CA1298557C - Compositions comprising 1-substituted azacyclo-alkanes - Google Patents
Compositions comprising 1-substituted azacyclo-alkanesInfo
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- CA1298557C CA1298557C CA000528478A CA528478A CA1298557C CA 1298557 C CA1298557 C CA 1298557C CA 000528478 A CA000528478 A CA 000528478A CA 528478 A CA528478 A CA 528478A CA 1298557 C CA1298557 C CA 1298557C
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- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues 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
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- C—CHEMISTRY; METALLURGY
- C05—FERTILISERS; MANUFACTURE THEREOF
- C05G—MIXTURES OF FERTILISERS COVERED INDIVIDUALLY BY DIFFERENT SUBCLASSES OF CLASS C05; MIXTURES OF ONE OR MORE FERTILISERS WITH MATERIALS NOT HAVING A SPECIFIC FERTILISING ACTIVITY, e.g. PESTICIDES, SOIL-CONDITIONERS, WETTING AGENTS; FERTILISERS CHARACTERISED BY THEIR FORM
- C05G3/00—Mixtures of one or more fertilisers with additives not having a specially fertilising activity
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- Animal Behavior & Ethology (AREA)
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- Agricultural Chemicals And Associated Chemicals (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
ABSTRACT OF THE
DISCLOSURE
This invention provides compositions comprising a physiologically-active agent and a compound having the structural formula
DISCLOSURE
This invention provides compositions comprising a physiologically-active agent and a compound having the structural formula
Description
~;~98557 .COMPOSITIONS
)MPRISING l-~UBSTIT~TE~2 ~ACYCI.QAIJKA~ES
BACKGROUND OF THE IN~7ENTION
1. EiÇ1~ Qf the Invention This invention relates to compositions comprising a physiologically-active agent and a l-alkyl azacycloalkane, which is substituted by oxygen or ~ulfur atoms pendant from the alpha carbon atom of the l-alkyl group, in an amount effective to enhance the penetration of the phys~ologically-active agent through the skin or other membrane of the body of an animal.
)MPRISING l-~UBSTIT~TE~2 ~ACYCI.QAIJKA~ES
BACKGROUND OF THE IN~7ENTION
1. EiÇ1~ Qf the Invention This invention relates to compositions comprising a physiologically-active agent and a l-alkyl azacycloalkane, which is substituted by oxygen or ~ulfur atoms pendant from the alpha carbon atom of the l-alkyl group, in an amount effective to enhance the penetration of the phys~ologically-active agent through the skin or other membrane of the body of an animal.
2. ~çk~s~n~Ls~ A~
Many physiologically active agents are best applied topically to obtain desir~ble results. Toplcal appl ication, as contrasted to systemic application, can avoid metabolic degradation of the agents, largely avoids side effects of the agents and permits high local concentrations of the agents~
The greatest problem ;n applying physiologically active agents topi~ally is that the ~kin is ~uch an effective barrier to penet~ation. The epidermis o the skin has an exterivr layer of dead cells called the stratum corneum which is tightly compacted and oily and which provides an effective barrier against gaseous, ~olid .
[L/N0539.RB01.1086CC]
~Z9~3~;S7 or liquid chemical agents, whether used alone or in water or oil solutions. If a physiologically active agent penetrates the stratum corneum, it can readily pass through the basal layer of the epidermis and into the dermis.
Although the effectiveness of the stratum corneum as a barrier provides great protectlon, lt also frustrates efforts to apply beneficial agents directly to local areas of the body. The inability of physiologically active agents to penetrate the stratum corneum prevents their effective use to treat such conditlons as inflammation, acne, psoriasis, herpes simplex, eczema, infections due to fungus, virus or other microorganisms~ or other disorders or conditions of the skin or mucous membranes, or oE
conditions beneath the exterior surface of the skin or mucous membranes. The stratum corneum also prevents the skin from ahsorbing and retaining cosmetic-type materials such as sunscreens, perfumes, mosquito repellants and the like.
Physiologically active agents may be applied to locally affected parts of the body through the vehicle system described herein. Vehicles such as USP cold cream, ethanol and various ointments, oils, aolvents, and emulsions have been used heretofore $o apply physiologically active ingredients locally. Most such vehicles are not effective to carry significant amounts of physiologically active agents through the skin. One such vehicle is dimethyl sulfoxide.
The l-lower alkyl substituted azacyclopentan-2~ones having 1-4 carbon atoms in the alkyl group are known to moderately enhance percu~aneous absorption of chemicals, ~Z~ i7 e.g. drugs. It was earlier recognized that it would be desirable to obtain the same or higher level of percutaneous absorption with substantially lower concentrations of the penetration-enhancing compound.
Therefore, a new class of N-substituted azacycloalkan-2-ones were invented having the desired properties. This new class of penetration-enhancing agents are described in U.S. Patents ~,~89/815; 3,989,816; 3,991/203; 4,122,170;
4,316,893; 4,405,616; 4,415~563; 4r423~040; 4,424,210; and 4944~,762.
It is an object of this invention to provide new penetration-enhancing agents having the deslrable property of enhancing the percutaneous absorptlon of physiologically-active agents at concentrations lower t,han the l-lower alkyl substituted azacyclopentan-2-ones.
It is also an object of this invention to provide penetration-enhancing agents that are equivalent to the aforesaid new class penetration-enhancing agents described in the above U.S. patents.
Other objects and advantages of the instant invent~on will be apparent from a careful reading of the specification below.
In this description, the term "animal" includes human beings as well as other forms of animal life, and especially domesticated animals and pets.
~L298S57 SU MMARY O F TH ~ I NV ENT I ON
This invention relates to compositions for carrying physiologically active agents through body membranes such as skin and for retaining these agents in ~ody tissues.
More specifically, the invention relate~ to compositions useful in topically administering a physiologically active agent to a human or animal comprising the agent and an effective, non-toxic amount of a compound having the structural formula R' (CH ~ m \ N-~-(CH2)n-R
~ 2 wherein X is selected from the group consisting of oxygen and sulfur; R' is ~l or a lower alkyl group having 1-4 carbon atoms; m is 2-S; n is 0-17 and R is -CH30 Preferably R is -CH3 and R' is H.
In a more preferred embodiment of ~he present invention R is -CH3, R' is H and m equals 4. Even more preferably n is 4-17l e.g. 10.
It has been found that the physiologically active agents are carried through body membranes by the above penetration-enhancing agents and are retained in body tissue.
~298SS7 DETAILED DESCRIPl'ION OF THE
INVENTION
The N-alkyl substituted azacycloalkanes useful as penetration-enhancing additives in the compositions of the instant invention may be made by the method described below. Typical examples of compounds represented by the above structural formula include:
l-n-undecylformylazacycloheptane l-n-decylormy1azacycloheptane l-n-octylformyla~acycloheptane l-n-nonylformylazacycloheptane l-n-dodecylformylazacycloheptane l-n-tridecylformylazacycloheptane 1 n-tetradecylformylazacycloheptane l-n-hexadecylformylazacycloheptane l-n-pentadecylformylaæacycloheptane l-n-heptadecylPormylazacycloheptane 1~16-methylhexadecyl)formylazacycloheptane The compounds represented by the above general formula, wherein X is oxygen, may be prepared by reacting the corresponding azacycloalkane with an alkanoyl halide in the presence of a base, eOg. sodium hydride. The reaction is carried out under anhydrous conditions in a hydrocarbon solYent, for example, dry toluene at reflux temperature for about 10 to 72 hours ~n an inert atmosphere, for example, nitrogen. This method is outlined below for the alkylformyl subst~tuted-azacycloalkane:
: ~ 2 (C~12) \ N H (1) NaH ~ O
\ / (2) R-(CI~2tn ~-Cl /
~9!8~;57 Any of the above compounds may be converted to the corresponding sulfur analog by reacting the oxygen-containing compound with phosphorus pentasulfide.
The amount of l-substituted azacycloalkane which may be used in the present invention is an effective, non-toxic amount for enhancing percutaneous absorption.
Generally, this amount ranges between about 0~01 to about 5 and preferably about 0.1 to 2 percent by weight of the composition.
The subject compositions may find use with many physiologically active agents which are soluble in the vehicles disclosed.
Fungi~tatic and fungicidal agents such asr for example, thiabendazole, chloroxine, amphotericin B, candicidin, fungimycin, nystatin, chlordantoin, clotrimazole, miconazole nitrate, pyrrolnitrin, ~alicyllc acid, fezatione, tolnaftate, triacetin and ~inc and sodium pyrithione may be dissolved in the penetration-enhancing agents descIibed herein and topically applied to affected areas o~ the skin. For example, fungi~tatic or fungicidal agents so applied are carried through the stratum corneum, and thereby successfully treat fungus-caused skin problems. These agents, thus applied, not only penetrate more ~uickly than when applied in the vehicles of the prior art, but additionally enter the animal tissue in high concentrations and are retained ~or substantially longer time periods whereby a far more successful treatment is effected.
For example, the subject compositions may also be employed in the treatment of fun~us infections on the ~kin caused by candida and dermatophytes which cause athlete's ;;S7 foot or ringworm, by dissolving thiabendazole or similar antifungal agents in one of the above-described penetration-enhancing agents and applying it to the affected area.
The subject compositions are also useful in treating skin problems, for example, herpes simplex, which may be treated by a solution of iododeoxyuridine dissolved in one of the penetration-enhancing agents or such problems as warts which may be treated with agents such as podophylline dissolved in one of the penetration-enhancing agents. Skin problems such as psoriasis may be treated by topical application of a solution of a conventional ~opical steroid in one of the penetration-enhancing agents or by treatment with theophylline or antagonists of ~-adrenergic blockers such as isoproterenol in one of the penetration~enhancing agents. Scalp conditions such as alopecia areata may be treated more effectively by applying steroids such as triamcinolone acetonide dissolved in one of the penetration-enhancing agents of this invention directly to the scalp.
The subject compositions are also useful for treating mild eczema, for example, by applying a solution of 1uocinolone acetonide or its derivatives; hydrocortisone triamcinolone acetonider indomethacin, or phenylbutazone dissolved in one of the penetration-enhancing agents to the a~fected area~
Examples of other physiologically active steroids which may be used with the vehi~les include corticosteroids such as, for example, cortisone, cortsdoxone, flucetonide, fluorocortisone, difluorsone diacetate, flurandrenolone acetonide, medry~one, amcinafel, amcinafide~ betamethasone and its esters, chloroprednisone, clocortelone, descinolone, desonideS
~29~3557 dexamethasone, dichlorisone, defluprednate, flucloronide, fl~methasone, flunisolide, fl~ocinonide, flucortolone, ~luoromethalone~ fluperolone, fluprednisolone, meprednisone, methylmeprednisolone, paramethasone, prednisolone and prednisone.
The subject compositions are also useful in antibacterial chemotherapy/ e.g. in the treatment of skin conditions involvin~ pathogenic bacteria. qypical antibacterial agents which may be used in this invention include sulfonamides, penicillins, cephalosporins, penicillinase~ erythromycins, lincomycins, vancomycins, tetracyclines, chloramphenicols, streptomycins, etc.
Typical examples of the foregoing include erythromycin, erythromycin ethyl carbonate, erythromycin estolate, erythromycin glucepate, erythromycin ethylsuccinate, ery~hromycin lactobionate, lincomycin, clindamycin, tetracycline, chlortetracycline, demeclocycline, doxycycline, methacycline, oxytetracycline, minocycline, etc The subject compositions are also useful in protecting ultra-sensitive skin or even normally ~ensitive skin from damage or discomfort due to sunburn. Thus, dermatitis actinica may be avoided by application of a sunscreen, such as para~aminobenzoic acid or its well-known derivatives dissolv~d in one of the above-described penetration-enhancing agents, to skin surfaces that are to be exposed to the sun; and the protective para-aminobenzoic acid or it~ derivatives will be carried into the stratum corneum more uccessfully and will therefore be retained even when exposed to water or washing for a substantially longer period of ~ime than when applied to E3S~7 the skin in conventional vehicles. This invention is particularly useful for ordinary suntan lotions used in activities involving swimming because the ultraviolet screening inyredients in the carriers of the prior art are washed off the skin when it ls immersed in water.
The subjec~ compositions may also find use in treating scar tissue by applying agents which soften collagen, such as aminopropionitrile or penicillamine dissolved in one of the penetration-enhancing agents of this invention topically to the scar tissue.
Agents normally applied as eye drops, ear drops, or nose drops are more effective when dissolved in the penetration-enhancing agents of this invention.
Agent~ used in diagnosis may be used more effectively when applied dissolved in one of the penetration-enhancing agents of this invention. Patch tests to diagnose allergies may be effected promptly without scratching the skin or covering the area subjected to an allergen when the allergens are applied in one of the penetration-enhancing agents of this invent~on.
The subje~t compositions are also useful for topical application of cosmekic or esthetic agents. For example, compounds such as melanin-stimulating hormone (MSH) or dihydroxyacetone and the like are more efectively applied to skin ~o stimulate a suntan when they are dissolved in one o the penetration-enhancing agents of this invention~ The agent is carr~ed into the skin more quickly and in greater quantity when applied in accordance with this invention. Hair dyes also penetrate more completely and effectively when diæsolved in one of the penetration-enhancing agents of this invent~on.
lZ~35~7 ;--10--The effectiveness o 6uch topically applied materials as insect repellants or fragrances, such as perfumes and colognes, can be prolonged when such agent~ are applied dissolved in one of the penetration-enhancing agents of this invention.
It is to be emphasized that the foregoing are simply examples of physiologically active agents including therapeutic and cosmetic agents having known effects for known conditions, which may be used more effectively for their known properties in accordance with this invention.
In addition, the penetration-enhancing ayents of the present invention may also be used to produce therapeutic effects which were not previously known. That is, by use of the penetration-enhancing agents described herein, therapeutic effects heretofore not known can be achieved.
As an example o the foregoing, griseofulvin is known as the treatment of choice for fungal infections of the skin and nails. Heretofore, the manner of delivery of griseoulvin has been oral. E~owever, it has long been known that oral treatment is not preferred because of side effects resulting from exposure of the entire body to griseoulvin and the fact that only the outer layers of affected skin need to be treated. Therefore, because fungal infec~ions are generally infections of the skin and nails, it would be advantageous to utilize griseofulvin topically. However, despite a long-felt need for a topical griseofulvin, griseo~ulvin has been used orally to trea~ topical fungal conditions because there was not heretofore known any formulation which could be delivered topically which would cause ~ufficient retention of griseofulvin in the skin to be useful therapeutically ~ owever, it has now been discovered that griseofuïvin, in a range of therapeutic concentrations ~LZ98~i57 between about 0.1% and about 10% may be used effectively topically if combined with one of the penetration-enhancing agents described herein.
As a further example, acne is the name commonly applied to any inflammatory disease of the ~ebaceous glands; also acne vulgaris. The mlcroorganism typically responsible for the acne infection is Corynebacterium acnes. Various therapeutic methods for ~reating a~ne have been attempted including topical antibacterialsg e.g.
hexachlorophene, and systemic antibiotics such as tetracycline~ While the systemic antibiotic treatments are known to be partially e~fective, the topical treatments are generally not e~fective.
It has long been known that systemic treatment of acne is not preferred because of side effects resulting from exposure of the entire body to antibiotics and the fact that only the affected skin need be treated.
~lowever, despite a long-felt need for a topical treatment for acne, antibiotics generally have been used only systemically to treat acne because there was not heretofore known an antibacterial formulation which could be used topically which would be effective therapeutically in the treatment of acne. HoweYer, it has now been discovered that antibiotics, especially those of the lincomycin and erythromycin families of antibiotics, may be used in the treatment of acne topically if combined with one of the penetration-enhancing agen~s described herein.
The antibiotics composi~ion so applied is carried into and through the epidermis and deeper layers o~ the skin as well as into follicles and comedones (sebum-plugged follicles which contain C. acnes) in ~Z~8~
therapeutically effective amounts and thereby successfully may be used to temporarily eliminate the signs and symptoms of acne.
The term "physiologically active agent'l is used herein to refer to a broad class of useful chemical and therapeutic agents including physiologically active steroids, antibiotics, antifungal agents, antibacterial agents, antineoplastic agent~, allergens, antihistaminic agents, anti-inflammatory agents, ultraviolet screening agents,diagnostic agents, perfumes, insect repellants, hair dyes, etc.
Dosage forms for topical a~plication may include solution nasal sprays, lotions, ointments, creams, gels, suppositories, sprays, aerosols and the like. Iypical inert carriers which make up the foregoing dosage forms include water, acetone, isopropyl alcohol, freons~ ethyl alcohol, poJyvinylpyrrolidone, propylene glycol, Eragrances, yel-producing materials, mineral oil, stearyl alcohol, stearic acid, spermaceti, ~orbitan monooleate, "Polysorbates", "Tweens", sorbital, methyl cellulose, etc.
~ he amount of the composition, and thus of the physiologically active agent therein, to be administe~ed will obviously be an effective amount for the desired result expected therefromO This, of course, will be ascertained by the ordinary ~kill of the practitioner.
Due to enhanced activity which is achieved, the dosage of physiologically active agent may often be decreased from that generally applicable. In accordance with the usual prudent formulating practices, a dosage near the lower end of the useful range of the particular physiologically active agent may be employed initially and the dosage increased as indicated from the observed response, as in the routine procedure of the phys;cian.
129~355~
The invention is further illustrated by the following examples which are illustratîve of various aspects of the invention, and are not intended as limiting the scope of the invention as defined by the appended claims.
A flame-dried flask was charged with a stirred suspension of 1.63g (67.8mmol~ of Na~(60% dispersion in mineral oil; washed free of oil with 2x20ml portion of dry petroleum ether) in 200ml dry toluene under N2. ~D the suspension 5.60g (56.5mmol) of hexamethyleneimine (azacycloheptane) was added dropwise and the mixture refluxed for 30 min. After cooling, 9.14ml (113mmol) of pyridine was added followed by a dropwise addition of 12.3g (56.5mm) o lauroyl chloride (n-dodecanoyl chloride) in lOOml of dry toluene. The mixture s~irred over the weekend at room temperature. Water was added to quench and the mixture extracted twice with ethyl acetate. The combined organic layers were dried with MgSO4 and concentrated i~ vac~10. The residue was subjected to flash chromatography, on silica (utllizing a 95/5:V/V solution of hexane and ethyl acetate) to give ~.62g (61%) of l-n-undecylformylazacycloheptane.
129~7 The compound of Example 1 was tested as penetration enhancing agents according to the below procedure:
Skin from female hairless mice, 4-6 weeks old, was removed from the animal and placed over penetration wells with normal saline bathing the corium. A plastic cylinder 1.4 cm in diameter was glued onto each piece on the epidermal side. O.l~ triamcinolone acetonide H3 was applied tO.Ol cc) to the epidermal surface within the 1.4 cm diameter cylinder. The skin was incubated at room temperature and ambient humldity.
At 6 hours and 24 hours, 2 cc were removed from the 10 cc reservoir o~ normal saline bathing ~he corium. The 2 cc of normal saline removed were replaced after the 6 hour sample with 2 cc of normal saline.
The 2 cc aliquots were put in~o ~cintillation fluid and the radioactivity determined in a scintillation counter. The amount penetrating was calculated as per cent of dose applied.
In this experiment the H3 triamcinolone acetonide was dissolved in ethanol and l-n-undecylformylazacycloheptane was added to the desired concentration.
The controls were ethanol~ alone, and l-n-dodecylazacycloheptan-2-one~ a compound described in the U.S. patent~, noted abovet as having superlor penetration-enhancing properties. Five separate tests for l-n-undecylformylazacycloheptane and the controls were made and the re~ults averaged.
The results, as reported in the Table below, show that the compound of Example 1 has superior penetration-enhancing properties.
~:9~57 . TABLE
Pene~ration-Enhancing Percent Penetration Agent 6 hr. 24 hr.
Example 1 13.02 60.28 l~n-dodecylcycloheptan-2-one 16.64 60.94 Ethanol (only) 0, 56 6 . 7 8 Ethanol (only, repeat) 0.5 5.64 As can be shown from the above results the compound of Example 1 has penetration-enhancing properties approximately equal to l-n-dodecylcycloheptan-2-ooe.
The following formulation is prepared:
.
. Solution (%) Griseofulvin l-n-undecylformylazacycloheptane Isopropyl myristate 5 Fragrance 0.1 Ethanol ~2.9 This formulation is effective in ~he treatment of fungal infections.
98~5~
An aerosol form of the formulation of Example 3 is prepared by peeparing the following mixture:
Formulation 25%
Freon*l Freon is 75/25 Freon 114/12.
~ he following cream formulation is prepared.
-.
Clindamycin base 1.0 Stearyl alcohol, U.S.P. 12.0 Ethoxyla~ed cholesterol 0.4 Synthetic spermaceti 7.5 Sorbitan monooleate 1.0 Polysorbate 80, U.S.P. 3.0 1-n-undecylformylazacycloheptane 0.5 Sorbitol solution, U.S.P. 5.5 Sodium citrate 0.5 Chemoderm*~844 Fragrance 0.2 Puri~ied water 68.4 ~ his formulation is effective in the treatment of acne.
*Trade mark '~
.
lZ~3BSS7 -17~
The following solutlon formulations are prepared:
_ Clindamycin base -- 1.0 Clindamycin phosphate acid 1.3 --Sodium hydroxide 0O077 --1.0 Molar hydrochloric acid -- 2.27 Di~odium edetate: 2H2o 0.003 0.003 Fragrances 0~5 0.5 1-n-undecylformylazacycloheptane 1.0 1.0 Purified water 20.0 17~73 _ _ IsoprorYnsL~ 71~12 77.~97 These solutions are effec~ive ~or the treatment of acne in humans.
The Eollowing solution formulation is prepared:
Neomycin sulfa~e 0.5 Lidocaine 0,5 l~ydrocortisone 0.25 - l-n-undecylformylazacycloheptane 0.5 Propvlene ~lycol _ _ ~8 ~5 __ This solution i~ effective for the treatment of otitis in domestic animals.
~LZ98S~7 The following sunscreen emulsion is prepared:
.
-- -- --p~aminobenzoic acid 2.0 senzyl alcohol 0,5 l-n-undecylEormylazacycloheptane 1.0 Polyethylene glycol 500 MS 10.0 Isopropyl lanolate 3~0 Lantr ol 1 . O
Acetylated lanolin 0.5 Isopropyl myristate 5.0 I.ight mineral oi.l 8.0 Cetyl alcohol 1~0 Veegum 1.0 Propylene glycol 3.0 Pur~ied w~er 64.0 The following antineoplastic solution is prepared:
_ - 5 Fluorouracil 5-~
l-n-undecylformylazacycloheptane 0.1 Polyethylene glycol 5.0 _ ~uri~i~d water ~2 ~298~S7 The followiny insect repellant atomizing spray i~
prepared:
.
Diethyltoluamide 0.1 l-n-undecylformylazacycloheptane 0~1 _ Ethanol . 99.8 The following lotion formulation may be prepared containing about 0.001 to 1 percent, with preferably 0.1 percent fluocinolone acetonide:
_ Fluocinolone acetonide 0.001-1 Cetyl alcohol 15.0 Propylene glycol 10.0 Sodium lauryl sulfate 15.0 l-n-undecylformylazacycloheptane 1.0 _ ~ate~ (to mak~ 100%) : The steroid is dissolved in the vehicle and added to a ~tirred, cooling melt of the other ingredientsO The preparation is particularly u5eful for the treatment of inflamed dermatoses by topical applicativn to the affected skin area. The amount and frequency of application is in accordance with ~tandard practice for topical application of this steroid. Penetration of the steroid into the inflamed tissue is enhanced and a therapeutic level is achieved more rapidly and sustained for longer duration than when the steroid is applied in conventional formulations.
Examples 3-11 are repeated except that l-n-undecylformylazacycloheptane is replaced with the following penetration-enhancing agents:
l-n-decylformylazacycloheptane l-n-octyl~ormylazacycloheptane l-n-nonylforrllylazacycloheptane l~n-dodecyl.formylazacycloheptane l-n-tridecylformylazacycloheptane l-n-tetradecylformylazacycloheptane l-n-hexadecylformylazacycloheptane l-n-pentadecylformylazacycloheptane l-n-heptadecylformylazacycloheptane 1-(16~methylhexadecyl)formylazacycloheptane Comparable results are obtained.
While particular embodiments of the invention have been described it will be understood o~ course that the invention is not limited thereto since many obvious modif icatlons can be made and it is intended to include within ~his invention any such modifications as will fall within the ECOpe of the appended claims.
Many physiologically active agents are best applied topically to obtain desir~ble results. Toplcal appl ication, as contrasted to systemic application, can avoid metabolic degradation of the agents, largely avoids side effects of the agents and permits high local concentrations of the agents~
The greatest problem ;n applying physiologically active agents topi~ally is that the ~kin is ~uch an effective barrier to penet~ation. The epidermis o the skin has an exterivr layer of dead cells called the stratum corneum which is tightly compacted and oily and which provides an effective barrier against gaseous, ~olid .
[L/N0539.RB01.1086CC]
~Z9~3~;S7 or liquid chemical agents, whether used alone or in water or oil solutions. If a physiologically active agent penetrates the stratum corneum, it can readily pass through the basal layer of the epidermis and into the dermis.
Although the effectiveness of the stratum corneum as a barrier provides great protectlon, lt also frustrates efforts to apply beneficial agents directly to local areas of the body. The inability of physiologically active agents to penetrate the stratum corneum prevents their effective use to treat such conditlons as inflammation, acne, psoriasis, herpes simplex, eczema, infections due to fungus, virus or other microorganisms~ or other disorders or conditions of the skin or mucous membranes, or oE
conditions beneath the exterior surface of the skin or mucous membranes. The stratum corneum also prevents the skin from ahsorbing and retaining cosmetic-type materials such as sunscreens, perfumes, mosquito repellants and the like.
Physiologically active agents may be applied to locally affected parts of the body through the vehicle system described herein. Vehicles such as USP cold cream, ethanol and various ointments, oils, aolvents, and emulsions have been used heretofore $o apply physiologically active ingredients locally. Most such vehicles are not effective to carry significant amounts of physiologically active agents through the skin. One such vehicle is dimethyl sulfoxide.
The l-lower alkyl substituted azacyclopentan-2~ones having 1-4 carbon atoms in the alkyl group are known to moderately enhance percu~aneous absorption of chemicals, ~Z~ i7 e.g. drugs. It was earlier recognized that it would be desirable to obtain the same or higher level of percutaneous absorption with substantially lower concentrations of the penetration-enhancing compound.
Therefore, a new class of N-substituted azacycloalkan-2-ones were invented having the desired properties. This new class of penetration-enhancing agents are described in U.S. Patents ~,~89/815; 3,989,816; 3,991/203; 4,122,170;
4,316,893; 4,405,616; 4,415~563; 4r423~040; 4,424,210; and 4944~,762.
It is an object of this invention to provide new penetration-enhancing agents having the deslrable property of enhancing the percutaneous absorptlon of physiologically-active agents at concentrations lower t,han the l-lower alkyl substituted azacyclopentan-2-ones.
It is also an object of this invention to provide penetration-enhancing agents that are equivalent to the aforesaid new class penetration-enhancing agents described in the above U.S. patents.
Other objects and advantages of the instant invent~on will be apparent from a careful reading of the specification below.
In this description, the term "animal" includes human beings as well as other forms of animal life, and especially domesticated animals and pets.
~L298S57 SU MMARY O F TH ~ I NV ENT I ON
This invention relates to compositions for carrying physiologically active agents through body membranes such as skin and for retaining these agents in ~ody tissues.
More specifically, the invention relate~ to compositions useful in topically administering a physiologically active agent to a human or animal comprising the agent and an effective, non-toxic amount of a compound having the structural formula R' (CH ~ m \ N-~-(CH2)n-R
~ 2 wherein X is selected from the group consisting of oxygen and sulfur; R' is ~l or a lower alkyl group having 1-4 carbon atoms; m is 2-S; n is 0-17 and R is -CH30 Preferably R is -CH3 and R' is H.
In a more preferred embodiment of ~he present invention R is -CH3, R' is H and m equals 4. Even more preferably n is 4-17l e.g. 10.
It has been found that the physiologically active agents are carried through body membranes by the above penetration-enhancing agents and are retained in body tissue.
~298SS7 DETAILED DESCRIPl'ION OF THE
INVENTION
The N-alkyl substituted azacycloalkanes useful as penetration-enhancing additives in the compositions of the instant invention may be made by the method described below. Typical examples of compounds represented by the above structural formula include:
l-n-undecylformylazacycloheptane l-n-decylormy1azacycloheptane l-n-octylformyla~acycloheptane l-n-nonylformylazacycloheptane l-n-dodecylformylazacycloheptane l-n-tridecylformylazacycloheptane 1 n-tetradecylformylazacycloheptane l-n-hexadecylformylazacycloheptane l-n-pentadecylformylaæacycloheptane l-n-heptadecylPormylazacycloheptane 1~16-methylhexadecyl)formylazacycloheptane The compounds represented by the above general formula, wherein X is oxygen, may be prepared by reacting the corresponding azacycloalkane with an alkanoyl halide in the presence of a base, eOg. sodium hydride. The reaction is carried out under anhydrous conditions in a hydrocarbon solYent, for example, dry toluene at reflux temperature for about 10 to 72 hours ~n an inert atmosphere, for example, nitrogen. This method is outlined below for the alkylformyl subst~tuted-azacycloalkane:
: ~ 2 (C~12) \ N H (1) NaH ~ O
\ / (2) R-(CI~2tn ~-Cl /
~9!8~;57 Any of the above compounds may be converted to the corresponding sulfur analog by reacting the oxygen-containing compound with phosphorus pentasulfide.
The amount of l-substituted azacycloalkane which may be used in the present invention is an effective, non-toxic amount for enhancing percutaneous absorption.
Generally, this amount ranges between about 0~01 to about 5 and preferably about 0.1 to 2 percent by weight of the composition.
The subject compositions may find use with many physiologically active agents which are soluble in the vehicles disclosed.
Fungi~tatic and fungicidal agents such asr for example, thiabendazole, chloroxine, amphotericin B, candicidin, fungimycin, nystatin, chlordantoin, clotrimazole, miconazole nitrate, pyrrolnitrin, ~alicyllc acid, fezatione, tolnaftate, triacetin and ~inc and sodium pyrithione may be dissolved in the penetration-enhancing agents descIibed herein and topically applied to affected areas o~ the skin. For example, fungi~tatic or fungicidal agents so applied are carried through the stratum corneum, and thereby successfully treat fungus-caused skin problems. These agents, thus applied, not only penetrate more ~uickly than when applied in the vehicles of the prior art, but additionally enter the animal tissue in high concentrations and are retained ~or substantially longer time periods whereby a far more successful treatment is effected.
For example, the subject compositions may also be employed in the treatment of fun~us infections on the ~kin caused by candida and dermatophytes which cause athlete's ;;S7 foot or ringworm, by dissolving thiabendazole or similar antifungal agents in one of the above-described penetration-enhancing agents and applying it to the affected area.
The subject compositions are also useful in treating skin problems, for example, herpes simplex, which may be treated by a solution of iododeoxyuridine dissolved in one of the penetration-enhancing agents or such problems as warts which may be treated with agents such as podophylline dissolved in one of the penetration-enhancing agents. Skin problems such as psoriasis may be treated by topical application of a solution of a conventional ~opical steroid in one of the penetration-enhancing agents or by treatment with theophylline or antagonists of ~-adrenergic blockers such as isoproterenol in one of the penetration~enhancing agents. Scalp conditions such as alopecia areata may be treated more effectively by applying steroids such as triamcinolone acetonide dissolved in one of the penetration-enhancing agents of this invention directly to the scalp.
The subject compositions are also useful for treating mild eczema, for example, by applying a solution of 1uocinolone acetonide or its derivatives; hydrocortisone triamcinolone acetonider indomethacin, or phenylbutazone dissolved in one of the penetration-enhancing agents to the a~fected area~
Examples of other physiologically active steroids which may be used with the vehi~les include corticosteroids such as, for example, cortisone, cortsdoxone, flucetonide, fluorocortisone, difluorsone diacetate, flurandrenolone acetonide, medry~one, amcinafel, amcinafide~ betamethasone and its esters, chloroprednisone, clocortelone, descinolone, desonideS
~29~3557 dexamethasone, dichlorisone, defluprednate, flucloronide, fl~methasone, flunisolide, fl~ocinonide, flucortolone, ~luoromethalone~ fluperolone, fluprednisolone, meprednisone, methylmeprednisolone, paramethasone, prednisolone and prednisone.
The subject compositions are also useful in antibacterial chemotherapy/ e.g. in the treatment of skin conditions involvin~ pathogenic bacteria. qypical antibacterial agents which may be used in this invention include sulfonamides, penicillins, cephalosporins, penicillinase~ erythromycins, lincomycins, vancomycins, tetracyclines, chloramphenicols, streptomycins, etc.
Typical examples of the foregoing include erythromycin, erythromycin ethyl carbonate, erythromycin estolate, erythromycin glucepate, erythromycin ethylsuccinate, ery~hromycin lactobionate, lincomycin, clindamycin, tetracycline, chlortetracycline, demeclocycline, doxycycline, methacycline, oxytetracycline, minocycline, etc The subject compositions are also useful in protecting ultra-sensitive skin or even normally ~ensitive skin from damage or discomfort due to sunburn. Thus, dermatitis actinica may be avoided by application of a sunscreen, such as para~aminobenzoic acid or its well-known derivatives dissolv~d in one of the above-described penetration-enhancing agents, to skin surfaces that are to be exposed to the sun; and the protective para-aminobenzoic acid or it~ derivatives will be carried into the stratum corneum more uccessfully and will therefore be retained even when exposed to water or washing for a substantially longer period of ~ime than when applied to E3S~7 the skin in conventional vehicles. This invention is particularly useful for ordinary suntan lotions used in activities involving swimming because the ultraviolet screening inyredients in the carriers of the prior art are washed off the skin when it ls immersed in water.
The subjec~ compositions may also find use in treating scar tissue by applying agents which soften collagen, such as aminopropionitrile or penicillamine dissolved in one of the penetration-enhancing agents of this invention topically to the scar tissue.
Agents normally applied as eye drops, ear drops, or nose drops are more effective when dissolved in the penetration-enhancing agents of this invention.
Agent~ used in diagnosis may be used more effectively when applied dissolved in one of the penetration-enhancing agents of this invention. Patch tests to diagnose allergies may be effected promptly without scratching the skin or covering the area subjected to an allergen when the allergens are applied in one of the penetration-enhancing agents of this invent~on.
The subje~t compositions are also useful for topical application of cosmekic or esthetic agents. For example, compounds such as melanin-stimulating hormone (MSH) or dihydroxyacetone and the like are more efectively applied to skin ~o stimulate a suntan when they are dissolved in one o the penetration-enhancing agents of this invention~ The agent is carr~ed into the skin more quickly and in greater quantity when applied in accordance with this invention. Hair dyes also penetrate more completely and effectively when diæsolved in one of the penetration-enhancing agents of this invent~on.
lZ~35~7 ;--10--The effectiveness o 6uch topically applied materials as insect repellants or fragrances, such as perfumes and colognes, can be prolonged when such agent~ are applied dissolved in one of the penetration-enhancing agents of this invention.
It is to be emphasized that the foregoing are simply examples of physiologically active agents including therapeutic and cosmetic agents having known effects for known conditions, which may be used more effectively for their known properties in accordance with this invention.
In addition, the penetration-enhancing ayents of the present invention may also be used to produce therapeutic effects which were not previously known. That is, by use of the penetration-enhancing agents described herein, therapeutic effects heretofore not known can be achieved.
As an example o the foregoing, griseofulvin is known as the treatment of choice for fungal infections of the skin and nails. Heretofore, the manner of delivery of griseoulvin has been oral. E~owever, it has long been known that oral treatment is not preferred because of side effects resulting from exposure of the entire body to griseoulvin and the fact that only the outer layers of affected skin need to be treated. Therefore, because fungal infec~ions are generally infections of the skin and nails, it would be advantageous to utilize griseofulvin topically. However, despite a long-felt need for a topical griseofulvin, griseo~ulvin has been used orally to trea~ topical fungal conditions because there was not heretofore known any formulation which could be delivered topically which would cause ~ufficient retention of griseofulvin in the skin to be useful therapeutically ~ owever, it has now been discovered that griseofuïvin, in a range of therapeutic concentrations ~LZ98~i57 between about 0.1% and about 10% may be used effectively topically if combined with one of the penetration-enhancing agents described herein.
As a further example, acne is the name commonly applied to any inflammatory disease of the ~ebaceous glands; also acne vulgaris. The mlcroorganism typically responsible for the acne infection is Corynebacterium acnes. Various therapeutic methods for ~reating a~ne have been attempted including topical antibacterialsg e.g.
hexachlorophene, and systemic antibiotics such as tetracycline~ While the systemic antibiotic treatments are known to be partially e~fective, the topical treatments are generally not e~fective.
It has long been known that systemic treatment of acne is not preferred because of side effects resulting from exposure of the entire body to antibiotics and the fact that only the affected skin need be treated.
~lowever, despite a long-felt need for a topical treatment for acne, antibiotics generally have been used only systemically to treat acne because there was not heretofore known an antibacterial formulation which could be used topically which would be effective therapeutically in the treatment of acne. HoweYer, it has now been discovered that antibiotics, especially those of the lincomycin and erythromycin families of antibiotics, may be used in the treatment of acne topically if combined with one of the penetration-enhancing agen~s described herein.
The antibiotics composi~ion so applied is carried into and through the epidermis and deeper layers o~ the skin as well as into follicles and comedones (sebum-plugged follicles which contain C. acnes) in ~Z~8~
therapeutically effective amounts and thereby successfully may be used to temporarily eliminate the signs and symptoms of acne.
The term "physiologically active agent'l is used herein to refer to a broad class of useful chemical and therapeutic agents including physiologically active steroids, antibiotics, antifungal agents, antibacterial agents, antineoplastic agent~, allergens, antihistaminic agents, anti-inflammatory agents, ultraviolet screening agents,diagnostic agents, perfumes, insect repellants, hair dyes, etc.
Dosage forms for topical a~plication may include solution nasal sprays, lotions, ointments, creams, gels, suppositories, sprays, aerosols and the like. Iypical inert carriers which make up the foregoing dosage forms include water, acetone, isopropyl alcohol, freons~ ethyl alcohol, poJyvinylpyrrolidone, propylene glycol, Eragrances, yel-producing materials, mineral oil, stearyl alcohol, stearic acid, spermaceti, ~orbitan monooleate, "Polysorbates", "Tweens", sorbital, methyl cellulose, etc.
~ he amount of the composition, and thus of the physiologically active agent therein, to be administe~ed will obviously be an effective amount for the desired result expected therefromO This, of course, will be ascertained by the ordinary ~kill of the practitioner.
Due to enhanced activity which is achieved, the dosage of physiologically active agent may often be decreased from that generally applicable. In accordance with the usual prudent formulating practices, a dosage near the lower end of the useful range of the particular physiologically active agent may be employed initially and the dosage increased as indicated from the observed response, as in the routine procedure of the phys;cian.
129~355~
The invention is further illustrated by the following examples which are illustratîve of various aspects of the invention, and are not intended as limiting the scope of the invention as defined by the appended claims.
A flame-dried flask was charged with a stirred suspension of 1.63g (67.8mmol~ of Na~(60% dispersion in mineral oil; washed free of oil with 2x20ml portion of dry petroleum ether) in 200ml dry toluene under N2. ~D the suspension 5.60g (56.5mmol) of hexamethyleneimine (azacycloheptane) was added dropwise and the mixture refluxed for 30 min. After cooling, 9.14ml (113mmol) of pyridine was added followed by a dropwise addition of 12.3g (56.5mm) o lauroyl chloride (n-dodecanoyl chloride) in lOOml of dry toluene. The mixture s~irred over the weekend at room temperature. Water was added to quench and the mixture extracted twice with ethyl acetate. The combined organic layers were dried with MgSO4 and concentrated i~ vac~10. The residue was subjected to flash chromatography, on silica (utllizing a 95/5:V/V solution of hexane and ethyl acetate) to give ~.62g (61%) of l-n-undecylformylazacycloheptane.
129~7 The compound of Example 1 was tested as penetration enhancing agents according to the below procedure:
Skin from female hairless mice, 4-6 weeks old, was removed from the animal and placed over penetration wells with normal saline bathing the corium. A plastic cylinder 1.4 cm in diameter was glued onto each piece on the epidermal side. O.l~ triamcinolone acetonide H3 was applied tO.Ol cc) to the epidermal surface within the 1.4 cm diameter cylinder. The skin was incubated at room temperature and ambient humldity.
At 6 hours and 24 hours, 2 cc were removed from the 10 cc reservoir o~ normal saline bathing ~he corium. The 2 cc of normal saline removed were replaced after the 6 hour sample with 2 cc of normal saline.
The 2 cc aliquots were put in~o ~cintillation fluid and the radioactivity determined in a scintillation counter. The amount penetrating was calculated as per cent of dose applied.
In this experiment the H3 triamcinolone acetonide was dissolved in ethanol and l-n-undecylformylazacycloheptane was added to the desired concentration.
The controls were ethanol~ alone, and l-n-dodecylazacycloheptan-2-one~ a compound described in the U.S. patent~, noted abovet as having superlor penetration-enhancing properties. Five separate tests for l-n-undecylformylazacycloheptane and the controls were made and the re~ults averaged.
The results, as reported in the Table below, show that the compound of Example 1 has superior penetration-enhancing properties.
~:9~57 . TABLE
Pene~ration-Enhancing Percent Penetration Agent 6 hr. 24 hr.
Example 1 13.02 60.28 l~n-dodecylcycloheptan-2-one 16.64 60.94 Ethanol (only) 0, 56 6 . 7 8 Ethanol (only, repeat) 0.5 5.64 As can be shown from the above results the compound of Example 1 has penetration-enhancing properties approximately equal to l-n-dodecylcycloheptan-2-ooe.
The following formulation is prepared:
.
. Solution (%) Griseofulvin l-n-undecylformylazacycloheptane Isopropyl myristate 5 Fragrance 0.1 Ethanol ~2.9 This formulation is effective in ~he treatment of fungal infections.
98~5~
An aerosol form of the formulation of Example 3 is prepared by peeparing the following mixture:
Formulation 25%
Freon*l Freon is 75/25 Freon 114/12.
~ he following cream formulation is prepared.
-.
Clindamycin base 1.0 Stearyl alcohol, U.S.P. 12.0 Ethoxyla~ed cholesterol 0.4 Synthetic spermaceti 7.5 Sorbitan monooleate 1.0 Polysorbate 80, U.S.P. 3.0 1-n-undecylformylazacycloheptane 0.5 Sorbitol solution, U.S.P. 5.5 Sodium citrate 0.5 Chemoderm*~844 Fragrance 0.2 Puri~ied water 68.4 ~ his formulation is effective in the treatment of acne.
*Trade mark '~
.
lZ~3BSS7 -17~
The following solutlon formulations are prepared:
_ Clindamycin base -- 1.0 Clindamycin phosphate acid 1.3 --Sodium hydroxide 0O077 --1.0 Molar hydrochloric acid -- 2.27 Di~odium edetate: 2H2o 0.003 0.003 Fragrances 0~5 0.5 1-n-undecylformylazacycloheptane 1.0 1.0 Purified water 20.0 17~73 _ _ IsoprorYnsL~ 71~12 77.~97 These solutions are effec~ive ~or the treatment of acne in humans.
The Eollowing solution formulation is prepared:
Neomycin sulfa~e 0.5 Lidocaine 0,5 l~ydrocortisone 0.25 - l-n-undecylformylazacycloheptane 0.5 Propvlene ~lycol _ _ ~8 ~5 __ This solution i~ effective for the treatment of otitis in domestic animals.
~LZ98S~7 The following sunscreen emulsion is prepared:
.
-- -- --p~aminobenzoic acid 2.0 senzyl alcohol 0,5 l-n-undecylEormylazacycloheptane 1.0 Polyethylene glycol 500 MS 10.0 Isopropyl lanolate 3~0 Lantr ol 1 . O
Acetylated lanolin 0.5 Isopropyl myristate 5.0 I.ight mineral oi.l 8.0 Cetyl alcohol 1~0 Veegum 1.0 Propylene glycol 3.0 Pur~ied w~er 64.0 The following antineoplastic solution is prepared:
_ - 5 Fluorouracil 5-~
l-n-undecylformylazacycloheptane 0.1 Polyethylene glycol 5.0 _ ~uri~i~d water ~2 ~298~S7 The followiny insect repellant atomizing spray i~
prepared:
.
Diethyltoluamide 0.1 l-n-undecylformylazacycloheptane 0~1 _ Ethanol . 99.8 The following lotion formulation may be prepared containing about 0.001 to 1 percent, with preferably 0.1 percent fluocinolone acetonide:
_ Fluocinolone acetonide 0.001-1 Cetyl alcohol 15.0 Propylene glycol 10.0 Sodium lauryl sulfate 15.0 l-n-undecylformylazacycloheptane 1.0 _ ~ate~ (to mak~ 100%) : The steroid is dissolved in the vehicle and added to a ~tirred, cooling melt of the other ingredientsO The preparation is particularly u5eful for the treatment of inflamed dermatoses by topical applicativn to the affected skin area. The amount and frequency of application is in accordance with ~tandard practice for topical application of this steroid. Penetration of the steroid into the inflamed tissue is enhanced and a therapeutic level is achieved more rapidly and sustained for longer duration than when the steroid is applied in conventional formulations.
Examples 3-11 are repeated except that l-n-undecylformylazacycloheptane is replaced with the following penetration-enhancing agents:
l-n-decylformylazacycloheptane l-n-octyl~ormylazacycloheptane l-n-nonylforrllylazacycloheptane l~n-dodecyl.formylazacycloheptane l-n-tridecylformylazacycloheptane l-n-tetradecylformylazacycloheptane l-n-hexadecylformylazacycloheptane l-n-pentadecylformylazacycloheptane l-n-heptadecylformylazacycloheptane 1-(16~methylhexadecyl)formylazacycloheptane Comparable results are obtained.
While particular embodiments of the invention have been described it will be understood o~ course that the invention is not limited thereto since many obvious modif icatlons can be made and it is intended to include within ~his invention any such modifications as will fall within the ECOpe of the appended claims.
Claims (34)
1. A composition comprising an effective amount of a physiologically active agent and a non-toxic, effective penetrating amount of a compound having the structural formula wherein X is selected from the group consisting of oxygen and sulfur; R' is H or a lower alkyl group having 1-4 carbon atoms; m is 2-6; n is 0-17 and R is -CH3.
2. The composition of claim 1 wherein the physiologically active agent is an antibacterial agent.
3. The composition of claim 2, wherein the antibacterial agent is an antibiotic.
4. The composition of claim 3 wherein the antibiotic is selected from the group consisting of lincomycin, clindamycin, erythromycin and pharmaceutically useful salt thereof.
5. The composition of claim 1 wherein the physiologically active agent is a physiologically active steroid.
6. The composition of claim 1 wherein the physiologically active agent is an antifungal agent.
7. The composition of claim 1 wherein the physiologically active agent is iododeoxyuridine.
8. The composition of claim 1 wherein the physiologically active agent is 5-fluorouracil.
9. A composition useful for topically administering a physiologically active agent to a human or animal comprising an effective amount of a physiologically active agent and a non-toxic, effective penetrating amount of a compound having the structural formula wherein X is selected from the group consisting of oxygen and sulfur; m is 4; n is 4-17 and R is -CH3.
10. The composition of claim 9 wherein the physiologically active agent is an antibacterial agent.
11. The composition of claim 9 wherein the antibacterial agent is an antibiotic.
12. The composition of claim 11 wherein the antibiotic is selected from the group consisting of lincomycin, clindamycin, erythromycln and pharmaceutically useful salts thereof.
13. The composition of claim 9 wherein the physiologically active agent is a physiologically active steroid.
14. The composition of claim 9 wherein the physiologically active agent is an antifungal agent.
15. The composition of claim 9 wherein the physiologically active agent is iododeoxyuridine.
16. The composition of claim 9 wherein the physiologically active agent is 5-fluorouracil.
17. The composition of claim 9 wherein X is oxygen.
18. A use of an effective amount of a physiologically active agent in the presence of a non-toxic compound having the structural formula wherein X is selected from the group consisting of oxygen and sulfur; R' is H or a lower alkyl group having 1-4 carbon atoms; m is 2-6; n is 0-17 and R is -CH3.
19. The use of claim 18 wherein the physiologically active agent is an antibacterial agent.
20. The use of claim 19, wherein the antibacterial agent is an antibiotic.
21. The use of claim 20 wherein the antibiotic is selected from the group consisting of lincomycin, clindamycin, erythromycin and pharmaceutically useful salts thereof.
22. The use of claim 18 wherein the physiologically active agent is a physiologically active steroid.
23. The use of claim 18 wherein the physiologically active agent is an antifungal agent.
24. The use of claim 18 wherein the physiologically active agent is iododeoxyuridine.
25. The use of claim 18 wherein the physiologically active agent i s 5-fluorouracil.
26. A. use of a physiologically active agent in the presence of a non-toxic, effective penetrating amount of a compound having the structural formula wherein X is selected from the group consisting of oxygen and sulfur, m is 4; n is 4-17 and R is -CH3.
27. The use of claim 26 wherein the physiologically active agent is an antibacterial agent.
28. The use of claim 27 wherein the antibacterial agent is an antibiotic.
29. The use of claim 28 wherein the antibiotic is selected from the group consisting of lincomycin, clindamycin, erythromycin and pharmaceutically useful salts thereof.
30. The use of claim 26 wherein the physiologically active agent is a physiologically active steroid.
31. The use of claim 26 wherein the physiologically active agent is an antifungal agent.
32. The use of claim 26 wherein the physiologically active agent is iododeoxyuridine.
33. The use of claim 26 wherein the physiologically active agent is 5-fluorouracil.
34. The use of claim 26 wherein X is oxygen.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US82504186A | 1986-01-31 | 1986-01-31 | |
| US825,041 | 1986-01-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1298557C true CA1298557C (en) | 1992-04-07 |
Family
ID=25242979
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000528478A Expired - Fee Related CA1298557C (en) | 1986-01-31 | 1987-01-29 | Compositions comprising 1-substituted azacyclo-alkanes |
Country Status (5)
| Country | Link |
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| EP (1) | EP0258385A4 (en) |
| JP (1) | JPS63502590A (en) |
| AU (1) | AU7031887A (en) |
| CA (1) | CA1298557C (en) |
| WO (1) | WO1987004593A1 (en) |
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|---|---|---|---|---|
| ATE84667T1 (en) * | 1986-01-31 | 1993-02-15 | Whitby Research Inc | SKIN PENETRATION IMPROVING COMPOSITIONS. |
| US4755535A (en) * | 1986-04-23 | 1988-07-05 | Nelson Research & Development Co. | Compositions comprising 1-substituted azacycloalkenes |
| US4801586A (en) * | 1986-04-23 | 1989-01-31 | Nelson Research & Development Co. | Penetration enhancers for transdermal delivery of systemic agents |
| DE4341986A1 (en) * | 1993-12-09 | 1995-06-14 | Bayer Ag | Use of carboxylic acid amides as crystallization inhibitors |
| CN1852690B (en) | 2003-09-19 | 2010-04-14 | 制药技术有限公司 | Medicament conveying system |
| EP2710892B1 (en) | 2009-07-21 | 2016-12-14 | Marrone Bio Innovations, Inc. | Use of sarmentine and its analogs for controlling weeds |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4021224A (en) * | 1971-12-09 | 1977-05-03 | Stauffer Chemical Company | Herbicide compositions |
| US3966806A (en) * | 1973-11-19 | 1976-06-29 | Stauffer Chemical Company | Insect repellent compounds |
| US3960922A (en) * | 1973-11-19 | 1976-06-01 | Stauffer Chemical Company | N-cyanomethyl-N-methyl-3,5-dimethylbenzamide |
| NL7609725A (en) * | 1975-09-06 | 1977-03-08 | Hoechst Ag | ALKOXY DERIVATIVES OF N-SUBSTITUTED CYCLIC AMINES AND PROCEDURE FOR THEIR PREPARATION. |
| JPS54943A (en) * | 1977-06-06 | 1979-01-06 | Panafacom Ltd | Data processor |
| US4264594A (en) * | 1979-02-02 | 1981-04-28 | The United States Of America As Represented By The Secretary Of Agriculture | Insect repellents |
| US4356180A (en) * | 1979-02-02 | 1982-10-26 | The United States Of America As Represented By The Secretary Of Agriculture | Insect repellants |
| US4230726A (en) * | 1979-06-29 | 1980-10-28 | The United States Of America As Represented By The Secretary Of Agriculture | Control of parasitic mites with alkyl amines |
| DE2947648A1 (en) * | 1979-11-27 | 1981-08-06 | C.F. Spiess & Sohn GmbH & Co, 6719 Kleinkarlbach | USE OF TERTIARY HETEROCYCLIC AMINES AS A POTENCING AGENT FOR INSECTICIDES |
| US4374851A (en) * | 1980-03-26 | 1983-02-22 | The United States Of America As Represented By The Secretary Of Agriculture | Method of controlling parasitic ticks |
| US4743588A (en) * | 1984-06-13 | 1988-05-10 | Allergan Pharmaceuticals, Inc. | Compositions and methods of enhancing transdermal and transmembrane penetration systemic agents |
| US4621143A (en) * | 1984-06-27 | 1986-11-04 | The United States Of America As Represented By The Secretary Of Agriculture | Cockroach repellants |
-
1987
- 1987-01-29 AU AU70318/87A patent/AU7031887A/en not_active Abandoned
- 1987-01-29 WO PCT/US1987/000189 patent/WO1987004593A1/en not_active Application Discontinuation
- 1987-01-29 JP JP50134087A patent/JPS63502590A/en active Pending
- 1987-01-29 EP EP19870901793 patent/EP0258385A4/en not_active Withdrawn
- 1987-01-29 CA CA000528478A patent/CA1298557C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| AU7031887A (en) | 1987-08-25 |
| JPS63502590A (en) | 1988-09-29 |
| WO1987004593A1 (en) | 1987-08-13 |
| EP0258385A4 (en) | 1989-04-12 |
| EP0258385A1 (en) | 1988-03-09 |
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