Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1999-05-28
2002-05-07
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S451000, C424S455000, C514S772200
Reexamination Certificate
active
06383515
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to medicinal solutions suitable for encapsulation in soft gelatin capsules. More particularly, the invention relates to pharmaceutically acceptable solvent systems capable of producing a highly concentrated solution of a medicament, such as acetaminophen or naproxen, for use in a soft gelatin capsule.
2. Description of Related Art
Soft gelatin capsules or “softgels” are, as their name implies, gelatin capsules that are softer than conventional caplets, capsules or tablets. They are commonly used to encapsulate liquids containing an active ingredient or ingredients. Softgels are used to contain consumables, such as vitamins or pharmaceuticals, including products in the over-the-counter market. Softgels are also used in many other industries, and have been used to encapsulate such diverse substances as industrial adhesives and bath oils.
In the pharmaceutical industry, softgels provide many benefits over conventional liquid and solid administration vehicles. They dissolve in the stomach faster than compressed tablets. Tablets must dissolve in the stomach or intestines and so generally retard the speed of onset of a medicament administered in a tablet form. Tablets are also generally unsuited for administration of liquids. Hard gelatin or starch-based capsules may be used for liquid or solid delivery systems. But, capsules are generally not appropriate for liquids because the hard gelatin or starch capsules may be either softened or entirely dissolved by a liquid medicament. In addition, some air is usually trapped in a hard gelatin capsule, where a liquid “fill” is put into the capsule. This air bubble can affect the active ingredients and detract from the appearance of the product. Softgels are better than direct liquid administration because liquids spill, and some medicaments may have unacceptable or unpleasant taste even with taste masking agents. Softgels, on the other hand, dissolve rapidly in the stomach and the body quickly absorbs the liquid interior of the softgel, so softgels offer an attractive means of administering a medicament.
Not all liquids may be enclosed in a softgel. Liquids containing more than about 20% water by weight are generally not enclosed in softgels, because the water tends to dissolve the gelatin shell. Propylene glycol, glycerin, low molecular weight alcohols, ketones, acids, amines, and esters all tend to degrade or dissolve the softgel layer gelatin to some extent. Thus, formulations that are enclosed in a softgel cannot contain significant amounts of many well-known solvents.
Softgels are also somewhat sensitive to pH, and generally require a pH in the encapsulated liquid from about 2.5 to about 7.5. Highly acidic liquids may hydrolyze the gelatin, resulting in leaks, while basic liquids may tan the gelatin, resulting in decreased solubility of the gelatin shell.
Pharmaceutical liquids are usually enclosed in softgels as either viscous solutions or suspensions. Suspensions are pharmaceutically less desirable because they can settle during manufacture, which leads to a less uniform product. If a suspension is used, the solid particles in a suspension should be smaller than about 80 mesh, otherwise the softgel filling equipment might not function optimally.
Suitable softgel solutions, however, can be difficult to achieve. The walls of a softgel are thicker than the walls of a caplet or a hard gelatin capsule. The softgel should be small enough for patient acceptance. The thickness of the walls reduces the available space for the medicament. But, the softgel must contain sufficient quantities of the medicament to be effective. One approach, of course, is simply to require the consumer to swallow more than one softgel to achieve any adequate dose of the medicament. Consumers, however, prefer taking one or two softgels, tablets or capsules and resist taking more than three.
The solution in the softgel must thus be highly concentrated. High concentration levels, though, strain the ability of conventional solvent systems to dissolve a sufficient quantity of the pharmaceutical agent. A strong solvent, on the other hand, can degrade the gelatin coating. So, a frequent problem in softgel applications is dissolving the active ingredient or ingredients in a sufficiently small amount of solvent to provide a potent dose of the medicament in the softgel. Solvent systems must be used that are tailored to the specific needs of a specific medicament or blend of medicaments. For example, U.S. Pat. No. 3,557,280 to Weber et al., issued January 1971, used a magnesium salt, polyvinylpyrrolidone and water to dissolve oxytetracycline for injection or oral liquid administration. U.S. Pat. No. 5,071,643 to Yu et al., issued Dec. 10, 1991 and U.S. Pat. No. 5,360,615 also to Yu et al., issued Nov. 1, 1994, used polyethylene glycol and an acid or a base to dissolve ibuprofen, naproxen, indomethacin or acetaminophen (among others).
Another solvent system, found in U.S. Pat. No. 5,505,961 to Shelley et al., issued Apr. 9, 1996, used polyethylene glycol and sodium or potassium acetate to enhance the solubility of acetaminophen.
Despite these efforts, there is still a strong need in the art for solvent systems that can dissolve large amounts of a medicament, especially without the addition of large amounts of an acid or base.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a solvent system capable of producing a highly concentrated solution of a pharmaceutical agent suitable for encapsulation into a softgel of suitable size without neutralizing large amounts of the agent.
It is a further object of the present invention to create such a solvent system that can be safely consumed by human beings.
It is a further object of the present invention to use such a solvent system to create a highly concentrated solution of a medicament, like acetaminophen or naproxen, suitable for use as a fill in a softgel. About a one ml softgel should encapsulate about 325 mg of acetaminophen or about 220 mg of naproxen.
It is a further object of the present invention to create a solvent system for enhancing the solubility of medicaments, including such over-the-counter medicaments as pain relievers and cold remedies.
It is an advantage of the invention that one of the ingredients in the solvent system may itself be an antifungal agent, thereby increasing the safety of the solvent system during storage and handling.
Additional objects and advantages of the invention will be set forth in part in the description that follows, and in part will be obvious from the description.
To achieve the foregoing objects and in accordance with the purpose of the invention, as embodied and broadly described herein, the invention provides a pharmaceutically acceptable solution comprising a medicament and a solvent system. The solvent system comprises a low molecular weight polymer and a salt of an organic acid containing at least three carbon atoms.
To further achieve the foregoing objects and in accordance with the purpose of the invention, as embodied and broadly described herein, the invention provides a method for dissolving a large amount of a medicament in a small amount of solvent. The solvent comprises a low molecular weight polymer and a salt of an organic acid containing at least three carbon atoms.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
We will now describe the preferred embodiments of the invention.
The formulation of the invention comprises three types of systems: (a) a solvent system; (b) a solvent system and a medicament; and (c) a solvent system, at least one medicament dissolved in the solvent system, and a softgel surrounding the medicament and solvent system.
The solvent system of the invention comprises a low molecular weight polymeric material and a salt of an organic acid containing at least three carbon atoms. The system may also contain additional ingredients as set out below.
One part of the solvent system of the invention is a low molecular weight polymeric material. As used herein, “a
Ekpe Anthony Efiong
Sawyer MaryJean
Wu Maw-Sheng
Child, Jr. John S.
Dinola-Baron Liliana
Page Thurman K.
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