Laboratory scale milling process

Details Laboratory scale milling process Laboratory scale milling process

2001-12-05

2004-11-09

Rosenbaum, Mark (Department: 3725)

Solid material comminution or disintegration

Processes

With application of fluid or lubricant material

Reexamination Certificate

active

06814319

ABSTRACT:

FIELD OF THE INVENTION
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
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 established between the in vitro dissolution time determined by standard assay procedures for an oral dosage form and the rate of in vivo drug release. This correlation is so firmly established in the art that dissolution time has become generally descriptive of drug release potential for the active component of the particular dosage form.
When the process of in vivo drug release is slower than the process of absorption, absorption is said to be dissolution rate-limited. Since dissolution precedes absorption in the overall process, any change in the drug release or dissolution process will subsequently influence drug absorption. See for example Lieberman et al. (1989),
Pharmaceutical Dosage Forms: Tablets
, Vol. 1, pp. 34-36. Marcel Dekker, New York. It is clear, therefore, that dissolution time determined for a composition is one of the important fundamental characteristics for consideration when evaluating compositions intended for rapid-onset delivery, particularly where drug absorption is dissolution rate-limited.
It is well known that one way to improve dissolution of drugs of low water solubility is to reduce drug particle size thereby increasing the specific surface area of the drug. Indeed, patent and other literature relating to nanoparticulate drug compositions teaches that, in general, the smaller the drug particle size, the greater is the advantage in speed of onset of therapeutic effect, or other pharmacodynamic benefit, obtained upon oral administration. For example, at least the following patents propose reduction of particle size to about 400 nm or smaller.
U.S. Pat. No. 5,145,684 to Liversidge et al.
U.S. Pat. No. 5,298,262 to Na & Rajagopalan.
U.S. Pat. No. 5,302,401 to Liversidge et al.
U.S. Pat. No. 5,336,507 to Na & Rajagopalan.
U.S. Pat. No. 5,340,564 to Illig & Sarpotdar.
U.S. Pat. No. 5,346,702 to Na & Rajagopalan.
U.S. Pat. No. 5,352,459 to Hollister et al.
U.S. Pat. No. 5,429,824 to June.
U.S. Pat. No. 5,503,723 to Ruddy et al.
U.S. Pat. No. 5,510,118 to Bosch et al.
U.S. Pat. No. 5,534,270 to De Castro.
U.S. Pat. No. 5,552,160 to Liversidge et al.
U.S. Pat. No. 5,573,783 to Desieno & Stetsko.
U.S. Pat. No. 5,585,108 to Ruddy et al.
U.S. Pat. No. 5,591,456 to Franson et al.
U.S. Pat. No. 5,662,883 to Bagchi et al.
U.S. Pat. No. 5,665,331 to Bagchi et al.
Mills are among the most commonly used kinds of particle size reduction equipment for preparation of drugs and drug compositions. While there are many different types of mills, most have at least three basic components in common: (1) a structure for feeding material into the mill, (2) a milling chamber with working parts, and (3) a take-off to a receiver or collector in which the milled product is deposited. See Lieberman et al. (1989), op. cit., Vol. 2., p. 113. Non-limiting examples of mills commonly used to prepare and process drugs include fluid energy mills, ball or rod mills, hammer mills, cutting mills, oscillating granular mills, wet mills, high energy mills, etc.
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 &mgr;m, 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 drugs—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 often delayed until larger quantities of drug are available.
Additionally, milling is a very inefficient unit operation with only approximately 0.05% to 2% of the applied energy being utilized in the actual reduction of particle size. Although milling efficiency is dependent upon the type of mill and the characteristic of the material being milled, in general, a large portion (e.g., about 10% to about 50%) of the energy expended during milling is converted to heat. This heat is generated by friction of particles contacting the mill, by plastic deformation of particles that are not fractured, by friction of particles colliding with each other, and/or by friction of mechanical mill parts, etc. In many instances, this heat generation leads to drug degradation. Consequently, common milling processes are suitable only for drugs which are thermally stable. Alternatively, expensive heat removal equipment must be employed to maintain drug stability.
A further difficulty is that traditional milling equipment suitable for particle size reduction to less than 1 &mgr;m is generally very expensive and as such, is not widely available. Moreover, given the complexity of size reduction processes, few theories of general applicability have been developed. Therefore, most size reduction problems in the pharmaceutical industry must be solved empirically rather than theoretically. See Lieberman et al. (1989), op. cit., Vol. 2., pp. 107-112. Even when available, traditional milling equipment designed for heavy industry or large scale use is often not amenable to small scale empirical problem solving.
A yet further difficulty with traditional milling is that steel or some similar grinding media are typically employed. Use of metals in milling a suspension introduces the risk of metal contamination and consequent chemical decomposition.
Therefore, if an inexpensive, widely available, energy-efficient, laboratory-scale process for milling drugs of low water solubility to a nanoparticulate size range could be developed, a significant advance would be realized in preparation of drugs and drug compositions used in the treatment of a wide variety of disorders, particularly disorders where rapid onset of therapeutic action is desired.
SUMMARY OF THE INVENTION
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 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 &mgr;m; and (d) a step of separating the resulting milled suspension from the grinding media and the magnetically activatable means for stirring.
In one embodiment of the invention, the process further comprises (e) a step of drying the milled suspension resulting from step (c) to form a drug powder. In this embodiment, the drying step (e) can occur prior to or after step (d). Drug powders prepared according to this process can be further formulated to provide a pharmaceutical composition.
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