DRUG DELIVERY ENHANCEMENT VIA MODIFIED SAPONINS

Abstract: Disclosed herein are modified saponins or fractions thereof obtainable by modification of a crude Quillaja saponaria extract or by modification of purified saponins obtainable from a crude Quillaja saponaria extract useful in pharmaceutical compositions for enhancing the transport of pharmacologically active substances across mucous membranes of an animal. Also disclosed are modified saponins having reduced irritability wherein the aldehyde group is reduced and the fatty acid moiety may be removed by hydrolysis. Also disclosed are pharmaceutical compositions comprising the modified saponins of the invention.

Description: Drug Delivery Enhancement via Modified Saponins Field of the Invention The present invention is in the field of medicinal chemistry. In particular, the invention relates to modified saponins useful for enhancing drug delivery transdermally and across mucosal membranes of an animal. The modified saponins of the present invention frequently exhibit reduced irritation to mucosal membranes when compared to the natural saponins. Background of the Invention It is known that certain small peptides can be absorbed through the nasal mucosa as a "snuff" or directly from aqueous solution. Gordon, G.S. et al , Proc. Natl. Acad. Sci. USA 52:7419-7423 (1985). However, the efficacy of absorption is typically low and variable and therapeutically important peptides of larger molecular size, such as insulin, are not absorbed to any appreciable degree. Hirai et al. , Diabetes 27:296-299 (1978). A number of researchers have attempted to increase the delivery of polypeptides with detergents. For example, Gordon, G.S. et al., Proc. Natl. Acad. Sci. USA 52:7419-7423 (1985), report that the nasal absorption of insulin can be increased by hydrophobic bile salts. Longenecker, J.P. et al. , J. Pharm. Sci. 76:351-355 (1987), disclose that sodium taurodihydrofusidate is an effective increaser of mucosal permeation of drugs, in particular, insulin. Morimoto, K. et al , J. Pharm. Pharmacol. 57:134-136 (1984), disclose that the nasal absorption of insulin and calcitonin can be increased with polyacrylic acid gel. See also Moses, A. C. et al , Diabetes 52:1040-1047 (1983), who disclose the administration of insulin as part of an insulin-bile salt aerosol; and Aungst, B. J. et al. , J. Pharm. Exp. Ther. 244:23-21 (1988), who compared the nasal, rectal, buccal, sublingual and intramuscular insulin efficacy and the effects of a bile salt absorption promoter. Maitani, Y. et al , Drug Design Del 1:65-10 (1986), disclose the intranasal administration of 3-interferon with and without surfactants (non- ionic, anionic and amphoteric). When no surfactant was used, β-interferon was not absorbed in rabbits. Sodium glycocholate was the most effective in enhancing the absorption of interferon following nasal administration. However, the total absorption of S-interferon with sodium glycocholate was 2.2% of the total absorption by intravenous aώriinistration. Other detergents that have been employed to increase the uptake of polypeptides by mucosal tissue include saponins. Saponins occur widely in plant species (over 400) and exhibit a range of biological properties, some of which are beneficial and some deleterious. When agitated in water, they form a soapy lather and it is this characteristic that gives the group its name. Other properties generally ascribed to saponins include, for example, hemolytic activity, cholesterol-binding properties and bitterness. For a review of the chemistry and a biological significance of saponins, reference is made to Price, K.R. et al. , CRC Crit. Rev. Food Sci. Nutr. 26:21 (1987). Solutions of saponin have been employed to increase the delivery of polypeptides across mucosal membranes. For example, Pillion, D.J. et al. , Invest. Opthal. Vis. Sci. 52:3021-27 (1991) disclose that adiriiriistration of insulin in eyedrops containing unpurified saponin from Gypsophilla as a 1 % solution causes a rapid and reproducible reduction in the blood levels of D-glucose in rats. Insulin eyedrops lacking saponin were ineffective. Japanese Abstract No. JP 62126135 (1987) discloses the nasal administration of growth hormone releasing factor employing a saponin having a steroidal or triterpene structure. See also, Chiou, G. C. Y. et al , J. Pharm. Sci. 75:815- 818 (1989); and Chiou G. C. Y. et al. , J. Ocul Pharm. 5:81-91 (1989) who disclose the systemic delivery of insulin by its admimstration as a component of eyedrops containing saponin (obtained from Sigma Chemical Company). See also, Chiou, G. C. Y. et al , Diabetes Care 11:150-51 (1988) (source of saponin undisclosed). See also, Hirari, S. et al , Int. J. Pharm. 9:173-84 (1981) and Hirari, S. et al , Int. J. Pharm. 9: 165-72 (1989), who disclose the nasal administration of insulin in rats with a solution comprising saponin (source not disclosed other than that the saponin was obtained from the Wako Pure Chemical Ind., Ltd, Osaka, Japan). Kensil et al. in U.S. Patent No. 5,057,540 disclose pure saponins that are useful as immune adjuvants and, in admixture with an antigen, provide immune response-provoking compositions. Higuchi et al. , Phytochemistry 26(1) :229-235 (1987) isolated two major desacylsaponins, designated DS-1 and DS-2, by treating a triterpenoid saponin obtained from the bark of Quillaja saponaria with weak alkali. DS-1 has the same structure as the compound referred to herein as QA-21-H. Further, the compound referred to herein as QH-957 has the same structure as compound 4 of Higuchi et al. While surfactants hold great promise for enhancing the uptake of drugs across mucosal membranes, a major drawback is that they cause irritation. Thus, the long-term use of pharmaceutical compositions comprising a surfactant cannot be possible. However, for acute therapies, local effects are less important because the mucosal membrane can easily repair itself. Long- term local toxicity effects are even more important when increasers are used to increase nasal membrane permeability. Chronic erosion of the mucous membrane by certain surfactants such as polyoxyethylene-9 lauryl ether could result in inflammation, hyperplasia, metaplasia and deterioration of normal nasal functions. Lee, W. A. and Longenecker, J. P. , BioPharm. 30-37 (1988). Literature reports indicate that biosalts break down mucous membrane structure (Martin, G. P. and Marriot, C, J. Pharm. Pharmacol. 31:154 (1981), accelerate phospholipid and protein release from membranes (Whitmore, D. A. et al. , J. Pharm. Pharmacol. 31:211 (1979), and damage intestinal mucosa (Kimura, T. et al. , J. Nut. Sci. Vitaminol 25:483 (1982). Chronic erosion also exposes nasal circulation to a constant stream of air¬ borne bacteria and related toxins. Lee, W. A. and Longenecker, J. P., Biopharm. 30-37 (1988). Thus, a need continues to exist for the development of new surfactants that increase the delivery of drags across mucosal membranes without causing irritation. Summary of the Invention The present invention relates to a saponin or fraction thereof obtained from a crude Quillaja saponaria extract, said chemically modified saponin or fraction thereof having the structure: wherein Rj is a methylenealcohol or methyleneamino group; R 2 is hydrogen or SAC 2 ; and SAC, and SA are independently selected saccharide groups. The invention also relates to a pharmaceutical composition for increasing systemic uptake by an animal of a pharmacologically active substance, comprising (A) at least one chemically modified saponin or fraction thereof obtained from a crude Quillaja saponaria extract, said chemically modified saponin or fraction thereof having the structure: wherein R, is -CHO, a methylene alcohol, or methyleneamino group; R 2 is hydrogen or SAC 2 ; and SACj and SACj are independently selected saccharide groups; (B) a pharmacologically active substance, and, optionally, (C) a pharmaceutically acceptable carrier. The invention is also directed to a method for increasing systemic uptake of a pharmacologically active substance by an animal, comprising administration of a pharmaceutical composition comprising (A) at least one chemically modified saponin or fraction thereof obtained from a crude Quillaja saponaria extract, said chemically modified saponin or fraction thereof having the structure: wherein R, is -CHO, a methylene alcohol, or methyleneamino group; R 2 is hydrogen or SAC 2 ; and SACj and SA are independently selected saccharide groups; (B) a pharmacologically active substance, and, optionally, (C) a pharmaceutically acceptable carrier. Brief Description of the Figures Figure 1 depicts the structural relationships of QA-17, QA-I8, and QA-21. The m/z listed in the table is for [M+Na] + for each of the sarrønins. Figure 2 A depicts a graph showing the hemolytic activity of phosphate buffered saline, PBS, (O), QA-21 (•), and QA-21 (A) wherein the aldehyde group is reduced to methylenealcohol. Figure 2B depicts a graph showing the hemolytic activity of QA-18-H (O), QA-21-H (•), QA-7 (D), and QA-21 (A). Figure 3A depicts a graph showing blood glucose levels of rats after ocular administration of 20 μl of saline. Figure 3B depicts a graph showing blood glucose levels of a rat after ocular administration of 20 μl of 0.5 % of a commercially available crude Gypsophilla saponin (Sigma Chemical Corporation) + 0.4 % porcine insulin. Figure 3C depicts a graph showing blood glucose levels of a rat after ocular administration of 20 μl of 0.5% of crude Quillaja saponaria saponin (purified from an aqueous extract by ultrafiltration) + 0.5% porcine insulin. Figure 4 shows the effect of the ocular administration of 0.1 % QA-21- H (without insulin) on the blood glucose levels of rats. Figure 5 depicts the results of the ocular administration of 20 μl of 0.025% QA-21-H and 0.4% regular pork insulin on the mean of the blood glucose levels of three rats. Figure 6 is a graph showing the results of the ocular administration of 0.05% QA-21-H and 0.4% regular pork insulin on the mean of the blood glucose levels of three male rats. Figure 7 is a graph showing the results of the ocular administration of 0.1 % QA-21-H and 0.4% regular pork insulin on the mean of the blood glucose levels of four male rats. Figure 8 is a graph showing the blood glucose lowering effect of the ocular administration of 10 μl/eye, 0.01 % QA-21-H and 0.4% regular pork insulin to a first rat (■); 10 μl/eye of 0.01 % pure QA-21-H and 0.4% regular pork insulin to a second rat ( ♦ ); and 20 μl/eye of 0.01 % QA-21-H and 0.4% regular pork insulin to a third rat (x). Figure 9A depicts a reversed-phase HPLC analysis of Quillaja saponaria bark extract. Figure 9B depicts a reversed-phase HPLC analysis of Quillaja saponaria bark extract after alkaline hydrolysis. Figure 10A depicts a reversed-phase HPLC analysis of purified QA-18- H obtained from QA-18 after alkaline hydrolysis. Figure 10B depicts a reversed-phase HPLC analysis of purified QA-21-H obtained from QA-21 after alkaline hydrolysis. The HPLC analysis was carried out by the same method used for analysis of the extracts in Figure 9. Figure 11 is a graph showing the adjuvant activities of QA-21 (o), QA-21 modified at the triterpene aldehyde by reductive amination with glycine (•), QA-21 modified at the triterpene aldehyde by reductive amination with ethylenediamine (D), and QA-21 modified at the triterpene aldehyde by reductive amination with ethylamine (Δ). Figure 12 is a graph showing the adjuvant activities of QA-21 (o) and QA-21 modified at the triterpene aldehyde by reduction to the corresponding methylenealcohol (•). Figure 13 shows infrared spectra of QA-21, QA-21-H, and QA-21- H,R. Figure 14A shows an analysis by reversed-phase HPLC of the total saponin fraction from Quillaja saponaria after partial purification by diafiltration; Figure 14B shows the purity after hydrolysis and precipitation in 1-propanol and Figure 14C shows the purity after silica chromatography. Figures 15A and 15B are graphs showing the analyses of purified QA- 18-H and QA-21-H, respectively, by reversed-phase HPLC. (See Example 10). Figure 16 shows the effect of QA-21 concentration on ocular delivery of insulin. Figure 17 shows the effect of QA-21-H concentration on ocular delivery of insulin. Figure 18 shows the effect of QA-21-H.R concentration on ocular delivery of insulin. Figure 19 shows the ratio of glucose levels at 120 minutes post- administration to glucose levels at time = 0 (time of administration) as a function of concentration of QA-21, QA-21-H, and QA-21-H.R. Figure 20 shows the effect of QA-21-H on nasal delivery of insulin into rats. Figure 21 shows the effect of QA-18-H on nasal delivery of insulin into rats. Figure 22 shows the effect of a mixture of QA-18-H and QA-21-H on nasal delivery of insulin into rats. Figure 23 is a graph showing blood D-glucose levels as a function of time after nasal administration of 2 units of insulin for three different concentrations of accompanying QH-957. Figure 24 is a graph showing gentamicin levels in serum as a function of time after administration of 5 mg/kg of gentamicin with and without 1.32 mM of QH-957. Figure 25 is a graph showing blood D-glucose levels as a function of time after nasal administration of 2 units of insulin for four different concentrations of accompanying QA-7-H. Figure 26 is a graph showing gentamicin levels in serum as a function of time after administration of 5 mg/kg of gentamicin with and without 1.32 mM of QA-7-H. Figure 27 is a bar graph showing areas under the serum gentamicin concentration curves with 5 mg/kg doses of gentamicin containing 1.32 mM of eight different permeation enhancers. Detailed Description of the Preferred Embodiments The present invention relates to the discovery that the irritation caused by saponins employed as part of a pharmaceutical composition to increase the rate of delivery of pharmacologically active substances across mucosal membranes can frequently be reduced by hydrolyzing at least one ester group of a saponin obtained from Quillaja saponaria, or a purified fraction thereof, and/or modifying the aldehyde group bonded to the C4 carbon atom of the quillaic acid moiety by reduction or reductive amination to methylenealcohol or a methyleneamino group, respectively. The present invention includes modified saponins that have substantially no adjuvant activity or irritability when administered to an animal, but that retain sufficient lytic effect for drug transport. Such modified saponins can be obtained in several ways. For example, the aldehyde group bonded to the C4 carbon atom of the quillaic acid moiety of either crude or purified saponin from Quillaja saponaria Molina bark can be reduced with a mild reducing agent, such as sodium or lithium borohydride, to give the corresponding alcohol. See Scheme I. Alternatively, the aldehyde can be subjected to reductive amination with a primary amine and a reducing agent to give the corresponding amino derivative. See Scheme II. Examples of primary amines that can be used in the reductive alkylation procedure include, but are not limited to methy lamine, ethylamine, propylamine, ethylenediamine, propylenediamine, 2-methyl-2- aminoethylamine, 3-methyl-3-aminopropylamine, 4-methyl-4- aminobutylamine, 5-methylaminopenty lamine, 6-methylaminohexylamine, 3 -methylamino-2-methy lpropylamine , 2-ethy laminoethy lamine , 3-ethylaminopropylamine, 4-ethylaminobutylamine, 5-ethylaminopenty lamine, 6-ethylaminohexy lamine, 3-propylaminopropylamine, 4-propylaminobuty lamine, 5-propylaminopentylamine, 6-propylaminohexy lamine, 2-(N,N'-dimethylamino)ethylamine, 3-dimethylaminopropylamine, 4-dimethylaminobutylamine, 5-dimethylaminopentylamine, 6-dimethylaminohexylamine, 3-dimemylamino-2-memylpropylamine, 2-(N,N'-die±ylammo)emylamine, 3-dieΛylammopropylamine, 4-diethylaminobutylamine, 5-diethylaminopenty lamine, 6-diethylaminohexylamine, 3-dipropylaminopropylamine, 4-dipropylammobutylamine, 5-dipropylaminopentylamine, 6-dipropylaminohexylamine, 5-diemylanιmopentan-2-amine and amino acids such as glycine, tyrosine, phenylalanine, methionine, alanine, serine, isoleucine, ^threonine, valine, proline, lysine, histidine, glutamine, glutamic acid, tryptophan, arginine, aspartic acid, asparagine or cysteine. Scheme I Scheme II Preferably, a purified fraction of the saponin from Quillaja saponaria is employed, wherein the ester side chain has been hydrolyzed to decrease adjuvant activity. See Scheme III. The products of this hydrolysis, QA-18-H and QA-21-H, increase the uptake of drags across mucosal membranes. Such hydrolysis can be carried out from purified saponins or can be carried out with a crude mixture, with subsequent purification of the modified saponins. Figure 10 shows the reversed-phase HPLC analysis of QA-18-H and QA-21-H obtained from purified QA-18 and QA-21 , respectively. Figure 9 shows that QA-18-H and QA-21-H are the predominant products and can be easily purified after alkaline hydrolysis of a crude extract from Quillaja saponaria bark. Scheme III Preferably, QA-18-H and QA-21-H are further modified to reduce the inflammatory response and residual adjuvant effect. As shown in Scheme IV, the aldehyde group of QA-18-H and QA-21-H can be reduced with sodium or lithium borohydride to give the corresponding methylenealcohol. Alternatively, the aldehyde group can be subjected to reductive amination with a primary amine and sodium or lithium borohydride to give the corresponding secondary amine. See Scheme IV. Scheme IV Those skilled in the art will note that the products obtained in Schemes III and IN, above, still retain an ester linkage between the quillaic acid and the fucose sugar. This ester can also be hydrolyzed to form the product referred to herein as QH-957. See Scheme V. It is expected that any and all of the saponins in the Quillaja saponaria bark extract could produce QH-957. Scheme V Thus, the present invention relates to a chemically modified saponin or a fraction thereof obtainable from a crude Quillaja saponaria extract, wherein the saponin or fraction that is to be chemically modified preferably comprises at least one of QA-7, QA-17, QA-18, QA-21, QH-957, QA-21-V1, and QA-21-V2, and wherein the chemical modification of the saponin or fraction thereof comprises (1) the reduction of the aldehyde group of the quillaic acid moiety to a methylenealcohol or a methyleneamino group; in combination with (2) the hydrolysis of at least one of the ester linkages of the saponin. More specifically, the present invention relates to a chemically modified saponin or fraction thereof obtained from a crude Quillaja saponaria extract, said chemically modified saponin or fraction thereof having the structure: wherein R, is a methylene alcohol or methyleneamino group; R 2 is hydrogen or SAC 2 ; and SACj and SAC 2 are independently selected saccharide groups; The present invention also relates to a pharmaceutical composition for increasing systemic uptake by an animal of a pharmacologically active substance, comprising (A) at least one chemically modified saponin or fraction thereof obtained from a crude Quillaja saponaria extract, said chemically modified saponin or fraction thereof having the structure: wherein Ri is -CHO, a methylene alcohol, or memyleneamino group; R 2 is hydrogen or SA ; and SACj and SACj are independently selected saccharide groups; (B) a pharmacologically active substance, and, optionally, (C) a pharmaceutically acceptable carrier. In another aspect, the present invention relates to a method for increasing systemic uptake of a pharmacologically active substance by an animal, comprising administering a pharmaceutical composition comprising (A) at least one chemically modified saponin or fraction thereof obtained from a crude Quillaja saponaria extract, said chemically modified saponin or fraction thereof having the structure: wherein Rj is -CHO, a methylene alcohol, or methyleneamino group; R 2 is hydrogen or SAC 2 ; and SAC ! and SAC 2 are independently selected saccharide groups; (B) a pharmacologically active substance, and, optionally, (C) a pharmaceutically acceptable carrier. Administration of the pharmaceutical composition can be accomplished by bringing it into contact either with mucous membranes for uptake or with a dermal surface for transdermal uptake. Where reductive amination is employed in the practice of the present invention, the amino groups produced have the formula -N(R)-R 3 , wherein R is hydrogen or together with R 4 , as described below, forms a ring and R 3 is selected from the group consisting of hydrogen, C r C 8 alkyl, -C^ alkyl- aminoalkyl, allyl, aralkyl, C 3 -C 8 cycloalkyl, aryl, and a group having the formula I -CH-CO 2 H, wherein R 4 is hydrogen, C r C 4 alkyl, or C r C 4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C r C alkyltbio, hydroxy, carboxy, amino, guanidino, imidazolyl or carbamyl; or wherein R and R, together form a pyrrolidinyl or piperidinyl ring. Typical C,-C 8 alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl groups and isomers thereof. Typical -Cg cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Typical aryl groups include phenyl, naphthyl, phenanthryl, anthracyl and fluorenyl groups. Typical aralkyl groups include a C r C 8 alkyl group, as described above, substituted by one of the above-listed aryl groups, e.g. phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, and phenylhexyl groups, as well as the branched chain isomers thereof. Typical -C^ alkylaminoalkyl groups include 2-meΛylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, 5-methylaminopentyl, 6-methylaminohexyl, 3-memylamino-2-methylpropyl, 2-ethylaminoethyl, 3-ethylaminopropyl, 4-ethylaminobutyl, 5-ethylaminopentyl, 6-ethylaminohexyl, 3-propylaminopropyl, 4-propylaminobutyl, 5-propylaminopentyl, 6-propylaminohexyl, 2-(N,N'-dimethylamino)ethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl, 6-dimethylaminohexyl, 3-dimethylamino-2-methylpropyl, 2-(N,N'-diethylamino)ethyl, 3-diethylaminopropyl, 4-diethylaminobutyl, 5-diethylaminopentyl, 6-diethylaminohexyl, 3-dipropylaminopropyl, 4-dipropylaminobutyl, 5-dipropylaminopentyl, 6-dipropylaminohexyl, 5-diethylaminopentan-2-yl and the like. SAC ! and SA are independently selected saccharide groups. As used herein, the term "saccharide" is intended to include both mono- and polysaccharides, e.g., disaccharides, trisaccharides, tetrasaccharides, etc., as occur naturally in the various saponins extracted from Quillaja saponaria bark. Among those intended to be included may be listed, for example, xylose, glucuronic acid, galactose, apiose, rhamnose, and the like. Those skilled in the art will recognize that such monosaccharides as these, as well as others, may be linked together to form polysaccharides that are intended to be within the scope of the definitions of SACj and SA . Those skilled in the art will also recognize that mixtures of the above- described modified saponins and fractions thereof can be employed in the formulation of the pharmaceutical compositions described herein. According to U.S. Patent No. 5,057,540, the contents of which are fully incorporated by reference herein, saponins can be purified from an aqueous extract of the bark of the South American tree, Quillaja saponaria Molina. At least 22 peaks with saponin activity were separable. The predominant purified Quillaja saponins are QA-7, QA-17, QA-18, and QA-21. These saponins have been purified by high pressure liquid chromatography (HPLC) and low pressure silica chromatography. QA-21 can be further purified using hydrophilic interaction chromatography (HILIC) and resolved into two peaks, QA-21-V1 and QA-21-V2, that are different compounds. Thus, "QA-21 " designates the mixture of components QA-21-V1 and QA-21- V2 that appear as a single peak on reversed-phase HPLC on VYDAC C4 (5 μm particle size, 330 A pore, 4.6 mm ID x 25 cm L) in 40 mM acetic acid in methanol/ water (58/42, v/v). The component fractions are referred to specifically as QA-21-V1 and QA-21-V2 when describing experiments or results performed on the further purified components. In order to purify saponins from Quillaja saponaria Molina bark, aqueous extracts of the Quillaja saponaria Molina bark are dialyzed against water. The dialyzed extract is lyophilized to dryness, extracted with methanol and the methanol-soluble extract is further fractionated by silica gel chromatography and by reversed-phase high pressure liquid chromatography (RP-HPLC). The individual saponins are separated by reversed-phase HPLC. At least 22 peaks (designated QA-1 to QA-22) are separable. Each peak corresponds to a carbohydrate peak that exhibits only a single band on reversed-phase thin layer chromatography. The individual components were identified by retention time on a VYDAC C4 HPLC column as follows: Peak Retention Time (minutes) QA-1 solvent front QA-2 4.6 QA-3 5.6 QA-4 6.4 QA-5 7.2 QA-6 9.2 QA-7 9.6 QA-8 10.6 QA-9 13.0 QA-10 17.2 QA-11 19.0 QA-12 21.2 QA-13 22.6 QA-14 24.0 QA-15 25.6 QA-16 28.6 QA-17 35.2 QA-18 38.2 QA-19 43.6 QA-20 47.6 QA-21 51.6 QA-22 61.0 The substantially pure QA-7 saponin is characterized as having immune adjuvant activity, containing about 35% carbohydrate (as assayed by anthrone) per dry weight, having a UV absorption maximum of 205-210 nm, a retention time of approximately 9-10 minutes on RP-HPLC on a VYDAC C4 column having 5 μm particle size, 330 A pore, 4.6 mm ID x 25 cm L in a solvent of 40 mM acetic acid in methanol-water (58/42; v/v) at a flow rate of 1 mI min, eluting with 52-53% methanol from a VYDAC C4 column having 5 μm particle size, 330 A pore, 10 mm ID x 25 cm L in a solvent of 40 mM acetic acid with gradient elution from 50 to 80% methanol, having a critical micellar concentration of .06% (w/v) in water and .07% (w/v) in phosphate buffered saline, causing no detectable hemolysis of sheep red blood cells at concentrations of 200 μg/mL or less, and containing the monosaccharide residues terminal rhamnose, terminal xylose, terminal glucose, terminal galactose, 3-xylose, 3,4-rhamnose, 2,3-fucose, 2,3-glucuronicacid, and apiose (linkage not determined). The substantially pure QA-17 saponin is characterized as having adjuvant activity, containing about 29% carbohydrate (as assayed by anthrone) per dry weight, having a UV absorption maximum of 205-210 nm, a retention time of approximately 35 minutes on RP-HPLC on a VYDAC C4 column having 5 μm particle size, 330 A pore, 4.6 mm ID x 25 cm L in a solvent of 40 mM acetic acid in methanol- water (58/42; v/v) at a flow rate of 1 mL/min, eluting with 63-64% methanol from a VYDAC C4 column having 5 μm particle size, 330 A pore, 10 mm ID x 25 cm L in a solvent of 40 mM acetic acid with gradient elution from 50 to 80% methanol, having a critical micellar concentration of .06% (w/v) in water and .03% (w/v) in phosphate buffered saline, causing hemolysis of sheep red blood cells at 25 μg/mL or greater, and containing the monosaccharide residues terminal rhamnose, terminal xylose, 2-fucose, 3-xylose, 3,4-rhamnose, 2,3-glucuronic acid, terminal glucose, 2 - arabinose, terminal galactose and apiose (linkage not determined). The substantially pure QA-18 saponin is characterized as having immune adjuvant activity, containing about 25-26% carbohydrate (as assayed by anthrone) per dry weight, having a UV absorption maximum of 205-210 nm, a retention time of approximately 38 minutes on RP-HPLC on a VYDAC C4 column having 5 μm particle size, 330 A pore, 4.6 mm ID x 25 cm L in a solvent of 40 mM acetic acid in methanol/water (58/42; v/v) at a flow rate of 1 mL/min, eluting with 64-65% methanol from a VYDAC C4 column having 5 μm particle size, 330 A pore, 10 mm ID x 25 cm L in a solvent of 40 mM acetic acid with gradient elution from 50 to 80% methanol, having a critical micellar concentration of .04% (w/v) in water and .02% (w/v) in phosphate buffered saline, causing hemolysis of sheep red blood cells at concentrations of 25 μg/mL or greater, and containing the monosaccharides terminal arabinose, terminal apiose, terminal xylose, terminal glucose, terminal galactose, 2-fucose, 3-xylose, 3,4-rhamnose, and 2,3-glucuronic acid. The substantially pure QA-21 saponin is characterized as having immune adjuvant activity, containing about 22% carbohydrate (as assayed by anthrone) per dry- weight, having a UV absorption maximum of 205-210 nm, a retention time of approximately 51 minutes on RP-HPLC on a VYDAC C4 column having 5 μm particle size, 330 A pore, 4.6 mm ID x 25 cm L in a solvent of 40 mM acetic acid in methanol/water (58/42; v/v) at a flow rate of 1 mL/min, eluting with 69 to 70% methanol from a VYDAC C4 column having 5 μm particle size, 330 A pore, 10 mm x ID 25 cm L in a solvent of 40 mM acetic acid with gradient elution from 50 to 80% methanol, with a critical micellar concentration of about .03% (w/v) in water and .02% (w/v) in phosphate buffered saline, and causing hemolysis of sheep red blood cells at concentrations of 25 μg/mL or greater. The component fractions, substantially pure QA-21-V1 and QA-21-V2 saponins, have the same molecular weight and identical spectra by fast atom bombardment - mass spectroscopy (FAB-MS). They differ only in that QA-21-V1 has a terminal apiose that is xylose in QA-21-V2 (which therefore has two terminal xyloses and no apiose). The two components additionally contain the monosaccharides terminal arabinose, terminal apiose, terminal xylose, 4-rhamnose, terminal galactose, 2-fucose, 3-xylose, and 2,3-glucuronic acid. The alkaline hydrolysis products can be prepared as follows. Treatment of QA-18 by brief alkaline hydrolysis yielded one major carbohydrate-containing alkaline hydrolysis product (designated QA-18-H). Purified QA-18-H was prepared from QA-18 and isolated in the following manner: One mL QA-18 (5 mg/ml) was incubated with 25 μl 1 N NaOH for 15 minutes at room temperature. The reaction was stopped with the addition of 100 μl 1 N acetic acid. Using these hydrolysis conditions, QA-18 was completely converted to a major hydrolysis product (QA-18-H) eluting in a peak with retention time of 8.0 min compared to 66.8 min for unhydrolyzed QA-18, indicating the increased hydrophilicity of QA-18-H. (Chromatography on VYDAC C4 (4.6 mm ID x 25 cm L) in 0.1 % trifluoroacetic acid in 55/45 methanol/water (v/v) and eluted in a gradient to 64/36 methanol/water (v/v) over 180 minutes, flow rate of 1 mL/minute). The peak containing pure QA- 18-H (retention time 8.0 min) was pooled for further characterization. The hydrolysis product of QA-21, designated QA-21-H, was prepared and purified in the same manner. QA-21-H had a retention time of 9.3 minutes compared to 80.4 minutes for its unhydrolyzed precursor, QA-21. These hydrolysis products were shown by retention time on HPLC and by reversed-phase thin layer chromatography to be identical to the major hydrolysis products generated using the method of Higuchi et al, Phytochemistry 26:229 (1987) using mild alkaline hydrolysis in NH 4 HCO 3 (Table 1). In addition, these products, QA-18-H and QA-21-H, were shown to be the major breakdown products from hydrolysis of "Quil-A", a crude saponin mixture containing QA-7, QA-17, QA-18, and QA-21 as well as other saponins, indicating that the hydrolysis products QA-21-H and QA-18-H are the same hydrolysis products isolated by Higuchi et al, supra, for structural characterization. TABLE 1 Retention Time of Major Alkaline Hydrolysis Products QA-17-H 8.0 a QA-18-H 8.0 a 8.2 b QA-21-H 9.3 a 9.5 b Hydrolyzed - "Quil-A" 8.2 a , 9.3 a a Cambridge Biotech hydrolysis conditions: 5 mg/ml saponin, pH 13, reaction time = 15 minutes at room temperature b Higuchi et al. hydrolysis conditions: 5 mg/ml saponin, 6% NH 4 HCO 3 , methanol/H 2 O (1/1, v/v), reaction time = 60 minutes at 100°C HPLC Conditions: VYDAC C4, 5 μm particle size, 330 A pore size, .46 x 25 cm Solvent A = 0.1 % trifluoroacetic acid in water Solvent B - 0.1 % trifluoroacetic acid in methanol Gradient = 55 - 64% B/ 180 minutes Flow rate - 1 ml/min The compositions of the invention comprising the modified saponins can be employed to increase the uptake across mucosal membranes and skin surfaces of any one of a large number of pharmacologically active substances. Preferably, such pharmacologically active substances are polypeptides. However, the invention is not intended to be so limited. The compositions comprising the modified saponins of the invention can be used to increase the uptake of any pharmacologically active substance, so long as its molecular weight is less than about 200,000 daltons. Examples of such polypeptides that can be administered together with the compositions of the present invention include, but are not limited to, insulin, insulin-like growth factor, growth hormone, parathyroid hormone, renin, prolactin, thyroid stimulating hormone, corticotropin, follicle stimulating hormone, chorionic gonadotropin, luteinizing hormone, luteinizing releasing factor, - interferon (alpha, beta, and gamma), lymphokines, interleukin, tumor necrosis factor, antibodies (monoclonal and polyclonal), e.g. IgG, enkephalins (see Su, K.S.E., et al, J. Pharm. Sci. 74:394-98 (1985)), calcitonin (McMartin, C. and Peters, G., Delivery Systems For Peptide Drugs, S.S. Davis et al (eds.), pp. 249-53, Plenum Press New York (1986)), somatostatin (McMartin, C. and Peters, G., Delivery Systems For Peptide Drugs, Davis, S.S., et al. (eds.), pp. 255-63, Plenum Press New York (1986)), methionyl growth hormone (Moore, J.A. et al, Delivery Systems For Peptide Drugs, Davis, S.S., et al. (eds.), pp. 317-329, Plenum Press New York (1986)), oxytocin (Hendricks, CH. and Pose, S.V., J.A.M.A. 775:384-387 (1961)), vasopressin and desmopressin (Richson, D.W. and Robinson, A.G., Ann. Int. Med. 103:228-239 (1985)), luteinizing hormone releasing hormone (Fink, G. et al, J. Endocr. 65:351-360 (1974)), nafarelin acetate (Anik, S.T. et al, J. Pharm. Sci. 75:684-685 (1984), secretin (Ohwaki, T. et al, J. Pharm. Sci. 74(5):550-552 (May, 1985)), glucagon (Pontiroli, A.E. et al, Acta Diabetol Let. 22:102-110 (1985)), pimolol (Kaila, T. et al, J. Ocular Pharm. 1:19-83 (1985)), thyrotropin- releasing hormone (Sandow, J. and Petri, W., Trans Nas. System. Med. , (Chien, Y.W. ed.) Elsevier Science Publishers B.B., Amsterdam, pp. 183-199 (1985)). In addition, the compositions of the present invention can also be employed to increase the uptake across mucosal membranes and skin surfaces of enzymes, transferases, hydrolases, isomerases, proteases, ligases and oxidoreductases such as esterases, phosphatases, glycosidases and peptidases; enzyme inhibitors such as leupeptin, chymostatin and pepstatin and growth factors, such as tumor angiogenesis factor. Other suitable pharmacologically active substances are fat-soluble steroids such as progesterone, estrogens and androgens, as well as the fat soluble vitamins A, D, E and K. In addition to low and high molecular weight polypeptides, the pharmacologically active substance can be an anti-inflammatory agent (e.g., indomethacin, flurbiprόfen, ketoprofen, ibuprofen, phenylbutazone), antibiotics (e.g., beta-lactams, aminoglycosides, macrolides, tetracyclines, pryridonecarboxylic acids, phosphomycin), anti-tumor agents (e.g., adriamycin, cisplatin, bleomycin, mitomycin, fluorouracil, vinblastine, vincristine), amino acids (e.g., ascorbic acid, N-acetyltryptophan), antifungal agents, prostaglandins, vitamins, steroids, vaccine antigens, vaccine adjuvants, and antiviral agents (AZT, DDI, acyclovir, idoxuridine, amantadine, and vidarabine). The compositions of the present invention can be applied to any mucous membrane including the conjunctiva, nasopharynx, orthopharnyx, vagina, colon, urethra, urinary bladder, lung, large (rectal) and small (enteral) intestine. The compositions of the present invention can also be administered transdermally, for example, as part of a patch. Preferably, the compositions of the present invention are aά'ministered to the eye as part of eye drops, nasally as part of an aerosol or buccally as part of a solid wafer. In addition, the pharmaceutical compositions of the present invention can also be formulated in sustained release compositions. For example, the modified saponin and drug can be combined with a silicone elastomer that releases the saponin and drug over a long period of time. The silicone elastomer can also comprise albumin. See U.S. Patent No. 4,985,253, the contents of which are fully incorporated by reference herein. The release rate of the drug from the silicone elastomer can be controlled by incorporation of a water soluble or fat soluble mixing agent or cosolvent (e.g., polyethylene glycol 400, polysorbate 80, sodium alginate, L-alanine, sodium chloride, polydimethylsiloxane) into the silicone elastomer. Any other additive can also be incorporated into the silicone elastomer for the purpose of accelerating the release rate. In addition, the pharmacologically active substance and saponin can be formulated in a controlled release composition comprising a polylactide and/or polyglycolide copolymer, a cellulose polymer (methyl-, methylhydroxy ethyl-, hydroxypropyl-, hydroxyethyl-, sodium carboxyethyl-cellulose), polyacrylic acid, polymethylmethacrylate, cross-linked polyacrylic acid, polyvinylpyrrolidone, polyvinylalcohol, polyethylene glycol, agarose or a copolymer of styrene and hydroxyethylmethacylate crosslinked with divinylazobenzene. Alternatively, the pharmacologically active substance and saponin can be formulated as part of DEAE-dextran microspheres, starch microspheres, or albumin microspheres. When the saponin and pharmacologically active substance are formulated in a sustained release composition, the content of the pharmaceutical substance can be appropriately controlled depending upon the dose to be administered and the release rate. When the composition is shaped in matrix type preparation, the content of the pharmaceutical substance can usually be from 5 to 40% by weight and, more preferably, not more than 15% by weight, for example, 9% by weight or less. When administering a peptide hormone, its content should be no more than about 6 to 10% by weight. Albumin, if employed, is present at not more than 50% by weight, preferably from about 20 to 30% by weight. The silicone elastomer can be contained in an amount of not less than 50% by weight, preferably from 70 to 90% by weight. The sustained release compositions can be prepared by mixing the components in any optional order. When albumin is added, the drug and albumin are first combined, preferably in a solid state. Alternatively, an aqueous solution of the pharmaceutical substance and albumin can be mixed and the resulting mixture lyophilized to make a solid mixture. This mixture is then dispersed uniformly with an elastomer base, optionally, with a plasticizer (e.g., dimethylpolysiloxane), adding a curing agent thereto and stirring the resultant mixture. The mixture is then placed in an appropriate mold and cured at room temperature to give a shaped composition. In the alternative, a core material not containing a pharmaceutical substance can be covered with the composition comprising a silicone elastomer containing a pharmaceutical substance, optionally containing albumin, to make a shaped composition. Such core material can comprise any non-toxic material. Preferably, such core material is an elastic polymer. The sustained release compositions of the present invention can have any shape that is suitable for effective contact with mucous membranes in body cavities. For example, when the pharmacologically active substance is administered buccally, the sustained release composition can be in the form of a wafer. When the pharmacologically active substance is administered vaginally, the sustained release composition can be in the form of a ring. When administered ocularly, the sustained release composition can be in the form of thin ocular implants. The compositions of the present invention can also be formulated as part of a chewing gum comprising the gum from the latex of the sapodilla. Preferably, the chewing gum composition also comprises sweeteners (sugar, aspartame and the like) and flavorants (spearmint, wintergreen or peppermint oil and the like) that mask any unpleasant taste associated with the pharmacologically active substance. When administered ocularly or nasally, the compositions of the present invention can be formulated in an aqueous solution buffered to a pH of between 3.0 and 8.0, most preferably pH 5.0-5.4, by means of a pharmaceutically acceptable buffer system. Any pharmaceutically acceptable buffering system capable of mamtaining the pH in the preferred ranges can be used in the practice of this invention. A typical buffer will be, for example, an acetate buffer, a phosphate buffer, a citrate buffer, a succinate buffer, or the like. The concentration of buffer can range from between 0.005 and 0.1 molar, most preferably about 0.02 molar. When the compositions of the present invention are administered ocularly, the composition can comprise a solution containing sodium, potassium, magnesium, calcium, chloride and bicarbonate ions as well as dextrose and glutathione. See, for example, U.S. Patent Nos. 4,550,022 and 4,443,432. Alternatively, the ocular fluid can comprise an aqueous solution containing sodium chloride, potassium chloride, calcium chloride and N-2- hydroxyethylpiperazine-N-2-ethanesulphonic acid. Sodium hydroxide can be included to establish a pH value of about 7.25 and magnesium sulfate can also be included. See UK Patent Application GB 2,064,320. See also U.S. Patent No. 4,938,970, which discloses irrigation solutions that do not cause pain when administered to the eye. According to this patent, the electrolyte solution comprises 2-10 meq/L of K + , 0-3 meq/L of Ca + + , 1-5 meq/L of Mg ++ and 110-150 meq/L of Na + , buffered to a pH of 6.85 - 8.0. Other materials, such as preservatives, salts to achieve the tonic value of tissue, or other additives indicated by known nasal or ocular formulation chemistry, can be added to these formulations. By the term "animal" is intended all animals that might derive a benefit from the compositions of this invention. Foremost among such animals are humans; however, the invention is not intended to be so limited, it being within the contemplation of the invention to treat any and all such animals that can experience the beneficial effects of the present invention. For nasal administration, the compositions of the invention will preferably be in a container provided with means for enabling application of the contained composition to the nasal mucosa, e.g., with a nasal applicator device. Suitable applicators are known in the art and include those adapted for administration of liquid compositions to the nasal mucosa in drop or spray form. Since dosing with polypeptides should be as accurately controlled as possible, the use of spray applicators for which the administered quantity is susceptible to precise regulation is generally preferred. Suitable adhiinistrators include e.g. , atmosing devices, e.g. , pop-atomizers and aerosol dispensers. In the latter case, the applicator will contain the composition of the present invention together with a propellant medium suitable for use in a nasal applicator. The atomizing device will be provided with an appropriate spray adaptor allowing delivery of the contained composition to the nasal mucosa. Such devices are well known in the art. The container, e.g. nasal applicator or eye drop bottle, can contain sufficient composition for a single nasal or ocular dosing or for several sequential dosages, e.g. over a period of days or weeks. The following examples are illustrative, but not limiting of the method and compositions of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and that are obvious to those skilled in the art are within the spirit and scope of the present invention. Example 1 Conjugation of Glycine and Ethylenediamine to QA-21 Triterpene Aldehyde Via Reductive Alkylation To react glycine with the QA-21 triterpene aldehyde, 20 mg of QA-21 was dissolved in 0.8 ml of 50% methanol, 50 mM sodium phosphate, pH 6.0. A 0.5 ml solution of glycine was prepared in water. A total of 0.1 ml of glycine was added to the QA-21 solution. A 0.1 M solution of sodium cyanoborohydride was prepared in methanol (32 mg in 5 ml). A total of 0.1 ml of the sodium cyanoborohydride was added to the QA-21 solution. The addition of sodium cyanoborohydride was repeated at 2.5, 21, 25, and 46 hours. The reaction mixture was purified by reversed-phase HPLC. A new peak at 31.3 minutes was collected. The new product was confirmed by FAB-MS To react emylenediamine with the QA-21 triterpene aldehyde, 6 mg of QA-21 was dissolved in 1 ml 50% methanol, 20 mM triemylamine phosphate, pH 6. A total of 0.15 ml of a 0.1 M ethylenediamine solution in water was added, followed by 0.06 ml of 50 mM sodium cyanoborohydride in methanol. Additional aliquots of the sodium cyanoborohydride were added at 45 minutes and 16 hours. The reaction was purified by reversed-phase HPLC on a 30- 60% B method. A new peak at 19.6 minutes was collected. This material was freeze-dried. The resulting peak was analyzed by reversed-phase thin layer chromatography and shown to be reactive with ninhydrin, indicating the addition of a free amino group to QA-21. Example 2 Reduction of the QA-21 Triterpene Aldehyde to Methylen ealcohol Twelve mg of QA-21 in four ml of water was mixed with 8 ml of 0.1 M sodium phosphate, pH 6.0 for a final QA-21 concentration of 1 mg/ml. A stock solution of 1 M sodium borohydride was prepared in 0.01 M NaOH. A total volume of 0.580 ml of sodium borohydride was added to the QA-21 in small increments (approximately 50 μl increments). The final concentration of sodium borohydride was 0.05 M. This reaction mixture was incubated for one hour at room temperature. The reaction was quenched with 1 ml of 1 N acetic acid. To remove sodium borohydride, the QA-21 was adsorbed to C18. Four mis of reaction mixture was passed through a cartridge containing C18. The cartridge was then washed with two 5 ml water washes. The QA-21 was then eluted from the C18 with 5 ml of methanol. This process was repeated with the remaining 8 ml of reaction mixture. The methanol was evaporated under a stream of N 2 . The reduced QA-21 was then redissolved in 30% acetonitrile/0.15% trifluoroacetic acid and purified by HPLC to remove residual unreduced QA-21 (VYDAC C4, 5 μm particle size, in a gradient of 25-40% B over 60 minutes at a flow rate of 3 ml/min (Solvent A - 0.15% trifluoroacetic acid (TFA) in water, Solvent B - 0.15% TFA in acetonitrile)). The reduced QA-21 eluted with a retention time of 46.8 minutes (compared to a retention time of 48.1 minutes for unreduced QA-21). The peak corresponding to the reduced QA-21 was pooled, diluted 1/2 with water and collected on C18 cartridges as described above. The final product was lyophilized and used for immunization studies. Example 3 Adjuvant Activities of Modified QA-21 Saponins Modified QA-21 saponins, as prepared above, were tested for adjuvant activity. C57 bl/6 mice (5 per group) were immunized subcutaneously with 25 μg ovalbumin and 10-50 μg QA-21 or one of its derivatives in saline. A booster immunization was given at day 14. Antibody response (total IgG) was tested by enzyme immunoassay after the second immunization. The two derivatives prepared by reductive alkylation at the triterpene aldehyde did not retain adjuvant activity at the doses tested (Figure 11). The modified QA-21 in which the triterpene aldehyde was reduced to an alcohol retained some adjuvant activity, but with a higher minimum effective dose than QA-21 (Figure 12). Results from similar experiments in which two booster immunizations were given at two week intervals are summarized in Table 2. TABLE 2 Adjuvant Activity of OA-21 and Derivatives Saponin (10 μg) Anti-ovalbumin IgG, administered with Total (log titer) ovalbumin (10 μg) none 2.59 ± 0.81 QA-21 4.06 ± 0.30 QA-2 l-A-ethylamine* 2.69 ± 0.59 QA-21-A-ethylene 2.68 ± 0.36 diamine 1 QA-21-A-glycine 1 2.00 ± 0.19 "Modified at triterpene aldehyde. Example 4 Hemolytic Activity of Modified Saponins The hemolytic assay provides a rough measure of the ability of a detergent to increase the uptake of pharmacologically active substances across mucous membranes by determining membrane permeabilization. Briefly, dilutions of the modified saponins are made on a round bottom, microtiter plate with 1:2 dilutions in phosphate buffered saline in successive rows (100 μl/well). 10 μl normal sheep blood in Alsevers solution (Whittaker) was added to each well and mixed. Plates were incubated for one hour at room temperature followed by centrifugation of the plates in a Sorvall RT6000 to sediment unhemolyzed cells. Absence of hemolysis was determined by the presence of a pellet of unhemolyzed cells in the bottom of the well. Hemolytic activity is determined by the increase of release of hemoglobin from sheep red blood cells (measured as absorbance at 562 or 570 nm in the red blood cell supernatant). As shown in Figure 2, QA-21 substantially increases membrane permeabilization at very low concentrations. Reduced QA-21 also increases membrane permeabilization, but at a lower level and at higher concentrations compared to QA-21. Example 5 Ocular Administration of Insulin Increased by Modified Saponins Protocol Male Sprague-Dawley rats were anesthetized with xylazme-ketamine and 30 minutes later (time 0), eye drops composed of saline plus or minus 0.4% insulin (100 U/mL) and one of the following saponins: Sigma crude saponin extracted from Gypsophilla Sigma Chemical Company, St. Louis, Mo.); crude saponin extracted from Quillaja; QA-21-H purified saponin hydrolytic derivative from QA-21. Typically, 20 μl of eye drops was delivered to one eye, but, occasionally, 20 μl was delivered to both eyes. Blood D-glucose -levels were measured using an AccuCheck-II glucometer (Boehringer-Mannheim). Data represent the level of blood glucose at various times before and after eye drop administration. Each single line represents the data obtained from one experimental animal, except where indicated. Results As shown in Figure 3 A, when saline was administered to the eyes of rats as a control, there was very little change in the blood glucose levels. However, when 0.5 % of Sigma Gypsophilla saponin was coadministered with 0.4% regular pork insulin, a significant hypoglycemic effect was observed. See Figure 3B. When 0.5% of crude Quillaja saponin (unmodified) was coadministered with 0.4% regular pork insulin, a less significant reduction in glucose serum levels was obtained. See Figure 3C. Figure 4 depicts a graph showing the effect of the ocular administration of a control solution of 0.1 % pure saponin (without insulin) on the blood glucose levels of 3 male rats. As can be seen from the graph, no significant hypoglycemic effect could be observed in the absence of insulin. Figure 5 depicts a graph showing the results of the administration of 20 μl of 0.025% QA-21-H and 0.4% regular pork insulin on the blood glucose levels of three rats. As can be seen from the graph, a significant hypoglycemic effect was observed. Figure 6 depicts a graph showing a graph showing the results of the adniimstration of 0.05 % QA-21-H and 0.4% regular pork insulin on the blood glucose levels of three male rats. As can be seen from the graph, a significant hypoglycemic effect was observed. Figure 7 depicts a graph showing the results of the administration of 0.1 % QA-21-H and 0.4% regular pork insulin on the blood glucose levels of four male rats. As can be seen from the graph, a significant hypoglycemic effect was observed. Figure 8 depicts a graph showing the blood glucose lowering effect of the ocular administration of 10 μl/eye, 0.01 % QA-21-H and 0.4% regular pork insulin to a- first rat; 10 μl/eye of 0.01% pure QA-21-H and 0.4% regular pork insulin to a second rat; and 20 μl/eye of 0.01 % QA-21-H and 0.4% regular pork insulin to a third rat. The results show that even at 0.01 % QA-21-H, some marginal transport of insulin was observed. These experiments allow one to derive the following conclusions: 1. The effect of all the saponins tested on insulin absorption displayed a rapid onset, with maximal hypoglycemic action observed after 60 minutes. 2. Compared to Sigma saponin, Quillaja saponin was less potent at stimulating systemic absorption of insulin from eye drops, whereas QA-21-H was considerably more potent. 3. Ocular irritation decreased as the concentration of saponin decreased; 0.1% purified QA-21-H did cause ocular irritation, while 0.05% and 0.025% QA-21-H caused progressively less irritation; however, the two lower non-irritating doses were effective in inducing transport, indicating that this product can be used effectively for transport in the absence of irritation. Partially purified (crude) Quillaja saponin caused ocular irritation at 0.5%, a dose that was minimally effective in inducing transport, indicating that this crude product cannot be used effectively in absence of irritation. Example 6 Preparation of QA-21-H from QA-21 QA-21 (10 mg/ml in water) was subjected to alkaline hydrolysis in 0.1 N sodium hydroxide for 15 minutes at ambient temperature. At the end of the incubation period, the pH was adjusted with glacial acetic acid to pH 4. The resulting primary hydrolysis product was isolated by preparative HPLC on VYDAC C4 (5 μ, 330 A pore size, 1.0 cm internal diameter x 25 cm length) in a gradient of 20 to 50% solvent B at a flow rate of 4 ml/minute and a UV detector setting of 214 nm (solvent A = 0.15% TF A/water; solvent B = 0.15 % TFA/acetonitrile). QA-21-H (which eluted with a retention time of 23 minutes) was collected and lyophilized. Example 7 Preparation of QA-21-H,R from QA-21-H QA-21-H (10 mg/ml in 10 mM phosphate buffer, pH 6.5, total of 38.2 mg) was incubated with 0.33 M sodium borohydride for two hours at 4° C to produce a product in which the triterpene aldehyde was reduced to an alcohol (designated QA-21-H,R). The residual sodium borohydride was separated from QA-21-H,R by dialysis through a 1000 dalton molecular weight cutoff dialysis membrane, using a 62.5 fold volume excess of water. The QA-21-H,R was retained by the dialysis membrane. The dialysis step was repeated three additional times. The dialyzed QA-21-H,R solution was lyophilized, yielding 28 mg. Example 8 Analysis of QA-21, QA-21-H, and QA-21-H,R QA-21, QA-21-H, and QA-21-H.R were compared by analytic reversed-phase HPLC (Dynamax C8, 300 A pore size, 5 micron particle size, 0.46 cm x 25 cm (i.d. x length), 1 ml/min. flow rate, 30-45% solvent B / 30 minutes (where solvent A = 0.15% TFA in water and solvent B = 0.15% TFA in acetonitrile)). Comparative retention time for QA-21, QA-21-H, and QA-21-H,R in this particular system were determined to be 28.0 min., 10.4 min., and 10.3 min., respectively. QA-21-H, and QA-21-H,R were mixed and injected on HPLC, confirming that these yielded separate peaks. Infrared spectra are shown in Figure 13. Primary changes are observed in the C=O stretch region between 1600 to 1800, consistent with removal of two ester bonds from QA-21 during the preparation of QA-21-H and with elimination of the aldehyde in the preparation of QA-21-H,R. Comparative FAB-MS spectra of QA-21-H, and QA-21-H,R yielded pseudomolecular ions of 1536 and 1538, respectively, consistent with the structure [M+Na] + where M = C 69 H 108 O 36 for QA-21-H and M = C 69 H„ 0 O 36 for QA-21-H,R, indicating mat reduction of the triterpene aldehyde to a methylenealcohol yielded the expected increase of 2 in the molecular weight. Example 9 Preparation of a Mixture of QA-18-H and QA-21-H A crude mixture of Quillaja saponaria bark extract (dark brown in appearance) was partially purified by diafiltration through a 10,000 dalton molecular weight cartridge to an approximate purity of 8% QA-21 in the membrane retentate. A total of 400 mg of the 8% purity mixture was suspended in 12 ml of 90% n-propanol. This solution was adjusted to 0.2 N sodium hydroxide by addition of a 5 N sodium hydroxide stock solution. This was vortexed and incubated for two hours at room temperature. The suspension was then centrifuged for five minutes at 50 x g, yielding a yellow colored supernatant and a dark brown grainy precipitate. This precipitate was washed three times with 12 ml of 90% propanol. The resulting pellet was redissolved in 12 ml water and adjusted to pH 3.8 with addition of glacial acetic acid. A total volume of 12 ml of n-propanol was added for a final propanol percent of approximately 50%. This solution was then allowed to adsorb to two grams of silica (Lichroprep Si60) followed by removal of the solvent under a gentle stream of nitrogen. This preadsorbed silica was loaded evenly on top of a Lichroprep Si60 column (2.5 cm internal diameter x 14 cm height) equilibrated in 1 -propanol. Approximately 1 column volume of 1- propanol was eluted through the column. This was followed by 3 column volumes of 85% 1 -propanol, 2.5 column volumes of 80% 1 -propanol, and 2.5 column volumes of 75% 1-propanol. QA-18-H and QA-21-H eluted together in a single pool with 75% 1 -propanol. These were collected and lyophilized yielding 113 mg of a white powder. A total of 48 mg was dissolved in 0.6 ml of 20 mM acetic acid and adsorbed to a VYDAC C18 column (20-30 μ, 1 cm internal diameter x 10 cm length). The column was washed with 20 mM acetic acid (10 column volumes) and the peak containing QA-18-H and QA- 21-H as a mixture was eluted with 30% acetonitrile / 20 mM acetic acid and lyophilized, yielding 39 mg. The purity was determined by analytical reversed-phase HPLC to be approximately 52% QA-18-H and 22% QA-21-H. Figure 14 A shows an analysis by reversed-phase HPLC of the total saponin fraction from Quillaja saponaria after partial purification by diafiltration; Figure 14B shows the purity after hydrolysis and precipitation in 1 -propanol and Figure 14C shows the purity after silica chromatography. Example 10 Purification of QA-18-H and QA-21-H Directly from Hydrolyzed Crude Mixture A total of 100 mg of diafiltered Quillaja saponaria bark extract was dissolved in 3 ml of 90% propanol and hydrolyzed as in Example 9. The brown pellet yielded after hydrolysis was redissolved in 5 ml of 30% acetonitrile / 20 mM acetic acid. A total of 5 ml was loaded onto a column of VYDAC C18 (20-30 μ, 2.5 cm I.D. x 14 cm length) and was eluted with 30% acetonitrile / 20 mM acetic acid. Fractions 21-30 were pooled and lyophilized for QA-18-H, yielding 14.3 mg. This fraction was analyzed by reversed-phase HPLC (Figure 15A) to be 81.9% QA-18-H (retention time = 8.68 min. on Dynamax C8, 0.46 cm I.D. x 25 cm length, 300 A pore size, 5 micron particle size, flow rate = 1 ml/min, gradient = 30-45% B/30 min where solvent A = 0.15% TFA/water and solvent B = 0.15% TFA/acetonitrile) and 16.6% of a preceding peak -42- (retention time = 8.23 min.). These two peaks were isolated and were analyzed by HPLC comparison to a QA-18-H standard and by FAB-MS. The main peak was confirmed by HPLC analysis and FAB-MS to be QA-18-H. The preceding minor peak was shown to have a molecular weight 14 daltons higher than QA-18-H, consistent with this being a closely related compound to QA-18-H. Hence, QA-18-H could be purified directly from a hydrolyzed crude mixture that originally contained QA-17 and QA-18 (precursors of QA- 18-H) as well as directly from hydrolyzed purified QA-17 and QA-18. Fractions 31-41 were pooled and lyophilized for QA-21-H, yielding 7.7 mg of QA-21-H. Analysis by reversed-phase HPLC (Figure 15B) showed that the product consisted of 78.7% QA-21-H (retention time = 10.04 min.) and 13.3% of a preceding peak (retention time = 9.46 min.). These two peaks were isolated and the main peak was analyzed by analytic reversed-phase HPLC comparison to QA-21-H standard run on the same day to confirm its identity as QA-21-H. Hence, QA-21-H could be purified directly from a hydrolyzed crude mixture that originally contained QA-21 as well as from hydrolyzed purified QA-21. Example 11 Delivery of Insulin by Eye Drop Route to Test Effect of Deletion of Fatty Acid and Reduction of Triterpene Aldehyde on Delivery Molecules The activity of QA-21 (unmodified), QA-21-H (fatty acid domain deleted), and QA-21-H,R (fatty acid domain deleted and triterpene aldehyde reduced to an alcohol) was tested for delivery of insulin through ocular delivery in the anesthetized rat model described supra. A total volume of 20 μl of insulin and varying doses of test delivery agents (at concentrations of 0.01 %, 0.025%, 0.05%, and 0.1 %) was delivered to both eyes (10 μl per eye). Glucose levels were monitored at frequent time intervals in the post- administration period. Figure 16 shows the effect of QA-21 concentration on ocular delivery of insulin. Figure 17 shows the effect of QA-21-H concentration on ocular delivery of insulin. Figure 18 shows the effect of QA-21-H,R concentration on ocular delivery of insulin. The results are listed as a mean and standard deviation of the results from three rats at each concentration. Control formulations containing of 0.1 % test delivery agent, but no insulin, did not stimulate a reduction of glucose concentration, indicating that none of the three test delivery agents caused a non-insulin dependent drop in glucose levels. Insulin transport was observed with QA-21-H,R only at a concentration of 0.1 %. However, transport was observed with QA-21 and QA-21-H at concentrations of 0.025%. No effect was observable at 0.01%. Figure 19 shows the ratio of glucose levels at 120 minutes post- administration to glucose levels at time = 0 (time of administration) as a function of concentration of QA-21, QA-21-H, and QA-21-H,R. The results indicate that QA-21 and QA-21-H appear to be equally potent in enhancing insulin transport. Hence, deletion of the fatty acid domain did not seem to affect transport activity. The QA-21-H,R was also able to promote ocular transport of insulin although higher concentrations were required, suggesting that the reduction of the triterpene aldehyde decreased (but did not eliminate) the transport activity. Example 12 Delivery of Insulin by the Nasal Route Test of QA-21-H, QA-18-H, and a Mixture of QA-18-H AND QA-21-H as Delivery Agents Figure 20 shows the effect of QA-21-H on nasal delivery of insulin into rats. A total of 20 μl of 0.05% QA-21-H and 0.2% insulin was administered to the right nostril of two rats at 0 and 5 minutes. Serum glucose levels were monitored before and after administration. Figure 21 shows the effect of QA-18-H (prepared as described above) on nasal delivery of insulin. It was shown to be effective at 0.1 % and 0.05 % , but lost potency for transport at 0.025%. Figure 22 shows the effect of a mixture of QA-18-H and QA-21-H (prepared as described above) on nasal delivery of insulin. The mixture tested contained approximately 52% QA-18-H and 22% QA-21-H with the remainder being closely related molecules. It was effective at 0.1 % and 0.05%, but lost most of the potency for transport at 0.025%. The nasal delivery data on QA-21-H (shown above to be effective at increasing transport through the ocular route) suggest that these molecules are effective in other delivery routes, as well. Although QA-18-H and QA-18-H, QA-21-H mixture were not tested via the ocular route, their efficacy at increasing delivery through the nasal route indicates their potential for increasing delivery through other mucosal membranes. Example 13 Hydrolysis Product QH-957 as a Permeation Enhancer QH-957 theoretically would be produced from all of the saponins in the Quillaja bark extract. A. Preparation The hydrolysis product, QH-957, was prepared by heating a QA-21 solution in phosphate-buffered saline at pH 6-7 for 48-72 hours at 100-105 °C. The hydrolysis products were purified by reverse-phase HPLC in a water/acetonitrile gradient, containing 0.15% trifluoroacetic acid, and were lyophilized to dryness. Molar recovery of QH-957 from starting material was 10-20% of theoretical. B. Identification QH-957 was identified and characterized by FAB-MS, NMR, lit spectroscopy, and carbohydrate linkage analysis. The two main products of the hydrolysis are produced by cleavage between the triterpene ring and the fucose sugar. (QH-957 contains the triterpene ring). (M + Na) + = 979 g/mole. QH-957 Glycosyl Linkage Relative Area Percent terminal rhamnose 4.8 4-linked rhamnose 2.8 terminal xylose 24.0 terminal galactose 44.0 terminal glucose 2.0 3-Iinked glucuronic acid 2.4 2,3-linked glucuronic acid 16.0 C. Hemolytic Properties QH-957 was not hemolytic at concentrations up to 3 mM (2.9 mg/ml). D. Intranasal Drug Delivery Insulin QH-957 was tested for intranasal delivery of insulin in concentrations from 0.66 to 5.2 mM (0.6-5 mg/ml). Enhanced permeation of insulin was observed by decreased serum glucose levels occurred at QH-957 concentrations greater than or equal to 2.6 mM. The QH-957 concentration necessary for enhancement of insulin absorption was dependent on the weight of the animal. Larger rats only showed response to the higher QH-957 concentrations. See Figure 23. Experimental Conditions: Sprague-Dawley rats (male, 220-350 g) were anesthetized by intramuscular injection of 7.5 mg/kg xylazine with 50 mg/kg ketamine at time = -20 minutes. This combination of anesthetic increases blood glucose levels. Insulin, 40 μl, was administered intranasally at time 0. Formulations contained 5 U/kg insulin and various concentrations of QH-957. Blood was withdrawn from the tail vein at various timepoints. Blood glucose levels were measured with glucometer strips. Groups of 3 animals were used. Data are presented as ± standard error of the mean. Gentamicin QH-957 was tested for intranasal delivery of gentamicin, an aminoglycoside antibiotic. QH-957 enhanced permeation of a 5 mg/kg dose of gentamicin at a concentration of 1.32 mM, in which significant serum levels of gentamicin were detected. Gentamicin was not detected in serum in the absence of QH-957. See Figure 24. Experimental Conditions: Sprague-Dawley rats (male, 205-240 g) were anesthetized by intramuscular injection of 7.5 mg/kg xylazine with 50 mg/kg ketamine. Gentamicin (40 μl) was administered intranasally at time 0. Formulations contained 5 mg/kg gentamicin, with and without 1.32 mM QH-957. Blood was withdrawn from the tail vein at various timepoints. Serum gentamicin levels were measured using a fluorescence polarization immunoassay. The assay was linear from 0.3-10.0 μg/ml, and the limit of detection was 0.3 μg/ml. A value of 0.3 μg/ml was used in plotting the timepoints with serum levels below the limit of detection. Groups of 3 animals were used. Data are presented as ± standard error of the mean. Example 14 QA-7-H as a Permeation Enhancer A. Preparation QA-7-H was prepared as follows. The parent compound, QA-7, was purified by RP-HPLC of the crude Quillaja saponaria bark extract in a water/acetonitrile gradient, containing 0.15% trifluoroacetic acid. The fractions containing QA-7 were pooled and lyophilized to dryness. The QA-7 was reconstituted in water and sodium hydroxide was added to 0.1 N final concentration. The hydrolysis reaction was allowed to proceed for 2 hours, and was terminated by the addition of glacial acetic acid to a final pH 4-5. The QA-7-H was purified by RP-HPLC in a water/acetonitrile gradient, containing 0.15% trifluoroacetic acid. The fractions containing QA-7-H were pooled and lyophilized to dryness. B. Preliminary Identification QA-7-H was characterized by FAB-MS analysis. (M+Na) + = 1844 g/mole. Hydrolysis of QA-7, to produce QA-7-H, results in a molecular weight loss of 41. C. Intranasal Drug Delivery Insulin QA-7-H was tested for intranasal delivery of insulin in concentrations from 0.125 to 1.0 mM (0.2-2 mg/ml). Enhanced permeation of insulin was observed by decreased serum glucose levels occurred at QA-7-H concentrations greater than or equal to 0.25 mM (0.5 mg/ml). See Figure 25. Experimental Conditions: Sprague-Dawley rats (male, 220-350 g) were anesthetized by intramuscular injection of 7.5 mg/kg xylazine with 50 mg/kg ketamine at time = -20 minutes. This combination of anesthetic increases blood glucose levels. Insulin, 40 μl, was administered intranasally at time 0. Formulations contained 5 U/kg insulin and various concentrations of QA-7-H. Blood was withdrawn from the tail vein at various timepoints. Blood glucose levels were measured with glucometer strips. A single animal was tested. Gentamicin QA-7-H was tested for intranasal delivery of gentamicin, an aminoglycoside antibiotic. QA-7-H enhanced permeation of a 5 mg/kg dose of gentamicin at a concentration of 1.32 mM, in which significant serum levels of gentamicin were detected. Gentamicin was not detected in serum in the absence of QA-7-H. See Figure 26. Experimental Conditions: Sprague-Dawley rats (male, 205-240 g) were anesthetized by intramuscular injection of 7.5 mg/kg xylazine with 50 mg/kg ketamine. Gentamicin (40 μl) was aά^ninistered intranasally at time 0. Formulations contained 5 mg/kg gentamicin, with and without 1.32 mM QA-7-H. Blood was withdrawn from the tail vein at various timepoints. Serum gentamicin levels were measured using a fluorescence polarization immunoassay. The assay was linear from 0.3-10.0 μg/ml, and the limit of detection was 0.3 μg/ml. A value of 0.3 μg/ml was used in plotting the timepoints with serum levels below the limit of detection. Groups of 3 animals were used. Data are presented as ± standard error of the mean. Example 15 Comparison of Modified Quillaja Saponins with Other Permeation Enhancers A. Permeation Enhancers Tested The modified Quillaja saponins QA-21-H, QA-21-H,R, QH-957, QA-18-H, QA-7-H, and the purified original compound QA-21 were compared for their ability to enhance the intranasal delivery of gentamicin in rats. The bile salt sodium glycocholate and the surfactant glycyrrhizic acid were included in the study because of the similarity of their triterpenoid structures to the modified Quillaja saponins. Sodium glycocholate (Pontiroli, A.E. et al , J. Clin. Endocrinol Metab. 65:821-824 (1989)) and glycyrrhizic acid (Mishima, M. et al , J. Pharmacobio-Dyn. 12:31-36 (1989)) are known permeation enhancers for drag delivery. B. Experimental Conditions The permeation enhancers were tested for intranasal delivery of gentamicin, an aminoglycoside antibiotic. Sprague-Dawley rats (male, 205-240 g) were anesthetized by intramuscular injection of 7.5 mg/kg xylazine with 50 mg/kg ketamine. Gentamicin (40 μl) was administered intranasally at time 0. Formulations contained 5 mg/kg gentamicin with 1.32 mM permeation enhancer in phosphate buffered saline. Blood was withdrawn from the tail vein at various timepoints. Serum gentamicin levels were measured using a fluorescence polarization immunoassay. The assay was linear from 0.3-10.0 μg/ml, and the limit of detection was 0.3 μg/ml. The area under the serum gentamicin concentration curve (AUC) was calculated using the trapezoidal rale. A value of 0.3 μg/ml was used to determine the AUC for the timepoints with serum levels below the limit of detection. Groups of 3 animals were used. Data are presented as ± standard error of the mean. See Figure 27. C. Results The purified original compound, QA-21, and the modified saponins enhanced drag delivery of gentamicin at 1.32 mM concentration, while sodium glycocholate and glycyrrhizic acid did not. Efficacy of drug delivery for the modified saponins is demonstrated at molar concentrations 15-20 fold lower than the concentrations needed for sodium glycocholate (20.5 mM) (Pontiroli, A.E. et al , J. Clin. Endocrinol Metab. 65:821-824 (1989)) and glycyrrhizic acid (23.8 mM) (Mishima, M. et al , J. Pharmacobio-Dyn. 12:31-36 (1989)). The study did not include enough animals per group to make any conclusions about differences among the modified saponins and QA- 21. From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions, without undue experimentation.

Claims: What is Claimed is: 1. A chemically modified saponin or fraction thereof obtained from a crade Quillaja saponaria extract, said chemically modified sapomn or fraction thereof having the structure: wherein R, is a methylenealcohol or methyleneamino group; R 2 is hydrogen or SAC 2 ; and SAC j and SA are independently selected saccharide groups. 2. The composition of claim 1, wherein said chemically modified saponin or fraction thereof is QA-7-H, wherein R, is methylenealcohol. 3. The composition of claim 1, wherein said chemically modified saponin or fraction thereof is QH-957, wherein R, is methylenealcohol. 4. The composition of claim 1, wherein said chemically modified saponin or fraction thereof is QA-7-H, wherein R ! is a methyleneamino group. 5. The composition of claim 1, wherein said chemically modified saponin or fraction thereof is QH-957, wherein Rj is a methyleneamino group. 6. The composition of claim 4, wherein said methyleneamino group is -CH 2 -N(R)-R 3 , wherein R is hydrogen, R 3 is selected from the group consisting of hydrogen, C r C g alkyl, C 2 -Cι 2 alkylaminoalkyl, allyl, aralkyl, C 3 - C 8 cycloalkyl, aryl and a group having the formula R 4 I -CH-CO 2 H, wherein R 4 is hydrogen, C r C 4 alkyl, or C,-C 4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C,-C 4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazolyl or carbamyl; or wherein R and R 4 together form a pyrrolidinyl or piperidinyl ring. 7. The composition of claim 5, wherein said methyleneamino group is -CH 2 -N(R)-R 3 , wherein R is hydrogen and R 3 is selected from the group consisting of hydrogen, C,-C 8 alkyl, -C^ alkylaminoalkyl, allyl, aralkyl, C 3 -C 8 cycloalkyl, aryl and a group having the formula wherein R, is hydrogen, C,-C 4 alkyl, or C,-C 4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C C 4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazolyl or carbamyl; or wherein R and R 4 together form a pyrrolidinyl or piperidinyl ring. 8. A pharmaceutical composition for increasing systemic uptake by an animal of a pharmacologically active substance, comprising (A) at least one chemically modified saponin or fraction thereof obtained from a crade Quillaja saponaria extract, said chemically modified sapomn or fraction thereof having the structure: wherein R, is -CHO, a methylene alcohol, or methyleneamino group; R 2 is hydrogen or SAC 2 ; and SACj and SA are independently selected saccharide groups; (B) a pharmacologically active substance, and, optionally, (C) a pharmaceutically acceptable carrier. 9. The pharmaceutical composition of claim 8, wherein said saponin or fraction thereof is QA-7-H, wherein R, is -CHO. 10. The pharmaceutical composition of claim 8, wherein said saponin or fraction thereof is QA-7-H, wherein R, is methylenealcohol. 11. The pharmaceutical composition of claim 8, wherein said saponin or fraction thereof is QA-7-H, wherein R, is a methyleneamino group. 12. The pharmaceutical composition of claim 8, wherein said saponin or fraction thereof is QH-957 and wherein R, is -CHO. 13. The pharmaceutical composition of claim 8, wherein said saponin or fraction thereof is QH-957 and wherein R, is methylenealcohol. 14. The pharmaceutical composition of claim 8, wherein said saponin or fraction thereof is QH-957 and wherein R, is a methyleneamino group. 15. The pharmaceutical composition of claim 8, wherein said saponin or fraction thereof is QA-18-H and wherein R, is -CHO. 16. The pharmaceutical composition of claim 8, wherein said saponin or fraction thereof is QA-18-H and wherein R ! is methylenealcohol. 17. The pharmaceutical composition of claim 8, wherein said saponin or fraction thereof is QA-18-H and wherein Rj is a methyleneamino group. 18. The pharmaceutical composition of claim 8, wherein said saponin or fraction thereof is QA-21-H and wherein R, is -CHO. 19. The pharmaceutical composition of claim 8, wherein said saponin or fraction thereof is QA-21-H and wherein Rj is methylenealcohol. 20. The pharmaceutical composition of claim 8, wherein said saponin or fraction thereof is QA-21-H and wherein R, is a methyleneamino group. 21. The pharmaceutical composition of claim 11, wherein said methyleneamino group is -CH 2 -N(R)-R 3 , wherein R is hydrogen and R 3 is selected from the group consisting of hydrogen, C,-C 8 alkyl, C 2 -C ]2 alkyl- aminoalkyl, allyl, aralkyl, C 3 -C 8 cycloalkyl, aryl and a group having the formula wherein R 4 is hydrogen, C r C 4 alkyl, or C r C 4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C,-C 4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazolyl or carbamyl; or wherein R and R 4 together form a pyrrolidinyl or piperidinyl ring. 22. The pharmaceutical composition of claim 14, wherein said methyleneamino group is -CH 2 -N(R)-R 3 , wherein R is hydrogen and R 3 is selected from the group consisting of hydrogen, C,-C 8 alkyl, -C^ alkyl¬ aminoalkyl, allyl, aralkyl, C 3 -C 8 cycloalkyl, aryl and a group having the formula R» I -CH-CO 2 H, wherein R, is hydrogen, C C 4 alkyl, or C,-C 4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C r C 4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazolyl or carbamyl; or wherein R and R, together form a pyrrolidinyl or piperidinyl ring. 23. The pharmaceutical composition of claim 17, wherein said methyleneamino group is -CH 2 -N(R)-R 3 , wherein R is hydrogen and R 3 is selected from the group consisting of hydrogen, C,-C 8 alkyl, C 2 -C 12 alkyl- aminoalkyl, allyl, aralkyl, C 3 -C 8 cycloalkyl, aryl and a group having the formula R, -CH-CO 2 H, wherein R 4 is hydrogen, C r C 4 alkyl, or C r C 4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C,-C 4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazolyl or carbamyl; or wherein R and R 4 together form a pyrrolidinyl or piperidinyl ring. 24. The pharmaceutical composition of claim 20, wherein said methyleneamino group is -CH 2 -N(R)-R 3 , wherein R is hydrogen and R 3 is selected from the group consisting of hydrogen, C,-C 8 alkyl, -C^ alkyl¬ aminoalkyl, allyl, aralkyl, C 3 -C 8 cycloalkyl, aryl and a group having the formula I -CH-CO 2 H, wherein R, is hydrogen, C,-C 4 alkyl, or C,-C 4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C r C 4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazolyl or carbamyl; or wherein R and R, together form a pyrrolidinyl or piperidinyl ring. 25. A method for increasing systemic uptake of a pharmacologically active substance by an animal, comprising administering a pharmaceutical composition, comprising (A) at least one chemically modified saponin or fraction thereof obtained from a crade Quillaja saponaria extract, said chemically modified saponin or fraction thereof having the structure: wherein Ri is -CHO, a methylene alcohol, or methyleneamino group; R 2 is hydrogen or SA ; and SAC ! and SAC 2 are independently selected saccharide groups; (B) a pharmacologically active substance, and, optionally, (C) a pharmaceutically acceptable carrier. 26. The method of claim 25 wherein the pharmaceutical composition is brought into contact with mucous membranes for uptake. 27. The method of claim 25 wherein the pharmaceutical composition is brought into contact with a dermal surface for transdermal uptake. 28. The method of claim 25, wherein said saponin or fraction thereof is QA-7-H and wherein Rj is -CHO. 29. The method of claim 25, wherein said saponin or fraction thereof is QA-7-H and wherein R, is methylenealcohol. 30. The method of claim- 25, wherein said saponin or fraction thereof is QA-7-H and wherein R, is a methyleneamino group. 31. The method of claim 25, wherein said saponin or fraction thereof is QH-957 and wherein R, is -CHO. 32. The method of claim 25, wherein said saponin or fraction thereof is QH-957 and wherein R, is methylenealcohol. 33. The method of claim 25, wherein said saponin or fraction thereof is QH-957 and wherein R, is a methyleneamino group. 34. The method of claim 25, wherein said saponin or fraction thereof is QA-18-H and wherein R, is -CHO. 35. The method of claim 25, wherein said saponin or fraction thereof is QA-18-H and wherein R, is methylenealcohol. 36. The method of claim 25, wherein said saponin or fraction thereof is QA-18-H and wherein Rj is a memyleneamino group. 37. The method of claim 25, wherein said saponin or fraction thereof is QA-21-H and wherein R, is -CHO. 38. The method of claim 25, wherein said saponin or fraction thereof is QA-21-H and wherein R, is methylenealcohol. 39. The method of claim 25, wherein said saponin or fraction thereof is QA-21-H and wherein Rj is a methyleneamino group. 40. The method of claim 30, wherein said methyleneamino group is -CH 2 -N(R)-R 3 , wherein R is hydrogen and R 3 is selected from the group consisting of hydrogen, C r C 8 alkyl, C 2 -C 12 alkylaminoalkyl, allyl, aralkyl, C 3 - C 8 cycloalkyl, aryl and a group having the formula R, I -CH-CO 2 H, wherein R 4 is hydrogen, C r C 4 alkyl, or C,-C 4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C r C 4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazolyl or carbamyl; or wherein R and R 4 together form a pyrrolidinyl or piperidinyl ring. 41. The method of claim 33, wherein said methyleneamino group is -CH 2 -N(R)-R 3 , wherein R is hydrogen and R 3 is selected from the group consisting of hydrogen, C r C 8 alkyl, -C^ alkylaminoalkyl, allyl, aralkyl, C 3 - C 8 cycloalkyl, aryl and a group having the formula R, I -CH-CO 2 H, wherein R, is hydrogen, C r C 4 alkyl, or C r C 4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C r C 4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazolyl or carbamyl; or wherein R and R, together form a pyrrolidinyl or piperidinyl ring. 42. The method of claim 36, wherein said methyleneamino group is -CH 2 -N(R)-R 3 , wherein R is hydrogen and R 3 is selected from the group consisting of hydrogen, C r C 8 alkyl, C 2 -Cι 2 alkylaminoalkyl, allyl, aralkyl, C 3 - C 8 cycloalkyl, aryl and a group having the formula R. I -CH-CO 2 H, wherein R 4 is hydrogen, C r C 4 alkyl, or C,-C 4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C,-C 4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazolyl or carbamyl; or wherein R and R 4 together form a pyrrolidinyl or piperidinyl ring. 43. The method of claim 39, wherein said methyleneamino group is -CH 2 -N(R)-R 3 , wherein R is hydrogen and R 3 is selected from the group consisting of hydrogen, C,-C 8 alkyl, C 2 -Cι 2 alkylaminoalkyl, allyl, aralkyl, C 3 - C 8 cycloalkyl, aryl and a group having the formula R. I -CH-CO 2 H, wherein R, is hydrogen, C,-C 4 alkyl, or C r C 4 alkyl substituted by phenyl, hydroxyphenyl, indolyl, mercapto, C r C 4 alkylthio, hydroxy, carboxy, amino, guanidino, imidazolyl or carbamyl; or wherein R and R, together form a pyrrolidinyl or piperidinyl ring. 44. The method of claim 26, wherein said mucous membrane is present in the conjunctiva, nasopharynx, orthopharnyx, vagina, colon, urethra, urinary bladder or intestine. 45. The method of claim 26, wherein said pharmaceutical composition is contacted with said membrane by ocular administration to an animal. 46. The method of claim 26, wherein said pharmaceutical composition is contacted with said membrane by nasal administration to an animal. 47. The method of claim 26, wherein said pharmaceutical composition is contacted with said membrane by sublingual administration to an animal. 48. The method of claim 26, wherein said pharmaceutical composition is contacted with said membrane by vaginal administration to an animal. 49. The method of claim 26, wherein said pharmaceutical composition is contacted with said membrane by buccal administration to an animal.

Inventors: KENSIL CHARLOTTE A, MARCIANI DANTE J, RECCHIA JOANNE, SOLTYSIK SEAN, KENSIL, CHARLOTTE, A., MARCIANI, DANTE, J., RECCHIA, JOANNE, SOLTYSIK, SEAN
Applicants: CAMBRIDGE BIOTECH CORP, CAMBRIDGE BIOTECH CORPORATION
Application year: 1996
Main classification: A61K35
IPC codes: A61K9, A61K38, A61K39, A61K47, C07J63