It is well known that many drugs if taken orally, are destroyed on the first past through the liver. It is also well known that when many drugs are taken orally, their rate of absorption into the body is not constant. In view of such difficulties, a number of different drug delivery systems have been developed. Recently, the use of transdermal delivery systems have met with increasing interest by researchers in the pharmaceutical drug delivery field.
U.S. Pat. No. 4,291,015 to Keith, et al. discloses the use of a polymeric diffusion matrix for the sustained release of pharmaceutically active drugs. The matrix is covered by a backing layer and applied to the skin where diffusion of the pharmaceutically active drug occurs and the drug is transdermally delivered to the patient. Although U.S. Pat. No. 4,291,015 discloses transdermal delivery of nitroglycerin, other drugs may be delivered by utilizing the same or a similar matrix, as disclosed in U.S. Pat. Nos. 4,294,820; 4,292,302; and 4,292,303.
U.S. Pat. No. 4,409,206 discloses the use of a different type of transdermal delivery system whereby the pharmaceutically active drug is dispersed within an adhesive (see also U.S. Pat. No. 4,390,520). In accordance with such systems, the pharmaceutically active drug is dispersed in a pressure-sensitive adhesive which is adhered to the skin. The drug then diffuses from the adhesive through the skin for delivery to the patient.
Other transdermal systems involve the use of a matrix which is in diffusional contact with a reservoir which contains the pharmaceutically active drug. The drug diffuses to the matrix and then to the skin and eventually to the patient. Still other compositions include an active ingredient in a salve or ointment which is applied to skin. The active ingredient diffuses from the salve to the skin and enters the body transdermally.
Each of the systems have various advantages and disadvantages with respect to the transdermally delivery of pharmaceutically active drugs. Certain systems may be useful in connection with one type of pharmaceutically active drug and not useful in connection with another. The ability to include one pharmaceutically active drug within a given system depends on various factors such as the compatibility of the drug with the system and the effects of the drugs on the system such as its ability to dissolve in the system.
Pharmaceutically active drugs for use in the present invention include transdermally deliverable physiologically or pharmacologically active substances for producing a localized or systemic effect in mammals, especially humans. The active drugs that can be used in the present invention are well known. See for example, U.S. Pat. No. 3,921,636 wherein one may find the following list of transdermally deliverable drugs: drugs acting on the central nervous system, such as hypnotics and sedatives such as pentobarbital sodium, phenobarbital, secobarbital, thiopental, etc.; heterocyclic hypnotics such as dioxopiperidines, and glutarimides; hypnotics and sedatives such as amides and ureas exemplified by diethylisovaleramide and .alpha.-bromoisovaleryl urea and the like; hypnotics and sedative alcohols such as carbomal, naphthoxyethanol, methylparaphenol and the like; and hypnotics and sedative urethans, disulfanes and the like; psychic energizers such as isocarboxacid, nialamide, phenelzine, imipramine, tranylcypromine, pargylene and the like; tranquilizers such as chloropromazine, promazine, fluphenazine, reserpine, deserpidine, meprobamate, benzodiazepines such as chlordiazepoxide and the like; anticonvulsants such as primidone, diphenylhydantoin, ethotoin, pheneturide, ethosuximide and the like; muscle relaxants and antiparkinson agents such as mephenesin, methocarbomal, trihexylphenidyl, biperiden, levo-dopa, also known as L-dopa and 1-.beta.-3-4-dihydroxyphenylalanine, and the like; analgesics such as morphine, codeine, meperidine, nalorphine and the like; anti-pyretics and anti-inflammatory agents such as aspirin, salicylamide, sodium salicylamide and the like; local anesthetics such as procaine, lidocaine, naepaine, piperocaine, tetracaine, dibucaine and the like; antispasmodics and antiulcer agents such as papaverine, prostaglandins such as PGE.sub.1, PGE.sub.2, PGF.sub.1a, PGF.sub.2a, PGA and the like; antimicrobials such as pencillin, tetracycline, oxytetracycline, chlorotetracycline, chloramphenicol, sulfonamides and the like; anti-malarials such as 4-aminoquinolines, 8-aminoquinolines and pyrimethamine; hormonal agents such as prednisolone, cortisone, cortisol and triamcinolone; androgenic steroids, for example methyltestosterone, fluoximesterone and the like; estrogenic steroids, for example, 17.beta.-estradiol and ethinyl estradiol; progestational steroids, for example 17.alpha.-hydroxyprogesterone acetate, 19-nor-progesterone, norethindrone and the like; sympathomimetic drugs such as epinephrine, amphetamine, ephedrine, norepinephrine and the like; cardiovascular drugs, for example procainamide, amyl nitrate, nitroglycerin, dipyridamole, sodium nitrate, mannitol nitrate and the like; diuretics, for example, chlorothiazide, flumethiazide and the like; antiparastic agents such as bephenium hydroxynaphthoate and dichlorophen, dapsone and the like; neoplastic agents such as mechlorethamine, uracil mustard, 5-fluorouracil, 6-thioguanine, procarbazine and the like; hypoglycemic drugs such as insulins, protamine zinc insulin suspension and other art known extended insulin suspensions, sulfonylureas such as tolbutamide, acetohexamide, tolazamide, and chlorpropamide, the biguanides and the like; nutritional agents such as vitamins, essential amino acids, essential fats and the like; and other physiologically or pharmacologically, active agents. Also the drugs can be present as the pharmacologically acceptable derivatives, such as ethers, esters, amides, acetals, etc. that lend themselves to passage into the circulatory system.
As indicated above, the systems have various advantages, disadvantages, and degrees of usefulness in connection with different types of drugs. Without experimentation, it is often impossible to accurately predict the usefulness of any particular system with any particular pharmaceutically active drug. However, the present inventor has found that all the systems do have certain similarities and more importantly a common undesirable feature. More specifically, they all operate by transporting the pharmaceutically active drug to the skin for transdermal delivery. In order to accomplish this, the system must be placed in intimate contact with the skin. Since normal skin will perspire such will create an aqueous layer between the skin and the system. It is this aqueous layer which causes the common disadvantage.
Perspiration may well be increased beneath a transdermal delivery system and any perspiration beneath a delivery system causes an outflow of water and other water soluble body salts from the skin. This increased outflow increases the size of the aqueous layer and thus hinders the desired inflow of the pharmaceutically active drug through the skin. When the system remains in place for a substantial period of time (24 hours is common), the outflow of perspiration can build up a substantial aqueous layer between the delivery system and the skin. This impediment is especially great if the pharmaceutically active drug is insoluble with respect to the aqueous layer or if the drug is in any way incompatible with the aqueous layer or coagulates upon contact with it. The present invention is directed to elimination of the undesirable outflow of perspiration from the skin and the undesirable accumulation of that perspiration (aqueous layer formation) between the skin and the drug delivery system.