| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | August 3, 1999 |
| PATENT TITLE |
Multidose transdermal drug delivery system |
| PATENT ABSTRACT |
A multidose transdermal drug delivery system comprises a laminate composite with a plurality of compartments. Each compartment is a reservoir for a unit dose of a drug active to be transdermally administered. The assembly is adhesively secured to the skin of a patient. Individual seals are provided for resealably enclosing the drug active in each of the reservoirs. The individual enclosing seals are removable to release the unit dose into contact with the skin of the patient and are actuable to control the transdermal absorption of the drug actives. Provisions are also made to automatically indicate the activation of the drug and to prevent an accidental release of medicament. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | December 8, 1997 |
| PATENT REFERENCES CITED |
Retardation by Aminoguanidine of Development of Albuminuria, Mesangial Expansion, and Tissue Fluorescence in Streptozocin-Induced Diabetic Rat", (Soulis-Liporata et al.), Diabetes, vol. 40, Oct. 1991, pp. 1328-1334. "Mechanistic Studies of Advanced Glycosylation and Product Inhibition by Aminoguanidine", (Edelstein et al), Diabetes, vol. 41, Jan. 1992, pp. 26-29. "Effect of Aminoguanidine on Functional and Structural Abnormalities in Peripheral Nerve of STZ-Induced Diabetic Rats", (Yagihashi et al.), Diabetes, vol. 41, Jan. 1992, pp. 47-52. "Aminoguanidine, a Novel Inhibitor of Nitric Oxide Formation, Prevents Diabetic Vascular Disfunction", (Corbett et al.), Diabetes, vol. 41, Apr. 1992, pp. 552-556. "Transdermal Delivery of Drugs", (Vaidyanathan et al.), vol. II, Chapter 5, pp. 63-83, published by CRL Press, Boca Raton, Florida; 1990. "Transdermal Insulin Application in Type II Diabetic Patients", Arzneim.-Forsch./Drug Research 40 (II), No. 8, 1990--Insulin, pp. 880-883. "Effects of Oral and Transdermal Insulin Applications on Blood Glucose Concentration of Mice", Arzneim.-Forsch./Drug Research 40 (II), No. 8, 1990--Insulin, pp. 884-886. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
We claim: 1. A multidose transdermal drug delivery assembly, comprising a laminate composite having a plurality of reservoirs formed therein, unit doses with transdermal drug actives disposed in respective ones of said reservoirs for transdermal administration, individual seal means for enclosing said drug in each of said reservoirs, said unit doses being in the form of a multiphase composition of microspheres wherein an internal phase comprises the drug actives and adjuvants, and said internal phase is surrounded by an outer phase of film-forming polysaccharides engrafted with transdermal promoters, said microspheres being distributed through a diffusable matrix for said composition; said individual seal means having means for disrupting said microspheres upon activation of said seal means to release the drug actives and adjuvants in said unit dose compartment to diffuse through said matrix to a patient's skin. 2. The assembly according to claim 1, including means for adhesively securing said laminate composite to a patient's skin. 3. The assembly according to claim 1, including indicating means being freed by said seal means for signalling initiation and administration of the unit dose from each individual reservoir, and means for preventing accidental release of medicament. |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to transdermal medication assemblies and more particularly to such assemblies comprising multiple unit-dose reservoirs with each reservoir having individual tear-and-release or pull-and-release resealable closure means for initiation and administration of the medication. 2. Description of the Related Art Transdermal drug administration has recently come to the forefront as a useful route for continuous dosing of useful drugs where other means of administration are either discontinuous, labor intensive or where other routes present absorption or inactivation problems. Whereas per os administration has been time honored i.e. "a teaspoonful three times a day", such unit dose administration was subject to erratic blood levels of the actives due to non-uniform absorption from the gut due to other gut contents or inactivation of the drug actives by the digestion process or the normal action of the liver. In addition, the need for active periodic administration i.e. three times a day, required active and willing participation by the patient or in home or hospital settings by the caregiver i.e. mother or nurse. All these shortcomings are obviated by transdermal application where possible, of the drugs. A patch is adhered to a clear area of the skin and the drug is continually absorbed through the skin into the bloodstream for systemic distribution. The skin is particularly useful as it presents large areas for drug administration, as the skin is the largest organ of the body. The utility of such a mode of administration has been promoted with the discovery and development of a group of compounds that promote transdermal penetration of the various active drugs. Such compounds are known in the art as penetration enhancers. They are generally characterized to be from the group of monovalent branched or unbranched aliphatic, cycloaliphatic or aromatic alcohols of 4-12 carbon atoms; cycloaliphatic or aromatic aldehydes or ketones of 4-10 carbon atoms, cycloalkanoyl amides of C 10-20 carbons, aliphatic, cycloaliphatic and aromatic esters, N, N-di-lower alkylsulfoxides, unsaturated oils, terpenes and glycol silicates. These compounds and their specific activity as penetration enhancers, are more fully discussed in the text "Transdermal Delivery of Drugs, A. F. Kydonie US (Dd)-1987 CRL Press and in such as U.S. Pat. Nos. 4,913,905, 4,917,676 and 5,032,403. As a result of these penetration enhancers, almost any drug, to some degree, can be administrated transdermally cf. U.S. Pat. Nos. 4,917,676, 3,598,122; 3,598,123; 3,742,951; 3,797,494; 3,948,254; 3,996,734; 4,284,444; and 4,597,961. Examples of such pharmacological actives include administration of antibacterial such as the penicillins, tetracyclines, second and third generation cephalosporins, chlor-amphenicol sulfonamides; sedatives and/or hypnotics, such as barbiturates, carbromal, antijussives such as codeine and dextromethorphan; anti-anxiety drugs such as the benzodiazepines including diazepam, buspirone; psychostimulants such as imipramine amitriptyline and other tricyclic anti-depressants; anti psychotic drugs and tranquilizers such as lithium, chlorpromazine and haloperidol, reserpine, thiopro-pazate; Parkinsonism control agents such as bromotriptine, percolide, the anticholmergics including benzotropine, pro-cyclidine, amantadine (also an antiviral); hormones and hormone antagonists and agonists, including adrenocortico-steroids; insulin, androgenic steroids, estrogenic and pro-gestrogenic steroids, thyroxin and its agonist 5-FU(fluoro-uracil), tamoxifen; antipvretics and analgesics such as aspirin/acetaminophen and other non-steroidal anti-inflammatory drugs (NSAID), analgesics based on morphine; morphine antagonists; vasodilating agents such as nitro-glycerine, isorbide dinitrate; alpha beta-blockers and other cardioactive drugs; antimalarials; anti-histamines and anti-cholinergics including atropine hyoscyamine or methscopalo-mine (for motion sickness; weaning agents such as nicotine for addiction to tobacco; and antiasthmatic bronchodilators such as formoterol; and combinations of such pharmaceutical actives. Of course, while feasible, not all of these actives have yet been completely tested for efficacy by transdermal administration but many are under vigorous scrutiny. Other actives at this time are not economically viable for such administration, as the cost of full safety testing is too great for the specific number of patients involved. As can be seen from this background discussion and the history of this type of medication, it is apparent that application by transdermal patch is a useful form for the administration of medication. However, a single dose per patch requires uneconomical repeated application. SUMMARY OF THE INVENTION It is an object of this invention to provide a multiple unit-dose transdermal patch assembly. It is a further object of this invention to provide each unit dose in the multiple dose patch with an indicating means, visual or olfactory to inform the wearer or attendant concerning the activation for administration of each unit dose in the multidose patch assembly. It is another object where a single application steady state dosing may not serve the best needs of the patient and be inconsistent with accepted clinical practice to provide a method of multiple sequential dosing in those cases. Additionally, this invention allows for the variation where needed in dose levels within a single "patch". A further object is to provide a patch which is secured against accidental release of the medicament. This object is attained by providing a security strip. Yet a further object of the invention is to provide a patch which may readily be refilled or the medication of which may be varied by insertion of medicament through a filling septum. The patch assembly consists of a base in which the steady state dosage is or may be contained as needed by the patient and individual medicament reservoirs which may be activated by either a "tear-and-release" or "pull-and-release" mechanism. The reservoirs contain medicament which can be the same as contained in the base or various unit dosages of the base or entirely different synergistic medicaments. Further objects and ancillary benefits will be apparent from the disclosure of the invention which comprises a multiple unit-dose transdermal drug deliverly system or patch assembly. This invention includes the various drugs that can be delivered in unit doses, configurations of such assemblies, storage of the drugs within the assembly and includes delivery systems for the drugs from storage areas in the assembly to the skin, various systems for activating each unit-dose of the assembly, various means for indication activation of each unit-dose, various means to assure that the dosages are only delivered upon command and demand by the patient and to prevent accidental release and various means for insertion of medicament through a filling septum. With the foregoing objects of the invention in view there is provided, in accordance with the claimed invention, a multidose transdermal drug delivery assembly, comprising a laminate composite of a drug-permeable membrane to be placed in contact with a patient's skin; a transfer gel layer disposed on the membrane; a permeable membrane disposed on the transfer gel layer; overlaid impervious drug enclosure means for receiving and protectively enclosing a drug active to be transdermally administered; the drug enclosure means and the permeable membrane defining a plurality of compartments therebetween defining reservoirs for respective unit doses of the drug active; and individual activation means for releasing unit doses of the drug active from respective ones of the compartments for contacting with the patient's skin. In accordance with added features of the invention, assembly includes means for enclosing the drug active in each of the reservoirs. In accordance with a further feature of the invention, the assembly includes actuating means for controlling transdermal absorption of the drug active and means for adhesively securing the laminate composite to the patient's skin. In accordance with an additional feature of the invention, the reservoirs have a periphery which is smaller than a periphery of the permeable membrane and a periphery of the overlaid impervious layer, so that the permeable membrane and the overlaid impervious layer extend outwardly of the reservoir periphery. In accordance with a further feature of the invention, the enclosing means are individual resealable strips disposed on the reservoirs for activating respective unit doses by peeling back respective ones of the strips. Also, the enclosing means may be individual sealing strips disposed between the reservoirs and the permeable membrane, the strips being removable from the assembly through a resealing strip for activating respective unit doses. In accordance with yet additional features of the invention, the system includes means for indicating initiation of administration of a unit dose from a respective reservoir upon activation, which may be visual of olfactory signal means. In accordance with yet a further feature of the invention, the reservoirs comprise microencapsulations of the drug active, the drug active may be insulin encapsulated into capsules of substantially 1 to 150 microns diameter, the microencapsulations are formed of a layer of polymer encapsulating the drug active, the polymer layer having drug-penetration moieties engrafted thereon; the moiety can be laurocapram; 1-dodecylhexahydro-2H-azepin-2-one. In accordance with again an added feature of the invention, the transfer gel includes medicament for steady state dosage transdermal delivery. In accordance with again a further feature of the invention, the assembly includes a plurality of security strips disposed above each of the individual activation means for preventing accidental activation of the drug active. In accordance with again an additional feature of the invention, the compartments have openings in the form of fill ports formed therein for allowing introducing or withdrawing medicament from the reservoirs, and including a sealing filling septum closing the fill ports. With the objects of the invention in view, there is further provided, a multidose transdermal drug delivery assembly, comprising a laminate composite having a plurality of reservoirs formed therein, unit doses with transdermal drug actives disposed in respective ones of the reservoirs for transdermal administration, individual seal means for enclosing the drug in each of the reservoirs, the unit doses being in the form of a multiphase composition of microspheres wherein an internal phase comprises the drug actives and adjuvants surrounded by an outer phase of film-forming polysaccarides engrafted with transdermal promoters, the microspheres being distributed through a diffusable matrix for the composition; the individual seal means having means for disrupting the microspheres upon activation of the seal means to release the drug actives and adjuvants in the unit dose compartment to diffuse through the matrix to a patient's skin. The laminate composite may include means for adhesively securing to a patient's skin. In accordance with a concomitant feature of the invention, the assembly includes indicating means being freed by the seal means for signalling initiation and administration of the unit dose from each individual reservoir, and means for preventing accidental release of medicament. In other words, the drug delivery assembly of this invention comprises a laminate composite having therein a series of at least two compartments, each compartment being a reservoir for a unit-dose of the drug-actives to be transdermally administered, adhesive means for adhering the support with the open face of the reservoir containing the drug actives being juxtaposed to the skin. Individual resealable closure means are provided containing the drug actives within the reservoir. The resealable closure means on each unit dose reservoir are preferably provided with indicia for indicating that the unit dose has been released for administration. Among such indicia useful for indication of actuation and initiation of release of the unit dose, are colored stains or olfactory substances such as perfumes released upon actuation of the unit dose seal. The laminate composite forming reservoirs for the drug actives and associated vehicles may be formed from flexible or rigid materials. Useful impervious materials include fabrics impregnated with film rendering the fabrics impervious to the drugs and vehicles, regenerated cellulose (cellophane), ABS polymer/cellulose acetate, ethyl cellulose, copolymers of plasticized vinylacetate-vinylchloride, polyethylene terephthlate; polyethylene, polypropylene, nylon film or nylon fabric impregnated with drug impervious films, polyvinylidene chloride, impregnated and coated papers and metallic foils, metalized shaped films of PVC, ABS and other shapeable polymeric sheets or films. The unit dose reservoirs of the assembly may be impressed or molded into the polymeric and impregnated materials or they may be formed by sealing the peripheries of impervious material layers to form pouches which, upon loading through openings, will become drug reservoirs. Useful dimensions for the patch are approximately one inch by two inches and up to about one quarter to half inch in thickness. The size of each reservoir is determined by the volume of the unit dose to be administered. The volumes exemplified are sufficient for most unit doses for transdermal delivery of the drugs, but larger or smaller volumes may be used. The drugs and their adjurants are dissolved, suspended, absorbed or contained in matrices or solutions. Useful matrices are gels of bipolymers i.e. alginates, gelatins, chitin, PVP, etc. While the examples above disclose rectangular reservoirs, as they permit adjacent positioning of individual unit doses in a multiple dose assembly, the reservoirs in pouch or container form may also be circular, oval or irregular in form depending on positioning of the assembly on the body or limbs. Configuration of the assembly is dictated by the ultimate positioning of the assembly in areas where adhesion, absorption, and contact with clothes, limbs and body hair are to be taken into account. The number of unit doses included in each assembly depends on the size of the reservoirs to configure a convenient size. Generally, four to ten unit doses are convenient with seven units preferred as permitting a single application of the drug once a day, or several times a day depending on the medicament and clinical application. The principle of single unit doses in the multiple dose assembly is particularly useful as only a limited amount of the drug actives is exposed to the skin for transdermal absorption. When non-segregated multiple doses, as taught by the prior art are used, there arise problems. A variant reservoir, which is a novel aspect of this invention consists of the micro encapsulation of the drug actives in a biopolymer to protect the drug from ambient degradation as well as to serve as a reservoir for the dosage volume. Insulin is an example of such a drug active. A specific advantage for the encapsulation of the drug in such a polymer is that it allows for the controlled rate of release of the medicament by adjustment of the crosslinking, density and specific type of polymer selected for the encapsulation. In addition, passage of the relatively large molecule of the exemplified insulin as well as other hormone enzymes and proteins through the skin has been found to require some method of penetration enhancement. Several chemicals alone or in combination with certain solvents have been noted to promote transdermal penetration. It has been suggested that some of these materials perform their penetration by enlarging the intersticial spaces between the cells of the dermis. Such penetration vehicles or enhancers are known to the art and many are mentioned in the "Transdermal Delivery of Drugs". Suitable penetration enhancers (flux enhancers are preferably monovalent, saturated or unsaturated aliphatic, cycloaliphatic or aromatic alcohols having from 4 to 12 carbon atoms. e.g. n-hexanol or cyclohexanol, aliphatic, cycloaliphatic or aromatic hydrocarbons having from 5 to 12 carbon atoms, e.g. hexane, cyclohexane, isopropylbenzene and the like, cyclo-aliphatic or aromatic aldehydes and ketones having from 4 to 10 carbon atoms, such as cyclohexanone, acetamide, N,N-di-lower alkylacetamides such as N, N-dimethylacetamide or N, N-diethyl-acetamide, c.sub.10 -c.sub.20 -alkanoylamides, e.g. N, N-dimethyllauroylamide, 1-n-C.sub.10 -c.sub.20 -alkylazcycloheptan-2-one, e.g. 1-n-dodeclyazacycloheptan-2-one(Azone.RTM. laurocapram), or N-2-hydroxyethylacetamide, and known vehicles and/or penetration enhancers such as aliphatic, cycloaliphatic and aromatic esters N, N-di-lower alkylsulphoxides, unsaturated oils, halogenated or nitrated aliphatic or cyclo-aliphatic hydrocarbons, salicylates, polyalkylene glycol silicates, and mixtures thereof. |
| PATENT EXAMPLES | This data is not available for free |
| PATENT PHOTOCOPY | Available on request |
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