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WO1988003799A1 - Vehicules pharmaceutiques de reduction du flux transdermique - Google Patents

Vehicules pharmaceutiques de reduction du flux transdermique Download PDF

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Publication number
WO1988003799A1
WO1988003799A1 PCT/US1986/002544 US8602544W WO8803799A1 WO 1988003799 A1 WO1988003799 A1 WO 1988003799A1 US 8602544 W US8602544 W US 8602544W WO 8803799 A1 WO8803799 A1 WO 8803799A1
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WO
WIPO (PCT)
Prior art keywords
zinc
agents
skin
pharmacologically active
ndga
Prior art date
Application number
PCT/US1986/002544
Other languages
English (en)
Inventor
Larry M. Allen
Original Assignee
Chemex 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 Chemex Pharmaceuticals, Inc. filed Critical Chemex Pharmaceuticals, Inc.
Priority to PCT/US1986/002544 priority Critical patent/WO1988003799A1/fr
Priority to KR1019880700847A priority patent/KR890700022A/ko
Publication of WO1988003799A1 publication Critical patent/WO1988003799A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/27—Zinc; Compounds thereof
    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
    • 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
    • A61Q7/00—Preparations for affecting hair growth

Definitions

  • the ideal vehicle for topically applied pharmaceuticals is therefore one which can produce a "reservoir effect" in the skin of mucous membranes to which the topical treatment is applied.
  • This "reservoir effect” is defined as an enhancement of the skin or membrane's ability to both absorb and retain pharmacologically active agents, i.e., to increase skin or membrane residence time, decrease drug transit time and reduce transdermal flux.
  • a number of compounds are known to enhance the ability of pharmacologically active agents to penetrate the skin and mucous membranes, for example, N-bis- azacyclopentan-2-onyl-alkanes, 1-substituted azacyloheptan-2-ones and higher alkyl-substituted azacyclopentan-2-ones, as well as dimethylsulfoxide and lower alkyl sulfoxides.
  • These compounds however, have the disadvantage of allowing rapid systemic dispersion of the pharmacologically active agents away from the localized site of pathology.
  • retinoids used in the treatment of acne,- and methotrexate, used in the treatment of psoriasis
  • retinoids are systemically toxic.
  • the retinoids for example,are known to cause damage to unborn fetuses.
  • a method of enhancing the ability of such medicaments to penetrate into the skin or mucous membrane so that a lesser total dosage may be used, while at the same time retarding their ability to move from the skin to the interior of the body.
  • This invention is a method for inducing a reservoir effect in skin and mucous membranes so as to enhance penetration and retention of topically applied pharmacologically active therapetuic and cosmetic agents therein.
  • the invention also relates to topical treatment methods involving such reservoir effect enhancers, and to pharmaceutical compositions containing them.
  • the additives of this invention are water-soluble zinccontaining compounds, preferably zinc halide, zinc sulfate, zinc nitrate, zinc acetate, and/or zinc stearate, and most preferably zinc chloride.
  • the pharmacologically active agents with which the water-soluble zinc-containing compounds are used are preferably those containing hydroxyl, oxo, sulfhydryl, amine, carboxyl, and other anionic groups in configurations which readily allow complexation or chelation with zinc ions.
  • the water-soluble zinc-containing compounds of this invention act as potentiators for the pharmacologically active agents. Potentiation is defined as overcoming or reducing undesirable effects such as systemic toxicity and extending the range of effectiveness of the pharmacologically active agent, or both. DESCRIPTION OF THE DRAWINGS
  • Fig. 1 is a graph of test results showing the skin reservoir effect achieved by the method of this invention utilizing nordihydroguaiaretic acid with zinc chloride, as compared to the same compound without zinc chloride.
  • the nordihydroguaiaretic acid was labelled with carbon-14 for radiotracer analysis.
  • the graph shows immediate absorption and longer retention of larger amounts of the nordihydroguaiaretic acid with zinc chloride present than without.
  • the availability of nordihydroguaiaretic acid, a lipoxygenase inhibitor, to therapeutically act upon localized pathologies, both with and without added zinc chloride, is measured by the areas under the respective curves. It is apparent that skin bioavailability is greatly enhanced in the presence of a zinc-containing compound.
  • the drug flux rate can be calculated as a function of the area under the curve by dividing this area by dose. As is apparent, drug flux rate is substantially decreased over the entire dosage range by the addition of zinc chloride.
  • the zinc-containing compounds of this invention are generally any water-soluble organic or inorganic zinc salts which dissociate in the topical vehicle so as to provide zinc ions which may complex or chelate with the pharmacologically active agents present in the vehicle.
  • suitable zinc-containing compounds are zinc halide, zinc sulfate, zinc nitrate, zinc acetate, and/or zinc stearate.
  • the most preferred zinc-containing compound is zinc chloride.
  • Such water-soluble zinc-containing compounds may be prepared by means known to the art, and many are commercially available.
  • the topical preparations of this invention having enhanced reservoir inducing capacities may be prepared by mixing, by means known to the art, a water-soluble zinc-containing compound into the pharmaceutical preparation or vehicle in which a reservoir-inducing capacity is to be created so as to promote the presence of zinc ions in the mixture which may complex or chelate with the pharmacologically active agents. It is believed that such a complexation or chelation is not necessary to obtaining the benefits of the invention provided zinc ions are present in a mixture containing the pharmacologically active agent. In any event, the presence of other metallic ions which would unfavorably compete with zinc for complexation or chelation sites is to be avoided.
  • the zinc salt can also be mixed with the pharmacologically active agent which is then incorporated into the pharmaceutical carrier.
  • the mechanism by which the reservoir-inducing effect of this invention is produced is not known; however, it is preferred that the pharmacologically agents contain hydroxy, oxo, sulfhydryl, amine, carboxyl, or other anionic groups, or combination thereof in conformations which allow complexation and/or chelation by zinc ions.
  • the zinc-containing compounds are preferably present in an equimolar ratio with the pharmacologically active agents, so as to cause maximum enhancement of reservoir inducing capacities. Where stratum corneum destruction, i.e., decornification, is desirable, an excess of such zinc-containing compounds which also act as escharotics, e.g., zinc chloride, may be used.
  • additives may be added to the preparations, including coloring agents, stability-enhancing agents, antioxidants, and the like.
  • these additives will not compete with the pharmacologically active agents for zinc; however, when necessary, excess zinccontaining compounds may be used to compensate for the zinc complexing or chelating effecting of such additives.
  • the pharmacologically active agents of this invention are those intended for topical application to achieve localized therapeutic or cosmetic effects.
  • a partial list of suitable pharmacologically active agents includes steroids, antifungals, anti-unicellular microorganism agents, antiviral agents, antiparasitic agents, antineoplastic agents, anti-leprosy agents, antimetabolites, cell-regulatory agents, immuno pharmacological agents, allergens, antihistaminic agents, anti-inflammatory agents, anesthetic agents, analgesic agents, anti-seborrheic agents, analgesics, anti-pretic agents, anti-asthma agents, anti-gout agents, anti-convulsant agents, anti-hypertensive agents, anti-diabetic agents, anti-migraine agents, anti-ychotic agents, anti-Parkinson agents, anti-allergy agents, anti-spasmodic agents, anti-tussive agents, anti-asthmatic agents, anti-anginal agents, hypolipidemic
  • the catecholic butanes useful in the compositions of the instant invention are of the formula
  • D,E,F,X,Y,Z may be H;OH; O-Alkyl or O-Acyl optionally substituted with hydroxy, alkoxy, substituted amino, carboxyl, or carbalkoxy;
  • R 1 -R 6 may be H; lower alkyl or lower alkoxyl optionally substituted with hydroxy, alkoxy, substituted amino, carboxyl, or carbalkoxyl; hydroxy; carbonyl; alkoxy; aryl; aralkyl;
  • n may be 0 to 5;
  • any of the aromatic rings in the molecule may contain up to 3 substituents from the following list: hydroxy; alkenoxy; alkyl, alkoxy or alkanoyl optionally substituted by hydroxy, alkoxy, substituted amino, carboxy, or carbalkoxy; CF 3 ; halo; carboxy; carbalkoxy; cyano; hydroxymethyl; sulfonic acid; sulfonamido; aminosulfonyl (i.e. - NHSO 2 R) ; nitro; alkoxycarbonyloxy; aminocarbonyloxy; aroyloxy; aralkanoyloxy; heteroaroyloxy; glycosidyloxy; and
  • any two phenolic groups may be joined together by the following groups:
  • r either of the rings A or B may be replaced by cyclohexyl, napthyl, tetrahydronapthyl, pyridyl, piper idinyl, quinolinyl, indanyl, indenyl;
  • any of the groups R 1 to R 6 may be joined together to form together with the other carbons to which they are attached, a5, 6, or 7 membered ring optionally interrupted by an oxygen atom, or containing an oxygen atom and a carbonyl substituent, or containing a carbonyl substituent;
  • any of the groups R 3 to R 6 may be joined to ring A to form with it a 5, 6, or 7 membered ring;
  • any of the carbons in the chain between rings A and B may be attached by a bond to the ⁇ position on ring A to form a 5, 6, or 7 membered ring.
  • R 1 and R 2 are independently H, lower alkyl or lower acyl
  • R 3 , R 4 , R 5 and R 6 are independently H or lower alkyl;R 7 , R 8 , and R 9 are independently H, hydroxy, lower alkoxy or lower acyloxy;
  • R 10 , R 11 , R 12 , and R 13 are independently H or lower alkyl.
  • Lower alkyl is intended to generally mean C 1 -C 6 alkyl, and preferably R- and R. are C 1 - C 3 , alkyl.
  • Lower acyl is intended to generally mean [C 1 -C 6 ] acyl,, with [C 2 - C 6 ] being preferred. It will be appreciated by those skilled in this are that Formula II is directed to both the phenolic compounds and the conventional esters and ethers thereof.
  • R 10 , R 12 , and R 13 are H, e.g., those wherein R 5 is H, R 5 and R 6 , are H or R 5 , R 6 and R 7 are H and R 8 and R 9 are OH or OR 1 ;
  • R 3 and R 4 each are CH 3 or C 2 H 5 including those of a), especially those wherein R 5 , R 6 , and R 7 are H and/or R 8 and R 9 are OH and OR 1 ;
  • R 1 and R 2 are lower acyl, e.g., hydrocarbonacyl, preferably, alkanoyl, e.g., acetyl, propionyl, etc., including those of a) and b);
  • R 1 and R 2 are alike and R 8 and R 9 are OR 1 including those of a), b) and c); and
  • lower alkyl represents, inter alia, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, and the like.
  • Lower acyl represents groups having the general formula RCO-, e.g., acetyl (CH 3 CO-), propionyl (CH 3 CH 2 CO-), butyryl (CH 3 CH 2 CH 2 CO-), and the like.
  • RCO- acetyl
  • propionyl CH 2 CO-
  • butyryl CH 3 CH 2 CH 2 CO-
  • the corresponding groups are acetoxy (CH 3 CO 2 -), propionyloxy (CE 3 CH 2 CO 2 -), and butyroyloxy (CH 3 CH 2 CH 2 CO 2 -).
  • Antineoplastic agents including NDGA (nordihydroguaiaretic acid), VP-16 (epipodophyllotoxin beta-D ethylidene glucopyranoside--etoposide), VM-26 (epipodophyllotoxin beta-D thenylidene glucopyranoside- -teniposide), 4' dimethyl epipodophyllotoxin, diethylstibestrol, dithranol, cyclophosphamide, mitomycin, daunomycin, plantinum cis-diamine - dichloride, adriamycin, allopurinol, 5-fluorouracil, and methotrexate.
  • NDGA nonordihydroguaiaretic acid
  • VP-16 epipodophyllotoxin beta-D ethylidene glucopyranoside--etoposide
  • VM-26 epipodo
  • Immunopharmacological agents which may be topically applied including polypeptide nanoparticles comprising interleuken or active fragments thereof, antibodies or active-fragments thereof, interferons, and iiposomes. Such delivery systems providing sustained release of pharmacologically active agents are effectively localized or held in place by zinc according to this invention.
  • Steroids which are utilized for a wide range of therapeutic purposes including anti-inflammation, antipruritic, enhancement of moisture retention, etc., including: dexamethasone, hydrocortisone, hydrocortisone acetate, hydroxy hydrocortisone, hydrocortisone valerate, triamcinolone acetonide, triamcinolone hexacetonide, amoinonide, fluocinolone acetonide, fluocinonide, flurandrenolide, difluorasone diacetate, betamethasone dipropionate, betamethasone, betamethasone benzoate, betamethasone valerate, halcinoide, desoximethasone, desonide, prednisolone, and clocortolone pivalate.
  • Antifungal agents which are used to treat fungus infections on the skin, hair, and nails, such as athlete's foot (tinea pedis), jock itch (tinea cruris), and ringworm (tinea corporis), which can be caused by a number of fungi, particularly Tricophyten rubrum, Trichophyten mentagrophytes, Eoidermoohyton floccosum, and Microsoorum canis.
  • antifungal agents include haloprogin, iodochloro, miconazole nitrate, tolnaftate, thiabendazole, chloroxine, amphotericin, candicin, fungimycin, nystatin, chlordantoin, clotrimazole, ethonam nitrate, miconazole itrate, pyrrolnitrin, fezatione, ticlatone, tolnaftate, triacetin, carbonic acid derivatives; dithiocarbamate, thiourea, thiocynates; aromatic carboxylic acids and the amides thereof, benzoic acid, salicylic acid, salicylic acid amide and anilide; aromatic sulfides, polysulfides, and sulfoxides, 5,5-dichloro-2,2 dihydroxydiphenylsulfide; invert soaps, quaternary ammonia and phosphonium compounds, decamethylene-bis-(4-
  • Antifungal agents are also used to treat vaginal infections caused by Candida albicans and related yeasts; these agents include dioctyl sodium sulf ⁇ succinate, haloprogin, miconazole nitrate, potassium sorbate, propionate compounds, such as calcium propionate and sodium propionate, sodium lauryl sulfate, cl ⁇ trimazole, tolnuftate, griseofulvin, ketronazole, moc ⁇ nazole and nystatin.
  • Antibacterial agents which are utilized for treating skin infections such as impetigo, ecthymus, folliculitis, boils, and acute pronychia, and for treating skin wounds and as a wound cleanser, and which may be used in this invention, including sulfonomides, penicillins, cephalosporins, peniciilinase, lincomycins, vancomycins, tetracylines, chloramphenicols, and streptomycins; including within this group the following compounds: gramicidin, neomycin, polymyxin beta sulfate, tetracycline, benzethonium chloride, gentamicin sulfate, nitrofurazone, benzalkonium chloride, hexylresorcinol, chloroxylenol, cloflucarban, carbolic acid (phenol), triclocarban, and triclosan.
  • sulfonomides penicillins, cephalo
  • Antiviral agents including those used to treat warts, such as glacial acetic acid, ascorbic acid, calcium pantothenate, lactic acid, salicylic acid, cantharidin, and podophyllin, and antiviral agents used to treat cold sores or herpes simplex such as acyclovir, benzalkonium chloride, alcohol, allantoin, anhydrous glycerin, benzocaine, camphor, carbamide peroxide, lanolin, menthol, petrolatum, and phenol; and antiviral agents including those used to treat herpes genitalis such as urea, idoxuridine, amantadine, methisazone, cytarabine, interferons, chloroform, ether, bacillus calmette-guerin and levamisole.
  • warts such as glacial acetic acid, ascorbic acid, calcium pantothenate, lactic acid, salicylic acid, cantharidin, and podophyll
  • Antiparasitic agents including antihelmintic agents (agents that destroy or expel intestinal worms) capable of penetrating the skin of the animal to be treated, e.g., benzimidazole compounds, tetramisole, levamisole, and isoquinoline compounds, diloxanide, metronidazole, suramin, quinine, primethamine, primaquine PO 4 , benzyl benzoate.
  • Pediculicides for mites (or scabies) and lice, including lidane, pyrethrins, piperonyl butoxide, malathion, and crotamiton.
  • Acne treatment compounds including benzoyl peroxide, resorcinol, resorcinol monoacetate, sulfur, povidoneiodine, salicylic acid, phenol, fluocinolone acetonide, para-aminobenzoic acid, sodium thiosulfate, meclocyline sulfosalicylate, sodium sulfacetamide, tetracycline hydrocholoride, aliphatic dicarboxylic acids, e.g., adipic and azelaic acids, and sulfurated lime.
  • Antipsoriasis agents comprising cytostatic agents, which retard skin-cell growth, keratolytic agents, which loosen and dissolve scales, tar preparations, whose mode of action is uncertain; hydrocortisone preparations, which reduce itching and inflammation; anti-itch preparations, and antimicrobials.
  • These antipsoriasis agents include coal tar preparations, juniper tar, pine tar, allantoin, saponated cresol, menthol, mercury oleate, phenol preparations, resorcinol, salicylic acid, anthralin, and methotrexate.
  • Leprosy agents including 4-4'-diaminodiphenyl sulfone.
  • Anesthetic agents for pain and itching, inflamed skin, sunburn, insect bites, wounds, hemorrhoids, poison ivy, and poison oak including: benzocaine, lidocaine, lidocaine hydrochloride, dibucaine, dibucaine hydrochloride, procaine, tetracaine, tetracaine hydrochloride, pramoxine hydrochloride, benzyl alcohol, diperodon, butamben pierate, cyclomethycaine sulfate, and dimethisoquin hydrochloride.
  • Analgesic agents for pain and itching, inflamed skin, sunburn, insect bites, burns, wounds, hemorrhoids, poison ivy, poison oak including: salicylic acid derivatives; N,N-dimethyl aspartic acids; N-N-dimethyl glutamic acid, trolamine salicylate, methyl salicylate; antipyrine, aspirin, and salicylamide.
  • Counter-irritants agents applied locally to produce an inflammatory reaction with the object of distracting and relieving a deep seated inflammatory process
  • agents applied locally to produce an inflammatory reaction with the object of distracting and relieving a deep seated inflammatory process including methyl salicylate, camphor, menthol, eugenol, eucalyptol, thymol, allyl isothiocyanate (mustard oil), capsicum preparations, histamine dihydrochloride, methyl nicotinate, and turpentine oil.
  • Antihistamines which are used principally against itching but are also midly anesthetic, including diphenhydramine hydrochloride, phenyltoloxamine dihydrogen citrate, pyrilamine maleate, tripelennamine hydrochloride. 16.
  • Diagnostic agents including allergenic extracts for diagnosis and immunotherapy of specific allergy offenders from the following categories: pollens, foods, dusts, epidermals, insects and stinging insects, fungi, molds, yeasts, tests for sensitivity to therapeutic pencillin (benzyl-penicilloyl-polylsine); tests for sensitivity to tetanus antigens, diphtheria antigens, streptococcus antigens, tuberculin, Candida antigens, Trichophyton antigens, and Proteus antigens.
  • Vitamins and nutrients for skin, hair, and scalp conditions including anti-scarring agents, vitamins B,, B 5 , B 6 , A, D, and E.
  • Cosmetic agents and perfumes including compositions to reduce the appearances of wrinkles such as water soluble elastin and pregnenolone; skin depigmenting agents and bleaches, including hydroquinone and monobenzone.
  • Sunscreens including: dioxybenzone, oxybenzone, padimate 0, padimate A, aminobenzoic acid, cinoxate, diethanolamine p-methoxycinnamate, ethyl 4-
  • Antimetabolites including methoprexate, 5 fluorouraul, cytosine arabinoside, 5-azacytidine, and mercaptopurine.
  • Immunomodulators including cyclosporin A, cyclophosphamide, chlomabucil, azathiopr ine, BCG, levamisole, thymosin.
  • Hair restorers including minuxidil, hydralazine. sodium nitroprusside, captopril.
  • Dosage forms for topical application may include lotions, ointments, creams, gels, suppositories, nasal solutions, mouthwashes, sprays, aerosols and the like.
  • Typical carriers which make up the foregoing dosage forms include water, acetone, isopropyl alcohol, stearyl alcohol, freons, ethyl alcohol, polyvinyl pyrrolidone, propylene glycol, polyethylene glycol, fragrances, gel- producing materials, mineral oil, stearic acid, spermaceti, sorbitan, monoleate, polysorbates, "Tweens,” sorbitol, methyl cellulose, etc.
  • Typical formulations of the pharmaceutical compositions of this invention are set forth in Table I below:
  • the amount of the composition, and thus of the pharmacologically active agent therein to be administered will obviously be an effective amount for the desired result expected therefrom. This, of course, will be ascertained by the practitioner utilizing his ordinary skill. Due to enhanced activity which is achieved, the dosage of agent may often be decreased from that generally applicable. In accordance with usual prudent formulatin ⁇ practices, a dosa ⁇ e near he lower useful range of the particular agent may be employed initially and the dosage increased as indicated from the observed response.
  • the nordihydroguaiaretic acid used in the instant examples was the meso-isomer and is designated NDGA.
  • Other isomers are indicated, e.g., d, 1-NDGA.
  • compositions utilizing zinc chloride, nordihydroguaiaretic acid (NDGA), acid (EDTA), butylated hydroxytolulene (BHT), stearyl alcohol, purified water, polyethylene glycol having an average molecular weight of 400 (PEGO 400), and polyethylene glycol having an average molecular wight of 3350 (PEGO 3350) were prepared in the following manner: the purified water was placed in a clean glass container of suitable capacity; the water was heated to about 80-90°C with stirring; and zinc chloride was added to the heated water, continuing the stirring until the zinc chloride dissolved. The ethylenediaminetetraacetic acid was slowly added with mixing until dissolved.
  • the polyethylene glycol 400 was heated to about 80-90°C with stirring; the NDGA was added thereto; then the BHT; and this mixture was added to the zinc chlorideethylenediaminetetraacetic acid solution with stirring. The entire mixture was then cooled to about room temperature and passed through a number 3 roller mill until smooth. The polyethylene glycol 3350 was then heated to about 80-90°C in a suitable container and the milled ingredients added thereto with mixing.
  • the 14 C-NDGA compound exhibited a specific radioactivity of 20.2 Ci/mole (66.9 micro Ci/mg) and a purity of 96.9% by mass spectrometry and by radioautography of thin-layer chromatography plates developed in benzene: isopropanol: acetic acid: water (25:5:2:10).
  • the compounds were dermally applied to young adult Sprague-Dawley rats by the following protocol: under ether anesthesia, the back skin of the rat was prepared by removing the hair from a 5 x 5-cm area with a clipper and the residual hair stubble was removed with a wax depilatory. Then the skin was stripped repeatedly (5X) with adhesive tape until the stratum corneum was removed. Then 0.5 gm of the formulation was weighted on a 5 x5-cm sheet of polypropylene, which was applied to the prepared skin. It was secured in place by hypoallergenic tape.
  • the bandage was overwrapped with bandage tape.
  • the rats were caged individually in metabolism cages, which allowed free access to food and water and provided for separate collection of urine and feces.
  • Groups of three rats were bled terminally- and tissues were taken at 4, 24, 48, 72, and 96 hr after dosing. As each sacrifice time, those three rats scheduled to be sacrificed next were also bled nonterminally from the orbital sinus. The wrappings and wipes of the skin site were taken at the time of sacrifice and added to acetone as described above.
  • zinc chloride was first dissolved in the PEGO 400 to prepare a stock solution containing 0.69% zinc chloride, and this solution was added with mixing to the vials containing the organic compounds being tested.
  • compositions and organic compounds not previously known as antineoplastic agents were prepared with and without zinc chloride according to the procedure of Example 3 and tested for their ability to eradicate turmors following the protocol described in Example 3. Results are set forth in Table 4.
  • Both types of tumors were grown intradermally or subcutaneously in the mice.
  • the B-16 melanoma was grown in BDF1 mice and the S-180 tumor was grown in ICR mice.
  • Each mouse was injected intrademally with about 0.01 ml of a saline suspension containing about 1 x 10 cells of the tumor cells per 0.01 ml into a preshaven area on the back of the neck of the mouse.
  • the tumors were allowed to grow until they had an approximate size of about 25- 100 mg, calculated by the length of the tumor multiplied by the width and height of the tumor measured in millimeters and dividing the product by two.
  • the animals with tumor sizes outside of the size range were culled and the remaining animals were randomly divided into control and test groups.
  • the tumors When the tumors had reached the appropriate size, usually at about day six, the tumors were punctured uniformly and then treated with either a test compound or a control by topical application to the surface of the tumor. Generally, two topical applications were made 24 hours apart. The materials were applied to obtain from about a 1 to about 2 mm coating over the surface of the tumor. The animals were thereafter observed and their weights and the size of their tumors were periodically measured.
  • Mixture No. 1 was prepared by dissolving the NDGA in absolute ethanol by warming and stirring; thereafter the water was added slowly to the NDGA solution. The mixture was heated to evaporate sufficient solvent to obtain a mixture of about 130% of the weight of the NDGA, and was then incorporated into the PEGO base.
  • Mixture No. 2 was made by simply dissolving the NDGA in the PEGO base with warming and stirring.
  • Example 5 The NDGA formulations of Example 5 were tested for potential antitumor activity against B-15 melanoma grown in mice. The procedure utilized was that previously described. The results are given below in Table 6.
  • formulations of zinc chloride in a PEGO base were prepared by first dissolving the zinc chloride in water and then mixing the zinc chloride solution into the PEGO base.
  • the formulations had approximately the following weight/weight percent compositions as set forth in Table 7.
  • Example 7 Mixtures of Example 7 were tested for potential antitumor activity against B-16 melanoma and S-180 solid tumor grown in mice in accordance with the procedures previously described. The results are given in Table 8.
  • Mixtures of zinc chloride, EDTA and NDGA were prepared and formulated in a PEGO base.
  • the mixtures were prepared by dissolving the NDGA and EDTA in a portion of the PEGO base by warming and stirring until dissolved.
  • the zinc chloride was dissolved in water and warmed.
  • the zinc chloride solution was added to the warm PEGO containing the NDGA and EDTA and stirred until cooled to room temperature.
  • the composition of the mixtures is given in approximate weight/weight percentage as set forth in Table 9.
  • Example 9 The mixtures of Example 9 were tested for thier potential antitumor activities against B-16 melanomas grown in mice in accordance with the procedure previously described. The results are given in Table 10.
  • Examples 5-10 show the potentiating effect of zinc chloride on antineoplastic agents topically applied, showing improvement over the antineoplastic activity of zinc chloride alone, and comparable amounts of NDGA even when the NDGA is injected into the tumor.
  • EXAMPLE 11 Appropriate human and animal modes are chosen for the disease conditions treated by the following compounds as hereinabove described, and the compounds tested to determine effective and toxic dosages with and without the addition of equimolar amounts of zinc chlordie, zinc iodide, zinc bromide, zinc sulfate, zinc nitrate, zinc stearate, and zinc acetate.

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  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Procédé d'induction d'un effet réservoir dans la peau et les membranes muqueuses de manière à améliorer la pénétration et la rétention et réduire le flux transdermique d'agents thérapeutiques et cosmétiques pharmacologiquement actifs et appliqués localement. L'invention concerne également des procédés de traitements locaux utilisant de tels agents d'amélioration à effet réservoir, ainsi que des compositions pharmaceutiques les contenant.
PCT/US1986/002544 1986-11-19 1986-11-19 Vehicules pharmaceutiques de reduction du flux transdermique WO1988003799A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/US1986/002544 WO1988003799A1 (fr) 1986-11-19 1986-11-19 Vehicules pharmaceutiques de reduction du flux transdermique
KR1019880700847A KR890700022A (ko) 1986-11-19 1986-11-19 피부 관통 유동을 감소시키는 약제 비히클

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1986/002544 WO1988003799A1 (fr) 1986-11-19 1986-11-19 Vehicules pharmaceutiques de reduction du flux transdermique

Publications (1)

Publication Number Publication Date
WO1988003799A1 true WO1988003799A1 (fr) 1988-06-02

Family

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Family Applications (1)

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PCT/US1986/002544 WO1988003799A1 (fr) 1986-11-19 1986-11-19 Vehicules pharmaceutiques de reduction du flux transdermique

Country Status (2)

Country Link
KR (1) KR890700022A (fr)
WO (1) WO1988003799A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990015603A1 (fr) * 1989-06-12 1990-12-27 Shiseido Company, Ltd. Composition antipruritique
EP0490583A1 (fr) * 1990-12-06 1992-06-17 Unilever Plc Composition pour le traitement de la chevelure
US5219847A (en) * 1989-06-12 1993-06-15 Shiseido Company, Ltd. Antipruritic composition
EP0788305A4 (fr) * 1994-03-28 1999-05-26 Univ Columbia Composition pour l'inactivation d'agents irritants dans des liquides
US7462369B2 (en) * 2002-11-04 2008-12-09 Jeffrey B. Smith Anti-viral compositions and methods of making and using the anti-viral compositions
US7879365B2 (en) 2002-02-07 2011-02-01 The Trustees Of Columbia University In The City Of New York Zinc salt compositions for the prevention of dermal and mucosal irritation
USRE45435E1 (en) 2002-02-07 2015-03-24 The Trustees Of Columbia University In The City Of New York Zinc salt compositions for the prevention of dermal and mucosal irritation
US9421263B2 (en) 2003-07-17 2016-08-23 The Trustees Of Columbia University In The City Of New York Antimicrobial compositions containing synergistic combinations of quaternary ammonium compounds and essential oils and/or constituents thereof

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3660578A (en) * 1957-04-06 1972-05-02 Kyowa Hakko Kogyo Kk Mitomycin c
US4039663A (en) * 1975-03-19 1977-08-02 Societa' Farmaceutici Italia S.P.A. Daunomycins, process for their uses and intermediates
US4203969A (en) * 1977-07-06 1980-05-20 Drythanol Limited Dithranol compositions for topical applications
US4406881A (en) * 1980-05-20 1983-09-27 Vipont Laboratories Antimicrobial agent
US4469684A (en) * 1982-10-15 1984-09-04 The Procter & Gamble Company Storage stable topical pharmaceutical composition containing zinc erythromycin and low dielectric solvents
US4537883A (en) * 1982-11-12 1985-08-27 Mead Johnson & Company Lyophilized cyclophosphamide
US4564675A (en) * 1982-11-26 1986-01-14 Nippon Kayaku Kabushiki Kaisha Process for producing 4'-demethyl-epipodophyllotoxin-β-D-ethylidene-glucoside and acyl-derivative thereof
US4567253A (en) * 1984-02-03 1986-01-28 Tony Durst 2-Substituted derivatives of podophyllotoxin and etoposide

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3660578A (en) * 1957-04-06 1972-05-02 Kyowa Hakko Kogyo Kk Mitomycin c
US4039663A (en) * 1975-03-19 1977-08-02 Societa' Farmaceutici Italia S.P.A. Daunomycins, process for their uses and intermediates
US4203969A (en) * 1977-07-06 1980-05-20 Drythanol Limited Dithranol compositions for topical applications
US4406881A (en) * 1980-05-20 1983-09-27 Vipont Laboratories Antimicrobial agent
US4469684A (en) * 1982-10-15 1984-09-04 The Procter & Gamble Company Storage stable topical pharmaceutical composition containing zinc erythromycin and low dielectric solvents
US4537883A (en) * 1982-11-12 1985-08-27 Mead Johnson & Company Lyophilized cyclophosphamide
US4564675A (en) * 1982-11-26 1986-01-14 Nippon Kayaku Kabushiki Kaisha Process for producing 4'-demethyl-epipodophyllotoxin-β-D-ethylidene-glucoside and acyl-derivative thereof
US4567253A (en) * 1984-02-03 1986-01-28 Tony Durst 2-Substituted derivatives of podophyllotoxin and etoposide

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990015603A1 (fr) * 1989-06-12 1990-12-27 Shiseido Company, Ltd. Composition antipruritique
AU628588B2 (en) * 1989-06-12 1992-09-17 Chuji Yanagawa Antipruritic composition
US5219847A (en) * 1989-06-12 1993-06-15 Shiseido Company, Ltd. Antipruritic composition
EP0490583A1 (fr) * 1990-12-06 1992-06-17 Unilever Plc Composition pour le traitement de la chevelure
EP0788305A4 (fr) * 1994-03-28 1999-05-26 Univ Columbia Composition pour l'inactivation d'agents irritants dans des liquides
US5965610A (en) * 1994-03-28 1999-10-12 The Trustees Of Columbia University In The City Of New York Composition for inactivating irritants in fluids
US6037386A (en) * 1994-03-28 2000-03-14 The Trustees Of Columbia University In The City Of New York Composition for inactivating irritants in fluids
US7879365B2 (en) 2002-02-07 2011-02-01 The Trustees Of Columbia University In The City Of New York Zinc salt compositions for the prevention of dermal and mucosal irritation
USRE45435E1 (en) 2002-02-07 2015-03-24 The Trustees Of Columbia University In The City Of New York Zinc salt compositions for the prevention of dermal and mucosal irritation
US7462369B2 (en) * 2002-11-04 2008-12-09 Jeffrey B. Smith Anti-viral compositions and methods of making and using the anti-viral compositions
US9421263B2 (en) 2003-07-17 2016-08-23 The Trustees Of Columbia University In The City Of New York Antimicrobial compositions containing synergistic combinations of quaternary ammonium compounds and essential oils and/or constituents thereof

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