United States Patent (11) 3,598,122 72 Inventor Alejandro Zafaroni Atherton, Calif
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United States Patent (11) 3,598,122 72 Inventor Alejandro Zafaroni Atherton, Calif. 3,249,109 511966 Maeth et al................... 128/268 2l Appl. No. 812,116 3,339,546 9, 1967 Chen............................ 1281 156 22 Filed Apr. 1, 1969 3,444,858 5/1969 Russell ......................... 128/268 X 45 Patented Aug. 10, 1971 3,464,413 9/1969 Goldfarb et al............... 28/268 (73) Assignee Alza Corporation 3,518,340 6, 1970 Raper........................... 424/19 3,520,949 7/1970 Shepherd et al.............. 1281 156 UX Primary Examiner-Charles F. Rosenbaum 54) BANDAGE FOR ADMINISTERING DRUGS Attorney-Steven D. Goldby 15 Clains, 3 Drawing Figs. (52) U.S.C....................................................... 128/268, 424/20, 424/28 ABSTRACT: Bandage for use in the continuous administra 5 int. Cli........................................................ A61f 7702 tion of systemically active drugs by absorption through the 50 Field of Search............................................ skin or oral mucosa comprising a backing member having on 1281 155 one surface thereof a reservoir containing a systemically ac - 156,268,296; 424/19-20, 28 tive drug. The reservoir has a wall distant from the backing 56 References Cited member and permeable to passage of the drug. A pressure UNITED STATES PATENTS sensitive adhesive layer, also permeable to passage of the drug, is carried by the reservoir. The drug is in a form accepta 2,629,378 21 1953 Barton.......................... 128/268 ble for absorption through the skin or the mucosa of the 3,053,255 91.962 Meyer.......................... 128/268 mouth. AO /4 YZ222222222222A46583&A2%.2% s /2 Af // r’AENTF AUG O 197, 3.598 l 22 A. 27 2777 2 7777,777.7 272 Af // SfSSR388's Six 4'asa's SaaSPS NYNNYNY YNNNNVNY NYNYNY YNNS sy N. S. NLN w ZZZZZYZZZZZZZZZZZYZZZ Af / INVENTOR Alejandro Zaffaroni " .. 83.0Attorney - 3,598,122 2 Dosage forms described above all bring about a pulse entry BANDAGE FOR ADMINISTERING DRUGS of drugs, that is, a concentrated dose of drug is brought into BACKGROUND OF THE INVENTION contact with an organ of entry at a particular time unit. Un doubtedly, this creates drug concentrations beyond the This invention relates to a bandage for use in the continuous capacity of the active centers to accept (that is, the saturation administration of systemically active drugs. point is exceeded by many orders of magnitude) and, also, One primary objective of drug therapy is to achieve a par until dilution in body fluids takes place, may exceed the ticular (uniform, variable, or modulated) blood level of drug capacity of metabolic and excretory mechanisms. The result is in circulation for a period of time (hours, days, months). O that a toxic level of drug is allowed to build, for a period of Many drugs, such as the steroidal hormones, are absorbed in a time, with detrimental effects for particular tissues or organs. relatively short period of time, and are not long acting due to To obtain persistence of effect, the usual industrial approach rapid metabolism and excretion following administration. To is to make the initial dose high or to modify the drug structure obtain the desired therapeutic effect, it is necessary in most to obtain a longer metabolic half-life of the drug in circulation. cases to establish a dosage regime of multiple unit doses over a 15 Raising the initial dosage only worsens the problem. Many 24 hour period. Most drugs are administered orally or by in derivatives with long half-lives have a lower therapeutic index jection and neither of these modes of administration achieves (ratio between the median toxic dose and the median effective the desired blood level or drug in circulation in the typical dose) than that of the parent compounds; and therefore these CaSc. approaches are not the answer to the problem. With oral administration of drugs, it is difficult if not im 20 To avoid the problems discussed above, it has been sug possible to achieve a constant blood level of drug in circula gested that systemically active drugs can be administered tion. This is true even though the drug is administered at through the skin. Percutaneous administration can have the periodic intervals according to a well-defined schedule. One advantage of permitting continuous administration of drug to reason for this is that the rate of absorption of drugs through circulation over a prolonged period of time to obtain a the gastrointestinal tract is affected by the contents of the 25 tract. Such variables as whether the drug is administered be uniform delivery rate and blood level of drug. Commence fore or after eating and the type and quantity of food eaten ment and termination of drug therapy are initiated by the ap (for example, high or low fat content) or administered before plication and removal of the dosing devices from the skin. Un or after a bowel movement, can control the rate of absorption certainties of administration through the gastrointestinal tract of the drug in the gastrointestinal tract. As most of the absorp 30 and the inconvenience of administration by injection are tion of drugs takes place in the small intestine, the time of eliminated. Since a high concentration of drug never enters passage through the small intestine is another governing fac the body, problems of pulse entry are overcome and metabolic tor. This in turn is affected by the rate of peristaltic contract half-life is not a factor of controlling importance. ing, adding further uncertainty. Also important is the rate of Despite these advantages of administering systemically ac circulation of blood to the small intestine. 35 tive drugs through the skin, prior devices designed for this pur The almost inevitable result of oral administration of drugs pose were either impractical or inoperative and did not pro through the gastrointestinal tract is that the level of drug in vide continuous administration and delivery rate. This form of circulation surges to a high each time the drug is administered, administration has not been accepted by the medical profes followed by a decline in concentration in the blood and body sion and the only prior art manner of obtaining continuous compartments. Thus, a plot of drug in circulation following a 40 delivery rate remains the continuous intravenous drip. dosage schedule of several tablets a day has the appearance of a series of peaks, which may surpass the toxic threshold, and SUMMARY OF THE INVENTION valleys. Each time the blood level decreases below a critical Accordingly, an object of this invention is to provide a point needed to achieve the desired therapeutic effect that ef device for the administration of systemically active drugs fect will no longer be obtained. Worse still, with antimicrobial 45 which overcomes the aforesaid disadvantages inherent in prior drugs, the disease producing micro-organisms rapidly multiply art modes of administration. when the concentration of drug in circulation descends below Another object of this invention is to provide a reliable and a critical point. It is likely that the drug-resistant mutant easily applied device for continuously administering con strains which are becoming increasingly prevalent and trolled quantities of systemically active drugs through the skin. represent one of the major problems in the therapeutics of in SO Still another object of this invention is to provide a device fectious diseases are formed precisely at such times. for administering systemically active drugs through the oral One approach to this problem has been the advent of the so COSa. called sustained release or time capsule in oral dosage form. A further object of this invention is to provide a complete While many of these perform satisfactorily in vitro and in dosage regime for a particular time period, the use of which animal or clinical studies under controlled conditions of nutri 55 requires patient intervention only for initiation and termina tion and activity, there is little or no evidence that these tion. dosage forms are effective for achieving a continuous and pre In accomplishing these objects, one feature of this invention dictable level of drug in circulation over a prolonged period of resides in a bandage for use in the continuous administration time under the normal conditions encountered by the outpa 60 of systemically active drugs by absorption through the skin or tient. oral mucosa. The bandage is comprised of a backing member, Many effective therapeutic agents are destroyed by a reservoir containing a systemically active drug on one sur microbial flora or G.I. secretions or are poorly absorbed in the face of the backing member, the reservoir having a will distant. gastrointestinal tract. from the backing member and permeable to passage of the Administration of drugs by injection is inconvenient, pain 65 drug, and a pressure-sensitive adhesive layer on the exterior ful, and the risk of local tissue reaction and of infection is seri surface of the distant wall of the backing member, the pres ous. Moreover, the typical result of administration by injec sure-sensitive adhesive layer also being permeable to passage tion is a surge in blood level concentration of the drug im of the drug. The drug is in a form suitable for absorption mediately after injection, followed by a decline and another through the skin or oral mucosa. surge in concentration upon subsequent injections. 70 Another feature of this invention resides in a bandage as Other dosage forms such as rectal suppositories and sublin described above including a solubility membrane interposed gual lozenges also produce nonuniform levels of the therapeu between the wall of the reservoir and the pressure-sensitive tic agent in circulation. These dosage forms require great pa adhesive layer. tient cooperation, have low patient acceptability, and are Other objects, features, and advantages of the invention will sparingly used throughout most of the world.