Prodrugs for Improved Oral β-Estradiol Bioavailability

Prodrugs of -estradiol (1) were prepared with the objective of improving its oral bioavailability. -Estradiol-3-acetylsalicylate (2), -estradiol-3-salicylate (3), and -estradiol-3-anthranilate (4) were synthesized. With these prodrugs the 3-phenolic hydroxy group of estradiol was protected, so that first-pass conjugative metabolism could be reduced. Prodrug hydrolysis rates in dog and human plasma in vitro were determined. Deacetylation of estradiol-3-acetylsalicylate was much more rapid than its hydrolysis to estradiol. In dogs, oral estradiol bioavailability after administration of 2 and 4 was 17-fold and 5-fold higher, respectively, than after oral 1.     

Naltrexone-3-salicylate (a Prodrug of Naltrexone): Synthesis and Pharmacokinetics in Dogs

Naltrexone-3-salicylate (3), a prodrug of naltrexone (1), was prepared by a simple procedure from naltrexone-3-acetylsalicylate (2). The plasma (dog and human) hydrolysis half-life of 3 was found to be approximately 30 min. Compound 2 was previously shown to hydrolyze in dog and human plasma with a fast deacetylation step to 3, followed by slower hydrolysis of 3 to 1 (t _1/2, 30 min). Oral naltrexone bioavailability was greatly improved (30-fold) after oral administration of 3 to dogs, similar to the improvement observed after oral administration of 2. The half-life of naltrexone in dogs after oral administration of 3 was similar to that observed after oral administration of 2 (1 hr).     

Selective Precipitation of Interleukin-4 Using Hydrophobic Ion Pairing: A Method for Improved Analysis of Proteins Formulated with Large Excesses of Human Serum Albumin

In order to ensure the stability of protein pharmaceuticals, human serum albumin (HSA) is often added as an excipient, frequently in large excess. This makes chromatographic analysis of the stability of the active protein difficult. In the case of interleukin-4 (IL-4), separation from HSA can be achieved to some degree by size exclusion chromatography, but some HSA co-elutes with the IL-4. Hydrophobic ion pairing provides a method for selective precipitation of IL-4 from HSA. Hydrophobic ion pairing involves the electrostatic interaction of ionic detergents with oppositely charged polypeptides. Even when HSA is present in fifty-fold excess (w/w), the resulting precipitate contains greater than 70% of the IL-4. Selective precipitation with SDS produces enhancements in IL-4 over HSA of more than 2000-fold. This approach permits subsequent facile analysis of IL-4 by conventional reverse phase HPLC.     

Zn(II)-theophylline-ethylenediamine: structure and pH stability

A zinc-containing salt of theophylline, Zn(II)-aminophylline, was synthesized and its structure determined by X-ray diffraction techniques. The zinc ion is coordinated to two theophylline anions and a molecule of ethylenediamine in a tetrahedral arrangement. The solubility of the compound in water at 30 degrees (0.047 mg/ml) is 180-fold lower than that of theophylline (8.40 mg/ml). The complex is relatively stable in the alkaline pH range, but it hydrolyzes, releasing theophylline in acidic environments. The rate of theophylline release is pH dependent. These properties are useful in formulating chewable tablets and liquid suspension dosage forms that overcome the characteristic bitter taste of theophylline, yet provide for efficacious treatment of diseases involving the respiratory tract.     

Crystal structure analysis of the desolvation of the chloroform solvate of griseofulvin

The crystal structures of the chloroform solvate and a non-solvated form of griseofulvin were determined by X-ray diffraction methods. There are substantial differences in the packing arrangements of the two forms. The chloroform molecules in the solvate are arranged in layers perpendicular to the c-axis. This dictates the direction which the solvent can exit from the crystal.     

Stereochemical studies on medicinal agents. 19. X-ray crystal structures of two (+/-)-allylprodine diastereomers. The role of the allyl group in conferring high stereoselectivity and potency at analgetic receptors.

X-Ray crystallographic studies have been performed on the two diasteromeric racemates of 3-allyl-1-methyl-4-propionoxypiperidine hydrochloride (allylprodine hydrochloride) in an effort to determine the role of conformation in their interaction with analgetic receptors sites. The chiral orientation of the phenyl group in the highly potent isomer, (+)-1, is qualitatively in conformity with the stereo structure-activity relationship found among other analgetic 4-phenylpiperdines. The fact that (+)-2, a relatively weak analgetic with no stereoselectivity, also possesses this feature indicates that this conformational arrangement per se does not ensure high potency. The data suggest that the very potency and stereoselectivity which the allylic double bond confers to (+)-1 are due primarily to the interaction of this bond with an accessory site on the receptor.     

Analysis of N-glycosyl bond length in crystal structures of nucleosides and nucleotides.

A relationship was found between the N-glycosyl bond length in beta-nucleosides and nucleotides and the spatial relationship of this bond with respect to the lone-pair orbitals on the furanose ring oxygen. This relationship may be relevant to the geometry involved in the hydrolysis of the glycosidic bond.     

Dissolution behavior of 17β-estradiol (E2) from povidone coprecipitates. comparison with microcrystalline and macrocrystalline E2

The dissolution rates of macrocrystalline 17β-estradiol (E₂), microcrystalline E₂and E₂-povidone coprecipitates and physical mixtures varying in weight ratio from 1 : 1 to 1:49 were determined at 37°C. E₂ dissolution from the coprecipitates was markedly faster than that from either macro- or microcrystalline forms of the drug and was found to increase with decreasing E₂-to-povidone weight ratio. Based on the results of X-ray diffraction, differential scanning calorimetric. Raman spectroicopic, and thermal gravi metric analysis studies, it is concluded that the formation of a more water soluble, high energy state of E₂ is responsible for the increased dissolution rate of this natural cstrogen from low weight ratio povidone coprecipitates. These findings suggest that the use of E₂-povidone coprecipitates may increase the systemic availability of E₂.