Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-01-07
2004-12-07
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S326000, C514S369000, C514S058000, C514S060000, C514S557000, C514S772200, C514S772300, C514S773000, C514S777000, C514S779000, C514S781000, C424S451000, C424S489000, C424S462000, C424S464000, C424S440000, C424S493000, C424S500000, C536S103000, C536S120000, C536S122000
Reexamination Certificate
active
06828334
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel pharmaceutical compositions having a high dissolution profile. In particular, the invention relates to compositions including cyclodextrin, inclusion complexes and methods for preparing the same.
BACKGROUND OF THE INVENTION
Fenofibrate corresponds to the nomenclature of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl propionate and is insoluble in water. Fenofibrate has the formula:
With an aqueous solubility of less than 0.5 mg/liter, the dissolution of fenofibrate likely represents the rate limiting steps before the drug becomes adsorbed in the body. Fenofibrate is a neutral, lipophilic compound having a lipid water distribution coefficient, log P=5.24, and is a well-known hypolipemiant from the family of fibrates, which is commercially available in various doses (100 and 300 mg for example Secalip®) but in a form leading to poor bioavailability of the active ingredient.
Bioavailability is the degree to which or rate at which a drug or other substance is absorbed or becomes available at the site of physiological activity after administration. Drugs having a high dissolution profile have a higher bioavailability than drugs that have a low dissolution profile. A hypolipemiant is a drug that reduces the amount of lipids (fats) in the blood. Lipophilic is a substance having affinity for, tending to combine with, or capable of dissolving in lipids. Fenofibrate is both hypolipemiant and lipophilic. Due to its poor hydrosolubility (solubility in water), however, fenofibrate is poorly absorbed in the digestive tract and consequently its bioavailability is incomplete, irregular and often varies from one person to another. As a result, commercially available doses must be of higher strength and require application several times a day.
EPA-0330532 to Curtet et al., describes a method for improving bioavailability of fenofibrate by co-micronizing fenofibrate with a surfactant, for example sodium lauryl sulphate, in order to improve fenofibrate solubility. According to this invention, 200 mg of co-micronized fenofibrate was found to be bioequivalent to 300 mg of non-micronized fenofibrate. However, this improvement in dissolution and bioavailability is not satisfactory because the technique of co-micronizing with a surfactant still leads to incomplete dissolution of fenofibrate.
U.S. Pat. No. 6,277,405 B 1 to Stamm, et al., describes a fenofibrate pharmaceutical composition having enhanced bioavailability . It comprises spraying a suspension of a micronized fenofibrate with hydrophilic polymer, for example, polyvinyl pyrrolidone onto an inert carrier. Following granulation, the granulate formed consists of crystals of, for example, lactose which are isolated and particles of micronized fenofibrate and PVP adhere to the crystal surface. The granulate obtained is compressed to form tablets. This composition has been shown to have a dissolution of at least 10% in 5 minutes, 20% in 10 minutes, 50% in 20 minutes and 75% in 30 minutes as measured by using the rotating blade method at 75 rpm, in a dissolution medium constituted by water with 2% by weight polysorbate 80 or with 0.025 M sodium lauryl sulphate. Although the composition described in the '405 patent appears to show improved bioavailability, its method of preparation is complex and expensive. For example, the process described by Stamm et al. involves spray coating of fenofibrate with polyvinyl pyrrolidone onto an inert carrier. This process not only involves the material loss of fenofibrate but also requires expensive equipment such as a fluidized bed coater/granulator that is difficult to scale up for a commercial product.
U.S. Pat. No. 6,294,192 To Patel, et al, describes triglyceride free compositions and methods for improved delivery of hydrophobic therapeutic agent, for example fenofibrate. Prepared by simple physical mixing, the compositions include a hydrophobic therapeutic agent and a carrier, where the carrier is formed from a combination of a hydrophilic surfactant and a hydrophobic surfactant. Upon dilution with an aqueous solvent, the composition forms a clear aqueous dispersion of the surfactant containing a hydrophobic therapeutic agent. Patel et al. also refer to fenofibrate as one of the hydrophobic therapeutic agent but do not provide any bioavailability improvement data on fenofibrate. The carrier described in Patel et al. further comprises cyclodextrin or cyclodextrin derivatives as an additional solubilizer to enhance the solubility of the hydrophobic therapeutic agent and not as the carrier itself. Further, Patel et al. do not provide any information or data for the use and effect of such solubilizers and their concentrations. By gently mixing or shaking the cyclodextrin with the carrier, the drug employed in the compositions of Patel et al. gains only marginal improvement in solubility (dissolution) and/or bioavailability.
This invention provides an inclusion complex of fenofibrate with cyclodextrin, the complex having enhanced bioavailability as compared to either fenofibrate alone or a suspension of a micronized fenofibrate with hydrophilic polymer, such a s PVP. As such, the present invention overcomes the limitations still existing in available fenofibrate products so as to improve the dissolution profile, improve absorption characteristics improve bioavailability of fenofibrate and reduce the dose required for administration to attain a desired effect as compared to that for a fenofibrate pharmaceutical composition that is not part of a complex with cyclodextrin. Thus, there is still a need to provide fenofibrate pharmaceutical compositions and dosage forms having enhanced bioavailability where the dissolution of fenofibrate in the body is increased to a level of 100% within a short period of time after administration in comparison to a level of dissolution that fenofibrate has by itself, before it forms an inclusion complex with cyclodextrin. That is, the fenofibrate pharmaceutical composition has a characteristic that allows a dosage form of the inclusion complex of fenofibrate with cyclodextrin to be completely dissolved within a short time after administration.
SUMMARY OF THE INVENTION
An aspect of the present invention resides in providing an immediate release pharmaceutical composition comprising an inclusion complex of fenofibrate with cyclodextrin which complex shows rapid and complete dissolution of fenofibrate, resulting into enhanced bioavailability.
Another aspect of the invention resides in a method for the preparation of an inclusion complex of fenofibrate with cyclodextrin which is efficient and economical, simple and less time consuming than conventional techniques, and which is suitable for manufacture of a product on commercial scale.
Preferably, the complex of fenofibrate with cyclodextrin renders the active drug fenofibrate highly soluble and/or rapidly dissoluble in physiological fluids including gastric fluid. Dissolution levels of fenofibrate can reach from about 80% to about 100% in a relatively short amount of time from about 10 to about 30 minutes, preferably from about 10 to about 20 minutes.
A further aspect of the present invention is to provide pharmaceutical compositions of an inclusion complex of fenofibrate with cyclodextrin, which renders the active drug fenofibrate highly soluble and/or rapidly dissoluable and safe for use as a pharmaceutical.
Still another aspect of the present invention is to provide a method for the preparation of pharmaceutical compositions having an inclusion complex of fenofibrate with cyclodextrin, which results in a product safe for use as a pharmaceutical and which renders the active drug fenofibrate highly soluble in physiological as well as in gastric fluid pH.
Other improvements which the present invention provides over the prior art will be identified as a result of the following description which sets forth the preferred embodiments of the present invention. The description is not in any way intended to limit the scope of the present invention, but rather only to p
Gidwani Suresh Kumar
Singnurkar Purushottam Sharshikant
Gibbons Del Deo Dolan Griffinger & Vecchione
Khare Devesh
USV Limited
Wilson James O.
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