|Número de publicación||US3797494 A|
|Tipo de publicación||Concesión|
|Fecha de publicación||19 Mar 1974|
|Fecha de presentación||9 Ago 1971|
|Fecha de prioridad||1 Abr 1969|
|Número de publicación||US 3797494 A, US 3797494A, US-A-3797494, US3797494 A, US3797494A|
|Cesionario original||Alza Corp|
|Exportar cita||BiBTeX, EndNote, RefMan|
|Citas de patentes (6), Citada por (478), Clasificaciones (25)|
|Enlaces externos: USPTO, Cesión de USPTO, Espacenet|
United States Patent [191 Zaffaroni ]*Mar. 19, 1974 1 1 BANDAGE FOR THE ADMINISTRATION OF DRUG BY CONTROLLED METERING THROUGH MICROPOROUS MATERIALS  Inventor: Alejandro Zaffaroni,Atherton,
 Assignees Alza Corporation, Palo Alto, Calif.
[ Notice: The portion of the term of this patent subsequent to Aug. 10, 1988, has been disclaimed.
 Filed: Aug. 9, 1971  Appl. No.: 169,976
Related US. Application Data  Continuation-impart of Ser. Nos. 812,116, April 1, 1969, Pat. No. 3,598,122, and Ser. No. 812,117, April 1, 1969, Pat. No. 3,598,123, and Ser. No. 150,085, June 4, 1971, Pat. No. 3,731,683.
 US. Cl. 128/268  Int. Cl A611 15/06  Field of Search l28/260, 268, 156, 155,
 References Cited UNITED STATES PATENTS 3,598,122 8/1971 Zaffaroni 128/268 3,598,123 8/1971 Zaffaroni 128/268 3,426,754 2/1969 Bierenbaum.... 128/268 X 3,053,255 9/1962 Meyer 128/268 3,464,413 9/1969 Goldfarb et 3].. 128/268 3,512,997 5/1970 Cohly et a1. 128/296 X Primary Examiner-Dalton L. Truluck Assistant Examiner-.1. C. McGowan 5 7 ABSTRACT or distributed throughout a reservoir matrix. The drug passes through drug release rate controlling micropo' rous material which continuously meters the flow of drug by viscous or diffusive transfer to the skin or mucosa at a controlled and predetermined rate over a period of time. i
7 Claims, 5 Drawing Figures PATENTEUIAR I 9 1914 INVENTOR.
BY Alejandro Zaffaroni BANDAGE FOR THE ADMINISTRATION OF DRUG BY CONTROLLED METERING THROUGH MICROPOROUS MATERIALS RELATED APPLICATIONS This application is a continuation-in-part of Ser. No. 812,1 l6, filed Apr. 1, 1969, and now issued on Aug. 10, 1971 as US. Pat. No. 3,598,122 entitled Bandage for Administering Drugs"; Ser. No. 812,1 l7, filed Apr. 1, 1969, and now also issued on Aug. 10, 1971 as US. Pat. No. 3,598,123 entitled Bandage; and Ser. No. 150,085, filed June 4, 1971, and now issued on May 8, 1973 as US. Pat. No. 3,731,683 entitled Bandage for the Controlled Metering of Topical Drugs to the Skin; all being applications of Alejandro Zaffaroni.
BRACKGROUND OF THE INVENTION This invention relates to a device for the administration of drug and, more particularly, to a medical bandage for the controlled continuous metering of flow of systemically or topically active drug to the skin or mucosa over a period of time.
Topically active drugs, as that term is used in this specification and the appended claims, are agents which, when applied to the skin or mucosa, primarily cause a pharmacological or physiological response at or near the site of their application. systemically active drugs, as that term is used in this specification and the appended claims, are agents which, when applied to the skin or mucosa, are absorbed through the body surface to which applied and are transported from their site of application by the recipients circulatory system or lymphatic system, to cause a pharmacologic or physiologic response at a remote site in the body.
systemically active drugs are conventionally administered either orally or by injection, with the primary objective of the mode being to achieve a given desired blood level of drug in circulation over a period of time. However, these prior art methods possess certain shortcomings resulting in the failure to obtain these goals. For example, the oral route is inadequate for several reasons even though the drug is administered at periodic intervals according to a well defined schedule. The rate of absorption of drug through the gastrointestinal tract is affected by both the contents of the tract and the time of passage of drug through the small intestine. Therefore, such variables as whether the drug is administered before or after eating and the type and quantity of food eaten (for example, high or low fat content), or whether administered before or after a bowel movement, affect the. rate of absorption of the drug which takes place in the small intestine. Additionally, the time of passage of drug through the small intestine is affected by the rate of peristaltic contracting, adding further uncertainty. Also important is the rate of circulation of blood to the small intestine and the fact that many drugs administered by this route are rendered inactive by gastric acid and digestive enzymes of the gastrointestinal tract or liver where the drug can be metabolized to an inactive product by that organ. These factors make it difficult to achieve a desired time course of concentration of the drug in the blood. The almost inevitable result of oral administration of drugs through the gastrointestinal tract is, that the level of drug in circulation surges to a peak level at the time the drug is administered, followed by a decline in concentration in 2 the blood and body compartments. Thus, a plot of drug in circulation after'administration of several tablets a day has the appearance of a series of peaks which may surpass the toxic threshold of the drug, and valleys which fall below the critical point needed to achieve the desired therapeutic effect.
The administration of drugs by injection can entail certain disadvantages. For example, very strict asepsis must be maintained to avoid infection of the blood, the vascular system or heart. Drug administration by poor intravenous injection technique may result in perivascular injection when it is not intended; and the typical result of injection into the blood is a sudden rise in the blood concentration followed by an uncontrolled decline. Additionally, administration of drugs by injection is inconvenient and painful. Other dosage forms for systemic administration of drug, such as rectal suppositories and sublingual lozenges, also produce non-uniform levels of the therapeutic agent in circulation. These dosage forms require great patient cooperation, have low patient acceptability, and are sparingly used throughout most of the world.
A large number of locally acting drugs are available to treat skin disorders or other conditions which manifest themselves in a manner such that they are susceptible to treatment via the skin. These drugs are conventionally topically administered to the skin with the active agent carried in the form of ointments, creams, salves, liniments, powders, dressings, and the like. The popularity of these types of formulations resides in the fact that it is quite easy to topically apply the agent to the skin in this manner. In most cases, however, it is not possible to determine how much of the preparation has been taken up or effectively administered to the sking since only non-uniform levels of the agent are available, nor is there any assurance that sufficient medication will be available for the duration of periods that it is required. A further undesirable feature is the unsightliness of these formulations which often discourages patients from using them during their waking hours of the day when they are most likely to be seen by others. Further, the preparations are subject to rub off onto clothing, thus causing much inconvenience and annoyance tothe user.
SUMMARY OF THE INVENTION Accordingly, an object of this invention is to provide a bandage for the improved continuous administration of a predetermined controlled quantity of topically or systemically active drug to or through the skin or body mucosa over a period of time, which overcomes the disadvantages inherent in the aforesaid prior art modes of administration.
Another object of this invention is to provide a bandage which can be adapted to deliver controlled quantities of drug having a wide variety of chemical and physical properties and over a wide range of drug delivery rates.
In accomplishing these objects, one feature of the invention resides ina bandage for the continuous administration of controlled quantities of drug to the skin or mucosa, comprised of a laminate of: (l) a backing member; bearing (2) a discrete middle reservoir layer containing a drug confined within a body, the body being formed from drug release rate controlling microporous material permeable to the passage of the drug, to continuously meter the flow of a therapeutically effective amount of the drug to the skin or mucosa from the reservoir at a controlled and predetermined rate over a period of time; and (3) a pressure-sensitive adhesive surface adapted for contact with the skin or mucosa and positioned on one surface of the reservoir remote from the backing member.
Another aspect of this invention resides in a bandage comprised of a laminate of: (l) a backing member; bearing (2) a discrete middle reservoir containing a drug confined therein, the reservoir being formed of material permeable to passage of the drug; and (3) a pressure-sensitive adhesive surface adapted for contact with the skin or mucosa and positioned on one surface of the reservoir remote from the backing member and wherein one or more drug release rate controlling microporous membranes are interposed between the surface of the reservoir and pressure-sensitive adhesive so as to continuously meter the flow of a therapeutically effective amount of the drug from the reservoir at a controlled and predetermined rate over a period of time. The reservoir can be a container having the agent confined therein or a solid or microporous matrix having agent dispersed therein.
Still another embodiment of this invention resides in an adhesive bandage comprising a laminate of: (l) a backing member; bearing (2) a pressure-sensitive adhesive on one surface thereof adapted for contact with the skin or mucosa, said pressure-sensitive adhesive having distributed therethrough, (3) a plurality of discrete microcapsules, each of which microcapsules comprises a drug confined within a body of drug release rate controlling porous material to continuously meter the flow of a therapeutically effective amount of the drug to the skin or mucosa of the patient from the microcapsules at a controlled and predetermined rate over a period of time.
Other objects, features and advantages of the invention will become more apparent from the following description when taken in conjunction with the accompanying drawings.
The term reservoir, as used herein to define the drug containing portion of the subject bandage, is intended to connote a broad class of structures capable of fulfilling'the intended function, and includes both discrete porous microcapsules, as well as distinct reservoir compartments or layers. Likewise, as will be hereinafter more completely developed, the foregoing term encompasses containers having one or more interior drug containing chambers, as well as solid matrices and microporous matrices having a systemically or topically active drug distributed therethrough.
The term drug or agent, when not further qualitied, includes both topically active and systemically active drugs. as hereinbefore defined.
BRIEF DESCRIPTION OF THE DRAWINGS In the drawings:
FIG. 1 is a cross-sectional view of an embodiment of the medical bandage of the invention, wherein the drug is uniformly distributed throughout a matrix of microporous material permeable to the passage of the drug by flow through the pores of the material and the material is laminated to a backing member. The matrix material which acts as a reservoir for the drug bears a coating of the pressure-sensitive adhesive thereon;
FIG. 2 is a cross-sectional view of still another embodiment of the invention, wherein the adhesive bandage of the invention is comprised of a backing member having a reservoir on one surface thereof of drug uniformly distributed throughout a matrix material permeable to passage of the drug, and on the surface of the reservoir remote from the backing member bearing a pressure-sensitive adhesive coating. A microporous membrane is interposed between the reservoir layer and the pressure-sensitive adhesive coating;
FIG. 3 is a cross-sectional view of another embodiment of the bandage of the invention, wherein the reservoir laminated to the backing member is a hollow container permeable to passage of drug by flow through the pores of one surface thereof, and having the drug confined within the interior chamber thereof. The reservoir bears a coating of pressure-sensitive adhesive thereon;
FIG. 4 is a perspective view of the medical adhesive bandage of the invention, wherein the drug is microencapsulated with a porous material permeable to the passage of the drug, and the microcapsules are uniformly distributed throughout the pressure-sensitive coating;
FIG. 5 is a cross-sectional view of the bandage of the invention shown in FIG. 4.
DETAILED DESCRIPTION OF THE INVENTION In accordance with this invention there is provided a bandage suitable, by virtue of the microporous materials employed therein, for the predetermined controlled administration of drug to the skin or mucosa of the body over a period of time. To use the bandage of the invention it is applied to the patients skin or mucosa and should be in firm contact therewith so as to form a tight seal. Flow of drug from the reservoir is metered through the pores of the rate release controlling material in accordance with the laws of hydrodynamics or diffusion, as hereinafter discussed, at a predetermined rate. In operation, drug molecules are continuously removed from the reservoir and migrate to the skin or mucosa of the patient. In the case of systemic drugs, the drugs are absorbed by the skin or mucosa and enter circulation through the capillary network.
The reservoir containing the drug is formed of material permeable to the drug to permit passage of the drug. Depending upon the particular embodiment as described above, the drug reservoir can be of microporous material or otherwise. However, as is apparent in the latter case, the drug must first pass through a microporous membrane material prior to reaching the skin or mucosa. It is therefore critical to the practice of this invention for all embodiments that, at some point after or concurrent with the release of drug from the reservoir and prior to reaching the skin or mucosa, the drug pass through the drug release rate controlling microporous membrane or matrix material to meter the flow thereof. The rate of passage or permeation of drug through the microporous material is determined by the transfer mechanism which can be either by:
l. diffusive flux of drug molecules as is the case, as hereinafter described, where the micropores of the rate controlling microporous membrane or matrix material are impregnated with a diffusive medium for the drug in which the drug molecules can dissolve in and flow through to a direction of lower chemical potential; or
2. pressure induced viscous type flow of drug molecules through the pores in the microporous membrane or matrix rate controlling material.
Thus, the microporous material has a structure that enables the drug to pass through the pre-existing pores or capillaries, either by diffusive permeability or microporous hydrodynamic flow, depending upon the mode of use as describd hereinafter. Since the microporous rate controlling material is preferably selected so that the drug is substantially insoluble therein, as hereinafter described, flow of drug through the structure of the material can be neglected.
For drug transfer mechanism 1) set forth above, i.e., wherein the drug diffuses through a diffusive medium for the drug, the release rate can be controlled in accordance with Ficks First Law, depending on the particular design by selection of dependent variables such as the diffusivity and solubility of the drug in the diffusive medium and the thickness and porosity of the material properly modified by a tortuosity factor. For drug transfer mechanism (2), i.e., flow of drug through the pores of the microporous rate controlling material, the pressure differential, the thickness of the membrane, the viscosity of the permeant drug, the size of the permeant molecule relative to the pore size, the absolute value of the pore size, and the number of pores or percent voids in the material are the controlling factors governing permeability. For the simplest type of flow mechanism of this type, e.g., viscous flow, the amount of drug passing through the porous structure is given by Poiseuilles equation for viscous flow.
Therefore, the selection of appropriate materials for fabricating the microporous rate controlling membrane or matrix material will be dependent on the particular drug to be used in the bandage. Both organic and inorganic polymeric materials can be shaped into a wide variety of forms with tailored morphology and a wide range of chemical and physical properties to advantageously control release of a wide variety of drugs, including those with large molecular structures such as insulin, and over a large dosage range rate appropriate pore size selection. Additionally, by impregnating the interconnected pores of the microporous structure with a diffusive medium for the drug to be administered, a given microporous membrane or matrix material can be adapted to control the release of drugs having a wide range of chemical properties by diffusive permeability. Thus, by varying the composition, pore size, and effective thickness of the microporous rate controlling material, the viscosity of the drug to be administered by appropriate formulation or by impregnating the material with suitable solvent, the dosage rate per area of bandage can be controlled since the material functions to meter the flow of drug from the device. Therefore, bandages of the same surface area can provide different dosages of a drug by varying the above discussed parameters.
The microporous rate controlling materials of this invention are known in the art and can be visualized as a plurality of sponge-like fused polymer particles which provide a supporting structure having therethrough a dispersion of microscopic sized interconnecting voids or pores. The rate controlling structures formed from the materials can be isotropic, wherein the structure is homogeneous throughout the cross-section of the matrix or membrane material, or anisotropic wherein the structure is non-homogenous. These rate controlling structures are commercially available and can be made by a multitude of different methods, e.g., etched nuclear track, and materials employed, e.g., polyelectrolyte, ion exchange polymers, as described in R. E. Kesting, Synthetic Polymer Membranes, McGraw Hill, Chapters 4 and 5, 1971; J. D. Ferry, Ultrafiltration Membranes, Chemical Review, Vol. 18, Page 373, 1934. Materials possessing from 5 percent to 95 percent voids and having an effective pore size of from about 10 angstroms to about 100 microns can be suitably employed in the practice of this invention. Materials with pore sizes significantly below angstroms can be considered to be molecular diffusion type membranes and matrices. In order to obtain the most advantageous results, the materials should be formed into structures with the desired morphology in accordance with methods known to those skilled in the art to achieve the desired release rate of drug. Additionally, the material must have the appropriate chemical resistance to the drug used and be non-toxic when used as an element of the bandage of the invention.
Materials useful in forming the microporous rate controlling materials used in this invention include, but are not limited to the following.
Polycarbonates, i.e., linear polyesters of carbonic acids in which carbonate groups recur in the polymer chain, by phosgenation of a dihydroxy aromatic such as bisphenol A. Such materials are sold under the trade designation Lexan'by the General Electric Company.
Polyvinylchlorides; one such material is sold under the trade designation Geon 121 by B. G. Goodrich Chemical Company.
Polyamides such as polyhexamethylene adipamide and other such polyamides popularly known as nylon. One particularly advantageous material is that sold under the trade name NOMEX by E. I. DuPont de Nemours & Co.
Modacrylic copolymers, such as that sold under the trade designation DYNEL and formed of polyvinylchloride percent) and acrylonitrile (40 percent), styrene-acrylic acid copolymers, and the like.
Polysulfones such as those of the type characterized by diphenylene sulfone groups :in the linear chain thereof are useful. Such materials are available from Union Carbide Corporation under the trade designation P-l700.
Halogenated polymers such as polyvinylidene fluoride sold under the trade designation Kynar by Pennsalt Chemical Corporation, polyvinylfluoride sold under the trade name Tedlar by E. I. DuPont de Nemours & Co. and the polyfluorohalocarbon sold under the trade name Aclar by Allied Chemical Corporation.
Polychloroethers such as that sold under the trade name Penton by Hercules Incorporated, and other such thermoplastic polyethers.
Acetal polymers such as the polyformaldehyde sold under the trade nambe Delrin by I. DuPont de Nemours & Co., and the like.
Acrylic resins such as polyacrylonitrile polymethyl poly (vinyl alcohol); polyelectrolyte structures formed of two ionically associated polymers of the type as set forth in U.S. Pat. Nos. 3,549,016 and 3,546,142; derivatives of polystyrene such as poly (sodium styrenesulfonate) and polyvinylbenzyltrimethyl-ammonium chloride); poly( hydroxyethyl methacrylate poly(isobutyl vinyl ether), and the like, may also be utilized. A large number of copolymers which can be formed by reacting various proportions of monomers from the aforesaid list of polymers are also useful for preparing rate controlling structures useful in the invention.
As illustrated in FIG. 1, the bandage of the invention is comprised of drug 24 uniformly distributed in the interstices of the microporous matrix material forming reservoir 22. The matrix material is laminated to backing member 21 and bears a pressure-sensitive adhesive coating 23 thereon. The microporous matrix material 22 functions to control the release rate of the drug impregnated therein. The reservoir can be prepared by employing any of the known impregnating techniques. Thus, the drug can be added to the rate controlling material in liquid form and uniformly distributed therethrough by mixing, and subsequently converted to a microporous structure by the various methods known to the art. One such method calls for dissolving a natural or synthetic polymer in a suitable solvent in which it has sufficient solubility to permit the preparation of a solution that is sufficiently viscous for conventional film casting. The preferred method is to cast a film of a polymer solution having the drug therein, and, shortly after casting, to immerse it in a non-solvent or diluent, a medium which is compatible with the solvent, but not a solvent for the polymer. The original solution then forms two phases, one polymer-rich and one polymer-poor. Under the proper conditions, both of these phases are physically continuous, so that the resulting polymer membrane is mechanically reasonably strong, but it is completely interlaced with continuous pores. The size and uniformity of the pores depend on the conditions of preparation. Alternatively, preformed microporous materials can be impregnated with drug by immersion in a bath of the drug to diffuse the drug into the material. While the matrix material can be of any convenient thickness, typically a thickness of from 20 to 200 microns is employed.
FIG. 2 illustrates a further modified form of the invention wherein the adhesive bandage 30 of the invention is comprised of a backing member 21 having a reservoir 32 on one surface thereof. A microporous rate controlling membrane 35 is interposed between the reservoir 32 and a pressure-sensitive adhesive coating 23. Drug 24 is confined in polymeric matrix material 32 which acts as the reservoir for the drug. Matrix material 32 can be solid material as illustrated, or microporous as illustrated for reservoir 22 in FIG. 1. If desired, additional membranes can be juxtaposed next to membrane 35 in order to achieve optimum rate release properties. The matrix material 32 when solid or microporous should have a release rate to drug which is higher than that of the rate controlling microporous membrane 35, such that passage through the latter is the rate controlling step. Materials used to form the matrix reservoir 32 of FIG. 2, when solid, can be those heretofore exemplitied for preparing the microporous rate controlling material and, in addition, include hydrophobic polymers such as plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized soft nylon, plasticized polyethyleneterephthalate, natural rubber, C -C olefins, e.g., polyethylene, polyisoprene, polyisobutylene, polybutadiene; silicone rubbers, especially the medical grade polydimethylsiloxanes, as described in US. Pat. No. 3,279,996, hydrophilic polymers such as the hydrophilic hydrogels of esters of acrylic and methacrylic acid (as described in US. Pat. Nos. 2,967,576 and 3,220,960, and Belgian Patent No. 701,813), modified collagen, cross-linked polyvinylalcohol, and crosslinked partially hydrolyzed polyvinylacetate. Of course, these materials used to form the matrix must be permeable to passage of the drug, as by diffusion. Accordingly, selection of appropriate materials will, in each instance, be dependent on the particular drug to be administered.
FIG. 3 illustrates a further form of the invention wherein bandage 40 includes a backing member 21 and a reservoir 42 in the form of a hollow container having an interior chamber 43 containing drug 34. Wall or surface 45 of reservoir 42, remote from backing member 21, is of a microporous membrane structure permeable to passage of drug 34, to meter the flow of drug to pressure-sensitive adhesive layer 23 on the outer surface thereof. The sides of the reservoir 42, other than rate controlling microporous membrane 45, preferably are impermeable to passage of the drug, and can be made of the same materials used to make the backing member as hereinafter described. As discussed, one face surface of the drug reservoir bears a backing member 21. The purpose of the backing is to prevent passage of the drug through the surface of the reservoir distant from the adhesive layer. An ancillary purpose of the backing is to provide support for the bandage where needed. When the outer surface of the reservoir 33 is impermeable to the drug and strong enough, the backing becomes unnecessary. The other surface of the reservoir bears a coating of a pressure-sensitive adhesive.
If desired, additional microporous rate controlling membranes can be juxtaposed on top of membrane 45 to further tailor the rate of flow of drug. Of course, in each instance, the membrane will have different characteristics than the reservoir membrane 45 of the particulardevice. This use of a pair of multiplicity of membranes, that is, the reservoir wall and the further membrane, allows for precise metering of drug out of the reservoir; for the thickness, porosity and composition of both membranes can be varied to provide for wide range of dosage levels for a given area of bandage. It will be appreciated that this type of membrane can be used with either the matrix (FIGS. 1 or 2) or container type (FIG. 3) of reservoir. To provide additional mechanical strength, if necessary, the rate controlling microporous membrane 45 can be supported by an appropriate mesh or screen having a greater release rate to drug than does membrane 45. v
The reservoir of the embodiment in FIG. 3 can be formed by molding into the form of a hollow container with the drug trapped therein. While the non-rate controlling walls of the reservoir can be of any convenient thickness, usually they have a thickness of from 0.01 to 7 millimeters. The rate controlling membranes 35 and 45, in FIGS. 2 and 3, respectively, can have varying thickness depending upon the nature of the membrane, its porosity and the number of membranes used in combination. Typically, a thickness of from 20 to 200 microns is employed.
It will, of course, be appreciated that the pressuresensitive adhesive surface need not form a continuous layer on the subject bandage. Particularly in the case of a bandage having a distinct reservoir layer, equally advantageous results are obtained by providing an annu lar surface of adhesive around the periphery of the bandage face. In this manner a liquid tight adhesive seal between the bandage and the patients skin or mucosa is maintained, and at the same time, drug may be directly absorbed by the skin from the exposed surface of the drug reservoir layer without first migrating through an adhesive layer. As a further alternative, in the embodiment of the invention employing a distinct reservoir layer, to prevent passage of the drug into the adhesive layer prior to use, the adhesive can be supplied separately from the reservoir and backing, with the device assembled at the point of use. For example, the adhesive in sheet form can have both surfaces protected with a release film and the wall of the reservoir can be similarly protected. At the point of use, the release films can be removed from the reservoir and one surface of the adhesive, the adhesive sheet applied to the reservoir wall to complete assemblage of the bandage, the remaining release film then removed from the adhesive, and the bandage then applied to the patient.
As previouslydiscussed, one type of drug transfer mechanism is that of flow through the pores or pinholes in microporous rate controlling material. A driving force, Le, a pressure differential across the microporous material, is necessary to cause the flow of drug by this mode. The bandage of the type illustrated in FIG. 3, wherein the reservoir is a hollow container, can be conveniently adapted to meter the flow of drug by a microporous hydrodynamic mechanism by pressurizing the container. This can suitably be accomplished by admixing with the drug a solid particulate material which liberates gas on contact with the drug formulation. For example, in the case wherein the formulation is of an aqueous nature, a conventional effervescent powder such as a mixture of citric acid and sodium bicarbonate can be inserted immediately prior to use through an opening in the reservoir wall so provide for this purpose. After insertion of the effervescent material, the opening is sealed, for example, by means of an adhesive tape. The pressure can be controlled by adjusting the particle size of the effervescent powder composition and the quantity thereof. Pressure in an amount of from 1 mm to 50 mm of mercury can be satisfactorily employed, with the actual amount depending upon the desired release rate and the other parameters previously discussed regarding viscousflow.
FIGS. 4 and 5 illustrate an adhesive bandage of the invention including a backing member 11 bearing a pressure-sensitive adhesive coating 12 on one surface thereof. Adhesive coating 12 has uniformly distributed therethrough microcapsules 13 comprising drug encapsulated with a microporous rate controlling material permeable to passage of the drug. Thus, in the embodiment illustrated herein, porous microcapsules 13 constitute the drug reservoir.
To provide the microcapsules, the encapsulating material can be uniformly impregnated with the drug to form microcapsules which are a porous matrix having the drug distributed therethrough. Alternatively, particles of drug can be encapsulated with a thin microporous-coatingof the encapsulating material to form microcapsules having an interior chamber containing the drug. If desired, particles of a matrix, such as starch, gum acacia, gum tragacanth, and polyvinylchloride, can be impregnated with the drug and encapsulated with other materials such as the microporous rate controlling materials previously described, which function to meter the flow of drug to the adhesives; use of a microporous matrix and a different rate controlling membrane coating to slow the passage of the drug from the microcapsules, which is desirable: with drugs that are released too rapidly from available encapsulating materials, is therefore also contemplated herein.
Any of the encapsulation or impregnation techniques known in the art can be used to prepare the microcapsules to be incorporated into the pressure-sensitive adhesive in accord with the embodiment of FIGS. 4 and 5. The porous microcapsules can be made by techniques as set forth in US. Ser. No. 751,251, corresponding to German Patent No. 1,939,066, entitled Microcapsules with Anisotropic MicroporousLiquid Permeable Polymeric Outer Skin and Internal Macroporous Support Partitions or Structure, Bixler, Michaels, and Sternberg, or by standard coacervation methods. The coacervation method of fabrication, as conventionally employed, consists essentially of the formation of three immiscible phases, a liquid manufacturing phase, a core material phase and a coating phase with deposition of the liquid polymer coating on the core material and rigidizing the coating, usually by thermal, cross-linking or desolvation techniques to form microcapsules. Usually, the microcapsules made by the above techniques have an average particle size of from several tenths of a micron to 5,000 microns, although this feature is not critical to the practice of the invention. Techniques for preparing microcapsules, such as the classic Bungenberg de long and Kass method are reported in Biochem. Z, Vol. 232, Pg. 338 to 345, I931; Colloid Science, Vol. 11, Reversible System,edited by H. R. Kruyt, 1949, Elsevier Publishing Company, Inc., New York; J. Pharm. Sci, Vol. 59, No. 10, Pg 1367 to 1376, 1970; and, Remingtons Pharmaceittical Science, Vol. XIV, Pg. 1676 to 1677, 1970, Mack Publishing Company, Easton, Pennsylvania. Thus, the drug can beadded to the encapsulating material in liquid form and uniformly distributed therethrough by mixing and then forming the microcapsules by any of the above set forth methods. Alternatively, the porous microparticles can be made by the above techniques and impregnated with drug. Still another method is to impregnate a porous solid encapsulating material with a drug by immersion in a bath of the drug to diffuse the drug-into the material, and subsequently the solid material can be, reduced to fine microcapsules by grinding, each of the microcapsules comprising drug coated with and distributed throughout the encapsulating material. Further, drug can be encapsulated with a microporouscoating by suspending dry particles of the drug in an air stream and contacting that stream with a stream containing the encapsulating material to coat the drug particles. Usually, the micro-capsules have an average particle size of form 1 to 1000 microns, although this is not critical to the invention. The microcapsules, however made, are then mixed by conventional methods, e.g., stirring, ballmilling, and the like, with a pressure-sensitive adhesive. The mixture of microcapsules and pressure-sensitive adhesive is then coated onto a backing member, usually to provide an adhesive layer 0.01 to 7 millimeters thick, although these limits can be exceeded if more or less drug is required. The purpose of the backing is to provide support for the bandage and to prevent passage of the drug through the adhesive surface away from the body surface to which the bandage is applied.
As above discussed, the microporous rate controlling materials can be adapted to control the release of drug 1 by diffusive permeation wherein the micropores are impregnated or otherwise filled with a diffusive medium for the drug to be administered. The material can be impregnated with the diffusive medium by methods well known to the art, e.g., as by immersion in a bath of the material to permit the diffusive medium material to fully saturate the micropores. The impregnation technique can be employed with any of the embodiments represented herein. In embodiments illustrated in FIGS, 1, 4 and 5 the micropores can be concurrently impregnated with both drug and diffusive medium material.
In cases where the pressure-sensitive adhesive and microporous rate controlling material employed are water permeable, body fluids will self-migrate into the microporous material after the bandage has been in contact with the skin for a suitable period of time to provide the diffusive medium, as hereinafter described, without the necessity of carrying out a separate impregnation step. Additionally, the pores can be self-filled by migration of the diffusive medium by contact with the composition employed to prepare the drug formulation, as later described.
The diffusive medium is one which enables the drug to dissolve therein and flow by diffusion at the desired rate. It can be either of a liquid or solid nature and be a poor or good solvent for the drug. A medium with poor solvent properties for the drug is desired when the required release rate is low and of course the converse is true when the desired release rate is high.
The art provides many useful approaches to enable selection of particular solvent-drug systems. Specific attention is called to Remingtons Pharmaceutical Sciences, Chapters 19 and 71. The solvent selected must be non-toxic and one in which the rate controlling microporous material has the required solubility. The materials which are useful for impregnating the micropores can be polar, semi-polar or non-polar. Exemplary are any of the pharmaceutically acceptable solvents such as water, alcohols containing 2 to carbon atoms, such as hexanol, cyclohexanol, benzylalcohol, 1,2-butanediol, glycerol, and amyl alcohol; hydrocarbons having 5 to 12 carbon atoms such as n-hexane, cyclohexane, and ethyl benzene; aldehydes and ketones having 4 to 10 carbon atoms such as heptyl aldehyde, cyclohexanone, and benzaldehyde; esters having 4 to 10 carbon atoms such as amyl acetate and benzyl propionate; etheral oils such as oil of eucalyptus, oil of rue, cumin oil, limonene, thyme], and l-pinene; halogenated hydrocarbons having 2 to 8 carbon atoms such as n-hexyl chloride, n-hexyl bromide, and cyclohexyl chloride; or mixtures of any of the foregoing materials.
Also suitable are many of the conventional non-toxic plasticizers used in the fabrication of microporous rate controlling material, e.g., octyl diphenyl phosphate. When these plasticizers are suitable diffusive materials for the drug used, advantageously, the necessity for filling the pores by a separate step is thus obviated. Other plasticizers known to the art can be employed, such as long-chain fatty amides, higher alcohols, and high boiling esters such as di(isooctyl) sebacate or di(2-ethyl hexyl) phthalate.
It is preferred that the diffusive medium also be incorporated in the reservoir in combination with the drug in the form of a pharmaceutically acceptable carrier as hereinafter described.
In practicing this invention one can employ any systemically active drug which will be absorbed by the body surface to which the bandage is applied, consistent with their known dosages and uses. Of course, the amount of drug necessary to obtain the desired therapeutic effect will vary depending on the particular drug used. Suitable systemic drugs include, without limitation, Anti-microbial Agents such as penicillin, tetracycline, oxytetracycline, chlortetracycline, chloramphenicol, and sulfonamides; Sedatives and Hypnotics such as pentabarbital sodium, phenobarbital, secobarbital sodium, codeine, (oz-bromoisovaleryl) urea, carbromal, and sodium pheno-barbital; Psychic Energizers such as 3-( Z-aminopropyl) indole acetate and 3-( 2- aminobutyl) indole acetate; Tranquilizers such as reserpine, chlorpromazine hydrochloride, and thiopropazate hydrochloride; Hormones such as adrenocorticosteroids, for example, 6a-methylprednisolone; androgenic steroids, for example, methyltestosterone, and fluoxymesterone; estrogenic steroids, for example, estrone, l7B-estradiol and ethinyl estradiol; progestational steroids, for example, l7a-hydroxyprogesterone acetate, medroxyprogesterone acetate, 19-norprogesterone, and norethindrone; and thyroxine; Antipyretics such as aspirin, salicylamide, and sodium salicylate; morphine and other narcotic analgesics; Antidiabetics, e.g., insulin; Cardiovascular Agents, e.g., nitroglycerin, and cardiac glycosides such as digitoxin, digoxin, ouabain; Anti-spasmodics such as atropine, methscopolamine bromide, methscopolamine bromide with phenobarbital; Anti-malarials such as the 4-aminoquinolines, 9-amino-quinolines, and pyrimethamine; and Nutritional Agents such as vitamins, essential amino acids, and essential fats.
Additionally, in practicing this invention one can employ a wide variety of topically active drugs consistent with their known dosages and uses. Suitable drugs include, without limitation: Antiperspirants, e.g., aluminum chloride; Deodorants, e.g., hexachlorophene, methylbenzethonium chloride; Astringents, e. g., tannic acid; Irritants, e.g., methyl salicylate, camphor, cantharidin', Keratolytics, e.g., benzoic acid, salicylic acid, resorcinol, iodochlorhydroxyquin; Antifungal Agents, such as tolnaftate, griseofulvin, nystatin and amphotericin; Anti-inflammatory Agents, such as corticosteroids, e.g., hydrocortisone, hydrocortisone-acetate, prednisolone, methylprednisolone, triamcinolone acetonide, fludrocortisone, flurandrenolone, flumethasone, dexamethasone sodium phosphate, bethamethasone valerate, fluocinolone acetonide; fluorometholone; and pram'ox'ine fiCl; Anti-neoplastic Agentsiegl, methotrexate; and Antibacterial Agents, such as bacitracin, neomycin erythromycifi,tetfacycline HCl, chlortetracycline I-lCl, chloramphenicol, oxytetracycline, polymyxin B, nitrofuraxone, mafenide (a-amino-ptoluenesulfonamide), hexachlorophene, benzalkonium chloride, cetalkonium chloride, methylbenzethonium chloride, and neomycin sulfate.
It will be appreciated, with regard to the aforesaid list of drugs, that characterization of the drug as either systemically or topically active is done for purposes of convenience only. Further, a given drug can be both systemically and topically active depending upon its manner of use.
In addition to the aforementioned drugs, simple pharmacologically acceptable derivatives of the drugs, such as ethers, esters, amides, acetals, salts, etc., or formulations of these drugs, having the desired polymeric permeability or transport properties can be prepared and used in practicing the invention. Drugs mentioned above can be used alone or in combination with others and each other. Of course, the derivatives should be such as to convert to the active drugs within the body through the action of body enzyme assisted transformations, pH, etc.
The above drugs and other drugs can be present in the reservoir alone or in combination form with pharmaceutical carriers. The pharmaceutical carriers acceptable for the purpose of this invention are the art known carriers that do not adversely affect the drug, the host, or the material comprising the drug delivery device. Suitable pharmaceutical carriers include sterile water; saline, dextrose; dextrose in water or saline; condensation products of castor oil and ethylene oxide combining about 30 to about 35 moles of ethylene oxide per mole of castor oil; liquid glyceryl triester of a lower molecular weight fatty acid; lower alkanols; oils such as corn oil; peanut oil, sesame oil and the like, with emulsifiers such as mono-or di-glyceride of a fatty acid, or a phosphatide, e.g., lecithin, and the like; glycols; polyalkylene glycols; aqueous media in the presence of a suspending agent, for example, sodium carboxymethylcellulose; sodium alginate; poly(vinylpyrrolidone); and the like, alone, or with suitable dispensing agents such as lecithin; polyoxyethylene stearate; and the like. The carrier may also contain adjuvants such as preserving, stabilizing, wetting, emulsifying agents, and the like.
The drug can also be mixed in the reservoir with a transporting agent, that is, a material that aids or assists the drug delivery device to achieve the administration of a drug to a drug receptor, for example, by enhancing penetration through the skin. The transporting aids suitable for the purpose of the invention are thetherapeutically acceptable transporting aids that do not adversely affect the host, the drug, or alter or adversely affect the materials forming the drug delivery device. The transporting aids can be used alone or they can be admixed with acceptable carriers and the like. Exemplary of transporting aids include manovalent, saturated and unsaturated aliphatic cycloaliphatic and aromatic alcohols having 4 to 12 carbon atoms, such as hexanol, cyclohexane and the like; aliphatic cycloaliphatic and aromatic hydrocarbons having from 5 to 12 carbon atoms such as hexane, cyclohexane, isopropylbenzene and the like; cycloaliphatic and aromaticaldehydes and ketones having from 4 to carbon atoms such as cyclohexanone; acetamide; N,N-di(lower) alkyl acetamides such as N,N-diethyl acetamide, N,N- dimethyl acetamide, N-( Z-hydroxyethyl) acetamide, and the like; and other transporting agents such as aliphatic, cycloaliphatic and aromatic esters; N,N-dilower alkyl sulfoxides; essential oils; halogenated or nitrated aliphatic, cycloaliphatic and aromatic hydrocar- T4 bons; salicylates; polyalkylene glycol silicates; mixtures thereof; and the like.
The amount of active agent to be incorporated in the bandage to obtain the desired therapeutic effect will vary depending upon the desired dosage, the permeability of the rate controlling materials of the bandage which are employed to the particular agent to be used, and the length of time the bandage is to remain on the skin or body mucosa. Since the bandage of this invention is designed to control drug administration for an extended period of time, such as 1 day or more, there isno critical upper limit on the amount of agent incorporated into the bandage. The lower limit is determined by the fact that sufficient amounts of the agent must remain in the bandage to maintain the desired dosage. In order to achieve a therapeutic effect in a human adult, the daily release dosage of atropine should be in the range of between 200 and 600 micrograms per day. Thus, for example, using atropine and with a bandage intended to remain in place for 1 week, and with a release rate of 500 micrograms of atropine per day, at least 3.5 mg of atropine would be incorporated in the bandage. Generally, the drug delivery bandages made according to the invention can release at a controlled rate about 25 nanograms to about 1 gram of drug or larger amounts per day. Of course, other devices for use for different time periods such as Week or month are also readily made by the invention.
The effective rate of release of the active agent to the skin or mucosa can be in the range of from 0.5 to 1000 micrograms per square centimeter of bandage per day. The exactamount will depend on the desired dosage as well as the condition to be treated. The desired effective rate of release of active agent can be obtained by altering the earlier discussed parameters affecting the release ratecontrolling barrier. In the case of the micro-encapsulated active agent, the release rate can also be controlled by varying the number of microcapsules present in a given volume of the matrix of the device. This is a particularly desirable feature of this aspect of the invention. Additionally, the duration of action of the device can be altered by controlling the amount of active agent initially incorporated consistent with the release rate. Further, the release rate of drug, as well as the duration of release of the drug from the device, can be predetermined to be in consonance with the optimum therapeutic values. Once thisdosage level in micrograms per square centimeter of bandage has been determined, the total amountof drug to be incorporated in the bandage can be established by obtaining the release rate of the agent in the particular material or materials which are to be used; Those skilled in the art can readily determine the rate of permeation of agent through the porous rate controlling material or selected combinations of rate controlling materials. Standard techniques are described in Encyl. Polymer Science and Technology, Vo. Sand 9, Pg. 65 to and 795 to 807, 1968; and the references cited therein.
Any of the well-known dermatologically acceptable pressure-sensitive adhesives can be used in practicing this invention. Exemplary adhesives include acrylic or methacrylic resins such as polymers of esters of acrylic or methacrylic acid with alcohols such as n-butanol, npentanol, isopentanol, 2-methyl butanol, l-methyl butanol, l-methyl pentanol, Z-methyl pentanol, 3-methyl pentanol, 2-ethyl .butanol, isooctanol, n-decanol, or ndodecanol, alone or copolymerized with ethylenically unsaturated monomers such as acrylic acid, methacrylic acid, acrylamide, methacrylamide, N-
alkoxymethyl acrylamides, N-alkoxymethyl methacrylamides, N-tert. butylacrylamide, itaconic acid, vinylacetate, N-branched alkyl maleamic acids wherein the alkyl group has to 24 carbon atoms, glycol diacrylates, or mixtures of these; natural or synthetic rubbers such as silicone rubber, styrenebutadiene, butylether, neoprene, polyisobutylene, polybutadiene, and polyisoprene; polyurethane elastomers; vinyl polymers, such as polyvinylalcohol, polyvinyl ethers, polyvinyl pyrrolidone, and polyvinylacetate; ureaformaldehyde resins; phenolformaldehyde resins; resorcinol formaldehyde resins, cellulose derivatives such as ethyl cellulose, methyl cellulose, nitrocellulose, cellulose acetatebutyrate, and carboxymethyl cellulose; and natural gums such as guar, acacia, pectins, starch, dextrin, albumin, gelatin, casein, etc. The adhesives may be compounded with tackifiers and stabilizers as is well know in the art.
When the adhesive layer covers one face surface of the bandage or when the reservoir is in the form of microcapsules distributed throughout the adhesive, the adhesive must be permeable to passage of the drug to allow drug released from the reservoir to reach the outer surface of the bandage in contact with the patient. In such cases, the rate of release of drug from the adhesive should exceed the rate of release of drug from the reservoir so that release from the reservoir by passage through the drug release controlling microporous material is the rate limiting step for drug administration by the device of the invention. Of course, when the adhesive is disposed only about the periphery of the bandage face, the adhesive need not be permeable to passage of the drug.
Various occlusive and non-occlusive, flexible or nonflexible backing members can be used in the adhesive bandage of the invention. Suitable backings include cellophane, cellulose acetate, ethylcellulose, plasticized vinylacetate-vinylchloride copolymers, polyethylene terephthalate, nylon, polyethylene, polypropylene, polyvinylidenechloride, paper, cloth, and aluminum foil. Preferably, a' flexible occlusive backing is employed to conform to the shape of the body member to which the adhesive tape is applied and to enhance administration of the agent to the skin.
To prevent passage of the drug away from the exposed surface of the pressure-sensitive adhesive prior to use, the adhesive surface of the tape generally is covered with a protective release film or foil such as waxed paper. Alternatively, the exposed rear surface of the backing member can be coated with a low-adhesion backsize and the bandage rolled about itself. To enhance stability of the active compounds, the therapeutic bandage usually is packaged between hermetically sealed polyethylene terephthalate films under an inert atmosphere, such as gaseous nitrogen.
To use the adhesive bandage of the invention, wherein the drug is topical, it is applied directly to the area of skin to be treated, to release a therapeutically effective amount of the agent to the affected area. For administration of systemic drugs the bandage can be applied to any area of the patients skin, with the lower back and buttocks being the areas of choice. In like manner, the bandage can be applied to the mucosa of the mouth, for example, by application to the palate or the buccal mucosa, to obtain absorption of the drug by the oral mucosa. Although obtaining a liquid tight adhesive seal between the skin and bandage is important, it becomes critical in the mouth. Without such a seal, irrigation of the oral mucosa by saliva will transfer the drug to the gastrointestinal tract, rather than to circulation through the oral mucosa. In addition, the bandage of the invention can be used to administer drugs to other mucosa of the body, for example, it can be applied to the vaginal mucosa, rectal mucosa, etc. By use of this invention, one ensures that an accurately measured quantity of the active drug is available to the site of application.
The following examples are merely illustrative to the present invention and should not be construed as limiting the scope of the invention in any way, as these examples and other equivalents thereof will become apparent to those versed in the art in light of the present disclosure, drawings and accompanying claims.
EXAMPLE 1 Porous, discrete particles of polymerized poly(vinyl chloride) of about 100 microns in diameter are prepared by mixing 100 grams of suspension grade poly(- vinyl chloride) resin with 50 grams of octyl diphenyl phosphate and 10 grams of nitroglycerin. These ingredients are mixed at room temperature into a sticky, wet mass. Next, the solvent is allowed to escape to form dry, free flowing, discrete micro-capsules. 10 grams of the resulting microcapsules of polyvinylchloride/nitroglycerin are mixed with 100 grams of a 22 percent solution in hexane: isopropyl-acetate (:30) of a viscoelastic copolymer of isooctyl acrylate and acrylic acid (94:6) adhesive to uniformly distribute the microcapsules throughout the adhesive solution. The resulting slurry is coated onto a cellophane sheet 10 centimeters in width by centimeters in length and the solvent removed from the coated film.
When a 5 centimeter by 5 centimeter section is cut from the above sheet and applied to the skin of a human adult, the resulting bandage is effective to control the continuous administration of a daily therapeutically effective dosage of nitroglycerin for the prophylactic treatment of angina pectoris.
EXAMPLE 2 Dry crystalline powdered megesterol acetate (0.3 gram) in 10 ml. ethanol is mixed with 25 parts by weight of polydimethylsiloxane, 5 parts by weight of silicone oil and 0.25 parts by weight of stannous octoate catalyst. The ingredients are mixed until a homogenous mixture is produced. The mixture is then cast into a mold and allowed to cure to prepare a matrix having a surface area of 10 square centimeters and 9 mils thick. One face surface of the matrix is bonded to a sheet of cellophane. On the other face surface is placed an ethanol impregnated microporous membrane of the same external surface area as the matrix. The membrane is sold by Millipore Corporation and designated to the trade as HA, and is characterized by a porosity of 60 percent, a pore size of 0.45 microns, and a thickness of 4 mils. Dimethyl silicone rubber adhesive is coated to a thickness of 2 mils on the membrane. The adhesive face surface of the completed bandage has an area of 10 square centimeters. The bandage is effective to slowly release megesterol acetate, and when applied to the female skin, is useful for fertility control.
EXAMPLE 3 10 milligrams of betamethasone in 10 ml. of propylene glycol is placed on a sheet of dimethyl silicone rubber having a thickness of 10 mils. The sheet is folded to provide a surface area of l square centimeters on each face and the flaps sealed with silicone adhesive to provide a thin envelope containing the drug. The top face of the envelope is removed and replaced with a propylene glycol impregnated microporous membrane sold by Amicon Corporation under the designation of PM 30. The membrane is secured to the envelope by means of adhesive to form a tight seal therewith. The membrane is characterized by having an anisotropic structure, with a minimum pore size of 70 angstrom units, an overall porosity of 70 percent, and a thickness of 4 units.
Pressure-sensitive adhesive is prepared by mixing together 90 grams of polyacrylate solution (ethylacetate: hexane/:1) containing 25 percent non-volatile matter (obtained by the catalytic polymerization of isomylacrylate and acrylic acid in the ratio of 95:5 in ethylacetate and then diluting with hexane), 5 grams polyvinylethylether (reduced viscosity= 0.3 i 0.1), 1 gram Castor oil (fislfiand l gra r n s pblyethyleneglycol 400.
One face surface of the envelope is bonded to a sheet of cellophane while the external membrane surface is coated with adhesive prepared above to a thickness of 2 millimeters. The adhesive face surface of the bandage has an area of 100 square centimeters. The bandage is effective to release a therapeutically effective daily dosage of the drug when applied to the skin for control of psoriasis.
EXAMPLE 4 3 grams of a polyacrylonitrile fiber sold under the trade designation Orlon by E. I. DuPont de Nemours & Co. was dissolved in 30 grams of an aqueous solution comprising 70 percent by weight of zinc chloride. After the solution was cooled to about 25C, 0.250 grams of DIGOXIN was added to the solution. Thereupon, the solution was added drop-wise through a No. 21 hypodermic needle into an acetone bath whereupon particles were formed. After being stirred for about thirty minutes in the acetone, the particles were removed and placed in a water bath for four hours at room temperature to leach our residual acetone and salt.
grams of polyvinylethylether (reduced visosity= 5 .0 i 0.5) 4 grams of polyvinylethylether (reduced viscosity= 4 grams of glycerol ester of hydrogenated rosin and 2 grams polyethyleneglycol 400 The resulting DIGOXIN capsules are mixed with pressuresensitive adhesive prepared above to uniformly distribute the microcapsules throughout the adhesive. Immediately thereafter, the adhesive mixture is coated onto one surface of a 1000 square centimeter Mylar sheet. A 5 centimeter by 5 centimeter area of the resulting bandage can be used for control of cardiac disorders.
Thus, this invention provides an easy to use device for administering systemically active drugs through the skin or oral mucosa and other body mucosa. Uncertainties of administration through the gastrointestinal tract are avoided and a controlled constant level of drug in circulation can be obtained. Treatment is begun by applying the bandage to the skin or mucosa and terminated by removing it therefrom. The bandage can contain and administer the complete dosage requirements for a particular time period, for example, 24 hours. Intervention by the patient is required only to apply and remove the bandage, so that uncertainties through patient error are eliminated.
Moreoventhis invention provides a reliable and easy to use device for administering topically active drugs directly to the affected areas of skin or mucosa. Uncertainties resulting from topical application of these agents, from creams and solutions, are not encountered; and a precisely determined amount of the drug is applied in a controlled manner.
Although the product of this invention has been referred to as an adhesive bandage, those skilled in the art will appreciate that the term adhesive bandage" as used herein includes any product having a backing member and a pressure-sensitive adhesive face surface. Such products can be provided in various sizes and configurations, including tapes, bandages, sheets, plasters, and the like.
What is claimed is:
l. A medical bandage for the continuous administration of controlled quantities of drug to the skin or mucosa, comprised of a laminate of: (l) a backing mem' ber; bearing (2) a discrete middle reservoir layer containing a drug confined within a body, the body being comprised of drug release rate controlling microporous material permeable to the passage of drug, to continuously meter the flow of a therapeutically effective amount of the drug to the skin or mucosa from the reservoir at a controlled and predetermined rate over a period of time; and (3) a pressure-sensitive adhesive surface adapted for contact with the skin or mucosa and postitioned on one surface of the reservoir remote from the backing member.
2. The bandage as defined by claim 1 wherein the pores of the microporous rate controlling material are filled with a medium to permit controlled diffusion of the drug from the reservoir.
3. A medical bandage for the continuous administration of controlled quantities of drug to the skin or mucosa, comprised of a laminate of: (l) a backing member; bearing (2) a discrete middle reservoir containing a drug confined therein, the reservoir being formed of material permeable to passage of the drug; and (3) a pressure-sensitive adhesive surface adapted for contact with the skin or mucosa and positionedon one surface of the reservoir remote from the backing member and wherein one or more drug release rate controlling microporous membranes are interposed between the surface of the reservoir and pressure-sensitive adhesive so as to continuously meter the flow of a therapeutically effective amount of the drug from the reservoir at a controlled and predetermined rate over a period of time.
4. The bandage as defined by claim 3 wherein the reservoir is a container having the drug confined therein.
5. The bandage as defined by claim 4 wherein the reservoir is pressurized to permit controlled microporous flow of the drug from the reservoir.
6. The bandage as defined by claim 3 wherein the reservoir is a solid or microporous matrix having the drug dispersed therein.
7. The bandage as defined by claim 3 wherein the pores of the microporous rate controlling material are filled with a medium to permit controlled diffusion of the drug from the reservoir.
|Patente citada||Fecha de presentación||Fecha de publicación||Solicitante||Título|
|US3053255 *||16 Dic 1958||11 Sep 1962||Meyer Friedrich||Process of percutaneously administering exact doses of physiologically active agents and composite unit therefor|
|US3426754 *||14 Sep 1966||11 Feb 1969||Celanese Corp||Breathable medical dressing|
|US3464413 *||26 May 1967||2 Sep 1969||United Merchants & Mfg||Medical bandages|
|US3512997 *||29 Sep 1966||19 May 1970||Tee Pak Inc||Extrusion of microporous collagen articles|
|US3598122 *||1 Abr 1969||23 Nov 1982||Título no disponible|
|US3598123 *||1 Abr 1969||10 Ago 1971||Alza Corp||Bandage for administering drugs|
|Patente citante||Fecha de presentación||Fecha de publicación||Solicitante||Título|
|US3972995 *||14 Abr 1975||3 Ago 1976||American Home Products Corporation||Dosage form|
|US4031894 *||7 Sep 1976||28 Jun 1977||Alza Corporation||Bandage for transdermally administering scopolamine to prevent nausea|
|US4039653 *||21 Jul 1975||2 Ago 1977||Defoney, Brenman, Mayes & Baron||Long-acting articles for oral delivery and process|
|US4060084 *||28 Ene 1977||29 Nov 1977||Alza Corporation||Method and therapeutic system for providing chemotherapy transdermally|
|US4201211 *||12 Jul 1977||6 May 1980||Alza Corporation||Therapeutic system for administering clonidine transdermally|
|US4230105 *||13 Nov 1978||28 Oct 1980||Merck & Co., Inc.||Transdermal delivery of drugs|
|US4262003 *||14 Mar 1977||14 Abr 1981||Alza Corporation||Method and therapeutic system for administering scopolamine transdermally|
|US4286592 *||4 Feb 1980||1 Sep 1981||Alza Corporation||Therapeutic system for administering drugs to the skin|
|US4341208 *||14 Jul 1980||27 Jul 1982||Whitman Medical Corporation||Moisture-retentive covering for ointment application|
|US4432756 *||27 Nov 1981||21 Feb 1984||Alza Corporation||Parenteral controlled therapy|
|US4460372 *||1 Abr 1983||17 Jul 1984||Alza Corporation||Percutaneous absorption enhancer dispenser for use in coadministering drug and percutaneous absorption enhancer|
|US4479793 *||11 Oct 1983||30 Oct 1984||Alza Corporation||Parenteral administration using drug delivery device|
|US4479794 *||11 Oct 1983||30 Oct 1984||Alza Corporation||System for intravenous therapy|
|US4484909 *||17 Oct 1983||27 Nov 1984||Alza Corporation||Parenteral therapy using solid drug|
|US4493702 *||17 Oct 1983||15 Ene 1985||Alza Corporation||Parenteral administration using osmotically motivated delivery system|
|US4511351 *||14 May 1984||16 Abr 1985||Alza Corporation||Parenteral delivery system utilizing a hollow fiber cellular unit|
|US4511352 *||14 May 1984||16 Abr 1985||Alza Corporation||Parenteral delivery system with in-line container|
|US4511353 *||9 Oct 1981||16 Abr 1985||Alza Corporation||Intravenous system for delivering a beneficial agent|
|US4515585 *||31 Oct 1983||7 May 1985||Alza Corporation||System for parenteral administration of agent|
|US4525162 *||9 Mar 1984||25 Jun 1985||Alza Corporation||Parenteral controlled delivery|
|US4548599 *||5 Ene 1984||22 Oct 1985||Alza Corporation||Parenteral controlled therapy|
|US4552556 *||4 Ene 1985||12 Nov 1985||Alza Corporation||Parenteral controlled therapy|
|US4573996 *||3 Ene 1984||4 Mar 1986||Jonergin, Inc.||Device for the administration of an active agent to the skin or mucosa|
|US4579553 *||7 Ene 1985||1 Abr 1986||Alza Corporation||Parenteral controlled therapy|
|US4583981 *||7 Ene 1985||22 Abr 1986||Alza Corporation||Parenteral controlled therapy, using a porous matrix with parenteral agent|
|US4585452 *||12 Abr 1983||29 Abr 1986||Key Pharmaceuticals, Inc.||Transdermal systemic dosage forms|
|US4586922 *||15 Feb 1985||6 May 1986||Alza Corporation||Intravenous system for delivering a beneficial agent|
|US4596555 *||28 Ene 1985||24 Jun 1986||Alza Corporation||Parenteral delivery system utilizing a hollow fiber cellular unit|
|US4615697 *||9 Nov 1984||7 Oct 1986||Bio-Mimetics, Inc.||Bioadhesive compositions and methods of treatment therewith|
|US4624665 *||1 Oct 1984||25 Nov 1986||Biotek, Inc.||Method of transdermal drug delivery|
|US4645502 *||3 May 1985||24 Feb 1987||Alza Corporation||Transdermal delivery of highly ionized fat insoluble drugs|
|US4655767 *||26 Sep 1985||7 Abr 1987||Dow Corning Corporation||Transdermal drug delivery devices with amine-resistant silicone adhesives|
|US4661105 *||9 Jun 1986||28 Abr 1987||Alza Corporation||Medical bandage for administering vasodilator drug|
|US4664650 *||31 Oct 1983||12 May 1987||Alza Corporation||Apparatus for parenteral infusion of fluid containing beneficial agent|
|US4666441 *||17 Dic 1985||19 May 1987||Ciba-Geigy Corporation||Multicompartmentalized transdermal patches|
|US4671953 *||1 May 1985||9 Jun 1987||University Of Utah Research Foundation||Methods and compositions for noninvasive administration of sedatives, analgesics, and anesthetics|
|US4680172 *||5 Mar 1985||14 Jul 1987||Ciba-Geigy Corporation||Devices and methods for treating memory impairment|
|US4690683 *||2 Jul 1985||1 Sep 1987||Rutgers, The State University Of New Jersey||Transdermal varapamil delivery device|
|US4698062 *||30 Oct 1985||6 Oct 1987||Alza Corporation||Medical device for pulsatile transdermal delivery of biologically active agents|
|US4704119 *||19 Nov 1986||3 Nov 1987||Alza Corporation||Method comprising transdermal and buccal treatment of angina|
|US4710191 *||16 Dic 1985||1 Dic 1987||Jonergin, Inc.||Therapeutic device for the administration of medicaments|
|US4725272 *||29 Jun 1981||16 Feb 1988||Alza Corporation||Novel bandage for administering beneficial drug|
|US4738670 *||10 Jul 1987||19 Abr 1988||Bayer Aktiengesellschaft||Medicinal plasters|
|US4740103 *||15 Feb 1985||26 Abr 1988||Alza Corporation||Intravenous system for delivering a beneficial agent|
|US4740197 *||14 Feb 1985||26 Abr 1988||Alza Corporation||Intravenous system for delivering a beneficial agent via polymer delivery|
|US4740198 *||15 Feb 1985||26 Abr 1988||Alza Corporation||Method of administering intravenous drug using rate-controlled dosage form|
|US4740199 *||14 Feb 1985||26 Abr 1988||Alza Corporation||Intravenous system for delivering a beneficial agent|
|US4740200 *||15 Feb 1985||26 Abr 1988||Alza Corporation||Intravenous system for delivering a beneficial agent|
|US4740201 *||19 Feb 1985||26 Abr 1988||Alza Corporation||Intravenous system for delivering a beneficial agent|
|US4741734 *||15 Feb 1985||3 May 1988||Alza Corporation||Releasing means for adding agent using releasing means to IV fluid|
|US4741735 *||14 Feb 1985||3 May 1988||Alza Corporation||Intravenous system for delivering a beneficial agent|
|US4743249 *||10 Jun 1987||10 May 1988||Ciba-Geigy Corp.||Dermal and transdermal patches having a discontinuous pattern adhesive layer|
|US4752478 *||17 Dic 1984||21 Jun 1988||Merck & Co., Inc.||Transdermal system for timolol|
|US4756710 *||7 Mar 1986||12 Jul 1988||Merck & Co., Inc.||pH-Mediated drug delivery system|
|US4764379 *||24 Ago 1987||16 Ago 1988||Alza Corporation||Transdermal drug delivery device with dual permeation enhancers|
|US4765985 *||20 May 1987||23 Ago 1988||Ciba-Geigy Corporation||Devices and methods for treating memory impairment|
|US4776850 *||12 May 1986||11 Oct 1988||Beiersdorf Aktiengesellschaft||Nitrate-containing plaster|
|US4790820 *||25 Oct 1984||13 Dic 1988||Alza Corporation||Parenteral agent dispensing equipment with drug releasing member|
|US4795436 *||22 Sep 1986||3 Ene 1989||Bio-Mimetics, Inc.||Bioadhesive composition and method of treatment therewith|
|US4812305 *||9 Nov 1987||14 Mar 1989||Vocal Rodolfo S||Well medicine strip|
|US4812313 *||14 Dic 1987||14 Mar 1989||Alza Corporation||Method for lessening the incidence of anginal attacks|
|US4820720 *||29 Mar 1988||11 Abr 1989||Alza Corporation||Transdermal drug composition with dual permeation enhancers|
|US4833172 *||15 Sep 1988||23 May 1989||Ppg Industries, Inc.||Stretched microporous material|
|US4834979 *||14 Dic 1987||30 May 1989||Alza Corporation||Medical bandage for administering beneficial drug|
|US4836217 *||23 Sep 1985||6 Jun 1989||Fischer Torkel I||Hypersensitivity test means|
|US4839174 *||5 Oct 1987||13 Jun 1989||Pharmetrix Corporation||Novel transdermal nicotine patch|
|US4846826 *||21 Nov 1986||11 Jul 1989||Alza Corporation||Method for treating ischemic conditions|
|US4849226 *||14 Dic 1987||18 Jul 1989||Alza Corporation||Method for increasing oxygen supply by administering vasodilator|
|US4857052 *||4 May 1987||15 Ago 1989||Alza Corporation||Intravenous system for delivering a beneficial agent|
|US4861644 *||30 Ago 1988||29 Ago 1989||Ppg Industries, Inc.||Printed microporous material|
|US4863737 *||8 Jun 1987||5 Sep 1989||University Of Utah||Compositions and methods of manufacture of compressed powder medicaments|
|US4863738 *||23 Nov 1987||5 Sep 1989||Alza Corporation||Skin permeation enhancer compositions using glycerol monooleate|
|US4871360 *||21 Abr 1986||3 Oct 1989||Alza Corporation||System for intravenous delivery of a beneficial drug at a regulated rates|
|US4877618 *||18 Mar 1988||31 Oct 1989||Reed Jr Fred D||Transdermal drug delivery device|
|US4885173 *||8 Jun 1987||5 Dic 1989||University Of Utah||Methods and compositions for noninvasive dose-to-effect administration of drugs with cardiovascular or renal vascular activities|
|US4898920 *||15 Oct 1987||6 Feb 1990||Dow Corning Corporation||Adhesive compositions, controlled release compositions and transdermal delivery device|
|US4904475 *||24 Feb 1987||27 Feb 1990||Alza Corporation||Transdermal delivery of drugs from an aqueous reservoir|
|US4906463 *||8 Abr 1988||6 Mar 1990||Cygnus Research Corporation||Transdermal drug-delivery composition|
|US4906475 *||16 Feb 1988||6 Mar 1990||Paco Pharmaceutical Services||Estradiol transdermal delivery system|
|US4908019 *||16 Sep 1988||13 Mar 1990||Alza Corporation||Apparatus comprising dual reservoirs for parenteral infusion of fluid containing beneficial agent|
|US4911707 *||10 Ago 1988||27 Mar 1990||Ciba-Geigy Corporation||Monolithic user-activated transdermal therapeutic system|
|US4917688 *||27 Jun 1988||17 Abr 1990||Nelson Research & Development Co.||Bandage for transdermal delivery of systemically-active drug|
|US4938759 *||2 Sep 1986||3 Jul 1990||Alza Corporation||Transdermal delivery device having a rate controlling adhesive|
|US4943435 *||28 Oct 1988||24 Jul 1990||Pharmetrix Corporation||Prolonged activity nicotine patch|
|US4954344 *||10 Nov 1988||4 Sep 1990||Alza Corporation||Method for treating nocturnal angina|
|US4969871 *||15 Feb 1989||13 Nov 1990||Alza Corporation||Intravenous system for delivering a beneficial agent|
|US4971800 *||18 Sep 1989||20 Nov 1990||The Regents Of The University Of California||Method and compositions for enhancing the cutaneous penetration of pharmacologically active agents|
|US4973307 *||25 Abr 1989||27 Nov 1990||Alza Corporation||Method for administering drugs to a patient|
|US4973468 *||22 Mar 1989||27 Nov 1990||Cygnus Research Corporation||Skin permeation enhancer compositions|
|US4983392 *||20 Dic 1988||8 Ene 1991||Bio-Mimetics, Inc.||Bioadhesive compositions and methods of treatment therewith|
|US4985017 *||25 Abr 1989||15 Ene 1991||Alza Corporation||Parenteral therapeutical system comprising drug cell|
|US4994031 *||17 Abr 1989||19 Feb 1991||Alza Corporation||Intravenous system for delivering a beneficial agent|
|US5006342 *||10 Feb 1989||9 Abr 1991||Cygnus Corporation||Resilient transdermal drug delivery device|
|US5024657 *||4 May 1990||18 Jun 1991||Baxter International Inc.||Drug delivery apparatus and method preventing local and systemic toxicity|
|US5028435 *||22 May 1989||2 Jul 1991||Advanced Polymer Systems, Inc.||System and method for transdermal drug delivery|
|US5035894 *||8 Sep 1989||30 Jul 1991||Dow Corning Corporation||Controlled release compositions and transdermal drug delivery device|
|US5045059 *||15 Ago 1990||3 Sep 1991||Alza Corporation||Intravenous system for delivering a beneficial agent|
|US5045317 *||20 Sep 1990||3 Sep 1991||The Regents Of The University Of California||Enhancing the cutaneous penetration of pharmacologically active agents|
|US5051260 *||20 Sep 1990||24 Sep 1991||The Regents Of The University Of California||Method and composition for enhancing the cutaneous penetration of pharmacologically active agents|
|US5053227 *||12 Jun 1990||1 Oct 1991||Cygnus Therapeutic Systems||Skin permeation enhancer compositions, and methods and transdermal systems associated therewith|
|US5059189 *||8 Sep 1987||22 Oct 1991||E. R. Squibb & Sons, Inc.||Method of preparing adhesive dressings containing a pharmaceutically active ingredient|
|US5059426 *||12 Jun 1990||22 Oct 1991||Cygnus Therapeutic Systems||Skin permeation enhancer compositions, and methods and transdermal systems associated therewith|
|US5069671 *||23 Jun 1988||3 Dic 1991||Alza Corporation||Intravenous medication|
|US5071656 *||14 Nov 1988||10 Dic 1991||Alza Corporation||Delayed onset transdermal delivery device|
|US5080646 *||3 Oct 1988||14 Ene 1992||Alza Corporation||Membrane for electrotransport transdermal drug delivery|
|US5091087 *||25 Jun 1990||25 Feb 1992||Hoechst Celanese Corp.||Fabrication of microporous PBI membranes with narrow pore size distribution|
|US5091186 *||15 Ago 1989||25 Feb 1992||Cygnus Therapeutic Systems||Biphasic transdermal drug delivery device|
|US5122127 *||5 Sep 1989||16 Jun 1992||University Of Utah||Apparatus and methods for use in administering medicaments by direct medicament contact to mucosal tissues|
|US5124157 *||18 Ago 1989||23 Jun 1992||Cygnus Therapeutic Systems||Method and device for administering dexmedetomidine transdermally|
|US5132114 *||5 Sep 1989||21 Jul 1992||University Of Utah Research Foundation||Compositions and methods of manufacture of compressed powder medicaments|
|US5141750 *||14 Nov 1988||25 Ago 1992||Alza Corporation||Delayed onset transdermal delivery device|
|US5147296 *||28 Ago 1991||15 Sep 1992||Alza Corporation||Membrane for electrotransport transdermal drug delivery|
|US5151271 *||24 Oct 1989||29 Sep 1992||Nitti Electric Industrial Co., Ltd.||Pressure-sensitively adhering composite medicinal preparation|
|US5160320 *||14 Feb 1990||3 Nov 1992||Alza Corporation||Intravenous system for delivering a beneficial agent|
|US5164189 *||11 Mar 1991||17 Nov 1992||G. D. Searle & Co.||Single layer transdermal drug administration system|
|US5164416 *||8 May 1991||17 Nov 1992||Lintec Corporation||Transdermal therapeutic formulation containing a limonene|
|US5169382 *||30 Ene 1991||8 Dic 1992||Alza Corporation||Membrane for electrotransport transdermal drug delivery|
|US5169383 *||2 Oct 1989||8 Dic 1992||Alza Corporation||Control membrane for electrotransport drug delivery|
|US5213965 *||16 Jul 1990||25 May 1993||Cholestech Corporation||Solid-phase precipitation assay device|
|US5232438 *||15 Jun 1992||3 Ago 1993||Alza Corporation||Membrane for electrotransport transdermal drug delivery|
|US5234690 *||23 Ago 1991||10 Ago 1993||Cygnus Therapeutic Systems||Transdermal drug delivery device using an unfilled microporous membrane to achieve delayed onset|
|US5268179 *||14 Feb 1992||7 Dic 1993||Ciba-Geigy Corporation||Ultrasonically sealed transdermal drug delivery systems|
|US5273755 *||23 Ago 1991||28 Dic 1993||Cygnus Therapeutic Systems||Transdermal drug delivery device using a polymer-filled microporous membrane to achieve delayed onset|
|US5273756 *||23 Ago 1991||28 Dic 1993||Cygnus Therapeutic Systems||Transdermal drug delivery device using a membrane-protected microporous membrane to achieve delayed onset|
|US5288497 *||5 Sep 1989||22 Feb 1994||The University Of Utah||Compositions of oral dissolvable medicaments|
|US5290561 *||10 Abr 1992||1 Mar 1994||G. D. Searle & Co.||Single layer transdermal drug administration system|
|US5298257 *||19 Mar 1992||29 Mar 1994||Elan Transdermal Limited||Method for the treatment of withdrawal symptoms associated with smoking cessation and preparations for use in said method|
|US5322502 *||13 Ene 1993||21 Jun 1994||Alza Corporation||Membrane for electrotransport transdermal drug delivery|
|US5340585 *||17 May 1993||23 Ago 1994||University Of Southern California||Method and formulations for use in treating benign gynecological disorders|
|US5340586 *||17 May 1993||23 Ago 1994||University Of Southern California||Methods and formulations for use in treating oophorectomized women|
|US5378730 *||3 Dic 1992||3 Ene 1995||Alza Corporation||Permeation enhancer comprising ethanol and monoglycerides|
|US5405614 *||11 Ene 1993||11 Abr 1995||International Medical Associates, Inc.||Electronic transdermal drug delivery system|
|US5411740 *||8 Feb 1994||2 May 1995||Alza Corporation||Transdermal administration of oxybutynin|
|US5422118 *||21 Sep 1992||6 Jun 1995||Pure Pac, Inc.||Transdermal administration of amines with minimal irritation and high transdermal flux rate|
|US5451407 *||21 Jun 1993||19 Sep 1995||Alza Corporation||Reduction or prevention of skin irritation or sensitization during transdermal administration of a irritating or sensitizing drug|
|US5484602 *||20 Ene 1995||16 Ene 1996||University Of Utah Research Foundation||Methods and compositions for noninvasive dose-to-effect administration of drugs with cardiovascular or renal vascular activities|
|US5498417 *||12 May 1994||12 Mar 1996||Coating Sciences, Inc.||Transdermal delivery of appetite suppressant drug|
|US5500222 *||15 Feb 1995||19 Mar 1996||Alza Corporation||Transdermal administration of oxybutynin|
|US5505958 *||31 Oct 1994||9 Abr 1996||Algos Pharmaceutical Corporation||Transdermal drug delivery device and method for its manufacture|
|US5508039 *||16 Oct 1992||16 Abr 1996||Alza Corporation||Controlled transdermal administration of melatonin|
|US5512292 *||21 Dic 1994||30 Abr 1996||Alza Corporation||Transdermal contraceptive formulations methods and devices|
|US5582836 *||16 Oct 1991||10 Dic 1996||Vectorpharma International S.P.A.||Transdermal therapeutic compositions|
|US5591767 *||6 Jun 1995||7 Ene 1997||Pharmetrix Corporation||Liquid reservoir transdermal patch for the administration of ketorolac|
|US5612382 *||15 Jul 1994||18 Mar 1997||Frances B. Fike||Composition for percutaneous absorption of pharmaceutically active ingredients|
|US5633009 *||12 Nov 1993||27 May 1997||Sano Corporation||Transdermal administration of azapirones|
|US5641507 *||26 Oct 1995||24 Jun 1997||Devillez; Richard L.||Delivery system for dermatological and cosmetic ingredients|
|US5643596 *||7 Jun 1995||1 Jul 1997||Clarion Pharmaceuticals, Inc.||Hemostatic patch|
|US5643905 *||10 Ene 1994||1 Jul 1997||Therapie-System Gmbh & Co., Kg||Pharmaceutical formulation for the treatment of nicotine dependence|
|US5645849 *||7 Jun 1995||8 Jul 1997||Clarion Pharmaceuticals, Inc.||Hemostatic patch|
|US5650165 *||7 Nov 1995||22 Jul 1997||Nitto Denko Corporation||Percutaneous absorption preparation|
|US5668143 *||3 Nov 1994||16 Sep 1997||Merrell Pharmaceuticals Inc.||Heterocyclic benzenesulfonylimine derivatives as inhibitors of IL-1 action|
|US5684017 *||3 Nov 1994||4 Nov 1997||Merrell Pharmaceuticals Inc.||Benzenesulfonylimine derivatives as inhibitors of IL-1 action|
|US5707612 *||8 Abr 1996||13 Ene 1998||Alzo, Inc.||Use urethane polymers of castor oil skin and personal care product compositiions|
|US5728688 *||7 Jun 1995||17 Mar 1998||Endoreoherche, Inc.||Therapeutic methods and delivery systems utilizing sex steroid precursors|
|US5747065 *||29 Sep 1994||5 May 1998||Lee; Eun Soo||Monoglyceride/lactate ester permeation enhancer for oxybutynin|
|US5750137 *||29 Sep 1994||12 May 1998||Taskovich; Lina Tormen||Monoglyceride/lactate ester permeation enhancer|
|US5756117 *||10 Ago 1992||26 May 1998||International Medical Asscociates, Inc.||Multidose transdermal drug delivery system|
|US5762952 *||27 Abr 1993||9 Jun 1998||Hercon Laboratories Corporation||Transdermal delivery of active drugs|
|US5776923 *||18 Ene 1994||7 Jul 1998||Endorecherche, Inc.||Method of treating or preventing osteoporosis by adminstering dehydropiandrosterone|
|US5780460 *||7 Jun 1995||14 Jul 1998||Endoreoherche, Inc.||Therapeutic methods and delivery systems utilizing sex steroid precursors|
|US5785991 *||7 Jun 1995||28 Jul 1998||Alza Corporation||Skin permeation enhancer compositions comprising glycerol monolaurate and lauryl acetate|
|US5798347 *||7 Jun 1995||25 Ago 1998||Endorecherche, Inc.||Therapeutic methods and delivery systems utilizing sex steroid precursors|
|US5807571 *||7 Oct 1997||15 Sep 1998||Lts Lohmann Therapie-Systeme Gmbh||Transdermal therapeutic systems for administering indole serotonin agonists|
|US5807849 *||13 Jun 1995||15 Sep 1998||Endorecherche, Inc.||Therapeutic methods and delivery systems utilizing sex steroid precursors|
|US5817331 *||7 Jun 1995||6 Oct 1998||Sano Corporation||Transdermal administration of azapirones|
|US5820876 *||6 Jun 1995||13 Oct 1998||Lts Lohmann Therapie-Systeme Gmbh & Co. Kg||Transdermal therapeutic system|
|US5824671 *||7 Jun 1995||20 Oct 1998||Endorecherche Inc||Therapeutic methods and delivery systems utilizing sex steroid precursors|
|US5827529 *||10 Jun 1994||27 Oct 1998||Teikoku Seiyaku Kabushiki Kaisha||External preparation for application to the skin containing lidocaine|
|US5837280 *||7 Jun 1995||17 Nov 1998||Sano Corporation||Transdermal administration of azapirones|
|US5837700 *||7 Jun 1995||17 Nov 1998||Endorecherche, Inc.||Therapeutic methods and delivery systems utilizing sex steroid precursors|
|US5840327 *||15 Ago 1996||24 Nov 1998||Alza Corporation||Transdermal drug delivery device having enhanced adhesion|
|US5843468 *||13 May 1996||1 Dic 1998||Alza Corporation||Skin permeation enhancer compositions comprising glycerol monolaurate and lauryl acetate|
|US5843932 *||7 Jun 1995||1 Dic 1998||Endorcaherche, Inc.||Therapeutic methods and delivery systems utilizing sex steroid precursors|
|US5854229 *||7 Jun 1995||29 Dic 1998||Endorecherche, Inc.||Therapeutic methods and delivery systems utilizing sex steroid precursors|
|US5855908 *||15 Nov 1994||5 Ene 1999||University Of Utah Research Foundation||Non-dissolvable drug-containing dosage-forms for use in the transmucosal delivery of a drug to a patient|
|US5861170 *||22 Mar 1994||19 Ene 1999||Lts Lohmann Therapie-Systeme Gmbh & Co. Kg||Acetylsalicyclic acid-containing transdermal application system for antithrombotic therapy|
|US5869086 *||25 Abr 1994||9 Feb 1999||Lts Lohmann Therapie-Systeme Gmbh||Systems for the controlled release of pilocarpine|
|US5872114 *||7 Jun 1995||16 Feb 1999||Endorecherche, Inc.||Therapeutic methods and delivery systems utilizing sex steroid precursors|
|US5891868 *||21 Nov 1997||6 Abr 1999||Kaiser Foundation Health Plan, Inc.||Methods for treating postmenopausal women using ultra-low doses of estrogen|
|US5900250 *||30 Abr 1998||4 May 1999||Alza Corporation||Monoglyceride/lactate ester permeation enhancer for oxybutnin|
|US5912009 *||29 Oct 1997||15 Jun 1999||Theratech, Inc.||Fatty acid esters of glycolic acid and its salts|
|US5919478 *||24 Jun 1994||6 Jul 1999||Alza Corporation||Incorporating poly-N-vinyl amide in a transdermal system|
|US5922700 *||7 Jun 1995||13 Jul 1999||Endorecherche, Inc.||Therapeutic methods and delivery systems utilizing sex steroid precursors|
|US5932240 *||8 Dic 1997||3 Ago 1999||Americare Technology, Inc.||Multidose transdermal drug delivery system|
|US5939095 *||6 Dic 1994||17 Ago 1999||Lts Lohmann Therapie-Systeme Gmbh||Transdermal therapeutic system and a process for the combined transdermal application of physostigmine and scopolamine for the prophylaxis and pretreatment of a poisoning caused by highly toxic organophosphorus neurotoxins in particular soman|
|US5948434 *||7 Jun 1995||7 Sep 1999||Endorecherche, Inc.||Therapeutic methods and delivery systems utilizing sex steroid precursors|
|US5952000 *||29 Oct 1997||14 Sep 1999||Theratech, Inc.||Fatty acid esters of lactic acid salts as permeation enhancers|
|US5955455 *||13 Nov 1997||21 Sep 1999||Endorecherche, Inc.||Therapeutic methods and delivery systems utilizing sex steroid precursors|
|US5962011 *||24 Jun 1997||5 Oct 1999||Schering-Plough Healthcare Products, Inc.||Device for delivery of dermatological ingredients|
|US6001390 *||18 Dic 1996||14 Dic 1999||Alza Corporation||Formulations for transdermal delivery of pergolide|
|US6004578 *||23 Oct 1997||21 Dic 1999||Alza Corporation||Permeation enhances for transdermal drug delivery compositions, devices and methods|
|US6007837 *||3 Feb 1999||28 Dic 1999||Alza Corporation||Drug delivery devices and process of manufacture|
|US6074665 *||24 Jun 1996||13 Jun 2000||Lts Lohmann Therapie-Systeme Gmbh||Transdermal therapeutic system for administering active agents to the human body via the skin|
|US6110488 *||6 Jun 1995||29 Ago 2000||Lts Lohmann Therapie-Systeme Gmbh & Co. Kg||Transdermal therapeutic system, its use and production process|
|US6117448 *||6 Jun 1995||12 Sep 2000||Lts Lohmann Therapie-Systeme Gmbh & Co. Kg||Transdermal therapeutic system, its use and production process|
|US6126963 *||6 Jun 1995||3 Oct 2000||Lts Lohmann Therapie-Systeme Gmbh & Co. Kg||Transdermal therapeutic system, its use and production process|
|US6139868 *||6 Jun 1995||31 Oct 2000||Lts Lohmann Therapie-Systeme Gmbh & Co. Kg||Transdermal therapeutic system, its use and production process|
|US6143303 *||14 Ago 1999||7 Nov 2000||Janakiram; Chodavarapu||Analgesic anti-inflammatory composition and method of preparing from dodonaea sp|
|US6163720 *||3 Dic 1998||19 Dic 2000||Alza Corporation||Layered rate controlling membranes for use in an electrotransport device|
|US6174545||3 Feb 1999||16 Ene 2001||Alza Corporation||Drug delivery devices and process of manufacture|
|US6187322 *||5 Ene 1995||13 Feb 2001||Lts Lohmann Therapie-Systeme Gmbh||Process and a device for the production of a flat administration form comprising a preparation which contains pharmaceutical active substances|
|US6203817||5 Jun 1998||20 Mar 2001||Alza Corporation||Reduction of skin reactions caused by transdermal drug delivery|
|US6224900||9 Mar 1998||1 May 2001||Lts Lohmann Therapie-Systeme Gmbh & Co. Kg||Sealing bag for a transdermal therapeutic system|
|US6238700||5 May 1998||29 May 2001||Alza Corporation||Method for preventing crystal formation in a dispersion of a liquid in a matrix|
|US6264977||28 Oct 1999||24 Jul 2001||Lts Lohmann Therapie-Systeme Gmbh & Co. Kg||Transdermal therapeutic system, its use and production process|
|US6267984||17 Dic 1998||31 Jul 2001||Alza Corporation||Skin permeation enhancer compositions comprising a monoglyceride and ethyl palmitate|
|US6300327||6 Feb 1997||9 Oct 2001||The University Of Southern California||Compositions and methods for potentiation of neurotrophin activity|
|US6326524 *||2 Mar 2000||4 Dic 2001||Bristol-Myers Squibb Company||Hydrocolloid foam dressing|
|US6348210||10 Nov 1999||19 Feb 2002||Alza Corporation||Methods for transdermal drug administration|
|US6375978||17 Dic 1998||23 Abr 2002||Alza Corporation||Rate controlling membranes for controlled drug delivery devices|
|US6465440||4 Jun 2001||15 Oct 2002||Wellstat Therapeutics Corporation||Antimutagenic compositions for treatment and prevention of photodamage to skin|
|US6465445||11 Jun 1998||15 Oct 2002||Endorecherche, Inc.||Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors|
|US6512010||14 Jul 1997||28 Ene 2003||Alza Corporation||Formulations for the administration of fluoxetine|
|US6537571||18 Ago 1998||25 Mar 2003||Lts Lohmann Therapie-Systeme Ag||Transdermal therapeutic system containing the active substance scopolamine base|
|US6548510||8 Feb 2000||15 Abr 2003||Lts Lohmann Therapie Systeme Ag||Pharmaceutical composition containing deoxypeganine for the treatment of nicotine dependence|
|US6569448||17 Oct 1997||27 May 2003||Alza Corporation||Method for preventing crystal formation in a dispersion of a liquid in a matrix|
|US6572879||7 Jun 1995||3 Jun 2003||Alza Corporation||Formulations for transdermal delivery of pergolide|
|US6592892||29 Ago 2000||15 Jul 2003||Tepha, Inc.||Flushable disposable polymeric products|
|US6627631 *||8 Feb 2000||30 Sep 2003||Lts Lohmann Therapie-Systeme Ag||Pharmaceutical composition containing desoxypeganine for the treatment of alcoholism|
|US6649681 *||5 Feb 2001||18 Nov 2003||Ferro Corporation||Adhesive composition primarily intended for use in medical applications|
|US6660295||29 Sep 1998||9 Dic 2003||Alza Corporation||Transdermal drug delivery device package with improved drug stability|
|US6670346||11 Jun 1999||30 Dic 2003||Endorecherche, Inc.||Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors|
|US6692763||21 Nov 1998||17 Feb 2004||The Regents Of The University Of California||Methods for treating postmenopausal women using ultra-low doses of estrogen|
|US6698162 *||20 Mar 2001||2 Mar 2004||Teikoku Pharma Usa, Inc.||Methods of producing a terminally sterilized topical patch preparation|
|US6699497||23 Jul 1999||2 Mar 2004||Alza Corporation||Formulations for the transdermal administration of fenoldopam|
|US6775570||18 Abr 2002||10 Ago 2004||Ceramatec, Inc.||Iontophoretic treatment device|
|US6933321||14 Feb 2003||23 Ago 2005||Endorecherche, Inc.||Antiandrogenic biphenyls|
|US6960353||29 Sep 2003||1 Nov 2005||Alza Corporation||Formulations for the transdermal administration of fenoldopam|
|US6974588||7 Dic 1999||13 Dic 2005||Elan Pharma International Limited||Transdermal patch for delivering volatile liquid drugs|
|US7011844||22 Nov 2002||14 Mar 2006||Alza Corporation||Formulations for the administration of fluoxetine|
|US7047069||4 Feb 2002||16 May 2006||Ceramatec, Inc.||Iontophoretic fluid delivery device|
|US7063859||18 Sep 2002||20 Jun 2006||Noven Pharmaceuticals, Inc.||Barrier film lined backing layer composition and method for topical administration of active agents|
|US7087640||14 Mar 2003||8 Ago 2006||Technology Commercialization Corp||Substance with sedative effect|
|US7166617||26 Feb 2001||23 Ene 2007||Mitsubishi Pharma Corporation||Cyclic amide derivatives|
|US7169409||8 Sep 2003||30 Ene 2007||Alza Corporation||Method for preventing crystal formation in a dispersion of a liquid in a matrix|
|US7349733||2 Nov 2001||25 Mar 2008||Ceramatel, Inc.||Iontophoretic drug delivery systems|
|US7429576||30 Dic 2003||30 Sep 2008||Endorecherche, Inc.||Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors|
|US7553923||26 Oct 2007||30 Jun 2009||Metabolix, Inc.||Medical devices and applications of polyhydroxyalkanoate polymers|
|US7622136||18 Jun 2004||24 Nov 2009||Alza Corporation||Transparent transdermal nicotine delivery devices|
|US7641825||29 Jul 2005||5 Ene 2010||Tepha, Inc.||Method of making a polyhydroxyalkanoate filament|
|US7732430||23 May 2002||8 Jun 2010||Pantarhei Bioscience B.V.||Drug delivery system comprising a tetrahydroxilated estrogen for use in hormonal contraception|
|US7795038||8 Abr 2003||14 Sep 2010||Cholestech Corporation||High-density lipoprotein assay device and method|
|US7824879||9 Ene 2008||2 Nov 2010||Cholestech Corporation||Device and method for measuring LDL-associated cholesterol|
|US7871995||23 May 2002||18 Ene 2011||Pantarhei Bioscience B.V.||Drug delivery system comprising a tetrahydroxylated estrogen for use in hormonal contraception|
|US7884092||3 Oct 2006||8 Feb 2011||Endorecherche, Inc.||Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors|
|US7923440||11 Jun 2003||12 Abr 2011||Pantarhei Bioscience B.V.||Method of treating or preventing immune mediated disorders and pharmaceutical formulation for use therein|
|US7943603||3 Oct 2006||17 May 2011||Endorecherche, Inc.||Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors|
|US7943604||11 Jun 2003||17 May 2011||Pantarhei Bioscience B.V.||Method of treating human skin and a skin care composition for use in such a method|
|US7943683||31 Oct 2007||17 May 2011||Tepha, Inc.||Medical devices containing oriented films of poly-4-hydroxybutyrate and copolymers|
|US7988991 *||7 Mar 2002||2 Ago 2011||Hisamitsu Pharmaceutical Co., Inc.||Adhesive patch|
|US8017598||16 May 2007||13 Sep 2011||Knopp Neurosciences, Inc.||Compositions of R(+) and S(−) pramipexole and methods of using the same|
|US8026228||23 May 2002||27 Sep 2011||Pantarhei Bioscience B.V.||Estrogenic compounds in combination with progestogenic compounds in hormone-replacement therapy|
|US8034270||30 Abr 2004||11 Oct 2011||Tepha, Inc.||Polyhydroxyalkanoate medical textiles and fibers|
|US8048869 *||17 May 2002||1 Nov 2011||Pantarhei Bioscience B.V.||Pharmaceutical composition for use in hormone replacement therapy|
|US8075911||20 Ago 2007||13 Dic 2011||Alza Corporation||Transparent transdermal nicotine delivery devices|
|US8084125||11 Dic 2009||27 Dic 2011||Tepha, Inc.||Non-curling polyhydroxyalkanoate sutures|
|US8124689||6 Jun 2007||28 Feb 2012||Dow Corning Corporation||Silicone acrylate hybride composition and method of making same|
|US8188066||3 Oct 2006||29 May 2012||Endorecherche, Inc.||Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors|
|US8197844||8 Jun 2007||12 Jun 2012||Activatek, Inc.||Active electrode for transdermal medicament administration|
|US8207159||18 Abr 2002||26 Jun 2012||Hf Arzneimittelforschung Gmbh||Use of galanthamine for the treatment of pathological manifestations of the central nervous system based on intoxications with psychotropic substances|
|US8236785||7 Ene 2008||7 Ago 2012||Pantarhei Bioscience B.V.||Method of treating or preventing infertility in a female mammal and pharmaceutical kit for use in such method|
|US8241662||21 Dic 2006||14 Ago 2012||Watson Laboratories, Inc.||Unoccluded topical oxybutynin gel composition and methods for transdermal oxybutynin therapy|
|US8246979||22 Jul 2003||21 Ago 2012||Ucb Pharma Gmbh||Transdermal delivery system for the administration of rotigotine|
|US8246980 *||28 Jul 2003||21 Ago 2012||Ucb Pharma Gmbh||Transdermal delivery system|
|US8329734||27 Jul 2009||11 Dic 2012||Afgin Pharma Llc||Topical therapy for migraine|
|US8361272||27 Jun 2007||29 Ene 2013||Ferring B.V.||Polyurethane elastomers|
|US8361273||6 Sep 2012||29 Ene 2013||Ferring B.V.||Polyurethane elastomers|
|US8389548||18 Feb 2005||5 Mar 2013||Endorecherche, Inc.||Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors|
|US8440222 *||31 Dic 2009||14 May 2013||Acino Ag||Reservoir system with closed membrane|
|US8445474||5 Ago 2011||21 May 2013||Knopp Neurosciences, Inc.||Compositions of R(+) and S(−) pramipexole and methods of using the same|
|US8460707||26 Mar 2012||11 Jun 2013||Ferring B.V.||Stabilised prostaglandin composition|
|US8491934||28 Jul 2005||23 Jul 2013||Ferring B.V.||Stabilised prostaglandin composition|
|US8518926||14 Dic 2007||27 Ago 2013||Knopp Neurosciences, Inc.||Compositions and methods of using (R)-pramipexole|
|US8519148||14 Mar 2008||27 Ago 2013||Knopp Neurosciences, Inc.||Synthesis of chirally purified substituted benzothiazole diamines|
|US8524254||15 Oct 2007||3 Sep 2013||Ferring B.V.||Bioresorbable polymers|
|US8524695||14 Mar 2008||3 Sep 2013||Knopp Neurosciences, Inc.||Modified release formulations of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and methods of using the same|
|US8557281||13 Jul 2010||15 Oct 2013||Ferring B.V.||Water-swellable polymers|
|US8569416||21 Oct 2011||29 Oct 2013||Dow Corning Corporation||Single phase silicone acrylate formulation|
|US8592424||29 Jun 2009||26 Nov 2013||Afgin Pharma Llc||Topical regional neuro-affective therapy|
|US8614278||29 Nov 2011||24 Dic 2013||Dow Corning Corporation||Silicone acrylate hybrid composition and method of making same|
|US8617591||27 Abr 2012||31 Dic 2013||Ucb Pharma Gmbh||Transdermal delivery system for the administration of rotigotine|
|US8628798||10 Ago 2012||14 Ene 2014||Ferring B.V.||Water-swellable polymers|
|US8663680||5 Dic 2011||4 Mar 2014||Alza Corporation||Transparent transdermal nicotine delivery devices|
|US8696637||28 Feb 2011||15 Abr 2014||Kimberly-Clark Worldwide||Transdermal patch containing microneedles|
|US8709482||31 May 2013||29 Abr 2014||Ferring B.V.||Stabilised prostaglandin composition|
|US8715723||26 Feb 2007||6 May 2014||Noven Pharmaceuticals, Inc.||Compositions and methods for delivery of amino-functional drugs|
|US8753555||11 Abr 2011||17 Jun 2014||Tepha, Inc.||Medical devices containing oriented films of poly-4-hydroxybutyrate and copolymers|
|US8758657||16 Jul 2013||24 Jun 2014||Tepha, Inc.||Process of making polyhydroxyalkanoate medical textiles|
|US8778382||30 Abr 2004||15 Jul 2014||Purdue Pharma L.P.||Tamper resistant transdermal dosage form|
|US8790689||18 Nov 2005||29 Jul 2014||Purdue Pharma L.P.||Tamper resistant transdermal dosage form|
|US8862223||18 Ene 2008||14 Oct 2014||Activatek, Inc.||Active transdermal medicament patch and circuit board for same|
|US8883830||13 Ene 2012||11 Nov 2014||Afgin Pharma LLC.||Topical therapy for the treatment of migraines, muscle sprains, muscle spasms, spasticity and related conditions|
|US8974813||27 Jun 2007||10 Mar 2015||Ferring B.V.||Hydrophilic polyurethane compositions|
|US8987240||23 Oct 2003||24 Mar 2015||Pantarhei Bioscience B.V.||Pharmaceutical compositions comprising estetrol derivatives for use in cancer therapy|
|US8999379||27 Feb 2014||7 Abr 2015||Alza Corporation||Transparent transdermal nicotine delivery devices|
|US9012480||7 Dic 2012||21 Abr 2015||Afgin Pharma Llc||Topical therapy for migraine|
|US9034854||11 Jul 2003||19 May 2015||Pantarhei Bioscience B.V.||Pharmaceutical composition comprising estetrol derivatives for use in cancer therapy|
|US9040509||31 Ene 2011||26 May 2015||Pantarhei Bioscience B.V.||Method of treating human skin and a skin care composition for use in such a method|
|US9090651||7 Ene 2005||28 Jul 2015||Endorecherche, Inc.||Helix 12 directed pharmaceutical products|
|US9125719||8 Sep 2011||8 Sep 2015||Tepha, Inc.||Polyhydroxyalkanoate medical textiles and fibers|
|US9205059||23 Feb 2015||8 Dic 2015||Alza Corporation||Transparent transdermal nicotine delivery devices|
|US9284345||9 Abr 2008||15 Mar 2016||Endorecherche, Inc.||17alpha-substituted steroids as systemic antiandrogens and selective androgen receptor modulators|
|US9333066||13 May 2014||10 May 2016||Tepha, Inc.||Method of making a medical textile from polyhydroxyalkanoate fibers|
|US9468630||13 Ago 2013||18 Oct 2016||Knopp Biosciences Llc||Compositions and methods for treating conditions related to increased eosinophils|
|US9480770||28 Feb 2014||1 Nov 2016||Covidien Lp||Methods for preparation of medical dressing containing antimicrobial agent|
|US9512096||21 Dic 2012||6 Dic 2016||Knopp Biosciences, LLP||Synthesis of amine substituted 4,5,6,7-tetrahydrobenzothiazole compounds|
|US9522262||27 Abr 2011||20 Dic 2016||Kimberly-Clark Worldwide, Inc.||Medical devices for delivery of siRNA|
|US9522263||27 Abr 2011||20 Dic 2016||Kimberly-Clark Worldwide, Inc.||Device for delivery of rheumatoid arthritis medication|
|US9526883||27 Abr 2011||27 Dic 2016||Kimberly-Clark Worldwide, Inc.||Composite microneedle array including nanostructures thereon|
|US9545507||27 Abr 2011||17 Ene 2017||Kimberly-Clark Worldwide, Inc.||Injection molded microneedle array and method for forming the microneedle array|
|US9555155||10 Dic 2015||31 Ene 2017||Tepha, Inc.||Methods of orienting multifilament yarn and monofilaments of poly-4-hydroxybutyrate and copolymers thereof|
|US9561238||12 Feb 2015||7 Feb 2017||Donesta Bioscience B.V.||Pharmaceutical compositions comprising estetrol derivatives for use in cancer therapy|
|US9586044||27 Abr 2011||7 Mar 2017||Kimberly-Clark Worldwide, Inc.||Method for increasing the permeability of an epithelial barrier|
|US9642840||13 Ago 2014||9 May 2017||Knopp Biosciences, Llc||Compositions and methods for treating plasma cell disorders and B-cell prolymphocytic disorders|
|US9662313||28 Feb 2014||30 May 2017||Knopp Biosciences Llc||Compositions and methods for treating amyotrophic lateral sclerosis in responders|
|US9681936 *||30 Nov 2012||20 Jun 2017||Covidien Lp||Multi-layer porous film material|
|US9682068||19 May 2014||20 Jun 2017||Mylan Inc.||Transdermal therapeutic system for extended dosing of pramipexole in treating neurological disorders|
|US9682960||11 Dic 2014||20 Jun 2017||Endorecherche, Inc.||Non-steroidal antiandrogens and selective androgen receptor modulators with a pyridyl moiety|
|US9763918||13 Ago 2014||19 Sep 2017||Knopp Biosciences Llc||Compositions and methods for treating chronic urticaria|
|US9808554||21 Jul 2014||7 Nov 2017||Covidien Lp||Super soft foams|
|US20030088204 *||2 Nov 2001||8 May 2003||Joshi Ashok V||Novel iontophoretic drug delivery systems|
|US20030118653 *||10 Jun 2002||26 Jun 2003||Lavipharm Laboratories Inc.||Quick dissolving oral mucosal drug delivery device with moisture barrier coating|
|US20030181516 *||14 Mar 2003||25 Sep 2003||Krylov Boris Vladimirovich||Substance with sedative effect|
|US20030212094 *||26 Feb 2001||13 Nov 2003||Haruko Yamabe||Novel cyclic amide derivatives|
|US20030224471 *||8 Abr 2003||4 Dic 2003||Jones Ronald M.||High-Density lipoprotein assay device and method|
|US20040006134 *||14 Feb 2003||8 Ene 2004||Endorecherche, Inc.||Antiandrogenic biphenyls|
|US20040081683 *||28 Jul 2003||29 Abr 2004||Schacht Dietrich Wilhelm||Transdermal delivery system|
|US20040096491 *||7 Mar 2002||20 May 2004||Tetsuro Tateishi||Adhesive patch|
|US20040116406 *||18 Abr 2002||17 Jun 2004||Klaus Opitz||Utilization of galanthamine for the treatment of pathologies of the central nervous system owing to intoxications with psychotropic substances|
|US20040132751 *||18 Abr 2002||8 Jul 2004||Klaus Opitz||Use of desoxypeganine for treating central nervous system symptoms resulting from intoxications by psychotrops|
|US20040142022 *||10 Dic 2003||22 Jul 2004||Jutaro Shudo||Methods of producing a terminally sterilized topical patch preparation|
|US20040157812 *||30 Dic 2003||12 Ago 2004||Endorecherche, Inc.||Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors|
|US20040167145 *||5 Jul 2002||26 Ago 2004||Klaus Opitz||Active ingredient combination for the pharmacological therapy of nicotine dependence|
|US20040186086 *||17 May 2002||23 Sep 2004||Bunschoten Evert Johannes||Use of estrogen compounds to increase libido in women|
|US20040192620 *||23 May 2002||30 Sep 2004||Bunschoten Evert Johannes||Drug delivery system comprising a tetrahydroxylated estrogen for use in hormonal contraception|
|US20040192683 *||15 Jun 2002||30 Sep 2004||Joachim Moormann||Active ingredient combination for treating a dependence on addictive substances or narcotics using medicaments|
|US20040198671 *||17 May 2002||7 Oct 2004||Bunschoten Evert Johannes||Pharmaceutical composition for use in hormone replacement therapy|
|US20040198706 *||10 Mar 2004||7 Oct 2004||Carrara Dario Norberto R.||Methods and formulations for transdermal or transmucosal application of active agents|
|US20040198710 *||23 May 2002||7 Oct 2004||Bunschoten Evert Johannes||Drug delivery system comprising a tetrahydroxilated estrogen for use in hormonal contraception|
|US20040209909 *||9 Abr 2002||21 Oct 2004||Su Il Yum||Novel formulations for transdermal delivery of pergolide|
|US20040234576 *||30 Abr 2004||25 Nov 2004||Tepha, Inc., State Of Incorporation Delaware||Polyhydroxyalkanoate medical textiles and fibers|
|US20040234585 *||18 Jun 2004||25 Nov 2004||Gale Robert M.||Transparent transdermal nicotine delivery devices|
|US20040258742 *||20 Jul 2004||23 Dic 2004||Van Osdol William Woodson||Transdermal administration of N-(2,5-disubstituted phenyl)-N'-(3-substituted phenyl)-N'-methyl guanidines|
|US20050002997 *||30 Abr 2004||6 Ene 2005||Howard Stephen A.||Tamper resistant transdermal dosage form|
|US20050025809 *||8 Jul 2004||3 Feb 2005||Tepha, Inc.||Poly-4-hydroxybutyrate matrices for sustained drug delivery|
|US20050048104 *||30 Jun 2003||3 Mar 2005||Venkatraman Subramanian S.||Transdermal drug delivery devices comprising a polyurethane drug reservoir|
|US20050053647 *||16 Sep 2004||10 Mar 2005||Rudolf Matusch||Pharmaceutical product comprising the active substance diamorphine, and its use in a process for treating opiate addiction|
|US20050059645 *||2 Ago 2004||17 Mar 2005||Bodor Nicholas S.||Methods for the treatment of male and female sexual dysfunction|
|US20050065062 *||24 Sep 2003||24 Mar 2005||3M Innovative Properties Company||Method of formulating a pharmaceutical composition|
|US20050070488 *||23 May 2002||31 Mar 2005||Coelingh Bennik Herman Jan Tijmen||Estrogenic compounds in combination with progestogenic compounds in hormone-replacement therapy|
|US20050079206 *||22 Jul 2003||14 Abr 2005||Schacht Dietrich Wilhelm||Transdermal delivery system for the administration of rotigotine|
|US20050142475 *||30 Dic 2003||30 Jun 2005||Moudry Ronald J.||Dry toner comprising encapsulated pigment, methods and uses|
|US20050186277 *||15 Mar 2005||25 Ago 2005||Gale Robert M.||Novel formulations for the administration of fluoxetine|
|US20050215538 *||11 Jun 2003||29 Sep 2005||Coelingh Bennink Herman J T||Method of treating human skin and a skin care composition for use in such a method|
|US20050250749 *||7 Ene 2005||10 Nov 2005||Endorecherche, Inc.||Helix 12 directed pharmaceutical products|
|US20050250750 *||3 Sep 2003||10 Nov 2005||The Regents Of The University Of California||Methods for treating postmenopausal women using ultra-low doses of estrogen|
|US20050261209 *||11 Jun 2003||24 Nov 2005||Bunschoten Evert J||Method of treating or preventing immune mediated disorders and pharmaceutical formulation for use therein|
|US20050276807 *||15 Jun 2004||15 Dic 2005||Advanced Biotherapy, Inc.||Treatment of acne|
|US20060008432 *||7 Jul 2004||12 Ene 2006||Sebastiano Scarampi||Gilsonite derived pharmaceutical delivery compositions and methods: nail applications|
|US20060058470 *||29 Jul 2005||16 Mar 2006||Tepha, Inc.||Non-curling polyhydroxyalkanoate sutures|
|US20060063723 *||11 Jul 2003||23 Mar 2006||Coelingh Bennink Herman Jan T||Pharmaceutical composition comprising esterol derivatives for use in cancer therapy|
|US20060177445 *||11 Ago 2005||10 Ago 2006||Boris Skurkovich||Treatment of inflammatory skin diseases|
|US20060177513 *||27 Ene 2006||10 Ago 2006||Tepha, Inc.||Embolization using poly-4-hydroxybutyrate particles|
|US20060199866 *||16 Abr 2004||7 Sep 2006||Joachim Moormann||Combination of desoxypeganine and mecamylanine for the treatment of alcohol abuse|
|US20060210613 *||14 Mar 2006||21 Sep 2006||Carliss Richard D||Therapeutic wound care product|
|US20060247221 *||23 Oct 2003||2 Nov 2006||Coelingh Bennink Herman J T||Pharmaceutical compositions comprising estetrol derivatives for use in cancer therapy|
|US20060269475 *||11 Abr 2006||30 Nov 2006||Ryu Wonhyoung||Multi-layer structure having a predetermined layer pattern including an agent|
|US20060287659 *||20 Ago 2004||21 Dic 2006||Tepha, Inc.||Polyhydroxyalkanoate nerve regeneration devices|
|US20070027122 *||3 Oct 2006||1 Feb 2007||Endorecherche, Inc.||Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors|
|US20070027123 *||3 Oct 2006||1 Feb 2007||Endorecherche, Inc.||Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors|
|US20070065463 *||21 Jun 2004||22 Mar 2007||Ronald Aung-Din||Topical therapy for the treatment of migranes, muscle sprains, muscle spasms, spasticity and related conditions|
|US20070148195 *||21 Dic 2006||28 Jun 2007||Ebert Charles D||Compositions and methods for transdermal oxybutynin therapy|
|US20070179210 *||31 Ene 2007||2 Ago 2007||Tyco Healthcare Group Lp||Super soft foams|
|US20070212314 *||27 Jul 2005||13 Sep 2007||Dow Corning Corporation||Silicone Adhesive Formulation Containing An Antiperspirant|
|US20070212410 *||26 Feb 2007||13 Sep 2007||Noven Pharmaceuticals, Inc.||Compositions and methods for delivery of amino-functional drugs|
|US20070237812 *||9 Mar 2007||11 Oct 2007||Tyco Healthcare Group||Multi-layer wound dressings|
|US20070259930 *||10 Abr 2007||8 Nov 2007||Knopp Neurosciences, Inc.||Compositions and methods of using r(+) pramipexole|
|US20080014259 *||16 May 2007||17 Ene 2008||Knopp Neurosciences, Inc.||Compositions of R(+) and S(-) Pramipexole and Methods of Using the Same|
|US20080031933 *||20 Ago 2007||7 Feb 2008||Alza Corporation||Transparent transdermal nicotine delivery devices|
|US20080051490 *||9 Ago 2007||28 Feb 2008||Williams Simon F||Medical Devices and Applications of Polyhydroxyalkanoate Polymers|
|US20080090894 *||3 Dic 2007||17 Abr 2008||Ronald Aung-Din||Transdermal migraine therapy|
|US20080095823 *||26 Oct 2007||24 Abr 2008||Metabolix, Inc.||Medical Devices and Applications of Polyhydroxyalkanoate Polymers|
|US20080119449 *||3 Dic 2007||22 May 2008||The Regents Of The University Of California||Methods for treating postmenopausal women using ultra-low doses of estrogen|
|US20080132602 *||31 Oct 2007||5 Jun 2008||Tepha, Inc.||Medical devices containing oriented films of poly-4-hydroxybutyrate and copolymers|
|US20080160065 *||12 Jul 2007||3 Jul 2008||Janet Anne Halliday||Drug delivery polymer with hydrochloride salt of clindamycin|
|US20080166745 *||9 Ene 2008||10 Jul 2008||Cholestech Corporation||Device and method for measuring LDL-associated cholesterol|
|US20080177219 *||23 Ene 2007||24 Jul 2008||Joshi Ashok V||Method for Iontophoretic Fluid Delivery|
|US20080188791 *||2 Feb 2007||7 Ago 2008||Difiore Attilio E||Active iontophoresis delivery system|
|US20080227985 *||14 Mar 2008||18 Sep 2008||Knopp Neurosciences, Inc.||Synthesis of chirally purified substituted benzothiazoles|
|US20080305154 *||8 Jun 2007||11 Dic 2008||Activatek, Inc.||Transdermal medicament patch and active electrode for same|
|US20090042844 *||9 Abr 2008||12 Feb 2009||Endorecherche, Inc.||17alpha-substituted steroids as systemic antiandrogens and selective androgen receptor modulators|
|US20090042956 *||14 Dic 2007||12 Feb 2009||Knopp Neurosciences, Inc.||Compositions and methods of using (r)-pramipexole|
|US20090047334 *||12 Ago 2008||19 Feb 2009||Patricia Williams||Transdermal patch for extended delivery of calcium|
|US20090054504 *||14 Mar 2008||26 Feb 2009||Knopp Neurosciences, Inc.||Modified Release Formulations of (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine and Methods of Using the Same|
|US20090098069 *||12 Sep 2008||16 Abr 2009||Drugtech Corporation||Transdermal, alcohol-free, pharmaceutical compositions|
|US20090169602 *||23 Nov 2006||2 Jul 2009||Universität Zürich||Allergy Treatment by Epicutaneous Allergen Administration|
|US20090196911 *||6 Jun 2007||6 Ago 2009||Loubert Gary L||Silicone Acrylate Hybride Composition and Method Of Making Same|
|US20090209983 *||10 Sep 2008||20 Ago 2009||Tepha, Inc.||Polyhydroxyalkanoate nerve regeneration devices|
|US20090291120 *||27 Jun 2007||26 Nov 2009||Jukka Tuominen||Hydrophilic Polyurethane Compositions|
|US20090324692 *||27 Jun 2007||31 Dic 2009||Controlled Therapeutics (Scotland) Limited||Polyurethane Elastomers|
|US20100055437 *||27 Ago 2009||4 Mar 2010||Tyco Healthcare Group Lp||Anti-microbial fibers and related articles and methods|
|US20100093237 *||11 Dic 2009||15 Abr 2010||Tepha, Inc.||Non-curling polyhydroxyalkanoate sutures|
|US20100113346 *||7 Ene 2008||6 May 2010||Pantarhei Bioscience B.V.||Method of Treating or Preventing Infertility in a Female Mammal and Pharmaceutical Kit for Use in Such Method|
|US20100172959 *||31 Dic 2009||8 Jul 2010||Acino Ag||Reservoir system with closed membrane|
|US20100317745 *||15 Oct 2007||16 Dic 2010||Donald Magnus Nicolson||Bioresorbable Polymers|
|US20110009460 *||21 Jun 2010||13 Ene 2011||Valentin Gribkoff||Compositions and methods for treating amyotrophic lateral sclerosis|
|US20110021596 *||27 Jul 2009||27 Ene 2011||Ronald Aung-Din||Topical therapy for migraine|
|US20110033515 *||4 Ago 2009||10 Feb 2011||Rst Implanted Cell Technology||Tissue contacting material|
|US20110091488 *||13 Jul 2010||21 Abr 2011||Controlled Therapeutics (Scotland) Limited||Water-swellable polymers|
|US20110160173 *||31 Ene 2011||30 Jun 2011||Pantarhei Bioscience B.V.||Method Of Treating Human Skin And A Skin Care Composition For Use In Such A Method|
|US20110189475 *||11 Abr 2011||4 Ago 2011||Tepha, Inc.||Medical devices containing oriented films of poly-4-hydroxybutyrate and copolymers|
|US20110190356 *||19 Ago 2009||4 Ago 2011||Knopp Neurosciences Inc.||Compositions and Methods of Using (R)- Pramipexole|
|US20120245538 *||2 Dic 2010||27 Sep 2012||Michael Horstmann||Transdermal Therapeutic System for the Administration of Peptides|
|US20140034058 *||29 Mar 2012||6 Feb 2014||Resmed R&D Germany Gmbh||Cushion for patient interface|
|US20140155916 *||30 Nov 2012||5 Jun 2014||Covidien Lp||Multi-Layer Porous Film Material|
|USRE34365 *||5 Ago 1991||31 Ago 1993||Intravenous system for delivering a beneficial agent|
|USRE35474 *||13 Oct 1994||11 Mar 1997||Dow Corning Corporation||Transdermal drug delivery devices with amine-resistant silicone adhesives|
|USRE37934||3 Feb 2000||10 Dic 2002||Lts Lohmann Therapie-Systeme Ag||Transdermal therapeutic system|
|CN101010065B||27 Jul 2005||29 Feb 2012||陶氏康宁公司||Silicone adhesive formulation containing an antiperspirant|
|DE2604718A1 *||6 Feb 1976||19 Ago 1976||Alza Corp||Therapeutische vorrichtung zur verabreichung von skopolaminbase|
|DE2647581A1 *||21 Oct 1976||27 Abr 1978||Henkel Kgaa||Blisterpackung|
|DE3205258A1 *||15 Feb 1982||16 Sep 1982||Alza Corp||Dosierungseinheit zur gleichzeitigen verabreichung von wirkstoffen und die perkutane absorption verstaerkenden mitteln|
|DE4241128A1 *||7 Dic 1992||24 Jun 1993||Lohmann Therapie Syst Lts||Transdermal aspirin dosage forms - for antithrombotic therapy or cancer prophylaxis|
|DE102010053792A1||8 Dic 2010||14 Jun 2012||Frank Becher||Device for germ-free keeping of surfaces, such as door handles, handrails, grip bars, handles of shopping carts and toilet seating surfaces, has flat support material and self-adhesive portion formed on one side of flat support material|
|EP0114125A2 *||18 Ene 1984||25 Jul 1984||Almedco, Inc.||Medication application systems|
|EP0114125A3 *||18 Ene 1984||22 May 1985||Almedco, Inc.||Medication application systems|
|EP0153200A2 *||21 Feb 1985||28 Ago 1985||Yamanouchi Pharmaceutical Co., Ltd.||Medicinal patch|
|EP0153200A3 *||21 Feb 1985||25 Sep 1985||Yamanouchi Pharmaceutical Co., Ltd.||Medicinal patch|
|EP0174108A2 *||9 Ago 1985||12 Mar 1986||Leonora I. Jost||Transdermal delivery devices|
|EP0174108A3 *||9 Ago 1985||25 Mar 1987||Leonora Jost||Transdermal delivery devices and method of producing them|
|EP0196769A2 *||24 Feb 1986||8 Oct 1986||Rutgers, The State University of New Jersey||A novel transdermal pharmaceutical absorption dosage unit|
|EP0196769B1 *||24 Feb 1986||8 Jul 1992||Rutgers, The State University of New Jersey||A novel transdermal pharmaceutical absorption dosage unit|
|EP0261402A1 *||20 Ago 1987||30 Mar 1988||LTS Lohmann Therapie-Systeme GmbH & Co. KG||Transcutaneous therapeutic device; use and preparation thereof|
|EP0272918A2 *||22 Dic 1987||29 Jun 1988||Cygnus Therapeutic Systems||Diffusion matrix for transdermal drug administration and transdermal drug delivery devices including same|
|EP0272918A3 *||22 Dic 1987||24 Ago 1988||Cygnus Research Corporation||Diffusion matrix for transdermal drug administration and transdermal drug delivery devices including same|
|EP0273004A2 *||16 Nov 1987||29 Jun 1988||Ciba-Geigy Ag||User-activated therapeutical system|
|EP0273004A3 *||16 Nov 1987||13 Jul 1988||Ciba-Geigy Ag||User-activated therapeutical system|
|EP0285563A1||24 Mar 1988||5 Oct 1988||Ciba-Geigy Ag||Transdermal therapeutic systems for combinations of active agents|
|EP0316168A1 *||10 Nov 1988||17 May 1989||Theratech, Inc.||Device for administering an active agent to the skin or mucosa|
|EP0439430A2 *||17 Ene 1991||31 Jul 1991||Ciba-Geigy Ag||Transdermal administration of zwitterionic drugs|
|EP0439430A3 *||17 Ene 1991||25 Sep 1991||Ciba-Geigy Ag||Transdermal administration of zwitterionic drugs|
|EP0481443A1 *||15 Oct 1991||22 Abr 1992||Vectorpharma International S.P.A.||Transdermal therapeutic compositions|
|EP0593807A1 *||22 Oct 1992||27 Abr 1994||LTS Lohmann Therapie-Systeme GmbH & Co. KG||Patch for transdermal administration of volatile pharmaceutically active ingredients of chemically basic nature and a process for preparation|
|EP0648264A1 *||2 Jun 1993||19 Abr 1995||Case Western Reserve University||Bandage for continuous application of biologicals|
|EP0648264A4 *||2 Jun 1993||1 Oct 1997||Univ Case Western Reserve||Bandage for continuous application of biologicals.|
|EP0841056A2 *||21 Feb 1996||13 May 1998||Hisashi Mineta||Personal clothing with effects caused by weak electromagnetic waves|
|EP0841056A3 *||21 Feb 1996||24 Nov 1999||Hisashi Mineta||Personal clothing with effects caused by weak electromagnetic waves|
|EP1674068A1||19 Feb 1997||28 Jun 2006||Acrux DDS Pty Ltd||Dermal penetration enhancers and drug delivery systems involving same|
|EP2087892A2||22 Jun 2000||12 Ago 2009||Pharmacia & Upjohn Company LLC||(S,S) reboxetine for treating age associated learning and mental disorders|
|EP2090312A1||22 Jun 2000||19 Ago 2009||Pharmacia & Upjohn Company LLC||(S,S) reboxetine for treating attention deficit disorder|
|EP2158903A2||14 Dic 1999||3 Mar 2010||ALZA Corporation||Transparent Transdermal Nicotine Delivery Devices|
|EP2584016A1||19 Oct 2012||24 Abr 2013||Dow Corning Corporation||Single phase silicone acrylate formulation|
|EP2599847A1||29 Nov 2012||5 Jun 2013||Dow Corning Corporation||A Silicone Acrylate Hybrid Composition and Method of Making Same|
|WO1980001139A1 *||6 Dic 1979||12 Jun 1980||Svedman Paul||Device for treating tissues,for example skin|
|WO1982000005A1 *||26 Jun 1981||7 Ene 1982||Key Pharma||Polymeric diffusion matrix containing a vasodilator|
|WO1987000042A1 *||27 Jun 1986||15 Ene 1987||Rutgers, The State University Of New Jersey||Transdermal verapamil delivery device|
|WO1987001938A1 *||11 Sep 1986||9 Abr 1987||The Regents Of The University Of California||Liposome transdermal drug delivery system|
|WO1987003477A1 *||12 Dic 1985||18 Jun 1987||Flexcon Company, Inc.||Transdermal methods and adhesives|
|WO1988001516A1 *||20 Ago 1987||10 Mar 1988||Lohmann Gmbh & Co. Kg.||Transdermal therapeutic system, its use and production process|
|WO1992001498A2 *||15 Jul 1991||6 Feb 1992||Cholestech Corporation||Solid-phase precipitation assay device and method|
|WO1992001498A3 *||15 Jul 1991||5 Mar 1992||Cholestech Corp||Solid-phase precipitation assay device and method|
|WO1993003692A1 *||14 Ago 1992||4 Mar 1993||Cygnus Therapeutic Systems||Transdermal drug delivery device using a membrane-protected microporous membrane to achieve delayed onset|
|WO1993003693A1 *||17 Ago 1992||4 Mar 1993||Cygnus Therapeutic Systems||Transdermal drug delivery device using a polymer-filled microporous membrane to achieve delayed onset|
|WO1994008571A2 *||20 Oct 1993||28 Abr 1994||Lts Lohmann Therapie-Systeme Gmbh & Co. Kg||Plaster for the transdermal administration of volatile, pharmaceutically active, chemically alkaline ingredients, and processs for producing the same|
|WO1994008571A3 *||20 Oct 1993||26 May 1994||Lts Lohmann Therapie-Systeme Gmbh & Co. Kg||Plaster for the transdermal administration of volatile, pharmaceutically active, chemically alkaline ingredients, and processs for producing the same|
|WO1997004818A2 *||24 Jun 1996||13 Feb 1997||Lts Lohmann Therapie-Systeme Gmbh||Transdermal therapeutic sysgtem for administering active agents to the human body via the skin|
|WO1997004818A3 *||24 Jun 1996||13 Mar 1997||Lohmann Therapie Syst Lts||Transdermal therapeutic sysgtem for administering active agents to the human body via the skin|
|WO1999011265A1 *||18 Ago 1998||11 Mar 1999||Lts Lohmann Therapie-Systeme Ag||Transdermal therapeutic system containing the active substance scopolamine base|
|WO2000030693A1 *||23 Sep 1999||2 Jun 2000||Deotexis Inc.||Dressing|
|WO2002062292A2 *||23 Ene 2002||15 Ago 2002||Ferro Corporation||Adhesive composition primarily intended for use in medical applications|
|WO2002062292A3 *||23 Ene 2002||31 Oct 2002||Ferro Corp||Adhesive composition primarily intended for use in medical applications|
|WO2005066194A1||6 Ene 2005||21 Jul 2005||Endorecherche, Inc.||Helix 12 directed steroidal pharmaceutical products|
|WO2008104032A1 *||29 Feb 2008||4 Sep 2008||D-Swell Pty Ltd||Body wrap with sodium carbonate dosage pack|
|WO2008124922A1||11 Abr 2008||23 Oct 2008||Endorecherche, Inc.||17alpha-substituted steroids as systemic antiandrogens and selective androgen receptor modulators|
|WO2011135530A2||27 Abr 2011||3 Nov 2011||Kimberly-Clark Worldwide, Inc.||Device for delivery of rheumatoid arthritis medication|
|WO2011135531A2||27 Abr 2011||3 Nov 2011||Kimberly-Clark Worldwide, Inc.||MEDICAL DEVICES FOR DELIVERY OF siRNA|
|WO2011135532A2||27 Abr 2011||3 Nov 2011||Kimberly-Clark Worldwide, Inc.||Composite microneedle array including nanostructures thereon|
|WO2017095730A1 *||28 Nov 2016||8 Jun 2017||Elliptical Therapeutics, Llc||Systems and methods for transdermal drug delivery|
|Clasificación de EE.UU.||424/434, 424/448, 424/449|
|Clasificación internacional||A61K9/00, A61L15/58, A61F9/00, A61M31/00, A61L15/16, A61K9/70|
|Clasificación cooperativa||A61K9/7076, A61M31/002, A61K9/7061, A61K9/7092, A61K9/7084, A61K9/0004, A61L15/58, A61F9/0017|
|Clasificación europea||A61M31/00D, A61F9/00B2, A61K9/00L4, A61L15/58, A61K9/70E2B6B2, A61K9/70E2D, A61K9/70E2B8, A61K9/70E2K|