Laboratory scale milling process

a technology of laboratory scale and milling process, which is applied in the direction of centrifuges, instruments, and pharmaceutical product form changes, etc., can solve the problems preventing the use of known mill types in certain situations, and reducing the efficiency of drug manufacturing, so as to achieve the effect of reducing the particle size of drugs

Inactive Publication Date: 2005-02-03
HASKELL ROYAL J
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0029] Accordingly, the present invention provides a process for reducing particle size of a drug, the process comprising (a) a step of dispersing about 10 g or less of the drug in a suitable volume of a liquid dispersion medium to form a suspension; (b) a step of bringing together in a vessel grinding media, magnetically activatable

Problems solved by technology

When the process of in vivo drug release is slower than the process of absorption, absorption is said to be dissolution rate-limited.
Although, as described above, dissolution and bioavailability advantages can be realized by milling drugs, particularly drugs of low water solubility, to smaller particle sizes, many difficulties preclude use of known types of mills in certain situations.
For example, no practical means of milling small amounts (e.g., less than about 10 grams) of drug material to nanoparticulate dimensions, i.e., to particle sizes smaller than about 1 μm, have hitherto been available.
This has made the entire approach of preparing nanoparticulate drugs (either suspensions or solid compositions), for the purpose of studying enhancement of dissolution, inaccessible for new drugs in discovery and early development phases, and for cold- or radioactively-labeled drug—situations in which the quantity of drug available for such studies is usually very limited.
Consequently, development of important drug formulations, for example rapid-onset formulations, is ofte

Method used

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Examples

Experimental program
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Effect test

example 1

[0101] Dispersions D1-D4 containing 5% by weight celecoxib were prepared by the process described below. The dispersions differed only in the particle size range of the celecoxib. [0102] 1. Celecoxib was micronized in an air jet mill to form a drug powder. [0103] 2. The drug powder was added to an aqueous solution containing 2.5% low viscosity hydroxypropylcellulose (HPC-SL) and 0.12% sodium dodecyl sulfate, to form a suspension. [0104] 3. The suspension was wet milled to form a milled suspension according to the following protocol. A sample amount of 6.0 ml of the suspension (containing 20% celecoxib), a 19 mm magnetic stir bar made by VWR, 8 ml of lead-free glass beads, and 50 μl of antifoaming agent (Sigma Antifoam A Concentrate) were added to a 20 ml scintillation vial. To provide a milled suspension having a target particle size range of 6-7 μm (i.e., the size range achieved in the micronizing step, used to provide a comparative composition), the vial was shaken for two minutes...

example 2

[0106] Celecoxib particle size in milled suspensions D1-D4 as prepared in Example 1 was determined by laser (Fraunhofer) diffraction and by optical microscopy.

[0107] Fraunhofer scattering was measured on static suspensions samples using a Sympatec spectrometer. Samples were diluted with water into a static cell at a concentration that maintained a reduction in laser intensity of approximately 20%. The choice of collection lens was determined by the population of large material present in suspension, and thus was different for each sample. However, the smallest focal length optic appropriate was used in each case. No Mie scattering corrections were applied. The results, presented in FIG. 5, show a D50 particle size consistent with the target size range. D50 and other particle size parameters shown in FIG. 5 are believed to be overestimated for the 0.2-0.4 μm celecoxib dispersion, since this size range is at the very limit of detection by this technique.

[0108] In order to visually c...

example 3

[0109] Samples of milled suspensions prepared in Example 1 were dried individually by rotovapping according to the following procedure: 3 ml of each 5% celecoxib suspension was placed in a 10 ml recovery flask and attached to a conventional laboratory roto-evaporator (Buchi, RE11 Rotovapor). The flask was suspended in water at a temperature of 40° C. and rotated at approximately 100 rpm. A gentle vacuum was pulled on the flask for 0.5-1 hour to avoid bubbling of the suspension. After this time, a full house vacuum was employed and the evaporation proceeded for not less than 48 hours.

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Abstract

There is provided a process for reducing particle size of a drug, the process comprising (a) a step of dispersing about 10 g or less of the drug in a suitable volume of a liquid dispersion medium to form a suspension; (b) a step of bringing together in a vessel grinding media, magnetically activatable means for stirring and the suspension; (c) a step of magnetically activating the means for stirring to effect milling of the suspension to a weight average particle size not greater than about 1 μm; and (d) a step of separating the resulting milled suspension from the grinding media and the magnetically activatable means for stirring.

Description

[0001] This application claims priority of U.S. provisional application Ser. No. 60 / 251,750 filed on Dec. 6, 2000.FIELD OF THE INVENTION [0002] The present invention relates to a process for milling drugs on a small scale and to use of drugs milled by such a process in manufacture of medicaments. BACKGROUND OF THE INVENTION [0003] The bioavailability of an orally administered drug, as measured by its entry into systemic circulation in the bloodstream, depends on at least two fundamental processes: drug dissolution in gastrointestinal fluids (in vivo drug release) and subsequent absorption of the dissolved drug. Several factors influence dissolution of a drug from its carrier, including surface area of the drug presented to the dissolution solvent medium, solubility of the drug substance in the specific solvent medium, and driving forces of the saturation concentration of dissolved materials in the solvent medium. Notwithstanding these factors, a strong correlation has been establish...

Claims

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Application Information

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IPC IPC(8): A61J3/02A61K9/08A61K9/10A61K9/14A61K9/16A61K9/48A61K47/04A61K47/20A61K47/32A61K47/34A61K47/38A61K47/44A63G31/16B02C17/00B02C17/16B02C17/20G09B5/14G09B9/08
CPCA61K9/14A61K9/145A61K9/146G09B9/08B02C17/163B02C17/20G09B5/14B02C17/005
Inventor HASKELL, ROYAL J.
Owner HASKELL ROYAL J
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