US 2241331 A
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Description (OCR text may contain errors)
Patented May 6,1941
NITED-f STATE "sorrosrroay mm s. Shelton, inn-1mm, and Louis ma;
Beading, Ohio, assignors 'to The Wm.
$.Merrell Company, Reading, Ohio, acorporationofDelaware No Drawing. Application January Serial N- 253,22
This invention relates to improved suppositories. It relates more particularly to improved suppositories having a base including, as a principal ingredient, an ester of apolyhydric alcohol having four to six hydroxyl groups or an anhydride thereof, particularly an ester of a sugar alcohol, or a mixture of such esters.
Suppositories are widely used for various types of medical-treatment, including the treatment of hemorrhoids and other rectal conditions, vaginitis, leucorrhea, constipation, etc, as well as for the administration of drugs or other therapeutic agents intended to be absorbed, as for narcosis and the like. The suppository vehicles or bases most commonly used include glycerin, gelatin,
soap, cocoa butter, etc. Cocoa butter, which is approximately the same as that of body temperature, is widely used. Such oily or fatty compositions as cocoa butter have many objectionable properties. With certain medicaments, they tend to mask or hinder the action of the drug and interfere with the treatment, so that in many cases administration is inaccurate, unreliable, and in some cases, where such hindrance is extreme, may even be completely prevented. Cocoa butter on melting yields an odorous yellow oily material which tends to leak out of the body cavities. Its oily nature tends to prevent contact of water soluble medicaments with the mucous membranes, and to hold oil soluble medicaments in solution so that they are not readily available to the parts to be treated. Many common therapeutic agents, particularly such insoluble solids as the bismuth or zinc compounds increase the viscosity of melted cocoa butter and prevent ready liquefaction oi the mixture in the body, with the result that the medicament may not be released, but may be held in the agglomerated lump of the suppository, and may be excreted without exerting its therapeutic effect.
The present invention provides suppository vehicles or bases which have important advantages over previously proposed or used suppository vehicles or bases and which permit more effective and reliable suppository medication. The suppository bases or vehicles of the invention, while unctuous and plastic, are not oily or fatty in namm, 1. e., they have the plasticity and unctuousness required for a suppository base, but are hydrophilic rather than hydrophobic in nature. They are capable of absorbing substantial quantitles of water. Their melting point and viscosity after melting is readily adjusted so that a suppository having a proper melting point and fluidity in use is readily prepared irrespective of the relatively inexpensive and has a melting point nitan, mannide, etc.
nature of the medicament which it cont n- As the new suppository bases or vehicles are not of an oily or fatty nature, they may be .used with either water soluble or oil soluble medicaments. or, insoluble medicaments, with the important advantage that irrespective of the nature oi the medicaments, it is carried in the suppository in a condition such that it is readily available and capable of contact with, or absorption by, the mucous membranes of the body cavities. The capacity of the new vehicle orbase for absorbing water, and of swelling to a bulk which may be several times greater than its originalbulk is an important advantage, both because it permits penetration of the suppository body by the aqueous fluids oi the body for extraction of any medicaments from the suppository base or vehicle by permeation and difiusion of the water soluble materials and because the swelling of the suppository base conforms it to the shape of the body cavity or canal, bringing it into constant, intimate contact with the mucous membranes and bringing about more eilective medication. The ready adjustment of the melting point of the suppository bases or vehicles of the invention is an important advantage, because it-permits the productionoi suppositories containing a wide variety of therapeutic materials, some of which may effect the melting point and some of which may not, all having the property of melting at body temperature.
In accordance with the present invention, suppositories are prepared with the use of a suppository base or vehicle containing, as a principal constituent, an organic ester of a p y ydric a1- cohol having from four to six hydroxyl groups or an anhydride of such an alcohol, derived therefrom by the removal of one or two molecules of water, such as the organic esters of penta-erythritol, erythri tol, mannitol, sorbitol, dulcitol, iditol, talitol, arabitol, xylitol, etc., as well as their anhydrides, including sorbi-tan, man- The organic esters of the sugar alcohols have important advantages for use in preparing the new suppositories. By the term sugar alcohol, we mean those alcohols which correspond to the tetroses, pentcses and hexoses, including not only .the tetrahydric, penta-hydric and hexahydric alcohols, but also their anhydrides, including the alcohols derived from such pentahydric or hexahydric alcohols by the removal of oneor twomolecules of water, and mixtures which may contain one or more of the pentahydric or hexahydric alcohols, and one or more of the anhydridesof such alcohols. Included among thesugar alcoholsare ,niannitol,
of one or more equivalents of the acid withone mole of the alcohol, with the production of monoacid esters, di-acid esters, tri-acid esters, etc., and mixtures of these various esters of a more or less complex nature. These esters are unctuous bodies, having v ying melting points, depending upon the particular alcohol, the particular acid or acids used in. esterifying, and the degree of esteriflcation, that is, whether the ester is a mono-acid ester, a di-acid ester, etc.
liquid at ordinary temperatures or body temperatures, whereas others, for example, sorbitol stearate and penta-erythritol stearate, have melting points as high as about 50 0., or even higher. The melting points of the bemodifledbyadmixtureoftwoormoreesters, or by the addition of other modifying agents as will be hereinafter explained.
Along with the alcohol ester or esters it is advantageous to include in the suppository base or vehicle an emulsifying or wetting agent. Such agents increase the capacity of the ester base to absorb water and swell, and also increase the permeation or penetration of the base by aqueous liquids and hence increase the rate of transfer of water soluble or othermedicaments from the suppository base to the mucous membranes. Among the emulsifying or wetting agents which may be used with advantage are the gums, such as gum trasacanth, gum acacia, karaya gum, etc., soaps, including the ordinary sodium soaps, such as sodium palmitate or oleate, the amsuperglycerinated fats, stearate, fatty acid esters of ethyleneglycol and hydroxypolyalkylene oxides, such as glycol monostearate, glycol mono-oleate,
products of oleic acid and mono-ethanoiamine, etc. It is advaninclude both a gum. and a wetting algent, e. g., Karaya gum and triethanolamm' e Where the ester used in forming the suppository base or vehicle has a melting point which is too high or too low for the production or! a suppository with a proper melting point, giving due consideration to the effect of any medicament used upon the melting point, it is readily adjusted by the addition of a suitable modifying agent, such as a petroleum; oil or wax, e. 8-. light mineral oil U. 8. P., paraflin or ceresine, or b the addition of a vegetable or animal wax, such as carnauba wax, spermaoetti or beeswax, bythe additionof avegetableor animal oilsuch as sunflower seed oil by the addition such as ethyl palmitate, butyl stearate. ethyl laurate, methyl undecylineate, ethyl myristate, or the mixed esters of fatty acids derived from animal or vegetable oils with low molecular weight alcohols such as methyl alcohol, ethyl alcohol, etc. The mixed ethyl esters of the fatty acids derived from sunflower seed oil have important advantages for use as an agent to lower the melting point of a high melting ester in a suppository base because these mixed ethyl esters do not tend to exude and because they blend very well with other ingredients used in suppositories.
Along with the polyhydric alcohol ester, and advantageously an emulsifying or wetting agent, with such melting point modifying agent as my be necessary or desirable, the suppositories will ordinarily include one or more therapeutic agents, such as antiseptics, anaesthetics, analgesics, healing agents, vaso-pressor compounds, alkaloids, as'tringents, bismuth or zinc compounds, etc., either intended for medication by local application or for absorption. through the mucous membrances. Thus the suppositories may include such local anaesthetics as piperidlno-propanediol-diphenyl-urethrane, such antiseptics as organic mercurials, ammonium salts, oiwquinoline benzoate, ethylmeta-amino-parahydroxy benzoate, etc., such bismuth compounds as bismuth subiodide, bismuth subgallate, bismuth resorcinate, and bismuth iodotannate, zinc oxide, tannic acid, witch hazel extract, etc., intended for the treatment of hemorrhoids, vaginitis, leucorrhea, etc., by local application, as well as products such as the barbiturates, chloral hydrate and the like intended to be absorbed through the mucous membranes. In any event, suppository medication with the use of such products is greatly improved where the new bases or vehicles of the present invention are used, both because of improved transfer of the med; rents from the vehicle or baseto the mucous membranes or the aqueous fluids in which they are bathed, because of the increase in contact between the walls of the body cavity and the suppositories and because of the desirable physical properties and proper melting point of the suppositories.
The higher fatty acid esters of sorbitol and mannitoL- that is, the esters of sorbitol and mannitol with fatty acids having at least twelve carbon atoms and ordinarily derived from the naturally occurring fats and oils, and particularly sorbitol and mannitol stearate, laurate. oleate. and ricinoieate, have important advantages for the production of suppository bases or vehicles in accordance with the present invention. The sorbitol stearates and oleates are commercially available at relatively low prices, are quite stable, lend themselves to the preparation of suppositories which readily absorb or emulsify with relatively large amounts of water to swell and conform to the shape of the body cavities, readily yield medicaments to the aqueous fluids, are free from disagreeable odor and are completely bland and unctuous. The commercially available esters, e. g., sorbitol stearate, consist of mixtures of mono-, diand tri-acid esters of sorbitol and sorbitan, produced by reaction of sorbitol with the fatty acid in the presence of a small amount of an acid catalyst, or in other ways. During such process, one or two molecules of water may split off from a portion of the sorbitol, with formation of anhydrides of sorbitol in the mixture, so that the flnal product is probably a mixture of sorbitol and sorbitan fatty acid esters. In referring to sorbitol stearate in the present a,241,ss1
application and claims; such commercially occurring mixtures are included. The sorbitol stearates may be produced with relatively high melting points, for example, about40 to 50 0., or may be produced with lower melting points, for example, such that they are liquid at ordinary room temperatures. The melting points of the final suppositories in which sorbitol stearate is employed as a base or vehicle is readily adjusted by the addition of mineral oilsor waxes or vegetable or animal oils or waxes, alkyl esters of .fatty acids, etc. The melting point of the sorbitol stearate will depend largely upon the extent of the esterification, that is, on the proportion of the mono-, diand tri-stearates of the sorbitol and sorbitan present, and also upon the extent to which anhydrides of sorbitol, that is, sorbitan and its esters are present in the product. The sorbitol oleates and ricinoleates which similarly have important advantages for use in the present invention, in general are liquid at body and somewhat lower temperatures, and the melting point of suppositories in which sorbitol oleate or ricinoleate is used as a base or vehicle may be adjusted by the addition of mineral, vegetable or animal waxes, or medicaments which raise the melting point, so that the final product has the proper melting point for a suppository. The corresponding mannitol derivatives are almost identical in their properties, and
uses. In general, with the sorbitol and mannitol oleates, stearates and ricinoleates, there are important advantages in including in the suppositories an emulsifying agent and a wetting agent,
advantageously a wetting agent such as triethanolamine oleate and a gum, such as karaya The following examples illustrate specific suppository compositions which embody the invention and involve the use of sorbitol stearate or sorbitol oleate as a base or vehicle; but it will be understood that the invention is not limited thereto, but includes suppositories having a base made from any one or more of the wide range of sugar alcohol esters described above, together with one or more of the various wetting or dispersing agents, modifying agents, such as mineral oils, or waxes, vegetable oils or waxes, animal oils or waxes, other or different medicaments, etc.
Exsmam I.-Local anaesthetic suppository Parts Sorbitol stearate (M. P. 41 C.) .r 72. Parailin (M. P. 50 C.) 8. 0 Light mineral oil (U. S. P.) 11. 9 Triethanolamine 1.5 Oleic Mid 3.0 Karaya gum, powd, 2.5 Piperidinopropanediol diphenyl urethrane free base v I i 1.0 Oxyquinoline benzoate 0.1 EXAMPLE II.Hem0rrhoid suppositories Parts Bismuth slibindide 3. 33 Bismuth subgallate 3. 33 Zinc oxide 3. 33 Resorcinol 0. 34 Balsam of Peru 1. 67 Penta-erythritol stearate 37.5 Paraflln (M. P. 50 C.) 6.0 Light mineral oil (U. S. P.) 37. Triethanolamine 1. 50 Oleic acid 3. 0 Karaya gum, powd 2. 5
- Exlmrta Ill-Astringent hemorrhoidrsuppositories Parts Bismuth iodotannate. 10.25 Bismuth resorcinate 10.25 Zinc oxide 16.40 Balsam of Peru -s 4. 10 sorbitol oleate 34.50 Ceresine (M. P. 56 C.) 17. 50 Triethanolamine 1.50 Oleic aci 3.00 Karaya gum, powd u 2.- 50 Exmu: IY.-Astrinaent hemorrhoid suppositories Suppositories are prepared with the same composition as in Exmple III, except that 17.50' parts of spermacettiare substituted for the 17.50 parts of Ceresine.
EXAMPLE VII-Witch hazel suppositories Parts Pilulae extract of Hama'melis 5.00 sorbitol stearate (M. P. 41 C.) 70.00 Paraflin (M. P. 50 C.) 7.00 Ethylated sunflower seed oil fatty acids--- 11.00 Lauryl ethanolamine sulfate-- 4.50 Karaya gum, powd 2.50
A base or vehicle which has important ad vantages for use in suppositories has the general approximate formula:
Parts sorbitol stearate (M. P. 41 C.) 73.0 Paraiiin (M. P. 50 C.) 8.0 Light mineral oil (U. S. P.) 12.0 Triethanolamine 1.5 Oleic acid 3.0 Karaya g 2.5
The proportions of sorbitol stearate, paraflin, mineral oil, etc. in this formula may be varied over a relatively wide range, and'may be adjusted foruse with various medicaments to givea'suppository of proper melting point. For example, if medicaments which tend to increase the melting point are incorporated, the proportion of sorbitol stearate. or paraflln, or both may be decreased and the proportion of mineral oil increased, or other agents, such as liquid fatty acid esters, may be added to compensate for the increase in melting point caused by the medicant. Use of the corresponding mannitol derivative in place of the sorbitol derivative in the foregoing general formula gives products almost identical with those of the examples. Penta-erythritol stearate, having a melting point of about 47 to 55 C. and a desirable consistency may also be used with advantage, with proper modiflcation of the proportions of the other constituents to give the flnal suppository the proper melting point. Mannitol mono laurate and penta erythritol ricinoleate, viscous liquids, may also be used, with addition of proper modifying agents, as may the wide range of esters referred to above.
1. Suppositories which have the propertie of absorbing substantial quantities of water, and swelling on contact with aqueous fluids, said suppositories having a basecontaining as a principal ingredient an unctuous fatty acid ester of a fatty acid having at least twelve carbon atoms with a compound of the clas consisting of polyhydric alcohols having an unbroken carboniinked chain and having four to six hydroxyl groups and their anhydrides.
2. Suppositories which have the properties of absorbing substantial quantities of water, and swelling on contact with aqueous fluids, said suppositories having a base containing as a principal ingredient anunctuous fatty acid ester of a fatty acid having at. least twelve carbon atoms with a sugar alcohol.
3. Suppositories which have the properties of absorbing substantial quantities of water, and swelling on contact with aqueous fluids, said suppositories having a base containing as a principal ingredient an unctuous fatty acids ester of a compound of the class consisting of polyhydric alcohols having an unbroken carbon-linked chain and having four to six hydroxyl groups and their anhydrides, said base also including an emulsifying agent.
4. Suppositories which have the properties of absorbing substantial quantities of water, and swelling on contact with aqueous fluids, said suppositories having a base containing as a principal ingredient an unctuous fatty acid ester of a sugar alcohol, said base also including an emulsifying agent.
5. Suppositories which have the properties of absorbing substantial quantities of water, and swelling on contact with aqueous fluids, said suppositories having a base containing as a principal ingredient an unctuous fatty acid ester of a fatty acid having at least twelve carbon atoms with a compound of the class consisting of polyhydric alcohols having an unbroken carbonllnked chain and having four to six hydroxyl groups and their anhydrides, said base also containing an emulsifying agent and an oleaginous material.
6. Suppositories which have the properties of absorbing substantial quantities of water, and swelling on contact with aqueous fluids. said suppositories having a base containing as a principal ingredient an unctuous fatty acid ester of a fatty acid having at least twelve carbon atoms with a sugar alcohol, said base also containing an emulsifying agent and an oleaginous material.
"I. Suppositories which have the properties of absorbing substantial quantities of water, and swelling on contact with aqueous fluids, said suppositories having a base containing as a princiswelling on contact with aqueous fluids. said suppositories having a base containing as a principal ingredient an unctuous fatty acid ester of a fatty acid having at least twelve carbon atoms with a sugar alcohol, said base also containing a gum.
9. Suppositories which have the properties of absorbing substantial quantities of water, and swelling on contact with aqueous fluids, said suppositorie having a base containing as a principal ingredient an unctuous fatty acid ester of a fatty acid having at least twelve carbon atoms with'a sugar alcohol, said alkyl ester of a higher fatty acid.
10. Suppositories having a base containing as a principal ingredient an unctuous fatty acid ester of a fatty acid having at least twelve carbon atoms with a compound of the class consisting of sorbitol and mannitol.
11. Suppositories having a base containing as a principal ingredient a fatty acid ester of a fatty acid having at least twelve carbon atoms with a compound of the clas consisting of sorbitol and mannitol.
12. Suppositories having a base containing a a principal ingredient a compound of the class consisting of sorbitol stearate and mannitol stearate. a
13. Suppositories having a base containing as a sisting of sorbitol oleate and mannitol oleate.
14. Suppositories having a base containing as a principal ingredient a fatty acid ester of a fatty acid having at least twelve carbon atoms wit: a compound of the class consisting of manmtol and sorbitol, said base also including an emulsifying agent and an added oleaginous material of the class consisting of hydrocarbon oils and waxes, vegetable and animal oils, vegetable and animal waxes and alkyl esters of -iigher fatty acids.
15. Suppositories having a base containing as a principal ingredient an unctuous fatty acid ester of a fatty acid having at least twelve carbon atoms with penta-erythritol.
16. Suppositories having a base contalningas a principal ingredient penta-erythritol stearate.
ROBERT S. SHELTON. LOUIS MAGID.
base also containing an