ZA200101153B

ZA200101153B - Transdermally delivered aspirin.

Info

Publication number: ZA200101153B
Application number: ZA200101153A
Authority: ZA
Inventors: Alexander Galat
Original assignee: Alexander Galat
Priority date: 1999-06-10
Filing date: 2001-02-09
Publication date: 2002-05-09
Also published as: HUP0103110A3; EP1104236A1; IL141348A0; JP2003501447A; HUP0103110A2; BR9912954A; CA2340120A1; MXPA01001490A; TR200100452T1; KR20010072412A; WO2000076315A1; AU4552399A

Description

TRANSDERMALLY DELIVERED ASPIRIN

FIELD AND BACKGROUND OF THE INVENTION

This application is a continuation-in-part of my previous application co-pending herewith, Serial No. 08/988,651, filed December 11, 1997, which is incorporated herein by reference in its entirety.

The present invention relates in general to aspirin compositions, and in particular to a new and useful aspirin composition and a device which is capable of effectively administering aspirin transdermally to a mammal over a period of days [or effective therapeutic purposes, and a method of making and administering the composition.

Aspirin is the most widely used drug in the world. It has a number of important uses in medicine: It is a valuable analgesic, antipyretic, and heart attack and stroke-preventive. However, many heart attacks and strokes occur during the night, when orally ingested medicines are least effective because blood serum levels are typically at a minimum. Aspirin is also one of the most potent anti-inflammatory agents, and is the drug of choice and mainstay of arthritis therapy. It stimulates the immune system, reduces opportunistic infections and is potentially uscful as an adjunct in treating cancer, AIDS, and other immune disorders. It shows promise in treatment of Alzheimer’s

Disease; it is used in rheumatic fever, gout and cataracts; it provides pain relief from tendinitis, headaches, backaches, muscle strains. and other injuries. It has a specific analgesic effect in migraine headaches, a condition in which acetaminophen and ibuprofen show no activity. No other drug in the history of medicine has exhibited such an array of multifaceted therapeutic properties. 23 Despite all these important medical applications, aspirin is known chicfly for its analgesic properties. However, its range of application is greatly reduced by virtue of the fact that aspirin is substantially insoluble in both water (sol.: 0.3%) and glycerol (sol.: 0.3%). Aspirin exhibits better solubility in both alcohol and acetone (sol.: ~20%), but these solvents are too volatile for use with transdermal applications, among other characteristics.

An additional disadvantage of aspirin’s low solubility is that millions of drug consumers have swallowing problems and need transdermal or liquid medication. By some estimates, 20% of all adults are affected, including those suffering from arthritis, Parkinsonism, multiple sclerosis, Lou Gehrig's disease and others. It is significant that 30% of the popular acctaminophen product, 16 TYLENOL (a trademark), had been in capsule form to facilitate swallowing. (Capsules were eventually replaced by gelatin-coated tablets in response to a need for a tamper-resistant dosage form.)

Because of these disadvantages, aspirin is not widely used as an anti- inflammatory agent, even though it is actually the mainstay and drug of choice , 15 in arthritis -- a disease directly caused by inflammation. Instead, its use in arthritis is limited mostly to alleviating pain, for which low 325-500 mg . dosages suffice. To be an effective anti-inflammatory agent, daily aspirin dosages of 5,000+ mg are required. Such daily dosages are possible since the toxicity of aspirin is low. (For example, the LDs for aspirin is about 1.75 g/kg body weight.) However, at such effective anti-inflammatory levels, large amounts of undissolved aspirin particles adhere to the gastrointestinal mucosa, greatly aggravating irritation and side effects 1n the gut.

Many of the above problems presented by oral ingestion of aspirin can be alleviated by delivering aspirin to a patient though the skin. Such administration can provide a comfortable and convenient way of providing medication. Using the skin as portal for drug entry not only solves many of the aforementioned problems, it also provides unique advantages. For example, transdermal delivery allows close control over the rate of drug delivery. With transdermal delivery, the intervening factors associated with oral ingestion such as unpredictable absorption in the gastrointestinal tract from fluctuating acidity and food content are avoided. In addition, a transdermally delivered drug does not undergo initial metabolism by the liver.

Aspirin administered to the skin passes into the blood through the skin and is carried to a site of effective medicinal function. This type of administration, known as percutaneous administration, is often difficult to achieve since the function of skin and its keratin layer (the outermost layer) is to act as a proiective wali against permeation of substances into the hody. For this reason, a device 1s necessary both to control and permit the permeability of aspirin through the keratin layer of the skin and enhance the percutaneous absorption of aspirin.

Many attempts to produce a transdermally delivered aspirin are well- documented, such as in U.S. Patents 3,551,554; 4,537.776: 4,654,209: 4,789,607; 4,867,970; 4,900,554; 4,940,587; 4,948,588; 5,023.08 1; 5,234,957; and 5,240,917. None of the compositions suggested in those patents was entirely successful, as a number of technical and chemical factors prevented development of a working transdermal aspirin, and no known commercial product having adequate pharmaceutical effectiveness has ever resulted from these attempts. In prior attempts, simple topical application of analgesic drugs followed by absorption through the unbroken skin has often been found to be ineffective, at times because the rate of absorption or penetration through the skin was too slow to be effective and because the molecular size of the analgesics was large. Among the factors contributing to the failure of the prior compositions is the poor solubility in known solvents, as discussed above. In order to provide an effcctive dosage of the aspirin, the solvent used must permit high concentrations of aspirin in solution. Moreover. the solvent used

4 WO 00/76315 PCT/US99/12793 must also meet the requirement of being pharmaceutically acceptable and non- toxic to humans.

Aspirin as an undissolved solid may also be a skin irritant as well. To be of value, an acceptable solvent must adequately dissolve the aspirin to be placed in solution to prevent irritation from contact with undissolved aspirin.

Propylene glycol is well-known for use with transdermal medicines because of its ability to enhance skin penetration by the medicine being administered. Aspirin is soluble in propylene glycol at about 10 wt.%.

However, this concentration is still below that level that is fully useful for 1c practical application. In order to propel a drug or other substance through the skin, a difference in osmotic pressure must be established across the skin barrier, that is, between the epidermis skin surface and the dermas region immediately therebelow and indeed the entire skin structure. Skin penetrability is proportional to the concentration of the transported substance ] 15 (here, aspirin) in accordance with Fuch’s Law.

Concentration of the transported substance is also important with ) respect to the size of the device employed for transdermal application required to deliver an effective dosage to the user. For example. when using aspirin in prevention of heart attacks, a generally accepted dosage is 81 mg/day. If it is desired to deliver this dosage daily over a two week period from a single transdermal patch, approximately 1100 mg of aspirin must be dissolved in a solvent. If propylene glycol were to be used bascd on its preferable characteristics and its 10% aspirin solubility, about 11 ml of solvent are required. This quantity of solvent would require an undesirably large patch.

Another factor to be considered in developing a transdcrmally delivered aspirin composition. is the stability of the composition over time.

Many aspirin solutions are inherently unstable and rapidly break down into

J salicylic and acetic acids, and related compounds. This instability has prevented many liquid forms of aspirin from being produced commercially as well. Generally speaking, it is considered that any solvent having sufficient polarity to dissolve aspirin at a concentration sufficiently useful for practical 5 employment is also a solvent that will lead to an unacceptable level of decomposition of aspirin. It is believed that an aspirin composition should be relatively stable for between about 10-15 days to be of any practical use in a transdermal delivery system.

Accordingly, in the state of the art today there remains a necd for a transdermally deliverable form of aspirin, as in a suitably-sized patch applied to the skin, for introduction of an aspirin-containing solution substantially free of undissolved aspirin particles as well as of toxic solvents which could cause unacceptable side-effects.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide an aspirin . composition adapted and suitable for transdermal delivery over an extended period of time, wherein the aspirin composition is acceptably soluble in . pharmaceutically acceptable solvents at adequately high concentrations so as to assist in propelling the composition through the skin, while avoiding unacceptable irritation of the skin, and which resulting aspirin composition will exhibit acceptable stability for a minimum of about 10 days.

It is a further object of the invention to provide a suitable device or patch tor transdermally delivering the aspirin composition.

Another object of the invention is to provide a method for the preparation of the aspirin composition and for the transdermal application of the aspirin composition.

: -

As used herein, the term “aspirin” is used for simplicity to refer to the organic molecular entity generally known as acetyl salicylate, whether present as acetyl salicylic acid (aspirin) or as the sodium (or another alkali metal) salt of acetyl salicylic acid, or more particularly as an amine salt of acetyl salicylic acid.

Accordingly, by thc present invention a composition of aspirin, an organic amine and a pharmaceutically acceptable solvent is provided wherein the concentration of aspirin in the solvent is at least about 40%. A transdermal delivery patch is also provided so as to contain the separated components of (a) aspirin and (b) an organic amine in combination with a primary solvent until they are combined to at least an effective degree at the point and time of use. The then resulting dissolved composition has acceptable stability as to the aspirin solute for at least a period of between 10-16 days. Espccially suitable organic amines include ethanolamines, while propylene glycol is conveniently provided as the primary solvent.

The various features of novelty, which characterize the invention, arc \ pointed out with particularity in the claims annexed hereto and forming a part of this disclosure. For a better understanding of the invention, its operating advantages and specific objccts attained by its uses, reference is also made to 2¢ the accompanying drawing and descriptive matter in which a preferred embodiment of the invention is illustrated.

BRIEF DESCRIPTION OF THE DRAWING

The accompanying drawing shows a schematic representation of one form of a transdermal patch suitable for storing and delivering the composition of the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the composition of the invention, dissolved aspirin is present in a relatively high concentration in solution of an organic amine and a pharmaceutically acceptable solvent. While not wishing to be bound by any theory as to the precise manner in which this invention is effective, it is believed that the organic amine operates to form a desirably and suitably soluble amine salt of the acetyl salicylic acid in the polar solvent so as to permit a reasonably rapid dissolution of the aspirin therein at an relatively high and efficacious concentration as a practical mater.

It is of course desirable that the aspirin be present in a suitably comminuted form both as to particle size and particle size distribution.

Suitable mesh particle sizes include the commonly available 325 mesh and are believed to range from about 80 mesh to about 600 mesh, or so. By and large, the rate of dissolution is a function of particle size, or conversely specific surface area, such that the smaller the particle, the more rapid the dissolution is likely to be. However, this can also be affected by the presence of pharmaceutically-acceptable agent additives which, while not essential to operability, are also contemplated in the practice of this invention. In the practice of this invention the pharmaceutically acceptable primary solvent is 26 generally a lower alkyl compound usually having at least two hydroxyl groups.

Such species include propylene glycol, glycerin and diethylene glycol.

However, the invention specifically also contemplates mixtures of such alkyl hydroxyl compounds. For instance, a mixture of glycerin and isopropanol is a useful pharmaceutically acceptable primary solvent and provides a desirably high concentration of dissolved aspirin. Frequently, an initially overly viscous solution in the primary solvent will, upon addition of such a second alkyl hydroxyl compound lead to a less viscous solution with complete clarity. Such additional alkyl hydroxy compounds may include cthamol, isopropanol ,

isooctanol, etc. The material factor in formulating mixtures of the primary solvent components is that they be entirely miscible with each other. at least up to about a 50 vol. % mixture.

As the organic aminc. it is generally desirable that this component be selected for its acceptable miscibility or solubility if it is a solid, at ambient temperatures, in the selected primary solvent. Such species preferably have at

Icast two substituents of the amine or hydroxyl nature. and generally include the lower alkyl amines, diamines and hydroxyamines. Compounds having from 2 to about 10) carbon atom compounds are generally suitable and may be employed. As with the primary solvent component, more that one of the organic amine entities may also be used in combination with the primary solvent, including mixtures of such solvent components. Suitable species of lower alkyl organic amines include diamines such as ethylenediamine. propylene diamine, and hydroxy! group substituted hydroxyamines such as ethanolamine, diethanolamine, triethanolamine, etc. Of course. the components of the resulting aspirin solution should also be pharmaceutically suitable and generally free from such characteristics as would, for instance, lead to irritation of the skin. Dimethyl sulfoxide could. for instance, also be used in a composition according to this invention but this is a compound that, while pharmaceutically acceptable, can also cause imitation to the skin for at least some patients.

It is also generally useful to select the components of the resulting solvent combination such that only a low volatility is exhibited in the ulnmate transdermal patch device.

The following exampic is provided as an illustration of one embodiment of the invention. but the invention should not be comstrued as lemited thereto.

Example 1

First, tri-ethanolamine was mixed with propylene glycol to produce a solution having 419% wt/vol of tricthanolamine. One thousand milligrams of powdered aspirin (mesh #325) was stirred into 2 ml of the combined triethanolamine in propylene glycol. The aspirin rapidly dissolved into solution to produce a mixture having a final volume of about 2.5 ml. The concentration of aspirin in this solution is thus in excess of 40%.

The aspirin solution was kept at room temperature for 16 days. At that time a measurement was made of the free salicylic acid content of the solution to test and measure the stability of the solution. The free salicylic acid content was between 3.5% and 4.0%, indicating that 96% to 96.5% of the aspirin was still in solution, with little hydrolysis of the acetyl group. The solution thus exhibited good stability.

This aspirin solution was applied to several subjects’ skin for 15 days.

After 15 days, the subjects’ skin was examined and no skin irritation was observed.

Other organic amines which are considered particularly useful with the aspirin solution include other ethanolamines, such as mono-ethanolamine and di-ethanolamine. Solutions similar to that of Example 1, above, were obtained using mono and di-ethanolamine. These amines are not volatile, have little or no odor and they cause little or no irritation to the skin when combined with aspirin.

4 WO 00/76315 PCT/US99/12793

Further illustrative examples incluce the following:

Example 2

N,N-Dimethylethanolamine with Propyleneglycol.

These components are shown to be fully compatible and miscible in proportions ranging from 25:75; 50:50; and 75:25. In each case, aspirin (mesh #325) is fully soluble up to at least 1.00g (in the total volume of 2.5 ml) resulting in clear viscous solutions. It was also determined that 2-butanol is fully compatible with such mixture and slightly decreases the viscosity of the formulation.

Example 3

Triethanolamine with Dipropyleneglycol.

These components arc shown to be fully compatible and miscible in . proportions ranging from 25:75; 50:50; and 75:25. In each case, aspirin (mesh #325) is fully soluble up to at least 1.00g (in the total volume of about 2.5 ml) } 15 resulting in clear viscous solutions.

Example 4

Ethanolamine with Propyleneglycol.

These components are shown to be fully compatible and miscible in proportions ranging from 25:75: 50:50; and 75:25. In each case, aspirin (mesh #325) is fully soluble up to at least 1.00 g (in the total volume of 2.5 ml) resulting in clear viscous solutions. In one example, as much as 1.50 g of aspirin was soluble. It was also determined that addition of dimcthoxyethane and separately also of dimethylformamide are fully compatible and when added slightly decreased the viscosity of the formulation.

Example 5

Triethanolamine (1.00 g) was mixed with propyleneglycol (1.00 ml) to produce a fully miscible, clear solution. Aspirin (1.25 g. mesh #325) was added portionwise to give a clear, viscous solution having a pH of 5. s Example 6

Triethanolamine (0.50 g) was mixed with propyleneglycol (1.50 ml) to produce a fully miscible, clear solution. Aspirin (1.00 g mesh #325) was added portionwise to give a slightly cloudy solution (less viscous than example 6) having a pH of 5.

Example 7

Triethanolamine (1.50 g) was mixed with propyleneglycol (0.50 ml) to produce a fully miscible, clear solution. Aspirin (1.25 g mesh #325) was added portionwise to give a clear solution (morc viscous than Example 1) having a pH of 5. .

Example 8

The clear, viscous solution from example 5 was treated with dimethylsulfoxide which was added portionwise in 0.20 ml increments up to a total volume of 1.00 mil of dimethylsulfoxide. The solution became less viscous and remained completely clear and had a pH of 5.

Example 9

The viscous solution from example 6 was treated with 100% ethanol which was added portionwise in 0.10 mi increments up to a total volume of 0.40 ml of ethanol. The solution became less viscous, was completely clear, and had a pH of 5.

4 WO 00/76315 PCT/US99/12793

Example 10

The clear, viscous solution from example 7 was treated with 100% ethanol which was added portionwise in 0.10 ml increments up to a total volume of 0.40 ml of ethanol. The solution became less viscous and remained completely clear and had a pH of 5.

Example 11

Ethylenediamine (1.00 ml) was mixed with propyleneglycol ( 1.00 ml) to produce a fully miscible, clear solution. Aspirin (1.00 g, mesh #325) was added portionwise to give a clear, viscous solution which had a pH of 9.

Example 12

Ethylenediamine (0.50 ml) was mixed with propyleneglycol (1.50 ml) to produce a fully miscible, clear solution. Aspirin (1.00 g, mesh #325) was added portionwise to give a clear, viscous solution having a pH of 8.

Example 13 Ethylenediamine (1.50 ml) was mixed with propyleneglycol (0.50 ml) to produce a fully miscible, clear solution. Aspirin (1.00 g, mesh #325) was added portionwise to give a clear, viscous solution having a pH of 10. lixample 14

Triethanolamine (1.00 g) was mixed with glycerol (1.00 ml) to produce a fully miscible, clear solution. Aspirin (1.00 g, mesh #325) was added portionwise to give a clear, viscous solution having a pH of 7.

Example 15

Triethanolamine (0.30 g) was mixed with glycerol (1.50 ml) to produce a fully miscible clear solution. Aspirin (0.50 g, mesh #325) was added portionwise to give a clear viscous solution having a pH of 7. The addition of more aspirin (.25 g) resulted in the formation of a viscous suspension having a pH of 6.

Example 16

Triethanolamine (1.50 g) was mixed with glycerol (0.50 ml) to produce a fully miscible, clear solution. Aspirin (1.00 g, mesh #325) was added portionwise and a clear, pasty, viscous solution was obtained. The solution had a pH of 8. -¢ Example 17

The clear, viscous solution from Example 14 was treated with 1-propanol which was added portionwise in 0.10 ml increments up to a total volumc of 0.40 ml of I-propanol. The solution became less viscous, remained completely clear, and had a pH of 7. : zs Example 18

The viscous suspension from Example 15 was treated with I-propanol which was added portionwise in 0.10 ml increments up to a total volume of 0.80 ml of 1-propanol. The solution became less viscous, became completely clear, and had a pH of 6. 206 Example 19

The clcar, viscous solution from Example 16 was trcated with 2-octanol, which was added portionwise in 0.10 ml increments up to a total volume of 0.80 ml of 2-octanol. The solution became less viscous, remained completely clear, and had a pH of 8.

4 WO 00/76315 PCT/US99/12793

Example 20

Triethanolamine (1.00 g) was mixed with diethyleneglycol (1.00 ml) to produce a fully miscible, clear solution. Aspirin (1.00 g, mesh #325) was added portionwise to give a clear, viscous solution having a pH of 7.

Example 21

Triecthanolamine (0.50 g) was mixed with dicthylencglycol (1.50 ml) to produce a fully miscible, clear solution. Aspirin (1.00 g, mesh #325) was added portionwise to give a clear, viscous solution which had a pH of 6.

Example 22

Triethanolamine (1.50 g) was mixed with diethyleneglycol (0.50 ml) to produce a fully miscible, clear solution. Aspirin (1.00 g, mesh #325) was added portionwise to give a clear, pasty, viscous solution having a pH of 8.

Example 23

The pasty, viscous solution from Example 22 was treated with 2-propanol which was added portionwise in 0.10 ml increments up to a total volume of 0.50 m! of 2-propanol. The solution became less viscous. became completely clear, and had a pH of 8.

Example 24

N,N-Dimethylethanolamine (1.00 ml) was mixed with propyleneglycol (1.00 ml) to produce a fully miscible, clear solution. Aspirin (1.000 g, mesh #325) was added portionwise to give a clear, slightly viscous solution which had a Ph of 9.

Example 25

N.N-Dimethylethanolamine (0.50 ml) was mixed with propyleneglycol (1.50 ml) to produce a fully miscible, clear solution. Aspirin (1.000 g, mesh #325) was added portionwisc to give a clear, slightly viscous solution which had a pH of ~6.

Example 26

N,N-Dimethylethanolamine (1.50 ml) was mixed with propyleneglycol (0.50 m}) to produce a fully miscible, clear solution. Aspirin (1.000 g, mesh #325) was added portionwise to give a clear, slightly viscous solution which had a 1c pHof ~10.

Example 27

The clear solution from Example 24 was treated with 2-butanol which was added portionwise in 0.10 ml increments up to a total volume of 0.50 mi of 2- butanol. The solution became less viscous and remained completely clear and had a pH of ~9.

Example 28

Triethanolamine (1.00 g) was mixed with dipropyleneglycol (1.00 ml) to produce a fully miscible, clear solution. Aspirin (1.000 g. mesh #325) was added portionwise to give a clear, slightly viscous solution which had a pH of 20-6.

Example 29

Triethanolamine (0.50 g) was mixed with dipropyleneglycol (1.50 ml) to produce a fully miscible, clear solution. Aspirin (1.000 g, mesh #325) was added portionwise to give a clear, viscous solution which had a pH of ~5.

tv WO 0076315 PCT/US99/12793

Example 30

Triethanolamine (1.50 g) was mixed with dipropyleneglycol (1.50 ml) to produce a fully miscible, clear solution. Aspirin (1.000 g, mesh #325) was added portionwise to give a clear, viscous solution which had a pH of ~8.

Example 31

Ethanolamine (1.00 ml) was mixed with propylencglycol (1.00 ml) to produce a fully misciblc, clear solution. Aspirin (1.000 g, mesh #325) was added portion wise to give a clear solution which had a pH of ~10. An additional quantity of aspirin (0.500 g, mesh #325) was added and the solution remained clear and fully soluble with-a pH of ~9.

Example 32 }

Ethanolamine (0.50 mi) was mixed with proplyleneglycol (1.50 ml) to produce : a fully miscible, clear solution. Aspirin (1.000 g. mesh #325) was added } portion wise to give a clear solution which had a pIl of ~9. : B

Example 33

Ethanolamine (1.50 ml) was mixed with propyleneglycol (0.50 ml) to produce a fully miscible, clear solution. Aspirin (1.000 g, mesh #325) was added portionwise to give a clear solution which had a pH of ~10.

Example 34

The clear solution from Example 31 was treated with dimethoxyethane which as added portion wise in 0.10 ml incremenets up to a total volume of 1.00 ml - : of dimethoxyethane. The solution remained completely clear and had a pH of ~9.

AMENDED SHEET 2002 -07- 3g

Example 35

The clear solution from Example 32 was treated with dimethyltormamide which was added portionwise in 0.10 ml increments up to 2 total volume of 1.00 ml! of dimethylformamide. The solution remained completely cicar and oo had a pil of ~7. ,

Example 36

Triethanolamine (1.00 g) was made mixed with 1,5-pentanediol (1.00.ml) to produce a fully miscible, clear solution. Aspirin (1.000 g, mesh #325) was added portionwise to give a viscous, pasty solution which had 4 pH of ~7. The pasty solution became clear on standing for 30 minutes.

Example 37

Triethanolamine (0.50 g) was mixed with 1,5-pentamediol (1.50 ml) to produce a fully miscible, clear solution. Aspirin (1.000 g, mesh #325) was . addedd portionwise to give a viscous, pasty solution, which had a pH of ~6. :

The pasty solution became clear on standing for 30 minutes.

Example 38

Triethanolamine (1.50 g ) was mixed with 1,5-pentanediol (0.50 ml) to producc a fully miscible, clear solution. Aspirin (1.000 g, mesh #325) was added portionwise to give a viscous, pasty solution which had a pH of ~8. The pasty solution became clcar on standing for 30 minutes.

Example 39

Triethanolamine (1.00 g) ws mixed with poly(ethyleneglycol) (1.00 ml; :

Mw,,.300) to produce a fully miscible, clear solution. Aspirin (1.000 g. mesh : AMENDED SHEET 2002 -07- 3 ¢

#325) wus added portionwise to give a very viscous, pasty slurry which had a pH of ~7. The pasty slurry became clear on standing for 30 minutes. . :

Example 40

Triethanolamine (0.50 g) was mixed with poly(ethyleneglycol) (1.50 ml; Mw ave300) to produce a fully miscible, clear solution. Aspirin (1.000 g, mesh #325) was added portionwise Lo give a very viscous, pasty slurry which hada pH of ~6.

Example 41

Triethanolamine (1.50 g) was mixed with poly(ethyleneglycol) (0.50 ml:

Mw,,,300) to produce a fully miscible, clear solution. Aspirin (1.000 g. mesh #325) was added portionwise to give a very viscous, pasty slurry which had a pH of ~8. The pasty slurry became clear on standing for 30 minutes. : Example 42

Propanolamine (1.00 ml) was mixed with propyleneglycol (1.00 ml) to ~ produce a fully miscible, clear solution. Aspirin (1,000 g, mesh #325) was added portionwise 10 give a clear solution which had a pH of -8.

Example 43

Propanolamine (0.50 ml) was mixed with propyleneglycol (1.50 ml) to produce a fully miscible, clear solution. Aspirin (1.000 g. mesh #325) was added portionwise to give a clear solution which had a pH of ~7.

Example 44 ;

Propanolamine (1.50 ml) was mixed with propyleneglycol (0.50 ml) to produce a fully miscible. clear solution. Aspirin (1.000 2. mesh #325) was added portionwise to give a clear solution which had a pH of ~8.

AMENDED SHEET 2002 -07- 3.0

: Example 45 .

Diethanolamine (1.00 ml) was mixed with propyleneglycol (1.00 ml) to produce a fully miscible, clear solution. Aspirin (1.000 g. mesh #325) was added portionwise to give a viscous, cloudy solution which had a pH of -8.

The solution cleared on standing for 15 minutes.

Example 46 © Diethanolamine (0.50 ml) was mixed with propyleneglycol (1.50 ml) to produce a fully miscible. clear solution. Aspirin (1.000 g. mesh #325) was added portionwise to give a viscous, cloudy solution which had a pH of ~7.

The solution cleared on standing for 15 minutes.

Example 47

Diethanolamine (1.50 ml) was mixed with propyleneglycol (0.50 ml) to produce a fully miscible, clear solution. Aspirin (1.000 g, mesh #325) was B added portionwise to give a viscous, cloudy solution which had a pH of ~8. :

The solution cleared on standing for 15 minutes.

Example 48 oo Triethanolamine (1.00 ml) was mixed with 1,3-propanediol (1.00 ml) to produce a fully miscible, clear solution. Aspirin (1.000 g. mesh #325) was added portionwise to give a very viscous, thick solution which had a pH of -8. :

The solution cleared on standing for 30 minutes.

Example 49

Triethanolamine (0.50 ml) was mixed with 1,3-propancdiol (1.50 ml) to produce a fully miscible, clear solution. Aspirin (1.000 g. mesh #325) was

AMENDED SHEET 2002 -07- 3.0 added portionwise to give a viscous, cloudy solution which had a pH of ~6.

The solution cleared on standing for 30 minutes.

Example 50

Triethanolamine (1.50 ml) was mixed with 1,3-propanediol (0.50 ml) to produce a fully miscible, clear solution. Aspirin (1.000 g, mesh #325) was : added portionwise to give a very viscous, pasty solution which had a pH of -8.

The solution cleared on standing for 30 minutes.

Frequently the solutions of the previous examples are of a consistency resembling a gel, flowing somewhat in the manner of honey, even though otherwise clear and essentially colorless.

It is within the scope of the present invention to employ the above solutions of aspirin in the primary solvent with thc amine component and additives as desired in the transdermal patch, with the proviso that initially the : aspirin component should be kept separate from the said solvent/amine combination and prior to actual use. It will be understood that the . solvent/amine combinations and any desired additives should be essentially water-free for purposes of avoiding deterioration of the aspirin component after mixing therewith.

Triethanolamine is generally preferred as the organic amine used with the aspirin solution because it is the least irritating to skin.

Propylene glycol is preferred as a pharmaceutically acceptable primary solvent because of its properties as a transdermal propellant and because it is : not a skin irritant. It is envisioned that other solvents having similar properties could be used in place of propylene glycol. In combination with a suitable organic amine, even glycerin exhibits adequate solubility at a level of at least about 40 wt. %, 50 wt, % or more, and may therefore be employed as well.

AMENDED SHEET 2002 -07- 30 a2; = 30

\

The addition of various alkanols to glycerol is generally effective to provide clear, less viscous solutions.

Other mesh sizes of aspirin may also be uscd with these solutions, such as mesh #200 or #100, with similar results. These mesh sizes require more time to fully dissolve in the organic amine and primary solvent mixture. As 81 mg per day is considered an acceptable adult dose of aspirin, the particular quantity of aspirin to be dissolved in solution depends on the length of time it is anticipated the aspirin solution will be transdermally delivered. Thus, for a 14-day patch. about 1,100 mg of aspirin must be dissolved in solution.

Similarly, a 10-day patch would require about 810 mg of aspirin to be dissolved in solution.

Both lower and higher concentrations of aspirin in the solutions of the examples, illustrative of the practices according to the invention, are possible as well. Solutions having aspirin concentrations of 50 wt. % or more may be produced according to this invention. By making solutions of even higher concentrations of aspirin, such as more than 50 wt. %, the overall size of the ] patch may be reduced for equivalent dosages, or even longer use patches may be provided. : )

The primary solvent is preferably a saturated acyclic aliphatic diol and may be of the following general formula:

H-O-R-(0—R),-0O--H wherein R may be the same or different linear or branched chain acyclic hydrocarbyl radical of from 2 to about 6 carbon atoms and y may be a number from O to about 5.

4 WO 00176315 PCT/US99/12793

The amino components may be of the formula. 1

R>—N—(CH,),—X wherein n represents a number from 2 to about 4, Ry and R, may each independently represent H or an acyclic hydrocarbyl radical of from 2 to about 4 carbon atoms including hydroxy- or amino-substituted radicals; and X may represent H, OH. or a primary, secondary or tertiary amine substituted in turn by either or both of R; or R,. Non-reactive substituents may also be present on the hydrocarbyl radicals and on the “CH2" moieties as well, including halogens such as chlorine or an -O-hydrocarbyl entity, such as ethoxy.

The primary solvent may also contain compatible. acceptably miscible, or soluble, pharmaceutically acceptable additives such as a primary or secondary alkanol having from 2 to about 6 carbon atoms, or the additive may be dimethylsulfoxide, dimethoxyethane, dimethylformamide or a lower hydrocarbyl acyclic or cyclic ester such as ethyl acetate or a lactone such as butyrolactone or amyllactone, or cyclic ethers such as tetrahydrofuran. ) Mixtures of such additives may also be used as desired. 2C The components are desirably substantially water free in order to avoid undue decomposition of the acetyl salicylate moiety.

Of course, mixtures of any of the above materials may be employed. the selection of the specific hydroxy primary solvent, amino compound or the additive being within the skill of those persons in this the art having knowledge of the disclosure of this invention, with due regard to such factors as the materials used in making the transdermal patch, the rate at which transdermal delivery of aspirin is desired for a given medical objective. the volatility and stability of the resulting mixtures, etc.

In general, the resulling mixtures may exhibit a pH ranging from about to about 10. The amino compounds generally exhibit a pKb of from about 3 to about 4.5.

DETAILED DESCRIPTION OF THE DRAWING

5 Fig. 1 shows a transdermal patch 10 suitable for storing the components of the solution until use. The patch 10 has two reservoirs 20, 30 separated by a divider 60. Powdered aspirin 25 of suitable mesh size is kept in reservoir 20. A solution 35 of the organic amine and pharmaceutically acceptable solvent is kept on reservoir 30. A removable slide 40 covers each reservoir 20, 30 and prevents contact of the aspirin 25 and solution 35 prior to use of the patch 10.

In this embodiment of the patch, just prior to use the slide 40 may be pulled away from the tops of the reservoirs 20, 30, thereby permitting the aspirin 25 and solution 35 to mix and form the aspirin solution for transdermal delivery through permeable membrane 50, which is placed in contact with the : user's skin in a suitable location. The patch 10 may be shaken following removal of the slide 40 to hasten the dissolution of the aspirin 25 in solution - 35.

Alternatively, the transdermal patch may be constructed in other forms the essential requirement being that the particulate aspirin be isolated from the solvent combination until the point of use. Various approaches to this requirement will be apparent to those skilled in the art of providing transdermal patches and may include the provision of a frangible membrane arranged lateraly between the two walls of the patch device, suitably sealed at the edges so as to be impermeable until fractured to the solvent. and which may be ruptured by mechanical manipulation of the patch device, such as is illustrated in U.S. Patent 4,900,552, without being hound to the specific

. ~ WO 00176315 PCT/US99/12793 construction of that patent. Alternatively, use may be made of such techniques as encapsulating, including microencapsulation, of the solvent until the time of use when the capsulation means are fractured by suitable forces 10 release the solvent for contact with the solid comminuted aspirin. Still another alternative - is to assemble the patch al the time and point of usc from entirely separate elements, i.e. separate reservoirs containing respectively the solid particulate ~ aspirin and the solvent combination. For instance the aspirin can be maintained in a permeable packet within a hermetically sealed envelope which opened just ° prior to use. Similarly, the solvent combination can be in a separate vial typy device which is openable by fracturing or otherwise. These elements can then be secured together adjacent each other with a suitable bonding member and including appropriate means to adhere the assembly to the skin surface.

While specific embodiments of the invention have been shown and described in detail to illustrate the application of the principles of the 1S invention, it will be understood that the invention may be embodicd otherwise : ' without departing from such principles.

Conversion Table 1410 1190 1000 60 J2s0

EO vA

SMENDED SHEET 2002 -07- 30

Claims

J WHAT IS CLAIMED IS:

1. A solution containing relatively high concentrations of aspirin for transdermal delivery, the solution comprising: a pharmaceutically acceptable primary solvent; an organic amine; and aspirin in an amount suitable to provide a medically acceptable dosage.

2. A solution according to claim 1, wherein the solvent is propylene glycol.

3. A solution according to claim 2, wherein the organic amine i$ an ethanolamine.

4. A solution according to claim 3, wherein thc organic amine is triethanolamine.

5. A solution according to claim 1, wherein the organic amine is an cthanolamine. 1s

6. A solution according to claim 5, wherein the organic amine is triethanolamine.

7. A method of storing aspirin to be delivered transdermally to a patient, the method comprising: providing a transdermal patch having at least a pair of reservoirs which are initially separated from each other by a divider, with a remavable slide to permit the reservoirs to be in communication with each other when the slide is removed;

6315 PCT/US99/12793 providing a pharmaceutically acceptable primary solvent in at least one = of the reservoirs; providing an organic amine in the reservoir containing the primary solvent; providing aspirin in at least one other reservoir.-such that it is separated from and not dissolved in the combination of the primary solvent and organic amine in the first reservoir until the removable slide is removed.

8. A method according to claim 7, wherein the organic amine is an ethanolamine. -

- 9. A method according to claim 8. wherein the primary solvent is propylene glycol. Co

10. A method according to claim 9, wherein the organic amine is triethanolamine.

11. A method according to claim 7, wherein the primary solvent is : 15 propylene glycol.

12. A medicament made by dissolving a medically acceptable dosage amount of aspirin for administration to a patient over a predetermined period of time in a pharmaceutically acceptable primary solvent in combination with an organic amine to form a solution having a concentration of aspirin of at least 30%; for use in a method of administering aspirin transdermally to a = patient by applying the solution to the skin of the patient for the effective period of time. AMENDED SHEET 2002 07- 3.0

13. A medicament according to claim 12, wherein the pharmaceutically acceptable primary solvent is propylene glycol. ’ 14. A medicament according to claim 13, wherein the organic amine is an

A . s ethanolamine. : }

15. A medicament according to claim 13, wherein the organic amine is triethanolamine.

16. A medicament according to claim 12, wherein the organic amine is an ethanolamine.

17. A medicament according to claim 12, wherein the concentration of aspirin is at least 40%.

18. A medicament according to claim 12, wherein the period of time is between 10 and 15 days.

19. A device for delivery of aspirin transdermally to a mammal which comprises providing at least one chamber for separately containing : . aspirin in solid comminuted form and providing a separately retained solubilizing solvent combination component having . (1 at least one first phariaceutically-acceptable lower polyhydroxyl acyclic hydrocarbyl component, liquid at normal temperatures, and functioning as a primary solvent, in combination with - (1) at least one pharmaceutically-acceptable acyclic aliphatic amine having a pKa capable of forming an amine salt with acetylsalicylic acid without substantial hydrolysis of the acetyl AMENDED ©" 2002 -07- 30

4 WO 00776315 PCT/US99/12793 group and effectively miscible or soluble in said primary solvent, said solvent combination of (i) and (ii) having the capability upon admixture with each other of dissolving the acetylsalicylic acid component at least in part as an amine acetylsalicylate complex which is in turn capable of dissociating pharmacologically at least in part into its constituent parts including an effective amount of acetylsalicylate, said device being operative coincident with the time of its application to said mammal to provide an intermixing of the acetylsalicylate with said solubilizing component combination to achieve thereby a substantial and effective formation and dissolution of the amine acetylsalicylate salt at a concentration level sufficient to permit delivery of a therapeutic amount of the dissolved acetylsalicylate component for percutaneous absorption through the mammalian epidermus and dermis.

20. A method for the manufacture of a transdermal patch device operative in use for the delivery of aspirin which comprises: ) forming at least one exterior wall member permeable to a liquid and 26 adapted for attachment to the surface of the skin of a mammal; and forming at least one relatively impermeable second exterior wall member positioned oppositely to said liquid-permeable exterior wall member: forming a at least one interior wall member arranged between said exterior wall members and so as to respectively define at least two separate chambers therewithin; constructing at least one of said interior wall members so as to maintain separate from each other a solid component in one of said chambers from a liquid component in a second of said chambers, and providing at least one interior wall member to be removable upon use of said device;

{ placing a desired quantity of solid comminuted aspirin in at least one of said separate chambers; and placing a desired quantity of a normally liquid primary solvent combination in at least one other of said separate chambers, and wherein said solvent combination has the capability of dissolving said solid aspirin upon mixing thercwith and the resulting solution having the capability of transmission through said permeable wall member so as to contact said skin surface with the dissolved aspirin component therein.

21. A method for the manufacture of a transdermal patch device which comprises: forming at least one liquid-permeable extcrior wall member adapted for attachment to the skin of a mammal; and forming at least one relatively impermeable exterior wall member positioned oppositely to said liquid-permeable exterior wall member; forming a plurality of interior wall members arranged between said exterior wall members and so as to respectively define a plurality of separate chambers; : constructing at least one of said interior wall members to maintain separate from each other a solid component in at least one of said chambers : from a liquid component in at least one of the second of said chambers: and providing at least one interior wall member to be removable upon use of said device; wherein said at least one of said separate chambers has the capability of containing solid comminuted aspirin; and wherein said at least one other of said separate chambers has the capability of containing a normally liquid solvent.

22. A method for the manufacture of a transdermal patch device : operative in use for the transdermal delivery of aspirin which comprises: : obtaining the transdermal patch device of claim 20 or 21; : : placing a desired quantity of solid comminuted aspirin in at least one of said separatc chambers; ' : placing a desired quantity of a normally liquid primary solvent combination in at lcast one other of said separate chambers; a wherein said primary solvent combination has the capability of dissolving said solid aspirin upon mixing therewith; placing said transdermal patch device containing aspirin and the primary solvent combination within an enveloping sealable solvent impermeable envelope; and sealing said envelope. a

23. A device for delivery of aspirin transdermally to a mammal : which comprises: | BE : at least one chamber for separately containing aspirin in solid comminuted form; and ~ a separately retained solubilizing solvent combination cornponent having: (i) at least one first pharmaceutically-acceptable saturated : acyclic aliphatic diol represented by formula: _ H-0O-R-(0—R),-O-—H AMENDED SHEET p09 0 5 wherein R may be the same or different linear or branched chain acyclic hydrocarbyl radical of from 2 to about 6 carbon atoms and y may be a number from Oto 3. in combination with (ii) at least one pharmaceutically-acceptable lower alkyl amine represented by the formula: I Ry—N—(CHa),—X wherein n represents a number from 2 to about 4, R; and R; may each independently represent H or an acyclic hydrocarbyl radical of from 2 to about 4 carbon atoms including hydroxy- or amino-substituted radicals; and X may represent OH, or a primary, secondary or tertiary amine substituted in turn by either or both of R; or Ra; said solvent combination of (i) and (ii) having the capability upon admixture with each other of dissolving the acetylsalicylic acid ; component at least in part as an amine acetylsalicylate complex which is in turn capable of dissociating pharmacologically at least in part into . its constituent parts including an effective amount of acetylsalicylate, said device being operative coincident with the time of its application to said mammal to provide an intermixing of the acetylsalicylate with said solubilizing component combination to achieve thereby a substantial and effective dissolution of the amine acetylsalicylate salt at a concentration level 2s sufficient to permit delivery of a therapeutic amount of the dissolved acetylsalicylate component for percutaneous absorption through the mammalian epidermus and dermis.

A WO 00/76315 PCT/US99/12793

.

24. The device according to claim 23, wherein said acyclic * hydrocarbyl diol also includes at least one additive selected from the group ~ consisting of a primary alkanol having from 2 to about 6 carbon atoms, a : secondary alkanol having from 2 to about 6 carbon atoms, dimethylsulfoxide, dimethoxyethane, dimethylformamide, a lower hydrocarbyl acyclic or cyclic oo ester, a lactone or tetrahydrofuran. .

25. The combination of : (1) a pharmaceutically acceptable primary solvent of the : : formula

10 . H-0-R-(0—R),-0O--H : wherein R may bc the same or different linear or branched chain acyclic hydrocarbyl radical of from 2 to about 6 carbon atoms and y may be a number from 0 to about 5, and Co (2) at least one pharmaceutically-acceptable lower alkyl amine 15s represented by the formula: | i. . Rr, : . oo Ri;—N—(CHa),—X } : 20 wherein n represents a number from 2 to about 4, R; and R, may each independently represent H or an acyclic hydrocarbyl radical of from 2 to about 4 carbon atoms including hydroxy- or amino-substituted radicals; and X may a represent OH, or a primary, secondary or tertiary amine substituted in turn by either or both of R; or Ry; and (2) dissolved acetylsalicylic acid in the combination of (1) and (2) at a concentration of at least about 20 wt. %. AMENDED SHEET 2002 .g7- 3 ¢