EP1104236A1 - Transdermally delivered aspirin - Google Patents

Transdermally delivered aspirin

Info

Publication number
EP1104236A1
EP1104236A1 EP99928460A EP99928460A EP1104236A1 EP 1104236 A1 EP1104236 A1 EP 1104236A1 EP 99928460 A EP99928460 A EP 99928460A EP 99928460 A EP99928460 A EP 99928460A EP 1104236 A1 EP1104236 A1 EP 1104236A1
Authority
EP
European Patent Office
Prior art keywords
aspirin
solution
solvent
combination
aspmn
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99928460A
Other languages
German (de)
French (fr)
Inventor
Alexander Galat
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP1104236A1 publication Critical patent/EP1104236A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates in general to aspirin compositions, and in paiticulai to a new and useful aspirm composition and a device which is capable of effectively administering aspirm transdermally to a mammal over a pe ⁇ od of days for effective therapeutic purposes, and a method of making and ddministenng the composition
  • Aspirm is the most widely used drug in the woild It has a numbei of impoitant uses in medicine It is a valuable analgesic, antipyretic, and heait attack and stroke-preventive
  • Aspirm is also one of the most potent anti-inflammatory agents, and is the drug of choice and mainstay of aith ⁇ tis therapy It stimulates the immune system, reduces opportunistic infections and is potentially useful as an adjunct in treating cancel , AIDS, and othei immune disordeis 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 othei injuries It has a specific analgesic effect in migiaine headaches, a condition in which acetamin
  • aspmn is not widely used as an anti- inflammatoiy agent, even though it is actually the mainstay and diug of choice in aithutis — a disease directly caused by inflammation Instead, its use in aithutis is limited mostly to alleviating pain, for which low 325-500 mg dosages suffice
  • daily aspirin dosages of 5,000+ mg aie required
  • Such daily dosages are possible since the toxicity of aspirin is low (For example, the LD-, 0 for aspirm is about 1 75 g/kg body weight ) Howevei, at such effective anti-inflammatory levels, large amounts of undissolved aspirin particles adhere to the gastrointestinal mucosa, gieatly aggravating notation and side effects in the gut
  • tiansdermal deliver ⁇ allows close conti ol ovei the rate of diug deliveiy With tiansdeimal delivery, the inteivening factois associated with oi al ingestion such as unpredictable absorption in the gastiointestinal tiact fiom fluctuating acidity and food content aie avoided
  • a tiansdeimally delivered drug does not undeigo initial metabolism by the liver
  • Aspmn administered to the skin passes into the blood thiough the skin and is carried to a site of effective medicinal function
  • This type of admimstiation 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 protective wall against permeation of substances into the body Foi this reason, a device is necessary both to contiol and permit the permeability of aspmn through the keratin layei of the skin and enhance the pei cutaneous absorption of aspirin
  • Aspirin as an undissolved solid may also be a skin l ⁇ itant as well
  • an acceptable solvent must adequately dissolve the aspmn to be placed in solution to prevent irritation from contact with undissolved aspirm
  • Piopylene glycol is well-known for use with transdermal medicines because of its ability to enhance skin penetration by the medicine being admi steied Aspirin is soluble in propylene glycol at about 10 wt % Howevei, this concentiation is still below that level that is fully useful foi practical application
  • a diffeience in osmotic pressuie must be established acioss the skin bai ei, that is, between the epidermis skin surface and the deimas legion immediately theiebelow and indeed the entue skin devisctme Skin penetrability is piopoitional to the concentration of the transpoited substance (here, aspirin) in accordance with Fuch's Law
  • Concentration of the transported substance is also important with lespect to the size of the device employed for transdeimal application required to delivei an effective dosage to the usei
  • a generally accepted dosage is 81 mg/da If it is desued to deliver this dosage daily over a two week peuod from a single tiansdeimal patch, appioximately 1 100 mg of aspmn must be dissolved in a solvent If piopylene glycol were to be used based on its preferable chaiactenstics and its 10% aspirin solubility , about 1 1 ml of solvent are required This quantity of solvent would requne an undesirably laige patch
  • Anothei object of the invention is to provide a method foi the piepaiation of the aspirm composition and toi the tiansdeimal application of the aspmn composition
  • the tei ' aspirin' is used for simplicity to lefer to the organic moleculai entity generally known as acetyl sahcylate, whethei present as acetyl salicylic acid (aspmn) 01 as the sodium (01 anothei alkali metal) salt of acetyl salicylic acid 01 moie particularly as an amine salt of acetyl salicylic acid
  • a composition of aspirin, an oiganic amme and a pharmaceutically acceptable solvent wherein the concentration of aspirm in the solvent is at least about 40%
  • a transdermal delivery patch is also provided so as to contain the separated components of (a) aspmn and (b) an organic amme in combination with a piimaiy solvent until the> aie combined to at least an effective degiee at the point and time of use
  • the then lesultmg dissolved composition has acceptable stability as to the aspirin solute for at least a period of between 10-16 days
  • Especially suitable organic amines include ethanolamines, while propylene glycol is conveniently piovided as the pnmaiy solvent
  • vanous featuies of novelty which chaiactenze the inv ention aie pointed out with paiticula ty in the claims annexed heieto and foiming a pait of this disclosuie Foi a bettei understanding of the invention, its opeiating advantages and specific objects attained by its uses leference is also made to the accompanying drawing and descriptive mattei in which a preferred embodiment of the invention is illustrated
  • the accompanying di awing shows a schematic lepresentation of one form of a transdermal patch suitable for storing and delivering the composition of the invention DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • dissolved aspirin is piesent in a relatively high concentration in solution of an organic amine and a phaimaceutically acceptable solvent
  • organic amme operates to form a desirably and suitably soluble amine salt of the acetyl salicylic acid in the polai solvent so as to peimit a reasonably rapid dissolution of the aspirin therein at an relatively high and efficacious concentration as a piactical matter
  • the aspirin be piesent in a suitably comminuted foim both as to particle size and particle size distnbution Suitable mesh paiticle sizes include the commonly available 325 mesh and are believed to lange from about 80 mesh to about 600 mesh, or so
  • the late of dissolution is a function of particle size, oi conveisely specific suiface aiea, such that the smaller the particle, the more rapid the dissolution is likety to be
  • pharmaceutically-acceptable agent additives which, while not essential to opei ability, are also contemplated in the practice of this invention
  • the pharmaceutically acceptable primary solvent is geneially a lower alkyl compound usually having at least two hydroxyl groups
  • Such species include propylene glycol, glycerin and diethylene glycol Howevei, the invention specifically also contemplates mixtuies of such alkyl hyd ⁇ ox ⁇ l compounds Foi instance
  • 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 least 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
  • moie that one of the organic amme entities may also be used in combination with the p ⁇ mary solvent, including mixtures of such solvent components
  • Suitable species of lower alkyl organic amines include diamines such as ethylenediamine, piopylene diamine, and hydroxyl group substituted hydroxyamines such as ethanolamine, diethanolamine, t ⁇ ethanolamine, etc 01 couise.
  • the components of the resulting aspirin solution should also be pharmaceutically suitable and generally free fiom such characteristics as would, foi instance, lead to irritation of the skin Dimethyl sulfoxide could, foi instance, also be used in a composition according to this invention but this is a compound that, while pharmaceutically acceptable, can also cause notation to the skin for at least some patients.
  • Fust, to-ethanolamine was mixed with propylene glycol to produce a solution having 41 % wt/vol of toethanolamine
  • One thousand milligrams of powdered aspmn (mesh #325) was stirred into 2 ml of the combined toethanolamine in propylene glycol
  • the concentiation of aspirin in this solution is thus in excess of 40%
  • the aspirm solution was kept at room temperature for 16 days At that time a measuiement was made of the fiee salicylic acid content of the solution to test and measuie 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
  • Othei oi game amines which are considered paiticularly useful with the aspmn solution include othei ethanolammes, such as mono-ethanolamine and di-ethanolamme Solutions similar to that of Example 1 , above, weie obtained using mono and di-ethanolamine These amines aie not volatile, have little oi no odoi and they cause little oi no notation to the skm when combined with aspmn
  • aspirin (mesh #325) is fully soluble up to at least l.OOg (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.
  • aspirin (mesh #325) is fully soluble up to at least l.OOg (in the total volume of about 2.5 ml) resulting in clear viscous solutions.
  • Toethanolamine (0 50 g) was mixed with propyleneglycol (1 50 ml) to pioduce a fully miscible, clear solution Aspirin (1 00 g mesh #325) was added poitionwise to give a slightly cloudy solution (less viscous than example 6) having a pH of 5
  • Ethylenediamine (1 50 ml) was mixed with piopvleneglycol (0 50 ml) to pioduce a fully miscible, cleai solution Aspirin ( 1 00 g mesh #325) was added poitionwise to give a cleai, viscous solution having a pH of 10
  • Toethanolamine (0 50 g) was mixed with glyceiol ( 1 50 ml) to produce a fully miscible cleai solution Asp n (0 50 g, mesh #325) was added portionwise to give a clear viscous solution having a pH of 7
  • Asp n (0 50 g, mesh #325) was added portionwise to give a clear viscous solution having a pH of 7
  • Toethanolamine 1 50 g was mixed with glyceiol (0 50 ml) to produce a fully miscible, cleai solution Aspirm (1 00 g, mesh #325) was added portionwise and a cleai , pasty viscous solution was obtained The solution had a pH of 8
  • Example 15 The viscous suspension fiom Example 15 was treated with I-propanol which was added poitionwise in 0 10 ml increments up to a total volume of 0 80 ml of 1-p ⁇ opanol The solution became less viscous, became completely cleai, and had a pH of 6
  • Example 20 The cleai viscous solution from Example 16 was tieated with 2-octanol, which was added poitionwise in 0 10 ml increments up to a total volume of 0 80 ml of 2 octanol The solution became less viscous, lemamed completely cleai, and had a pH of 8 Example 20
  • Toethanolamine ( l OO g) was mixed with diethv leneglycol ( 1 00 ml) to pioduce a fully miscible cleai solution Aspmn ( 1 00 g mesh #325) was added poitionwise to give a cleai, viscous solution having a pH of 7
  • T ⁇ ethanolamine 1 50 g was mixed w ith diethyleneglycol (0 O ml) to produce a lull ⁇ miscible, cleai solution Aspmn ( 1 00 g, mesh #325) was added poi tionwise to e a cleai past) viscous solution having a pH of 8
  • Example 22 The pasty, viscous solution fiom Example 22 was tieated with 2-propanol which was added poitionwise in 0 10 ml increments up to a total volume of 0 50 ml of 2-p ⁇ opanol The solution became less viscous, became completely cleai, and had a pH of 8
  • N N-Dimethylethanolamine (0 50 ml) was mixed with piopyleneglycol ( 1 50 ml) to produce a fully miscible, clear solution
  • Aspirin 1 000 g, mesh #325 was added poitionwise to give a cleai, slightly viscous solution which had a pH of ⁇ 6
  • N N-Dimethylethanolamme 1 50 ml was mixed with propyleneglycol (0 50 ml) to pioduce a fully miscible, clear solution Aspirin ( 1 000 g, mesh #325) was added poitionwise to give a cleai , slightly viscous solution which had a pH of ⁇ 10
  • Example 24 The cleai solution from Example 24 was treated with 2-butanol which was added poitionwise in 0 10 ml increments up to a total volume of 0 50 ml of 2- butanol The solution became less viscous and remained completely clear and had a pH of -9
  • Toethanolamine (1 00 g) was mixed with dipropyleneglycol (1 00 ml) to pioduce a fully miscible clear solution Aspirin ( 1 000 g, mesh #325) was added poitionwise to give a cleai, slightly viscous solution which had a pH of -6
  • Ethanolamine (1 00 ml) was mixed with propyleneglycol (1 00 ml) to produce a fully miscible cleai solution
  • Aspirm (1 000 g mesh #325) was added poition wise to give a cleai solution which had a pH of -10
  • An additional quantity of aspirin (0 500 g, mesh #325) was added and the solution lemained cleai and fully soluble with a pH of -9
  • Ethanolamine (0 50 ml) was mixed with proplyleneglycol ( 1 50 ml) to pioduce a fully miscible, cleai solution Aspirin (1,000 g, mesh #325) w as added poition wise to give a cleai solution which had a pH of -9
  • Example 35 The cleai solution fiom Example 31 was tieated w ith dimethoxyethane which as added poition wise in 0 10 ml incremenets up to a total volume of 1 00 ml of dimethoxyethane The solution remained completelv cleai and had a pH of -9 Example 35
  • the cleai solution fiom Example 32 was tieated with dimethyltoimamide w hich was added poitionwise in 0 10 ml inciements up to a total volume oi 1 00 ml of dimethylfoimamide The solution lemained completely cleai and had a pH of -7
  • Toethanolamine (1 00 g) was made mixed with 1,5-pentanediol (1 00 ml) to pioduce a fully miscible, cleai solution Aspirin (1,000 g, mesh #325) was added poitionwise to give a viscous, pasty solution which had a pH of -7 The pastv solution became cleai on standing foi 30 minutes
  • Toethanolamine (0 50 g) was mixed with 1 5-pentamed ⁇ ol ( 1 50 ml) to pioduce a fully miscible, cleai solution Aspirin (1 ,000 g, mesh #325) was addedd poitionwise to give a viscous pasty solution which had a pH of ⁇ 6 The pasty solution became cleai on standing foi 30 minutes
  • Toethanolamine (1 50 g ) was mixed with 1,5-pentanediol (0 50 ml) to pioduce a fully miscible, cleai solution Aspirin (1,000 g, mesh #325) was added poitionwise to give a viscous pasty solution which had a pH of -8 The pasty solution became clear on standing foi 30 minutes
  • Toethanolamine (1 00 g) ws mixed with poly(ethyleneglycol) ( 1 00 ml, Mw a 300) to pioduce a fully miscible cleai solution Aspmn ( 1 000 g, mesh #325) was added poitionwise to give a veiy viscous, pasty sluiry which had a pH of ⁇ 7 The pasty sluny became cleai on standing for 30 minutes
  • Toethanolamine (0 50 g) was mixed with poly(ethyleneglycol) (1 50 ml, Mw avS 00) to produce a fully miscible, cleai solution Aspirin ( 1 ,000 g, mesh #325) was added portionwise to give a very viscous, pasty slurry which had a pH of -6
  • Toethanolamine 1 50 g was mixed with poly(ethyleneglycol) (0 50 ml Mw s , 00) to pioduce a fully miscible, clear solution Aspmn (1 ,000 g mesh #325) was added portionwise to give a very viscous, pasty sluny which had a pH of -8 The pasty sluny became cleai on standing foi 30 minutes
  • Piopanolamine 1 00 ml was mixed with propyleneglycol (1 00 ml) to pioduce a fully miscible, cleai solution Aspirin (1 ,000 g, mesh #325) was added poitionwise to give a clear solution which had a pH of ⁇ 8
  • Toethanolamine (0 50 ml) was mixed with 1 ,3-propanediol (1 50 ml) to pioduce a fully miscible, cleai solution Aspmn ( 1 ,000 g, mesh #325) was added poitionwise to give a viscous, cloudy solution which had a pH of -6 The solution cleai ed on standing foi 30 minutes
  • Toethanolamine (1 50 ml) was mixed with 1 ,3-propanediol (0 50 ml) to produce a fully miscible, cleai solution Aspir (1 ,000 g, mesh #325) was added portionwise to give a very viscous, pasty solution which had a pH of ⁇ 8 The solution cleaied on standing for 30 minutes
  • the solutions of the pievious examples are of a consistency resembling a gel, flowing somewhat in the mannei of honey, even though othei wise cleai and essentially colorless
  • Toethanolamine is generally preferred as the organic amme used with the aspirin solution because it is the least irritating to skin
  • Piopylene glycol is piefeired as a pharmaceutically acceptable pnmaiy sol ent because of its properties as a transdeimal propeUant and because it is not a skm liotant It is envisioned that other solvents having similai properties could be used in place of propylene glycol In combination with a suitable oiganic amme, even glyceim exhibits adequate solubility at a level of at least about 40 wt %, 50 wt, % oi moie, and may therefore be employed as well
  • the addition of vanous alkanols to glycerol is generally effective to piovide cleai , less viscous solutions
  • Othei mesh sizes of aspirin may also be used with these solutions, such as mesh #200 oi #100, with similar lesults These mesh sizes requne more time to fully dissolve in the oiganic amine and primary solvent mixtuie
  • the particulai quantity of aspmn to be dissolved in solution depends on the length of time it is anticipated the aspirin solution will be transdermally delivered
  • about 1.100 mg of aspirin must be dissolved in solution
  • a 10-day patch would require about 810 mg of aspmn to be dissolved in solution
  • the pnmaiy solvent is preferably a saturated acyclic aliphatic diol and mav be of the followin "gto & general formula
  • R may be the same oi diffeient hneai oi blanched chain acyclic hydiocarbyl ladical of fiom 2 to about 6 carbon atoms and y may be a numbei f l om 0 to about 5
  • the ammo components may be of the toimula
  • Ri and R 2 may each independently repiesent H or an acyclic hydrocarbyl radical of from 2 to about 4 caibon atoms including hydroxy- or ammo-substituted radicals and X may lepiesent H, OH, oi a primary, secondary or tertiary amme substituted in turn by either or both of Ri or R 2
  • Non-reactive substituents may also be present on the hydrocarbyl l successionls and on the "CH2' moieties as well including halogens such as chlonne oi an -O-hydrocarbyl entity such as ethoxy
  • the pomai y solv ent may also contain compatible acceptably miscible oi soluble, phaimaceutically acceptable additives such as a pnmai y oi secondai y alkanol having from 2 to about 6 carbon atoms, oi the additive may be dimethylsulfoxide, dimethoxyethane, dimethylformamide oi a lowei hydiocaibyl acyclic oi cyclic estei such as ethyl acetate oi a lactone such as butyi olactone oi amyllactone, or cyclic ethers such as tetrahydi ofuian Mixtuies of such additives may also be used as desued
  • the components aie desirably substantially watei fiee in ordei to avoid undue decomposition of the acetyl sahcylate moiety
  • Fig 1 shows a transdermal patch 10 suitable foi storing the components of the solution until use
  • the patch 10 has two reservons 20, 30 separated by a divider 60
  • Powdered aspirin 25 of suitable mesh size is kept in reseivo ⁇ 20
  • a solution 35 of the organic amine and pharmaceutically acceptable solvent is kept on reservoir 30
  • a removable slide 40 covers each leseivou 20, 30 and prevents contact of the aspirin 25 and solution 35 p or to use of the patch 10
  • just poor to use the slide 40 may be pulled away fiom the tops of the reservoirs 20, 30, theieby permitting the aspmn 25 and solution 35 to mix and form the aspirm solution foi tiansdeimal dehvery through permeable membrane 50, which is placed in contact with the user s sk in a suitable location
  • the patch 10 may be shaken following lemov al of the slide 40 to hasten the dissolution of the aspirin 25 in solution 35
  • the transdermal patch may be constructed in other forms the essential requirement being that the particulate aspmn be isolated fiom the solvent combination until the point of use
  • Various approaches to this lequirement will be apparent to those skilled in the art of piovidmg tiansdermal patches and may include the provision of a frangible membrane ai ranged lateraly between the two walls of the patch device, suitably sealed at the edges so as to be impermeable until fractuied to the solvent, and which may De ruptured by mechanical manipulation of the patch device, such as is lllustiated in U S Patent 4,900,552, without being bound to the specific constiuction of that patent
  • 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 foices to release the solvent foi contact with the solid comminuted aspirin
  • Still another alternative is to assemble the patch at the time and point of use from entirely separate elements, 1 e separate reservoirs containing respectively the

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Abstract

An aspirin formulation suitable for transdermal delivery has powdered aspirin dissolved in relatively high concentrations in a solution composed of a pharmaceutically acceptable solvent and an organic amine a. The primary solvent is preferably an organic hydroxy compound having good transdermal propellant characteristics. The resulting aspirin solution is nonirritating to the skin and exhibits good stability over the useful life of a transdermal delivery patch. A patch suitable for delivering the aspirin solution to the skin of a patient is also described.

Description

TRANSDERMALLY DELIVERED ASPIRIN
FIELD AND BACKGROUND OF THE INVENTION
This application is a continuation-m-part of my previous application co-pending heiewith, Serial No 08/988,651 , filed Decembei 1 1 , 1997, which is mcoiporated herein by refeience in its entirety
The present invention relates in general to aspirin compositions, and in paiticulai to a new and useful aspirm composition and a device which is capable of effectively administering aspirm transdermally to a mammal over a peπod of days for effective therapeutic purposes, and a method of making and ddministenng the composition
Aspirm is the most widely used drug in the woild It has a numbei of impoitant uses in medicine It is a valuable analgesic, antipyretic, and heait attack and stroke-preventive However, many heart attacks and stiokes occui duiing the night, when orally ingested medicines are least effective because blood seium levels are typically at a minimum Aspirm is also one of the most potent anti-inflammatory agents, and is the drug of choice and mainstay of aithπtis therapy It stimulates the immune system, reduces opportunistic infections and is potentially useful as an adjunct in treating cancel , AIDS, and othei immune disordeis 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 othei injuries It has a specific analgesic effect in migiaine headaches, a condition in which acetaminophen and lbuprofen show no activity No other drug in the history of medicine has exhibited such an array of multifaceted therapeutic properties
Despite all these important medical applications, aspirin is known chιefl for its analgesic properties Howevei, its range of application is greatly i educed b\ \ πtue of the fact that aspmn is substantially insoluble in both watei (sol 0 3%) and glyceiol (sol 0 3%) Aspmn exhibits bettei solubility in both alcohol and acetone (sol -20%), but these solvents are too volatile for use with transdeimal applications, among other characteristics
An additional disadvantage of aspirin's low solubility is that millions of diug consumers have swallowing problems and need transdermal or liquid medication By some estimates, 20% of all adults are affected, including those suffering from arthritis, Parkinsomsm, multiple sclerosis, Lou Gehπg's disease and othei s It is significant that 30% of the popular acetaminophen product, TYLENOL (a trademaik), had been in capsule form to facilitate swallowing (Capsules weie ev entually replaced by gelatin-coated tablets in response to a need foi a tamper-iesistant dosage foim )
Because of these disadvantages, aspmn is not widely used as an anti- inflammatoiy agent, even though it is actually the mainstay and diug of choice in aithutis — a disease directly caused by inflammation Instead, its use in aithutis 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 aie required Such daily dosages are possible since the toxicity of aspirin is low (For example, the LD-,0 for aspirm is about 1 75 g/kg body weight ) Howevei, at such effective anti-inflammatory levels, large amounts of undissolved aspirin particles adhere to the gastrointestinal mucosa, gieatly aggravating notation and side effects in the gut
Many of the above pioblems piesented by oi al ingestion of aspmn can be alleviated by delivering aspmn to a patient though the skin Such administration can provide a comfortable and convenient way of providing medication Using the skin as poital for drug entiy not only solves many of the aforementioned pioblems it also piovides unique advantages Foi example, tiansdermal deliver} allows close conti ol ovei the rate of diug deliveiy With tiansdeimal delivery, the inteivening factois associated with oi al ingestion such as unpredictable absorption in the gastiointestinal tiact fiom fluctuating acidity and food content aie avoided In addition, a tiansdeimally delivered drug does not undeigo initial metabolism by the liver
Aspmn administered to the skin passes into the blood thiough the skin and is carried to a site of effective medicinal function This type of admimstiation, 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 protective wall against permeation of substances into the body Foi this reason, a device is necessary both to contiol and permit the permeability of aspmn through the keratin layei of the skin and enhance the pei cutaneous absorption of aspirin
Many attempts to produce a transdermally delivered aspmn aie well- documented, such as in U S Patents 3,551 ,554, 4,537 776, 4,654,209 4,789,667, 4,867 970, 4,900,554, 4,940,587, 4,948,588, 5,023,081 , 5,234,957 and 5,240,917 None of the compositions suggested in those patents was entnely successful, as a number of technical and chemical factors prevented development of a woiking tiansdermal aspirin, and no known commercial product having adequate pharmaceutical effectiveness has evei resulted fiom these attempts In pooi 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 moleculai size of the analgesics was large Among the factors contnbuting to the failure of the p oi compositions is the pooi solubility in known solvents, as discussed above In oider to provide an effective dosage of the aspirin, the solvent used must pei mi t high concentrations of aspirm in solution the solvent used must also meet the lequnement of being pharmaceutically acceptable and non- toxic to humans
Aspirin as an undissolved solid may also be a skin lπitant as well To be of value, an acceptable solvent must adequately dissolve the aspmn to be placed in solution to prevent irritation from contact with undissolved aspirm
Piopylene glycol is well-known for use with transdermal medicines because of its ability to enhance skin penetration by the medicine being admi steied Aspirin is soluble in propylene glycol at about 10 wt % Howevei, this concentiation is still below that level that is fully useful foi practical application In oidei to propel a diug oi othei substance through the skin, a diffeience in osmotic pressuie must be established acioss the skin bai ei, that is, between the epidermis skin surface and the deimas legion immediately theiebelow and indeed the entue skin stiuctme Skin penetrability is piopoitional to the concentration of the transpoited substance (here, aspirin) in accordance with Fuch's Law
Concentration of the transported substance is also important with lespect to the size of the device employed for transdeimal application required to delivei an effective dosage to the usei For example when using aspmn in prevention of heart attacks, a generally accepted dosage is 81 mg/da If it is desued to deliver this dosage daily over a two week peuod from a single tiansdeimal patch, appioximately 1 100 mg of aspmn must be dissolved in a solvent If piopylene glycol were to be used based on its preferable chaiactenstics and its 10% aspirin solubility , about 1 1 ml of solvent are required This quantity of solvent would requne an undesirably laige patch
Anothei factoi to be consideied in developing a tiansdeimally dehveied aspmn composition is the stability of the composition ovei time Many aspirin solutions are inherently unstable and lapidly bieak down into salicylic and acetic acids and I elated compounds This instability has pi evented many liquid foims of aspirin from being produced commeicially as well Genei ally speaking it is consideied that any solvent having sufficient polanty to dissolv e aspmn at a concentration sufficiently useful for piactical employment is also a solvent that will lead to an unacceptable level of decomposition of aspirm It is believed that an aspirin composition should be lelatively stable foi between about 10-15 days to be of any practical use in a tiansdeimal delivery system
Accordingly, in the state of the art today theie lemams a need foi a tiansdeimally deli vei able form of aspmn, as in a suitably-sized patch applied to the skin, foi intioduction of an aspirin containing solution substantially fiee of undissolved aspmn pai tides 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 piovide an aspmn composition adapted and suitable for tiansdermal deli vei y ovei an extended period of time, wherein the aspirin composition is acceptably soluble in phaimaceutically acceptable solvents at adequately high concentrations so as to assist in propelling the composition thiough 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 fuithei object of the inv ention to provide a suitable dev ice oi patch toi tiansdermally delivering the aspirin composition
Anothei object of the invention is to provide a method foi the piepaiation of the aspirm composition and toi the tiansdeimal application of the aspmn composition As used heiein, the tei ' aspirin' is used for simplicity to lefer to the organic moleculai entity generally known as acetyl sahcylate, whethei present as acetyl salicylic acid (aspmn) 01 as the sodium (01 anothei alkali metal) salt of acetyl salicylic acid 01 moie particularly as an amine salt of acetyl salicylic acid
Accoidingly by the present invention a composition of aspirin, an oiganic amme and a pharmaceutically acceptable solvent is provided wherein the concentration of aspirm in the solvent is at least about 40% A transdermal delivery patch is also provided so as to contain the separated components of (a) aspmn and (b) an organic amme in combination with a piimaiy solvent until the> aie combined to at least an effective degiee at the point and time of use The then lesultmg dissolved composition has acceptable stability as to the aspirin solute for at least a period of between 10-16 days Especially suitable organic amines include ethanolamines, while propylene glycol is conveniently piovided as the pnmaiy solvent
The vanous featuies of novelty, which chaiactenze the inv ention aie pointed out with paiticula ty in the claims annexed heieto and foiming a pait of this disclosuie Foi a bettei understanding of the invention, its opeiating advantages and specific objects attained by its uses leference is also made to the accompanying drawing and descriptive mattei in which a preferred embodiment of the invention is illustrated
BRIEF DESCRIPTION OF THE DRAWING
The accompanying di awing shows a schematic lepresentation 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 piesent in a relatively high concentration in solution of an organic amine and a phaimaceutically acceptable solvent While not wishing to be bound by any theoiy as to the precise manner in which this invention is effective, it is believed that the organic amme operates to form a desirably and suitably soluble amine salt of the acetyl salicylic acid in the polai solvent so as to peimit a reasonably rapid dissolution of the aspirin therein at an relatively high and efficacious concentration as a piactical matter
It is of course desirable that the aspirin be piesent in a suitably comminuted foim both as to particle size and particle size distnbution Suitable mesh paiticle sizes include the commonly available 325 mesh and are believed to lange from about 80 mesh to about 600 mesh, or so By and laige, the late of dissolution is a function of particle size, oi conveisely specific suiface aiea, such that the smaller the particle, the more rapid the dissolution is likety to be However, this can also be affected by the presence of pharmaceutically-acceptable agent additives which, while not essential to opei ability, are also contemplated in the practice of this invention In the piactice of this invention the pharmaceutically acceptable primary solvent is geneially a lower alkyl compound usually having at least two hydroxyl groups Such species include propylene glycol, glycerin and diethylene glycol Howevei, the invention specifically also contemplates mixtuies of such alkyl hydιox\l compounds Foi instance, a mixture of glyce n and isopiopanol is a useful pharmaceutically acceptable primary solvent and provides a desirably high concentiation of dissolved aspirin Frequently, an initially overly viscous solution in the pnmaiy solvent will, upon addition of such a second alkyl hydroxyl compound lead to a less viscous solution with complete clarity Such additional alkyl hydiox) compounds may include ethanol, isopiopanol, isooctanol. etc The material factor in formulating mixtuies of the primary solvent components is that they be entnely miscible with each othei . at least up to about a 50 vol % mixtuie
As the organic amine. 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 least 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, moie that one of the organic amme entities may also be used in combination with the pπmary solvent, including mixtures of such solvent components Suitable species of lower alkyl organic amines include diamines such as ethylenediamine, piopylene diamine, and hydroxyl group substituted hydroxyamines such as ethanolamine, diethanolamine, tπethanolamine, etc 01 couise. the components of the resulting aspirin solution should also be pharmaceutically suitable and generally free fiom such characteristics as would, foi instance, lead to irritation of the skin Dimethyl sulfoxide could, foi instance, also be used in a composition according to this invention but this is a compound that, while pharmaceutically acceptable, can also cause notation 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 ultimate transdermal patch device
The following example is provided as an illustration of one embodiment of the invention, but the invention should not be constiued as limited thereto Example 1
Fust, to-ethanolamine was mixed with propylene glycol to produce a solution having 41 % wt/vol of toethanolamine One thousand milligrams of powdered aspmn (mesh #325) was stirred into 2 ml of the combined toethanolamine in propylene glycol The aspirin lapidly dissolved into solution to pioduce a mixture having a final volume of about 2 5 ml The concentiation of aspirin in this solution is thus in excess of 40%
The aspirm solution was kept at room temperature for 16 days At that time a measuiement was made of the fiee salicylic acid content of the solution to test and measuie 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 aspmn solution was applied to seveial subjects' skin foi 15 days Aftei 15 days, the subjects' skm was examined and no skm notation was obsei ved
Othei oi game amines which are considered paiticularly useful with the aspmn solution include othei ethanolammes, such as mono-ethanolamine and di-ethanolamme Solutions similar to that of Example 1 , above, weie obtained using mono and di-ethanolamine These amines aie not volatile, have little oi no odoi and they cause little oi no notation to the skm when combined with aspmn
Further illustrative examples include 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 l.OOg (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
Toethanolamine with Dipropyleneglycol.
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 l.OOg (in the total volume of about 2.5 ml) resulting in clear viscous solutions.
Example 4
Ethanolamine with Propyleneglycol.
These components are shown to be fully compatible and miscible in pioportions 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 dimethoxyethane and separately also of dimethylformamide are fully compatible and when added slightly decreased the viscosity of the formulation. Example 5
Toethanolamine (1 00 g) was mixed with propyleneglycol (1 00 ml) to produce a fully miscible, cleai solution Aspirin (1 25 g mesh #325) was added poitionwise to give a cleai, viscous solution having a pH of 5
"• Example 6
Toethanolamine (0 50 g) was mixed with propyleneglycol (1 50 ml) to pioduce a fully miscible, clear solution Aspirin (1 00 g mesh #325) was added poitionwise to give a slightly cloudy solution (less viscous than example 6) having a pH of 5
o Example 7
Toethanolamine (1 50 g) was mixed with propyleneglycol (0 50 ml) to pioduce a fully miscible, cleai solution Aspirin (1 25 g mesh #325) was added poitionwise to give a clear solution (more viscous than Example 1) having a pH of 5
5 Example s
The cleai , 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 ml of dimethylsulfoxide The solution became less viscous and remained completely clear and had a pH of 5
0 Example 9
The viscous solution from example 6 was treated with 100% ethanol which was added poitionwise in 0 10 ml increments up to a total volume of 0 40 ml of ethanol The solution became less viscous, was completely cleai, and had a pH of 5 Example 10
The cleai, 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 lemained 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 cleai, 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, cleai solution Aspirm (1 00 g mesh #325) was added poitionwise to give a clear, viscous solution having a pH of 8
Example 13
Ethylenediamine (1 50 ml) was mixed with piopvleneglycol (0 50 ml) to pioduce a fully miscible, cleai solution Aspirin ( 1 00 g mesh #325) was added poitionwise to give a cleai, viscous solution having a pH of 10
Example 14
Toethanolamine (1 00 g) was mixed with glycerol (1 00 ml) to pioduce a fully miscible, cleai solution Aspirin (1 00 g mesh #325) was added poitionwise to give a cleai, viscous solution having a pH of 7 Example 15
Toethanolamine (0 50 g) was mixed with glyceiol ( 1 50 ml) to produce a fully miscible cleai solution Asp n (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) lesulted in the foimation of a viscous suspension having a pH of 6
Example 16
Toethanolamine ( 1 50 g) was mixed with glyceiol (0 50 ml) to produce a fully miscible, cleai solution Aspirm (1 00 g, mesh #325) was added portionwise and a cleai , pasty viscous solution was obtained The solution had a pH of 8
Example 17
The cleai , viscous solution fiom Example 14 w as treated with 1 -pιopanol which w as added poitionwise in 0 10 ml increments up to a total volume of 0 40 ml of 1 -pιopanol The solution became less viscous, lemained completely cleai , and had a pH of 7
Example 18
The viscous suspension fiom Example 15 was treated with I-propanol which was added poitionwise in 0 10 ml increments up to a total volume of 0 80 ml of 1-pιopanol The solution became less viscous, became completely cleai, and had a pH of 6
Example 19
The cleai viscous solution from Example 16 was tieated with 2-octanol, which was added poitionwise in 0 10 ml increments up to a total volume of 0 80 ml of 2 octanol The solution became less viscous, lemamed completely cleai, and had a pH of 8 Example 20
Toethanolamine ( l OO g) was mixed with diethv leneglycol ( 1 00 ml) to pioduce a fully miscible cleai solution Aspmn ( 1 00 g mesh #325) was added poitionwise to give a cleai, viscous solution having a pH of 7
Example 21
Toethanolamine (0 50 g) was mixed with diethvleneglycol (1 50 ml) to pioduce a fully miscible, cleai solution Aspirin ( 1 00 g, mesh #325) was added poitionwise to give a cleai, viscous solution which had a pH of 6
Example 22
Tπethanolamine ( 1 50 g) was mixed w ith diethyleneglycol (0 O ml) to produce a lull} miscible, cleai solution Aspmn ( 1 00 g, mesh #325) was added poi tionwise to e a cleai past) viscous solution having a pH of 8
Example 23
The pasty, viscous solution fiom Example 22 was tieated with 2-propanol which was added poitionwise in 0 10 ml increments up to a total volume of 0 50 ml of 2-pι opanol The solution became less viscous, became completely cleai, and had a pH of 8
Example 24
N,N-Dιmethylethanolamιne (1 00 ml) was mixed with propyleneglycol (1 00 ml) to pioduce 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 piopyleneglycol ( 1 50 ml) to produce a fully miscible, clear solution Aspirin ( 1 000 g, mesh #325) was added poitionwise to give a cleai, slightly viscous solution which had a pH of ~6
Example 26
N N-Dimethylethanolamme ( 1 50 ml) was mixed with propyleneglycol (0 50 ml) to pioduce a fully miscible, clear solution Aspirin ( 1 000 g, mesh #325) was added poitionwise to give a cleai , slightly viscous solution which had a pH of ~ 10
Example 27
The cleai solution from Example 24 was treated with 2-butanol which was added poitionwise in 0 10 ml increments up to a total volume of 0 50 ml of 2- butanol The solution became less viscous and remained completely clear and had a pH of -9
Example 28
Toethanolamine (1 00 g) was mixed with dipropyleneglycol (1 00 ml) to pioduce a fully miscible clear solution Aspirin ( 1 000 g, mesh #325) was added poitionwise to give a cleai, slightly viscous solution which had a pH of -6
Example 29
Toethanolamine (0 50 g) was mixed with dipropyleneglycol ( 1 50 ml) to pioduce a fully miscible, cleai solution Aspir { \ 000 g, mesh #325) was aαded poitionwise to giv e a clear, viscous solution which had a pH of -5 Example 30
Toethanolamine ( 1 50 g) w as mixed with dipropyleneglvcol ( 1 50 ml) to pioduce a fully miscible, cleai 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 propyleneglycol (1 00 ml) to produce a fully miscible cleai solution Aspirm (1 000 g mesh #325) was added poition wise to give a cleai solution which had a pH of -10 An additional quantity of aspirin (0 500 g, mesh #325) was added and the solution lemained cleai and fully soluble with a pH of -9
Example 32
Ethanolamine (0 50 ml) was mixed with proplyleneglycol ( 1 50 ml) to pioduce a fully miscible, cleai solution Aspirin (1,000 g, mesh #325) w as added poition wise to give a cleai solution which had a pH of -9
Example 33
Ethanolamine (1 50 ml) was mixed with piopyleneglycol (0 50 ml) to produce a fully miscible clear solution Aspirin (1,000 g, mesh #325) was added poitionwise to give a cleai solution which had a pH of -10
Example 34
The cleai solution fiom Example 31 was tieated w ith dimethoxyethane which as added poition wise in 0 10 ml incremenets up to a total volume of 1 00 ml of dimethoxyethane The solution remained completelv cleai and had a pH of -9 Example 35
The cleai solution fiom Example 32 was tieated with dimethyltoimamide w hich was added poitionwise in 0 10 ml inciements up to a total volume oi 1 00 ml of dimethylfoimamide The solution lemained completely cleai and had a pH of -7
Example 36
Toethanolamine (1 00 g) was made mixed with 1,5-pentanediol (1 00 ml) to pioduce a fully miscible, cleai solution Aspirin (1,000 g, mesh #325) was added poitionwise to give a viscous, pasty solution which had a pH of -7 The pastv solution became cleai on standing foi 30 minutes
Example 37
Toethanolamine (0 50 g) was mixed with 1 5-pentamedιol ( 1 50 ml) to pioduce a fully miscible, cleai solution Aspirin (1 ,000 g, mesh #325) was addedd poitionwise to give a viscous pasty solution which had a pH of ~6 The pasty solution became cleai on standing foi 30 minutes
Example 38
Toethanolamine (1 50 g ) was mixed with 1,5-pentanediol (0 50 ml) to pioduce a fully miscible, cleai solution Aspirin (1,000 g, mesh #325) was added poitionwise to give a viscous pasty solution which had a pH of -8 The pasty solution became clear on standing foi 30 minutes
Example 39
Toethanolamine (1 00 g) ws mixed with poly(ethyleneglycol) ( 1 00 ml, Mwa 300) to pioduce a fully miscible cleai solution Aspmn ( 1 000 g, mesh #325) was added poitionwise to give a veiy viscous, pasty sluiry which had a pH of ~7 The pasty sluny became cleai on standing for 30 minutes
Example 40
Toethanolamine (0 50 g) was mixed with poly(ethyleneglycol) (1 50 ml, Mw avS 00) to produce a fully miscible, cleai solution Aspirin ( 1 ,000 g, mesh #325) was added portionwise to give a very viscous, pasty slurry which had a pH of -6
Example 41
Toethanolamine ( 1 50 g) was mixed with poly(ethyleneglycol) (0 50 ml Mws, 00) to pioduce a fully miscible, clear solution Aspmn (1 ,000 g mesh #325) was added portionwise to give a very viscous, pasty sluny which had a pH of -8 The pasty sluny became cleai on standing foi 30 minutes
Example 42
Piopanolamine ( 1 00 ml) was mixed with propyleneglycol (1 00 ml) to pioduce a fully miscible, cleai solution Aspirin (1 ,000 g, mesh #325) was added poitionwise to give a clear solution which had a pH of ~8
Example 43
Propanolamme (0 50 ml) was mixed with propyleneglycol ( 1 50 ml) to pioduce a fully miscible, cleai solution Aspirin ( 1 ,000 g, mesh #325) was added poitionwise to give a cleai solution which had a pH of ~7
Example 44
Piopanolamine ( 1 50 ml) was mixed with piopyleneglycol (0 50 ml) to produce a fully miscible cleai solution Aspmn ( 1 ,000 g, mesh #325) was added poitionwise to give a cleai solution which had a pH of -8 Example 45
Diethanolamine (1 00 ml) was mixed with piopyleneglycol ( 1 00 ml) to pioduce a fully miscible, clear solution Aspirin (1 ,000 g. mesh #325) was added poitionwise to give a viscous, cloudy solution which had a pH of -8 The solution cleai ed on standing foi 15 minutes
Example 46
Diethanolamine (0 50 ml) was mixed with propyleneglycol (1 50 ml) to pioduce a fully miscible. clear solution Aspir (1 ,000 g. mesh #325) was added portionwise to give a viscous, cloudy solution which had a pH of -7 The solution cleai ed on standing foi 15 minutes
Example 47
Diethanolamine (1 50 ml) was mixed with propyleneglycol (0 50 ml) to pioduce a fully miscible, cleai solution Aspirin (1 ,000 g, mesh #325) was added poitionwise to give a viscous, cloudy solution which had a pH of -8 The solution cleai ed on standing foi 15 minutes
Example 48
Toethanolamine (1 00 ml) was mixed with 1,3-propanediol (1 00 ml) to pioduce a fully miscible, cleai solution Aspirm (1,000 g, mesh #325) was added portionwise to give a very viscous, thick solution which had a pH of ~8 The solution cleai ed on standing foi 30 minutes
Example 49
Toethanolamine (0 50 ml) was mixed with 1 ,3-propanediol (1 50 ml) to pioduce a fully miscible, cleai solution Aspmn ( 1 ,000 g, mesh #325) was added poitionwise to give a viscous, cloudy solution which had a pH of -6 The solution cleai ed on standing foi 30 minutes
Example 50
Toethanolamine (1 50 ml) was mixed with 1 ,3-propanediol (0 50 ml) to produce a fully miscible, cleai solution Aspir (1 ,000 g, mesh #325) was added portionwise to give a very viscous, pasty solution which had a pH of ~8 The solution cleaied on standing for 30 minutes
Frequently the solutions of the pievious examples are of a consistency resembling a gel, flowing somewhat in the mannei of honey, even though othei wise cleai and essentially colorless
It is within the scope of the present invention to employ the above solutions of aspirin in the pnmaiy solvent with the amine component and additives as desued in the transdermal patch, with the pioviso that initially the aspirin component should be kept separate from the said solvent/amine combination and poor to actual use It will be understood that the solvent/amine combinations and any desired additives should be essentially watei-free foi purposes of avoiding deterioration of the aspirin component aftei mixing therewith
Toethanolamine is generally preferred as the organic amme used with the aspirin solution because it is the least irritating to skin
Piopylene glycol is piefeired as a pharmaceutically acceptable pnmaiy sol ent because of its properties as a transdeimal propeUant and because it is not a skm liotant It is envisioned that other solvents having similai properties could be used in place of propylene glycol In combination with a suitable oiganic amme, even glyceim exhibits adequate solubility at a level of at least about 40 wt %, 50 wt, % oi moie, and may therefore be employed as well The addition of vanous alkanols to glycerol is generally effective to piovide cleai , less viscous solutions
Othei mesh sizes of aspirin may also be used with these solutions, such as mesh #200 oi #100, with similar lesults These mesh sizes requne more time to fully dissolve in the oiganic amine and primary solvent mixtuie As 81 mg pei day is consideied an acceptable adult dose of aspirin, the particulai quantity of aspmn 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 aspmn to be dissolved in solution
Both lower and highei concentrations of aspmn in the solutions of the examples lllustiative of the practices according to the invention, aie possible as well Solutions having aspmn concentiations of 50 wt % oi moie may be pioduced accoidmg to this invention By making solutions of even highei concentiations of aspirin, such as more than 50 wt %, the overall size of the patch may be leduced foi equivalent dosages, or even longer use patches may be piovided
The pnmaiy solvent is preferably a saturated acyclic aliphatic diol and mav be of the followin "gto & general formula
H - O - R - (O— R\ -O- H
wherein R may be the same oi diffeient hneai oi blanched chain acyclic hydiocarbyl ladical of fiom 2 to about 6 carbon atoms and y may be a numbei f l om 0 to about 5 The ammo components may be of the toimula
R2_N— (CH2)„— X
wherein n represents a number from 2 to about 4, Ri and R2 may each independently repiesent H or an acyclic hydrocarbyl radical of from 2 to about 4 caibon atoms including hydroxy- or ammo-substituted radicals and X may lepiesent H, OH, oi a primary, secondary or tertiary amme substituted in turn by either or both of Ri or R2 Non-reactive substituents may also be present on the hydrocarbyl l adicals and on the "CH2' moieties as well including halogens such as chlonne oi an -O-hydrocarbyl entity such as ethoxy
The pomai y solv ent may also contain compatible acceptably miscible oi soluble, phaimaceutically acceptable additives such as a pnmai y oi secondai y alkanol having from 2 to about 6 carbon atoms, oi the additive may be dimethylsulfoxide, dimethoxyethane, dimethylformamide oi a lowei hydiocaibyl acyclic oi cyclic estei such as ethyl acetate oi a lactone such as butyi olactone oi amyllactone, or cyclic ethers such as tetrahydi ofuian Mixtuies of such additives may also be used as desued
The components aie desirably substantially watei fiee in ordei to avoid undue decomposition of the acetyl sahcylate moiety
Of course mixtures of any of the above materials may be employed, the selection of the specific hydroxy primary solvent ammo compound oi the additive being within the skill of those pei sons in this the ait having knowledge of the disclosuie of this invention, with due legard to such factoi s as the mateoals used in making the ti ansdei mal patch the l te at which tiansdeimal dehvei y ol aspmn is desued foi a giv en medical objectiv e the volatility and stability of the lesulting mixtures etc In genei l the lesulting mixtures may exhibit a pH l nging fiom about 5 to about 10 The ammo compounds generally exhibit a pKb of from about 3 to about 4 5
DETAILED DESCRIPTION OF THE DRAWING
Fig 1 shows a transdermal patch 10 suitable foi storing the components of the solution until use The patch 10 has two reservons 20, 30 separated by a divider 60 Powdered aspirin 25 of suitable mesh size is kept in reseivoπ 20 A solution 35 of the organic amine and pharmaceutically acceptable solvent is kept on reservoir 30 A removable slide 40 covers each leseivou 20, 30 and prevents contact of the aspirin 25 and solution 35 p or to use of the patch 10
In this embodiment of the patch, just poor to use the slide 40 may be pulled away fiom the tops of the reservoirs 20, 30, theieby permitting the aspmn 25 and solution 35 to mix and form the aspirm solution foi tiansdeimal dehvery through permeable membrane 50, which is placed in contact with the user s sk in a suitable location The patch 10 may be shaken following lemov al 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 aspmn be isolated fiom the solvent combination until the point of use Various approaches to this lequirement will be apparent to those skilled in the art of piovidmg tiansdermal patches and may include the provision of a frangible membrane ai ranged lateraly between the two walls of the patch device, suitably sealed at the edges so as to be impermeable until fractuied to the solvent, and which may De ruptured by mechanical manipulation of the patch device, such as is lllustiated in U S Patent 4,900,552, without being bound to the specific constiuction 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 foices to release the solvent foi contact with the solid comminuted aspirin Still another alternative is to assemble the patch at the time and point of use from entirely separate elements, 1 e separate reservoirs containing respectively the solid paiticulate aspmn and the solvent combination For instance the aspirm can be maintained in a permeable packet within a hermetically sealed envelope which opened just pooi to use Similaily, the solvent combination can be in a separate vial typy device which is openable by fracturing or other ise These elements can then be secuied togethei adjacent each other with a suitable bonding membei and including appropoate means to adhere the assembly to the skm surface
While specific embodiments of the invention have been shown and descobed in detail to lllustiate the application of the principles of the invention, it will be understood that the invention may be embodied othei wise without departing from such principles

Claims

WHAT IS CLAIMED IS
1 A solution containing relatively high concentiations of aspmn foi transdeimal dehveiy the solution composing
a pharmaceutically acceptable pnmaiy 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 piopylene glycol
3 A solution accoidmg to claim 2 wnerein the oiganic amine is an ethanolamine
4 A solution accoidmg to claim 3, wheiein the oiganic amme is toethanolamine
5 A solution accoidmg to claim 1 , wheiein the oiganic amine is an ethanolamine
6 A solution according to claim 5, wherein the oiganic amme is toethanolamine
7 A method of storing aspmn to be delivered tiansdeimally to a patient, the method composing
piovidmg a tiansdermal patch having at least a pan of leseivoii which aie initially separated from each othei by a dividei with a lemovable slide to permit the lesei voiis to be in communication with each other when the slide is lemoved. piovidmg a pharmaceutically acceptable primary solvent in at least one of the reseivoirs;
piovidmg an organic amme 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 amme in the fust reservoir until the removable slide is removed
8 A method accordin Όg to claim 7, wherein the organic amine is an ethanolamine
9 A method according to claim 8, wherein the pnmaiy solvent is propylene glycol.
10 A method according to claim 9, wherein the organic amine is toethanolamine
1 1 A method according to claim 7, wheiein the primary solvent is piopylene glycol
12 A method of administering aspirin transdermally to a patient, comprising
providing a medically acceptable dosage amount of aspirm for the patient for administration over a predetermined period of time,
dissolving the aspirin in a pharmaceutically acceptable primary solvent in combination with an organic amme to form a solution having a concentration of aspmn of at least 30%.
applying the solution to the skm of the patient foi the effective period of time 13 A method according to claim 12 wheiein the pharmaceutically acceptable pnmaiy solvent is propylene glycol
14 A method according to claim 13, wherein the organic amme is an ethanolamine
15 A method according to claim 13, wherein the organic amme is toethanolamine
A method according to claim 12, wheiein the organic amme is an ethanolamine
17 A method accoidmg to claim 12 wherein the concentration of aspmn is at least 40%
18 A method 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 foi separately containing aspmn in solid comminuted form and providing a separately retained solubihzmg solvent combination component having
(l) at least one fust pharmaceutically-acceptable lower polyhydioxyl acyclic hydiocarbyl component, liquid at normal temperatuies, and functioning as a primary solvent, in combination with (n) at least one pharmaceutically-acceptable acyclic aliphatic amine having a pKa capable of forming an amine salt with acetylsahcylic acid without substantial hydiolysis of the acetyl 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 acetylsahcylic acid 5 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 0 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 5 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 o 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 5 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 0 of said device; placing a desired quantity of solid comminuted aspirin in at least one of said separate chambeis, and placing a desired quantity of a normally liquid pnmaiy solvent combination in at least one other of said separate chambers, and wherein said solvent combination has the capability of dissolving said solid aspirm upon mixing therewith and the resulting solution having the capability of ti ansmission through said permeable wall member so as to contact said skm suiface 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 exterior wall member adapted foi attachment to the skm of a mammal, and foiming at least one relatively impermeable exteooi wall membei positioned oppositely to said liquid-permeable exteπoi wall membei , forming a plurality of interior wall members arranged between said exteooi wall members and so as to respectively define a plurality of separate chambers, consti ucting at least one of said interior wall members to maintain sepaiate fiom each othei a solid component in at least one of said chambers fiom a liquid component in at least one of the second of said chambeis, and piovidmg at least one interior wall membei to be removable upon use of said device, wherein said at least one of said separate chambeis has the capability of containing solid comminuted aspirin, and wherein said at least one othei of said sepaiate chambeis has the capability of containing a normally liquid solvent 22 A method for the manufacture of a transdeimal patch device opeiative in use foi the tiansdermal delivery of aspmn which composes obtaining the transdeimal patch device of claim 20 or 21 , placing a desired quantity of solid comminuted aspmn in at least one of said separate chambers, placing a desired quantity of a normally liquid pnmaiy solvent combination in at least one other of said separate chambers, wherein said primary solvent combination has the capability of dissolving said solid aspirin upon mixing therewith, placing said tiansdermal patch device containing aspirin and the pnmaiy solvent combination within an enveloping sealable solvent impermeable envelope, and sealing said envelope
23 A method for applying the transdeimal patch device of claim 22, composing opening the sealed envelope containing the device, lemoving the device from the envelope, removing at least one interior wall membei of the device, attaching the device to a skm surface of a mammal
24 A device for delivery of aspirin transdermally to a mammal which comprises at least one chambei foi separately containing aspirin in solid comminuted form, and a separately letamed solubilizing solvent combination component having (I) at least one fust pharmaceutically-acceptable satuiated acyclic aliphatic diol lepiesented by formula
H - O - R - (O— R)> -O-- H wheiein R may be the same 01 different lineai or blanched chain acyclic hydiocaibyl radical of fiom 2 to about 6 carbon atoms and y may be a numbei f i om 0 to 5
in combination with (u) at least one pharmaceutically-acceptable lower alkyl amine lepresented by the formula
R,_N— (CH2)„— X wherein n represents a number from 2 to about 4, Ri and R2 may each independently represent H oi an acyclic hydrocarbyl radical of from 2 to about 4 caibon atoms including hydroxy- or amino-substituted radicals, and X may lepiesent OH, oi a primary, secondary oi tertiary amme substituted in turn by eithei oi both of Ri or R2,
said solvent combination of (l) and (n) having the capability upon admixtuie with each other of dissolving the acetylsahcylic acid component at least in part as an amme acetylsalicylate complex which is in turn capable of dissociating pharmacologically at least in part into its constituent paits including an effective amount of acetylsalicylate, said device being opeiative 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 amme acetylsalicylate salt at a concentration level sufficient to permit delivery of a therapeutic amount of the dissolved acetylsalicylate component for percutaneous absorption thiough the mammalian epidermus and dermis
25. The device according to claim 24, 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 ester, a lactone or tetrahydrofuran.
26. The combination of
(1 ) a pharmaceutically acceptable primary solvent of the formula
H - O - R - (O— R)y -O- 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 0 to about 5, and
(2) at least one pharmaceutically-acceptable lower alkyl amine represented by the formula:
R2_N— (CH2)„— X
wherein n represents a number from 2 to about 4, Ri 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 Ri or R2; and
(2) dissolved acetylsahcylic acid in the combination of (1) and (2) at a concentration of at least about 20 wt. %.
EP99928460A 1999-06-10 1999-06-11 Transdermally delivered aspirin Withdrawn EP1104236A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US329349 1994-10-26
US32934999A 1999-06-10 1999-06-10
PCT/US1999/012793 WO2000076315A1 (en) 1999-06-10 1999-06-11 Transdermally delivered aspirin

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EP (1) EP1104236A1 (en)
JP (1) JP2003501447A (en)
KR (1) KR20010072412A (en)
AU (1) AU4552399A (en)
BR (1) BR9912954A (en)
CA (1) CA2340120A1 (en)
HU (1) HUP0103110A3 (en)
IL (1) IL141348A0 (en)
MX (1) MXPA01001490A (en)
TR (1) TR200100452T1 (en)
WO (1) WO2000076315A1 (en)
ZA (1) ZA200101153B (en)

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SE0103528D0 (en) 2001-10-21 2001-10-21 Jan Faergeman Topical compositions with enhanced effect
WO2011076401A1 (en) 2009-12-23 2011-06-30 Holger Schankin Substantially water-free pharmaceutical compositions containing acetylsalicylic acid

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US4725590A (en) * 1983-08-24 1988-02-16 Lever Brothers Company Method of relieving pain and inflammatory conditions employing substituted salicylamides

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Title
See references of WO0076315A1 *

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TR200100452T1 (en) 2001-07-23
AU4552399A (en) 2001-01-02
WO2000076315A1 (en) 2000-12-21
IL141348A0 (en) 2002-03-10
HUP0103110A3 (en) 2002-11-28
ZA200101153B (en) 2002-05-09
BR9912954A (en) 2001-05-08
JP2003501447A (en) 2003-01-14
MXPA01001490A (en) 2002-11-29
CA2340120A1 (en) 2000-12-21
HUP0103110A2 (en) 2002-05-29

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