Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-08-29
2002-05-14
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S451000, C424S452000, C424S456000
Reexamination Certificate
active
06387400
ABSTRACT:
FIELD OF THE INVENTION
The invention disclosed herein relates to the field of oral pharmaceutical formulations. In particular, the invention relates to an improved process for preparing pharmaceutical compositions for use in soft gel formulations. The inventive process allows for a given dose of active ingredient to be placed in a smaller dosage form.
BACKGROUND OF THE INVENTION
Filled one piece soft gels have been widely known and used for many years and for a variety of purposes. Because softgels have properties which are different from conventional telescoping two-piece hardshell capsules, the soft gels are capable of retaining liquid fill material. Typically, softgels are used to contain orally consumable materials such as vitamins and pharmaceutical compositions in a liquid vehicle or carrier.
In general, not all liquids are suitable as vehicles or carriers for inclusion in softgels. For example, water, propylene glycol, glycerin, low molecular weight alcohols, ketones, acids, amines and esters cannot be used as a carrier in softgels by themselves since they interact with the gel and, if present, they can only be present in relatively small amounts.
Another limitation associated with softgels is the ability to incorporate a single dose of the pharmaceutically active ingredient in solution in an acceptable fill volume. Often, it is difficult to dissolve the pharmaceutically active ingredient in a volume of solvent small enough to produce a softgel which delivers the desired dosage amount, is economically appropriate and comfortable to ingest by the patient. Developing solvent systems for pharmaceutically active ingredients that neither significantly interact with the active ingredient nor the softgel casing itself, has proven a difficult art.
The chemical properties of certain types of drugs have necessitated the development of special solvent systems for soft gel dosage forms. Yu et al., Australian Patent Application No. 81573/87 discloses pharmaceutical formulations suitable for filling soft gels comprising acidic pharmaceutical agents and solvent systems, the solvent systems comprising 10% to 80% by weight polyethylene glycol, 1% to 20% by weight water and hydroxide ion species. The solvent systems dissolve the pharmaceutical agent, e.g., ibuprofen, in concentrations sufficient for use in soft gelatin capsules.
Increasing the concentrations of active ingredients in soft gelatin dosage forms and/or units without necessitating an increase in overall fill volume (and thereby increasing overall size of the dosage form) and/or without increased disintegration of the gelatin casing have proven difficult to accomplish in the art. Also problematic is the maintenance of a workable viscosity during such processes. Hence, there exists a need for improved processes in the pharmaceutical industry which produce pharmaceutical formulations in a manner which are more economical to manufacture and increase patient comfort.
SUMMARY OF THE INVENTION
The invention herein provides for a process whereby the concentration of pharmaceutically active ingredients in soft gelatin dosage units can be increased, thereby permitting the use of reduced overall fill volumes or, alternatively, higher concentrations of the active ingredient per dosage unit or form. Furthermore, undesirable interactions between the fill ingredients and the gelatin casing can be reduced or altogether avoided when using the process of the invention.
The process according to the invention increases the achievable concentration of a pharmaceutically active ingredient relative to fill viscosity for use in soft gelatin dosage units comprises the gradual and incremental addition of pharmaceutically active ingredient and a hydroxide ion source to polyethylene glycol.
Thus, there is disclosed a process of increasing the concentration of pharmaceutically active ingredient relative to fill composition viscosity for dosage units comprising the steps of a) combining a first portion of pharmaceutically active ingredient with substantially the total amount of polyethylene glycol to be used in the fill composition to form an initial suspension; b) mixing said suspension; c) adding a first portion of hydroxide ion source to the suspension; d) mixing the ingredients until dissolved to an extent sufficient to produce a workable viscosity; e) adding a second portion of the pharmaceutically active ingredient to the solution to form another suspension; f) mixing the suspension; g) adding a second portion of hydroxide ion source to the suspension; and h) mixing the ingredients until dissolved in solution; wherein said first and second portions of the pharmaceutically active ingredient and first and second portions of the hydroxide ion source are each less than the total amount of the respective ingredient used in the resulting fill composition. The resulting fill composition contains the pharmaceutically active ingredient in a solvent system which is particularly suitable in the preparation of soft gelatin capsules, and permits higher doses of active ingredient to be administered without increasing overall fill volume and thereby dosage unit size. Alternatively, the resulting fill compositions permit increased concentrations of pharmaceutically active ingredient to be used per dosage unit size.
Pharmaceutically active ingredients suitable for use in the invention include, but are not limited to, acidic compounds such as ibuprofen, naproxen, indomethacin and acetaminophen. A preferred pharmaceutically active ingredient is ibuprofen.
The solvent system prepared in accordance with the invention comprises polyethylene glycol (PEG) and a hydroxide ion source. Polyethylene glycols which can be used in accordance with the invention include those having a molecular weight range from about 200 Daltons to about 100,000 Daltons, and preferably ranging from about 400 Daltons to about 700 Daltons. Suitable hydroxide ion sources for use in the invention include sodium hydroxide (NaOH) and potassium hydroxide (KOH), more preferably potassium hydroxide.
According to the process of the invention, a first portion of the pharmaceutically active ingredient is combined with polyethylene glycol and mixed together to form a first suspension. A first portion of hydroxide ion source is then added and the ingredients mixed to the extent sufficient to produce a workable viscosity. A second portion of pharmaceutically active ingredient is added and mixed to form a second suspension, and a second portion of hydroxide ion source is added to the suspension to form a solution. The first and second portions of the pharmaceutically active ingredient and hydroxide ion source, respectively, together comprise the total amount of each ingredient used to prepare the liquid fill composition.
In a further embodiment, the process can further comprise additional steps of adding the pharmaceutically active ingredient and adding hydroxide ion source. Accordingly, three or more portions each of the pharmaceutically active ingredient and hydroxide ion source can be used in the process of the invention.
The invention also provides for a soft gelatin capsule containing a fill composition prepared according to the process of the invention.
The invention further provides for fill composition for gelatin capsules comprising:
a) an acidic pharmaceutically active ingredient having a concentration of at least 50% by weight, preferably about 55% by weight, of the total fill composition;
b) polyethylene glycol; and
c) a hydroxide ion source having a concentration of about 5.5% or less by weight of the total fill composition.
Preparing a liquid fill composition according to the process of the invention increases the achievable concentration of pharmaceutically active ingredient in the solvent system for a given viscosity. One advantage of the invention is that lesser quantities of the ingredients for the fill composition other than the pharmaceutically active ingredient can be used. For example, smaller quantities of polyethylene glycol are needed for the same amount of active ingredient. Hence, the
Ferdinando Josephine Christine
Lewis Jacqueline Carol
Tindal Stephen Charles
Webster Christopher Clive
Nickey Donald D.
R.P. Scherer Technologies, Inc.
Rozycki Andrew G.
Spear James M.
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