EP0048280A1 - Composition pour la peau et les ongles contenant un complexe de phosphate-trialcanolamine - Google Patents

Composition pour la peau et les ongles contenant un complexe de phosphate-trialcanolamine

Info

Publication number
EP0048280A1
EP0048280A1 EP19810901083 EP81901083A EP0048280A1 EP 0048280 A1 EP0048280 A1 EP 0048280A1 EP 19810901083 EP19810901083 EP 19810901083 EP 81901083 A EP81901083 A EP 81901083A EP 0048280 A1 EP0048280 A1 EP 0048280A1
Authority
EP
European Patent Office
Prior art keywords
skin
topical
drug
phosphatide
lecithin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19810901083
Other languages
German (de)
English (en)
Inventor
Alec D. Keith
Philip Frest
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Key Pharmaceuticals Inc
Original Assignee
Key Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Key Pharmaceuticals Inc filed Critical Key Pharmaceuticals Inc
Publication of EP0048280A1 publication Critical patent/EP0048280A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A61K8/553—Phospholipids, e.g. lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/41—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63—Steroids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q3/00—Manicure or pedicure preparations

Definitions

  • the present invention provides a topical mode of applying drugs, including steroids and also drugs to clear up or prevent local skin conditions such as eczema.
  • drugs including steroids and also drugs to clear up or prevent local skin conditions such as eczema.
  • Critical to the present invention is the combination of the drug with a phosphatide that includes lecithin.
  • triethanolamine is also included.
  • the drugs are retained for a long period of time, permitting a pro ⁇ longed dispersal of the drug.
  • the phosphatides which can be used in the skin prepation of this invention include phosphatidyl choline (lecithin), phosphatidyl ethanolamine (cephalin), phosphatidyl serine, phosphatidyl inositol and phosphatidic acid.
  • lecithin phosphatidyl choline
  • cephalin phosphatidyl ethanolamine
  • phosphatidyl serine phosphatidyl serine
  • phosphatidyl inositol phosphatidic acid
  • a mixture of the above phosphatides can also be used.
  • the phosphatide should contain 10 to 40% lecithin.
  • soy phosphatide soy lecithin and egg phosphatide (egg lecithin) as the mixture of the phosphatides.
  • soy phosphatide soy lecithin and egg phosphatide (egg lecithin)
  • egg lecithin egg phosphatide
  • Such commercially available phosphatides contain various phosphatides and other components.
  • the amount of the phosphatides which are used in the skin preparation of this invention varies with the condi ⁇ tion or symptom to be treated, the formulation, and the kind and amount of the topically delivered drugs contained in the skin preparation.
  • the amount of the phosphatides is normally in the range of 0.5 ot 8% by weight, and preferably 1.5 to 5% by weight. If the phosphatide is used in too small amounts, the beneficial effects of this invention will be insufficient.
  • the effect of the skin preparation attained when the phosphatide is used in an excessive amount is not proportional to the amount of the phosphatide to be used, because the skin cannot absorb the excessive amount of the phosphatide.
  • the use of the excessive phosphatides causes stickiness. Therefore, in general, a not more than 5% composition will be satisfactory.
  • trial- kanolamines are used that may complex with the lecithin.
  • substituted and hindered trialkanolamines are considered such as triethanolamine and triisopropan- olamine.
  • the alkanolamine can be used in an amount of 0.2 to 25 moles per mole of the phosphatide, preferably 1 to 10 moles, and more preferably 1.5 to 5 moles are used.
  • aqueous mixture such as a solution, colloidal solution, emulsified lotion, oil-in-water cream (hydrophilic cream) and aqueous gel wherein the aqueous phase is the continuous one.
  • an oily mixture such as a solution, ointment, water-in-oil cream, gel base (e.g. Plastibase, a polyethylene and liquid petrolatum base), absorption base and hydrophilic ointment wherein the oil phase is the continuous one and a nonaqueous water-soluble base such as a mixture of polyethylene glycol.
  • a solution, ointment, water-in-oil cream, gel base e.g. Plastibase, a polyethylene and liquid petrolatum base
  • absorption base and hydrophilic ointment wherein the oil phase is the continuous one and a nonaqueous water-soluble base such as a mixture of polyethylene glycol.
  • Such water-in-oil formulations are especially useful in preventing transdermal water loss and serve as effective carriers for transdermal drug delivery.
  • a suspension base such as a shaking lotion, in which a solid dispersing agent is added can also be prepared.
  • Oily components, emulsifiers, dispersing agents, gelatinizers and solid materials which can be used to prepare such formulations are well known, as those used are in the preparation of cosmetics and topical products.
  • the oily components include hydrocarbons such as liquid paraffin, petrolatum, solid paraffin, microcrys- talline wax and the like; higher aliphatic alcolhols such as cetyl alcohol, hexadecyl alcohol, stearyl alcohol, oleyl alcohol and the like, esters of higher aliphatic alcohols such as bees wax, spermaceti and the like; esters of higher aliphatic acids with lower alcohols such as isopropyl myristate, isopropyl palmitate and the like, vegetable oils, modified vegetable oils, anhydrous lanolin and its derivative, squalene, squalane and the like. Higher aliphatic acids such as plamitic acid, stearic acid and the like can also be used. However, they should be used in a smaller amount, since they form a soap with alkanolamine.
  • Useful emulsifiers and dispersing agents include anionic, cationic and nonionic surfactants.
  • Nonionic surfactants are preferred because of their low level of irritation to skin.
  • Typical of nonionic surfactants are monoglycerides such as glyceryl monostearate and the like; sorbitan aliphatic esters such as sorbitan mono- laurate and the like; sucrose aliphatic esters; polyoxyethylene aliphatic esters such as polyoxyethylene stearate; and polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, polyoxyethylene fatty ethers and the like.
  • Gelatinizers include carboxymethylcellulose, cellulose gel, carbopol (carboxypolymethylene), polyvinyl alcohol, polyethylene glycol and various gums.
  • oily components emulsifiers, dispersing agents and gelatinizers can be used alone or in combination with each other.
  • Ethanol may be provided as a component of the skin composition, ethanol having bacteriostatic action and providing a cooling effect upon application to the skin.
  • antioxidants include butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, sodium pyrosulfite, acetone sodium bisulfate and the like.
  • the chelating agents include ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid, thioglycerol and the like.
  • the suitable antiseptics include methyl, ethyl, propyl and butyl esters of p-hydroxybenzoic acid, o-phenylphenol, dehydroacetic acid and the salts thereof, p-chloro-m-cresol, p-chloro-m-xylenol and the like.
  • the pH of the skin preparation of this invention by adding citric acid, lactic acid, tartaric acid or the like.
  • the pH value which should be adjusted to is dependent upon the stability of the skin preparation. In general, it is preferred that the skin preparation be slightly acidic to slightly alkaline.
  • a fragrance may be added in a slight amount, if desired.
  • the action of the drugs is strengthened, because the dispersion and retention in the skin of the drugs are enhanced to a considerable extent and pressure of the drugs maintained for a long period of time.
  • the phosphatide causing uniform distribution and release over the skin surface.
  • any drugs which are applicable to the skin can be used in the skin preparation of this invention.
  • topical steroid hormones such as hydrocortisone, prednisolone, methylprednisolone, dexamethasone, triamcinolone, triamcinolone acetonide, flumethasone, fluocinonide, beclomethasone, betamethasone, fluocinolone, fluorometholone, fludoxycortid, clometasone, clobetazol and their esters.
  • antibiotics such as kanamycin, erythromycin, tetracycline, gentamycin, fradiomycin, chloramphenicol and their salts
  • anti-mucotic agents such as griseofulvin, siccanin, trichomycin, nystatin, silver sulfadiazine, and the like
  • topical sulfa drugs such as sulfisoxazole and the like
  • topical antihistamines such as diphenhydramine, chlorphenilamine and the like
  • local anesthetics such as lidocaine, dibucaine, cyproheptazine and cocaine
  • non-steroidal antiinflammatory agents such as indomethacin, diflumidone, bufexamac and the like
  • anticoagulants such as heparin sodium
  • skin keratolytic agents such as urea, salicylic acid, resocinol, coal tar, anthralin and the like
  • agents such as heparin sodium
  • the opical steroid hormone can be applied in combination with one or more drugs of topical anticiotics, antihistaminics and antimycotic agents.
  • Anticancer drugs such as tetrahydrofluorouracil, fluorouracil, bleomycin, mitomycin and the like can also be applied to the skin preparation of this invention.
  • the amount of the .drugs to be added to the skin preparation should be determined on the basis of the activity of the drugs. When a larger amount of the drug is used, it is preferred to increase the amounts of the phosphatide and the alkanolamine to be used.
  • a drug can be added to the skin preparation either in the form of a solution in the oily components, water, propylene glycol, polyethylene glycol or ethanol, or in the form of a solid as it is or as pulverized powder.
  • the skin preparation of this invention containing a topical steriod hormone can be used to treat eczema, ichthyosis, lichen psoriasis and the like to attain the disappearance or alleviation of the sympton.
  • the skin preparation of this invention has the action of moisturizing and tenderizing skin and nail.
  • the skin preparation of the invention when used for the delivery of drugs, disperses and retains the drugs in the skin in a uniform manner. Therefore, the skin preparation of this invention is very useful for moisturizing skin, preventing keratinization, tenderizing nail and treating skin diseases.
  • OLEAGINOUS OINTMENT (A-l) Ointments prepared from petrolatum White petrolatum was melted on a water bath and warmed to about 70°C. The other ingredients were dispersed in the liquid paraffin and wnrmed to 70oC and then added to the petrolatum and v/as stirred until it congealed.
  • the above skin preparation has been tested on the skin and found to provide a good moisturizing effect.
  • the moisture barrier provided by the relatively large molecular complex (each mole of lecithin capable of complexing tightly with 10 to 12 molecules of water) and the lecithin staying near the surface due to the positively and negatively charged portions of the molecule, the skin preparation of the present invention provides relatively long protection for the skin against drying. Varying the ratio of triethanolamino to a phosphatide, tests have been made. Most advantageous effects have been found for 1 to 4 moles of triethanolamfne per mole of a phosphatide. Using these skin preparations, transepidermal water loss experiments were made.
  • Skin samples are obtained from fresh cadavers. All skin samples are from the abdominal area. Epidermis is separated from dermis by the procedure of Baumberger (J. of Natl. Cancer Inst. (US) 2, 413, 1941). Epidermal samples are wrapped in aluminum foil and are maintained at -20° until used.
  • Apparatus for transepidermal water loss is all glass with ground glass joints to secure the epidermis.
  • the opening in the apparatus over which the epidermis is placed occupied 2 cm 2 .
  • All of the apparatus is inside an analytical balance.
  • the balance chamber contains a humidity controller.
  • Weight measurements are made as a function of time.
  • Epidermal samples, about 2 cm on a side are placed onto the water reservoir portion of the TWL apparatus.
  • the open cover of the apparatus is clipped into place with the epidermis clamped between the ground glass surfaces.
  • the apparatus containing the epidermal sample and water is weighted. Thirty minutes are allowed for evaporation of surface water before measurements begin.
  • Gravimetric measurements allow for determinations of water loss to be made. 2-4 hours are required for steady state to be achieved. Measurements continue for several hours after steady state has been achieved.
  • the steady state rate at the 15th hour from the start of the measurement is used as the transdermal water loss rate.
  • the following skin preparations
  • the results are shown in the following table:
  • the transepidermal water loss (TWL) values represent averages of 3 sets of values carried out on 3 different samples of epidermal skin for each condition.
  • the data obtained with lipid extracted material (carried out with chloroform-methanol) demonstrate that the water loss through epidermis is substantially enhanced. This indicates that the barrier to water loss by epidermis and by stratum corneum is substantially determined by lipid content.
  • the untreated sample drops to a half value.
  • the rate of epidermal water loss of the epidermal skin sample treated with the conventional skin preparation decreases as the water content of the skin preparation decreases.
  • Topical steroid hormone skin preparations having the following composition were prepared.
  • Toneli method was used to measure the anti-inflammatory activity of this skin preparation [Endocrinology 77 625-634 (1965)].
  • a phlogistic solution comprising pyridine, ether and croton oil (50:45:5 V/V)) is applied to the right ear of the mouse and then the skin preparation is applied thereon. Five hours after the treatment, both of the ears are excised at a predetermined position and the wet weight of the ears are determined to calculate the edema ratio according to the following equation:
  • Inhibition ratio is calculated according to the following equation:
  • mice Ten male mice weighing 20 to 25 g are used as one group.
  • the skin preparation of this invention possesses higher anti-inflammatory activity as compared with the conventional ointment bases. Judging from these results, the pharmaceutical effects of the skin preparation of this invention are raised by the formation of a complex in which a phosphatide is non-convalently complexed with a steroid, because the complex increases the compatibility and retainability of the steroid in the skin.
  • the skin preparation having the following composition are prepared.
  • Anti-inflammatory activity is measured for the above skin preparations by skin carrageenan edema inhibition test.
  • the test is conducted by the following method.
  • Edema weight Edema skin weight - Normal skin weigh
  • Edema ratio Edema weight / Normal skin weight The results are shown in the following table.
  • the skin preparations having the following composition were prepared.

Abstract

Des medicaments topiques et des preparations pour la peau et les ongles comprennent un composant phosphatide (a) et un composant ethanolamine (b). Dans les preparations pour la peau et les ongles il n'est pas necessaire d'ajouter un troisieme composant, bien que des ingredients supplementaires puissent etre inclus. Dans le medicament topique, il y a trois composants, l'invention concernant les medicaments topiques etant une preparation d'application sur la peau d'un patient, qui contient un medicament pouvant traverser la peau pour produire un effet de soulagement topique, ce medicament topique comprenant un melange de: (a) au moins environ 1% en poids d'un phosphatide contenant de la lecithine, la quantite de lecithine dans le phosphatide etant d'environ 10% a environ 40% en poids; (b) au moins environ 0,2% en poids de triethanolamine; et (c) un medicament approprie a l'usage local du medicament topique sous une forme permettant la retention du medicament sur la peau du patient et protegeant la peau grace a la presence d'un complexe des composants (a) et (b).
EP19810901083 1980-03-26 1981-03-26 Composition pour la peau et les ongles contenant un complexe de phosphate-trialcanolamine Withdrawn EP0048280A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CA348458 1980-03-26
CA348,458A CA1134276A (fr) 1980-03-26 1980-03-26 Complexe d'alcanolamine et de phosphatide inferieur pour applications locales

Publications (1)

Publication Number Publication Date
EP0048280A1 true EP0048280A1 (fr) 1982-03-31

Family

ID=4116563

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19810901083 Withdrawn EP0048280A1 (fr) 1980-03-26 1981-03-26 Composition pour la peau et les ongles contenant un complexe de phosphate-trialcanolamine

Country Status (3)

Country Link
EP (1) EP0048280A1 (fr)
CA (1) CA1134276A (fr)
WO (1) WO1981002673A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3042365A1 (de) * 1980-11-10 1982-06-03 Harsanyi, Dr., Eugen, 5014 Kerpen Fluessige lecithin-haltige einphasige mehrstoffsysteme
JPS57167926A (en) * 1981-04-08 1982-10-16 Mitsubishi Chem Ind Ltd External base for skin
JPS58121209A (ja) * 1982-01-11 1983-07-19 Eisai Co Ltd 乳化型外用組成物
US5085856A (en) * 1990-07-25 1992-02-04 Elizabeth Arden Co., Division Of Conopco, Inc. Cosmetic water-in-oil emulsion lipstick comprising a phospholipid and glycerol fatty acid esters emulsifying system
EP0606590A1 (fr) * 1992-12-18 1994-07-20 Rhone-Poulenc Rorer Gmbh Composition pharmaceutique et/ou cosmétique contenant des N-acylalcanolamines et des N-acylphospho- ou lysophospholipides
US5552147A (en) * 1995-04-25 1996-09-03 Chesebrough-Pond's Usa Co., Division Of Conopco, Inc. Petroleum jelly with alpha hydroxy carboxylic acids
GB9610122D0 (en) 1996-05-15 1996-07-24 Reckitt & Colmann Prod Ltd Organic compositions
FR2777180A1 (fr) * 1998-04-10 1999-10-15 Lvmh Rech Compositions cosmetiques ou dermatologiques sous forme d'emulsions de type eau-dans-huile renfermant des hydrocarbures legers et des phospholipides et leur procede de preparation
BR9816113A (pt) 1998-12-23 2001-10-23 Idea Ag Formulação aperfeiçoada para aplicação tópica não-invasiva in vivo

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2484637A (en) * 1946-08-20 1949-10-11 Southern Res Inst Powdered ointment base of methyl cellulose and sorbitol
US2791534A (en) * 1952-12-18 1957-05-07 Ciba Ltd Cosmetic preparations
US3062721A (en) * 1957-03-20 1962-11-06 Grate Lorene Grigsby Skin care lotion
US3957971A (en) * 1974-07-29 1976-05-18 Lever Brothers Company Moisturizing units and moisturizing compositions containing the same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8102673A1 *

Also Published As

Publication number Publication date
CA1134276A (fr) 1982-10-26
WO1981002673A1 (fr) 1981-10-01

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Inventor name: KEITH, ALEC D.