WO1991006295A1

WO1991006295A1 - Analgesic composition containing optically pure s(+) flurbiprofen

Info

Publication number: WO1991006295A1
Application number: PCT/US1990/006442
Authority: WO
Inventors: William J. Wechter; James W. Young
Original assignee: Sepracor, Inc.
Priority date: 1989-11-06
Filing date: 1990-11-06
Publication date: 1991-05-16
Also published as: AU6758990A

Abstract

Optically pure S(+) flurbiprofen, which is substantially free of the R(-) enantiomer, is a potent analgesic for relieving pain and inflammation in humans and animals. A method and composition is disclosed utilizing the optically pure S(+) enantiomer of flurbiprofen for treating pain and inflammation.

Description

ANALGESIC COMPOSITION CONTAINING OPTICALLY PURE S(+) FLURBIPROFEN

Description

Background

Flurbiprofen is a drug belonging to the general class of compounds known as non-steroidal antiinflammatory drugs (NSAIDs). NSAIDs as a class exhibit analgesic, anti-inflammatory and antipyretic activity, and include well-known commercial

pain-relievers such as ibuprofen and aspirin.

Flurbiprofen is a very potent NSAID. It is believed that flurbiprofen inhibits biosynthesis of prostaglandins.

Flurbiprofen is a racemic mixture. That is, it is a mixture of optical isomers, called enantiomers. Enantiomers are structurally identical compounds which differ only in that one Isomer is a mirror image of the other and the mirror images cannot be superimposed. This phenomenon is known as

chirality. Most biological molecules exist as enantiomers and exhibit chirality. Al though

structurally identical, enantiomers can have

profoundly different effects in biological systems: one enantiomer is often biologically active while the other has no biological activity at all.

Summary of the Invention

The present invention relates to a method of treating pain and inflammation in an individual comprising administering to the individual an analgesic, anti-inflammatory amount of the S(+)

enantiomer of flurbiprofen, which is substantially free of the R(-) enantiomer. The method is useful in treating pain associated with toothaches, sprains, joint pain and surgical pain, for example, dental pain, (e.g., after periodontal surgery), and

ophthalmic pain, e.g., after cataract surgery. In these applications, it is important to have an analgesic and anti-inflammatory composition which is non-irritating and a potent pain killer. A

composition containing the S(+) isomer of

flurbiprofen is particularly useful for this

application because the S(+) isomer exhibits both of these desired characteristics. The present method provides a safe, highly effective method for treating severe pain and inflammation, such as pain and inflammation associated with peridontal and/or opthalmic surgery or other treatment. Detail ed Description of the Invention

The present invention relies on the analgesic activity of the dextrorotatory enantiomer of flurbiprofen, referred to as S(+) flurbiprofen, to provide enhanced relief from pain, such as pain associated with toothaches, sprains, joint pain and surgical pain, particularly pain associated with dental surgery (e.g., periodontal surgery) and with ophthalmic surgery (e.g., cataract surgery). In the present method, S(+) flurbiprofen which is substantially free of its R(-) enantiomer is administered alone, or in combination with other drugs in adjunctive treatment to an individual in whom pain relief is desired. ^mS(+) flurbiprofen" as used herein refers to the dextrorotatory or S(+) isomer of

2-(2-fluoro-4-biphenylyl) propionic acid, and to any biologically acceptable salt or ester thereof. The term "substantially free of the R(-) enantiomer" as used herein means that the composition contains at least 90 % by we i ght S ( + ) f lurb ip ro f en and 10 % by we i ght or less R(-) flurbiprofen. S(+) flurbiprofen is readily obtainable from racemic flurbiprofen by methods known to those of skill in the art.

In the present method, S(+) flurbiprofen is administered to an individual suffering from pain and/or inflammation. For example, S(+) flurbiprofen is administered to an individual after periodontal surgery, or after cataract surgery, to reduce, ameliorate or eliminate pain and inflammation resulting from the surgery. In another embodiment, S(+) flurbiprofen is administered prophylac tically, that is, before the surgery to reduce pain after the operation.

All amounts and percentages are by weight unless otherwise specified.

The drug can be administered orally, by subcutaneous or other injection, intravenously, topically, parenterally, transdermally, rectally or via an implanted reservoir containing S(+) flurbiprofen. The form in which the drug will be administered

(e.g., powder, tablet, capsule, solution, emulsion) will depend on the route by which it is administered. The quantity of the drug to be administered will be determined on an individual basis, and will be based at least in part on consideration of the individual's size, the severity of the symptoms to be treated and the result sought. In general, quantities of S(+) flurbiprofen sufficient to reduce, ameliorate or eliminate the pain will be administered. For

example, between about 1 and 4 mg per kg of body weight of S(+) flurbiprofen per day (if given in one dose) will produce the desired effect In most

individuals. Typically, a dose in the range of about 2-3 mg per kg of body weight per day will be

administered.

In the method of the present invention, S(+) flurbiprofen can be administered along with one or more other drugs. For example, codein, hydrocodone or caffeine can be given with or in close temporal proximity to administration of S(+) flurbiprofen. The two (or more) drugs (S(+) flurbiprofen and another drug) can be administered In one composition or as two separate entities. For example, they can be administered in a single capsule, tablet, powder, liquid, etc. or as individual compounds. The components included in a particular composition, in addition to S(+) flurbiprofen and another drug or drugs, are determined primarily by the manner in which the composition is to be administered. For example, a composition to be administered orally in tablet form can include, in addition to the drugs, a filler (e.g., lactose), a binder (e.g., carboxymethyl cellulose, gum arable, gelatin), an adjuvant, a flavoring agent, a coloring agent and a coating material (e.g., wax or a plasticizer). A composition to be administered in liquid form can include the combination of drugs and, optionally, an emulsifying agent, a flavoring agent and/or a coloring agent. The composition can also contain a small amount of its R(-) enantiomer. It has been found that the optically pure isomer has a higher melting point than a racemic mixture which contains a small amount of the non-active R(-) isomer. A mixture having a lower melting point is more readily absorbed by the body, because of its higher dissolution rate resulting in higher bloodstream levels than the pure isomer. A mixture containing 90% of the S(+) isomer can 10% of the R(-) isomer (i.e., has an enantiomeric excess of 80%) is particularly useful because it has the lowest melting point.

In general, according to the method of the present invention, S(+) flurbiprofen, alone or in combination with another drug(s), is administered to an individual periodically as necessary to reduce or ameliorate symptoms of the pain being treated. The length of time during which the drugs are administered and the dosage will depend on the pain being treated, the type and severity of the symptoms, and the physical condition of the Individual being treated.

The following Example details a protocol for producing the S(+) enantiomer of flurbiprofen. This Example is not intended to be limiting of the invention.

EXAMPLE

Preparation of s(+2)Flurbiprofen

The following is a description of the resolution of flurbiprofen by an enzymatic process. Included is a description of the synthesis of the water-soluble ester used (a two step procedure), as well as the actual enzymatic resolution, subsequent base

hydrolysis of the non-substrate ester, and the recovery of both enantiomers of flurbiprofen acid. A . Synthesis of Flurbiprofen Dimethylethanolamine

Ester

0.5 moles (122g) BP grade racemic flurbiprofen was added to 1.0 moles (73 mis) of SOCl₂ in a flask fitted with a drying tube.

250μl of dimethylformamide was added to the reaction mixture as a catalyst. The reaction mixture was then stirred and warmed gently until the flurbiprofen dissolved and gas evolution commenced. The heat was then

removed, and the reaction mixture allowed to stir at 20º-22°C for 18 hours, after which time the excess SOCl₂ was removed under reduced pressure. The remaining material was a liquid which slowly solidified. IR analysis of the liquid indicated total conversion of the carboxylic acid to the acid chloride. 131.0 g of flurbiprofen acid chloride were recovered, indicating a 99.7% conversion. This material was carried on to the next step without any further purification.

The entire quantity of acid chloride was then dissolved in 125 mis of THF, and added dropwise to a solution of 1.0 moles (100.5 mis) of N,N-dimethylethanolamine dissolved in 500 mis of THF in a flask fitted with a drying tube. The addition of the acid chloride solution was made over approximately 60 minutes during which time the reaction mixture was cooled to 0ºC by an ice/water bath. When addition was complete, the ice bath was removed, and the entire mixture allowed to stir at 20ºC-22ºC for 18 hours. The reaction was then worked-up by the careful addition of 500 mis of saturated aqueous K₂CO₃ solution. The resulting organic layer was separated, and remaining aqueous layer extracted twice with 250 mis of diethyl ether. The organic layers were combined, back-washed with saturated NaCl solution, dried over anhydrous

K₂CO₃, and evaporated under reduced pressure to leave a colourless, viscous oil. 112.0g of material were recovered, giving a 71% yield. IR analysis of the product indicated only an ester carbonyl function. B. Quaternization of the N, N- Dimethylethanolamine Ester

The entire quantity of the N , N- Dimethylethanolamine ester (0.355 moles) was di s s o lved in 500 mis of diethyl ether and stirred in a flask cooled to 0ºC by an ice/water bath. To this solution was added dropwise a solution of 1.0 equivalents (0.355 moles, 33.6 mis) of dimethyl sulphate, dissolved in 100 mis diethyl ether over approximately 60 minutes. The ice bath was then removed, and the reaction mixture allowed to stir at 20ºC-22ºC for 18 hours. The resulting solid material was removed by filtration, washed with diethyl ether and dried under vacuum at 20-22º C to leave 156.9g (100% yield in quaternization step, 70% yield from racemic flurbiprofen acid) of the N , N , N- trimethyl ethanolammonium ester (also known as the choline ester) of flurbiprofen.

C . Enzymatic Hydrolysis of the Racemic

Flu rbiprofen Choline Ester

75 mmols of the racemic choline ester were dissolved in 1L of 200 mM sodium phosphate buffer at pH 7.0. To this solution was adde d

2.0g of a protease derived from Aspergillus oryzae , which is available commercially from the Amano Enzyme Company under the name Prozyme 6. The reaction was allowed to stir gently at 20ºC-22°C for 48 hours. The entire enzymatic reaction mixture was then acidified to a pH of 2 to 3 by the careful addition of concentrated HCl, and the resulting mixture was extracted 3 times with 150 mis of diethyl ether. The ether layers were combined, dried over anhydrous K₂CO₃, and evaporated under reduced pressure to leave crude (R) - flurbiprofen acid, which was dried under vacuum, and an acidic aqueous solution containing (S)-flurbiprofen choline ester.

The remaining acidic aqueous mixture was then made basic, by the careful addition of NaOH, until the pH had risen to 12.5. The resulting mixture was. allowed to stir at

20ºC-22ºC for approximately two hours, after which time the pH was again brought to

approximately pH 2 by the careful addition of concentrated HCl in order to precipitate the flurbiprofen acid produced by the base

hydrolysis of the choline ester. The resulting mixture was extracted 3 times with 150 mis of diethyl ether. The ether layers were combined, dried over anhydrous K₂CO₃, and filtered into a clean flask. This solution was chilled to approximately -10°C in order to crystallize the (S) - flurbiprofen acid. The resulting crystals were collected by filtration, and dried under vacuum.

The enantiomeric excess of each isomer was determined by polarimetry, assuming an [α]_D value of +42.7° (c = 1.0, CHCl₃) for

(S) -flurbiprofen acid of 100% ee.

In order to prepare a reasonable amount of resolved flurbiprofen, the procedures outlined immediately above for the enzymatic hydrolysis of the racemic choline ester substrate, and the subsequent recovery of both the (R)- and (S) -flurbiprofen acid, were repeated exactly as described four times. The (R) - and (S)-acid products were combined to give the following yields of materials;

(R) -flurbiprofen 18.0g, [a ]_D = -31.2º ee = 73%

(S)-flurbiprofen 18.0g, [α]_D = +36.7º ee = 86%

Subsequent re-crystallization of the (S)-acid material from ether gave (S) - flurbiprofen of 95% enantiomeric excess.

Claims

CLAIMS 1. Use of the S(+) enantiomer of flurbiprofen,

which is substantially free of its R(-)

enantiomeric counterpart, for the manufacture of a medicament for the analgesic treatment of disorders or treatments that result in pain and inflammation.

2. The use of Claim 1 wherein the amount of S(+) flurbiprofen in said medicament is greater than about 90% by weight.

3. The use of Claim 2 wherein the amount of S(+) flurbiprofen in said medicament is greater than about 99% by weight.

4. The use of Claim 1 for the manufacture of a

medicament for the analgesic treatment of pain and inflammation which is the result of tooth disorders or treatments, periodontal treatments, sprains, joint disorders or treatments,

opthalmic treatments, or surgical treatments such as cataract surgery.

5. The use of Claim 1 for the manufacture of a

medicament in unit dosage form having between about 1 and 4 mg , and usually between about 2 and 3 mg, of S(+) flurbiprofen per kg of body weight per day.

6. Use of the S(+) enantiomer of flurbiprofen and at least one other drug for the manufacture of a medicament for the analgesic treatment of disorders or treatments that result In pain and inflammation.

7. The use of Claim 6 wherein said other drug is selected from the group consisting of cortisone, hydrocodone and caffeine.