WO1987002891A1

WO1987002891A1 - Compounds and method for the topical treatment of inflammation and pain

Info

Publication number: WO1987002891A1
Application number: PCT/US1985/002206
Authority: WO
Inventors: James Edward Mckie; George Mclean Milne
Original assignee: Pfizer Corp Belgium; Pfizer Corp SRL
Current assignee: Pfizer Corp Belgium; Pfizer Corp SRL
Priority date: 1985-11-07
Filing date: 1985-11-07
Publication date: 1987-05-21
Anticipated expiration: 1988-05-07

Abstract

Esters of methyl salicylate with certain non-steroidal antiinflammatory drugs (NSAID's) can be used for topical administration to mammals, to elicit a response which combines the antiinflammatory and analgesic effects of the NSAID and the counterirritant effect of the methyl salicylate. Typical NSAID's which can be used in this way are aspirin (acetylsalicilic acid), ibuprofen and indomethacin. Advantageously, the NSAID-methyl salicylate ester is administered in the form of a pharmaceutical composition, such as an ointment, gel, lotion, cream or the like.

Description

COMPOUNDS AND METHOD FOR THE TOPICAL TREATMENT OF INFLAMMATION AND PAIN Technical Field This invention relates to the treatment of inflammation and pain in mammalian subjects by topical administration of certain chemical substances.

Musculo-s eletal inflammation and pain are common afflictions of mammals. They often appear as a manifestation of a chronic, inflammatory disease state, such as one of the arthritides, but they also appear as acute conditions in which case they can be triggered by a variety of causative factors. Such factors include bacteria, radiation and hypersensitivity to one or more chemical agents. However, a common cause of acute inflammation and pain in humans is simple over-exertion, leading to sprains, strains, muscle spasms, muscle tension, and the like.

Background. Art Inflammation, both chronic and acute, can be treated by the use of steroids, and the narcotic analgesics are often used to alleviate pain. However, steroidal drugs can produce undesirable side-effects, such as fluid retention, and narcotic analgesics suffer from their high addictive potential. On the other hand, there are a variety of agents commonly used in medical practice which are non-narcotic and non-steroidal, but which nevertheless can be used to combat both inflammation and pain. These agents, which are often termed non-steroidal antunflammatory drugs (NSAID's) , are typified by aspirin (acetylsalicylic acid) and related salicylates, but there are now a variety of newer drugs available. Although the σhemical structures of these newer agents vary quite widely, a common structural feature of many of these compounds is the presence of a carboxylic acid group

(COOH) . For example, one group of NSAID's consists of propionic acid derivatives (the so-called "profens," e.g., ibuprofen) , and another group of NSAID's consists of acetic acid derivatives (e.g., indomethacin) .

NSAID's, and various salts thereof, are commonly administered orally, thereby achieving systemic levels of the drug entity. On the other hand, in many situa¬ tions, particularly when acute therapy is desired, a more convenient mode of treatment involves topical administration directly to the inflamed and/or painful situs. However, NSAID's are often not well-absorbed when administered topically.

In addition, acute inflammation and pain are often treated by the topical administration of a counter¬ irritant. In this regard, a widely-used agent is methyl salicylate, which is often applied to the skin in the form of an ointment or cream and which elicits a soothing, mildly-analgesic effect. However, methyl salicylate suffers from the disadvantage that it possesses an odor, which under certain circumstances, and to certain individuals, can be regarded as un- pleasant.

The ester of aspirin with methyl salicylate has been described by Reepmeyer, Journal of Pharmaceutical Sciences, 72, 322 (1983) , but no utility was reported for this compound. Disclosure of Invention

Accordingly, it is an object of this invention to provide a method for the treatment of inflammation and/or pain in a mammalian subject, by topical admin¬ istration of a chemical substance. Thus, in its broadest sense, this invention relates to the use of compounds of the formula

for the topical treatment of inflammation and/or pain associated with musculo-skeletal disorders in mammals, especially humans. In compounds of the formula I, the grouping Z-CO- represents an acyl radical of a carboxylic acid of the formula Z-CO-OH, wherein Z-CO-OH is a carboxy group-containing, non-steroidal antunflammatory drug (NSAID) . After application to the skin of a mammalian subject at an inflamed and/or painful situs, a compound of the formula I is absorbed, and then it breaks down by ester cleavage to give the NSAID of the formula Z-CO-OH and methyl salicylate. This results in concurrent delivery of the NSAID (which exerts an antunflammatory and/or analgesic effect) and methyl salicylate (which exerts a soothing, counter¬ irritant effect) . This coherent therapy with two complementary drug entities provides fast, effective relief, and has advantages of use in that: (i) absorption of the two components is converged, thereby delivering both components to the site of action at the same time; (ii) the odor of methyl salicylate is not observed because it is liberated only beneath the surface of the skin; and (iii) improved levels of absorption of the NSAID are achieved, compared to conventional formulations.

Further, this invention provides a pharmaceutical composition which comprises a topically-acceptable pharmaceutical carrier and an antunflammatory and analgesic response eliciting amount of a phenolic ester of methyl salicylate of the formula I, wherein Z is as defined above. Moreover, the compounds of the formula I above are novel compositions of matter, except in the case in which the NSAID component is derived from aspirin. Thus, this invention also provides a new genus of chemical compounds which can be represented by the following chemical formula

in which the grouping Z -CO- represents an acyl radical of a carboxylic acid of the formula Z -CO-OH, wherein Z -CO-OH is a carboxy group-containing NSAID other than aspirin.

A wide variety of NSAID's can be used as the NSAID component of a compound of the formula I. However, among the various carboxy group-containing compounds of the formula Z-CO-OH which can be used, four' sub-classes of NSAID's are particularly effective. There are:

(a) the salicylates;

(b) the propionic acids, or profens;

(c) the acetic acids; and

(d) the biphenylylcarboxylic acids. Typical examples of NSAID's of the above four types are: (a) aspirin; (b) carprofen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, pranoprofen and suprofen; (c) diclofenac, etodolac, ibufenac, indomethacin, sulindac, tolmetin and zomepirac; and (d) diflunisal and flufenisal. However, the preferred compounds of the formula I are those in which the acyl group Z-CO- is derived from aspirin, ibuprofen or indomethacin. Consequently, preferred groups for Z -CO- in compounds of the formula II are the acyl groups derived from ibuprofen and indomethacin. Detailed Description The compounds of the formula I can be prepared directly from the appropriate NSAID and methyl salicylate, viz:

This is a classical esterification reaction, and it can be carried out by standard methods for this type of transformation. For example, it can be carried out by activation of the carboxy group of the NSAID (such as by acid chloride formation) , followed by reaction with one molar equivalent of methyl salicylate, in an inert solvent, in the presence of one to four molar equiva¬ lents of a tertiary amine catalyst.

In a typical procedure for acid chloride formation, the acid of the formula 3-CO-OH is reacted with from one to four molar equivalents of thionyl chloride, in an inert solvent such as carbon tetra- chloride or chloroform, at a temperature from about 40 to about 80°C. The reaction proceeds quite quickly, and conversion into acid chloride is usually sub- stantially complete within about 12 hours. At that point, the volatile materials are removed by evaporation in vacuo to give the crude acid chloride. Although the crude acid chloride can be purified if desired, it is usually pure enough in the crude state for conversion into a compound of the formula I. During acid chloride formation, a small amount of aluminum trichloride can be added if desired.

In a typical procedure for conversion of the acid chloride Z-CO-C1 into a compound of the formula I, substantially equimolar quantities of the acid chloride and methyl salicylate are dissolved in a suitable, reaction-inert, organic solvent and the solution is treated cautiously with from about one to about four molar equivalents of a tertiary amine. Convenient reaction-inert solvents are ethers, such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane, and chlorinated hydrocarbons, such as chloroform and dichloromethane. Convenient tertiary amines are pyridine, triethylamine and N,N-dimethylaniline. The reagents are usually combined at or about room temperature, but it is then common to heat the reaction mixture at a temperature from about 30 to about 80°C, preferably about 40°C, for several hours to complete the reaction. The product can be isolated by standard procedures. For example, when a water-immiscible reaction solvent has been used, the reaction mixture can be washed with dilute hydrochloric acid, followed by dilute sodium bicarbonate solution. Evaporation of the dried organic solven€ then affords the crude product of formula I. The product can be purified by conventional methods, such as recrystallization and/or chromatograph .

If the Z grouping of the NSAID of the formula Z-CO-OH contains a functional group which can react with an acid chloride (e.g., OH, NH-, etc) , it is usually advantageous to protect this functional group prior to acid chloride formation. The protecting group is then removed after reaction with the methyl salicylate. Conventional protecting groups can be used for this purpose. Selection of an appropriate group, and methods for its attachment and removal, will be achieved readily by one skilled in the art.

An alternate method for the synthesis of the compound of the formula I, wherein Z-CO- is derived from aspirin is taught by Reepmeyer, Journal of Pharmaceutical Sciences, 72, 322 (1983) . As indicated hereinbefore the aforementioned compounds of the formula I are useful for topical administration to a mammalian subject, especially a human subject, for the treatment of inflammation and/or pain, both chronic and acute. Chronic conditions which can be treated using a compound of the formula I include rheumatoid arthritis, osteoarthritis, bursitis and the like; and acute conditions include sprains and strains, muscle tension, urticaria, eczema, dermatoses, insect bites and the like.

Advantageously, a compound of the formula I will be administered in combination with a topically- acceptable pharmaceutical carrier, in a pharmaceutical composition. Said pharmaceutical composition will be prepared according to standard pharmaceutical practice for a composition intended for topical use. For example, the pharmaceutical composition will be in the form of an ointment, gel, lotion or cream.

In the case of ointments, a compound of the formula I can be formulated with waxes, such as white wax or lanolin, and paraffins such as petrolatum. Emulsifying agents, such as sodium lauryl sulfate and stearyl alcohol, can also be added.

In the case of gels, a compound of the formula I can be formulated by adding a gelling agent to a solution or partial solution of the active ingredient in a suitable organic solvent, such as ethyl alcohol, propyl alcohol, propylene glycol, glycerol or mixtures thereof. Typical gelling agents which can be used are polyoxyethylated amines (e.g., PEG-15 cocamine) and carboxymethyl celluloses.

In the case of_ lotions and creams, a compound of the formula I can be formulated in aqueous propylene glycol containing various emulsifying agents and emollients. Typical emulsifying agents are glyceryl stearate, sorbitan monostearate, sorbitan mono-oleate, and the like; typical emollients are waxes and paraffins, such as lanolin or light mineral oil.

A pharmaceutical composition containing a compound of the formula I can also contain other additives conventionally used for topical pharmaceuticals, such as stabilizers, preservatives and antioxidants, and penetration enhancers, such as dimethyl sulfoxide and N-methylpyrrolidone. Conventional coloring and odor-enhancing substances can also be added.

In a pharmaceutical composition comprising a compound of the formula I, the ratio of pharmaceutical carrier to active ingredient will vary according to a variety of factors, such as the precise nature of the composition, the site of intended use and the dosage contemplated. However, in general, the weight ratio of carrier to active ingredient will normally be in the range from 1:1 to 10:1, preferably 1:2 to 2:1.

When a pharmaceutical composition comprising a compound of the formula I is used for topical treatment of a human subject, the dosage to be used will vary according to factors such as the severity of the symptom's being treated, the response of the individual patient, the frequency of administration and the antunflammatory and/or analgesic potency of the NSAID component of the compound of the formula I. However, having full regard for these factors, administration of an antunflammatory and analgesic response eliciting amount of a compound of a formula I will require topical administration of a pharmaceutical composition containing a compound of the formula I such that the

2 subject being treated receives from 0.1 to 10 mg/cm of said compound of formula I. This dosage may be repeated at intervals, as necessary; for example, every 4, 6 or 12 hours. The existence of only minor symptoms of inflammation and/or pain, and the use of a compound of the formula I in which the NSAID component is of relatively high potency, are factors which indicate that dosages towards the lower end of the above range will be preferred. Conversely, the existence of more severe inflammation and/or pain, and the use of a compound of the formula I in which the NSAID component is of relatively low potency, are factors which indicate that dosages towards the upper end of the above range will be preferred.

The following examples are being provided solely for further illustration. The term "flash chromato- graphy" refers to the procedure described by Still et. al. , Journal of Organic Chemistry, 43, 2923 (1978) .

EXAMPLE 1 Ester of Aspirin with Methyl Salicylate To 10.0 g of aspirin (acetylsalicylic acid) in 50 ml of carbon tetrachloride was added 0.5 g of aluminum trichloride, with stirring, and the mixture was stirred at 60°C for 1 hour. Thionyl chloride (15 ml) was added and stirring was continued at 60°C for 14 hours. The solvent was removed by evaporation to give the acid chloride of aspirin as a reddish liquid. The above acid chloride was dissolved in 20 ml of diethyl ether and 7.66 g of methyl salicylate was added, with stirring. After 10 minutes, 3.98 g of pyridine was added, dropwise, with stirring, during 30 minutes, and stirring was continued for 2 hours. The reaction mixture was then filtered, and the filtrate was washed with dilute hydrochloric acid, followed by 5% sodium bicarbonate solution, followed by water. The resulting organic solution was dried .(MgSO_d) and evaporated in vacuo. To the residue was added a small amount of toluene and the solid which did not dissolve was removed by filtration. The toluene solution was evaporated in vacuo and the residue was flash chromatographed on silica gel, eluting with 95:5 chloroform/ethyl acetate. Evaporation of the solvent from the product-containing fractions afforded a 30% yield of the title ester.

The H nuclear magnetic resonance spectrum (CDC1-,; 280 MHz) of the product showed absorptions at 2.3 (singlet, 3H) , 3.8 (singlet, 3H) and 7.2-8.5 (multiplet, 8H) ppm downfield from internal tetra- methylsilane.

The infrared spectrum of the product ( Br disc) showed prominent absorptions at 3200-2950, 1770, 1725, 1610, 1220-1190 and 1165 cm^-1. The mass spectrum of the product showed major peaks at mass-to-charge ratios (m/e) of 314.1, 282.9, 163.3, 151.9, 134.9 and 120.9.

Analysis:- Calσd. for C₁₇H₁₄0-: C, 64.97; H 4.46%. Found: C, 64.63; H, 4.32%.

EXAMPLE 2 Ester of Ibuprofen with Methyl Salicylate To a stirred mixture of 10.0 g of ibuprofen and 30 ml of carbon tetrachloride was added 8.0 g of thionyl chloride. The resulting mixture was stirred at room temperature for 1 hour and then at 60°C overnight. The volatile components were removed by evaporation in vacuo, leaving the acid chloride of ibuprofen as a dark colored liquid. The above acid chloride and 6.1 g of methyl salicylate were dissolved in 30 ml of diethyl ether, and 3.8 g of pyridine was added dropwise, with stirring. The resulting mixture was heated under reflux for 24 hours, and then it was cooled and filtered. The filtrate was washed with dilute hydrochloric acid, followed by 5% sodium bicarbonate, followed by water. The organic solution was dried (MgSO.) and evaporated _in vacuo to give a brown oil, which was flash chromatographed on silica gel, eluting with dichloromethane as solvent. Evaporation of the appropriate fractions afforded the title ester.

The H nuclear magnetic resonance spectrum (CDC1-,;

280 MHz) of the product showed absorptions at 0.9 (doublet, 6H) , 1.65 (doublet, 3H) , 1.8 (multiplet, 1H) , 2.5 (doublet, 2H) , 3.7 (singlet, 3H) , 4.1 (quartet, 8H) ppm downfield from internal tetramethylsilane .

The infrared spectrum of the product ( Br disc) showed prominent absorptions at 3100-2850, 1765, 1730, 1610, 1300, 1140 and 1080 cm^"1. The mass spectrum of the product showed major peaks at mass-to-charge ratios (m/e) of 341.0, 309.0, 188.2, 161.0, 145.0, 118.0 and 57.0.

EXAMPLE 3 Ester of Indomethacin with Methyl Salicylate The title compound can be prepared by conversion of indomethacin into its acid chloride, followed by reaction with methyl salicylate, using the procedure of Example 2.

EXAMPLE 4

Topical Formulations of the Ester of

Aspirin with Methyl Salicylate

OINTMENT NO. 1

Amount Ingredient (Parts by Weight)

1. Lanolin, anhydrous 3

2. Aspirin-Methyl 3-6 .Salicylate ester

3. Propylene glycol 1 4. White wax 1

5. Lanolin . 2

Ingredients 1 and 2 are blended until homogeneous at a suitable temperature, not to exceed 80°C, such that a molten mixture is obtained (Mixture A) . Ingredients 3, 4 and 5 are blended until homogeneous at a suitable temperature, not to exceed 80°C, such that a molten mixture is obtained (Mixture B) .

Mixtures A and B are combined while still molten and blended until homogeneous. The resulting mixture is allowed to cool to room temperature with slow stirring. OINTMENT NO . 2

Amount

Ingredient (Parts by Weight)

1. Stearyl alcohol 1

2. Petrolatum 2

3. Aspirin-Methyl 3-6 Salicylate ester

4. Water 2

5. Propylene glycol 2

6. Sodium lauryl sulfate 0.1

Ingredients 1, 2 and 3 are blended until homogeneous at a suitable temperature, not to exceed 80°C, such that a molten mixture is obtained (Mixture

A) . Ingredients 4, 5 and 6 are blended until homogeneous at a suitable temperature, not to exceed 80°C, such that a molten mixture is obtained (Mixture

B) .

Mixtures A and B are adjusted to the same temperature, mixed, and blended until homogeneous. The resulting mixture is allowed to cool to room temperature with slow stirring.

GEL

Amount Ingredient (Parts by Weight)

1. Ethyl alcohol, 4.3 denatured

2. Propylene glycol 2.5

3. Carbomer 0.1 4. Aspirin-Methyl 3-6

Salicylate ester

2

5. PEG-15 cocamine 0.1 A cross-linked polyacrylic acid

2

A polyoxyethylated derivative of the coconut amine

Ingredients 1, 2, 3 and 4 are blended until ^" homogeneous at a temperature between 22 and 30°C, to produce a molten mixture. Ingredient 5 is added slowly, with gentle mixing, until a gel forms. Mixing is continued until a uniform blend is obtained.

LOTION : Amount

Ingredient (Parts by Weight)

1. Glyceryl stearate 4

2. Lanolin 4

3. Mineral oil, light 4 4 4.. A Assppiirriinn--MMeetthhyyll 25-50

Salicylate ester

5. Propylene glycol 15

6. Water 30

1 . Carborner 0.5

Water 10

Potassium hvdroxide 0.2

A cross-linked polyacrylic acid

Ingredients 1, 2, 3, 4 and 5 are blended until homogeneous at a suitable temperature, not to exceed 80°C, such that a molten mixture is obtained (Mixture

A) .

Ingredient 7 is dispersed in ingredient 6 and heated to 60°C with agitation (Mixture B) .

Mixture A is blended into Mixture B at 60°C and stirred until uniform and then the mixture is cooled to 50°C (Mixture C) . A solution of ingredient 9 in ingredient 8 is heated to 50°C. This solution is added to Mixture C with gentle stirring and gradual cooling during the addition.

EXAMPLE 5 Topical Formulations of the Ester of Ibuprofen with Methyl Salicylate GEL

Amount

Ingredients (Parts by Weight)

1. Water 2

2. Glycerol 2

3. Ethyl alcohol 3

4. Ibuprofen-Meth l 3-6

Salicylate ester ι

5. Carbomer 0.1

2

6. PEG-15 cocamme 0.1

A cross-linked polyacrylic acid

2

A polyoxyethylated derivative of the coconut amine

Ingredients 3 and 4 are blended until homogeneous, and then a mixture of ingredients 1 and 2 is added. Blending is continued until homogeneous. The PEG-15 cocamine is added and blending is continued until a gel forms.

CREAM

Amount

Ingredients (Parts by Weight)

1. Stearic acid 10 2. Glyceryl stearate 7

3. Lanolin 2

4. Polysorbate 85 2

5. Sorbitan tristearate 1 CREAM

Amount

Ingredients (Parts by Weight)

6. Ibuprofen-Methyl 25-50 Salicylate ester

7. Water 40

8. Triethanolamine 1

Ingredients 1-6 are blended until homogeneous at a suitable temperature, not to exceed 60°C, such that a molten mixture is obtained (Mixture A) . A solution of the triethanolamine in the water is heated to the same temperature as Mixture A. Mixture A is added to the aqueous triethanolamine with vigorous agitation and cooling. As a cream forms, the rate of agitation is slowed, and a smooth, white product develops.

OINTMENT

Amount

Ingredients (Parts by Weight)

1. Lanolin 4

2. White wax 1

3. Ibuprofen-Methyl 3-6 Salicylate ester

4. Water

Ingredients 1, 2 and 3 are blended until homogeneous at a temperature which is just sufficient to give a molten mixture. The water is then added, with mixing, and mixing is continued until a homogeneous ointment is obtained. The ointment is cooled to room temperature. LOTION

Amount

Ingredients (Parts by Weight)

1. Propylene glycol stearate

2. Lanolin oil

3. Mineral oil, light

4. Ibuprofen-Me hyl 25-50

Salicylate ester

5^"., Water 30

6. Carbomer 0.5

7. Potassium hydroxide 0.2

8. ^■ Water 20

A cross-linked polyacrylic acid

Ingredients 1, 2, 3 and 4 are blended until homogeneous at a suitable temperature, not to exceed 80°C, such that a molten mixture is obtained (Mixture A) .

Ingredient 6 is dispersed in ingredient 5 and heated to 60°C with agitation (Mixture B) .

Mixture A is blended into Mixture B at 60°C and stirred until uniform and then the mixture is cooled to 50°C (Mixture C) .

A solution of ingredient 8 in ingredient 7 is heated to 50°C. This solution is added to Mixture C with gentle stirring and gradual cooling during the addition.

Claims

1. A method of eliciting an antunflammatory and/or an analgesic response in a mammalian subject, which comprises topically administering to said subject an antunflammatory and analgesic response eliciting amount of a phenolic ester of methyl salicylate of the formula

in which the grouping Z-CO- represents an acyl radical derived from a carboxylic acid of the formula Z-CO-OH, wherein Z-CO-OH is selected from the group consisting of aspirin, ibuprofen and indomethacin.

2. The method according to claim 1, wherein Z-CO-OH is aspirin.

3. The method according to claim 1 wherein Z-CO-OH is ibuprofen.

4. A pharmaceutical composition, suitable for topical administration to a mammalian subject to elicit an antunflammatory or analgesic response, which comprises a topically-acceptable pharmaceutical carrier and an antunflammatory and analgesic response eliciting amount of a phenolic ester of methyl salicylate of the formula

5. A composition according to claim 4, wherein the weight ratio of the carrier to the methyl salicylate ester is in the range from 1:1 to 10:1.

6. A composition according to claim 5, wherein the composition is in the form of a cream, oil, gel or lotion.

7. A phenolic ester of methyl salicylate of the formula

in which the grouping Z -CO- represents an acyl radical derived from a carboxylic acid of the formula Z -CO-OH, wherein Z -CO-OH is selected from the group consisting of ibuprofen and indomethacin.

^•

8. The compound of the formula

the compound of claim 7, wherein Z -CO-OH is ibuprofen.

9. The compound of the formula

the compound of claim 7, wherein Z -CO-OH is indometh¬ acin.