Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Pharmaceutical compositions of dispersions of drugs and neutral polymers

a technology of neutral polymer and pharmaceutical composition, which is applied in the direction of powder delivery, amide active ingredients, macromolecular non-active ingredients, etc., can solve the problems of drug degradation within the dispersion, loss of potency of the composition, and inability to chemically stable drugs in the dispersion, so as to improve the chemical stability of acid-sensitive drugs, enhance aqueous concentration and bioavailability, and minimize the loss of potency and generation of impurities

Inactive Publication Date: 2003-05-15
BEND RES
View PDF32 Cites 72 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009] The present invention relates to, in a first aspect, pharmaceutical compositions comprising a solid amorphous dispersion of an acid-sensitive drug and a neutral dispersion polymer, wherein said composition provides improved chemical stability relative to a control acidic dispersion comprising an equivalent quantity of said drug and an acidic polymer.

Problems solved by technology

However, regardless of whether the drug is poorly soluble, the inventors have determined that for some drug and polymer dispersions, the drug is not chemically stable in the dispersion.
In particular, the inventors have observed that for dispersions containing certain drugs and polymers, the drug degrades in the dispersion over time, resulting in a loss of potency for the composition.
Drug degradation within the dispersion is a particular problem for low-solubility, acid-sensitive drugs, since the increase in aqueous concentration of the drug provided by the dispersion is offset by decreasing drug purity.
However, the use of such acidic polymers within the dispersion is precluded due to the acid-sensitive nature of the drug.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Pharmaceutical compositions of dispersions of drugs and neutral polymers
  • Pharmaceutical compositions of dispersions of drugs and neutral polymers
  • Pharmaceutical compositions of dispersions of drugs and neutral polymers

Examples

Experimental program
Comparison scheme
Effect test

examples 1-2

[1313] This example discloses solid amorphous dispersions of an acid-sensitive, low-solubility drug and neutral polymer. For Example 1, a dispersion of quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-3-fluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl] amide (Drug 1) and the neutral polymer hydroxypropyl methyl cellulose (HPMC E3 Prem) was made by preparing a solution containing 0.125 wt % Drug 1 and 0.375 wt % HPMC in methanol, and spraying the solution into a drying chamber using an atomizing spray nozzle as described below. For Example 2, a dispersion of Drug 1 with the neutral polymer polyvinyl pyrollidone (PVP-Plasdone K-29 / 32 available from ISP Technologies Inc., Wayne, N.J.) was made by preparing a solution containing 0.33 wt % Drug 1 and 1.0 wt % PVP in acetone / methanol (9 / 1, wt / wt), and spray-drying the solution as described below.

[1314] For Control C1, a dispersion of Drug 1 with hydroxy propyl methyl cellulose acetate succinate, LF-grade (HPMCAS-LF) (with about 14-18 wt %...

example 3

[1316] In this example the chemical stability of the dispersions of Examples 1 and 2 was assessed by monitoring the potency of the drug before and after exposure to increased temperatures and relative humidity (RH) in accelerated-aging studies. Dispersions of Examples 1 and 2, and Control C1, were placed in two controlled atmosphere chambers: one chamber maintained at 70.degree. C. (no RH control); the second chamber maintained at 40.degree. C. and 75% RH. Potencies of the dispersions before and after storage were determined using HPLC. A Kromasil C.sub.4HPLC column was used with a mobile phase of 45 vol % of 0.2 vol % H.sub.3PO.sub.4, and 55 vol % acetonitrile. UV detection was measured at 245 nm. Drug 1 potency was the percent of the total HPLC peak area corresponding to the theoretical amount of drug originally present in the dispersion prior to storage based on the amount of drug present in the initial solutions before spray-drying. The results are shown in Table 2 below.

2TABLE ...

example 4

[1318] In this example the dispersions of Examples 1 and 2 were tested to show that the dispersions provided concentration-enhancement of the drug in aqueous solution. For Control C2, the crystalline form of the drug alone was used without further processing. For this test, 7.2 mg of the dispersions of Examples 1 and 2, and 3.6 mg of Control C2, was added to respective microcentrifuge tubes. The tubes were placed in a 37.degree. C. temperature-controlled bath, and 1.8 mL phosphate buffered saline (PBS) at pH 6.5 and 290 mOsm / kg was added to each. The samples were quickly mixed using a vortex mixer for about 60 seconds. The samples were centrifuged at 13,000 G at 37.degree. C. for 1 minute. The resulting supernatant solutions were then sampled and diluted 1:6 (by volume) with methanol and then analyzed by high-performance liquid chromatography (HPLC). The contents of the tubes were mixed on the vortex mixer and allowed to stand undisturbed at 37.degree. C. until the next sample was t...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
solubilityaaaaaaaaaa
solubilityaaaaaaaaaa
wt %aaaaaaaaaa
Login to View More

Abstract

In one aspect, pharmaceutical compositions comprising dispersions of an acid-sensitive drug and a neutral dispersion polymer are disclosed. The acid-sensitive drug has improved chemical stability relative to dispersions of the drug and acidic polymers. In another aspect, pharmaceutical compositions of low-solubility drugs and amphiphilic, hydroxy-functional vinyl copolymers are disclosed.

Description

[0001] This application claims the benefit of priority of provisional Patent Application Serial No. 60 / 300,255 filed Jun. 22, 2001, which is incorporated herein by reference in its entirety for all purposes.[0002] This invention relates to pharmaceutical compositions comprised of amorphous dispersions of drugs and neutral polymers that provide either improved chemical stability, concentration-enhancement, or both improved chemical stability and concentration-enhancement.[0003] It is sometimes desired to form a solid amorphous dispersion of a drug and a polymer. One reason for forming dispersions is that the aqueous concentration of a poorly soluble drug may be improved by forming an amorphous dispersion of the drug and a polymer. For example, Curatolo, et al., EP 0 901 786 A2 disclose forming pharmaceutical spray dried dispersions of sparingly soluble drugs and the polymer hydroxypropyl methyl cellulose acetate succinate. The spray dried dispersions disclosed in Curatolo et al. prov...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/14A61K31/17A61K31/426A61K31/4439A61K31/47A61K9/10A61K31/498A61K31/7048A61K38/55A61K47/32A61K47/34A61K47/36A61K47/38A61K47/42
CPCA61K9/1682A61K9/146A61K9/10A61K9/1617A61K9/1635A61K9/1652A61K31/4965
Inventor FRIESEN, DWAYNE T.GUMKOWSKI, MICHAEL J.KETNER, RODNEY J.LORENZ, DOUGLAS A.NIGHTINGALE, JAMES A. S.SHANKER, RAVI M.WEST, JAMES B.
Owner BEND RES
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com