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USOO7375139B2

(12) United States Patent (10) Patent No.: US 7,375,139 B2 Aldred (45) Date of Patent: May 20, 2008

(54) TRANSDERMAL METHOD AND APPARATUS (56) References Cited (76) Inventor: Katherine M. Aldred, 51 Birch St., U.S. PATENT DOCUMENTS Saugus, MA (US) 01960 4,286,592 A 9, 1981 Chandrasekaran ...... 424/448 5.948,101 A * 9/1999 David et al...... 713/2 (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 * cited by examiner U.S.C. 154(b) by 554 days. Primary Examiner Johann R. Richter (21) Appl. No.: 10/642,858 (74) Attorney, Agent, or Firm—George Kessey y x- - - 9 (22) Filed: Aug. 18, 2003 (57) ABSTRACT A transdermal patch for the treatment of iron deficiency (65) Prior Publication Data including a drug reservoir layer containing an hematinic US 2005/OO4227O A1 Feb. 24, 2005 Substance; a rate-controlling membrane secured to said reservoir layer; and a contact adhesive secured to said (51) Int. Cl. rate-controlling membrane, wherein said hematinic Sub A6DF 3/00 (2006.01) stance is selected from the class consisting of ferrous Sulfate, A6 IK 33/26 (2006.01) ferrous lactate, ferrous iodide, ferrous gluconate, ferrous (52) U.S. Cl...... 514/814; 424/449; 424/646; fumarate, ferrous citrate, ferrous carbonate saccharated, 424/648 ferrous carbonate mass, ferronascin, ferroglycine Sulfate, (58) Field of Classification Search ...... 424/489, and ferrocholinate. 424/600, 669, 709, 449, 646, 648; 514/814 See application file for complete search history. 10 Claims, 4 Drawing Sheets

U.S. Patent May 20, 2008 Sheet 1 of 4 US 7,375,139 B2

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U.S. Patent May 20, 2008 Sheet 2 of 4 US 7,375,139 B2

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U.S. Patent May 20, 2008 Sheet 3 of 4 US 7,375,139 B2

U.S. Patent May 20, 2008 Sheet 4 of 4 US 7,375,139 B2

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44-44-444-4-4-4-4-4 12 NY, N N N N N N N N N N N ZZZZZZZZZZZ-413 PASS-N-N-N-N-N-N-N-NS 14 4-44444444444 15 US 7,375,139 B2 1. 2 TRANSIDERMAL METHOD AND APPARATUS ferrous funarate, ferrous citrate, ferrous carbonate saccha rated, ferrous carbonate mass, ferronascin, ferroglycine Sul BACKGROUND OF THE INVENTION fate, and ferrocholinate. A protective peel strip can be placed on the contact adhesive, and a backing layer can be placed This invention relates to the continuous release of medi- 5 upon the drug reservoir layer. cation to an area of intact skin, and more particularly to the The hematinic Substance can be in the contact adhesive, continuous release of medication to correct iron deficiency. and the backing layer can be an aluminized polyester film. Various preparations are available for the treatment of The drug reservoir can be provided with mineral oil and anemia in patients. A typical product provides for the oral polyisobutylene. administration of iron elementals, such as ferrous fumarate. 10 In a method of the invention for manufacturing a trans This product is available in the form of a capsule that dermal patch, the steps include: (a) providing a drug reser illustratively contains about 100 mg of the iron elemental. voir layer containing an hematinic Substance; and (b) apply Unfortunately, iron in therapeutic doses can produce gas ing the layer to a rate-controlling membrane. trointestinal reactions, such as diarrhea or constipation. In Some cases, skin rash Suggesting allergy can follow the oral 15 BRIEF DESCRIPTION OF DRAWINGS administration of the iron elemental. In addition, overdosage can produce iron intoxication accompanied by pallor and Various other features, advantages and characteristics of cyanosis, vomiting, hematemesis, diarrhea, melena, shock, the invention will become apparent after considering several drowsiness, and coma. illustrative embodiments, taken in conjunction with the Other forms of iron deficiency medication can be in liquid drawings, in which: form, but this Substance can also have the same adverse FIG. 1A is a perspective view of a transdermal patch in effects as treatment in therapeutic doses by the use of accordance with the invention. capsules. FIG. 1B illustrates the removal of the protective peel strip Accordingly, it is an object of the invention to relieve of the transdermal patch of FIG. 1A, prior to application to many of the contra-indications that accompany the thera- 25 an area of intact skin. peutic treatment for iron deficiency by the use of liquid FIG. 1C illustrates application of the transdermal patch of elixirs and capsules. FIG. 1B after removal of the protective peel strip to an area of intact skin on the head, behind the ear. SUMMARY OF THE INVENTION FIG. 2 is a cross-section of the transdermal patch of FIG. 30 1A. In accomplishing the foregoing and related objects, the invention provides a transdermal patch for the treatment of DETAILED DESCRIPTION iron deficiency including a drug reservoir layer, a rate controlling membrane secured to the reservoir layer; and a With reference to the drawings, the transdermal patch 10 contact adhesive secured to the rate-controlling membrane, 35 in accordance with the invention, is illustratively formed wherein the reservoir contains an hematinic Substance. with a plurality of layers including a protective peel strip 11 In accordance with one aspect of the invention, the overlying a contact adhesive layer 12, which is positioned hematinic Substance is selected from the class consisting of against a rate controlling membrane 13 for a drug reservoir ferrous sulfate, ferrous lactate, ferrous iodide, ferrous glu layer 14 upon a backing layer 15. conate, ferrous fumarate, ferrous citrate, ferrous carbonate 40 The protective peel strip 11, which can be a siliconized saccharated, ferrous carbonate mass, ferronascin, ferrogly polyester, is removed in accordance with FIG. 1B, prior to cine Sulfate, and ferrochohnate. application of the remainder of the transdermal patch 10 of In accordance with another aspect of the invention, the FIG. 1A, to an area of intact skin. transdermal patch includes a protective peel strip on the As illustrated in FIG. 1C, the transdermal patch 10 of FIG. contact adhesive. The transdermal patch can further include 45 1B can be applied to an area of intact skin on the head, a backing layer upon the drug reservoir layer. The transder behind the ear. It will be understood that the transdermal mal patch can also include a hematinic Substance in the patch 10 may be applied to intact skin in any area of the contact adhesive. body. The area behind the ear is desirable because the patch In accordance with a further aspect of the invention, the is relatively inconspicuous and not easily disturbed, being transdermal patch can have a backing layer is aluminized 50 protected by the ear as a shield polyester film. The drug reservoir can include mineral oil The various layers of the patch 10 are shown in cross and polyisobutylene. A contact adhesive can include mineral section in FIG. 2. It will be appreciated that, although the oil and polyisobutylene. The protective peel strip can be of patch 10 is ellipsoidal, other configurations may be used as siliconized polyester. When the transdermal patch is a film well. Such as circular, rectangular, etc. In addition, the with a plurality of layers, they can range in thickness from 55 protective peel strip is provided with an intermediate undu 0.1 mm to 0.3 mm. lated edge to facilitate removal. Other forms of peel edge In a method of the invention for treating an iron defi may be used instead. ciency, the steps include (a) providing a drug reservoir layer The patch 10 contains a suitable amount of hematinic in containing an hematinic Substance; and (b) securing the drug the drug reservoir layer 14, ranging from about 0.1 to about reservoir layer to a skin surface. The method can further 60 2.0 milligrams. The amount of hematinic included in the include the step of applying a rate-controlling membrane to drug reservoir layer 14 depends upon the treatment regimen. the reservoir layer. The method can also include the step of The rate-controlling membrane is microporous to control the applying a contact adhesive to the rate-controlling mem rate of delivery from the patch to the skin surface and is brane. programmed to deliver between about 0.03 to about 0.7 The method further includes the step of selecting the 65 milligrams at an approximately constant rate to the systemic hematinic Substance from the class consisting of ferrous circulation over the lifetime of the patch 10, which can range Sulfate, ferrous lactate, ferrous iodide, ferrous gluconate, from about 2 days to 10 days. US 7,375,139 B2 3 4 An initial priming dose of hematinic can be released from Excess amounts of vasodilators can be used without the adhesive layer 12 of the patch 10 to saturate skin binding impacting performance. Examples of non-irritational sites and rapidly bring the concentration of the hematinic to vasodilators include, Sulphate, fuma a required steady-state level. Thereafter, a continuous con rate, benpurodil hemisuccinate, benzyl nicotinate, buflom trolled release of hematinic flows from the drug reservoir 14 edil hydrochloride, hydrochloride, butalamine through the rate-controlling membrane 13 to maintain the hydrochloride, cetledil citrate, , male release level constant. ate, , di-isopropylammonium dichloroacetate, The sole active ingredient of the patch 10 is the hematinic, ethyl nicotinate, hepronicate, hexyl nicotinate, which can be selected from among various Substances Such tartrate, , hydrochloride, kal as ferrous sulfate, ferrous lactate, ferrous iodide, ferrous 10 lidinogenase, methyl nicotinate, maftidropuryl oxalate, nica gluconate, ferrous fumarate, ferrous citrate, ferrous carbon metate citrate, niceritrol, nicobuxil, nicofuranose, nicotinyl ate Saccharated, ferrous carbonate mass, ferronascin, ferro alcohol, tartrate, nonidamide, oXpentifyl glycine Sulfate, and ferrocholinate. line, papaveroline, , pipratecol, propentofylline, Ferrous sulfate illustratively has a molecular weight of raubasine, , teasuprine, thymoxamine hydrochlo 151.91 and is approximately 37% iron, 42% oxygen, and 15 ride, nicotinate, diaZoxide, hydralazine, minoxidil 21%. Hydrates occur in mineral form including the mono and Sodium nitropusside. Centrally acting agents include hydrate which is a white to yellow crystalline powder that clonidine, quanaberZ and methyl dopa. Alpha-adrenocaptor loses moisture at about 300° C. The heptahydrate, which is agents include indoramin, , phentola prepared commercially by the action of Sulfuric acid on iron, mine and . Adrenergic neuron blocking agents is a blue-green monoclinic crystal which effloresces in dry include bethanidine, debrisoquine and guanethidine. ACE air and oxidizes in moist air to form a coating of basic inhibitors include benazepril, captopril, cilaZapril, enalapril, ferrous sulfate. Ferrous sulfate is soluble in water and fosinopril, lisinopril, perindopril, quinapril and ramipril. oxidizes slowly in air when cold, rapidly when hot and is a Ganglion-blocking agents include pentolinium and tri suitable therapeutic for iron deficiencies. metaphan. Calcium-channel blockers include amlodipine, Alternatively, the transdermal delivery system for deliv 25 diltiazem, felodipine, isradipine, nicardipine, nifedipine, ering a hematinic to the blood can include a vasodilator, the nimodipine and Verapamil. Prosteglandins include prosta hematinic, a permeation enhancer for the hematinic, and a cyclin, thrombuxane A. sub.2, leukotrienes, PGA, PGA. Sub. water-soluble gum binder. To control the microenvironment 1 PGA sub.2, PGE. sub. 1, PGE.sub.2, PGD, PGG and PGH. at the transport site on intact skin, a non-breathable layer can Angiotension II analogs include Saralasin. Other vasodila be used In addition, compression can be used to enhance the 30 tors include nitroglycerin, labetalol, thrazide, isosorbide blood Supply at the transport site. dinitrate, pentaerythritol tetranitrate, digitalis, hydralazine, A transdermal drug delivery system permits localized diazoxide and sodium nitroprusside. One or more vasodila delivery of drug molecules so that the drug delivery is tors can be used. target-specific, and avoids gastrointestinal complications Suitable penetration enhancers include vegetable oil or a that often accompany oral delivery. Transdermal drug deliv 35 vegetable oil/alcohol mix. Suitable vegetable oils include ery desirably employs patch technology, which is based on peanut oil, olive oil, Sunflower oil, soybean oil, monoi oil the ability of the patch to hold an active ingredient in and macadamia oil, with olive oil being preferred Suitable constant contact with the skin. Over time, drug molecules, alcohols for the vegetable oil/alcohol mix include ethyl held in the patch, will reach the bloodstream. alcohol, isopropyl alcohol, methanol and witch hazel. Olive 40 oil mixed with isopropyl alcohol is a preferred vegetable In order for the hematinic to reach the bloodstream, it oil/alcohol mix. Eucalyptol is a further suitable example of must pass through a dense layer of cells, known as the a vegetable oil/alcohol mix. Suitable ratios of vegetable stratum corneum, the dermis, and the capillary cell structure. oil: alcohol range from about 5:1 to about 1:10, preferably Although patch adhesion to the skin can cause skin trauma, 1:2. Suitable amounts of vegetable oil or vegetable oil/ as well as cosmetic problems, it is desirable to choose an 45 alcohol mix range from about 1% to about 66% by weight, inconspicuous area of the skin for patch application. more preferably from about 10% to about 33.3% by weight. In order to enhance the delivery of the hematinic, pen The penetration enhancer, the vasodilator, and the hema etration enhancers can be added, such as menthol, vegetable tinic are placed in a mixing vessel, and the combination oil or eucalyptol. The molecular delivery system can con agitated achieve a uniform mix. Other inactive ingredients tains, beside the active drug molecule, an ensemble of four 50 may be added if desired. elements, including, a vasodilator, a penetration enhancer, It will be appreciated that the foregoing embodiments are and a water soluble gum for linking the vasodilator, the merely illustrative and that other variations in form and penetration enhancer and active hematinic. Substance may be made without departing from the spirit The vasodilator enhances blood flow to the transport site. and scope of the invention as defined in the appended Regardless of metabolism, obesity or circulatory efficiency, 55 claims. the vasodilator increases blood flow to the transport site to I claim: reliably enhance absorption of the hematinic molecule. 1. A method of treating iron deficiency in a patient in need Where transport speed of the hematinic is sufficient, a patch thereof comprising the steps of: can be eliminated. (a) providing a drug reservoir layer containing an hema The vasodilator expands the blood supply to and from the 60 tinic Substance; and local vascular network as well as to the subdermal layer. (b) securing said drug reservoir layer to a skin Surface. Suitable ratios of vasodilators range from about 1% to about 2. The method as defined in claim 1, further including the 80% by weight, with ratios of from about 1% to about 33% step of applying a rate-controlling membrane to said reser being preferred The amount of vasodilator will vary due to voir layer. a number of factors, including the drug molecule size, drug 65 3. The method as defined in claim 1, further including the concentration, the desired delivery speed, the size of the step of applying a contact adhesive to said rate-controlling Surface area of an application, and the application site. membrane. US 7,375,139 B2 5 6 4. The method as defined in claim 1, further including the 8. The method as defined in claim 1, further including the step of selecting said hematinic Substance from the class step of providing said backing layer as aluminized polyester consisting of ferrous Sulfate, ferrous lactate, ferrous iodide, film. ferrous gluconate, ferrous fumarate, ferrous citrate, ferrous carbonate Saccharated, ferrous carbonate mass, ferronascin, 9. The method as defined in claim 1, further including the ferroglycine Sulfate, and ferrocholinate. step of providing said drug reservoir with mineral oil and 5. The method as defined in claim 1, further including the polyisobutylene. step of including a protective peel strip on said contact 10. The method of manufacturing a transdermal patch adhesive. comprising the steps of 6. The method as defined in claim 1, further including the 10 step of including a backing layer upon said drug reservoir (a) providing a drug reservoir layer containing an hema layer. tinic Substance; and 7. The method as defined in claim 1, further including the (b) applying said layer to a rate-controlling membrane. step of including a hematinic Substance in said contact adhesive.