X-refs: Remington’s Pharmaceutical Sciences, 18th Edition (A.R. Genrmo, ed.), 1990, Mack Publishing Company
Introduction:
Pharmaceutical Formulations relates to the composition, preparation, stabilization, manufacture, and delivery of pharmaceutical products, including active ingredients, excipients, buffers, stabilizers, preservatives, dosage forms, controlled-release systems, drug delivery vehicles, and formulations designed to improve stability, bioavailability, solubility, safety, or patient compliance.
Bioavailability:
Poor bioavailability is a significant problem encountered in the development of compositions in the therapeutic cosmetic agricultural and food industries, particularly those materials containing a biologically active material that is poorly soluble in water at physiological pH. An active material’s bioavailability is the degree to which the active material becomes availabe to teh target issue in the body or other medium after systemic adminsitration through, for example, oral or intravenous means. Many factors affect bioavailability, including the form of dosage and the solubility and dissolution rate of the active material. (Dodd, WO2010/121324A1)
Surface area/Particle size:
It is known that the rate of dissolution of a particulate drug will increase with increasing surface area. One way of increasing suface area is decreasing partcle size. Consequently, methods of making finely divided or sized drugs have been studied with a view to control the size and size range of drug particles for pharmaceutical compositions. There are several approaches used to formulate poorly solubel active agents. One approach is to prepare the active agent as a soluble salt. Where this approach cannot be employed, alternatie (usually physical) appraoches are employed to improve the solubility of the active agent. These include process technolgiew sucha s micronization, modificaiton of crystal or polymorphic structure, development of oil based solutions, sue of co-solvents, surface stabilizers or complexing agents, micro-emulsions, suepr cirtical fluid and production of solid dispersons or solutions. Dodd, WO2010/121324A1)
–Dry milling: techniques have been sued to reduce aprticle size and hence influence drug absorption. However, in conventional dry milling the limit of fineness is reached generally in thee region of about 100 micorons (100,000 nm) at which point material cakes on the milling chamber and prevents any further dimunution of partcile size. Alternatively, we grinding may be employed to reduce particle size, but flocculation restricts the lwoer particle sie limit to about 10 microns (10,000 nm). The we milling process, however, is prone to contamination, thereby leading to a bias in the pharmaceutical art against et milling. Antoehr alternative milling tecnique, commercial airjet milling, has provided particles ranging in average size form as low as about 1-50 microns (1-50k nm). (Dodd, WO2010/121324A1)
Dodd, WO2010/121324A1) discloses methods for an improved milling process which produces particles of active compound with increased surface area, that allows for higher volume fractions of the active material. The steps include dry milling a solid biological active material and a millable grinding matrix in a mill that includes a plurality of milling bodies, for a time period sufficient to produce particles of the biologically active material dispersed in an at elast partially milled grinding material wherein the composition produced by the method includes particles of the active material at or above a volume fraction of 25 v/v%. “v/v%” (volume/volume percent) refers to the fraction of the total volume occupied by the active ingredient particle. In one preferred embodiment, the average particle size was equal or less ranges from 2000 to 100 nm. The grinding matrix can be a single material or is a mixture of two or more materials such as mannitol, sorbitol, soy meal, cellulose. Milling bodies are preferably chemically inert and rigid and are desirably provided in the form of bodies which may ahve any of a vareity of smooth, regular shapes, flat or curved surfaces and lacking sharp or raised edges. Preferably, milling bodeis are provided in the form of one or mroe beads, balls, spheres, rods, right cylinders, drums or radiu-end right cylinders. A wide range of techniques can be used to characterize the particle size such as dynamic light scattering or photon correlation spectroscopy. The process results in the biologically active material having an improved dissolution profile. A highly advantageous application of the method is the use of a water soluble grinding amtrix in conjunction with a poorly water-solubel biolgocially acttive material (e.g., metaxalone). This gives two advantages; (1) when the powder containing the active material is placed into water, the matrix dissolves, releasing the particulate active material such as there is a maximum surface area exposed to solution,t hereby allowing a rpaid dissolution of the active compound and (2) the ability, if required, to remove or partically remove the matrix prior to further processing or formulation.
As an exaple the drug emtaxalone