WO2009069139A1

WO2009069139A1 - Dosage form providing an ibuprofen-containing liquid fill

Info

Publication number: WO2009069139A1
Application number: PCT/IN2008/000019
Authority: WO
Inventors: Sucheta Sharma; Mavuleti Krishna Prasad; Vemula Sathya Narayana; Amit Rajan; Mritunjay Kumar Sharma; Samprada Singh; Srinivas Raghupati; Vijay V Kumar
Original assignee: Alkem Laboratories Ltd.
Priority date: 2007-11-28
Filing date: 2008-01-14
Publication date: 2009-06-04

Abstract

The present invention relates to an ibuprofen liquid fill formulation comprising ibuprofen in amounts ranging from about 20% w/w to about 70% w/w and a surfactant in amounts ranging from about 15% w/w to about 70% w/w, wherein the said liquid fill formulation is essentially free of polyethylene glycol; and dosage forms containing the said liquid fill formulation. The invention also provides an ibuprofen dosage form comprising a drug delivery device and the ibuprofen liquid fill formulation of the invention.

Description

Dosage form providing an ibuprofen-containing liquid fill

The present invention relates to oral compositions of ibuprofen. More specifically this invention relates to of ibuprofen liquid fill formulations and dosage forms thereof.

BACKGROUND OF THE INVENTION

Soft gelatin capsules has been around in the pharmaceutical industry for many years and have become increasingly important as a medical dosage form since it became feasible, in the 1930's, to manufacture them by making and filling the capsules in one operation. A soft gelatin capsule, also called softgel is a solid capsule (outer shell) surrounding a liquid or semi solid center (inner fill). An active ingredient can be incorporated into the outer shell, the inner fill, or both. Compared to other medical dosage forms soft gelatin capsules show many advantages like ease of use; easy of swallowing; lack of obnoxious taste; convenience of unit dose delivery; tamper-proof nature; versatile wide variety of colors, shapes, and sizes; ability to accommodate a wide variety of therapeutic compounds filled as a semi-solid, liquid, gel or paste; possible use as immediate or delayed drug delivery; and possible usage to improve bioavailability of therapeutic compounds by delivering the therapeutic compounds in solution or other absorption enhancing media.

Soft gelatin capsules offer the possibility of delivering a liquid in a solid oral dosage form. The soft gelatin capsules can therefore contain the active ingredient in solution, suspension or emulsion, which will inherently lead to better absorption of the active ingredient as compared with delivery in a tablet or as a powder. Softgels are therefore the ideal solution and sometimes the only solution for delivery of compounds with poor oral bioavailability. Other properties that make softgels a useful and frequently applied dosage form include their aesthetic properties and 'swallowability', their tamper-resistance, their protection of the active ingredient from light and oxidation, their taste-masking of ingredients and their masking of unpleasant odours of ingredients.

Soft gelatin technology can be used for liquid and suspension fills encapsulated with a compatible gelatin shell formulation for the insoluble compounds, highly potent compounds, oxygen-sensitive materials, taste masking products, topical applications etc.

Ibuprofen is generally known as non steroidal anti-inflammatory substance having analgesic, anti-inflammatory and antipyretic action. The prior art patents reveal ibuprofen composition with polyethylene glycol, surfactants, alkalisers etc to form a stable dosage form of soft gelatin capsules but the present invention provides a much improved formulation wherein the ibuprofen composition is essentially free from polyethylene glycol (PEG)

Various compositions of ibuprofen soft gelatin capsules are known in prior art.

United States Patent No. 4,690,823 discloses soft gelatin capsules containing a solution of 15 to 30 parts by weight of ibuprofen in 70 to 85 parts by weight of polyoxyethylene- polyoxypropylene polymer or in a mixture of 30 to 76 parts by weight of polyalkylene glycol and 7 to 40 parts by weight of a surfactant and having a very rapid and high bioavailability of the active ingredient. The active ingredient is not re-precipitated there from by aqueous media such as artificial gastric juice.

United States Patent No. 5,173,304 relates to a composition of soft gelatin capsules containing about 30 to about 50 parts by weight of ibuprofen and about 1.5 to about 4 parts by weight of codeine and/or physiologically compatible salts thereof, partially dissolved and partially suspended in about,. 68.5 to about 46 parts by weight of polyoxyethylene-polyoxypropylene-diol or in a mixture comprising about 30 to about 76 parts by weight of polyoxyethylene-polyoxypropylene- diol or poly ethylene-glycol or polypropyleneglycol and from about 7 to about 40 parts by weight of a physiologically compatible surfactant.

United States Patent No. 6,251 ,426 describes liquid softgel fill formulations containing ibuprofen in free acid form, and softgel capsules which are prepared by dissolving more than 30% of ibuprofen in free acid form in polyethylene glycol and at least 10% by weight of a polyvinylpyrrolidone having an average molecular weight of from about 2,000 to about 54,000. The formulations may also include a surfactant to increase the bioavailability of the ibuprofen.

United States Patent No. 5,912,011 describes a pharmaceutical composition comprising gelatin capsules having encapsulated an aqueous solution .To increase the solubility of acidic medicines, a high concentration solvent system to be encapsulated comprises a) 10-80% by weight acidic medicine, b) 0.1-1.0 mole hydroxide ions for one mole equivalent of said medicine, and c) 1-20% by weight water included in polyoxyethylene sorbitan fatty acid ester as the solvent. This invention is devoid of propylene glycol which can ultimately lead to hardening of gelatin. Moreover the use of strong bases like potassium hydroxides, sodium hydroxides etc can react with the acidic medicines used in the invention.

PCT Application No. 2003013481 deals with the aspects of invention relating to a process for solubilizing poorly soluble active pharmaceutical ingredients in a mixture of low molecular and high molecular polyethylene glycol and polyvinyl pyrolidine. The resulting compositions can be encapsulated in a gelatin shell and the capsules provide an effective means for oral delivery of a wide variety of poorly soluble pharmaceutical actives. United States Patent No. 6,387,400 describes the preparation of soft gelatin capsules containing ibuprofen, naproxen, indomethacin, and acetaminophen, as the pharmaceutically active ingredient by combining a first portion of a pharmaceutically active ingredient with substantially the total amount of polyethylene glycol to be used in the fill composition to form an initial suspension. Polyethylene glycol is not suitable for the formulation of ibuprofen as the chemical reactivity of polyethylene glycol is mainly confined to the two terminal hydroxyl groups, which can be either esterified or etherified. However, all grades polyethylene glycol can exhibit some oxidizing activity owing to the presence of peroxide impurities and secondary products formed by autooxidation.

PCT Application No 2002069936 deals with the aspects of invention, avoiding the use of polyethylene glycol or hydroxide ion species as solubilizers for the preparation of soft gelatin capsules by using Labrasol, Transcutol or mixtures thereof and optionally containing amino acids. These formulations suffer from disadvantages in terms of cost effectiveness and need to be protected under the atmosphere of inert gases.

The prior art teaches soft gelatin capsules of ibuprofen which predominantly need polyethylene glycol to have a formulation which does not precipitate out on storage. However using polyethylene glycol has certain inherent disadvantages such as causing undesirable high decrease in content of the ibuprofen due to esterification of the ibuprofen by the polyethylene glycol. Whenever the prior art has tried soft gelatin formulations of ibuprofen without using polyethylene glycol, it has led to other formulation issues such as poor stability or cumbersome process of making the formulation. Therefore, a heretofore unaddressed need exists in the industry to address the aforementioned deficiencies and inadequacies which could be solved by providing dosage forms comprising ibuprofen liquid fill formulation comprising ibuprofen and a surfactant, wherein the said liquid fill formulation is essentially free of polyethylene glycol. So, surprisingly it has now been found that dosage forms comprising ibuprofen liquid fill formulation comprising ibuprofen and a surfactant, wherein the said liquid fill formulation is essentially free of polyethylene glycol, are more advantageous in terms of formulation and stability.

OBJECT OF THE INVENTION

It is the object of the present invention to provide ibuprofen liquid fill formulation, wherein the said liquid fill formulation is essentially free of polyethylene glycol and a process for making such formulations.

It is further the object of the present invention to provide ibuprofen dosage form comprising a drug delivery device and liquid fill formulation which is essentially free of polyethylene glycol and a process for making such dosage forms.

At least one of the preceding objects is met, in whole or in part, by the present invention, in which is provided an ibuprofen liquid fill formulation comprising ibuprofen in amounts ranging from about 20% w/w to about 70% w/w and a surfactant in amounts ranging from about 15% w/w to about 70% w/w, wherein the said liquid fill formulation is essentially free of polyethylene glycol.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, ibuprofen liquid fill formulation is provided, wherein the said liquid fill formulation is essentially free of polyethylene glycol.

According to another aspect of the present invention, ibuprofen dosage form comprising a drug delivery device and liquid fill formulation which is essentially free of polyethylene glycol is provided. According to another aspect of the present invention, stable ibuprofen dosage form comprising a drug delivery device and liquid fill formulation which is essentially free of polyethylene glycol is provided.

According to another aspect of the present invention, ibuprofen dosage form comprising a drug delivery device and liquid fill formulation which is essentially free of polyethylene glycol; and which is bioequivalent to the ibuprofen soft gelatin capsules (ADVIL LIQUI- GELS) commercially marketed in Canada by Wyeth, is provided.

According to another aspect of the present invention, ibuprofen capsule comprising liquid fill formulation which is essentially free of polyethylene glycol is provided.

According to another aspect of the present invention, a process of preparing ibuprofen liquid fill formulation comprising mixing ingredients comprising ibuprofen, a surfactant, an optional hydroxy! ion source and optionally water to form the liquid fill formulation, which is essentially free of polyethylene glycol, is provided.

According to another aspect of the present invention, a process of preparing an ibuprofen dosage form comprising mixing ingredients comprising ibuprofen, a surfactant, an optional hydroxyl ion source and optionally water to form a liquid fill formulation, which is essentially free of polyethylene glycol and incorporating the said liquid fill formulation in a drug delivery device, is provided.

Accordingly the present invention may be summarized as follows:

A. An ibuprofen liquid fill formulation comprising ibuprofen in amounts ranging from about 20% wAv to about 70% w/w and a surfactant in amounts ranging from about 15% w/w to about 70% w/w, wherein the said liquid fill formulation is essentially free of polyethylene glycol. B. An ibuprofen liquid fill formulation as in A above, wherein the surfactant is selected from the group consisting of esters of d-alpha-tocopheryl, polyoxyethylene castor oil derivatives, polyglycolyzed glycerides or a mixture thereof

C. An ibuprofen liquid fill formulation as in B above, wherein the surfactant is polyoxyethylene castor oil derivative.

D. An ibuprofen liquid fill formulation as in C above, wherein the polyoxyethylene castor oil derivative is used in amounts ranging from about 25% w/w to about 60% w/w.

E. An ibuprofen 'liquid fill formulation as in A above, further comprising a hydroxyl ion "source.

F. An ibuprofen liquid fill formulation as in A above, wherein the hydroxyl ion source is used in amounts ranging from about 0.1 % w/w to about 20% w/w.

G. An ibuprofen liquid fill formulation as claimed in A above, wherein the hydroxyl ion source is selected from the group consisting of sodium hydroxide, ammonium hydroxide, potassium hydroxide or a mixture thereof.

H. An ibuprofen liquid fill formulation as in G above, wherein the hydroxyl ion source is potassium hydroxide.

I. An ibuprofen liquid fill formulation as in A above, further comprising water.

J. An ibuprofen dosage form comprising a drug delivery device and the ibuprofen liquid fill formulation as in A above.

K. An ibuprofen dosage form as in J above, wherein the drug delivery device is a capsule. L. An ibuprofen dosage form as in K above, wherein said capsule comprises a soft gelatin capsule.

M. An ibuprofen dosage form as in K above, wherein said capsule comprises a hard gelatin capsule.

N. An ibuprofen dosage form as in L above, wherein the soft gelatin capsule comprises gelatin, one or more of a plasticizer and water.

O. A process of preparing ibuprofen liquid fill formulation comprising mixing ingredients comprising ibuprofen in amounts ranging from about 20% w/w to about 70% w/w, a surfactant in amounts ranging from about 15% w/w to about 70% w/w, an optional hydroxyl ion source and optionally water to form the liquid fill formulation, which is essentially free of polyethylene glycol.

P. A process of preparing an ibuprofen dosage form comprising mixing ingredients comprising ibuprofen in amounts ranging from about 20% w/w to about 70% w/w, a surfactant in amounts ranging from about 15% w/w to about 70% w/w, an optional hydroxyl ion source and optionally water to form a liquid fill formulation, which is essentially free of polyethylene glycol and incorporating the said liquid fill formulation in a drug delivery device.

DETAILED DESCRIPTION OF THE INVENTION

Before the present formulations and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed. The present invention relates to ibuprofen liquid fill formulation, wherein the said liquid fill formulation is essentially free of polyethylene glycol.

The present invention also relates to ibuprofen dosage form comprising a drug delivery device and liquid fill formulation which is essentially free of polyethylene glycol.

The present invention also relates to stable ibuprofen dosage form comprising a drug delivery device and liquid fill formulation which is essentially free of polyethylene glycol.

The present invention also relates to ibuprofen dosage form comprising a drug delivery device and liquid fill formulation which is essentially free of polyethylene glycol; and which is bioequivalent to the ibuprofen soft gelatin capsules (ADVIL LIQUI-GELS) commercially marketed in Canada by Wyeth.

The present invention also relates to ibuprofen capsule comprising liquid fill formulation which is essentially free of polyethylene glycol.

The present invention also relates to a process of preparing ibuprofen liquid fill formulation comprising mixing ingredients comprising ibuprofen, a surfactant, an optional hydroxyl ion source and optionally water to form the liquid fill formulation, which is essentially free of polyethylene glycol.

The present invention also relates to a process of preparing an ibuprofen dosage form comprising mixing ingredients comprising ibuprofen, a surfactant, an optional hydroxyl ion source and optionally water to form a liquid fill formulation, which is essentially free of polyethylene glycol and incorporating the said liquid fill formulation in a drug delivery device. As used herein, the term "dosage form" is intended to encompass any drug delivery device which can be use<i to incorporate the ibuprofen liquid fill formulation of the invention. Any drug delivery device known in the art may be used but capsules are the preferred dnig delivery devices.

As used herein, the term "capsule" is intended to encompass all kinds of capsules such as soft gelatin capsules and hard gelatin capsules which employ gelatin or gelatin- like casing. Numerous casing materials have been proposed for soft capsules including gums, carrageenans, hydroxypropylated starches, celluloses, and the like. The capsules may be two piece capsule or a one-piece, hermetically sealed capsule, which can be made by techniques known to the person skilled in the art.

^* The present invention provides a dosage form of an anti-inflammatory therapeutic agent like ibuprofen. The ibuprofen is used in the liquid fill formulation of the dosage form in amounts ranging from about 20% w/w to about 70% w/w. It is preferred that the ibuprofen in the liquid fill formulation is used in amounts ranging from about 30% w/w to about 40% w/w, In a preferred embodiment, the ibuprofen is used in amounts of about 200mg.

The present invention uses any surfactant known in the art in the liquid fill formulation of the invention. Surfactants are surface-active agents comprising of a hydrophobic portion, usually a long alkyl chain, attached to hydrophilic or water solubility enhancing functional groups and can be categorized according to the charge present in the hydrophilic portion of the molecule (after dissociation in aqueous solution) as anionic surfactants, nonionic surfactants , cation ic surfactants. The surfactant may be selected from the group consisting of esters of d-alpha-tocopheryL, polyoxyethylene castor oil derivatives, polyglycolyzed glycerides or a mixture thereof. Polyoxyethylene castor oil derivatives are the reaction products of ethylene oxide and castor oil or hydrogenated castor oil, sold, for example, as cremophors by BASF. Suitable polyglycolyzed glycerides are sold under the trademark Gelucire by Etablissements Gattefosse. A d- alpha-tocopheryl surfactant is d-alpha-tocopheryl polyethylene glycol 1000 succinate sold by Eastman Chemical Company under the trademark Vitamin E TPGS. The surfactant may be used in amounts ranging from about 15% w/w to about 70% w/w. It is preferred that the surfactant used is polyoxyethylene castor oil derivative. Preferred examples of polyoxyethylene castor oil derivative which are suitable for use in the present invention include Polyoxyl 35 Castor Oil (Peg 35CO) and Polyoxyl 40 Hydrogenated Castor Oil (Peg 40HCO). The polyoxyethylene castor oil derivative may be used in amounts ranging from about 15% w/w to about 70% w/w. It is preferred that the polyoxyethylene castor oil derivative is used in amounts ranging from about 25% w/w to about 60% w/w.

The present invention may optionally use a hydroxyl ion source known in the art, the in liquid fill formulation of the dosage form of the invention. The hydroxyl ion source may be preferably selected from the group consisting of sodium hydroxide, ammonium hydroxide, potassium hydroxide or a mixture thereof. The hydroxyl ion source may be used in amounts ranging from about 0.1% w/w to about 20% w/w. Potassium hydroxide is a preferred hydroxyl ion source in the composition of this invention. The potassium hydroxide may be used in amounts ranging from about 0.1% w/w to about 20% w/w. The potassium hydroxide is preferably used in amounts ranging from about 1 % w/w to about 5% w/w.

An aqueous solution known in the art may be optionally used as a vehicle m the liquid fill formulation of the dosage form of the invention. It is preferred that the aqueous solution is purified water. The aqueous solution may be used in amounts ranging from about 0.1% w/w to about 15% w/w. The liquid fill formulation of the dosage form of the invention may have other excipients known in the art such as propylene glycol, ethanol, wetting agents such as Tween 80 and the like.

The liquid fill formulation, is encapsulated or incorporated into drug delivery device to form the dosage form of the invention. The drug delivery device is preferably a capsule dosage form. The capsule may be a soft gelatin capsule or a hard gelatin capsule. The hard gelatin capsule can be a two-piece, standard gelatin capsule which typically includes a first capsule half and a second capsule half which is well known to those of ordinary skill in the art. The soft gelatin capsule can be a two-piece capsule wherein the two parts are sealed together or a one-piece, hermetically sealed capsule. More preferably, the drug delivery device is a soft gelatin capsule which is a one-piece, hermetically sealed gelatin based capsule which can be made by techniques known to those skilled in the art. However, the soft gelatin capsule is preferred to the conventional two-piece type capsule as the soft gelatin capsule does not require any additional sealing of the capsule halves as would be required with the liquid filled two-p.iece type capsule, and commensurately, is less prone to deliberate tampering or contamination. The soft gelatin capsule includes a plasticizer to control the softness and flexibility of the sheath, water, and optionally, other additives such as flavorants, colorants, opacifiers, etc. The soft gelatin capsules may be produced in a known manner with a rotary die process in which a molten mass of a gelatin sheath formulation is fed from a reservoir onto drums to form two spaced sheets or ribbons of gelatin in a semi-molten sate. These ribbons are fed around rollers and brought together at convergent angle into the nip of a pair of roller dies that include opposed die cavities. A fill formulation to be encapsulated is fed into the wedge-shaped joinder of the ribbons. The gelatin ribbons are continuously conveyed between the dies, with portions of the fill formulation being trapped between the sheets inside the die cavities. The sheets are then pressed together, and severed around each die so that opposed edges of the sheet flow together to form a continuous gelatin sheath around the entrapped therapeutic agent. The part of the gelatin sheet that is severed from the segments forming the capsules is then collected for recycling, and the soft capsules are dried. Various gelatin capsule formulations known in the prior art may be used to encapsulate the liquid fill formulations of the present invention. For example, suitable gelatin capsule may include from about 30% w/w to about 50% w/w gelatin; about 15% w/w to about 40% w/w of one or more plasticizer; and from 25% w/w to about 50% w/w of water. These formulations when formed into capsules and dried will result in capsule sheaths. The gelatin will normally have a bloom in the rage of about 150 to about 275, and may be Type A or B gelatins or mixture thereof. The sheath plasticizer may be selected from sorbitol, sorbitol special (mixture of sorbital and sorbitan), maltitol or a mixture thereof. The gelatin capsule formulations may also contain other ingredients, such as taste modifiers, coloring agents, and moisture retaining agents.

Typically the process of preparing ibuprofen liquid fill formulation comprises mixing ingredients comprising ibuprofen, a surfactant, an optional hydroxyl ion source and optionally water to form the liquid fill formulation, which is essentially free of polyethylene glycol.

Typically the process of preparing an ibuprofen dosage form comprises mixing ingredients comprising ibuprofen, a surfactant, an optional hydroxyl ion source and optionally water to form a liquid fill formulation, which is essentially free of polyethylene glycol and incorporating the said liquid fill formulation in a drug delivery device.

According to another aspect, the present invention relates to methods of treating pain, inflammation, fever and other related such conditions. The methods comprise 'administering to the patient a therapeutically effective amount of a composition according to the present invention. The frequency and amount of dosage will be determined by the clinician based on various clinical factors. The methods will typically comprise administration of the. unit dosage form of the present invention to the patient or the person in need thereof. The present invention is further directed to the use of a therapeutically effective amount of the compositions as described for the manufacture of medicament for treating pain, inflammation, fever and other related such conditions.

According to still another aspect, the present invention relates to articles of manufacture which include compositions of the invention packaged for distribution in conjunction with labeling or package inserts describing indications and giving dosage instructions. Packaging can be accomplished by any conventional methods utilized in the pharmaceutical industry. Examples of such packaging are: individual packs or blister packs or bottles or enclosed in a box or container along with package inserts and the like. Other modes of packaging would be readily apparent to one skilled in the pharmaceutical packaging arts.

The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.

EXAMPLE 1

The composition of ibuprofen dosage form as per the invention was prepared as described in Table 1 below.

Table 1

Soft gelatin capsule preparation:

The gelatin was soaked in the mixture of maltisorb, polysorb and water for lhr with the temperature of the mixture maintained at 4°C to 15°C. The soaked gelatin mass was transferred into a reactor and subjected to a melting process for 3-4 hrs with the temperature not exceeding more man 58°C. The gelatin mass was deaerated for 45 min. FD&C Green no # 3 was added in required quantity of water and added to the gelatin mass and mixed for 15 min. The above mass was deaerated for 45 min.

Liquid fill formulation

The required quantity of Cremophore EL was taken in a SS Vessel and ibuprofen was added to this vessel under stirring at room temperature. In another vessel, potassium hydroxide was dissolved in required quantity, of water. The solution of the potassium hydroxide was added to the mixture of ibuprofen and Cremophore EL under stirring to get clear solution.

The above liquid fill formulation was encapsulated using 10 minim oblong die role and subjected to drying to obtain ibuprofen soft gelatin capsules.

EXAMPLE 2

The ibuprofen soft gelatin capsule prepared in example I was subjected to dissolution testing. The dissolution testing was carried out in 900 ml of 7.2 pH Phosphate buffer in an USP Type I dissolution apparatus. The rate of agitation was kept atl50 RPM. The results are given in table 2 below.

Table 2

EXAMPLE 3

The ibuprofen soft gelatin capsules prepared in example 1 were subjected to stability testing at room temperature (RT) and at 40⁰C at a relative humidity of 75% (40°C/75%RH). The capsules were subjected to dissolution testing at the end of 1 month and 2 month. The capsules were also subjected to assay of the ibuprofen at the end of 1 month and 2 month to determine the stability of the formulation by measuring the degradation of ibuprofen over this time period by HPLC. The results are given in Table 3 below.

Table 3

It can be seen that the compositions of the present invention were stable for a period of 2 months at 40°C/75%RH.

EXAMPLE 4

The ibuprofen soft gelatin capsules (200mg ibuprofen) prepared in example 1 was subjected to bioequivalence studies. An open label, pilot, two-way crossover comparative bioavailability study of the ibuprofen soft gelatin capsules, 200mg (test) as prepared in example 1 with ADVIL LIQUI-GELS, ibuprofen soft gelatin capsules 200mg (reference) of Wyeth was done under fasting conditions.

Study design: Balanced, open label, randomized, two-treatment, two period, two sequence, single dose, crossover comparative bioavailability study under fasting conditions.

Study duration: Duration of clinical phase was 10 days including a washout period of at least 5 days between the two periods. Procedural details: The subjects were housed in clinical facilities at least 13 hours before dosing till the last blood collection in both the periods. A washout period of at least five days was maintained between the two periods. The subjects were not allowed to drink water from 1 hour before and 1 hour after dosing in each period (except the water given during dosing). The subjects were not allowed to eat anything 10 hours before and 4 hours after dosing.

Blood sample collection: A total of 16 samples (including predose) was taken per period, one prior to dosing at 0.0 and at 0.167, 0.33, 0.5, 0.75, 1.0, 1.25, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0 and 12.0 hours post dose.

Bioanalytical procedure: the plasma concentration of ibuprofen of the samples was quantified by validated methods.

Pharmacokinetic parameters: The concentration time profile of ibuprofen was used to calculate the various pharmacokinetic parameters such as C_max, AUCo-oo_, AUCo-_t, T_raax, t_\n by SAS statistical software.

Statistical evaluation: Summary statistics, ANOVA, intra subject variability, 90% confidence intervals and power were calculated using SAS statistical software. The bioequivalence between test and reference formulations was assessed by calculation of the 90% confidence interval of test/reference ratios (Least Square Mean) of C_maχ, AUCo_^> ' and AUCo-_t (after log transformation). To be considered bioequivalent, the 90% confidence interval of these parameters should fall within the interval 80.00% to 125.00%. the power of the ANOVA to detect a 20% difference between the formulations was determined.

The log-annova results of the study is given in Table 4 below. Table 4

It can be seen that compositions of the present invention were bioequivalent to the Ibuprofen soft gelatin capsules (200 mg Ibuprofen) available in Canada (ADVIL LIQUI- 5 GELS), manufactured by Wyeth.

EXAMPLES 5-10

The compositions of the liquid fill formulation for incorporation in ibuprofen dosage 10 form as per the invention were prepared as described in Table 5 below.

Table 5

The formulations of examples 5-10 were made as per the process described in example 1. Example 5 and 6 however, additionally involved heating of the mixed excipients at 50- 60⁰C to get a clear solution. 5

Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-

10 described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are proffered by way of example to facilitate comprehension of the invention and should not be construed to limit the

15 scope thereof.

Claims

Claims:

1. An ibuprofen liquid fill formulation comprising ibuprofen in amounts ranging from about 20% w/w to about 70% w/w and a surfactant in amounts ranging from about 15% w/w to about 70% w/w, wherein the said liquid fill formulation is essentially free of polyethylene glycol.

2. An ibuprofen liquid fill formulation as claimed in claim 1, wherein the surfactant is selected from the group consisting of esters of d-alpha-tocopheryl, polyoxyethylene castor oil derivatives, polyglycolyzed glycerides or a mixture thereof.

3. An ibuprofen liquid fill formulation as claimed in claim 2, wherein the surfactant is polyoxyethylene castor oil derivative.

4. An ibuprofen liquid fill formulation as claimed in claim 3, wherein the polyoxyethylene castor oil derivative is used in amounts ranging from about 25% w/w to about 60% w/w.

5. An ibuprofen liquid fill formulation as claimed in claim 1 further comprising a hydroxyl ion source.

6. An ibuprofen liquid fill formulation as claimed in claim 1, wherein the hydroxyl ion source is used in amounts ranging from about 0.1% w/w to about 20% w/w.

7. An ibuprofen liquid fill formulation as claimed in claim 1, wherein the hydroxyl ion source is selected from the group consisting of sodium hydroxide, ammonium hydroxide, potassium hydroxide or a mixture thereof.

8. An ibuprofen liquid fill formulation as claimed in claim 7, wherein the hydroxyl ion source is potassium hydroxide.

9. An ibuprofen liquid fill formulation as claimed in claim 1 further comprising water.

10. An ibuprofen dosage form comprising a drug delivery device and the ibuprofen liquid fill formulation as claimed in claim 1.

11. An ibuprofen dosage form as claimed in claim 10, wherein the drug delivery device is a capsule.

12. An ibuprofen dosage form as claimed in claim 11 , wherein said capsule comprises a soft gelatin capsule.

13. An ibuprofen dosage form as claimed in claim 11 , wherein said capsule comprises a hard gelatin capsule.

14. An ibuprofen dosage form as claimed in claim 12, wherein the soft gelatin capsule comprises gelatin, one or more of a plasticizer and water.

15. A process of preparing ibuprofen liquid fill formulation comprising mixing ingredients comprising ibuprofen in amounts ranging from about 20% w/w to about 70% w/w, a surfactant in amounts ranging from about 15% w/w to about 70% w/w, an optional hydroxyl ion source and optionally water to form the liquid fill formulation, which is essentially free of polyethylene glycol.

16. A process of preparing an ibuprofen dosage form comprising mixing ingredients comprising ibuprofen in amounts ranging from about 20% w/w to about 70% w/w, a surfactant in amounts ranging from about 15% w/w to about 70% w/w, an optional hydroxyl ion source and optionally water to form a liquid fill formulation, which is essentially free of polyethylene glycol and incorporating the said liquid fill formulation in a drug delivery device.