO-Y , (R³CO)₂0 , R20-CO-Y , (R20-CO)₂0 and R4-NCO

wherein R2-R5 are as defined above and Y is halogen. The reaction can conve- niently be carried out in the absence of a solvent or in an inert solvent such as acetonitrile, toluene, dichloromethane, dioxane or the like, or in a mixture of solvents such as water and methylene chloride, at a temperature of from 0°C to reflux, for about 1/2 to about 100 hours. An acid acceptor like triethylamine or pyridine may be added to the reaction mixture. Instead of acid chlorides including chloroformates, acid anhydrides or mixed anhydrides may be used.

Detailed descriptions of the preparation of some ketobemidone esters are given in Examples 1-3. The derivatives described all had spectroscopic properties (IR and 1H-NMR) and elemental analyses in agreement with their structures.

Example 1

O-Pivaloyl ketobemidone (Formula I, R1 = (CH₃)₃CCO)

Pivaloyl chloride ( 2.46 ml, 20 mmol) was added to a stirred mixture of ketobemi¬ done hydrochloride (1.4 g, 5 mmol), 40 ml of a 1 M aqueous solution of sodium bicarbonate (pH adjusted to 9.5) and 40 ml of methylene chloride. The mixture was stirred at room temperature (20-25°C) for 3 h whereupon the layers were sepa¬ rated. The organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the title compound as an oil. The hydrochloric acid salt of O-pivaioyl ketobemidone was prepared as follows: The oil obtained as described above was dissolved in ether (50 ml) and a 2.5 M metha- nolic hydrochloric acid solution (2.5 ml, 6.3 mmol) was added. After standing overnight at -18°C the precipitated hydrochloric acid salt of the title compound was filtered off and recrystallized from acetone-ether. The yield was 68%. Mp 214- 2 5°C.

Anal.: Calc. for C₂0H₂9NO3, HCI:

C, 65.29; H, 8.22; N, 3.81 ; Cl, 9.64. Found: C, 65.15; H, 8.14; N, 3.80; Cl, 9.52. Example 2

0-3,3-Dimethylbutyryl ketobemidone (Formula I, R1 = (CH3)₃CCH₂CO)

The compound was prepared by reacting 3,3-dimethylbutyryl chloride (2.79 ml, 20 mmol) with ketobemidone hydrochloride (1.4 g, 5 mmol) by a method analogous to that descibed in Example 1. The title compound was isolated as an oil in a yield of 76%.

The fumarate salt of 0-3,3-dimethylbutyryl ketobemidone was prepared as follows: The ketobemidone ester (3 mmol) was dissolved in ether (50 ml) and a solution of fumaric acid (383 mg, 3.3 mmol) in 2-propanol (5 ml) was added. After standing for 5 h at 5°C the crystalline 0-3,3-dimethylbutyryl ketobemidone fumarate was isolated by filtration. The compound was washed with ether and recrystallized from ethanol- ether (82% yield). Mp 172-173°C.

Anal.: Calc. for C25H35NO7:

C, 65.06; H, 7.64; N, 3.03. Found: C, 65.13; H, 7.69; N, 3.07.

Example 3

O-Ethoxycarbonyl ketobemidone (Formula I, R-i = CH₃CH₂OCO)

The compound was prepared by reacting ethyl chloroformate (1.9 ml, 20 mmol) with ketobemidone hydrochloride (1 .4 g, 5 mmol) by a method analogous to that described in Example 1. The title compound was isolated as an oil in a yield of 67%. The hydro-chloric acid salt of the title compound was prepared essentially as described in Example 1. Mp 85-86°C.

Anal.: Calc. for C18H25NO4, H₂0, HCI: C, 57.83; H, 7.55; N, 3.75; Cl, 9.48.

Found: C, 57.73; H, 7.57; N, 3.71 ; Cl, 9.41. Examples 4-10

By following the procedures of the foregoing examples several more esters accor- ding to the invention are obtained:

a Free base, Hydrochloric acid salt.

Solubility and Lipophilicitv of Ketobemidone Esters

The solubility of ketobemidone and various ketobemidone esters in isopropyl myristate and ethanol and their partition coefficients between octanol and pH 7.4 aqueous buffer (P) are shown in Table 1.

Table 1.

Solubilities and partition coefficients (P) of ketobemidone and various prodrugs at

21 °C.

Compound Log Pa Solubility .mg/ml. In Ethanol In IPMb

Ketobemidone O-Acetyl ketobemidone O-Pivaloyl ketobemidone 0-3,3-Dimethylbutyryl ketobemidone O-Benzoyl ketobemidone O-Methoxycarbonyl ketobemidone O-Ethoxycarbonyl ketobemidone O-lsopropoxycarbonyl ketobemidone O-lsobutoxycarbonyl ketobemidone O-Butoxycarbonyl ketobemidone 0-Hexyloxycarbonyl ketobemidone

a: Between octanol and pH 7.4 aqueous buffer, b- IPM_: Isopropyl myristate.

The apparent partition coefficients (P) of ketobemidone and the various prodrugs were determined at 21 °C in an octanol-0.02 M phosphate buffer (pH 7.4) system. The concentration of the compounds in the aqueous phase before and after partitioning was determined by HPLC analysis, and the partition coefficients determined.

From the data shown in Table 1 it can readily be seen that the ketobemidone prodrugs are more lipophilic than the parent drug in terms of octanol-aqueous buffer partition coefficients. It is also apparent that ketobemidone prodrugs with increased solubility in a polar solvent like ethanol and an apolar solvent like isopropyl myristate relative to ketobemidone can be obtained. This solubility and lipophilicity may be characteristics favourable for skin penetration. Enzvmatic Hvdrolvsis of Ketobemidone Esters

To demonstrate the capability of the compounds of Formula I to undergo conver¬ sion to the parent drug in-vivo, the stability of the compounds was examined in 80% human plasma at 37°C. Aliguots of 50 μl of aqueous or ethanolic solutions of the prodrug derivatives described in Examples 1-10 were added to 5 ml of preheated plasma solution, the initial concentration of the derivatives being 3 x 10-5 M. The solutions were kept in a water-bath at 37°C, and at appropriate intervals, 250 μl samples were withdrawn and added to 500 μl of a 2% solution of zinc sulfate in methanol-water (1 :1 v/v) or 1000 μl of ethanol in order to deproteinize the plasma. After mixing and centrifugation for 3 min at 13,000 rpm, 20 μl of the clear superna¬ tant was analyzed by HPLC for remaining derivative as well as for parent drug.

A reversed-phase HPLC procedure was used for the quantitative determination of the ketobemidone prodrugs and the parent drug. A reversed-phase Supelcosil LC- 8DB column (33 x 4.6 mm) was eluted with a mixture of methanol-acetonitrile-0.1% phosphoric acid containing triethylamine (10-3 M) in order to improve peak shape. For the analysis of ketobemidone the composition of the mixture was 5:15:80 (v/v) whereas for the prodrugs the amount of methanol was 5% v/v and that of acetoni- trile between 15 and 40% v/v in order to provide an appropriate retention time. The flow rate was 1-2 ml min-1 and the column effluent was monitored at 215 nm. Quantitation of the compounds was done by measurement of peak heights in relation to those of standards chromatographed under the same conditions.

The various prodrug derivatives were found to be cleaved quantitatively to ketobemi¬ done in human plasma solutions. The observed half-lives of hydrolysis are given in Table 2. As can be seen from the data the ketobemidone esters are rapidly conver¬ ted to the parent drug at conditions similar to those prevailing in-vivo. A demonstra¬ tion of the enzymatic conversion of the derivatives in plasma is provided by the fact that the half-lives of hydrolysis of the derivatives in Table 2 in the absence of plasma, i.e. in a pH 7.4 phosphate buffer at 37°C, exceeded 50-200 h. Table 2

Half-lives of hydrolysis of various ketobemidone esters in 80% human plasma solutions at 37°C.

Compound Half-life (min)

O-Acetyl ketobemidone 0.05

O-Pivaloyl ketobemidone 0.3

0-3,3-Dimethylbuturyl ketobemidone 1.8 O-Benzoyl ketobemidone 0.08

O-Methoxycarbonyl ketobemidone <0.05

O-Ethoxycarbonyl ketobemidone . <0.05

O-lsopropoxycarbonyl ketobemidone <0.05

O-lsobutoxycarbonyl ketobemidone 0.05 O-Butoxycarbonyl ketobemidone <0.05

O-Hexyloxycarbonyl ketobemidone 0.1

Skin Permeation Studies The feasibility of achieving transdermal delivery of ketobemidone via the prodrugs of the present invention was evaluated by diffusion experiments in-vitro using human skin samples.

Whole abdominal human skin obtained under autopsy from two donors was used. The skin was stored at -18°C and was allowed to thaw gradually at room tempera¬ ture before use. All subcutaneous fat was removed and the skin cut into pieces.

The excised skin was mounted in open Franz diffusion cells. They had an available diffusion area of 0.70 cm2.

The dermal side of the skin was exposed to the receptor medium (7.5 ml of 0.05 M isotonic phosphate buffer of pH 7.2) which was stirred magnetically and kept at a constant temperature of 37°C with a circulating water bath.

The compounds studied were applied as solutions or suspensions (200 μl) in isopropyl myristate (IPM), ethanol or ethanol-water (3:1 v/v). The solutions or suspensions were allowed to stir for 24 h prior to application to the skin surface. At appropriate intervals samples of 2 ml were removed from the receptor phase and replaced with fresh buffer.

The samples were stored at -20°C until they were analyzed for ketobemidone or prodrug content by HPLC as described above. The permeation studies of each com¬ pound were done in tri- or quadruplicate.

Only ketobemidone was found in the receptor phase after application of the ketobe¬ midone prodrugs on the skin, indicating complete enzymatic conversion of the . prodrugs to the parent drug during diffusion through the skin. The cumulative amounts of ketobemidone in the receptor phase divided by the surface area of the diffusion cell were plotted against the time of sampling. The steady-state fluxes were obtained from the slopes of the linear portions of these plots. The values obtained for ketobemidone and some prodrugs are given in Table 3.

Table 3

Steady-state fluxes for the delivery of ketobemidone through human skin from solutions or suspensions of ketobemidone or ketobemidone esters in isopropyl myristate (IPM), ethanol or ethanol-water mixtures.

a Saturated solution (i.e., suspension). b The solution applied was not saturated. It contained the compound at a concentra¬ tion of 500 mg/ml. c The solution applied was not saturated. It contained the compound at a concentra¬ tion of 200 mg/ml. The results obtained from the human skin permeation experiments show that it is possible to very markedly improve the skin penetration of ketobemidone via the prodrugs of the present invention. It should be noted that whereas ketobemidone was applied in the form of saturated solutions which provide the maximal driving 5 force for diffusion, the prodrug derivatives were applied in the form of non-saturated solutions. By applying these compounds in solutions of higher concentrations (cf. the solubility data in Table 1) or as suspensions fluxes greater than those shown in Table 3 for the esters are readily obtained.

o The feasibility of obtaining transdermal delivery of ketobemidone via the prodrug approach of the present invention can be assessed by comparing the doses of ketobemidone usually used in parenteral administration with those obtainable by transdermal delivery of the present invention. If the area of the patch, for example, for transdermal delivery is 25 cnrι2 and if a flux of 50 μg/cm^β/h is used, it would be 5 possible to deliver 1.25 mg ketobemidone/h or 30 mg over 24 hours. This amount is in the range as that usually given (20-40 mg) parenterally during 24 hours.

The actual administration of the transdermal analgesic compositions according to the present invention may be in any conventional form and by any of the methods o generally known in the art. Thus, the active ketobemidone prodrug of Formula I may be used in association with any pharmaceutical dosage form such as, but not limited to, any solution, ointment, lotion, paste, jelly, gel, cream, spray or aerosol as generally known in the art. As such, the narcotic analgetic prodrug form in associa¬ tion with the pharmaceutical dosage form can be used directly as a topical composi- tion or used in combination with an additional drug delivery device, for example, but not limited to, patches, gauzes, compresses, or the like, again, as generally known in the art. The dosage forms may contain any type of absorption enhancers such as fatty acids, fatty acid esters and fatty alcohols or any other non-toxic compound which is known to increase skin permeability. In particular, the transdermal analge- sic compositions can be administered in the form of a patch wherein the ketobemi¬ done prodrug is present, in a polymeric matrix or in a reservoir system combined with a polymeric rate controlling membrane.

Claims

1. A pharmaceutical composition comprising a compound represented by the following general Formula I

wherein Ri is a group

in which R is C₁-₂0 alkyl, C₂-₂0 alkenyl, aryl, cycloalkyl, adamantyl, cycloalkenyl, arylalkyi or -alkenyl, cycloalkylalkyl or -alkenyl, adamantyl, or cycloalkenylalkyl or - alkenyl; R3, R4 and R5 are each independently hydrogen or as R2; or a non-toxic pharmaceutically acceptable acid addition salt thereof.

2. A composition according to Claim 1 wherein R1 is formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyi, hexanoyi, octanoyi, ethoxycarbonyl, propoxycar- bonyl, butoxycarbonyl, isobutoxycarbonyl or hexyloxycarbonyl.

3. A composition according to Claim 1 or 2 which is a topical composition for transdermal delivery comprising a compound of Formula I in association with a topical pharmaceutical carrier which gives a solution, suspension, oinment, lotion, cream, gel, paste, jellie, spray or aerosol and optionally incorporated in a medical device for transdermal administering .

4. A composition according to any of Claims 1 , 2 or 3 containing a non-toxic additive acting as a skin penetration enhancer.

5. A composition according to any of Claims 1-4, which is a topical dosage 5 form consisting of a matrix type or reservoir type patch system containing a com¬ pound according to Formula I as defined in Claims 1-4.

6. A composition according to any of Claims 1-4, which is a topical dosage * form consisting of a compound according to Formula I as defined in Claim 1-4 in ιo combination with a penetration enhancing delivery device/process, preferably iontophoresis.

7. A composition according to any of Claims 1-4, which is a topical dosage form in which the composition according to any of Claims 1-4 is combined with an is additional drug delivery device such as a patch, gauze or compress.

8. Use of a compound represented by the general Formula I as defined in Claim 1 or a non-toxic pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for relieving pain or tranquilizing a mammal.

20

9. A method for relieving pain or tranquilizing a mammal comprising admini¬ stration of a compound represented by the general Formula I as defined in Claim 1 in a therapeuically effective dose to a patient in need thereof.

25 10. A compound represented by the general Formula I as defined in Claim 1 provided that R¹ may not be ethoxycarbonyl; or a non-toxic pharmaceutically acceptable acid addition salt thereof