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Pharmaceutical composition of glycogen phosphorylase inhibitors

A glycogen phosphorylase and inhibitor technology, which can be used in drug combinations, active ingredients of heterocyclic compounds, antibacterial drugs, etc. The effect of utilization

Inactive Publication Date: 2003-05-14
PFIZER PRODS ETAT DE CONNECTICUT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

GPIs that bind this indole pocket binding site are generally relatively hydrophobic, have poor water solubility and poor bioavailability when routinely administered in crystalline form

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0456] This example discloses GPI 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)dihydroxy-pyrrolidin-1-yl) - Preparation of an amorphous solid dispersion of 3-oxy-propyl]-amide ("Drug 1") having a solubility of 60-80 μg / mL in water and 183 μg / mL in MFD solution. To prepare a dispersion of 25% by weight of drug 1 and 75% by weight of polymer, drug 1 was first mixed with "medium fine" (AQUOT-MF) grade cellulosic enteric polymer HPMCAS (manufactured by Shin Etsu) Mixing produces a solution in the solvent acetone. The solution contained 1.25% by weight of Drug 1, 3.75% by weight of HPMCAS and 95% by weight of acetone. The solution was then passed through a directional atomized spray using a two-fluid external-mix spray at 2.6 bar (37 psig) and a feed rate of 175-180 g / min into the stainless steel chamber of a Niro XP spray dryer Spray drying, maintaining an inlet temperature of 180°C and an outlet temperature of 69°C.

[0457] The resulting amorphous ...

Embodiment 2-7

[0459] Examples 2-7 were prepared using the same method as Example 1, except that different dispersion polymers and different amounts of drug and polymer were used. The variables are shown in Table 1. The SDD of Example 2 was prepared using a Niro PSD-1 spray dryer. The SDDs of Examples 3-7 were prepared using a "miniature" spray dryer consisting of an atomizer located in the top cover of a vertically oriented stainless steel tube. The atomizer is a two-flow nozzle (Spraying Systems Co.1650 flow cap and 64 air cap), wherein the atomizing gas is nitrogen delivered to the nozzle at a flow rate of 15 gm / min at 100° C. Delivered to the nozzle at room temperature with a flow rate of 1 gm / min. A filter paper with a support screen was clamped at the bottom end of the tube to collect the solid spray dry and allow the nitrogen and evaporated solvent to escape.

[0460] implement

Embodiment 8

[0462] Example 8 was prepared by rotary evaporating the polymer:drug solution to dryness. The solution consisted of 7.5% by weight of Drug 1, 7.5% by weight of HPMCAS-MF, 80.75% by weight of acetone and 4.25% by weight of water. This solution was added to a round bottom flask. The flask was rotated at about 150 rpm in a 40°C water bath under reduced pressure of about 0.1 atm. The resulting solid dispersion was removed from the flask as finely divided particles and used without processing.

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PUM

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Abstract

The present invention relates to harmaceutical compositions that comprise a glycogen phosphorylase inhibitor and at least one concentration-enhancing polymer. The composition may be a simple physical mixture of glycogen phosphorylase inhibitor and concentration-enhancing polymer or a dispersion of glycogen phosphorylase inhibitor and polymer.

Description

Background of the invention [0001] The present invention relates to a pharmaceutical composition comprising a glycogen phosphorylase inhibitor (GPI) and at least one polymer at an elevated concentration, and the use of said pharmaceutical composition in the treatment of diabetes, hyperglycemia, hypercholesterolemia in mammals , hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis and myocardial ischemia. [0002] Whether it is the early discovery of insulin and its subsequent widespread use in diabetes treatment, or the later sulfonylureas such as chlorpropamide (Pfizer), glipizide (Pfizer), tolbutamide (Upjohn), Discovery and use of hexylurea acetate (E.I. Lilly), tolazamide (Upjohn)) and biguanides (eg, phenformin (Ciba Geigy), metformin (G.D. Searle)) as oral hypoglycemic agents, treatment of diabetes Still unsatisfactory. The use of insulin is necessary in about 10% of diabetics in whom synthetic hypoglycemic drugs are ineffective (type I diabetes, insulin-dep...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61K9/10A61K9/14A61K31/00A61K31/40A61K31/404A61K45/00A61K47/38A61P3/06A61P3/10A61P9/00A61P9/10A61P9/12A61P31/04A61P35/00A61P43/00C07D209/42
CPCA61K31/00A61K9/146A61K31/404A61P3/00A61P31/04A61P35/00A61P3/06A61P43/00A61P9/00A61P9/10A61P9/12A61P3/10A61K38/43
Inventor D·J·胡佛R·M·尚克D·T·弗里森D·A·罗伦茨J·A·S·奈廷格尔
Owner PFIZER PRODS ETAT DE CONNECTICUT
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