WO1993022334A1 - Compositions pharmaceutiques et procedes pour l'apport de corticosteroides au colon - Google Patents

Compositions pharmaceutiques et procedes pour l'apport de corticosteroides au colon Download PDF

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WO1993022334A1
WO1993022334A1 PCT/US1993/004202 US9304202W WO9322334A1 WO 1993022334 A1 WO1993022334 A1 WO 1993022334A1 US 9304202 W US9304202 W US 9304202W WO 9322334 A1 WO9322334 A1 WO 9322334A1
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prodrug
corticosteroid
dexamethasone
group
colon
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PCT/US1993/004202
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English (en)
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David R. Friend
Richard N. Fedorak
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Sri International
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/0026—Oxygen-containing hetero ring cyclic ketals
    • C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J17/005—Glycosides

Definitions

  • This invention relates to compositions and methods for colon-specific drug delivery. More specifically, the invention relates to colon-specific delivery of corticosteroid drugs using a prodrug composition which, when ingested by a mammal, undergoes reaction with enzymes which are produced by coionic microflora to release the free drug-
  • Implantable pumps, adhesive patches impregnated with drugs, vesicle- enclosed drugs, and drug carriers have been proposed to achieve site-specific delivery.
  • Another approach has been to use prodrugs (see Stella, V.J., and Himmelstein, K.J., J. Med. Chem. 23:1275-1282 (1980); Sinkula, A.A., and Yalkosky, S.H., J. Pharm. Sci. 64:181-210 (1975)) which, by virtue of their physicochemical properties, can reach specific sites and then be converted to the active drug in situ.
  • the azo-reductase activity of the coionic microflora is now known to activate certain sulfa drugs by reducing the azo-bond present in such compounds. See Mandel, G.L., and Sande, M.A., in "The Pharmacological Basis of Therapeutics," Sixth Ed. (A.G. Gilman, L.S. Goodman, and A. Gilman, Eds.) MacMillan, New York, N.Y., (1980) pp. 1106-1165. Also, the reduction of the azo-link between an unabsorbed polymer and certain aromatic amines form the basis of a recently developed colon-specific drug delivery system. See Parkinson, T.M., Brown, J.P., and indegard, R.E., U.S.
  • Patent 4,190,716 (Feb. 26, 1980); and Brown, J.P., Appl. Enviro. Microbiol. 41:1283-1286 (1981).
  • the present invention is specifically directed to methods and compositions for colon—specif c delivery of corticosteroid drugs.
  • the overall approach involves delivering the drug to the large intestine via a uronic acid carrier.
  • the active drug is liberated by enzymes produced by the gut microflora, which reside primarily in the large intestine. After drug absorption, much higher cecal and coionic tissue drug concentrations are possible than when such active agents are administered systemically at an equal dose. This approach to coionic delivery permits lower doses of corticosteroids to be administered while maintaining efficacy.
  • the advantages of the invention are many.
  • the development of a colon-specific delivery system for the administration of corticosteroid drugs will be useful to the many people who suffer from diseases, such as ulcerative colitis (approximately 65 cases per 100,000 in the population as a whole) and Crohn's disease (approximately 30 cases per 100,000).
  • the colon-specific corticosteroid delivery system of the invention is also useful in the treatment of radiation-induced colitis.
  • the invention eliminates the complications which are frequently encountered with the systemic administration of corticosteroids
  • the invention enables the use of far lower doses of corticosteroid drugs than previously possible; this is important, also, in reducing side effects.
  • the invention addresses the need in the art for a corticosteroid formulation which is orally active; it is well known that many corticosteroid drugs have little activity when administered orally. With the present prodrug compositions, however, even these drugs are rendered orally active for treatment of ulcerative colitis and Crohn's disease of the colon.
  • the invention addresses the need to deliver a corticosteroid not only to ascending and transverse colon, but also the descending and sigmoid colon.
  • the distal colon is the primary site of inflammation in patients with ulcerative colitis and Crohn's disease of the colon. As the disease proceeds, it moves to the proximal parts of the colon and increases in severity. Therefore, the invention should be useful to almost all individuals with ulcerative colitis and Crohn's disease of the colon regardless of the site of inflammation.
  • WO84/04041 entitled “Colon-Specific Drug Delivery System,” inventors Friend and Chang, and by Friend et al. in J. Med. Chem. 27:261-266 (1985) and J. Med. Chem. 28:51-57 (1985).
  • the efficacy of the formulations which were based on D-glucose, D- galactose and D-cellobiose—was found to be limited; the uronic acid-based prodrugs which have now been developed and are described and claimed herein surprisingly display far greater efficacy at lower doses than the earlier systems.
  • U.S. Patent Nos. 4,443,440 and 4,456,602 to Anderson et al. describe amine-containing ester prodrugs of corticosteroids which are stated to be “solution stable” in vitro but labile and thus converted in vivo to the active parent drug.
  • U.S. Patent Nos. 4,469,689 and 4,472,392 to Anderson et al. are similar but relate to sulfonate-containing ester prodrugs of corticosteroids, while U.S. Patent No. 4,588,718 to Anderson et al. relates to carboxy- containing ester prodrugs of corticosteroids.
  • U.S. Patent No. 4,221,787 to Bodor et al. describes esteramide prodrugs of corticosteroids formulated for delivery to the skin.
  • U.S. Patent Nos. 4,548,922 and 4,959,358 to Carey et al. describe pharmaceutical compositions for delivering a drug transmucosally, the compositions containing, as a permeation enhancer, a steroid optionally conjugated to an organic group such as a uronic acid.
  • corticosteroid is administered as a prodrug comprised of a corticosteroid glucuronide capable of being cleaved by glucuronidase enzymatic activity of coionic microflora but not capable of being significantly hydrolyzed by endogenous enzymes produced by the mammalian host.
  • the prodrugs of the present invention utilize a sugar moiety such as a uronic acid as the disabling moiety that substantially prevents liberation or absorption of the free drug until the prodrug reaches the area of the colon. Coionic microfloral glycosidases then act upon the prodrug, cleaving it to release the drug in active form.
  • the novel prodrugs comprise a corticosteroid drug bonded through the 21-hydroxyl group to the c, position of a sugar moiety such as ⁇ -D-glucuronic acid.
  • the prodrugs may be represented by the structural formula
  • R represents a sugar moiety as will be described in further detail below
  • St represents the corticosteroid moiety
  • X is oxygen or sulfur, preferably oxygen.
  • the sugar moiety is thus linked to the corticosteroid through an ether or thioether linkage.
  • the "parent" corticosteroid of the prodrug may be represented as StOH wherein the OH is located at the 21-position of the corticosteroid which may be depicted as follows:
  • a thiol may be present at the 21- position, giving rise to a thioether linkage between the corticosteroid and the sugar species.
  • Figures 1A-1C illustrate the specific activity (nmol/mg/min) of hydrolysis of p-nitrophenyl-glucosidase (p-NP-glc) and p-nitrophenyl-glucuronidase (p-NP-glrd) (substrate concentration, 2.0 mM) in homogenates of the luminal contents from various locations in the conventional rat ( Figure 1A) , the germ-free rat ( Figure IB) and the acetic acid-induced colitis rat ( Figure 1C) .
  • Figures 2A-2C illustrate the specific activity
  • Figures 3A-3C illustrate the specific activity (nmol/mg/min) of hydrolysis of p-nitrophenyl-glucosidase (p-NP-glc) and p-nitrophenyl-glucuronidase (p-NP-glrd) (substrate concentration, 2.0 mM) in homogenates of the intestinal tissues (muscle layer) from various locations in the conventional rat ( Figure 3A), the germ-free rat ( Figure 3B) and the acetic acid- induced colitis rat ( Figure 3C) .
  • p-NP-glc p-nitrophenyl-glucosidase
  • p-NP-glrd p-nitrophenyl-glucuronidase
  • Figure 5 illustrates results obtained upon treatment of carrageenan-induced colitis in guinea pigs with dexamethasone- ⁇ -D- glucuronide.
  • Figure 6 illustrates coionic fluid absorption in rats with and without acetic acid (4%)-induced colitis, treated with either dexamethasone or dexamethasone ⁇ -D-glucuronide, orally.
  • Figure 7 illustrates in graph form the results of ulcerated surface area measurements for groups of rats as described in detail in Example 3.
  • Figure 8 illustrates in graph form the coionic fluid flow data obtained in Example 4, for budesonide and budesonide- ⁇ -D- glucuronide.
  • Figure 9 illustrates in graph form the results of ulcerated surface area measurements for groups of rats as described in detail in Example 4.
  • prodrug intends a latent form of an active drug with certain physicochemical properties that allow it to reach a target organ or tissue. Once there, the active drug is formed chemically or enzymatically in situ .
  • corticosteroid is intended to mean not only steroids produced by the natural cortex but also synthetic equivalents, i.e., nonnaturally occurring steroids which possess physiological properties characteristic of naturally occurring corticosteroids. Typical corticosteroids useful in connection with the present invention include those set- forth in U.S. Patent No. 4,469,689 to Anderson et al., the disclosure of which is incorporated by reference herein. "Natural” intends compounds which are produced in nature, more particularly those produced in living organisms, while “synthetic” refers to compounds produced by chemical synthesis.
  • sugar as used herein is intended to mean monosaccharides and oligosaccharides containing 2-6 sugar residues. It is also intended that the term include those species in which one or more oxygen atoms in the sugar moiety have been replaced with sulfur atoms, or wherein one or more hydroxyl groups have been replaced with primary amine groups, or wherein the carbon atom bearing the primary hydroxyl group is oxidized to a carboxyl group, i.e., uronic acids.
  • lower alkyl as used herein in the description of chemical structures is intended to encompass alkyl groups having 1 through 6, preferably 1 through 4, carbon atoms.
  • colon-specific means that drug delivery is essentially exclusive to the coionic area of the mammalian gastrointestinal tract.
  • Cold-specific drug delivery means that at least about 30 wt.% of the drug administered reaches the large intestine.
  • an effective amount of a drug is meant a nontoxic but sufficient amount of the drug, to provide the desired local effect and performance at a reasonable benefit/risk ratio attending any medical treatment.
  • pharmaceutical carrier refers to a carrier suitable for oral administration of a drug, and includes any such materials known in the art, e.g., any liquid or nonliquid vehicle which is stable with respect to the prodrug and any other components present in the pharmaceutical composition.
  • Endogenous enzymes as used herein are enzymes produced by the mammalian host (as opposed to enzymes produced by bacteria found within the mammalian intestine) that are secreted into the mammalian gastrointestinal tract.
  • the corticosteroid prodrugs of the invention comprise a corticosteroid bound through its 21-OH group to a sugar species, and may thus be represented as R-X-St where R represents the sugar, X is ⁇ ulfur or oxygen, and St represents the corticosteroid.
  • R represents the sugar
  • X is ⁇ ulfur or oxygen
  • St represents the corticosteroid.
  • the prodrugs will fall within the following structural group represented by Formula (III)
  • R represents a sugar moiety
  • R 1 is selected from the group consisting of H, halogen and lower alkyl; is selected from the group consisting of H and halogen; is selected from the group consisting of H and lower alkyl;
  • R" is selected from the group consisting of OH and oxo;
  • R 5 is selected from the group consisting of H and OH;
  • R 6 is selected from the group consisting of H, lower alkyl and -OCOR 7 where R 7 is lower alkyl, or wherein R 5 and R 6 together form an -0-R 8 -0- bridge wherein R 8 is lower alkylene;
  • R 9 is selected from the group consisting of H and lower alkyl; and ⁇ represents an optional double bond.
  • corticosteroids examples include dexamethasone, betamethasone, beclomethasone, budesonide, prednisone, prednisolone, methyl prednisolone, flunisolide, triamcinolone acetonide, flucinolone acetonide, flumethasone, chlorprednisone, fluprednisolone, 11-deoxycorticosterone, 9 ⁇ -fluorohydrocortisone, paramethasone and dehydrocorticosterone.
  • the sugar moiety R should be selected so that it enables gradual hydrolysis of the prodrug, such that the corticosteroid can sugars are those which are hydrolyzed by glycosidases present in the caecum and colon at rates less than about 300 nmol/h/mg protein as measured using the procedure described by G.T. MacFarlane et al. in Letters in Applied Microbiology ,12.:3-7 (1991), the disclosure of which is incorporated by reference herein.
  • This group includes chitobide (hydrolyzed by chitobiase), a- and ⁇ -mannose (hydrolyzed by ⁇ - and ⁇ -mannosidase, respectively), and uronic acids.
  • R is a uronic acid, it will typically have a structure selected from the group consisting of
  • X is oxygen or sulfur
  • X' similarly, is either oxygen or sulfur
  • R' is selected from the group consisting of hydrogen and lower alkyl.
  • ⁇ -D-glucuronic acid and ⁇ -galacturonic acid hydrolyzed by ⁇ -D-glucuronidase and ⁇ -D-galacturonidase, respectively, are particularly preferred.
  • a sugar residue is attached to the drug aglycone to create a synthetic drug glucuronide.
  • drug glucuronides can be synthesized using known chemical techniques. See Igarashi, K. , Adv. Carbohvdr. Chem. Biochem. 3.4:243-283 (1977). An especially preferred method is the Koenigs-Knorr reaction. See Meystre, C, and Miescher, K., Helv. Chim. Acta. 28:1153-1160 (1944); Koenigs, W. , and Knorr, E., Ber.
  • the corticosteroid must be modified prior to conjugation to the sugar.
  • modification may be carried out using techniques well-known to those skilled in the art of synthetic organic chemistry.
  • One such method involves conversion of the C-21 hydroxyl functionality to a halogen, typically chloro or bromo, followed by reaction with hydrogen sulfide or the bisulfide ion.
  • the prodrug is preferably administered orally to the mammalian host.
  • the prodrug is then allowed to pass through the mammalian host's gastrointestinal system. Since the synthetic prodrug is larger and more hydrophilic than the parent drug, the prodrug is less permeable than the parent drug.
  • the glycosidic bond linking the uronic acid moiety to the steroid is a bond that will be substantially selectively cleaved by enzymes produced by coionic microflora, the synthetic prodrug will pass through the gastrointestinal tract without being significantly absorbed from the gastrointestinal tract or without being significantly hydrolyzed by endogenous enzymes produced by the mammalian host. Once in the area of the colon, the prodrug will be acted upon by bacterial glycosidases, thus releasing free drug for adsorption to or absorption by the coionic mucosa.
  • a pharmaceutically acceptable nontoxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonate and the like.
  • Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
  • Such compositions will typically contain 10% to 95% prodrug.
  • Preferred pharmaceutical compositions are solutions or suspensions, e.g., in water, saline, aqueous dextrose, glycerol, ethanol, or the like; a particularly preferred composition is a simple sterile aqueous solution.
  • compositions may contain, in addition to prodrug and carrier, auxiliary substances such as emulsifiers, pH buffering agents, and the like.
  • auxiliary substances such as emulsifiers, pH buffering agents, and the like.
  • Actual methods of preparing such compositions are known, or will be apparent to those ⁇ killed in the art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton PA.
  • an effective dosage of prednisone is in the range of approximately 0.5 to 1.0 mg/kg/day, preferably about 0.5 mg/kg/day. For an average 70 kg human, this would amount to approximately 35 mg per day.
  • an effective dosage is typically in the range of 0.08 to 0.16 mg/kg/day, preferably about 0.8 mg/kg/day (again, for an average 70 kg human, this amounts to about 5.6 mg per day).
  • the dosage will generally be about the same (i.e., equimolar) for the different prodrugs of the invention, formed from varying corticosteroids and sugar moieties.
  • the present prodrugs of the invention have been demonstrated to be highly effective in the colon-specific delivery of corticosteroids with a minimum of systemic side effects. While not wishing to be bound by theory, the fact that the present prodrugs are particularly suited for very specific coionic delivery is believed to be due at least in part to the fact that the prodrugs exhibit extensive first-pass metabolism in the colon and liver. The new prodrugs have been found to provide a significant "selective advantage" relative to previously known methods of administering corticosteroid drugs.
  • Solvents All solvents were redistilled and dried over molecular sieves, 4 angstrom, 4-8 mesh (Aldrich Chemical Co.). All solvent evaporations were performed with a rotary evaporator with water aspirator reduced pressure. Melting points were obtained on a Buchi melting point apparatus and are uncorrected. UV spectra were determined on a Cary 210 spectrometer. IR spectra were determined on a Perkin Elmer Model 137 spectrometer.
  • ⁇ NMR spectra were determined on a Gemini 300 MHz device at SRI International, Menlo Park, CA r and were recorded in dimethyl-d ⁇ sulfoxide; they are expressed in parts per million (delta) downfield from Me 4 Si with coupling constants (J) expressed in hertz.
  • High-pressure liquid chromatography was performed on a Waters 840 system consisting of two model 510 pumps, a model 481 UV detector, a model 710B WISP (automatic sampler), and a Digital Computer Model 350 (4.6 x 25 cm, 5 micrometer Ultrasphere C-18) . A flow rate of 1.2 mL/min was used, with absorbance monitoring at 254 nm. The solvent system for all separations was MeOH/0.01 M KH 2 P0 4 (56.5:43.5). Low-pressure preparative chromatography (flash chromatography, J.T. Baker Chem.
  • Example 1 Dexamethasone Glucuronide Prodrugs: Synthesis and Characterization (a.) Preparation of 9 ⁇ -fluoro-ll ⁇ ,17 ⁇ - dihydroxy-16 ⁇ -methyl-3,20-dioxopregna-l,4-dien-21-yl methyl 2,3,4- tri-O-acetyl- ⁇ -D-glucosiduronate: Dexamethasone-methyl acetyl glucuronate was prepared by dissolving dexamethasone (2.2 g, 5.6 mmol) in chloroform (300 mL) and heating to reflux in a 500 mL round bottom flask over 4-A. molecular sieves.
  • Octanol/Water Partition Coefficient of Dexamethasone- ⁇ - D-glucuronide The partitioning of dexamethasone- ⁇ -D-glucuronide
  • Budesonide Glucuronide Prodrugs Synthesis and Characterization (a.) Preparation of budesonide-21-yl methyl 2,3,4-tri- O-acetyl- ⁇ -D-glucosiduronate: Budesonide-methyl acetyl glucuronate was prepared by dissolving budesonide (650 mg, 1.5 mmol) in chloroform (200 L) and heating to reflux in a 500 mL round-bottom flask over 4-A molecular sieves.
  • Budesonide- ⁇ -D-glucuronide was prepared according to the procedure of Mattox et al., Biochemistry 8.:1188 (1969).
  • Budesonide-methyl acetyl glucuronate 200 mg, 0.7 mmol was dissolved in 0.1 N methanolic sodium hydroxide (50 mL) until homogeneous (about 5 min). After an additional 30 min, water (50 mL) was added and the reaction solution was stirred for 30 additional min. Then dilute acetic acid in methanol was added to neutralize the basic solution to pH 7.5.
  • the highest hydrolytic activity was observed in the cecal and coionic contents, whereas the contents of stomach, PSI, and DSI had much lower activity (see Figure 1A) .
  • the PSI has a significantly higher level of ⁇ -D-glucosidase activity compared with ⁇ -D-glucuronidase activity (p ⁇ 0.01, ANOVA) , while levels were comparable in the DSI.
  • the GF rats showed a much lower level of ⁇ -D-glucosidase activity and ⁇ -D-glucuronidase activity in the cecum and colon compared with conventional rats (see Figure IB). There was also a higher level of ⁇ -D-glucosidase activity in lumen of the PSI and DSI compared with luminal ⁇ -D-glucuronidase activity. While not wishing to be bound by theory, this activity is believed to be due to sloughed mucosal cells.
  • Figure 1C shows the same general pattern of glycosidase activity in the acetic acid-induced colitis model as observed in the conventional rats.
  • Luminal ⁇ -D-glucosidase activity was slightly higher in the PSI than in the DSI. In the cecum and colon, there was no difference statistically between luminal activity of conventional and colitis-induced rats. This relationship was also found with luminal ⁇ -D-glucuronidase activity in the PSI and DSI; in contrast, there was a statistically significant difference between the activities in the cecum (p ⁇ 0.05) and colon (p ⁇ 0.01).
  • Figure 2 shows the activities of ⁇ -D-glucosidase and ⁇ - D-glucuronidase in mucosal scrapings from conventional, GF, and colitis-induced rats.
  • Mucosal ⁇ -D-glucosidase activity was measured at pH 6.5; ⁇ -D-glucuronidase activity was measured at pH 6.5 and 4.5.
  • Lysosomal ⁇ -D-glucuronidase activity is greater at pH 4.5 than at pH 6.5, which is close to the optimum for bacterial ⁇ -D- glucuronidase (Hsu, L. , and Tappel, A.L., Biochim. Biophys. Acta 10-1:83-89 (1965); Hsu, L.
  • mucosal glycosidase activity varied only slightly along the entire length of the rat GIT. Mucosal scrapings from the cecum and colon of the colitis- induced rats showed qualitatively lower activity than the conventional rats at pH 4.5.
  • glucuronide prodrugs should be more stable in the PSI and hence more suitable than glucoside prodrugs.
  • the luminal contents of fed rats were removed following sacrifice by flushing with chilled 0.9% NaCl.
  • the contents were then homogenized (Ultra Turrax) for 2 min with cooling on ice.
  • the PSI and DSI contents were diluted to 20-25 g with 0.9% NaCl while the cecal and coionic contents were diluted to 40-45 g with 0.9% NaCl.
  • the mucosal scrapings were diluted with 6-10 with 0.9% NaCl.
  • Homogenization (Ultra Turrax) was performed for 30 s (ice cooling) .
  • 5 Homogenates of tissues (muscle layer) was performed by first cutting the tissues into small pieces and diluting to 20 g with 0.9% NaCl. The tissues were then homogenized for 30 s with a Polytron Homogenizer. All homogenates were centrifuged for 10 min at 1,500 g. The supernatants were used for hydrolysis experiments followed
  • the substrate (dexamethasone- ⁇ -D-glucuronide) concentration used was 0.5 mM. This concentration is K TM (determined in a preliminary experiment).
  • the pH of the incubation mixtures was adjusted to 6.5 and 4.5 with 0.1 M sodium phosphate buffer and 0.1 M
  • a reversed phase system consisting of Whatman Partisil ODS-3, 10 ⁇ m, 3.9 x 300 mm.
  • 2° mobile phase was 0.02 M acetate buffer, pH 4.8/acetonitrile (68:32).
  • the flow rate was 1 mL/min (room temperature) and the detector was set at 246 nm.
  • the Waters 840 chromatography system consisted of two model 510 pumps, a model 481 UV detector, a model 710B WISP (sample processor), and a Digital Computer model 350.
  • FIG 4A As shown in Figure 4A, there was an 80-fold increase in activity between the DSI and cecum. Compared with the hydrolysis of p-nitrophenyl- ⁇ -D-glucuronide, the rate of hydrolysis of the prodrug is about 10-50-fold lower in the cecum/colon contents.
  • the hydrolysis of dexamethasone- ⁇ -D-glucuronide in the mucosal scrapings along the rat GIT was much lower than that observed in the contents. From the relatively high level of activity in the cecal mucosa at pH 6.5, it appears that the contents may not have been completely removed from the mucosa.
  • the hydrolysis data at pH 4.5 provides a better measure of mucosal activity derived from lysosomes. As expected, the hydrolysis of the prodrug in the muscle tissues is very low (see Figure 4C) .
  • dexamethasone- ⁇ -D-glucoside In addition to dexamethasone- ⁇ -D-glucoside, a distribution and recovery experiment with the prodrug dexamethasone- ⁇ -D-cellobioside was also performed. The distribution of dexamethasone- ⁇ -D-cellobioside and dexamethasone in the luminal contents and tissues after oral administration of dexamethasone- ⁇ -D- cellobioside was similar to those obtained using dexamethasone- ⁇ -D- glucoside. The results indicated that the cellobioside prodrug delivered a significant amount of dexamethasone to the lumen of the cecum and, to a lesser extent, the colon. This result led to elevated tissue levels of dexamethasone.
  • Efficacy of dexamethasone- ⁇ -D-glucoside in treating carrageenan-induced colitis in guinea pigs Two studies were performed using guinea pigs with experimentally induced IBD. IBD was induced by 4-5 wt.% degraded carrageenan in the drinking water for 14 days; on day 15, the animals were dosed with an equivalent of 0.5 mg/kg or 0.25 mg/kg of dexamethasone- ⁇ -D-glucoside, dexamethasone, or with the dosing vehicle only, once daily for 5 days. The efficacy of the prodrug and drug was assessed by the number of ulcers in control and treated guinea pigs. Relative to control animals, the drug and prodrug treatments were found to result in significantly fewer ulcers. There was no difference statistically between the drug and prodrug groups at the dose examined.
  • Efficacy of dexamethasone- ⁇ -D-glucuronide in treating carrageenan-induced colitis in guinea pigs Substantially the same procedure was repeated using dexamethasone- ⁇ -D-glucuronide.
  • the animals were divided into three groups that received the following treatments from day 15 to 20: 1—H 2 0/EtOH (95:5, v/v); 2— dexamethasone (1.3 ⁇ mol/kg); and 3—dexamethasone- ⁇ -D-glucuronide (1.3 ⁇ mol/kg). These treatments were administered once daily in 1 mL of the H 2 0/EtOH dosing vehicle.
  • Results are summarized graphically in Figure 5, with the mean number of ulcers plotted for each treatment group. Using ANOVA followed by the Bonferroni t-test for multiple comparisons, it was found that the reduction in ulcers was significantly different (p ⁇ 0.05) in the animals treated with dexamethasone- ⁇ -D-glucuronide compared with control animals, while that obtained from only dexamethasone was insignificantly different. No ulcers were detected in animals treated only with the dosing vehicle (no carrageenan treatment) . Results were clearly better than those obtained with the glucoside prodrug of the preceding experiment. Efficacy of Dexamethasone- ⁇ -D-glucuronide in treating acetic acid-induced colitis in rats:
  • the prodrug dexamethasone- ⁇ -D-glucuronide was tested in the acetic acid-induced colitis rat model, as follows. Acetic acid colitis was induced as described by Fedorak et al., Gastroenterology 98:615-625 (1990) (incorporated by reference herein).
  • the animals were administered dexamethasone or dexamethasone- ⁇ -D-glucuronide at levels of 0.44, 0.22, 0.055, or 0.0137 ⁇ mol/kg/d orally (the typical human dose of dexamethasone is 0.22 ⁇ mol/kg/d for systemic treatment of colitis) at 24 and 48 h (once daily at days 1 and 2 following induction of colitis).
  • dexamethasone or dexamethasone- ⁇ -D-glucuronide at levels of 0.44, 0.22, 0.055, or 0.0137 ⁇ mol/kg/d orally (the typical human dose of dexamethasone is 0.22 ⁇ mol/kg/d for systemic treatment of colitis) at 24 and 48 h (once daily at days 1 and 2 following induction of colitis).
  • the in vivo coionic fluid absorption was measured 72 h after induction of colitis. Fluid absorption measurements in vivo provide a very sensitive measure of tissue damage.
  • dexamethasone was ineffective (0.0137 ⁇ mol/kg/d) compared with control animals (4% AAC) whereas dexamethasone- ⁇ -D-glucuronide at 0.0137 ⁇ mol/kg/d returned fluid flow to net absorption.
  • the coionic fluid flow data can oe expressed in a different manner to obtain a relative effectiveness of each agent in 50% of the animals (EDs,) .
  • EDs a nonlinear regression program Minim
  • a nonlinear regression program Minim (Version 1.8a, Dr. R. Purves, Department of Pharmacology, University of Otago, Dunedin, New Zealand) was used to fit the Hill equation to the coionic water-absorption data.
  • the equation was modified to include the term Effect 0 ( ⁇ l/h/cm), as follows:
  • Effect Effecto + (Effec MDose?) (ED 50 +Dose )
  • Effect Water flux ( ⁇ l/h/cm of intestine)
  • Effect 0 Water flux in animals with acetic acid- induced colitis ( ⁇ l/h/cm of intestine
  • Figure 6 shows the plot of fluid flow versus log dose using the Hill equation.
  • the ED J Q calculated for dexamethasone, based on in vivo fluid flow, is 1.8 x 10"' ⁇ mol/kg/d and 1.25 x 10 "1 ⁇ mol/kg/d for dexamethasone- ⁇ -D-glucuronide. Therefore, the prodrug is 16 times more effective than the parent drug dexamethasone. This means that a 16-fold lower dose, on a molar basis, of dexamethasone- ⁇ -D- glucuronide compared with dexamethasone can be used with similar antiinflammatory effect.
  • dexamethasone and dexamethasone- ⁇ -D-glucuronide did not significantly lower ACTH levels compared with the control colitis animals; however, the low dose dexamethasone was totally ineffective at controlling water secretion/absorption while the prodrug at this dose level was effective.
  • the higher dose dexamethasone and dexamethasone- ⁇ -D-glucuronide (0.44 ⁇ mol/kg/d) significantly depressed serum ACTH levels compared with the acetic acid control animals (ANOVA, Student-Newman-Keuls t-test, p ⁇ 0.05).
  • the corticosterone levels in the rats were elevated somewhat in the colitic animals (see Table 1).
  • Serum ACTH no/L. and Corticosterone in Rats With Acid-Induced Colitis Receiving No Therapy.
  • Dexamethasone or Dexamethasone- ⁇ -D-glucuronide'
  • the surface area of ulceration was measured macroscopically according to the procedure of Fedorak et al., Gastroenterology 8:615-625 (1990). Following removal of the colon from the rats at the time of sacrifice, the colon was opened longitudinally and placed flat, mucosal side upwards, on a glass plate chilled at 4°C. A transparent acetate was placed 5 mm above the mucosal surface and the area of ulceration and total surface area were traced by a single observer. Areas in square centimeters were then calculated using a Zeiss computerized videoscope
  • the prodrug budesonide- ⁇ -D-glucuronide was evaluated against budesonide in a manner similar to that used to evaluate dexamethasone and its glucuronide prodrug as described in Example 3. Fluid flow data collected is shown in Figure 8. The coionic fluid flow data ( Figure 8) was evaluated statistically. The results indicate that the prodrug is more effective than the drug at each dose examined (Student-Newman-Kulls t-test, ⁇ 0.05).
  • the Bonferroni t-test indicates that the low dose of prodrug (0.0137 ⁇ mol/kg/d) significantly improved coionic fluid relative to the control acetic-acid rats while the low dose drug (0.0137 ⁇ mol/kg/d) did not significantly improve coionic fluid flow.
  • Surface area of ulceration in the various groups is shown in Figure 9, while Table 2 shows corticosterone serum levels in the same animals.
  • Surface area measurements of ulceration ( Figure 9) were evaluated and it was found that the low dose prodrug (0.0137 ⁇ mol/kg/d) significantly lowered the area of ulceration while the low dose budesonide (0.0137 ⁇ mol/kg/d) did not (ANOVA, Student-Newman-Kulls t-test, p ⁇ 0.05).
  • Serum ACTH ng/L. and Corticosterone in Rats With Acid-Induced Colitis Receiving No Therapy, Budesonide, or Budesonide- ⁇ -D- ⁇ lucuronide'
  • Example 5 Dexamethasone Galacturonide Prodrugs (a-) Preparation of 9 ⁇ -fluoro-ll ⁇ ,17 ⁇ -dihydroxy-16 ⁇ - methyl-3,20-dioxopregna-l,4-dien-21-yl methyl 2,3,4-tri-O-acetyl- ⁇ - D-galactosiduronate: Dexamethasone-methyl acetyl galacturonide was prepared using the method described in Example 1(a), but substituting methyl (tri-O-acetyl- ⁇ -D-galactopyranosyl bromide)- uronate for methyl (tri-O-acetyl- ⁇ -D-glucopyranosyl bromide)- uranate. The product may be isolated in the same way as described for the product of Example 1, part (a) .
  • Budesonide Galacturonide Prodrugs (a.) Preparation of budesonide-21-yl methyl 2,3,4-tr-O- acetyl- ⁇ -D-galactosiduronate: Budesonide methyl acetyl galacturonide is prepared from budesonide as described in Example 2, part (a.), but substituting methyl (tri-O-acetyl- ⁇ -D- galactopyranosyl bromide)—uranate for methyl (tri-O-acetyl- ⁇ -D- glucopyranosyl bromide)-uranate. The product may be isolated in the same way as described for the product of Example 1, part (b.).
  • Budesonide- ⁇ -D-galactosuronidate is prepared as described in Example 2, part (b.), with respect to synthesis of budesonide- ⁇ -D-glucuronidate, to yield the deprotected prodrug. Its activity should be somewhat although not substantially less than the prodrug of Example 2, part (b.).
  • Example 7 Other Prodrugs
  • sugars such as chitobide, ⁇ -mannose and ⁇ -mannose to yield other dexamethasone and budesonide prodrugs conjugated to these sugars. Minor modifications in the synthetic method may be necessary to accommodate sugar moieties other than glucuronic and galacturonic acid, as may be readily deduced by those skilled in the art.
  • Examples 1, 2, 5 and 6 may also be used with respect to other corticosteroids such as betamethasone, beclomethasone, prednisone, prednisolone, methyl prednisolone, flunisolide, triamcinolone, acetonide, flucinolone acetonide, flumethasone, chlorprednisone, fluprednisolone, 11- deoxycorticosterone, 9 ⁇ -fluorohydrocortisone, paramethasone and dehydrocorticosterone.
  • corticosteroids such as betamethasone, beclomethasone, prednisone, prednisolone, methyl prednisolone, flunisolide, triamcinolone, acetonide, flucinolone acetonide, flumethasone, chlorprednisone, fluprednisolone, 11- deoxycorticosterone, 9 ⁇ -fluorohydrocortisone, paramet
  • Example 8 Studies in Human Stool Samples The rate of release of corticosteroid from corticosteroid prodrugs in human stool samples from patients with ulcerative colitis was measured.
  • the average % hydrolysis of dexamethasone from dexamethasone- ⁇ -glucuronide was 25% in 5 hours at 37°C in undiluted, unhomogenized feces (conditions for these in vitro hydrolysis studies are similar to those described above for hydrolysis of prodrugs in rat intestinal contents and tissues).
  • the procedures used were the same as those used in Examples 3 and 4, except that the samples were not homogenized, and were diluted approximately 5-fold instead of 20-fold. Therefore, the time over which drug will be released in the colon would be at least 20 hours and probably longer.
  • budesonide- ⁇ -glucuronide (20% hydrolyzed in 5 hours at 37°C) indicated a minimum period of drug release in the colon of 25 hours. Both these times for drug release will allow drug to be delivered throughout the colon, including the descending and sigmoid colon based on average or accelerated transit times through the human colon.

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Abstract

L'invention concerne des procédés et des compositions pharmaceutiques pour l'apport spécifique au colon de corticostéroïdes (I). Les corticostéroïdes sont administrés sous la forme de promédicaments qui réagissent avec des enzymes produites par la microflore du colon, libérant ainsi le médicament libre.
PCT/US1993/004202 1992-05-04 1993-05-03 Compositions pharmaceutiques et procedes pour l'apport de corticosteroides au colon WO1993022334A1 (fr)

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US5908833A (en) * 1993-01-08 1999-06-01 Aktiebolaget Astra Colon or ileum-specific steroid derivatives
US5945404A (en) * 1993-09-29 1999-08-31 Nissin Shokuhin Kabushiki Kaisha 21-Substituted steroid compound
WO2001051057A2 (fr) * 2000-01-14 2001-07-19 Strakan Limited Glycosides et glycosides d'orthoester de glucocorticoides et leurs utilisations
EP1625854A1 (fr) * 2004-08-09 2006-02-15 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Conjugés d'albumine contenant un lien glucuronique
US7314753B2 (en) * 1995-04-11 2008-01-01 Sanofi-Aventis Deutschland Gmbh Cytoplasmic expression of antibodies, antibody fragments and antibody fragment fusion proteins in E. coli
US8765696B2 (en) 2009-03-09 2014-07-01 Mikasa Seiyaku Co., Ltd. Steroid compound
WO2018217700A1 (fr) * 2017-05-23 2018-11-29 Theravance Biopharma R&D Ip, Llc Promédicaments glucuronides d'inhibiteurs de janus kinase
US10233174B2 (en) 2017-05-23 2019-03-19 Theravance Biopharma R&D Ip, Llc Thiocarbamate prodrugs of tofacitinib
US10435428B2 (en) 2015-11-24 2019-10-08 Theravance Biopharma R&D Ip, Llc Prodrugs of a JAK inhibitor compound for treatment of gastrointestinal inflammatory disease
US10472366B2 (en) 2017-03-08 2019-11-12 Theravance Biopharma R&D Ip, Llc Glucuronide prodrugs of tofacitinib
WO2022034582A1 (fr) * 2020-08-10 2022-02-17 P.I.F. Entrepreneurs Ltd. Conjugués de médicament ciblant des macrophages
WO2023144815A1 (fr) * 2022-01-25 2023-08-03 101 Therapeutics Ltd. Compositions et méthodes pour traiter la covid-19

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5908833A (en) * 1993-01-08 1999-06-01 Aktiebolaget Astra Colon or ileum-specific steroid derivatives
US6140308A (en) * 1993-01-08 2000-10-31 Aktiebolaget Astra Colon or ileum-specific glucocorticosteroid derivatives
US5945404A (en) * 1993-09-29 1999-08-31 Nissin Shokuhin Kabushiki Kaisha 21-Substituted steroid compound
US7314753B2 (en) * 1995-04-11 2008-01-01 Sanofi-Aventis Deutschland Gmbh Cytoplasmic expression of antibodies, antibody fragments and antibody fragment fusion proteins in E. coli
WO2001051057A2 (fr) * 2000-01-14 2001-07-19 Strakan Limited Glycosides et glycosides d'orthoester de glucocorticoides et leurs utilisations
WO2001051057A3 (fr) * 2000-01-14 2002-03-21 Strakan Group Plc Glycosides et glycosides d'orthoester de glucocorticoides et leurs utilisations
EP1625854A1 (fr) * 2004-08-09 2006-02-15 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Conjugés d'albumine contenant un lien glucuronique
TWI465459B (zh) * 2009-03-09 2014-12-21 Mikasa Seiyaku Co Ltd 類固醇化合物
US8765696B2 (en) 2009-03-09 2014-07-01 Mikasa Seiyaku Co., Ltd. Steroid compound
US10435428B2 (en) 2015-11-24 2019-10-08 Theravance Biopharma R&D Ip, Llc Prodrugs of a JAK inhibitor compound for treatment of gastrointestinal inflammatory disease
US10961267B2 (en) 2015-11-24 2021-03-30 Theravance Biopharma R&D Ip, Llc Prodrugs of a JAK inhibitor compound for treatment of gastrointestinal inflammatory disease
US11608354B2 (en) 2015-11-24 2023-03-21 Theravance Biopharma R&D Ip, Llc Prodrugs of a JAK inhibitor compound for treatment of gastrointestinal inflammatory disease
US10472366B2 (en) 2017-03-08 2019-11-12 Theravance Biopharma R&D Ip, Llc Glucuronide prodrugs of tofacitinib
WO2018217700A1 (fr) * 2017-05-23 2018-11-29 Theravance Biopharma R&D Ip, Llc Promédicaments glucuronides d'inhibiteurs de janus kinase
US10233174B2 (en) 2017-05-23 2019-03-19 Theravance Biopharma R&D Ip, Llc Thiocarbamate prodrugs of tofacitinib
CN110662747A (zh) * 2017-05-23 2020-01-07 施万生物制药研发Ip有限责任公司 Janus激酶抑制剂的葡糖苷酸前药
US10745405B2 (en) 2017-05-23 2020-08-18 Theravance Biopharma R&D Ip, Llc Glucuronide prodrugs of Janus kinase inhibitors
WO2022034582A1 (fr) * 2020-08-10 2022-02-17 P.I.F. Entrepreneurs Ltd. Conjugués de médicament ciblant des macrophages
WO2023144815A1 (fr) * 2022-01-25 2023-08-03 101 Therapeutics Ltd. Compositions et méthodes pour traiter la covid-19

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