SPRAY ABLE ANALGESIC COMPOSITIONS

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No. 62/077,581, filed on November 10, 2014, which is incorporated herein by reference in its entirety.

FIELD OF INVENTION

This invention relates to analgesic compositions. More particularly, this invention relates to sprayable compositions containing nonsteroidal anti-inflammatory drugs.

BACKGROUND OF THE INVENTION

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known medications with analgesic and antipyretic effects. NSAIDs are used to treat pain and discomfort such as muscle strain/sprain, fever, inflammation such as rheumatoid arthritis, joint pain, and the like.

The present invention provides topical dosage forms of NSAIDs that can be applied as a spray or as an aerosol.

SUMMARY OF INVENTION

A sprayable analgesic preparation contains a nonsteroidal anti-inflammatory drug (NSAID) together with lauryl lactate, lactic acid, and glyceryl monolaurate dissolved in a mixture of water and ethanol. The obtained aqueous ethanolic solution is useful for extended pain relief.

Optionally, the aqueous ethanolic solution can contain propylene glycol, a non-ionic surfactant having a HLB value of at least 12, and a thickener such as cellulose ethers, cross-linked alkyl acrylates, and the like.

Preferred NSAID 's are the propionic acid derivatives ketoprofen, ibuprofen and naproxen, as well as the acetic acid derivatives diclofenac, indomethacin and etodolac. BRIEF DESCRIPTION OF DRAWINGS

In the drawings,

FIGURE 1 is a bar graph showing skin permeation by ketoprofen, applied as spray compositions, at selected time intervals after application, and comparison with a commercially available, ketoprofen-containing topical gel (Profenid® Sanofi-Aventis; 2.5% ketoprofen);

FIGURE 2 is a bar graph showing skin permeation by naproxen, applied as spray compositions, at selected time intervals after application, and comparison with a commercially available naproxen-containing topical gel (Naprosyn®, Syntex, 10% naproxen free acid);

FIGURE 3 is a bar graph showing skin permeation by ibuprofen, applied as a spray composition, at selected time intervals after application, and comparison with a commercially available ibuprofen-containing topical gel (Ibuleve®, DDD ltd., 5% ibuprofen);

FIGURE 4 is a bar graph showing skin permeation by diclofenac, and pharmaceutically acceptable salts thereof, applied as spray compositions, and comparison with a commercially available diclofenac sodium gel (Swiss Relief™, Mika Pharma GmbH, Fug, Switzerland, 4% diclofenac sodium);

FIGURE 5 is a bar graph showing the effect of propylene glycol on skin permeation in ibuprofen-containing spray compositions, and comparison with a commercially available ibuprofen-containing topical gel (Ibuleve®, DDD ltd., 5% ibuprofen);

FIGURE 6 is a bar graph showing skin permeation by ketoprofen with Brij 58 as a permeation enhancer, applied as spray compositions, at selected time intervals after application, and comparison with a commercially available, ketoprofen-containing topical gel (Profenid®, Sanofi-Aventis; 2.5% ketoprofen);

FIGURE 7 is a bar graph showing skin permeation by ketoprofen with propylene glycol laurate as a permeation enhancer, applied as spray compositions, at selected time intervals after application, and comparison with a commercially available, ketoprofen-containing topical gel (Profenid®, Sanofi-Aventis; 2.5% ketoprofen);

FIGURE 8 is a bar graph showing skin permeation by ketoprofen with propylene glycol caprylate as a permeation enhancer, applied as spray compositions, at selected time intervals after application, and comparison with a commercially available, ketoprofen-containing topical gel (Profenid®, Sanofi-Aventis; 2.5% ketoprofen);

FIGURE 9 is a bar graph showing skin permeation by ketoprofen with Sorbitan monolaurate as a permeation enhancer, applied as spray compositions, at selected time intervals after application, and comparison with a commercially available, ketoprofen- containing topical gel (Profenid®, Sanofi-Aventis; 2.5% ketoprofen);

FIGURE 10 is a bar graph showing skin permeation by ketoprofen with various Brij derivatives as a permeation enhancer, applied as spray compositions, at selected time intervals after application, and comparison with a commercially available, ketoprofen-containing topical gel (Profenid®, Sanofi-Aventis; 2.5% ketoprofen);

FIGURE 1 1 is a bar graph showing skin permeation by ketoprofen, applied as a spray composition after 3 months stored at 25°C and 40°C, at selected time intervals after application, and comparison with a commercially available, ketoprofen-containing topical gel (Profenid®, Sanofi-Aventis; 2.5% ketoprofen);

FIGURE 12 is a bar graph showing skin permeation by naproxen using 5%

Naproxen sodium salt and Brij 58, applied as spray compositions, at selected time intervals after application, and comparison with a commercially available naproxen-containing topical gel (Naprosyn®, Syntex, 10% naproxen free acid);

FIGURE 13 is a bar graph showing skin permeation by naproxen using 2.5%) Naproxen sodium salt and Brij 58, applied as spray compositions, at selected time intervals after application, and comparison with a commercially available naproxen- containing topical gel (Naprosyn®, Syntex, 10% naproxen free acid);

FIGURE 14 is a bar graph showing skin permeation by ibuprofen with and without isopropyl myristate (IPM), applied as spray compositions, at selected time intervals after application, and comparison with a commercially available ibuprofen- containing topical gel (Ibuleve®, DDD ltd., 5% ibuprofen);

FIGURE 15 is a bar graph showing skin permeation by ibuprofen with isopropyl myristate (IPM) and Brij 58, applied as spray compositions, at selected time intervals after application, and comparison with a commercially available ibuprofen- containing topical gel (Ibuleve®, DDD ltd., 5% ibuprofen);

FIGURE 16 is a bar graph showing skin permeation by diclofenac, and pharmaceutically acceptable salts thereof, applied as cream compositions, and comparison with a commercially available diclofenac sodium gel (Voltaren®, Novartis Pharma Productions GmbH, Wehr, Germany, 1 % diclofenac sodium);

FIGURE 17 is a bar graph showing skin permeation by diclofenac, and pharmaceutically acceptable salts thereof, applied as spray compositions, and comparison with a commercially available diclofenac sodium gel (Swiss Relief™, Mika Pharma GmbH, Fug, Switzerland, 4% diclofenac sodium);

FIGURE 18 is a bar graph showing skin permeation by diclofenac sodium with Brij 58, and different levels of propylene glycol and lactic acid, applied as spray compositions, and comparison with a commercially available diclofenac sodium gel (Voltaren®, Novartis Pharma Productions GmbH, Wehr, Germany, 1% diclofenac sodium);

FIGURE 19 is a bar graph showing skin permeation by diclofenac diethylamine with Brij 58, and different levels of propylene glycol and lactic acid, applied as spray compositions, and comparison with a commercially available diclofenac sodium gel (Voltaren®, Novartis Pharma Productions GmbPI, Wehr, Germany, 1% diclofenac sodium); and

FIGURE 20 is a bar graph showing skin permeation by ketoprofen compositions containing different levels of propylene glycol and hydroxypropyl cellulose thickeners.

DESCRIPTION OF PREFERRED EMBODIMENTS

The present topical compositions are clear, sprayable, aqueous ethanolic solutions that contain dissolved therein a nonsteroidal anti-inflammatory drug (NSAID). Preferred NSAIDs are the acetic acid derivatives such as indomethacin, sulindac, etodolac, tolmetin, ketorolac, nabumetone, diclofenac, and the like, including the pharmaceutically acceptable salts thereof, as well as the propionic acid derivatives such as ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, and the like, including the pharmaceutically acceptable salts thereof.

Illustrative NSAID salts suitable for use as active ingredients in the spray compositions are pharmaceutically acceptable salts of the aforementioned acetic acid derivatives, e.g., indomethacin salts such as indomethacin sodium, indomethacin meglumine, and the like, tolmetin salts such as tolmetin sodium, and the like, ketorolac salts such as ketorolac tromethamine, and the like, diclofenac salts such as diclofenac sodium, diclofenac diethylamine, diclofenac epolamine, and the like, as well as pharmaceutically acceptable salts of the aforementioned propionic acid derivatives, e.g., ibuprofen salts such as ibuprofen lysine, ibuprofen methylglucamine, and the like, naproxen salts such as naproxen piperazine, naproxen sodium, and the like, fenoprofen salts such as fenoprofen calcium, and the like.

Also suitable are NSAIDs such as aspirin, the enolic acid derivatives such as pizoxicam, meloxicam, tenoxicam, and the like, the fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, and the like, and selective COX-2 inhibitors such as celecoxib and the like, including the pharmaceutically acceptable salts thereof.

The aqueous ethanolic solutions preferably contain the NSAID in an amount in the range of about 1 to about 10 percent by weight preferably about 5 percent by weight, based on the total weight of the solution.

Also present in the solutions is lauryl lactate (C ₁ 5H30O3), the ester of lauryl alcohol and lactic acid having the formula

O

II

CH ₃ CHC-OCH ₂ (CH2) ₁₀ CH3

I

OH

Preferably, lauryl lactate is present in the solution in an amount in the range of about 1 to about 5 weight percent, more preferably about 3 weight percent, based on the total weight of the solution.

The aqueous ethanolic solution also contains lactic acid (C3H6O3;

2-hydroxypropanoic acid), preferably in an amount in the range of about 0.5 to about 5 weight percent, more preferably about 1.5 weight percent, based on the total weight of the solution; glyceryl monolaurate (Ci 5H ₃ o0 ₄ ; dodecanoic acid 2,3-dihydroxypropyl ester), preferably in an amount in the range of about 2 to about 5 weight percent, more preferably about 3 weight percent, based on the total weight of the solution. Optionally, propylene glycol (C ₃ H ₈ 0 _2; propane- 1 ,2-diol) can be present, preferably in an amount in the range of about 5 to about 30 weight percent, more preferably about 10 weight percent, based on the total weight of the solution.

The remainder of the solution is constituted by water and ethanol, preferably present in a respective weight ratio of about 0.3 : 1 to about 2.6: 1, more preferably in a respective weight ratio of about 1 : 1.

The aqueous ethanolic solution can also contain, as an optional ingredient, a non-ionic surfactant having a Hydrophile-Lipophile balance (HLB) value of at least 12. Preferred non-ionic surfactants are the alkoxylated alcohols. Particularly preferred is polyethylene glycol ether of cetyl alcohol represented by the formula

CH ₃ (CH ₂ ) i ₄ CH ₂ (OCH ₂ CH2)nOH, where n has an average of 10, and having a HLB value of about 15.7.

The foregoing clear aqueous ethanolic solutions are prepared by first combining the NSAID with lauryl lactate, lactic acid, and glyceryl monolaurate and thereafter dissolving the obtained admixture by gradual addition, at ambient temperature, of propylene glycol followed by the addition of alternating aliquots of water and ethanol.

The non-ionic surfactant, if desired, is added to the admixture prior to the addition of water and ethanol.

Skin permeation studies of illustrative compositions embodying the invention were performed using dermatoned human female (46 years old) cadaver skin pieces from the back (Science Care, Aurora, CO; 250 Micrometers thick) Franz cells (3.65 ml volume, 0.55 cm ² surface area) at 35° C. using heating/stirring blocks. Receptor compartment contained saline with sodium azide (pH 7.4). Two or three replicates (25 μΐ and control 25 mg) were made for each solution. Sampling volume was 300 μΐ. Fresh buffer was replaced after each sample removal. Sampling was carried out at 2, 4, 6 and 24 hours. The samples were assayed using high performance liquid chromatography (HPLC).

Respective controls were NSAID containing gels: Profenid® gel (2.5% ketoprofen; Sanofi Aventis, France), Ibuleve® gel (5% ibuprofen; DDD Ltd., UK), Naprosyn® gel (10% naproxen free acid; Syntex, Turkey), Swiss Relief™ Spray Gel (4%> diclofenac sodium) Mika Pharma GmbH, Switzerland), and Voltaren® gel (1%> diclofenac sodium) Novartis Pharma Productions GmbH, Wehr, Germany.

The experimental results obtained with a ketoprofen spray composition are presented in Tables 1 and 2 below, and in FIGURE 1. TABLE 1

Ketoprofen Spray Composition

¹ CH ₃ (CH ₂ )i4CH ₂ (OCH ₂ CH ₂ ) _n OH, n average value 20; HLB 15.7; also Brij 58

Propylene glycol laurate, HLB 4-5

Propylene glycol monocaprylate, HLB 5-6

TABLE 2

Permeation Data

The above data show that spray compositions provided better skin permeation for ketoprofen than a ketoprofen containing gel composition, and that skin permeation could be further enhanced by an alkoxylated alcohol having an HLB value of 15.7.

The experimental results obtained with a naproxen spray composition are presented in Table 3 and 4 below, and in FIGURE 2.

TABLE 3

Naproxen Spray Composition

TABLE 4

Naproxen Permeation Data

The above data show that naproxen containing spray compositions provided better skin permeation for naproxen than the Naprosyn® 10% naproxen gel. The incorporation of higher levels of water did not reduce the permeation of naproxen. The experimental results obtained with an ibuprofen spray composition are presented in Tables 5 and 6 below, and in FIGURE 3. The experimental procedure was the same as that for the ketoprofen and naproxen spray compositions, except that the dermatomed cadaver skin was that of a human male, 72 years old.

TABLE 5

Ibuprofen Spray Composition

TABLE 6

Ibuprofen Permeation Data

The above data show that an ibuprofen containing spray composition provided better skin permeation for ibuprofen than the Ibuleve® ibuprofen gel.

The experimental results obtained with a diclofenac spray composition are presented in Tables 7 and 8 below, and in FIGURE 4. The experimental procedure was the same as that for the ketoprofen and naproxen spray compositions except that the dermatomed cadaver skin was that of a 79-year old human male. TABLE 7

Diclofenac Spray Composition

TABLE 8

Diclofenac Permeation Data

The above data show that a diclofenac containing spray composition provided better skin permeation for diclofenac than a spray gel composition that has a relatively larger concentration of diclofenac.

⁴ Swiss Relief™ spray gel contains 4 wt. % diclofenac sodium together with inactive ingredients isopropyl alcohol, soy bean lecithin, ethanol, disodium phosphate dodecahydrate, sodium dihodrogen phosphate dehydrate, sodium edetate, propylene glycol, peppermint oil, ascorbyl palmitate, hydrochloric acid (10% w/w), sodium hydroxide (10% w/w), purified water. The effect of propylene glycol in an ibuprofen spray composition was investigated using cadaver skin from a 72 year-old human male. The experimental results are presented in Tables 9 and 10 below, and in FIGURE 5.

TABLE 9

Ibuprofen Spray Compositions

TABLE 10

Ibuprofen Permeation Data

Cumulative Amount in Receptor, g/cm

Time,

hours Ibul7 ±SD Ibu24 ±SD Ibuleve ^® ±SD

2 20.22 5.59 19.36 12.52 7.17 12.42

4 69.45 5.95 71.08 27.82 8.65 1.80

6 127.06 2.01 138.70 35.68 20.97 8.20

The above data show that propylene glycol in the spray composition enhanced the skin penetration of ibuprofen.

The experimental results obtained with a ketoprofen spray composition and a nonionic surfactant, polyoxyethylene (20) cetyl ether (Brij 58), as a permeation enhancer are presented in Tables 1 1 and 12 below, and in FIGURE 6. TABLE 11

Ketoprofen and a Nonionic Surfactant Spray Composition

TABLE 12

Permeation Data

The above data show that the addition of Brij 58 helped to increase water levels. All formulations exhibited similar permeation behavior; however, KeS73 showed slightly higher permeation. KeS73a was slightly cloudy.

The experimental results obtained with a ketoprofen spray composition and propylene glycol laurate as a permeation enhancer are presented in Tables 13 and 14 below, and in FIGURE 7. TABLE 13

Ketoprofen and Propylene Glycol Laurate Spray Composition

TABLE 14

Permeation Data

Only formulations KeS47 and KeS74 gave clear solutions. The above data show that the KeS47 and KeS74 formulations exhibited nearly the same permeation behavior.

The experimental results obtained with a ketoprofen spray composition and propylene glycol caprylate as a permeation enhancer are presented in Tables 15 and 16 below, and in FIGURE 8. The experimental procedure was the same as that for the previous ketoprofen spray compositions, except that the dermatomed cadaver skin of a human male, 79 years old.

TABLE 15

Ketoprofen and Propylene Glycol Caprylate Spray Composition

TABLE 16

Permeation Data

The above data show that all of the formulations exhibited comparable permeation behavior.

The experimental results obtained with a ketoprofen spray composition and Sorbitan monolaurate as a permeation enhancer are presented in Tables 17 and 18 below, and in FIGURE 9. The experimental procedure was the same as that for the previous ketoprofen spray compositions, except that the dermatomed cadaver skin was that of a human male, 79 years old.

TABLE 17

Ketoprofen and Sorbitan Monolaurate Spray Composition

TABLE 18

Permeation Data

Only formulations KeS47 and KeS78 gave clear solutions. The above data show that permeation from KeS78 was slightly lower than KeS47.

The experimental results obtained with a ketoprofen spray composition and various Brij derivatives as a permeation enhancer are presented in Tables 19 and 20 below, and in FIGURE 10. The experimental procedure was the same as that for the previous ketoprofen spray compositions, except that the dermatomed cadaver skin was that of a human male, 79 years old.

TABLE 19

Ketoprofen and Non-ionic Surfactant Spray Composition

poly(oxyethylene)(4) lauryl ether

poly(oxyethylene)(23) lauryl ether

poly(oxyethylene)(2) stearyl ether

poly(oxyethylene)(20) oleyl ether

poly(oxyethylene)(21 ) stearyl ether TABLE 20

Permeation Data

The above data show that all formulations containing the non-ionic surfactants permitted higher water content while showing similar behavior with respect to permeation.

The experimental results showing permeation of a ketoprofen spray composition after storage for three (3) months at 25°C and 40°C is presented in Tables 21 and 22 below, and in FIGURE 1 1. The experimental procedure was the same as that for the previous ketoprofen spray compositions, except that the dermatomed cadaver skin was from the thigh of a human male, 79 years old.

TABLE 21

Ketoprofen Spray Composition

TABLE 22

Permeation Data

The above data show that both formulations exhibited similar permeation behavior after three months of storage. The experimental results obtained with a naproxen spray composition using 5% Naproxen sodium and Brij 58 are presented in Table 23 and 24 below, and in FIGURE 12. The experimental procedure was the same as that for the previous spray compositions, except that the dermatomed cadaver skin was from the thigh of a human male, 79 years old.

TABLE 23

Naproxen Spray Composition Using 5% Naproxen Sodium and a Non-ionic Surfactant

TABLE 24

Naproxen Permeation Data

Cumulative Amount in Receptor, g/cm

Time,

hours NapS05 ±SD NapS21a ±SD NapS23a ±SD Naprosyn® ±SD

2 60.77 16.57 44.92 14.84 22.70 18.23 1.67 2.90

4 139.90 28.22 101.66 22.94 52.91 36.06 2.37 4.10

6 186.06 27.93 147.81 27.39 77.01 48.09 3.61 6.25 The above data show that by decreasing the level of water and lactic acid, formulations with higher levels of ethanol were prepared. Reduction in lactic acid and addition of Brij 58 resulted in lower skin permeation. A precipitate was noted in NapS22a and NapS24.

The experimental results obtained with a naproxen spray composition using 2.5% Naproxen sodium and Brij 58 are presented in Table 25 and 26 below, and in

FIGURE 13. The experimental procedure was the same as that for the previous spray compositions, except that the dermatomed cadaver skin was from the thigh of a human male, 79 years old.

TABLE 25

Naproxen Spray Composition Using 2.5% Naproxen Sodium and a Non-ionic Surfactant

A precipitate was noted in NapS05, NapS25, NapS26 and NapS28. TABLE 26

Naproxen Permeation Data

The above data show that reduction of Naproxen levels to 2.5% caused a significant reduction in skin permeation.

The effect of isopropyl myristate in an ibuprofen spray composition was investigated. The experimental results are presented in Tables 27 and 28 below, and in FIGURE 14. The experimental procedure was the same as that for the previous spray compositions, except that the dermatomed cadaver skin was from the thigh of a human male, 79 years old.

TABLE 27

Ibuprofen with and without Isopropyl Myristate Spray Compositions

Composition, wt.%

Ingredients Ibu24 Ibu30

Ibuprofen 5 5

Propylene glycol 10 10

Isopropyl myristate 0 3

Lauryl lactate 3 3

Lactic acid 1.5 1.5

Glyceryl monolaurate 3 3

Ethanol 37.5 39.5

Water 40 35

TOTAL 100 100 TABLE 28

Ibuprofen with and without Isopropyl Myristate Permeation Data

Time, Cumulative Amount in Receptor, μg/cm ²

hours Ibu24 ±SD Ibu30 ±SD Ibuleve ^® ±SD

2 177.88 34.92 149.67 43.10 53.86 36.32

4 324.99 58.07 271.38 62.99 129.82 74.30

6 415.42 62.34 344.02 61.75 177.62 89.78 The above data show that addition of isopropyl myristate in the spray composition did not further enhance the skin permeation of ibuprofen.

The effect of isopropyl myristate and Brij 58 in an ibuprofen spray composition was investigated. The experimental results are presented in Tables 29 and 30 below, and in FIGURE 15. The experimental procedure was the same as that for the previous spray compositions, except that the dermatomed cadaver skin was from the back of a human male, 46 years old.

TABLE 29

Ibuprofen with Isopropyl Myristate and Brij 58 Spray Compositions

Composition, wt.%

Ingredients Ibu30 Ibu32 Ibu33

Ibuprofen 5 5 5

Propylene glycol 10 10 10

Isopropyl myristate 3 0 3

Lauryl lactate 3 3 3

Lactic acid 1.5 1.5 1.5

Brij 58 ¹ 3 3

Glyceryl monolaurate 3 3 3

Ethanol 39.5 28 31.5

Water 35 46.5 40

TOTAL 100 100 100 TABLE 30

Ibuprofen Permeation Data

The above data show that addition of Brij 58 helped to increase the level of water in the formulation; however, the addition of isopropyl myristate and Brij 58 in the spray composition did not further enhance the skin permeation of ibuprofen.

The effects of two types of diclofenac were investigated. The experimental results obtained with a diclofenac cream composition using diclofenac sodium and diclofenac diethylamine are presented in Tables 31 and 32, below, and in FIGURE 16. The dermatomed cadaver skin was from the back of a human male, 79 years old.

TABLE 31

Diclofenac Cream Composition

TABLE 32

Diclofenac Permeation Data

The above data show that skin permeation for diclofenac sodium and diclofenac diethylamine cream formulations was similar.

¹⁰ acrylic acid homopolymer

¹¹ cross-linked polyacrylic acid polymer The experimental results obtained with a diclofenac spray composition using diclofenac sodium and diclofenac diethylamine are presented in Tables 33 and 34, below, and in FIGURE 17. The experimental procedure was the same as that for the previous spray compositions, except that the dermatomed cadaver skin was from the back of a human male, 79 years old.

TABLE 33

Diclofenac Spray Composition

TABLE 34

Diclofenac Permeation Data

The above data show that a diclofenac containing spray composition provided better skin permeation for diclofenac than a spray gel composition that has a relatively larger concentration of diclofenac. The effects of propylene glycol, Brij 58 and lactic acid on diclofenac skin permeation were investigated. The experimental results obtained with a diclofenac spray composition using diclofenac sodium, Brij 58, and different levels of propylene glycol and lactic acid are presented in Tables 35 and 36, below, and in FIGURE 18. The experimental procedure was the same as that for the previous spray compositions, except that the dermatomed cadaver skin was from the thigh of a human male, 79 years old.

TABLE 35

Diclofenac Spray Composition

Composition DcS 12 was cloudy.

TABLE 36

Diclofenac Permeation Data

Cumulative Amount in Receptor, μg/cm ²

Time,

hours DcS02 ±SD DcS12a ±SD DcS14 ±SD Voltaren 1% ±SD

2 5.98 2.94 5.97 3.42 2.47 2.17 0.00 0.00

4 16.33 6.10 14.68 5.39 7.24 6.34 3.36 1.1 1

6 25.37 8.82 22.33 6.67 11.52 10.23 7.10 1.33 Addition of a higher level of propylene glycol enhanced the water content but caused formulation DcS12 to precipitate. The above data show that a diclofenac spray composition with a lower level of lactic acid showed a lower level of skin permeation of diclofenac.

The effects of propylene glycol, Brij 58 and lactic acid on diclofenac skin permeation were investigated. The experimental results obtained with a diclofenac spray composition using diclofenac diethylamine, Brij 58, and different levels of propylene glycol and lactic acid are presented in Tables 37 and 38, below, and in FIGURE 19. The experimental procedure was the same as that for the previous spray compositions, except that the dermatomed cadaver skin was from the thigh of a human male, 79 years old.

TABLE 37

Diclofenac Spray Composition

Compositions DcS13, DcS13a and DCS 15 were cloudy. TABLE 38

Diclofenac Permeation Data

Formulations DcS 13, DcS13a, and DcS15 were cloudy. The above data show that incorporation of Brij 58 reduced skin permeation of diclofenac.

The effects of propylene glycol and thickeners on ketoprofen skin permeation were investigated. The experimental results obtained with a ketoprofen spray formulation using ketoprofen, different levels of propylene glycol, and thickeners hydroxypropyl cellulose (100 cps) and hydroxypropyl cellulose (150-400 cps) are presented in Tables 39 and 40, below and in FIGURE 20. The experimental procedure was the same as that for the previous spray compositions, except that the dermatomed cadaver skin was from the thigh of a human male, 79 years old.

TABLE 39

Ketoprofen and Thickeners Spray Composition

TABLE 40

Permeation Data

All formulations above gave clear solutions. The above data show that

KeS84, KeS85, and KeS89 all exhibited significant permeation enhancement compared to KeS47. KeS86, with lower propylene glycol, showed similar permeation to KeS47.

¹² hydroxypropyl cellulose (100 cps)

¹ hydroxypropyl cellulose (150-400 cps) The foregoing discussion and the examples are to be taken as illustrative, but not limiting. Still other variants within the spirit and scope of the invention are possible, and will readily present themselves to those skilled in the art.