News Column

Patent Issued for Mesoporous Material Excipients for Poorly Aqueous Soluble Ingredients

July 28, 2014

By a News Reporter-Staff News Editor at Pharma Business Week -- Agency for Science, Technology and Research (Singapore, SG) has been issued patent number 8778401, according to news reporting originating out of Alexandria, Virginia, by NewsRx editors (see also Agency for Science, Technology and Research).

The patent's inventors are Shen, Shou-Cang (Jurong Island, SG); Ng, Wai Kiong (Jurong Island, SG); Chia, Leonard (Jurong Island, SG).

This patent was filed on February 18, 2009 and was published online on July 15, 2014.

From the background information supplied by the inventors, news correspondents obtained the following quote: "The poor solubility of active pharmaceutical ingredients (APIs) in water is one of the most challenging issues in the development of many pharmaceutical products for commercialization. More than one third of the drugs listed in the US Pharmacopoeia and half of the new chemical entities (NCEs), or new active ingredients are poorly water soluble or insoluble. The poorly water-soluble substances have a solubility of less than 10 g/L, in particular less than 5 g/L and more particularly, less than 1 g/l. Substances with aqueous solubility less than 0.1 g/L are classified as practically insoluble or an insoluble substance. When these drugs are administered, they usually have a very low bio-availability because of their poor solubility in the digestive fluid, causing erratic and incomplete absorption that may lead to a loss in therapeutic effect. Many NCEs fail to be commercialized due to their insolubility or poor solubility in water.

"Much effort has been made to enhance the dissolution rate of poorly water-soluble drugs to increase bioavailability. One strategy is to improve dissolution rates through specific formulation methods, the most common being particle size reduction (see, Jinno, J. et al., Journal of Controlled Release, 111:56-64 (2006); Kirsten, Westesen et al., Particles with modified physicochemical properties, their preparation and uses, U.S. Pat. No. 6,197,349 (2001)), inclusion in cyclodextrins (see, Palmieri, G. F. et al., ISTP Pharma Science 7:174-181 (1997); Xiang, Tian-Xiang et al., Pharmaceutical formulation for poorly water soluble camptothecin analogues, U.S. Pat. No. 6,653,319 (2003)), the use of inert water-soluble drug carriers in solid solutions or dispersions, nanocrystalline (see, Wunderlich, et al., Gelatin or collagen hydrolysate containing drug formulation that provides for immediate release of nanoparticle drug compounds, U.S. Pat. No. 5,932,245 (1999)) or amorphous forms of APIs.

"Among the various approaches, solid dispersion or solution formulations have been used to improve the dissolution rate of such kinds of drugs. Solid dispersions are usually formulated with soluble organic polymers (see, Yamane, Shogo et al., Solid formulation with improved solubility and stability, and method for producing said formulation, US Patent Pub. No. 2006/0153913 A1; Hoshino, Takafumi et al., Solid dispersion preparation, US Patent Pub. No. 2007/0248681A1), which typically have small-pore volume and low specific surface areas. Two reported methods involve the formation of solid drug dispersions in water-soluble carriers or the incorporation of surfactants and wetting agents (see, Storey, D. E. Drug information Journal 30:1039-1044 (1996)). Using water-soluble carriers, the solid dispersions are usually achieved through the processes of co-melting, quick cooling and pulverizing (see, Henricus, R. M. Oral Solid solution formulation of poorly water-soluble active substance, US Patent Pub. No. 2005/0008697 A1). It involves the melting of APIs together with other solid materials, such as PEG and glycol drug carriers, to form semi-solid and waxy in nature, and then hardened by cooling to very low temperatures. The mixture is then pulverized, sieved, mixed with relatively large amounts of excipients, and encapsulated into hard gelatin capsules or compressed into tablets. These operations are difficult to scale-up for the manufacture of dosage forms. Alternatively, the process of solvent removal (see, Straub, Julie et al., Porous Drug matrics and Methods of manufacture thereof, US Patent Pub. No. 2005/0048116 A1, Straub, Julie et al., Porous Drug Matrices and Methods of manufacture thereof, U.S. Pat. No. 6,932,983 B1 (2005)) can also be used to produce solid dispersions of drugs. The incorporation of soap-like surfactants in the formulation of poorly aqueous soluble drugs, may cause irritation side effects after oral administration in some cases.

"Generally, the commercial application of solid dispersion has been very limited, primarily because of manufacturing difficulties and stability problems. These dosage forms developed often have drawbacks, such as poor product thermodynamic stability, issues with manufacturability such as poor batch-to-batch reproducibility and limitations in scaling-up for commercial production (see, Serajuddin, A. T. M. Journal of Pharmaceutical Sciences, 88:1058-1066 (1999)).

"As mentioned above, another method is to reduce particle size, which is intended to increase the contact surface areas between the drug particle and the dissolution medium. The drawback of this technique lies in instability of particle size and agglomeration during post-milling storage, which causes variation in dissolution rate (see, Ng, W. K. et al., Pharmaceutical Research 25:1175-1185 (2008)). In some cases, a wide distribution of the particle size could have adverse side effects of gastric bleeding and nausea.

"An alternative approach is to produce drugs in the amorphous form by co-grinding the drugs with other additives such as porous powder (see, Yonemochi, E. et al., J. Colloid Interphase Sci. 173:186-191 (1995)). Spray drying and quench are also applied to produce amorphous pharmaceutical products as the quick drying and cooling prevents the crystal growth (see, Gupta, P. et al., Pharmaceutical Development and Technology, 10:273-281 (2005)). However, the biggest challenge is to stabilize APIs to achieve an acceptable shelf-life because amorphous materials are generally thermodynamically unstable and tend to revert back to the crystalline form upon storage. The improved dissolution rates due to amorphization would be lost during transportation and storage when the amorphous APIs revert back to the crystalline form.

"The discovery of a series of new ordered mesoporous material called MS41 family, having a regular pore size distribution that can be systematically varied between 2 and 10 nm, has opened up new possibilities in the field of catalysis, adsorption and pharmaceutical applications. Moreover, among the various structures of mesoporous silica materials, SBA-15 synthesized by nonionic polymer surfactant is the most extensively investigated due to its mesostructural diversity as well as the larger pore and thicker wall. The pore size is adjustable up to 30 nm. The feasibility to obtain different pore size and geometries offers wide potential for hosting molecules larger than the ones exhibited for classic microporous materials. In addition, the large surface areas of pore walls are occupied with high concentrations of silanol groups, which make the porous materials modifiable with different surface functional groups. Thus, the absorption properties are adjustable for different purposes of molecule hosting.

"In view of the foregoing, there is a need for formulating drugs and specialty chemicals that are poorly water soluble, practically insoluble or insoluble. Formulations are needed which improve the dissolution rates of these compounds in order to improve their absorption in the digestive tract and thereby improve their efficacy. It is highly desirable to develop new formulations and methods that can amorphize an API to improve dissolution rates as well as stabilize the amorphous form during subsequent extended storage. The present invention satisfies these and other needs."

Supplementing the background information on this patent, NewsRx reporters also obtained the inventors' summary information for this patent: "The present invention provides pharmaceutical and specialty chemical formulations that utilize mesoporous materials or compositions, which possess high surface areas and large pore volumes as excipients. In certain aspects, the formulations are prepared by methods of using a co-spray drying process to prepare amorphous active ingredients, which are entrapped in the nanosized mesoporous channels with high homogeneity.

"As such, in one embodiment, the present invention provides a pharmaceutical composition, comprising: a substantially water-insoluble pharmaceutical active ingredient; and a mesoporous composition having a plurality of nanopores, wherein the substantially water-insoluble pharmaceutical active ingredient is sprayed-dried together with the mesoporous composition to entrap the pharmaceutical active ingredient within the nanopores.

"In certain aspects, an amorphous form of the active ingredient is kept very stable by confinement in the nanospace. The preparation process is both reproducible and can be easily scaled. In certain aspects, the present invention overcomes product instability concerns and manufacturability issues of current solid dispersion methods.

"The present invention provides novel formulations and methods to improve the dissolution rates of poorly water-soluble active compounds, in particular active pharmaceutical ingredients (APIs). In certain aspects, a straightforward method of co-spray drying an active ingredient with a mesoporous material or composition is reproducible and can be easily scaled for commercial production as compared to other solid dispersion technologies.

"As such, in another embodiment, the present invention provides a method for preparing a pharmaceutical composition, the method comprising: admixing a substantially water-insoluble pharmaceutical active ingredient with a mesoporous composition having a plurality of nanopores in a suitable solvent or mixture of solvents; and spray-drying the substantially water-insoluble pharmaceutical active ingredient with the mesoporous composition to entrap the pharmaceutical active ingredient within said nanopores, thereby producing said pharmaceutical composition.

"In certain instances, the substantially water-insoluble pharmaceutical active ingredient is a member selected from an analgesic, an antipyretic, an anti-cholesterol or cholesterol-reducing agent, an anti-inflammatory agent, an antimicrobial, a decongestant and an antihistamine.

"These and other aspects, objects and embodiments will become more apparent when read with the figures and detailed description which follows."

For the URL and additional information on this patent, see: Shen, Shou-Cang; Ng, Wai Kiong; Chia, Leonard. Mesoporous Material Excipients for Poorly Aqueous Soluble Ingredients. U.S. Patent Number 8778401, filed February 18, 2009, and published online on July 15, 2014. Patent URL:

Keywords for this news article include: Agency for Science, Agency for Science Technology and Research, Technology, Technology and Research.

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Source: Pharma Business Week

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