PROCESS FOR PREPARING PHARMACEUTICAL COMPOSITIONS RESULTING IN REDUCTION IN OVERALL FILL VOLUME FOR USE WITH SOFT GELATIN FORMULATIONS

Abstract

The invention disclosed herein is a process for increasing the desired concentration of a pharmaceutically active ingredient relative to fill composition viscosity for dosage units. The process is particularly useful in the preparation of soft gelatin capsules containing pharmaceutically active ingredient. As a result of the process, lesser quantities of inactive ingredients are needed to accomplish the same therapeutically effective dosage, thereby significantly increasing the concentration of the pharmaceutically active ingredient resulting in either a reduction in overall fill volume and dosage unit size or an increase in concentration of pharmaceutically active ingredient per unit dosage form.

Claims

1. A fill composition with a high concentration of an acidic pharmaceutical ingredient viscosity for soft gelatin capsules, comprising: a) an acidic pharmaceutically active ingredient in an amount of about 50% to 60% by weight of the fill composition; b) a polyethylene glycol or a derivative thereof in an amount of about 25% to 40% by weight of the fill composition; c) an effective amount of a hydroxide ion source, wherein the effective amount between 2% and 8% by weight of the total fill composition; and d) purified water.

2. The fill composition of claim 1, wherein the effective amount between 3% and 7.5% of the total fill composition.

3. The fill composition of claim 1, wherein the effective amount between 5% and 5.5% of the total fill composition.

4. The fill composition of claim 1, wherein the acidic pharmaceutically active ingredient is selected from the group consisting of ibuprofen, naproxen, indomethacin, acetaminophen, diphenhydramine, and combinations thereof.

5. The fill composition of claim 1, wherein the acidic pharmaceutically active ingredient is ibuprofen.

6. The fill composition of claim 1, wherein the polyethylene glycol or derivative thereof has an average molecular weight of about 200 Daltons to about 800 Daltons.

7. The fill composition of claim 1, wherein the hydroxide ion source is sodium hydroxide (NaOH) or potassium hydroxide (KOH).

8. A process of preparing a fill composition with a high concentration of an acidic pharmaceutical ingredient, comprising: a) dissolving an effective amount of a hydroxide ion source in purified water to form a hydroxide solution; b) adding the hydroxide solution to a polyethylene glycol or a derivative thereof, followed by mixing to form a clear PEG solution; and c) adding the acidic pharmaceutical ingredient to the clear PEG solution, followed by mixing to form the fill composition containing the acidic pharmaceutical ingredient.

9. A process of preparing a fill composition with a high concentration of an acidic pharmaceutical ingredient, comprising: a) adding a first portion of an acidic pharmaceutically active ingredient to polyethylene glycol or a derivative thereof to form a viscous slurry; b) dissolving a hydroxide ion source in purified water to form a hydroxide solution, and adding the hydroxide solution to the viscous slurry; and c) adding a second portion of the acidic pharmaceutically active ingredient to the product of step b), followed by mixing until the acidic pharmaceutically active ingredient dissolves to form the fill composition.

10. The process of preparing the fill composition of claim 1, comprising: a) dissolving the hydroxide ion source in purified water to form a hydroxide solution; b) adding the hydroxide solution to a polyethylene glycol or a derivative thereof, followed by mixing to form a clear PEG solution; and c) adding the acidic pharmaceutical ingredient to the clear PEG solution, followed by mixing to form the fill composition containing the acidic pharmaceutical ingredient.

11. The process of claim 8, wherein the acidic pharmaceutically active ingredient is selected from the group consisting of Ibuprofen, Naproxen, Indomethacin, Acetaminophen and Diphenhydramine and combinations thereof.

12. The process of claim 9, wherein the acidic pharmaceutically active ingredient is selected from the group consisting of Ibuprofen, Naproxen, Indomethacin, Acetaminophen and Diphenhydramine and combinations thereof.

13. The process of claim 10, wherein the acidic pharmaceutically active ingredient is selected from the group consisting of Ibuprofen, Naproxen, Indomethacin, Acetaminophen and Diphenhydramine and combinations thereof.

14. The process of claim 8, wherein the pharmaceutically active ingredient is Ibuprofen.

15. The process of claim 9, wherein the pharmaceutically active ingredient is Ibuprofen.

16. The process of claim 10, wherein the pharmaceutically active ingredient is Ibuprofen.

17. The process of claim 8, wherein the polyethylene glycol or derivative thereof has an average molecular weight of about 200 Daltons to about 800 Daltons.

18. The process of claim 8, wherein the hydroxide ion source is sodium hydroxide (NaOH) or potassium hydroxide (KOH).

19. The process of claim 8, wherein the effective amount is between 3% and 7% of the total fill composition.

20. The process of claim 8, wherein the effective amount is between 5% and 5.5% of the total fill composition.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0030] As used herein, the term soft gelatin dosage unit is intended to encompass any dosage unit and/or form which employs a gelatin or gelatin-like casing. Numerous casing materials have been proposed for soft capsules including gums, carrageenans, hydroxypropylated starches, celluloses, and the like. As used herein, the term soft gelatin dosage unit means a dosage form constructed of mammalian gelatin, fish gelatin, gums, guars, carrageenans, modified starches and the like.

[0031] The terms fill and fill composition are meant to describe that portion of a dosage unit (e.g., pill, capsule, and the like) that is encased or otherwise contained within the outermost portion. When used in reference to soft gelatin dosage units, the terms refer to compositions encased inside the gelatin containment.

[0032] The general steps of the process of the invention comprise complete addition of the pharmaceutically active ingredient to be used in the fill composition to the total polyethylene glycol to be used in the fill composition. In the first step of the process, complete quantity of pharmaceutically active ingredient to be used in the fill composition is combined with all of the polyethylene glycol, to be used in the fill composition and mixed to form a viscous slurry. Subsequently, a complete quantity of hydroxide ion source to be used in the fill composition is added to the viscous slurry and the ingredients are mixed until dissolved to form a solution.

[0033] The general steps of the process of the invention comprise adding first portion of pharmaceutically active ingredient to the total polyethylene glycol to be used in the fill composition. In the first step of the process, a first portion of pharmaceutically active ingredient is added to the total polyethylene glycol to be used in the fill composition and mixed to form viscous slurry. Subsequently, a complete quantity of hydroxide ion source to be used in the fill composition is added to the viscous slurry and the ingredients are mixed until dissolved to form a solution. To the solution added, a second portion of pharmaceutically active ingredient and mixed to form solution.

[0034] The addition of the pharmaceutically active ingredient as described produces a solvent system for the active ingredient which balances the interaction between the active ingredient and the viscosity of the fill in such a manner that accommodates higher concentrations of the active ingredient per total volume of fill without creating excessively high viscosities.

[0035] Pharmaceutically active ingredients useful in the present invention include acidic compounds such as ibuprofen, naproxen, indomethacin, and acetaminophen. A preferred pharmaceutically active ingredient is ibuprofen.

[0036] The hydroxide ion source used in the invention is generally present in an amount of about 8% or less of the total fill composition volume, since degradation of gelatin casings tends to occur above about 8% hydroxide ion source content. Suitable hydroxide ion sources include, but are not limited to, potassium hydroxide and sodium hydroxide. A preferred hydroxide ion source is potassium hydroxide. Most preferred for use in the invention is a 50% aqueous solution of potassium hydroxide. Potassium hydroxide is preferred as the hydroxide ion source because it enhances the solubility of acidic pharmaceutical ingredients more than sodium hydroxide and is less likely to result in precipitation over a wide variety of concentrations at lower temperatures.

[0037] The initial suspension used in the process typically contains the total amount of polyethylene glycol which will be used for the fill composition. Polyethylene glycols (PEG) 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.

[0038] In an alternative embodiment, polyethylene glycol derivatives can be used in accordance with the invention. Suitable polyethylene glycol derivatives include, but are not limited to, polyethylene glycol ethers of alcohols and co-polymers of polyethylene glycol. An example of a polyethylene glycol ether of an alcohol is tetraglycol, which is a polyethylene glycol ether of tetrahydrofurfuryl alcohol.

[0039] In an alternative embodiment, other solvent systems can be used in accordance with the invention. For example, suitable solvent systems include those described in Makino et al. U.S. Pat. No. 5,912,011 and Morton et al. U.S. Pat. No. 5,376,688, the entire texts of which are incorporated herein by reference.

[0040] Additional ingredients which enhance the solubility of the active pharmaceutical ingredient in polyethylene glycol can be used as well, provided such ingredients are present only in amounts sufficient to preserve the desired viscosity and that do not degrade the gelatin capsule. Examples of additional ingredients include, but are not limited to, glycerin, propylene glycol, and polyvinylpyrrolidone, and combinations thereof. The amount and combination of additional ingredient(s) used will vary according to the chemical properties of the other ingredients used in the process.

EXAMPLE 1

Processes for Preparing Fill Compositions Containing Ibuprofen

[0041] Process 1 was carried out according to the invention as follows:

TABLE-US-00001 Qty/batch Ingredients 20,000caps Wt. % Ibuprofen 4.0 kg 58.8% Potassium Hydroxide 0.512 kg 7.5% PEG 600 1.948 kg 28.7% Purified Water 0.34 kg 5% [0042] 1. Dissolved complete 0.512 kg quantity of potassium hydroxide to be used in the fill composition into complete 0.34 kg quantity of purified water to be used in the fill composition into a SS vessels. and cooled to room temperature about 25 C. [0043] 2. Transferred complete 1.948 kg quantity of PEG 600 to be used in the fill composition into mixing vessels and added to the contents of step 1 and mixed until a clear solution is obtained. [0044] 3. Added complete 4.0 kg quantity of Ibuprofen into contents of step 2 and mixed until a clear solution is formed. [0045] Process 2 was carried out according to the invention as follows:

TABLE-US-00002 Qty/batch Ingredients 5,000caps Ibuprofen 1.0 kg Potassium Hydroxide 0.128 kg PEG 600 0.487 kg Purified Water 0.085 kg [0046] 1. Dissolving complete 0.128 kg quantity of potassium hydroxide to be used in the fill composition into complete 0.085 kg quantity of purified water to be used in the fill composition into a SS vessels and cooled to room temperature about 25 C. [0047] 2. Transferred complete 0.487 kg quantity of PEG 600 to be used in the fill composition into mixing vessels and added first portion of around 0.5 kg of Ibuprofen and mixed to get a viscous slurry. [0048] 3. Transferred the contents of step 1 into step 2 and mixed until a clear solution is obtained. [0049] 4. Added second portion of around 0.5 kg of Ibuprofen into contents of step 3 and mixed until clear solution is obtained.

INDUSTRIAL APPLICABILITY

[0050] When the process of the invention is used in manufacturing soft gelatin dosage units, the solubilization of pharmaceutically active ingredients such as ibuprofen can be significantly increased thereby permitting smaller fill volumes for a given dosage to be employed. Accordingly, smaller capsule sizes or fewer capsules need to be produced, thereby allowing more economical, cost effective manufacturing and improving patient comfort and compliance.

[0051] The complete disclosures of all patents, patent applications, and publications are incorporated herein by reference as if each were individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that reasonable variations and modifications are possible from the foregoing disclosure without departing from either the spirit or scope of the present invention as defined by the claims.