Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1997-07-31
2000-10-17
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
424461, 424480, 424468, 424501, A61K 914
Patent
active
061327727
DESCRIPTION:
BRIEF SUMMARY
FIELD OF INVENTION
The present invention is related to pharmaceutical extended release compositions for oral administration containing a drug having low solubility in aqueous media.
BACKGROUND
Pharmaceuticals with low solubility in water cause formulation problems due to their poor rate and extent of dissolution in aqueous media (including gastrointestinal fluids), which results in low absorption into systemic circulation after oral ingestion.
Examples of drugs with low solubility in water are some substituted dihydropyridine compounds, such as nifedipine, felodipine, ninodipine, isradipine, nitrendipine, nicardipine, niludipine, nisoldipine, and amlodipine. These compounds are classified as calcium antagonists, which are widely used for the treatment of cardiovascular disorders such as hypertension.
In order to make a composition containing such a drug that will enable maximum absorption from the gastro-intestinal tract, it is necessary to incorporate in the composition a feature that increases the solubility of the drug to enable it to dissolve in the gastrointestinal fluids.
Several ways to increase the solubility have been described in prior literature. One way is described in U.S. Pat. No. 4,673,564, wherein nicardipine is used in its amorphous form in order to obtain increased dissolution and absorption. British patent 1456618 discloses improving the dissolution and absorption of nifedipine by preparation of a solid solution of nifedipine in polyethylene glycol in the presence of a surface active agent.
U.S. Pat. No. 4,412,986 discloses improving the dissolution and absorption of nifedipine by preparing a co-precipitate with a water-soluble polymer.
A feature that increases the solubility of a drug and thereby increases the extent of absorption will generally also increase the rate of absorption of the drug. If a drug is absorbed rapidly, and particularly if it is also eliminated rapidly, it becomes necessary to administer the drug frequently (i.e. several times per day) in order to maintain uniform blood levels. This is an undesirable situation, as frequent dosing is inconvenient for the patient and may lead to noncompliance by the patient.
To overcome this problem, it is necessary to include in the composition, in addition to a first feature to increase solubility of the drug, a second feature to slow down and control the rate at which the drug is released from the composition and made available for dissolution and absorption. A composition with such a feature is referred to in the trade as "extended release" or "controlled release".
The prior literature discloses numerous ways to make extended release compositions which slow-down and control the rate of dissolution and absorption of a drug. Such formulations usually include a substance such as a wax, fatty material, or polymer which causes the composition (usually in the form of a tablet) to erode or dissolve slowly in gastrointestinal fluids thereby slowly releasing the drug contained in the composition.
Especially preferred substances to slow-down the dissolution are hydrophillic gel-forming polymers (usually water-soluble cellulose derivatives). When a composition containing sufficient quantity of such a polymer is ingested and comes into contact with the gastrointestinal fluids, the hydrophillic gel-forming polymer nearest the surface of the composition hydrates to form a viscous gel layer around the surface of the solid mass. Because of the high viscosity, the viscous layer dissolves away only gradually, exposing the material below to the same process. The mass thus dissolves away only slowly, thereby slowly releasing the active ingredient into the gastrointestinal fluid.
In order to produce an extended release composition of a drug having very low solubility in water, it is necessary to have one feature as aforesaid to increase the solubility and a second feature as aforesaid to slow down and control the rate of dissolution.
The prior art also discloses numerous compositions which include a feature of each type to achieve extended releas
REFERENCES:
patent: 4412986 (1983-11-01), Kawata et al.
patent: 4673564 (1987-06-01), Kawata et al.
patent: 4765989 (1988-08-01), Wong et al.
patent: 5455046 (1995-10-01), Baichwal
Database WPI, Section Ch, Week 9602, Derwent Publications Ltd., London, Great Britain; Class A96,, AN 96-017127, XP002002077 & JP, A, 07 291 854 (Tanabe Seiyaku), Nov. 7, 1995.
Benston, Jr. William E.
Page Thurman K.
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