CA1134276A - Phosphatide-lower alkanolamine complex for topical application - Google Patents
Phosphatide-lower alkanolamine complex for topical applicationInfo
- Publication number
- CA1134276A CA1134276A CA348,458A CA348458A CA1134276A CA 1134276 A CA1134276 A CA 1134276A CA 348458 A CA348458 A CA 348458A CA 1134276 A CA1134276 A CA 1134276A
- Authority
- CA
- Canada
- Prior art keywords
- preparation
- skin
- phosphatide
- skin preparation
- ointment
- 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.)
- Expired
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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Birds (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biophysics (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A preparntion for the treatment of skin and nail is disclosed which comprises a complex of a phosphatide containing about 10 to 40% by weight of lecithin and 0.2 to 10 moles of a lower alkanolamine per mole of phosphatide.
A preparntion for the treatment of skin and nail is disclosed which comprises a complex of a phosphatide containing about 10 to 40% by weight of lecithin and 0.2 to 10 moles of a lower alkanolamine per mole of phosphatide.
Description
.
~RIN ~YD NAIL COMPO~ITION GONTAINING
PHOSPHATIDE-TRIALK~NOL~TINE COMPLEX
_ This invention relates to a preparation for the treatment of skin and nails, referred to herein as a "skin preparation". More partieularly, this invention relates to a skin preparation having prolonged moisturizing action.
Furthermore, this invention relates to a skin preparation which is effective for ~ long period of time in dispersing and retaining drugs for topical delivery to a patient in a uniform manner in the topical zones of skin.
This invsntion is based upon t~e discovery that a complex of a phosphatide and an alkanolamine is particularly suited for keeping skin moist, and that the skin preparation of this invention, when applied to topically deliver drugs to a patient, disperses and retains the drugs in the topical zones of skin in a uniform manner for a longer period of time to render the drugs more effective.
Although the exace theory of the invention has not been conclusively established, it is believed that a comple~
of a phosphatide with an alkanolamine is formed, which has hydrophilic and hydrophobic end groups. W~en applied to skin, it interacts with a lipid and/or a phosph~tide in a double layer o~ lipids of the skin cells to be retained at the skin surface for a long period of time.
In addition, it is believed that each molecule of the complex closely binds 10 to 12 molecules of water, to the extent that the nature of the water molecule is sufficiently altered so that the water does not freeze (decreasing the transpiration of water from the skin). The comolex oi the phosphatide with the alkanolamine is believed to combine non-covalently with many drugs to dispers6 and retain them in the skin in a stable manner thereby permitting those drugs to e~ert their action effectively for a long period of time.
. ~ . .
~, . . . ~, . .
~RIN ~YD NAIL COMPO~ITION GONTAINING
PHOSPHATIDE-TRIALK~NOL~TINE COMPLEX
_ This invention relates to a preparation for the treatment of skin and nails, referred to herein as a "skin preparation". More partieularly, this invention relates to a skin preparation having prolonged moisturizing action.
Furthermore, this invention relates to a skin preparation which is effective for ~ long period of time in dispersing and retaining drugs for topical delivery to a patient in a uniform manner in the topical zones of skin.
This invsntion is based upon t~e discovery that a complex of a phosphatide and an alkanolamine is particularly suited for keeping skin moist, and that the skin preparation of this invention, when applied to topically deliver drugs to a patient, disperses and retains the drugs in the topical zones of skin in a uniform manner for a longer period of time to render the drugs more effective.
Although the exace theory of the invention has not been conclusively established, it is believed that a comple~
of a phosphatide with an alkanolamine is formed, which has hydrophilic and hydrophobic end groups. W~en applied to skin, it interacts with a lipid and/or a phosph~tide in a double layer o~ lipids of the skin cells to be retained at the skin surface for a long period of time.
In addition, it is believed that each molecule of the complex closely binds 10 to 12 molecules of water, to the extent that the nature of the water molecule is sufficiently altered so that the water does not freeze (decreasing the transpiration of water from the skin). The comolex oi the phosphatide with the alkanolamine is believed to combine non-covalently with many drugs to dispers6 and retain them in the skin in a stable manner thereby permitting those drugs to e~ert their action effectively for a long period of time.
. ~ . .
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-2- ~3~
It has been found that thin deformable films of appro~imately 2 to 50 micrometers thickness will form on the topical application of the skin preparation of this invention. The resultant film is permeable to atmospheric gas exchange and able to reduce the evaporative loss of water from the tissue surfaces. As described before, the skin preparation of this invention keeps skin moist.
Accordingly, the use of the skin preparation is particularly suited for the prevention o~ pathologically dry skin. In addition, this moisturizing action is believed to stren~then the action of topical drug delivery due to an effect similar to that of occlusive dressing technique.
The phosphatides which can be used in the skin preparation of this invention include phosphatidyl choline (lecithin), phosphatidyl ethanolamine (cephalin), phosphatidyl serine, phosphatidyl inositol and phosphatidic acid. A mi~ture of the above phosphatides can also be used. Optimally the phosphatide should contain 10 to ~0%
lecithin.
It is advanta~eous to use a commercially available lecithin containing a phosphatide mixture and especially soy phoSphRtide (30y lecithin) and egg phosphatide (egg lecithin) as the mi~ture of the phosphatides. 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 condition or symptom to be treated, the formulation, and the kind and amount of the topically delivered drugs contained in the skin preparation. ~owever, the amount of the phosphatides is normally in the range of 1 to 8~ by weight, and preferably 3 to ~ 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 e~cessive amount is not proportional to the ~mount of the phosphatide to be used, because the skin cannot ~bsorb the e~cessive amount of the phosphatide. In addition, the use of the e~cessive phosphatides causes stickiness. Therefore, ~-3~ 276 in general, a not more than 5~O composition will be satisfactory. The skin preparation of this invention, when applied to nail, may contain 15 to 30% by weight of phosphatides, because the nail can absorb more phosphatides, an optional preparation containing about 20% by weight. The alkanolamine which can be used in the skin preparation of this invention includes mono-, di-, and trialkanolamines~
Among these alkanolamines, substituted and hindered lower trialkanolamines are preferred.
Triethanolamine and triisopropanolamine are most preferred, because their safety for the human body has been proved.
Also useful are such isomers and homolo~s as tripropanolamine, tributanolanine and the like. The amount of the alkanolamine to be used is dependent upon the amount of the phosphatide to be used. If the al~anolamine is used in a smaller, less than equimolar amount, the phosphatide and the alkanolamine do not form the complex with each other to R sufficient e~tent. On the other hand, if the alkanolamine is used in an unnecessarily larger amount, the advantageous effect obtained does not correspond to the amount of the alkanolamine. 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.~ to 5 moles are used.
Depending upon the intended use of the skin preparation o~ this invention, other components can be incorporated into the skin preparation of this invention to prepare the skin preparation having various rheological properties.
For such formulations there can be used an aqueous mixture such as a solution, colloidal solution, emulsified lotion, oil-in-water cream (hydrophilic cream) and aqueous ~el wherein the aqueous phase is the continuous one.
For such formulations, there can also be used an oily mixture such as a solution, ointment, water-in-oil cream, gel base (e.~. Plastibase, a polyethylene and liquid petrolatum base), absorption base and hydrophilic ointment wherein the oil phase is the continuous one and a non-aqueous ~ater-soluble base such as a mi~ture of polyethylene . . ~
,,, .,:
~3~76 _4_ glycol. ~uch water-in-oil formulations are expecially 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 dispersin~ agent is added, ean 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, microcrystalline wax and the li~e; higher aliphatic alcohols 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 palmitic acid, stearic acid and the like can also be used. However, they should be used in a smaller arnount, since they form a soap with an al~anolamine.
Useful emulsifiers and dispersing agents inelude nnionic, 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 monolaurate and the like; sucrose aliphatic esters; polyo~yethylene aliphatic esters such as polyoxyethylene stearate; and polyoxyethylene higher alcohol ethers such as polyo~yethylene cetyl ether, polyoxyethylene oleyl ether, polyoxyethylene fatty ethers and the like.
Gelatinizers include carboxymethylcellulose, cellulose gel, carbopol (carboxypolymethylene), polyvinyl al~ohol, polyethylene glycol and various gums.
The`se oily components, emulsifiers, dispersing agents and gelatinizers can be used alone or in combination with each other.
, -_5_ ~3~7~
The incorporation into the skin preparation of this invention of propylene glycol~ glycerine, sorbitol or the like which have moisturizing action is preferred, because it enhances moisturizing action of the skin preparation of this invention.
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.
In order to increase the stability of the skin preparation of this invention and/or the drugs contained therein, it is preferred to add antioxidants, chelating agents, antiseptics and the like, if necessary. The antioxidants include butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, sodium pyrosulfite, acetone sodiurn bisulfate and the like. The chelating agents include ethylenedi~ninetetraacetic 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.
In addition, it is preferred to adjust the pH of the skin preparation of this in~ention 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 arnount, if desired.
~ hen the skin preparation of this invention is used for the delivery of drugs,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. Thus in the case of rnany steroids there appears to occur a complexing with the phosphatide causing uniform distribution~and release over the skin surface.
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-6- ~ ~3~27~
Any drugs which are applicable to the skin can be used in the skin preparlqtion of this invention. Examples of such drugs are topical steroid hormones such as hydrocortisone, prednisolone, methylprednisolone, dexamethasone, triarncinolone, triamcinolone aceton;de, flumethasone, fluocinonide, beclomethasone, betamethasone, fluocinolone, fluorometholone, fludoxycortid, clometasone, clobetazol and their esters.
Other drugs which can be applied to the skin preparation of this invention include topical antibiotics such as kanamycin, erythromycin, tetracycline, ~entamycin, fradiomycin, chloramphenicol and their salts; anti-mucotic agents such as griseofulvin, siccanin, trichomycin, nystatin, silver sulfadiazine, and the like; topical sulfa drugs such as sulfiso~azole and the like; topical antihistamines such as diphenhydramine, chlorphenilamine and the like; local anesthetics such as lidocaine, dibucaine, cyproheptazine and ***e; non-steroidal antiinflammatory agents such as indomethacin, diflumidone, bufe~amac and the like; anticoagulants such as heparin sodiurn; skin keratolytic agents such as urea, salicylic acid, resorcinol, coal tar, anthralin and the like; agents affecting pigmentation such as methozalen and the likes; vitamins such as vitamin A, vitamin E and the like; sex hormones such as ethinyl estradiol, testosterone, progesterone and the like;
antianginal drugs such as isosorbide dinitrate, nitroglycerin, verapamil, prenilarnine and the like; beta-blocking agents such as propanolol, pindolol, alprenolol and the like; antihypertensive agents such as hydralazine, reserpine, clonidine and the like and bronchodilators such as isoproterenol, meta-proterenol and the like; antiallergic agents such as cromolyn sodium and the like and antiserotonergic agents such as cyproheptazine.
The topical steroid hormone can be applied in combination with one or more drugs of topical antibiotics, antihistaminics and antimycotie agents.
Anticancer drugs such as tetrahydro~luorouracil, flourouracil, bleomycin, mitomycin and the like can also be applied to the skin preparation of this invention.
,. . ;
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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 eomponents, water, propylene glycol, polyethylene glycol or ethanol, or in the form of a solid as it is or as pulverized powder.
The symptoms of patients with a dry skin condition disappear or are alleviated by applica~ion of the skin preparation of this invention.
The skin preparation of this invention may also be used to treat burn victims to protect fro~ fluid loss. It has been found that thin deformable layers of approximately to 50 micrometers thickness will form upon the topical application of the skin preparation of this invention to a subject, which provides a strong flexible film. The resultant film is both permeable to atmospheric gas exchange and able to reduce the evaporative loss of water from the tissue surfaces. Silver sulfadiazine can be included in the skin preparation to avoid wound infection.
The skin preparation of this invention containing a topical steroid hormone can be used to treat eczema, ichthyosis, lichen psoriasis and the like to attain the disappearance or alleviation of the sympton. ~s described above, the sk;n preparation of this invention has the action of moisturizing and tenderizing skin and nail. In addition, 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.
8eyond the general description of this invention, a more complete understanding can be obtained by ex~nples ~hich are provided herein for purposes of illustration only and are not intended to be limiting in any manner.
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7~
A. OLEAGINOUS OINTMENT
(A-l) Ointments prepared from petrolat~m White petrolatum was melted on a water bath and warmed to about 70C. The other ingredients were dispersed in the liquid paraffin and warmed to 70C
and then added to the petrolatum and was stirred until it congealed.
(A-2) Ointments ere~ared from Plastibase All of the components are combined and stirred to obtain a uniform mixture.
B. POLYETHYLENE GLYCOL OINTM~NT
Polyethylene glycol 400 was heated on a water bath at 60 to 70C. Polyethylene glycol 400 and the other ingredients, previously dispersed in the liquid paraffin, wera added to this melt with stirring. Stirring was continued until the solidification takes place.
C. ~BSORPTION OINTMENT
Cetyl alcohol and white petrolatum were melted on a water bath, then the other ingredients were added to this melt and the mixture was heated to about 75C with stirring. Next, the deionized water was heated to the same temperature and added. The mixture was stirred until it congealed.
D. OIL-IN-WAT~R CRE~M (HYDROPHILIC OINTMENT) Stearyl alcohol, cetyl alcohol, polyoxyethylene 45 monostearate and white petrolatum were melted on a water bath, then the other ingredients were added to this melt and the mi~ture was heated to about 75C with stirring. Next, the deionized water was heated to the same temperature and added. The mi~ture was stirred until it congealed.
:
,.~ ~. . , ;
9 ~34276 E~ample 1 Oil-In-Water Cream The following skin preparation was made:
White petrolatum g.9% by weight liquid paraffin 12.9 stearyl alcohol 5.0 Cetyl alcohol 2.1 SLP-~.~ite (powdery soy 4.0 lecithin having a phos-phatide content of 95~) Triethanolamine 0.8 Citric acid monohydrate 0.35 Dibutyl hydroxytoluene 0.025 Polyo~yethylene 1000 cetyl ether 4.0 p-Chloro-m-cresol 0.2 ~eionized water remainder 1 00~6 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 (esch mols 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.
~lost advantageous effects have been found for 1 to 4 moles of triethanolamine per mole of a phosphatide.
. , ,: ,.
- .......................... ..... .
, :: :, ::: ., ~ 3~76 Eg~LES 2 to 5 The following skin preparations were made:
Polyethylene o/w Oleaginous Glycol Absor?tion cream Ointment Ointment Ointment _ EX~MPLE
No.
Composition _ 2 3 _ 4 5 SLP^~Yhite (Soybean lecithin) 4.0 4.0 4.0 4.0 Triisopropanolamine 1.0 1.0 1.0 1.0 Lactic Acid 0.58 0-.58 0.58 0.58 Butylated hydroxytoluene 0.025 0.025 0.025 0,025 tVhite petrolatum 9.9 ~ - 10.0 40.0 liquid paraffin 12.9 - - -Plastibase 50 W
(polyethylene and llquid petrolatum base) = ~ 94.395 ~ -Stearyl alcohol ~ 5.0 Cetyl alcohol 2.1 - - 18.0 Polyethylene glycol 4000 - - ~1.395 Sorbitan Sesquioleate - - - 5,0 Polyoxyethylene 45 Monostearate 4.0 Polyoxyethylene lauryl ether p-Chloro-m-cresol 0.2 - ~ 0.2 Deionized water 60.745 - -- 30.695 Total (~ by weight) 100.0 100.0 100.0 100.0 - : ', ..
. ~
- ~ . : : ,.
:: ' , : ?
' . :' :
: ' ' -~, , ": ' '' : ' '. . ;' '
It has been found that thin deformable films of appro~imately 2 to 50 micrometers thickness will form on the topical application of the skin preparation of this invention. The resultant film is permeable to atmospheric gas exchange and able to reduce the evaporative loss of water from the tissue surfaces. As described before, the skin preparation of this invention keeps skin moist.
Accordingly, the use of the skin preparation is particularly suited for the prevention o~ pathologically dry skin. In addition, this moisturizing action is believed to stren~then the action of topical drug delivery due to an effect similar to that of occlusive dressing technique.
The phosphatides which can be used in the skin preparation of this invention include phosphatidyl choline (lecithin), phosphatidyl ethanolamine (cephalin), phosphatidyl serine, phosphatidyl inositol and phosphatidic acid. A mi~ture of the above phosphatides can also be used. Optimally the phosphatide should contain 10 to ~0%
lecithin.
It is advanta~eous to use a commercially available lecithin containing a phosphatide mixture and especially soy phoSphRtide (30y lecithin) and egg phosphatide (egg lecithin) as the mi~ture of the phosphatides. 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 condition or symptom to be treated, the formulation, and the kind and amount of the topically delivered drugs contained in the skin preparation. ~owever, the amount of the phosphatides is normally in the range of 1 to 8~ by weight, and preferably 3 to ~ 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 e~cessive amount is not proportional to the ~mount of the phosphatide to be used, because the skin cannot ~bsorb the e~cessive amount of the phosphatide. In addition, the use of the e~cessive phosphatides causes stickiness. Therefore, ~-3~ 276 in general, a not more than 5~O composition will be satisfactory. The skin preparation of this invention, when applied to nail, may contain 15 to 30% by weight of phosphatides, because the nail can absorb more phosphatides, an optional preparation containing about 20% by weight. The alkanolamine which can be used in the skin preparation of this invention includes mono-, di-, and trialkanolamines~
Among these alkanolamines, substituted and hindered lower trialkanolamines are preferred.
Triethanolamine and triisopropanolamine are most preferred, because their safety for the human body has been proved.
Also useful are such isomers and homolo~s as tripropanolamine, tributanolanine and the like. The amount of the alkanolamine to be used is dependent upon the amount of the phosphatide to be used. If the al~anolamine is used in a smaller, less than equimolar amount, the phosphatide and the alkanolamine do not form the complex with each other to R sufficient e~tent. On the other hand, if the alkanolamine is used in an unnecessarily larger amount, the advantageous effect obtained does not correspond to the amount of the alkanolamine. 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.~ to 5 moles are used.
Depending upon the intended use of the skin preparation o~ this invention, other components can be incorporated into the skin preparation of this invention to prepare the skin preparation having various rheological properties.
For such formulations there can be used an aqueous mixture such as a solution, colloidal solution, emulsified lotion, oil-in-water cream (hydrophilic cream) and aqueous ~el wherein the aqueous phase is the continuous one.
For such formulations, there can also be used an oily mixture such as a solution, ointment, water-in-oil cream, gel base (e.~. Plastibase, a polyethylene and liquid petrolatum base), absorption base and hydrophilic ointment wherein the oil phase is the continuous one and a non-aqueous ~ater-soluble base such as a mi~ture of polyethylene . . ~
,,, .,:
~3~76 _4_ glycol. ~uch water-in-oil formulations are expecially 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 dispersin~ agent is added, ean 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, microcrystalline wax and the li~e; higher aliphatic alcohols 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 palmitic acid, stearic acid and the like can also be used. However, they should be used in a smaller arnount, since they form a soap with an al~anolamine.
Useful emulsifiers and dispersing agents inelude nnionic, 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 monolaurate and the like; sucrose aliphatic esters; polyo~yethylene aliphatic esters such as polyoxyethylene stearate; and polyoxyethylene higher alcohol ethers such as polyo~yethylene cetyl ether, polyoxyethylene oleyl ether, polyoxyethylene fatty ethers and the like.
Gelatinizers include carboxymethylcellulose, cellulose gel, carbopol (carboxypolymethylene), polyvinyl al~ohol, polyethylene glycol and various gums.
The`se oily components, emulsifiers, dispersing agents and gelatinizers can be used alone or in combination with each other.
, -_5_ ~3~7~
The incorporation into the skin preparation of this invention of propylene glycol~ glycerine, sorbitol or the like which have moisturizing action is preferred, because it enhances moisturizing action of the skin preparation of this invention.
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.
In order to increase the stability of the skin preparation of this invention and/or the drugs contained therein, it is preferred to add antioxidants, chelating agents, antiseptics and the like, if necessary. The antioxidants include butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, sodium pyrosulfite, acetone sodiurn bisulfate and the like. The chelating agents include ethylenedi~ninetetraacetic 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.
In addition, it is preferred to adjust the pH of the skin preparation of this in~ention 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 arnount, if desired.
~ hen the skin preparation of this invention is used for the delivery of drugs,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. Thus in the case of rnany steroids there appears to occur a complexing with the phosphatide causing uniform distribution~and release over the skin surface.
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Any drugs which are applicable to the skin can be used in the skin preparlqtion of this invention. Examples of such drugs are topical steroid hormones such as hydrocortisone, prednisolone, methylprednisolone, dexamethasone, triarncinolone, triamcinolone aceton;de, flumethasone, fluocinonide, beclomethasone, betamethasone, fluocinolone, fluorometholone, fludoxycortid, clometasone, clobetazol and their esters.
Other drugs which can be applied to the skin preparation of this invention include topical antibiotics such as kanamycin, erythromycin, tetracycline, ~entamycin, fradiomycin, chloramphenicol and their salts; anti-mucotic agents such as griseofulvin, siccanin, trichomycin, nystatin, silver sulfadiazine, and the like; topical sulfa drugs such as sulfiso~azole and the like; topical antihistamines such as diphenhydramine, chlorphenilamine and the like; local anesthetics such as lidocaine, dibucaine, cyproheptazine and ***e; non-steroidal antiinflammatory agents such as indomethacin, diflumidone, bufe~amac and the like; anticoagulants such as heparin sodiurn; skin keratolytic agents such as urea, salicylic acid, resorcinol, coal tar, anthralin and the like; agents affecting pigmentation such as methozalen and the likes; vitamins such as vitamin A, vitamin E and the like; sex hormones such as ethinyl estradiol, testosterone, progesterone and the like;
antianginal drugs such as isosorbide dinitrate, nitroglycerin, verapamil, prenilarnine and the like; beta-blocking agents such as propanolol, pindolol, alprenolol and the like; antihypertensive agents such as hydralazine, reserpine, clonidine and the like and bronchodilators such as isoproterenol, meta-proterenol and the like; antiallergic agents such as cromolyn sodium and the like and antiserotonergic agents such as cyproheptazine.
The topical steroid hormone can be applied in combination with one or more drugs of topical antibiotics, antihistaminics and antimycotie agents.
Anticancer drugs such as tetrahydro~luorouracil, flourouracil, bleomycin, mitomycin and the like can also be applied to the skin preparation of this invention.
,. . ;
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_7_ ~3~7~
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 eomponents, water, propylene glycol, polyethylene glycol or ethanol, or in the form of a solid as it is or as pulverized powder.
The symptoms of patients with a dry skin condition disappear or are alleviated by applica~ion of the skin preparation of this invention.
The skin preparation of this invention may also be used to treat burn victims to protect fro~ fluid loss. It has been found that thin deformable layers of approximately to 50 micrometers thickness will form upon the topical application of the skin preparation of this invention to a subject, which provides a strong flexible film. The resultant film is both permeable to atmospheric gas exchange and able to reduce the evaporative loss of water from the tissue surfaces. Silver sulfadiazine can be included in the skin preparation to avoid wound infection.
The skin preparation of this invention containing a topical steroid hormone can be used to treat eczema, ichthyosis, lichen psoriasis and the like to attain the disappearance or alleviation of the sympton. ~s described above, the sk;n preparation of this invention has the action of moisturizing and tenderizing skin and nail. In addition, 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.
8eyond the general description of this invention, a more complete understanding can be obtained by ex~nples ~hich are provided herein for purposes of illustration only and are not intended to be limiting in any manner.
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A. OLEAGINOUS OINTMENT
(A-l) Ointments prepared from petrolat~m White petrolatum was melted on a water bath and warmed to about 70C. The other ingredients were dispersed in the liquid paraffin and warmed to 70C
and then added to the petrolatum and was stirred until it congealed.
(A-2) Ointments ere~ared from Plastibase All of the components are combined and stirred to obtain a uniform mixture.
B. POLYETHYLENE GLYCOL OINTM~NT
Polyethylene glycol 400 was heated on a water bath at 60 to 70C. Polyethylene glycol 400 and the other ingredients, previously dispersed in the liquid paraffin, wera added to this melt with stirring. Stirring was continued until the solidification takes place.
C. ~BSORPTION OINTMENT
Cetyl alcohol and white petrolatum were melted on a water bath, then the other ingredients were added to this melt and the mixture was heated to about 75C with stirring. Next, the deionized water was heated to the same temperature and added. The mixture was stirred until it congealed.
D. OIL-IN-WAT~R CRE~M (HYDROPHILIC OINTMENT) Stearyl alcohol, cetyl alcohol, polyoxyethylene 45 monostearate and white petrolatum were melted on a water bath, then the other ingredients were added to this melt and the mi~ture was heated to about 75C with stirring. Next, the deionized water was heated to the same temperature and added. The mi~ture was stirred until it congealed.
:
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9 ~34276 E~ample 1 Oil-In-Water Cream The following skin preparation was made:
White petrolatum g.9% by weight liquid paraffin 12.9 stearyl alcohol 5.0 Cetyl alcohol 2.1 SLP-~.~ite (powdery soy 4.0 lecithin having a phos-phatide content of 95~) Triethanolamine 0.8 Citric acid monohydrate 0.35 Dibutyl hydroxytoluene 0.025 Polyo~yethylene 1000 cetyl ether 4.0 p-Chloro-m-cresol 0.2 ~eionized water remainder 1 00~6 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 (esch mols 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.
~lost advantageous effects have been found for 1 to 4 moles of triethanolamine per mole of a phosphatide.
. , ,: ,.
- .......................... ..... .
, :: :, ::: ., ~ 3~76 Eg~LES 2 to 5 The following skin preparations were made:
Polyethylene o/w Oleaginous Glycol Absor?tion cream Ointment Ointment Ointment _ EX~MPLE
No.
Composition _ 2 3 _ 4 5 SLP^~Yhite (Soybean lecithin) 4.0 4.0 4.0 4.0 Triisopropanolamine 1.0 1.0 1.0 1.0 Lactic Acid 0.58 0-.58 0.58 0.58 Butylated hydroxytoluene 0.025 0.025 0.025 0,025 tVhite petrolatum 9.9 ~ - 10.0 40.0 liquid paraffin 12.9 - - -Plastibase 50 W
(polyethylene and llquid petrolatum base) = ~ 94.395 ~ -Stearyl alcohol ~ 5.0 Cetyl alcohol 2.1 - - 18.0 Polyethylene glycol 4000 - - ~1.395 Sorbitan Sesquioleate - - - 5,0 Polyoxyethylene 45 Monostearate 4.0 Polyoxyethylene lauryl ether p-Chloro-m-cresol 0.2 - ~ 0.2 Deionized water 60.745 - -- 30.695 Total (~ by weight) 100.0 100.0 100.0 100.0 - : ', ..
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3~ 6 Using these skin preparations, transepidermal water loss e~periments were made.
I. 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.
II. ~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 cm2. All of the apparatus is placed inside an analytical balanee. 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 th-e 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 weighed. Thirty minutes are allowed for evaporation of surface water before measurements begin. ~ravimetric measurements allow for determinations of water loss to be made. 2-4 hours are required for s-teady state to be achieved. ~easurements 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.
- , : . ,;
- . .. ~
- - . : :. . : -. . ~.~ .
-12- ~3~6 The following skin preparations were used as references:
Cream Oleaginous Ointment . . . _ _ . . .. .. . . ... ..
Comparative Skin Preparation A B C
Composition _ _ _ ~ite petrolatum 9.9--~ - 100 Liquid paraffin 1~.9 Plastibase 50W - 100 Stearyl alcohol 5.0 Cetyl alcohol 2.1 Polyoxyethylene cetyl ether 1.7 - -P-Chloro-M-Cresol 0.1 Deionized water 68.3 Total (% by weight) 100.0 100.0 100.0 .
The results are shown in the following table:
Rate of Epiderm~l Water Loss (mg H2O/cm -hour) (at the 15th hour from Skin Preparationthe start of the experiment Untreated epidermal sample 0.49 llpid e~tracted material 1~0 carried out wlth CHC13/MeOH
Skin Preparation A 0.44 " 8 0.065 n C
Skin Preparation 2 0.25 " 3 ~.041 rt 4 0.055 " 5 0.13 -~.
" - ,: .~: .,. , :
. . : . ,: : :
-13- ~34~76 The transepidermal water loss (~L) values represent averages of 3 sets o 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) demons.rate that the water loss through epidermis is substantially enhanced. This indicates that the barrier to water loss by epidermis and by stratum corneum is sustantially 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. Although a decrease in the rate of epidermal water loss of the epidermal skin sample treated according to this invention is accompanied by a decrease in the water content of the skin preparation, the decrease is always smaller than that of the conventional skin preparation compared at the same water content. This demonstrates that phosphatide and triisopropanolamine contained in the skin preparation of this invention suppress the water loss.
F~LES 6, 6', 6", 7, 7' and 8 Topical ~teroid hormone skin preparstions having the following composition were prepared.
~L~3a~Llf~11~6 \
\ O U~ U~ 0 \ ~ lllo O, U~
~CO O C~ ~ O O U~ O O
1~ ~roOO I~ 1 1 lo _ ~ \
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t~ \ ~ I I I ~ I I I U~OOL~
O, U~ L7 ~1 ~ ~ U~ O
~ 0 ~ ~ 0 0 0 0 ~ ~ ~ 0 ~ ~r o' o o' o I I I ",~ O' ~; O
~ _ b u~ \ o ~ o ~ ~ ~ o ~ o ~ o ~ \ a~ I I o~o o O CO D O U~ O
~ ~ro'o'o' I I ~ I I I I I I I I I o U~ ,, o ' ' ~o o co ~o o a~ o ~ o ~ er O
...... .. . ...
~ ~r o o o ~ I I ~oo ~ I oo ~ / ~ oo ~
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I ~ a~
/ a~ o ~ ~ ~ ~ ~ 3 ~
/ ~ J `~ ~ (O ~1 o .~ h ~ 3 / ~O O ~ O o ~ 0 `~ ~
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/ O o r` >1 ~ ~ ~ ~ 5 rC ~1 ~1 ~ a~ O O O o O a) O
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The Toneli method was used to measure the anti-inflammatory QCtivity of this skin preparation (Endocrinology 77 625-634 (196~)).
A ph1Ogistic solution comprising pyridine, ether and croton oil (50:~5:5 (V/V)) is applied to the right ear of the mouse and then the skin prepartion is applied thereon. Eive hours after the treatment, both o~ the ears are excised at a predetermined position and the wet weights of the ears are determined to calculate the edema ratio according to the following equation:
Edema Ratio (~) = (Weight of Left Ear ~ 1) ~ 100 Inhibition ratio is calculated according to the following equation:
~nhibition Ratio (~) Edema r~tio when treated with ointment) = (1 - '''~-'~`~--Edema ratio when untreated ---- x 100 Ten male mice weighing 20 to 25 g are used as one group. The results are shown in the following table, '''~~Dr~ Preparaticn '' Edemfl Ratio Inhibition Effect*
%Ratio (?6) _ Ex~mple 6 22.9 7T.9 +++
~eclomethasone Example 6 2~.1 -7T.7 +++
17, 21-dipropionate Comparative D32.8 68.4 ++
~ Example 7 39.1 62.3 Hydrocortisone Comparative E -lS.l 56.5 Example 8 35.7 65.5 ++
Prednisolone Comparative F40.2 61.2 ++
Untreated 10~.6 0 Score Inhibition ~atio +++ -75-100%
++ 50-75~
+ 25-5~%
- 0-25%
., : . . .
- 1 s~ 3~7~;
As is apparent from the above table, 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.
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EY~.~LES 9, 10 and 101 The skin preparation having the following composition are prepared.
. _ . . ..
Oleaginous o/w cream Absorption _ Ointment _ _ _ Ointment Example No. Example Compara- Example Compara- Example tive tive Com~osition ~9) _ (G) (10) ~H)__ _ (10') Hydrocortisone 17-butylate 0.1 0.1 - - -Indomethacin - - 1.0 1.0 1-.0 ____________________________________________________________ SLP-White 4.0 - ~ 4.0 - 4.0 (Soy lecithin) Triisopro-panolamine 1.0 - 1.0 - 1.0 Lactic acid 0.58 - 0.58 - 0.58 Butylated hydroxytoluene0.025 - 0.025 - 0.025 ~ite Petrolatum - - 9.9 9.9 40.0 Liquid paraffin - - 12.9 12.9 Plastihase 50W94.29299.9 Stearyl alcohol - - 5.0 5.0 Cetyl alcohol - - 2.1 2.1 -18.0 Polyoxyethylene 45-monostearate - -- 4.0 4.0 p-Chloro-m-cresol - -- 0.2 0.2 0.2 ~eionized water - - qs qs 29.695 Sorbitan sesquioleate - - - -~~ 5.0 Polyoxyethylene lauryether - - - - o.5 _~ , Total (w/w~) 100.0 100.0 100.0 100.0 100.0 , ~ " . :
- , , -: ., -. . : , -18- ~3~7~
Anti-inflammatory activity is measured for the above skin preparations by skin carrageenan edema inhibition test. The test is condu~ted by the following method.
Male rats weighing 190-210 g are used in the following test. Their side abdominal hair is removed before the start of this test. 1~ carrageenin solution is injected intra-dermally at a predetermined position from each side of the abdomen.
Immediately after carrageenin injection, 1 ml of 1% pontamine sky blue saline is administered intravenously. ~urthermoe~ an accurately determined volume of topical formulation is applied on the surface of the abdominal skin.
Five hours after the treatment, the abdominal skin is removed from the body and score as to the following items.
Dye lealcage at the iniection site Calculated by measuring the ma~imum and minimum diameter of the dye blue spot.
Edema skin weight Calculated by measuring the weight of the perforated edema skin (lcm ~ lcm = round shape) _________________________________________________________________ Edema weight = Edema skin weight - Normal skin weight Edema ratio = Edema weight / Normal skin weight The results are shown in the following table.
- :
-19~ 6 _ . ... ... _ Hydrocortisone 17-alpha-butyrate - 0.1%
Example Comparative Untreated (9) (G) _ _ Edema weight -58.4 72.9- 111.7 (mg) ~47.7~) -(~-34~.7%) ( - ) Edema ratio 79.4 ~99.7 142.8 (--4~.~) (-30.2%) ( - ) ~lue ~rea 6S.7 79.3 123.3 (mm ) (-44.3~) (-35-.5~) ( _ ) ____________________________________________________________ Effect ++ ++
. . . _ . ~
Indomethacin 1~
E~ample Comparative Untreated (10) (H) _ Edema weight 51.6 62.9 - 67.6 (mg) (-23.7%) (- 7.0~) ( - ) Edema ratio -68.9 - -86.9 90.8-(-24.1~) (- 4.3~) ( - ) Blue area 72.5 68.2 77.9-(mm~) (- 6.9~) (-12.5%) ( - ) _________~__________________________________________________ Effect +
.. ~ . _ .
Score ~+ Inhibition ratio3~-45%
+ 15-30~
_ 0-15%
As is apparent from the above table, the skin preparation of this invention possesses higher anti-inflammatory aetivity as compared with the conventional topical formulations.
., ., .
.
: " .
-2~-~ .~.3~
Eg~MPLES 11 and 11' The skin preparations having the following composition were prepared.
o/w cre~m ~bsorption Ointment _ Example 11 ~xample 11' Chlorpheniramine Maleate 1.0 % by weight1.0 White petrolatum g.9 40.0 Liquid paraffin 12.9 Stearyl alcohol 5.0 Cetyl alcohol 2.1 18.0 SLP-White (Soy lecithin) 4.0 4.0 Triethanolamine 0.8 0.8 Citric acid monohydrate 0.35 0.3s Butylated hydroxytoluene 0.025 0.025 Polyo~yethylene 45-monostearate 4.0 p-Chloro-m-cresol 0.2 0.2 ~eionized water qs 30.125 Sorbitan sesquioleat - 5.0 Polyo~yethylene laurylether - 0,5 Total (~ by weight) 100.0 100.0 The above skin preparation has been tested on the guinea-pig baak skin and found to be more effective in preventing vascular permeability increase caused by 0.1% histamine 0.05 ml as compared with the conventional ointment bases.
.; , ,
I. 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.
II. ~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 cm2. All of the apparatus is placed inside an analytical balanee. 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 th-e 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 weighed. Thirty minutes are allowed for evaporation of surface water before measurements begin. ~ravimetric measurements allow for determinations of water loss to be made. 2-4 hours are required for s-teady state to be achieved. ~easurements 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.
- , : . ,;
- . .. ~
- - . : :. . : -. . ~.~ .
-12- ~3~6 The following skin preparations were used as references:
Cream Oleaginous Ointment . . . _ _ . . .. .. . . ... ..
Comparative Skin Preparation A B C
Composition _ _ _ ~ite petrolatum 9.9--~ - 100 Liquid paraffin 1~.9 Plastibase 50W - 100 Stearyl alcohol 5.0 Cetyl alcohol 2.1 Polyoxyethylene cetyl ether 1.7 - -P-Chloro-M-Cresol 0.1 Deionized water 68.3 Total (% by weight) 100.0 100.0 100.0 .
The results are shown in the following table:
Rate of Epiderm~l Water Loss (mg H2O/cm -hour) (at the 15th hour from Skin Preparationthe start of the experiment Untreated epidermal sample 0.49 llpid e~tracted material 1~0 carried out wlth CHC13/MeOH
Skin Preparation A 0.44 " 8 0.065 n C
Skin Preparation 2 0.25 " 3 ~.041 rt 4 0.055 " 5 0.13 -~.
" - ,: .~: .,. , :
. . : . ,: : :
-13- ~34~76 The transepidermal water loss (~L) values represent averages of 3 sets o 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) demons.rate that the water loss through epidermis is substantially enhanced. This indicates that the barrier to water loss by epidermis and by stratum corneum is sustantially 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. Although a decrease in the rate of epidermal water loss of the epidermal skin sample treated according to this invention is accompanied by a decrease in the water content of the skin preparation, the decrease is always smaller than that of the conventional skin preparation compared at the same water content. This demonstrates that phosphatide and triisopropanolamine contained in the skin preparation of this invention suppress the water loss.
F~LES 6, 6', 6", 7, 7' and 8 Topical ~teroid hormone skin preparstions having the following composition were prepared.
~L~3a~Llf~11~6 \
\ O U~ U~ 0 \ ~ lllo O, U~
~CO O C~ ~ O O U~ O O
1~ ~roOO I~ 1 1 lo _ ~ \
~ \ O O OU~OO
t~ \ ~ I I I ~ I I I U~OOL~
O, U~ L7 ~1 ~ ~ U~ O
~ 0 ~ ~ 0 0 0 0 ~ ~ ~ 0 ~ ~r o' o o' o I I I ",~ O' ~; O
~ _ b u~ \ o ~ o ~ ~ ~ o ~ o ~ o ~ \ a~ I I o~o o O CO D O U~ O
~ ~ro'o'o' I I ~ I I I I I I I I I o U~ ,, o ' ' ~o o co ~o o a~ o ~ o ~ er O
...... .. . ...
~ ~r o o o ~ I I ~oo ~ I oo ~ / ~ oo ~
~ / ~ o ~
I ~ a~
/ a~ o ~ ~ ~ ~ ~ 3 ~
/ ~ J `~ ~ (O ~1 o .~ h ~ 3 / ~O O ~ O o ~ 0 `~ ~
/ ~ ~
,1 O--~ ~ O ~ ,h / ~ U~ ~ ~
/ O o r` >1 ~ ~ ~ ~ 5 rC ~1 ~1 ~ a~ O O O o O a) O
, c~ ~ ~ m x ~ , ~ .
~4 . , , . ~ ..
: , .
- - ~
,. . , ... ~ . , ... ..... .. . .
-15- ~ ~3~2~
The Toneli method was used to measure the anti-inflammatory QCtivity of this skin preparation (Endocrinology 77 625-634 (196~)).
A ph1Ogistic solution comprising pyridine, ether and croton oil (50:~5:5 (V/V)) is applied to the right ear of the mouse and then the skin prepartion is applied thereon. Eive hours after the treatment, both o~ the ears are excised at a predetermined position and the wet weights of the ears are determined to calculate the edema ratio according to the following equation:
Edema Ratio (~) = (Weight of Left Ear ~ 1) ~ 100 Inhibition ratio is calculated according to the following equation:
~nhibition Ratio (~) Edema r~tio when treated with ointment) = (1 - '''~-'~`~--Edema ratio when untreated ---- x 100 Ten male mice weighing 20 to 25 g are used as one group. The results are shown in the following table, '''~~Dr~ Preparaticn '' Edemfl Ratio Inhibition Effect*
%Ratio (?6) _ Ex~mple 6 22.9 7T.9 +++
~eclomethasone Example 6 2~.1 -7T.7 +++
17, 21-dipropionate Comparative D32.8 68.4 ++
~ Example 7 39.1 62.3 Hydrocortisone Comparative E -lS.l 56.5 Example 8 35.7 65.5 ++
Prednisolone Comparative F40.2 61.2 ++
Untreated 10~.6 0 Score Inhibition ~atio +++ -75-100%
++ 50-75~
+ 25-5~%
- 0-25%
., : . . .
- 1 s~ 3~7~;
As is apparent from the above table, 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.
..
:.'' ' :. . ' ' :
., . "
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., ,' ,.. '' ' ~ ' ' ~'~ ' , -17- ~3~2~
EY~.~LES 9, 10 and 101 The skin preparation having the following composition are prepared.
. _ . . ..
Oleaginous o/w cream Absorption _ Ointment _ _ _ Ointment Example No. Example Compara- Example Compara- Example tive tive Com~osition ~9) _ (G) (10) ~H)__ _ (10') Hydrocortisone 17-butylate 0.1 0.1 - - -Indomethacin - - 1.0 1.0 1-.0 ____________________________________________________________ SLP-White 4.0 - ~ 4.0 - 4.0 (Soy lecithin) Triisopro-panolamine 1.0 - 1.0 - 1.0 Lactic acid 0.58 - 0.58 - 0.58 Butylated hydroxytoluene0.025 - 0.025 - 0.025 ~ite Petrolatum - - 9.9 9.9 40.0 Liquid paraffin - - 12.9 12.9 Plastihase 50W94.29299.9 Stearyl alcohol - - 5.0 5.0 Cetyl alcohol - - 2.1 2.1 -18.0 Polyoxyethylene 45-monostearate - -- 4.0 4.0 p-Chloro-m-cresol - -- 0.2 0.2 0.2 ~eionized water - - qs qs 29.695 Sorbitan sesquioleate - - - -~~ 5.0 Polyoxyethylene lauryether - - - - o.5 _~ , Total (w/w~) 100.0 100.0 100.0 100.0 100.0 , ~ " . :
- , , -: ., -. . : , -18- ~3~7~
Anti-inflammatory activity is measured for the above skin preparations by skin carrageenan edema inhibition test. The test is condu~ted by the following method.
Male rats weighing 190-210 g are used in the following test. Their side abdominal hair is removed before the start of this test. 1~ carrageenin solution is injected intra-dermally at a predetermined position from each side of the abdomen.
Immediately after carrageenin injection, 1 ml of 1% pontamine sky blue saline is administered intravenously. ~urthermoe~ an accurately determined volume of topical formulation is applied on the surface of the abdominal skin.
Five hours after the treatment, the abdominal skin is removed from the body and score as to the following items.
Dye lealcage at the iniection site Calculated by measuring the ma~imum and minimum diameter of the dye blue spot.
Edema skin weight Calculated by measuring the weight of the perforated edema skin (lcm ~ lcm = round shape) _________________________________________________________________ Edema weight = Edema skin weight - Normal skin weight Edema ratio = Edema weight / Normal skin weight The results are shown in the following table.
- :
-19~ 6 _ . ... ... _ Hydrocortisone 17-alpha-butyrate - 0.1%
Example Comparative Untreated (9) (G) _ _ Edema weight -58.4 72.9- 111.7 (mg) ~47.7~) -(~-34~.7%) ( - ) Edema ratio 79.4 ~99.7 142.8 (--4~.~) (-30.2%) ( - ) ~lue ~rea 6S.7 79.3 123.3 (mm ) (-44.3~) (-35-.5~) ( _ ) ____________________________________________________________ Effect ++ ++
. . . _ . ~
Indomethacin 1~
E~ample Comparative Untreated (10) (H) _ Edema weight 51.6 62.9 - 67.6 (mg) (-23.7%) (- 7.0~) ( - ) Edema ratio -68.9 - -86.9 90.8-(-24.1~) (- 4.3~) ( - ) Blue area 72.5 68.2 77.9-(mm~) (- 6.9~) (-12.5%) ( - ) _________~__________________________________________________ Effect +
.. ~ . _ .
Score ~+ Inhibition ratio3~-45%
+ 15-30~
_ 0-15%
As is apparent from the above table, the skin preparation of this invention possesses higher anti-inflammatory aetivity as compared with the conventional topical formulations.
., ., .
.
: " .
-2~-~ .~.3~
Eg~MPLES 11 and 11' The skin preparations having the following composition were prepared.
o/w cre~m ~bsorption Ointment _ Example 11 ~xample 11' Chlorpheniramine Maleate 1.0 % by weight1.0 White petrolatum g.9 40.0 Liquid paraffin 12.9 Stearyl alcohol 5.0 Cetyl alcohol 2.1 18.0 SLP-White (Soy lecithin) 4.0 4.0 Triethanolamine 0.8 0.8 Citric acid monohydrate 0.35 0.3s Butylated hydroxytoluene 0.025 0.025 Polyo~yethylene 45-monostearate 4.0 p-Chloro-m-cresol 0.2 0.2 ~eionized water qs 30.125 Sorbitan sesquioleat - 5.0 Polyo~yethylene laurylether - 0,5 Total (~ by weight) 100.0 100.0 The above skin preparation has been tested on the guinea-pig baak skin and found to be more effective in preventing vascular permeability increase caused by 0.1% histamine 0.05 ml as compared with the conventional ointment bases.
.; , ,
4:;~7~
E~amples 12-27 ~kin preparations are prepared having the composition shown in the following table E~MPLE NO.Example 12 Example 13 Example 14 _ DrugSulfiso~azole Tetracycline Chloramphenicol Hydrochloride
E~amples 12-27 ~kin preparations are prepared having the composition shown in the following table E~MPLE NO.Example 12 Example 13 Example 14 _ DrugSulfiso~azole Tetracycline Chloramphenicol Hydrochloride
5.0 3.0 2.0 SLP - White (Soy lecithin) 4.0 4.0 4.0 4.0 4.0 4.0 Triethanolamine 0.8 0.8 0.~ 0.8 0.8 0.8 Triisopropanolamine Lactic acid 0.62- - 0.62-- - 0.62 Citric Acid - 0.35 - 0.35 - 0.35 Butylated hydro~ytoluene 0.025 0.025 0.025 0.025 0.025 0.025 White petrolatum40.0 9.9~~ 86.555 9.9 - - 9.9 Liquid paraffin - 12.9 5.0 1.2.9 - 1~.9 Plastibase 50W - - - - 92.55S
Stearyl alcohol - 5.0 -- 5.0 - 5.0 Cetyl alcohol 18.0 2.1 - 2.1 - 2.1 Polyethylene Glycol 4000 - - - - - -Polyethylene Glycol 400 Polyo~yethylene 45 monostearate - 4.0 -~ 4.0 -~ 4.0 Sorbitan sesquioleate 5.0 - - - - -Polyoxyethylene laurylether 0.5 - - - - -p-Chloro-m-cresol 0.2 0.2-- - 0.2 - 0.2 Deionized water25-.855 55.725 - 57.725 - 58~725 _ . _ Total (~ by eight) 100.0_ 100.0_100.0 100.0_ 100.0 100.0 Type of Absorption o/w olea- o/w olea- o/w Formulation ointment cream ginuous cream ginuous cre~m _ ointment __ _ ointment . ~ ~ ' ' , ,. : . ~' ' :'' :
--22- ~ ~3~7~
E~LE N~. Example_15 Example 16 Example 17 , . . . _ .
Drug Gentamicin Acrisorcin Ichthammol sulfate 0.2 10.1 ~LP _ t~hite (Soy lecithin) 4.0 4.0 4.0 4.0 4.0 Triethanolamine 0.8 0.8 Triisopropanolamine - - 1.0 1.0 1.0 LRctic acid 0.62- - 0.58-- - 0.58 Citri~ Acid - 0.35 - 0.32 Butylated hydroxytoluene 0.025 0.025 0.0250.025 0.025 ~Yhite petrolatum - 9.9 - 40.0 - 9.9 -79.395 Liquid paraffin 10.0 12-.9 - 12.9 5.0 Plastibase 50W
Stearyl alcohol - 5.0 - 5,0 Cetyl alcohol - 2.1 18.0 2.1 Polyethylene Glycol 4000 42.455 Polyethylene Glycol 400 42.0 Polyoxyethylene 45 monostearate ~- 4.0 - 4.0 Sorbitan sesquioleate - -- 5.0 Polyo~yethylene laurylether - - 0.5 p-Chloro-m-cresol - 0.2 0.2 0.2 Deionized water - 60-.625 30.495 60.355 Total (% by weight) lO0.0 100.0 100.0 100.0 100.0 _ Type of Polyethyl- o/w Absorp olw 01ea-Formulation ene glycol cre~m tionous cream ginous ointment ointment ointment :. '' ' .
- .. :- ,:
,, , . , ~ .
--23~ L3'~'~76 [PLE `IY). Example 18 Example l9 Example 20 . . .. . _ . . _ .
Drug Undecylenic Nystatin Sodium Acid ~~ 5.0 Heparin 0.4 Zinc Undecyle- (50,000 units) nate 20.0 . . . _ . . .
SLP - IVhite (Soy lecithin) 4.0 4.0 4.0 4.0 Triethanolamine - - 0.8 0.8 Triisopropanolamine 1.0 1.0 Lactic acid 0.58 0.58 - 0.62 Citric Acid monohydrate - - - -- 0.3S
Butylated hydro~ytoluene 0.025 0.025 0.025 0.025 White petrolatum - - 40,0 - 9.9 Liquid paraffin 10.0 - - 12.9 Plastibase 50W - 90.895 Stearyl alcohol - - - 5.0 Cetyl alcohol - - 18.0 2.1 Polyethylene Glycol 4000 28.395 Polyethylene Glycol ~00 31.0 -Polyoxyethylene 45 monostearate - - - 4.0 Sorbitan ~esquioleate - - 5.0 Polyoxyethylene lAuryl ether - - - 0.5 p-Chloro-m-cresol - - 0.2 0.2 Deioni~ed water - 30.455 60.325 .. . .
Total (% by weight) 100.0 100.0 lOQ.0 100.0 Type of Polyethylene Oleaginous Absorp- o/w Formulation glycol ointment tion crearn ointment ointment ': ' ' , ' ' - ' . .
~, ~:~3~7~
EX~MPLE NO. E~ample 21 Example 22 Example 23 . _ _ , . . _ . .
Drug Urea 10.0 ~ 5-Fluoro- Bleomycin uracil sulf~te _ 5. Q 0.5 SLP - ~hite (Soy lecithin) 4.0 4.0 4.0 4.0 4-0 Triethanolamine - - - - -Triisopropanolamine 1.0 I.O 1.0 1.0 1.0 L~ctic acid 0.58 0.58 0.580.58 Citr~c Acid ~ 0.32 Butylated hydroxytoluene 0.025 0.025 0.0250.025 0.025 White petrolatum79.555 - 9.9 - 9.9 Liquid paraffin 5.0 ~ - 12.9 10.0 12.9 Plastibase 50W - 89.555 Stearyl alcohol - 5.0 5.0 ~ - 5.0 Cetyl alcohol - - 2.1 - 2.1 Polyethylene Glycol 4000 - - -- 42.055 Polyethylene Glycol 400 ~ - - - ~2.0 Polyoxyethylene 45 -~~
monostearate - -` 4.0 - 4.0 Sorbitan sesquioleate - - - - -Polyoxyethylene lauryl ether p-Chloro-m-cresol - - 0.2 ~~ - 0.2 Deionized water - - 55.295~-~ 80.055 Total (% by wei~ht) 100.0 100.0 ldO.O 100.0 100.0 Type of Oleaginous Olea- o/w Poly- o/w ~ormulation ointment ginous cream glycol craam _ _ ointment _ ointment : , , ,. . - .
,: ' ~ - :
- , :. .
.. . ... . .
: - : ~ .
_~5_ ~3~Z76 . _ _ _ .. . . .
E~PLE NO. Example 24 Example 25 Example 26 . _ . . _ _ . . _ _ . . .
Dru~ Lidocaine Ethiny- Testosterone 3.0 lestoradiol 1.0 . _ _ _ . ~ . _ _ _ ... . .
SLP - ~ite (Soy lecithin) 4.0 4~0 4.0 4.0 4.0 4.0 Triethanolamine 0.8 0.8 0.8 0.8 0.8 0.8 Triisopropanolamine - - - - - -Lactic acid 0.62 ~ 0.62 - 0.62 Citric Acid - 0.35 - 0.35 :` 0.35 Butylated hydro~ytoluene 0.025 0.025 0.025 0.025 0.025 0.025 Nhite petrolatum -86.555 9.9 89.545 9.9 - - 9.9 Liquid paraffin 5.0 12.9 5.0 12.9 10.0 12.9 Plastibase 50W
Stearyl alcohol - 5.0 - 5.0 - s.0 Cetyl al~ohol - 2.1 - 2.1 - 2.1 Polyethylene Glycol ~000 ~ 41-.555 Polyethylene Glycol 400 - - - - - 42.0 Polyo~yethylene 45 monostearate : 4.0 -- 4.0 - 4.0 Sorbitan se~quioleate Polyoxyethylene lauryl ether - - - - - -p-Chloro-m-cresol - 0.2 - 0.2 -~ - 0.2 ~eionized water - 5T.725 - 60.715 - 59.725 , .
Total (~ by weight) 100.0 100.0 100.0 100.0 100.0 100.0 ... . . . _ Type of oleaginou3 oJw olea- o/~ olea- o/w Formulation ointment cream ginous cream ginous cream ointment ointment , --26~ Z76 F.YAMPLE NO~ Ex~mple 27 Drug Nitroglycerin 2.0 .. . . . _ _ .
SLP - White (Soy lecithin) ~.0 4.0 Triethanolamine 0.8 0.8 Triisopropanolamine Lactic acid 0.62 Citric Acid - 0.35 Butylated hydroxytoluene 0.025 0.025 White petrolatum 87.555 9.9 Liquid paraffin 5.0 12.9 Plastibase 50W - -Stearyl alcohol - 5.0 Cetyl alcohol - 2.1 Polyethylene Glycol ~000 Polyethylene Glycol 400 Polyoxyethylene 45 monostearate - 4.0 Sorbitan sesquioleate Polyoxyethylene lauryl ether p-Chloro-m-cresol - 0.2 Deioni2ed water - 58.725 Total (% by weight) 100.0 100.0 Type of O!eaginous o/w Formulation ointment cream .
- --.' ~- . -.. . .,: . ; :, :
,: . . ..
Stearyl alcohol - 5.0 -- 5.0 - 5.0 Cetyl alcohol 18.0 2.1 - 2.1 - 2.1 Polyethylene Glycol 4000 - - - - - -Polyethylene Glycol 400 Polyo~yethylene 45 monostearate - 4.0 -~ 4.0 -~ 4.0 Sorbitan sesquioleate 5.0 - - - - -Polyoxyethylene laurylether 0.5 - - - - -p-Chloro-m-cresol 0.2 0.2-- - 0.2 - 0.2 Deionized water25-.855 55.725 - 57.725 - 58~725 _ . _ Total (~ by eight) 100.0_ 100.0_100.0 100.0_ 100.0 100.0 Type of Absorption o/w olea- o/w olea- o/w Formulation ointment cream ginuous cream ginuous cre~m _ ointment __ _ ointment . ~ ~ ' ' , ,. : . ~' ' :'' :
--22- ~ ~3~7~
E~LE N~. Example_15 Example 16 Example 17 , . . . _ .
Drug Gentamicin Acrisorcin Ichthammol sulfate 0.2 10.1 ~LP _ t~hite (Soy lecithin) 4.0 4.0 4.0 4.0 4.0 Triethanolamine 0.8 0.8 Triisopropanolamine - - 1.0 1.0 1.0 LRctic acid 0.62- - 0.58-- - 0.58 Citri~ Acid - 0.35 - 0.32 Butylated hydroxytoluene 0.025 0.025 0.0250.025 0.025 ~Yhite petrolatum - 9.9 - 40.0 - 9.9 -79.395 Liquid paraffin 10.0 12-.9 - 12.9 5.0 Plastibase 50W
Stearyl alcohol - 5.0 - 5,0 Cetyl alcohol - 2.1 18.0 2.1 Polyethylene Glycol 4000 42.455 Polyethylene Glycol 400 42.0 Polyoxyethylene 45 monostearate ~- 4.0 - 4.0 Sorbitan sesquioleate - -- 5.0 Polyo~yethylene laurylether - - 0.5 p-Chloro-m-cresol - 0.2 0.2 0.2 Deionized water - 60-.625 30.495 60.355 Total (% by weight) lO0.0 100.0 100.0 100.0 100.0 _ Type of Polyethyl- o/w Absorp olw 01ea-Formulation ene glycol cre~m tionous cream ginous ointment ointment ointment :. '' ' .
- .. :- ,:
,, , . , ~ .
--23~ L3'~'~76 [PLE `IY). Example 18 Example l9 Example 20 . . .. . _ . . _ .
Drug Undecylenic Nystatin Sodium Acid ~~ 5.0 Heparin 0.4 Zinc Undecyle- (50,000 units) nate 20.0 . . . _ . . .
SLP - IVhite (Soy lecithin) 4.0 4.0 4.0 4.0 Triethanolamine - - 0.8 0.8 Triisopropanolamine 1.0 1.0 Lactic acid 0.58 0.58 - 0.62 Citric Acid monohydrate - - - -- 0.3S
Butylated hydro~ytoluene 0.025 0.025 0.025 0.025 White petrolatum - - 40,0 - 9.9 Liquid paraffin 10.0 - - 12.9 Plastibase 50W - 90.895 Stearyl alcohol - - - 5.0 Cetyl alcohol - - 18.0 2.1 Polyethylene Glycol 4000 28.395 Polyethylene Glycol ~00 31.0 -Polyoxyethylene 45 monostearate - - - 4.0 Sorbitan ~esquioleate - - 5.0 Polyoxyethylene lAuryl ether - - - 0.5 p-Chloro-m-cresol - - 0.2 0.2 Deioni~ed water - 30.455 60.325 .. . .
Total (% by weight) 100.0 100.0 lOQ.0 100.0 Type of Polyethylene Oleaginous Absorp- o/w Formulation glycol ointment tion crearn ointment ointment ': ' ' , ' ' - ' . .
~, ~:~3~7~
EX~MPLE NO. E~ample 21 Example 22 Example 23 . _ _ , . . _ . .
Drug Urea 10.0 ~ 5-Fluoro- Bleomycin uracil sulf~te _ 5. Q 0.5 SLP - ~hite (Soy lecithin) 4.0 4.0 4.0 4.0 4-0 Triethanolamine - - - - -Triisopropanolamine 1.0 I.O 1.0 1.0 1.0 L~ctic acid 0.58 0.58 0.580.58 Citr~c Acid ~ 0.32 Butylated hydroxytoluene 0.025 0.025 0.0250.025 0.025 White petrolatum79.555 - 9.9 - 9.9 Liquid paraffin 5.0 ~ - 12.9 10.0 12.9 Plastibase 50W - 89.555 Stearyl alcohol - 5.0 5.0 ~ - 5.0 Cetyl alcohol - - 2.1 - 2.1 Polyethylene Glycol 4000 - - -- 42.055 Polyethylene Glycol 400 ~ - - - ~2.0 Polyoxyethylene 45 -~~
monostearate - -` 4.0 - 4.0 Sorbitan sesquioleate - - - - -Polyoxyethylene lauryl ether p-Chloro-m-cresol - - 0.2 ~~ - 0.2 Deionized water - - 55.295~-~ 80.055 Total (% by wei~ht) 100.0 100.0 ldO.O 100.0 100.0 Type of Oleaginous Olea- o/w Poly- o/w ~ormulation ointment ginous cream glycol craam _ _ ointment _ ointment : , , ,. . - .
,: ' ~ - :
- , :. .
.. . ... . .
: - : ~ .
_~5_ ~3~Z76 . _ _ _ .. . . .
E~PLE NO. Example 24 Example 25 Example 26 . _ . . _ _ . . _ _ . . .
Dru~ Lidocaine Ethiny- Testosterone 3.0 lestoradiol 1.0 . _ _ _ . ~ . _ _ _ ... . .
SLP - ~ite (Soy lecithin) 4.0 4~0 4.0 4.0 4.0 4.0 Triethanolamine 0.8 0.8 0.8 0.8 0.8 0.8 Triisopropanolamine - - - - - -Lactic acid 0.62 ~ 0.62 - 0.62 Citric Acid - 0.35 - 0.35 :` 0.35 Butylated hydro~ytoluene 0.025 0.025 0.025 0.025 0.025 0.025 Nhite petrolatum -86.555 9.9 89.545 9.9 - - 9.9 Liquid paraffin 5.0 12.9 5.0 12.9 10.0 12.9 Plastibase 50W
Stearyl alcohol - 5.0 - 5.0 - s.0 Cetyl al~ohol - 2.1 - 2.1 - 2.1 Polyethylene Glycol ~000 ~ 41-.555 Polyethylene Glycol 400 - - - - - 42.0 Polyo~yethylene 45 monostearate : 4.0 -- 4.0 - 4.0 Sorbitan se~quioleate Polyoxyethylene lauryl ether - - - - - -p-Chloro-m-cresol - 0.2 - 0.2 -~ - 0.2 ~eionized water - 5T.725 - 60.715 - 59.725 , .
Total (~ by weight) 100.0 100.0 100.0 100.0 100.0 100.0 ... . . . _ Type of oleaginou3 oJw olea- o/~ olea- o/w Formulation ointment cream ginous cream ginous cream ointment ointment , --26~ Z76 F.YAMPLE NO~ Ex~mple 27 Drug Nitroglycerin 2.0 .. . . . _ _ .
SLP - White (Soy lecithin) ~.0 4.0 Triethanolamine 0.8 0.8 Triisopropanolamine Lactic acid 0.62 Citric Acid - 0.35 Butylated hydroxytoluene 0.025 0.025 White petrolatum 87.555 9.9 Liquid paraffin 5.0 12.9 Plastibase 50W - -Stearyl alcohol - 5.0 Cetyl alcohol - 2.1 Polyethylene Glycol ~000 Polyethylene Glycol 400 Polyoxyethylene 45 monostearate - 4.0 Sorbitan sesquioleate Polyoxyethylene lauryl ether p-Chloro-m-cresol - 0.2 Deioni2ed water - 58.725 Total (% by weight) 100.0 100.0 Type of O!eaginous o/w Formulation ointment cream .
- --.' ~- . -.. . .,: . ; :, :
,: . . ..
Claims (22)
1. A preparation for use on human skin and nails which comprises a complex of a phosphatide containing about 10 to 40% by weight of lecithin and 0.2 to 25 moles of a lower alkanolamine per mole of phosphatide.
2. A skin preparation of Claim 1 wherein said phosphatide is contained in an amount of 0.5 to 8% by weight.
3. A skin preparation of Claim 2 wherein said phosphatide is contained in an amount of 1.5 - 5% by weight.
4. A preparation of Claim 1 wherein said phosphatide is soy phosphatide.
5. A preparation of Claim 1 wherein said alkanolamine is triethanolamine.
6. A preparation of Claim 1 wherein said alkanolamine is triisopropanolamine.
7. A skin preparation of Claim 5 wherein the trialkanolamine is contained in an amount of 1 to 10 moles per mole of said phosphatide.
8. A skin preparation of Claim 6 wherein said trialkanolamine is contained in an amount of 1 to 10 moles per mole of phosphatide.
9. A skin preparation of Claims 7 or 8 wherein said trialkanol-amine is contained in an amount of 1 to 5 moles per mole of phosphatide.
10. A nail preparation of Claim 1 wherein the phosphatide con-tent is about 15-30% by weight.
11. A skin preparation of Claim 1 which is an aqueous mixture in which the aqueous phase is the continuous phase.
12. A skin preparation of Claim 11 wherein said aqueous mix-ture is a colloidal solution, gel or emulsion.
13. A skin preparation of Claim 12 wherein said emulsion is an oil-in-water lotion or oil-in-cream.
14. A skin preparation of Claim 1, which is an oily mixture in which the oil phase is the continuous phase.
15. A skin preparation of Claim 14, wherein said mixture is an ointment.
16. A skin preparation of Claim 15 wherein said ointment is a water-in-oil cream.
17. A skin preparation of Claim 15 wherein said ointment is an anhydrous ointment, absorption ointment or hydrophilic ointment.
18. A preparation of Claim 1 including as an ingredient a human therapeutic dose of a topically active drug.
19. A preparation of Claim 18, wherein said drug is a steroid hormone.
20. A preparation of Claim 19, wherein steroid hormone is beclomethasone dipropionate, hydrocortisone l7-butyrate, hydrocortisone or prednisolone.
21. A preparation of Claim 18, wherein said drug is a topical antibiotic.
22. A preparation of Claim 18, wherein said drug is a silver sulfadiazine.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA348,458A CA1134276A (en) | 1980-03-26 | 1980-03-26 | Phosphatide-lower alkanolamine complex for topical application |
| PCT/US1981/000411 WO1981002673A1 (en) | 1980-03-26 | 1981-03-26 | Skin and nail composition containing phosphate-trialkanolamine complex |
| EP19810901083 EP0048280A1 (en) | 1980-03-26 | 1981-03-26 | Skin and nail composition containing phosphate-trialkanolamine complex |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA348,458A CA1134276A (en) | 1980-03-26 | 1980-03-26 | Phosphatide-lower alkanolamine complex for topical application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1134276A true CA1134276A (en) | 1982-10-26 |
Family
ID=4116563
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA348,458A Expired CA1134276A (en) | 1980-03-26 | 1980-03-26 | Phosphatide-lower alkanolamine complex for topical application |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0048280A1 (en) |
| CA (1) | CA1134276A (en) |
| WO (1) | WO1981002673A1 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3042365A1 (en) * | 1980-11-10 | 1982-06-03 | Harsanyi, Dr., Eugen, 5014 Kerpen | LIQUID LIQUID-CONTAINING SINGLE-PHASE MULTI-MATERIAL SYSTEMS |
| JPS57167926A (en) * | 1981-04-08 | 1982-10-16 | Mitsubishi Chem Ind Ltd | External base for skin |
| JPS58121209A (en) * | 1982-01-11 | 1983-07-19 | Eisai Co Ltd | Emulsion type composition for external use |
| 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 (en) * | 1992-12-18 | 1994-07-20 | Rhone-Poulenc Rorer Gmbh | Pharmaceutical or cosmetic composition containing N-acylalcanolamines and N-acylphospho- or lysophospholipids |
| 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 (en) * | 1998-04-10 | 1999-10-15 | Lvmh Rech | Stable water-in-oil cosmetic composition with non-greasy feel |
| DE69825495T2 (en) | 1998-12-23 | 2005-07-28 | Idea Ag | IMPROVED FORMULATION FOR TOPICAL, NON-INVASIVE APPLICATION IN VIVO |
Family Cites Families (4)
| 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 |
-
1980
- 1980-03-26 CA CA348,458A patent/CA1134276A/en not_active Expired
-
1981
- 1981-03-26 WO PCT/US1981/000411 patent/WO1981002673A1/en unknown
- 1981-03-26 EP EP19810901083 patent/EP0048280A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| EP0048280A1 (en) | 1982-03-31 |
| WO1981002673A1 (en) | 1981-10-01 |
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| Date | Code | Title | Description |
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| MKEX | Expiry |