US20100292139A1 - Topical drug delivery using phosphatidylcholine - Google Patents

Topical drug delivery using phosphatidylcholine Download PDF

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US20100292139A1
US20100292139A1 US12830857 US83085710A US2010292139A1 US 20100292139 A1 US20100292139 A1 US 20100292139A1 US 12830857 US12830857 US 12830857 US 83085710 A US83085710 A US 83085710A US 2010292139 A1 US2010292139 A1 US 2010292139A1
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phosphatidylcholine
composition
method according
insulin
skin
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Nicholas V. Perricone
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Perricone Nicholas V
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    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • AHUMAN NECESSITIES
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    • A61J3/00Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/07Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
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    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
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    • A61K38/22Hormones
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    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
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    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • AHUMAN NECESSITIES
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    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0014Skin, i.e. galenical aspects of topical compositions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/02Suppositories; Bougies; Bases therefor; Ovules
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/06Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
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    • A61K9/10Dispersions; Emulsions
    • A61K9/127Liposomes
    • A61K9/1277Processes for preparing; Proliposomes
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575Hormones
    • C07K14/62Insulins
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S514/00Drug, bio-affecting and body treating compositions
    • Y10S514/806Somatostatin or derivatives
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S514/00Drug, bio-affecting and body treating compositions
    • Y10S514/807Oxytoxin, vasopressin or derivatives
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S514/00Drug, bio-affecting and body treating compositions
    • Y10S514/808Calcitonin or derivatives
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S514/00Drug, bio-affecting and body treating compositions
    • Y10S514/866Diabetes
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S514/00Drug, bio-affecting and body treating compositions
    • Y10S514/97Containing designated ingredient to stabilize an active ingredient

Abstract

The present invention relates to compositions and methods for transdermal drug delivery comprising formulating a phosphatidylcholine carrier composition containing the drug and applying the composition to the skin.

Description

    PRIOR APPLICATION
  • The present application is a continuation of U.S. patent application Ser. No. 10/448,632 which claims priority benefits under 35 U.S.C. 119(e) of U.S. Provisional Patent Application Ser. No. 60/384,597 filed May 31, 2002.
  • FIELD OF THE INVENTION
  • The present invention relates to a topical drug delivery composition and method. More specifically, this invention relates to topical drug delivery compositions and methods using phosphatidylcholine.
  • BACKGROUND OF THE INVENTION
  • Transdermal drug delivery systems may be designed to act locally at the point of application or to act systemically by entering the body's blood circulation. In these systems, delivery may be achieved by direct topical application of a substance or drug in the form of an ointment or the like, or by adhesion of a patch with a reservoir that holds the drug and releases it to the skin in a time-controlled fashion.
  • Transdermal delivery systems for agents such as drugs, pain relieving compounds, vitamins, and skin improving compounds have been in use for a number of years. However, these systems have typically only been useful for transdermal delivery of relatively small molecules. The skin's porous structure permits such small molecules to pass from the epidermis to the dermis via diffusion. These transdermal delivery systems such as creams have been developed for use with analgesics and skin refining compounds. Transdermal systems using a patch have been developed for nicotine and estrogen therapies. Estradiol technologies are described in U.S. Pat. No. 6,521,250 to Meconi, et al. However, large molecules, such as insulin, are not able to diffuse through the skin. To date there has not been an effective and economical method to transport such molecules through the epidermis to enter the bloodstream via the dermal vasculature.
  • It has been proposed that molecules, potentially including larger molecules, can be transported through the skin when such molecules are contained within spherical vesicles, variously called microparticles, microspheres, liposomes, lipid vesicles, transfersomes, formed by hydrating a phospholipid. The resulting vessels are water-insoluble and are dispersed and suspended in a liquid base material which is applied to the skin to deliver the drug. U.S. Pat. No. 6,165,500 to Cevc discloses “transfersomes,” which are vesicles containing both a lipid and surfactant, to achieve transdermal delivery, based on a theory that osmotic pressure will drive the transfersomes through the dermis. Other solutions have been proposed, including the use of ultrasound devices to generating shock waves to enlarge pores, use of electric current to drive substances across skin, and the use of microneedles to pierce skin and deliver drugs into bloodstream. (See More Than the Patch: New Ways to Take Medicine Via Skin, New York Times, Jul. 2, 2002, page F5.
  • There remains a need for a transdermal drug delivery system with the improved skin permeability and ability to transport a wider range of substances or drugs. This problem is particularly apparent in the transdermal delivery of substances composed of large molecules, such as polypeptides or proteins, which do not readily pass through the pores of the skin. Absent such a transdermal drug delivery system, the use of injections to deliver these substances will remain the conventional dosage method, despite the pain, complicated administration and general invasiveness involved therein.
  • SUMMARY OF THE INVENTION
  • The present invention relates to compositions and methods of transdermal drug delivery comprising formulating a composition containing the drug in a crystallized phosphatidylcholine carrier and applying the composition to the skin.
  • DETAILED DESCRIPTION
  • Phosphatidylcholine is used as a carrier for the topical drug delivery of macromolecules in the practice of this invention. Phosphatidylcholine is a basic component of cell membrane bilayers and the main phospholipid circulating in the plasma. Phosphatidylcholine is highly absorbable and supplies choline which is needed to facilitate movement of fats and oils across and maintain cell membranes in animals.
  • Phosphatidylcholine compositions (herein abbreviated “PC compositions”) of the present invention are formulated to contain macromolecules soluble in PC, which are then applied to skin for transdermal delivery of the macromolecule. PC compositions of the invention are efficacious in the delivery of macromolecular drugs that are conventionally administered intramuscularly, intravenously or orally, including, but not limited to polypeptides such as insulin and somatropin, prostaglandins, glucocorticoids, estrogens, androgens, and the like.
  • It is an advantage of the invention that topical delivery is easier and pleasanter as an administration route than injections, particularly for drugs such as insulin that must be given to patients over a period of time, or for a lifetime. Furthermore, unlike oral administration where a substantial amount of the drug can be destroyed in the digestive process, the drugs in a topical application are not wasted. Topical application allows a steady diffusion of the drug to the desired target area without the cyclic dosages typical of orally or parenterally administered drugs.
  • Typical phosphatidylcholine compositions of the present invention are nonpolar and contain about 85% phosphatidylcholine. By “phosphatidylcholine” is meant a mixture of stearic, palmitic, and oleic acid diglycerides linked to the choline ester of phosphoric acid, commonly called lecithin. Many commercial lecithin products are available, such as, for example, Lecithol®, Vitellin®, Kelecin®, and Granulestin® because lecithin is widely used in the food industry. Compositions of the invention can contain synthetic or natural lecithin, or mixtures thereof. Natural preparations are preferred because they exhibit desirable physical characteristics and are both economical and nontoxic.
  • The macromolecular drugs are mixed with the PC composition under conditions to become entrapped in a phosphatidylcholine bilayer. Phosphatidylcholine forms a bilayer entrapping the macromolecular drug, which may be a polypeptide, contributing to the stability of the active molecule and enhancing penetration. The PC composition therein comprises a carrier-drug combination to be applied topically.
  • While not wishing to be bound by any particular theory, it is believed that the following mechanism illustrates how the PC composition acts to efficiently transport the drug across the epidermis, maximizing penetration of the drug. The PC composition, in liquid crystal phase, is loosely arranged in multilamellar fashion, with the drug being bonded and entrapped within the lipid bilayers formed by the PC composition. This forms a loosely arranged, yet stable, PC composition carrier-drug complex. When placed on the epidermis, the carrier-drug complex begins to diffuse through the epidermis. The phosphatidylcholine molecular chain remains loosely linked with the drug molecular chain and the diffusing phosphatidylcholine molecules“drag” the drug molecules along as they pass through the skin layers. Moreover, the phosphatidylcholine molecules may begin to separate from the loosely arranged carrier-drug complex and become integrated into the dermis. As the phosphatidylcholine molecules separate from the crystallized phophoslipid bilayer structure of the carrier-drug complex the drug molecules are released. As these drug molecules are released, they are now within into the dermis and may enter the dermal vasculature so they may act accordingly in the bloodstream. Drug molecules which were once too large to diffuse, by themselves, into the pores of the epidermis, have instead been forced through the epidermis by phosphatidylcholine carriers which naturally enter and integrate into lipid bilayer structures within the cells of the epidermis and/or dermis and resultantly are required to release their bonds to the drug molecules and set them free within the dermis.
  • Preferred PC compositions comprise phosphatidylcholine in crystal phase to increase fluidity of the lipid bilayer formed. By reducing rigidity and loosening the phospholipid bilayer of the PC composition, larger molecules may embed therein and penetration of the carrier-drug composition by the cell membrane is facilitated. The skin is more permeable to the fluid, less structured lipid bilayer of the PC/carrier-drug composition applied thereon than to the drug by itself, or entrapped in an organized, arranged vesicle such as a liposome. The loosely packed lipid bilayer of the crystallized carrier-drug composition integrates into the cell membrane, and as a result, has transported the drug so it can enter the bloodstream to act upon the body. The PC composition may be a multilamellar liquid crystal phase or a liquid crystal phase suspension in water which may be converted to multilamellar liquid lipid vesicles.
  • In preferred embodiments, nonpolar preparations of phosphatidylcholine are formulated to contain adjunct ingredients, e.g., lipoic acid and ascorbyl palmitate, in addition to the macromolecular drug. The adjunct ingredients act synergistically to help to minimize degradation and thus preserve the integrity of the insulin polypeptide chains, and to enhance transdermal penetration of active insulin so that it can be absorbed by the dermal vasculature.
  • Preferred PC compositions of the invention contain some polyenylphosphatidylcholine (herein abbreviated “PPC”) to enhance epidermal penetration. By “polyenylphosphatidylcholine” is meant any phosphatidylcholine bearing two fatty acid substituents, wherein at least one is an unsaturated fatty acid with at least two double bonds such as linoleic acid. Preferred PPCs contain a mixture of substitutents such as those found in natural products such as soybean lecithin, which contains 11.7% palmitic, 4.0% stearic, 8.6% palmitoleic, 9.8% oleic, 55.0% linoleic, and 4.0% linolenic acid substituents and is a by-product of soybean oil manufacture.
  • Certain types of soybean lecithin, for example, contain higher levels of polyenylphosphatidylcholine, with dilinoleoylphosphatidylcholine (18:2-18:2 phosphatidylcholine) as the most abundant phosphatidylcholine species, than conventional food grade lecithin, and are useful in formulating phosphatidylcholine insulin compositions of the invention. Alternatively, conventional soybean lecithin is enriched with PPC by adding soybean extracts containing high levels of PPC. As used herein, this type of phosphatidylcholine is called “PPC-enriched” phosphatidylcholine, even where the term encompasses lecithin obtained from natural sources exhibiting PPC levels higher than ordinary soybean varieties. These products are commercially available from American Lecithin, Rhne-Poulenc and other lecithin vendors. American Lecithin markets its products with a “U” designation, indicating high levels of unsaturation; Rhne-Poulenc's product is a soybean extract containing about 42% dilinoleoylphosphatidylcholine and about 24% palmitoyllinoleylphosphatidylcholine (16:0-18:2 PC) as the major PC components.
  • PC compositions are used for transdermal polypeptide delivery in some preferred embodiments. Polypeptide drugs that are delivered transdermally using formulations can be small, e.g., ocytocin and vasopressin nonapeptides or large, e.g., insulin, gonadotropin, and somatropin. PC compositions of the invention deliver drugs including, but are not limited to, oxytocin, vasopressin, insulin, somatotropin, calcitonin, chorionic gonadotropin, menotropins, follitropins, somatostatins, progestins, and combinations of any of these. These drugs are readily available from a variety of commercial sources. Insulin, for example, is marketed under the tradenames Humulin®, Novolin®, Humalog®, and Inutral®. Somatotropin is marketed under the tradenames Gentropin®, Humatrope®, Nutropin®, and Serostim®. Some of these products and other polypeptides contain porcine sequences. Preferable compositions of the invention are preferably formulated with recombinant human polypeptides. It is an advantage of the invention that PC insulin compositions are formulated with commercially available ingredients.
  • One, non-limiting, example of an insulin topical preparation was formulated by combining 0.75% methyl paraben with a commercial phosphatidylcholine preparation marketed as a solution denoted NAT-8729 (containing PEG-400 at 40% and P.G. at 5%) by mixing for an hour or more to emulsify. To this is slowly added Dow Corning Fluid 200-5 or 10 cst (1% by weight), the formulation is mixed, and then Dow Corning Fluid 190 (1% by weight) is slowly added, and the formulation is further mixed to provide a stock insulin carrier. Prior to topical administration, insulin is added at a level of about 3.8 mg/ml to provide about 100 insulin units per ml.
  • Another, non-limiting, example of a pituitary growth hormone (somatotropin) composition was formulated with 85% phosphatidylcholine to which lipoic acid and ascorbyl palmitate was added as antioxidants. Somatotropin readily dispersed in phosphatidylcholine and remained stable in it. Growth hormone appeared to penetrate the skin well when the composition was topically applied.
  • It is appreciated that the foregoing is illustrative and not limiting of the invention, and that various changes and modifications to the preferred embodiments described above will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention, and it is therefore intended that such changes and modification be covered by the following claims.

Claims (20)

  1. 1. A composition comprising crystallized phosphatidylcholine and molecules entrapped within said phosphatidylcholine.
  2. 2. A composition of claim 1, wherein the molecules comprise polypeptides.
  3. 3. The composition of claim 1 wherein the molecules are selected from the group consisting of oxytocin, vasopressin, insulin, somatotropin, calcitonin, chorionic gonadotropin, menotropins, follitropins, somatostatins, progestins, and combinations of any of these.
  4. 4. The composition of claim 1 wherein the composition contains about 85% phosphatidylcholine.
  5. 5. The composition of claim 1 wherein the phosphatidylcholine is soybean lecithin.
  6. 6. The composition of claim 1, wherein the phosphatidylcholine contains polyenylphosphatidylcholine.
  7. 7. The composition of claim 1, further comprising one or more of ascorbyl palmitate and lipoic acid.
  8. 8. A method for treating skin comprising formulating a composition containing a phosphatidylcholine carrier and applying the composition to the skin.
  9. 9. A method according to claim 8, wherein the composition contains about 85% phosphatidylcholine.
  10. 10. A method according to claims 8, wherein the phosphatidylcholine is soybean lecithin.
  11. 11. A method according to claims 8, wherein the phosphatidylcholine contains polyenylphosphatidylcholine.
  12. 12. A method according to claim 8 wherein the macromolecular drug is a polypeptide.
  13. 13. A method according to claim 12 wherein the polypeptide is selected from the group consisting of oxytocin, vasopressin, insulin, somatotropin, calcitonin, chorionic gonadotropin, menotropins, follitropins, somatostatins, progestins, and combinations of any of these.
  14. 14. A method according to claim 12 wherein the polypeptide is somatotropin.
  15. 15. A method according to claim 12 wherein the polypeptide is insulin.
  16. 16. A method for administering insulin to a patient comprising topically applying a composition comprising a crystal or non-polar phosphatidylcholine carrier and insulin to skin of the patient.
  17. 17. The method of claim 16, wherein the phosphatidylcholine carrier comprises about 85% phosphatidylcholine.
  18. 18. A method according to claims 17 wherein the phosphatidylcholine carrier contains polyenylphosphatidylcholine.
  19. 19. A composition for treating skin comprising phosphatidylcholine and at least one additional active ingredient.
  20. 20. The composition of claim 1, wherein the phosphatidylcholine is a polyenylphosphatidylcholine.
US12830857 2002-05-31 2010-07-06 Topical drug delivery using phosphatidylcholine Abandoned US20100292139A1 (en)

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US11334206 Abandoned US20060105955A1 (en) 2002-05-31 2006-01-18 Topical drug delivery using phosphatidylcholine
US11344442 Abandoned US20060127469A1 (en) 2002-05-31 2006-01-31 Methods of delivering stable topical drug compositions
US11506137 Abandoned US20060275353A1 (en) 2002-05-31 2006-08-17 Stable topical drug delivery compositions
US12830857 Abandoned US20100292139A1 (en) 2002-05-31 2010-07-06 Topical drug delivery using phosphatidylcholine
US13019101 Abandoned US20110123577A1 (en) 2002-05-31 2011-02-01 Method Of Delivering Stable Topical Drug Compositions
US13024689 Active US8273711B2 (en) 2002-05-31 2011-02-10 Topical drug delivery using phosphatidylcholine
US13926688 Abandoned US20130330380A1 (en) 2002-05-31 2013-06-25 Topical drug delivery using phosphatidylcholine
US13947353 Active 2023-08-29 US9050248B2 (en) 2002-05-31 2013-07-22 Methods of delivering stable topical drug compositions
US13947389 Abandoned US20130330381A1 (en) 2002-05-31 2013-07-22 Methods of delivering stable topical drug compositions
US13947329 Active 2023-08-17 US9060925B2 (en) 2002-05-31 2013-07-22 Methods of delivering stable topical drug compositions
US14296634 Abandoned US20150004196A1 (en) 2002-05-31 2014-06-05 Topical drug delivery using phosphatidylcholine
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US11334206 Abandoned US20060105955A1 (en) 2002-05-31 2006-01-18 Topical drug delivery using phosphatidylcholine
US11344442 Abandoned US20060127469A1 (en) 2002-05-31 2006-01-31 Methods of delivering stable topical drug compositions
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