United States Patent (19) 11 Patent Number: 5,837,289 Grasela Et Al

USOO5837289A United States Patent (19) 11 Patent Number: 5,837,289 Grasela et al. (45) Date of Patent: Nov. 17, 1998

54 TRANSIDERMAL DELIVERY OF 5,352,456 10/1994 Fallon et al...... 424/448 MEDICATIONS USING A COMBINATION OF 5,372,819 12/1994 Godbey et al...... 424/449 PENETRATION ENHANCERS 5,399,355 3/1995 Riedl et al...... 424/448 5,422,118 6/1995 Brown et al...... 424/449 76 Inventors: John C. Grasela, 4521 Saluto Ct., San 5,460,821 10/1995 Masiz ...... 424/449 Diego, Calif. 92130; Joseph E. 5,474,783 12/1995 Miranda et al. ... . 424/448 Grasela, 4767 Ocean Blvd., San Diego, 5,613,958 3/1997 Kochinke et al...... 604/307 Calif. 92109; Robert M. Jubenville, OTHER PUBLICATIONS 550 Washington St., San Diego, Calif. 92103; Joseph J. McCloskey, 1167 Chi et al., J. Pharm. Sci., 80(3):280–283 (1991). Cooperwood, Bloomfield Hills, Mich. Willimann et al., J. Pharm. Sci., 81 (9):871-874 (1992). Ballerini et al., J. Clin. Pharm. Res., VI:67–72 (1986) 483O2 Abstract Only). Appl. No.: 685,172 Primary Examiner Thurman K. Page Assistant Examiner Kathryne E. Shelborne Filed: Jul. 23, 1996 Attorney, Agent, or Firm-Brown, Martin, Haller & Int. Cl...... A61L 15/16; A61F 13/02 McClain, LLP U.S. Cl...... 424/484; 424/447; 424/448; 57 ABSTRACT 424/449 Field of Search ...... 424/447, 448, A composition and procedures for its formation and admin 424/449, 484; 514/946, 947 istration are described, which provide for a convenient, efficacious and Simple transdermal administration of medi References Cited cations from a topically applied cream. No transmission through a membrane is involved. The composition incorpo U.S. PATENT DOCUMENTS rates at least two Separate penetration enhancers which 4,011,319 3/1977 Kaiser et al...... 424/244 function Synergistically to provide for rapid but controllable 4,033,996 7/1977 Cragoe, Jr. et al. ... 260/490 transport of the medication from the cream into the skin. The 4,127,118 11/1978 Latorre .. ... 514/248 use of a plurality of penetration enhancers, at least one of 4,440,777 4/1984 Zupan ...... 424/274 which facilitates the Separation of medication from the 4,783,450 11/1988 Fawzi et al...... 514/78 cream and at least a Second of which alters the Structure of 4,801,587 1/1989 Voss et al...... 514/248 4,873,087 10/1989 Morishita et al...... 424/433 the Outer layers of skin, particularly the Stratum corneum, 4,879,119 11/1989 Konno et al...... 424/449 enhances migration of the drug through the Stratum cor 4,963,367 10/1990 Ecanow ...... 424/485 CU. 5,153,179 10/1992 Eibl ...... 514/34 5,290,561 3/1994 Farhadieh et al...... 424/449 22 Claims, 1 Drawing Sheet

ECHN FORMATION OF SOPROPY ORGANOGE PAMAE

SOUBIZATION SOLVENT OF DRUG

POLYOxYMER FORMATION OF CARREr AND DRUG RELEASE A GEN

pH ADJUSTMENT (F NECESSARY }

Fi Nished product U.S. Patent Nov. 17, 1998 5,837.289

LECHN FORMATION OF SOPROPYL ORGANOGEL PALMTATE

DRUG SOLUB, LZATION MX SOLVENT OF DRU G

POLYOXYMER, FoRMATION OF CARRER AND MX WATER DRUG RELEASE A GENT

pH ADJUSTMENT (F NECE SS ARY)

FN SHED PRODUCT 5,837.289 1 2 TRANSIDERMAL IDELIVERY OF material, and the membrane Side and the outer Side are MEDICATIONS USINGA COMBINATION OF joined around the perimeter of the patch, forming a reservoir PENETRATION ENHANCERS for the medication and carrier between the two layers. Numerous kinds of medications have been administered BACKGROUND OF THE INVENTION through the use of a patch, notably Scopolamine for pre 1. Field of the Invention venting motion Sickness, nicotine derivatives intended to The invention herein relates to the transdermal delivery of discourage an addicted Smoker from continuing the Smoking medications to a patient. More particularly it relates to habit and estrogen hormones. compositions which allow medication molecules to be Solu Patches have their own Set of disadvantages. A principal bilized and delivered transdermally and to methods for disadvantage is that, not withstanding the presence of a formation of Such compositions and for their therapeutic penetration enhancer, the delivery of the medication is Sc. necessarily limited by the rate of passage of the medication (For convenience herein the terms “drug” and “medica through the patch membrane to the skin. Since the medica tion' may be used interchangeably. We wish to emphasize, tion is not in contact with the skin while it is enclosed in the however, that this invention is applicable to the delivery of 15 patch, whatever length of time is required for the medication any type of compound or molecular species which is to permeate through the Skin itself to become effective is intended to be administered to a patient transdermally for a necessarily lengthened by the time needed for the medica therapeutic or physiological purpose. Whether the material tion first to exit from the patch through the membrane. In happens to meet a particular specific definition of a "drug” many cases membrane permeation rate is the Significant rate or “medication” or other applicable term is not critical for limiting Step of Speed of effectiveness of a particular the purposes of this invention, and the invention should not medication, and can render patch administration essentially be limited by the particular term applied to the material ineffective because the medication cannot reach the patient's being administered.) System rapidly enough to be efficacious. In addition, the 2. Description of the Prior Art 25 adhesive which is intended to Secure the patch to the In the past the delivery of medications transdermally to a patient's skin can fail, So that the patch disengages from the patient has been limited to administration by transcutaneous skin before completion of the transfer of the medication, injection or by transdermal migration from a patch placed on resulting in loSS of that quantity of medication which the outer surface of the patient’s skin. The deficiencies of remains within the patch's reservoir. administration by injection are obvious. With only a few Various methods have been used to increase skin perme exceptions injections must be administered by trained and ation of medications, including penetration enhancers, pro qualified medical perSonnel. The injection itself causes a drugs, Superfluous vehicles, iontophoresis, phonophoresis break in the skin which can lead to infection, despite and thermophoresis. For the purposes of this invention, only precautions, an injection needle may itself be contaminated the penetration enhancers are relevant. Ideal enhancers have causing infection to the patient, and, course, it is a simple 35 no irritancy and toxicity to the Skin, and the whole body, fact that injections are uncomfortable to almost all patients. together with having high enhancing effects. Enhancers Further, an injection is normally not “location Specific.’ themselves should be phisiochemically stable and not have Rather the injection is made at a location on the body remote pharmacologic effects, and preferably should not have Smell, from the affected area, and the injected medication must be color, or taste. A typical example of an enhancer is disclosed transported through the body to that location. This results in 40 in U.S. Pat. No. 4,783,450 (to Fawzi et al.) in which lecithin losses in transport, So that to administer an effective amount is used for penetration enhancement. of medication to the affected area, and exceSS of medication The Stratum corneum provides the principal barrier to the must be injected. percutaneous penetration of typically applied Substances. It In View of these deficiencies of injection administration, is the most Superficial cutaneous layer and is a horny layer Significant effort has been spent in the last few years in 45 that consists of flat, Scalelike "Squames' made up of the Seeking alternative methods of transdermal administration fibrous protein keratin. The Squames are continually being of medications. It has been necessary to meet two require replaced from below by epidermal cells that die in the ments. First, the method must provide for extended contain process of manufacturing keratin. It is unlikely that the ment of the drug and any carrier while in place on the emulsified fat on the skin Surface greatly affects permeabil patient's skin (in effect analogous to containment of the 50 ity. However, vehicles can control, to a great extent, the rate medication and carrier in the reservoir Vial of the injection of penetration of drugs that are applied to the Skin. The Syringe), in a form that does not lend itself either to intercellular lipids may be important for the permeability contamination of the medication and carrier or to loSS of the barrier in Skin. medication and carrier. Second, the Systems employed must It is known that Some combinations of enhancers and provide for a regulated and predictable rate of transfer of the 55 vehicles act Synergistically, Such as the combination of medication (with or without the carrier) from the contain ethanol as a vehicle for the enhancer laurocapram. However, ment device into and through at least Some layers of skin to many combinations are not Synergistic; for instance, where the medication will be dispersed throughout the n-decylmethylsulfoxide lowers the Zeta potential of the skin, affected area of the body. and thus enhancement due to conduction flow The only workable prior art embodiment of Such a device 60 (iontophoresis) is minimized, in the past, Synergism of has been what is commonly known as a “patch.” A patch is combinations could not be predicted. generally a flat hollow device with a permeable membrane Further, one must differentiate between penetration on one side and also Some form of adhesive to maintain the enhancer which act to improve the ability of the medication patch in place on the patient's skin, with the membrane in to pass through a patch membrane to reach the skin, and contact with the skin So that the medication can permeate out 65 those which act to enhance the Separation of the medication of the patch reservoir and into and through the skin. The from its carrier matrix or to enhance the diffusion of the outer Side the patch is formed of an impermeable layer of medication into and through the skin. 5,837.289 3 4 However, notwithstanding the various deficiencies forming an organogel comprising a first penetration mentioned, administration by injection or by patch remain enhancer which improves diffusion of the medication into only by viable transdermal administration techniques known and within the patient's skin, and a carrier for the Solubilized to the prior art. medication; forming a polymeric component comprising a Second penetration enhancer which improves diffusion of SUMMARY OF THE INVENTION the medication out of the composition for transdermal migration; and blending the Solubilized medication, orga We have now developed a system that provides for a nogel and polymeric component to form the composition convenient, efficacious and Simple System for transdermal having a Viscosity in a range Such that it may be applied administration of medications in which the medication is topically and conform to and adhere to the patient's skin for present in a composition for direct application to the skin, a period of time Sufficient for a significant portion of the commonly in the form of a cream or Similar material. The medication to be delivered transdermally to the patient. transdermal administration of the drug is therefore not In yet another principal embodiment, the invention is of hindered by having to penetrate a patch membrane, Since the a method for the transdermal administration of a medication cream and its medication content are directly in contact with which comprises Solubilizing a medication capable of being the skin and the medication needs only to Separate from the 15 administered transdermally; forming an organogel compris cream in order to be available for transdermal migration. In ing a first penetration enhancer which improves diffusion of addition, Since the composition is in the form of a cream or the medication into and within the patient's skin, and a other Viscous moldable and spreadable material, the drug carrier for the Solubilized medication; forming a polymeric may be effectively administered by application of the cream component comprising a Second penetration enhancer which to many bodily areas where a patch either will not fit or improves diffusion of the medication out of the composition cannot be shaped to conform to the skin contours. for transdermal migration; blending the Solubilized (As with the use of the terms “medication” and “drug.” medication, organogel and polymeric component to form the our invention is not to be limited by the term used to describe composition having a Viscosity in a range Such that it may the physical properties of the composition herein. We will 25 be applied topically and conform to and adhere to the for convenience use the term “cream,” but other terms Such patient's skin for a period of time Sufficient for a significant as “gel,” “lotion,” “paste” and the like also could be appli portion of the medication to be delivered transdermally to cable. As will be seen from the description below, the the patient; and applying the composition to the skin of a physical nature of the composition containing the medica patient for the period of time and allowing the medication to tion and to be applied to the patient's skin will be defined by diffuse out of the composition and through the skin, Such functional parameters, rather than being limited by an arbi that the medication is taken up by the body of the patient and trary descriptive term.) acts therapeutically on the patient. A key element in the Success of the present invention is In preferred embodiments the first penetration enhancer is our discovery that the use of at least two Separate penetration a lecithin organogel formed with isopropyl palmitate or enhancers of defined function results in a Synergism which 35 isopropyl myristate, and the Second penetration enhancer is provides rapid but controllable Separation of the medication a polyoxymer, preferably a polyoxyalkylene derivative of from the cream and its penetration into and within or through propylene glycol. A wide variety of medications can be the skin. At least one of the penetration enhancers acts to delivered by this invention. Further, while the invention facilitate the Separation of drug from the carrier within the herein is described in terms of the minimum number of cream and at least a Second penetration enhancer alters the 40 Synergistically acting penetration enhancers (i.e., two), it Structure of the outer layers of Skin, particularly the Stratum will be understood that additional penetration enhancers can corneum, Such that migration of the drug through the Stratum also be present. Thus there may be more than one enhancer corneum is enhanced and expedited. The medication is thus which operates with a Specific mechanism, or there may be taken up by the patient's System and is efficacious much additional enhancers which provide yet other modes of more rapidly than would be the case for administration of the 45 operation, or both. medication by means of the prior art patch System. Further, The methods and compositions described herein provide although permeation of the skin does not provide for as rapid a unique and highly effective technique for administering administration by the medication as would result from direct medication directly to an affected area of the body with the injection, the use of the present invention avoids the prob minimum amount of medication and with the avoidance of lems associated with injection administration. 50 unwanted Side effects. Unlike administration by injection or Therefore, in one principal embodiment, the invention is orally, the transdermal administration herein is site specific; of a composition for diffusional transdermal delivery of the cream is applied to the Skin directly at the affected area medication to a patient, which comprises a medication of the body. There are therefore no losses of medication capable of being administered transdermally; a carrier for during transport from a remote application site. Similarly, the medication; a first penetration enhancer which improves 55 the long delays in having an effective quantity of the diffusion of the medication into and within the patient's medication reach the affected area of the body, which are skin; and a Second penetration enhancer which improves inherent in injection and oral administration, are entirely diffusion of the medication out of the composition for eliminated in the present invention. transdermal migration; the composition having a Viscosity in The present method also avoids unwanted side effects. For a range Such that it may be applied topically and conform to 60 instance, in oral administration of a medication, the medi and adhere to the patient's skin for a period of time Sufficient cation itself can adversely affect the gastrointestinal tract as for a Significant portion of the medication to be delivered it is Swallowed and dissolved for assimilation into the transdermally to the patient. circulatory system. Those skilled in the art are well familiar In another principal embodiment, the invention is of a with the common caution required for many oral medica method for the preparation of a therapeutic composition to 65 tions that they must be administered only in conjunction be transdermally administered which comprises Solubilizing with a meal, or, conversely, that they cannot be administered a medication capable of being administered transdermally; in the presence of Specific types of food products, Such as 5,837.289 S 6 dairy products. These cautions are necessary Since the orally taken for and the remainder retained in refrigerated Storage. administered medication’s efficacy will be adversely The carrier/release agent mixture is then mixed with the affected by certain foods, or the person's gastrointestinal drug/organogel mixture to produce the final “cream” com tract will be irritated by the medication if the latter is not position. Details will be provided below. diluted by the presence of food in the gastrointestinal tract. Considering first the organogel, the blend of the two Such considerations are, of course, entirely absent in the components will be in the range of from about 25% to 75% present invention, where the same medications can be easily of the lecithin component, the remainder being the fatty acid and conveniently administered transdermally without incur ester component. (Unless Stated otherwise, all percentages, ring Such side effects. parts and concentrations are by weight.) The “lecithin com Futher, the transdermal administration avoids the “first ponent” may be lecithin, any comparable fatty acid phos pass effect,” which often results when a medication is pholipid emulsifying agent, Such as fatty acids and their administered orally and thus has to pass through various esters, cholesterol, tri-glycerides, gelatin, acacia, Soybean organs, including the liver, before reaching the affected area oil, rapeseed oil, cottonSeed oil, waxes or egg yolk, or any of the body. These organs can absorb or chemically alter other material which acts in the same manner as lecithin. Significant quantities of the passing medication, thus requir 15 ing that large exceSS quantities of the medication by admin The other component is an organic Solvent/emollient, istered initially to insure that an effective quantity of the particularly including fatty acid esters, of which the esters of medication will ultimately reach the affected area of the the Saturated alkyl acids are preferred. The preferred Solvent/ body. Since in this method the medication commonly passes emollient in the present invention is isopropyl palmitate or through the Skin directly to the affected Site, there is no isopropyl myristate. However, there are numerous com problem of loSS in intermediate organs, and therefore exces pounds available which exist in liquid form at ambient Sive quantities of medication do not need to be delivered to temperatures and will function in a manner equivalent to the counter Such losses. (As an example, ketoprofen is com fatty acid esters. These are all quite well known and monly administered orally in quantities of about 50-75 mg described. They include, but are not limited to, the follow per dose for the desired efficacy. In the present invention, 25 Ing: however, an equally effective dose of ketoprofen can be delivered by topical transdermal administration of only 3 Ethanol mg.) Propylene glycol Water Finally, Since the present invention is site specific, the Sodium oleate depth of delivery of the medication can be readily Leucinic acid controlled, as contrasted to injection delivery. Oleic acid Capric acid BRIEF SUMMARY OF THE DRAWING Sodium caprate Lauric acid The single FIGURE of the drawing is a flow chart 35 Sodium laurate illustrating Schematically formulation of a preferred Neodecanoic acid embodiment of a composition of this invention. Dodecylamine Cetyl lactate DETAILED DESCRIPTION AND PREFERRED Myristyl lactate Lauryl lactate EMBODIMENTS Methyl laurate 40 Phenyl ethanol The unique compositions of the present invention require Hexamthhylene lauramide a specific Sequence of Steps in their formation if a therapeu Urea and derivatives tically effective and pharmaceutically compatible composi Dodecyl n,n-dimethylamino acetate Hydroxyethyl lactamide tion is to be obtained. This is best understood by reference Phyophatidylcholine to the FIGURE of the drawing. 45 Sefsol-318 (a medium chain glyceride) The basic composition of this invention is a mixture of an Isopropyl myristate organogel, a Solubilized medication or drug and a carrier Isopropyl palmitate combined with a drug release agent. Penetration enhance Surfactants (including): ment is provided by the organogel and by the release agent. polyoxyethylene (10) lauryl ether In the exemplary process as illustrated in the FIGURE, an 50 diethyleneglycol lauryl ether organogel is formed, in this example from lecithin and Laurocapram (aZone) isopropyl palmitate. These two materials are thoroughly (1:1-dodecylazacycloheptan-2- blended and mixed until a Substantially uniform gel Structure one) forms. The organogel, which is the base for the cream Acetonitrile 55 1-decanol composition, should be formed at the time that the compo 2-pyrrollidone Sition is to be formulated. The drug or medication is Solu N-methylpyrrollidone bilized with a Solvent, Such as water, alcohol or other N-ethyl-1-pyrrolidone appropriate Solvent, again by mixing in a known manner. 1-methyl-2-pyrrolidone When it is desired to start formation of the actual 1-lauryl-2-pyrrollidone Sucrose monooleate composition, the Solubilized drug is mixed thoroughly into 60 Dimethylsulfoxide the organogel matrix, again by conventional mixing tech Decylmethylsulfoxide niques. The technique used will of course be Such that the Acetone Polyethylene glycol (100-400 mw) organogel's Structure is not broken down. Finally, a carrier, Dimethylacetamide Such as water or alcohol, and a drug release agent, Such as Dimethylformamide a polyoxymer, are blended. The carrier/release agent mixture 65 Dimethylisosorbide can be made up in large lots and Stored under refrigerator Sodium bicarbonate until needed, at which time an appropriate quantity can be 5,837.289 7 8 -continued be needed. For the purpose of this description, therefore, the term “solubilized” drug or medication shall be considered to Various C, to C alkanes Mentane include those drugs or medications which can be dispersed Menthone or dissolved into the cream with or without the presence of Menthol Terpinene a separate Solvent. Usually the amount each of medication D-terpinene and solvent which will be present, based on the entire Dipentene composition, will be in the range of up to <1%-20%, with the N-nomalol Limonene preferred concentration of each being about 10%. The Ethoxy diglycol concentrations of both need not be identical. A wide variety of drugs may be transported by this This combination of the phospholipid emulsifying agent method and through this type of composition. Typical of the and the fatty acid or fatty acid ester or equivalent thereof various drugs which can be Successfully incorporated into forms an organogel. In the example referred to in the the present composition and transdermally transported FIGURE, the organogel will be a lecithin organogel, which 15 include the following classes of Substances: is both isotropic and thermally reversible. At temperatures greater than about 40 C. the organogel will become a liquid and its viscosity will be greatly reduced. Water can be also Antidiabetic Agents be added to control the Viscosity of the organogel. The organogel Serves as one of the penetration enhancers in the Sulfonylureas cream, and acts on the Stratum corneum of the skin to Acetohexamide promote interaction between the phospholipids of the cream Chlorpropamide and the phospholipids of the skin. This causes a disruption Tolazamide Tolbutamide in the normal regular arrangement of layers in lipids in the Glipizide Stratum corneum So that openings are created which then 25 Glyburide allow the drug to pass more easily through the Skin. The Glimepiride organogel will be compatible with a wide variety of Metformin lipophilic, hydrophilic and amphoteric drugs and medica Acarbose Insulin tions. Glucose Elevating Agents Using the above-described lecithin organogel and its components as an example, the properties needed for inclu Diazoxide sion of a components in this invention will be evident. The Glucose various compounds, polymers, etc. comprising the Thyroid Hormones organogel, the Solubilized drug and the carrier/polyoxymer Levothyroxine components must all be compatible with each other, So that 35 Liothyronine Thyroid USP chemical reactions do not occur which would adversely Thyroglobulin affect the efficacy or Safety of the cream composition; they Liotrix must be mutually soluble so that they can be mixed and Thyroid Drugs blended to a uniform consistency; they must be Such that the Iodine resulting cream composition has a Viscosity under ambient 40 Propylthiouracil conditions which is low enough to allow it to be applied Methimazole easily and Smoothly to the skin, but not So low that the cream Parathyroid Drugs acts as at least in part like a liquid and cannot be retained on Calcitonin the skin where it is applied; they must not be toxic, irritating Etidronate or otherwise harmful to the patient; they must be sufficiently 45 Pamidronate stable that the overall composition will have a reasonable Alendronate Shelf life and Service life; and, as a practical matter, they Gallium Nitrate must be available at reasonable cost. Thus, it will generally Vitamins be found that the characteristics of a drug or medication Vitamin A which make it difficult to administer transdermally through 50 Vitamin D the present System include its having low Stability, particu Vitamin E Vitamin B1 larly at ambient temperatures, not being Soluble in the Vitamin B2 composition; having high molecular weight resulting in Vitamin B3 difficulty penetrating the Stratum corneum, even with the Vitamin B6 enhanced openings, and/or causing an adverse reaction with 55 Vitamin B12 Vitamin C the one or more skin layers. Multivitamin Preparations The drug or medication which is to be administered Vitamin Combinations usually must be solubilized in a solvent to enable it be Antihyperlipidemic Agents blended properly with the organogel and the carrier/release Fluvastatin agent. Typical Solvents for Such use include water, the low 60 Lovastatin molecular weight alcohols and other low molecular weight Pravastatin organic Solvents. Solvents Such as water, methanol, ethanol Simvastatin and the like are preferred. The purpose of Solubilizing is to Probucol Niacin enable the medication to become properly dispersed in the Dexothyroxine final cream. It is possible that a few drugs or medications 65 Clofibrate might themselves be sufficiently soluble in the cream that a Gemfibrozil Solvent, and therefore a separate Solubilizing Step, would not 5,837.289 9 10 -continued -continued Cardiac Drugs Antirheumatic Agents Cardiac Glycosides Gold Compounds Penicillamine Digitoxin Azathioprine Digoxin Methotrexate Antianginal Agents Agents for Gout Nitroglycerin Probenecid Isosorbide Dinitrate 1O Sulfinpyrazone Isosorbide Mononitrate Allopurinol Antiarrhythmic Agents Colchicine Agents for Migraine Moricizine Quinidine Sumatriptan Procainamide Methysergide Disopyramide 15 Ergotamine Derivatives Lidocaine Sedatives and Hypnotics Tocainide Mexiletine Zolpidem Flecanide Paraldehyde Encainide Chloral Hydrate Amiodarone Acetylcarbromal Respiratory Drugs Glutethimide Ethchlorvynol Bronchodilators Ethimate Temazepam AIbuterol Estazolam Metaproterenol 25 Flurazepam Terbutaline Quazepam isoproterenol Triazolam Ephedrine Phenobarbital Theophylline Mephobarbital Dyphylline Amobarbital Nasal Decongestants Butabarbital Secobarbital Phenylpropanolamine Pentobarbital Pseudoephedrine Antianxiety Agents Phenylephrine Ephedrine Meprobamate Naphazoline Alprazolam Oxymetazoline 35 Chlordiazepoxide Tetrahydrozoline Clonazepam Xylometazoline Clorazepate Propylhexedrine Diazepam Gastrointestinals Halazepam Lorazepam 40 Sucralafate Oxazepam Metoclopramide Prazepam Cisapride Buspirone Laxatives Hydroxyzine Mesalamine Doxepin Chlormezanone Olsalazine 45 Anticonvulsants Antidiarrheals Famotidine Phenytoin Nizaticine Mephenytoin Cimetadine Ethotoin Rantadine Ethosuximide Omeprazol 50 MethSuximide Cifapride Phensuximide Miscellaneous Paramethadione Trimethadione Finasteride Clonazepam Lamsoprazole Clorazepate Papaverine 55 Valproic Acid Prostaglandins Lamotrigine Primidone Amphetamines Gabapentin Phenacemide Dextroamphetamine Carbamazepine Anorexiants Phenobarbitol 60 Antidepressants Phentermine Benzphetamine Amitryptyline Phendimetrazine Clornipramine Diethylpropion Doxepin Mazindol Imipramine Fenfluramine 65 Trimipramine Dexfenfluramine Amoxapine 5,837.289 11 12 -continued -continued Desipramine Mefloquine Nortriptyline Quinacrine Protriptyline Doxycycline Venlafaxine 4-Aminoquinolone Maprotiline Compounds Trazodone 8-Aminoquinolone Bupropion Compounds uoxetine Folic Acid Antagonists aroxetine Antituberculous Drugs e tral li 1O uvoxamine Isoniazid ranylcypromine Rifampin henelzine Rifabutin efazodone Ethambutol HCI ntipsychotic Agents Pyrazinamide 15 Aminosalicylate Sodium Chlorpromazine Ethionamide Promazine Cycloserine Triflupromazine Streptomycin Sulfate Thioridazine Capreomycin Mesoridazine Amebicides Acetophenazine Perphenazine Paromomycin Fluphenazine Iodoquinol Trifluoperazine Metronidazole Chlorprothixene Emetime Thiothixene Chloroquine Haloperidol Antivirals Molindone 25 LOxapine Famciclovir Clozapine Stavudine Riperidone Zidovudine Pimozide Ribavarin Prochlorperazine Amantadine Other Psychotherapeutic Agents Foscarnet Didanosine Lithium Acyclovir Methylphenidate Ganciclovir Tacrine Zalcitabine Pemoline Rimantadine Antimicrobials 35 Miscellaneous Anti-infectives Antibacterials Trimethoprim Trimethoprim Penicillins Sulfamethoxazole Cephalosporins Erythromycin Carbapenems Sulfisoxazole Monobactams 40 Furazolidone Chloramphenicoi Pentamidine Fluoroquinolones Eflornithine Tetracyclines Atovaquone Macrollides Trimetrexate Glucuronate Spectinomycin Leprostatics Vancomycin 45 Lincosamides Dapsone Aminoglycosides Clofazime Colistin Antihelmintics Polymixin B Bacitracin Mebendazole Novobiocin 50 Diethylcarbamazine Metronidazole Citrate Antifungals Pyrantel Thiabendazole Flucytosine Piperazine Nystatin Quinacrine Miconazole 55 Nicosamide Ketoconazole Oxaminiquine Amphotericin B Praziquantel Griseofulvin Antihistamines Fluconazole Itraconazole Diphenhydramine Sulfonamides Chlorpheniramine 60 Pyrilamine Sulfadiazine Doxepin Sulfacytine Carbinoxamine Sulfamethoxazole Clemastine Suflamethiazole Tripelennamine Antimalarials Brompheniramine 65 Dexchlorpheniranune Quinine Sulfate Triprolidine 5,837.289 13 14 -continued -continued Methodilazine Ketoprofen Promethazine Naproxen Trimeprazine Oxaprozin Hydroxyzine HCl Diclofenac AZatadine Etodallac Cyproheptadine Indomethacin Phenindamine Ketorolac Astemizole Nabumetone Loratadine Sulindac Terfemadine 1O Tolmentin Cetirizine Meclofenamate Antimetabolites Flufenamic Acid Mefenamic Acid 5-Fluorouracil Meclofenamic Acid 6-Mercaptopurine Piroxicam Mycophenolic Acid 15 Salicylates Methotrexate Diflunisal Cytarabine Indomethacin Floxuridine Phenylbutazone Thioguanine Oxyphenbutazone Anticholinergics Sulfinpyrazone Allopurinol Atropine Penicillamine Scopolamine Colchicine Homatropine Probenicid Tropicamide Sunscreen Agents Pirenzepine Isopropamide Oxybenzone Propantheline 25 Dioxybenzone Methscopolamine p-Aminobenzoic Acid Methantheline Ethyl Dihydroxy Propyl PABA Trihexyphenidyl Padimate O Benztropine Glyceryl PABA Biperiden Cinoxate Steroidal Antiinflammatory Agents Ethylhexyl p-methoxycinnamate Octocrylene Cortisone Octyl Methoxycinnamate Hydrocortisone Ethylhexyl salicylate Hydrocortisone Acetate Homosalate Prednisone Octyl Salicylate Prednisolone 35 Menthyl Anthranilate Triamcinolone Digalloyl Trioleate Methylprednisolone AVobenzone Dexamethasone Muscle Relaxants Betamethasone Clobetasol Carisoprodol Diflorasone Chlorphenesin Halobetasol 40 ChlorZOxazone Amicinonide Cyclobenzaprine Desoximetasone Metaxalone Fluocinolone Methocarbamol Halcinomide Orphenadrine Clocortolone Diazepam Flurandrenolide 45 Baclofen Fluticasome Antihypertensives Mometasone Aclometasone Beta-Blockers Desonide Fludrocortisone Propranolol Local Anesthetics 50 Acebutolol Betaxolol Dibucaine Bisoprolol Lidocaine Esmolol Benzocaine Metoprolol Butamben Picrate Carteolol Tetracaine 55 Nadolol Dyclonine Penbutolol Pramoxine Pindolol Prilocaine Sotalol Antiplatelet Drugs Timolol Labetalol Dipyridamole Ace Inhibitors Ticlopidine 60 Warfarin Benazepril Coumarin Captopril Non-steroidal Antiinflammatory Agents Enalapril Fosinopril Fenoprofen Lisinopril Ibuprofen 65 Moexipril Flurbiprofen Quinapril 5,837.289 15 16 -continued -continued Ramipril Sex Hormones Calcium Channel Blockers Estogens Diltiazem Verapamil Estriol Nifedipine Estradiol Felodipine Estrone Nicardipine Testosterone Nimodipine Methyltestosterone Nisoldipine 1O Progesterone Isradipine Medroxyprogesterone Bepridil Hydroxyprogesterone Amlodipine Norethindrone Nisoldipine Megesterol Alpha Blockers Pituitary Hormones 15 Methyldopa DDAVP Clonidine Methylergonovine Phentolamine Uterine Hormones Guanabenz Phenoxybenzamine Carboprost Guanfacine Dinoprostone Yohimbine Adrenal Steriod Inhibitors Reserpine Guanethidine Aminoglutethimide Guandrel Doxazosin Prazosin In one preferred embodiment, the drug is ketoprofen. Terazosin 25 Finally, the carrier and drug release agent form a poly Vasodilators meric composition which provides the Separate penetration Hydralazine enhancement of facilitating the rapid release of the medica Minoxidil tion from the cream upon topical application to the patient. Nitroglycerin The purpose of this combination of materials is to provide Isosorbide Dinitrate for penetration enhancement of a different type than that of Isosorbide Mononitrate the organogel, i.e., by effecting rapid release of the drug Papaverine from the cream and transport by the carrier out of the cream Diuretics and into the Skin through the enhanced openings in the Stratum COrneum. Thiazides Loop Diuretics The drug release agent may be any of a variety of Spironolactone 35 polyoxymers, i.e., polyoxyalkylene derivatives of propylene Triamterene glycol. Preferred are those which contain mixtures of poly Acetazolamide oxyethylene and polyoxypropylene polymeric derivatives of Methazolamide Dichlorphenamide propylene glycol or methyl oxirane polymers. By acting Antiemetics essentially as an emulsifier, Stabilizer and dispersing agent, 40 the polyoxymer facilitates the Separation of the drug or Chlorpromazine medication from the other components of the cream and Triflupromazine Perphenazine transfers it to the carrier, which will normally be water or a Prochlorperazine low molecular weight alcohol or organic Solvent. Useful Promethazine polyoxymers are available under the trademark “Pluronic' Thiethylperazine 45 from Wyandotte Chemical Company. Metoclopramide The concentration of the carrier provided with the drug Cyclizine Meclizine release agent as a mixture in the cream will determine the Buclizine particular diffusion coefficient of the drug. With higher Dimenhydrinate concentrations of the carrier, the diffusion coefficient will be Trimethobenzamide 50 lower and the drug will be absorbed more slowly and Scopolamine produce more local effects. Conversely, lowering the con Diphenidol Benzquinamide centration of the carrier will Speed the absorption of the drug Hydroxyzine and enhance the ability of the drug to be absorbed systemi Analgesics cally. The normal concentration of the drug release agent in 55 the mixture with the cream will be approximately 20% to Codeine 30%, with the balance being the carrier, during the formation Hydrocodone of the carrier/drug release agent mixture. Hydromorphone Morphine The overall concentrations of the various components in Oxymorphone the composition will generally be in the ranges of: Oxycodone Meperidine 60 Methadone Medication <1%-20% Propoxyphene Solvent for medication <1%-20% Tramadol Organogel 20%-40% Acetaminophen Carrier/release agent 40%-70% Pentazocine Fentanyl 65 Salicylates It will of course be understood that these ranges represent the typical ranges for the Specific example upon which the 5,837.289 17 18 FIGURE is based, i.e., an example with a lecithin organogel, end of which a liquid of oil or Syrup consistency had formed. ketoprofen as the drug, and a “Pluronic NF-127' poly Alternatively one can mix the lecithin Soya and the isopropyl oxymer as the drug release agent. In general the ranges for palmitate at 50 to 60° C. until the dissolution is complete. other compositions of this invention in which other suitable At any point during formation of the mixture one can also organogels, drugs, carriers and release agents are used will add the drug or medication. If the latter is soluble in alcohol be similar, and those skilled in the art will have no difficulty it may be previously dissolved in the alcohol and the formulating Suitable compositions from the description alcohol/drug mixture incorporated into the lecithin Soya and herein. isopropyl palmitate mixture. Other factors will need to be considered in preparing EXAMPLE 2 Specific formulations. If the carrier concentration in the cream lies above the useful range, it becomes relatively Stiff Formation of a Carrier/Drug Release Agent and difficult to apply, or, conversely, if the concentration Component falls below the Suitable level, the cream will have a tendency A polymeric gel for use as a carrier was formed by mixing to Separate. Further, the pH of the cream must be adjusted to 20 grams of a commercial polyoxymer designated as “Plu match the pH of the solubilized medication component to 15 ronic NF-127 with 0.2 g of pure potassium Sorbate and maximize the amount of non-ionized drug present in the adding Sufficient refrigerated purified water to bring to cream. All Suitable medications have acid/base characteris volume of 100 ml. Other similar compositions were formed tics that can be altered by adjustment of the pH of the with 30 g and 40 of the “Pluronic NF-127” respectively. A composition. typical commercial mixer was used to mix the material. The greater proportion of non-ionized drug present, the Once all of the granules of the polymeric material had been greater the drug's Solubility and the greater the ability for wetted the gel was refrigerated So that dissolution took place larger quantities of the drug to be transported transdermally. upon cooling in the refrigerator. The compositions must be The control of the pH can also be used to is determine maintained under refrigeration because at ambient condi whether the drug is likely to become absorbed systemically tions they will Solidify, since (as opposed to water) poly or to be absorbed locally, Since the Speed of transdermal oxymer mixtures as prepared herein Solidify when heated transport will be dependent on the pH. 25 and liquefy when cooled. Stock Solutions of these materials The physical properties of the cream will also be impor may be made and kept in refrigerated Storage for repeated tant. AS noted the Viscosity must be Such that it can be use in the formulation of the compositions of the present applied topically and conform to and adhere to the patient's invention. skin for a period of time Sufficient for a significant portion EXAMPLE 3 of the medication to be delivered transdermally to the patient. It must also be capable of being removed from the Mixture of a Cream Containing Medication, patient's Skin with ordinary physiologically acceptable Lecithin Organogel and Carrier/Drug Release Agent cleansers or Solvents, so that the cream may be removed if In a typical procedure equivalent weights of the lecithin medically necessary, or the residue may be removed once Soya and the isopropyl palmitate are combined and a Small the treatment time period for each administration has been 35 quantity of Sorbic acid is incorporated to control pH. The completed. The components must be capable of being mixture is stirred until a syrup or oil consistency is obtained. blended into a Smooth, homogenous mixture with a cream Large quantities may be prepared and kept as a Stock or lotion-like consistency and appearance, which either has Solution. The drug or medication, e.g., ketoprofen, is dis a natural light colored appearance or can be lightly tinted if Solved in water, alcohol or an equivalent Solvent by using a flesh-compatible tones are desired. The cream must also be 40 the minimal amount of Solvent necessary to obtain complete capable of being covered with a light gauze or other type of Solubilizing. The dissolved drug is added to a Small portion dressing if desired, particularly where the cream would of the lecithin organogel and Stirred to disperse the drug in otherwise be in contact with the patient's clothing. the gel. The mixture of the carrier and the polyoxymer is Adjustment of pH, effects of concentration and achieve then added to bring the entire formulation to the desired ment of Suitable physical properties in compositions con 45 Volume, and, if necessary, the pH of the cream is adjusted. taining polyoxymers have been Studied and reported by Chi It will be evident that there are numerous embodiments of et al., J. Pharm. Sci., 80 (3): 280–283 (1991). Reference is this invention which, while not expressly described above, made to that article, and the prior references reported are clearly within the Scope and Spirit of the invention. The therein, for guidance in determining practical limits of pH, above description is therefore intended to be exemplary concentration, Viscosity and the like when varying the 50 only, and the Scope of the invention is to be limited Solely Specific materials herein. The techniques and methods by the appended claims. reported there are quite Suitable for use in the present We claim: invention. 1. A composition for diffusional transdermal delivery of Examples of the formation of different components are medication to a patient, which comprises: given below: a. <1 to 20 parts by weight of a medication capable of 55 being administered transdermally; EXAMPLE 1. b. <1 to 20 parts by weight of a solvent for said medica Formation of a Lecithin Organogel tion; A number of different lecithin organogels were formed by c. 20 to 40 parts by weight of a first penetration enhancer mixing different quantities of granular lecithin Soya with 60 which improves diffusion of Said medication into and isopropyl palmitate and a Solvent. In three different typical within Said patient’s skin, Said first penetration compositions the respective amounts of lecithin Soya and enhancer comprising an organogel which comprises a isopropyl palmitate were 25%/75%, 50%/50%, and 75%/ fatty acid phospholipid emulsifying agent and a fatty 25%. The first composition can be characterized as a thin oil, acid or ester thereof, and the Second as a medium oil and the third as a heavy oil. In 65 d. 40 to 70 parts by weight of a second penetration all cases the lecithin granules and isopropyl palmitate were enhancer which improves diffusion of Said medication allowed to sit for Several hours, commonly overnight, by the Out of Said composition for transdermal migration; 5,837.289 19 20 Said composition having a Viscosity in a range Such that 16. A method as in claim 15 further comprising Selecting it may be applied topically and conform to and as Said polymer a polyoxyalkylene derivative of propylene adhere to Said patient's skin for a period of time glycol. Sufficient for a significant portion of Said medication 17. A method as in claim 14 further comprising blending to be delivered transdermally to Said patient. 5 Said polyoxymer with a carrier for said medication. 2. A composition as in claim 1 wherein Said medication 18. A method as in claim 9 which comprises: comprises a lipophilic, hydrophilic or amphoteric therapeu a. Solubilizing <1 to 20 parts by weight of a medication tic compound. capable of being administered transdermally; 3. A composition as in claim 1 wherein Said first penetra tion enhancer enlarges openings in Said Stratum corneum, b. forming 20 to 40 parts by weight of an organogel whereby Said medication can diffuse through Said enhanced comprising a first penetration enhancer which com openings at a rate greater than its diffusion rate through prises a fatty acid phospholipid emulsifying agent and corresponding unenlarged openings. a fatty acid or ester thereof and which improves diffu 4. A composition as in claim 3 wherein Said emulsifying Sion of Said medication into and within Said patient's agent is lecithin and Said fatty acid ester is isopropyl palmitate or isopropyl myristate. 15 skin, and a Solvent for Said Solubilized medication; 5. A composition as in claim 1 wherein Said Second c. forming 40 to 70 parts by weight of a polymeric penetration enhancer alters the interaction between Said component comprising a Second penetration enhancer medication and Said composition to improve diffusion of which improves diffusion of said medication out of said Said medication out of Said composition for transdermal composition for transdermal migration; migration. d. blending Said Solubilized medication, organogel and 6. A composition as in claim 5 wherein Said Second polymeric component to form Said composition having penetration enhancer comprises a polyoxymer. a Viscosity in a range Such that it may be applied 7. A composition as in claim 6 wherein Said polyoxymer comprises a polyoxyalkylene polymer. topically and conform to and adhere to Said patient's 8. A composition as in claim 7 wherein Said polymer 25 skin for a period of time Sufficient for a Significant comprises a polyoxyalkylene derivative of propylene glycol. portion of Said medication to be delivered transder 9. A method for the preparation of a therapeutic compo mally to Said patient. Sition to be transdermally administered which comprises: 19. A method as in claim 18 further comprising adjusting a. Solubilizing a medication capable of being administered the pH of Said composition to control the rate of transdermal transdermally; transmission of Said medication. b. forming an organogel comprising a first penetration 20. A method as in claim 18 further comprising adjusting enhancer which comprises a fatty acid phospholipid the concentrations of each component within Said range to emulsifying agent and a fatty acid or ester thereof and control the rate of transdermal administration of Said medi which improves diffusion of Said medication into and cation. within Said patient's skin, and a Solvent for Said Solu 35 21. A method for the transdermal administration of a bilized medication; medication which comprises: c. forming a polymeric component comprising a Second a. Solubilizing a medication capable of being administered penetration enhancer which improves diffusion of Said transdermally; medication out of Said composition for transdermal b. forming an organogel comprising a first penetration migration; and 40 enhancer which comprises fatty acid phospholipid d. blending Said Solubilized medication, organogel and emulsifying agent and a fatty acid or ester thereof and polymeric component to form Said composition having which improves diffusion of Said medication into and a Viscosity in a range Such that it may be applied within Said patient's skin, and a Solvent for Said Solu topically and conform to and adhere to Said patient's bilized medication; skin for a period of time Sufficient for a Significant 45 c. forming a polymeric component comprising a Second portion of Said medication to be delivered transder penetration enhancer which improves diffusion of Said mally to Said patient. medication out of Said composition for transdermal 10. A method as in claim 9 further comprising Selecting as migration; Said medication a lipophilic, hydrophilic or amphoteric d. blending Said Solubilized medication, organogel and therapeutic compound. 50 polymeric component to form Said composition having 11. A method as in claim 9 further comprising Selecting as a Viscosity in a range Such that it may be applied Said first penetration enhancer a material which enlarges topically and conform to and adhere to Said patient's openings in Said Stratum corneum, whereby said medication skin for a period of time Sufficient for a Significant can diffuse through Said enhanced openings at a rate greater than its diffusion rate through corresponding unenlarged 55 portion of Said medication to be delivered transder openings. mally to Said patient; and 12. A method as in claim 11 further comprising Selecting e. applying Said composition to the skin of a patient for lecithin as Said emulsifying agent and isopropyl palmitate or Said period of time and allowing Said medication to isopropyl myristate as Said fatty acid ester. diffuse out of Said composition and through the Skin, 13. A method as in claim 9 further comprising Selecting as 60 Such that Said medication is taken up by the body of the Said Second penetration enhancer a material which increases patient and acts therapeutically on Said patient. the diffusion coefficient of Said medication through said 22. A method as in claim 21 wherein Said first penetration composition. enhancer in Said organogel acts upon the Stratum corneum of 14. A method as in claim 13 further comprising Selecting the skin to enhance diffusion of Said medication through Said as Said Second penetration enhancer a polyoxymer. 65 Stratum COrneum. 15. A method as in claim 14 further comprising Selecting as Said polyoxymer a polyoxyalkylene polymer.