Technical Field of the Invention
The technical field of the invention relates to ibuprofen-containing soft gelatin capsules, pharmaceutical compositions of a substantially clear ibuprofen solution, and process for their manufacture. It also relates to pharmaceutical compositions of substantially clear solutions containing ibuprofen and pseudoephedrine and use of said compositions for treatment of common cold and flu-like symptoms.
Background of the Invention
Soft gelatin capsules are a unique drug delivery system that can provide distinct advantages over traditional dosage forms such as tablets, hard-shell capsules, and liquids. Some of the major advantages of softgels include improved bioavaiiability (increased drug absorption, speed of product development, enhanced drug stability (protection against oxidation, photodegradation, and hydrolysis in lipophilic systems), superior patient compliance/consumer preference (ease of swallowing, appealing appearance, absence of objectionable taste, and convenience) and pharmaceutical elegance, excellent dose uniformity, better tamper evidence (tampering leads to puncturing and visible leakage) and safer handling of highly potent or cytotoxic drug compounds. Soft gelatin capsules filled with clear or transparent liquids are generally preferred due to their aesthetic appeal.
Soft gelatin capsules or softgels are predominantly used to contain liquids wherein the active ingredients are present in the dissolved or suspended state. Solutions are preferred over suspensions as they provide the liquid form to obtain optimal "content uniformity" in softgel fill. In addition, a solution provides a faster and more uniform absorption of a pharmaceutical agent than a suspension.
Common cold and flu-like illnesses are endemic, with a peak incidence during the winter months and a reported frequency of two to eight episodes per person per year. Exemplary formulations for treatment of cough, cold, cold-like, allergy, sinus and/or flu symptoms and the discomfort, pain, fever and general malaise associated therewith generally contain an analgesic (ibuprofen, aspirin or acetaminophen) and one or more antihistaminics, decongestants, cough suppressants, antitussives or expectorants.
The use of non-steroidal anti-inflammatory drugs to combat inflammation and attendant pain is accepted in medical practice. Among the most commonly used drugs of the non-

narcotic analgesic class of drugs are aspirin, acetaminophen, ibuprofen, ketoprofen, diclofenac and naproxen and their salts (e.g., lysine, arginine, sodium and potassium). Aspirin, acetaminophen and ibuprofen have heretofore been included as the pain reliever and fever-reducing component in conventional cough/cold multisymptom alleviating compositions. These commercially marketed products generally contain in addition to aspirin, acetaminophen or ibuprofen, one or more antihistaminics, decongestants, cough-suppressants, antitussives or expectorants.
Ibuprofen is a white powder which is practically insoluble in water. It is absorbed from the gastro-intestinal tract and the peak plasma concentrations occur approximately one to two hours after ingestion of the solid powder or crystal form.
Pseudoephedrine is a well-known nasal decongestant and a bronchodilator that relaxes and opens the air passages to the lungs to increase the flow of air, and thus is used in the treatment and/or prevention of symptoms of bronchial asthma and of reversible bronchospasm associated with chronic bronchitis and emphysema. It is typically administered to human beings in need of such medication in the form of a nasal spray, tablets and/or suspensions.
The combination of Ibuprofen and a decongestant (Pseudoephedrine hydrochloride) is commercially available as capsule, suspension and tablet dosage forms.
US Patent No.s 5,071,643; 5,360,615; 6,251,426; 6,221,391 and 5,141,961 describe concentrated solutions of ibuprofen suitable for filling softgels.
Ourcopending applications 1606/DEL/2003 and 1398/DEL/2004, which are incorporated herein in entirety, disclose the preparation of substantially clear solutions of ibuprofen as well as ibuprofen in combination with pseudoephedrine by utilizing the solubilizing properties of polyethylene glycol and ionizing properties of metal carbonates for the partial or complete conversion of ibuprofen into its metal salts. Metal carbonates facilitate the conversion of ibuprofen to ibuprofen salt with the help of the evolved carbon dioxide in the above reaction.
It has now been discovered that in the above-mentioned process, most of the carbon dioxide produced in the reaction escapes in the atmosphere. However, some amount of it remains as dissolved form in the polyethylene glycol base. This entrapped carbon

dioxide reacts with pseudoephedrine to form degradation impurities. In particular, the amino group of pseudoephedrine is susceptible to degradation by carbon dioxide leading to the formation of N-(2-hydroxy-1-methyl-2-phenylethyl) N-methyl formamide.
The inventors have now modified the process of preparation of the fill composition in such a way that the entrapped carbon dioxide is completely removed from the system before the addition of pseudoephedrine to it.
Summary
In one general aspect there is provided a clear ibuprofen composition that comprises:
a. from about 15% to about 40% w/w of ibuprofen,
b. from about 30% to about 70% w/w of polyethylene glycol,
c. from about 1 % to about 10% w/w of a metal carbonate, and
d. from about 1 % to about 10% w/w of water.
Embodiments of the composition may include one or more of the following features. For example, the ibuprofen may make up about 15% to about 30% w/w of the composition. The composition may be filled into soft gelatin capsules.
The composition may further include one or more active ingredients. The additional active ingredients may be one or more of glucosamine, pseudoephedrine, codeine, paracetamol, econazole, hydrocodone, COX-2 inhibitors, alprazolam, dextromethorphan, chlorpheniramine, and pharmaceutically acceptable salts thereof.
In another general aspect there is provided soft gelatin capsules of ibuprofen providing enhanced dissolution and bioavailability of ibuprofen, the soft gelatin capsules comprising clear solutions of ibuprofen comprising:
a. from about 15% to about 40% w/w of ibuprofen,
b. from about 30% to about 70% w/w of polyethylene glycol,
c. from about 1 % to about 10% w/w of a metal carbonate, and
d. from about 1 % to about 10% w/w of water.
In another general aspect there is provided a process of preparing a clear ibuprofen composition. The process may include the steps of (a) dissolving one or more metal

carbonates in water to form a solution, (b) adding ibuprofen and the solution of step (a) to polyethylene glycol, with optional heating, and (c) stirring to obtain a clear solution.
The process may further include one or more active ingredients. The additional active ingredients may be one or more of glucosamine, pseudoephedrine, codeine, paracetamol, econazole, hydrocodone, COX-2 inhibitors, alprazolam, dextromethorphan, chlorpheniramine, and pharmaceutically acceptable salts thereof.
In another aspect there is provided a clear composition of ibuprofen and pseudoephedrine that includes from about 15% to about 40% w/w of ibuprofen, from about 3% to about 6% w/w of pseudoephedrine or a pharmaceutically acceptable salt thereof, from about 30% to about 70% w/w of polyethylene glycol, from aboutl % to about 10% w/w of a metal carbonate, and from aboutl % to about 10% w/w of water.
Embodiments of the composition may include one or more of the following features. For example, the ibuprofen may make up about 15% to about 30% w/w of the composition. The composition may be filled into soft gelatin capsules.
In another aspect there is provided a process of preparing a clear composition of ibuprofen and pseudoephedrine or a pharmaceutically acceptable salt thereof. The process may include the steps of (a) dissolving one or more metal carbonates in water to form a solution, (b) adding ibuprofen and the solution of step (a) to polyethylene glycol, with optional heating, (c) stirring to obtain a clear solution, and (d) adding pseudoephedrine or a pharmaceutically acceptable salt thereof and stirring to obtain a clear solution.
In another general aspect there is provided a method of relieving one or more of pain, tenderness, inflammation and stiffness caused by one or more of arthritis and gout and pains from one or more of the common cold, backache, and pain after surgery or dental work. The method includes administering a clear ibuprofen composition that can include from about 15% to about 40% w/w of ibuprofen, from about 30% to about 70% w/w of polyethylene glycol, from about 1% to about 10% w/w of a metal carbonate, and from about 1% to about 10% w/w of water.

The method may include one or more of the following or the features described above. For example, the composition may further include one or more of glucosamine, pseudoephedrine, codeine, paracetamol, econazole, hydrocodone, COX-2 inhibitors, alprazolam, dextromethorphan and chlorpheniramine. The ibuprofen and the one or more active ingredients may be combined in a single pharmaceutical composition.
In another general aspect there is provided a clear ibuprofen composition that includes from about 15% to about 40% w/w of ibuprofen, from about 30% to about 65% w/w of polyethylene glycol, from about 1% to about 10% w/w of a metal carbonate, from about 1% to about 15% of a surfactant, and from about 1% to about 10% w/w of water.
In another general aspect there is provided a process of preparing a clear ibuprofen composition. The process may include the steps of (a) dissolving one or more metal carbonates in water to form a solution, (b) preparing a solution of one or more surfactants in polyethylene glycol with optional heating, (c) adding ibuprofen and the solution of step (a) to the solution of step (b), and (d) stirring to obtain a clear solution.
In another aspect there is provided a clear composition of ibuprofen and pseudoephedrine that includes from about 15% to about 40% w/w of ibuprofen, from about 3% to about 6% w/w of pseudoephedrine or a pharmaceutically acceptable salt thereof, from about 30% to about 65% w/w of polyethylene glycol, from aboutl % to about 10% w/w of a metal carbonate, from about 1% to about 15% of a surfactant, and from aboutl % to about 10% w/w of water.
In another aspect there is provided a process of preparing a clear composition containing ibuprofen and pseudoephedrine and pharmaceutically acceptable salts thereof. The process may include the steps of
a. dissolving one or more metal carbonates in water to form a solution/suspension,
b. preparing a solution of one or more surfactants in polyethylene glycol with optional
heating,
c. adding ibuprofen and the solution of step (a) to the solution of step (b),
d. stirring to obtain a clear solution, and
e. adding pseudoephedrine or a pharmaceutically acceptable salt thereof, to the
solution of step (d) with continuous stirring to obtain a clear solution.

It is yet another aspect to provide a process for preparing clear solutions of ibuprofen and pseudoephedrine comprising:
a. dissolving one or more metal carbonates in water to form a solution/suspension;
b. adding ibuprofen and solution of step (a) to polyethylene glycol;
c. removing carbon dioxide from the solution of step (b);
d. adding one or more surfactants to the solution of step (c) under constant stirring;
e. adding pseudoephedrine or a pharmaceutically acceptable salt thereof to the
solution of step (d) with constant stirring to obtain a clear solution.
Carbon dioxide may be removed by one or more of the following processes like holding for 2-7 days at room temperature; nitrogen purging and holding for 2-7 days at room temperature; keeping under vacuum for 5 days; membrane degassing; and treating with activated charcoal. The processes may be used alone or in combination.
Membrane degassing is driven by the differential concentration of the gas across the membrane. Dissolved gases are thus removed from the solution by passing them through the membrane which is a shell-and-tube like device contaning microporous hydrophobic hollow fibres that allows only gas molecules to pass through by means of a diffusion mechanism.
Activated charcoal is good at trapping carbon-based impurities. The huge surface area of activated charcoal gives it countless bonding sites. When certain chemicals pass next to the carbon surface, they attach to the surface and are trapped.
In another general aspect there is provided a method of treatment of cough, cold, allergy, sinus and/or flu symptoms and the discomfort, pain, fever, and general malaise associated with it. The method includes administering a clear ibuprofen-pseudoephedrine composition that can include from about 15% to about 40% w/w of ibuprofen, from about 3% to about 6% w/w of pseudoephedrine or a pharmaceutically acceptable salt thereof, from about 30% to about 65% w/w of polyethylene glycol, from about 1% to about 10% w/w of a metal carbonate, from about 1% to about 15% of a surfactant, and from about 1% to about 10% w/w of water.
The method may include one or more of the following or the features described above. For example, the composition may further include one or more of glucosamine, codeine,

paracetamol, econazole, hydrocodone, COX-2 inhibitors, alprazolam, dextromethorphan
and chlorpheniramine. The ibuprofen and the one or more active ingredients may be
combined in a single pharmaceutical composition.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.
Detailed Description
Pharmaceutical products are regulated in most countries by a government agency. For example, the U.S. Food & Drug Administration (FDA) generally requires an applicant to show safety and efficacy of the pharmaceutical product during the approval/review phase and continues to monitor the safety of the drug post-approval. Similar requirements exist in many European countries and elsewhere in the world. In order to satisfy safety concerns, the regulatory agencies generally require a manufacturing specification that sets the maximum amount of each identified impurity as well as the maximum amount for all remaining unidentified impurities in the product. Once approved, each batch or lot of the pharmaceutical product is tested to ensure that the specification is met. Further, stability testing is performed on the pharmaceutical product in order to show that the composition does not substantially or materially change over time; i.e. over its indicated shelf-life. It is important that before the administration of a pharmaceutical product to a patient it does not deviate from its approved specification in a way that might detract from its safety or efficacy. Good practice warrants keeping a sample from every commercial batch released to the public so that the stability can be monitored and any defect uncovered and corrected.
Accordingly, Pharmaceuticals are tested for purity both during manufacture and subsequently during its shelf-life. Typically, the product is tested by comparing certain analytical results with those of a standard reference result. For impurity detection, this normally means assaying the pharmaceutical product and comparing the result to the result obtained for a substantially pure form of the suspected impurity in the same assay.
Carbon dioxide is produced when metal carbonate solution/slurry is added to the Ibuprofen dispersed in polyethylene glycol. Pseudoephedrine reacts with this carbon dioxide to form degradation impurities. In particular, the amino group of pseudoephedrine

is susceptible to degradation by carbon dioxide leading to the formation of N-(2-hydroxy-1-methyl-2-phenylethyl) N-methyl formamide.
The process of preparation of the fill composition of the present invention has been modified in such a way that the entrapped carbon dioxide is completely removed from the system before the addition of pseudoephedrine to it.
Carbon dioxide may be removed by one or more of the following processes like holding for 2-7 days at room temperature; nitrogen purging and holding for 2-7 days at room temperature; keeping under vacuum for 5 days; membrane degassing; and treating with activated charcoal. The processes may be used alone or in combination.
The present invention provides clear and stable solutions of ibuprofen and pseudoephedrine and the process of preparing them.
The term 'clear solutions', as used herein, describes liquid pharmaceutical compositions that are stable with reduced degradation impurities, transparent and free from turbidity or cloudiness or any other foreign particulate matter.
The clear and stable solutions of ibuprofen generally include:
a. from about 15% to about 40% w/w of ibuprofen,
b. from about 3% to about 6% w/w of pseudoephedrine,
c. from about 30% to about 70% w/w of polyethylene glycol,
d. from about 1% to about 10% w/w of a metal carbonate,
e. from about 1% to about 15% w/w of a surfactant, and
f. from about 1 % to about 10% w/w of water.
Polyethylene glycols generally are clear, viscous liquids or white solids, which are soluble in water and many organic solvents. The polyethylene glycols useful herein are those which are liquids at room temperature or have a melting point slightly there above. Preferred polyethylene glycols are those having a molecular weight range from about 300 to about 1000. More preferred are the polyethylene glycols having a molecular weight range from about 400 to about 1000. Moreover, mixtures of two or more polyethylene glycols of different average molecular weight range can also be employed

in the present invention. Polyethylene glycols may be present in amounts from about 30% to about 70% by weight.
The ibuprofen may be used in its free acid form. Ibuprofen may be present from about 15% to about 40% of the solution by weight.
Pseudoephedrine may be present from about 3% to about 6% by weight of the solution.
Ibuprofen may be converted into its cationic salt by adding the metal carbonate as dry powder or as aqueous solution in polyethylene glycol, containing the active ingredient. Alternatively, ibuprofen and metal carbonate can also be added to polyethylene glycol. There may be partial or complete conversion of ibuprofen to its metal salt by the above mentioned process.
The term 'metal carbonate1, as used herein, means carbonates and bicarbonates of any of the alkali and alkaline earth metals, for example sodium, lithium, calcium, magnesium, aluminium, and potassium. Examples of metal carbonates include sodium bicarbonate, calcium carbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, magnesium carbonate, magnesium bicarbonate, or mixtures thereof.
A surfactant may be also be added to the composition to assist in dissolution and/or
dispersion of the ibuprofen after its release from the dosage form. Suitable surfactants
can be ionic hydrophilic surfactants or non-ionic hydrophilic surfactants. The surfactant
can be any surfactant suitable for use in pharmaceutical compositions. Suitable
hydrophilic surfactants may be anionic, cationic.zwitterionic or non-ionic; particularly non-
ionic hydrophilic surfactants. Suitable non-ionic hydrophilic surfactants include one or
more of polyoxyethylene alkylethers; polyethylene glycol fatty acids esters; polyethylene
glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters;
polyoxyethylene- polyoxypropylene block copolymers; polyglyceryl fatty acid esters;
polyoxyethylene glycerides ; polyoxyethylene vegetable oils; polyoxyethylene
hydrogenated vegetable oils; reaction mixtures of polyols and at least one member
selected front the group consisting of fatty acids, glycerides, vegetable oil hydrogenated
vegetable oils, and sterols; and mixtures thereof.
In particular, polyoxyethylene sorbitan fatty acid esters are employed. Suitable examples

of these are polyethylene glycol-20 laurate, polyethylene glycol-20 oleate, polyethylene glycol-35 castor oil (commonly known as Cremophor® EL), polyethylene glycol-40 palm kernel oil, polyethylene glycol-40 hydrogenated castor oil, polyethylene glycol-60 corn oil (commonly known as Labrafil®), polyethylene glycol-25 glyceryl trioleate, polyglyceryl-10 laurate, polyethylene glycol-6 caprate/caprylate glycerides, polyethylene glycol-8 caprate/caprylate glycerides (commonly known as Labrasol®), polyethylene glycol-30 cholesterol, polysorbate 20, polysorbate 80 (commonly known as Tweens 80), polyoxyethylene-9 lauryl ether, polyoxyethylene-23 lauryl ether, polyoxyethylene-10 oleyl ether, polyethylene glycol-24 cholesterol, sucrose monostearate, sucrose monolaurate and poloxamers. The surfactants may be present from about 1 to about 15%, by weight of the formulation.
The term 'pharmaceutical composition1, as used herein, relates to fill material or solution with the active ingredient ready to be filled into soft gelatin capsule.
T^ie pH of the composition before filling into the softgel may be in the range from about 2.5 to about 7.5. The temperature during the processing may be in the range from about 25°C to about 65°C to carry out the conversion of ibuprofen into its metal salt form.
The small amount of water present acts to form a solvation sphere around the acid salt permitting it to go into solution in the polyethylene glycol. Water may be present in amounts ranging from about 1% to about 10% by weight of the solution.
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 may vary according to the chemical properties of the other ingredients used in the process.
Conventional additives can also be used in conjunction with the process of the invention as well, including but not limited to, preservatives, stabilizers, wetting agents, coloring agents, and the like. A process of preparing the pharmaceutical composition includes the steps of:

a. dissolving one or more metal carbonates in water to form a solution / suspension;
b. adding ibuprofen and solution of step (a) to polyethylene glycol;
c. removing carbon dioxide from the solution of step (b);
d. adding one or more surfactants to the solution of step (c) under constant stirring;
e. adding pseudoephedrine or a pharmaceutically acceptable salt thereof to the
solution of step (d) with constant stirring to obtain a clear solution.
Generally speaking, the higher the temperature of a solution becomes, the less a gas dissolves provided it doesn't react with the solvent. Consequently, heating a solution can expel the remaining gas. Ultrasonication and stirring at high heat are also effective. This method needs no special apparatus and is easy to conduct. Another method involves placing a solution under reduced pressure or vacuum which makes the dissolved gas less dissolvable and easily removable. Ultrasonication and stirring under reduced pressure usually enhance the efficiency. An effective method of removing dissolved gases is nitrogen purging also known as sparging
In membrane degasification, pores in the gas-liquid separation membranes allow gas but not liquid to pass through. Liquid flows on the outside (shellside) of the hollow fibres. Applied vacuum creates a partial pressure between the liquid phase (shellside) and the gas phase (lumen side). This vacuum causes transfer of dissolved carbon-dioxide from the shellside to the lumenside and is discharged through the vacuum pump. This method has the advantage of being able to prevent redissolution of the gas.
Dissolved gases may also be removed using a granular material usually produced by roasting various grades of coal in the absence of air. It has a very porous structure and it is usually called "activated charcoal".
Activated charcoal is good at trapping carbon-based impurities. The huge surface area of activated charcoal gives it countless bonding sites. When certain chemicals pass next to the carbon surface, they attach to the surface and are trapped.
The clear solution may be encapsulated into one-piece gelatin sheath or shell that includes a plasticizer.

The softgel 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 state. These ribbons are fed around rollers and brought together at a 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 jointer 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 sheets flow together to form a continuous gelatin sheath around the entrapped medicament. 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 sheath formulations known in the prior art may be used to encapsulate the fill formulations of the present invention. For example, suitable sheath formulations may include from about 35 to about 50% by weight of gelatin; at least 20% by weight, and in particular, up to about 40% by weight of a plasticizer; and from about 25 to about 50% by weight of water. These formulations, when formed into capsules and dried, may result in capsule sheaths that includes from about 45 to about 75% by weight of gelatin; from about 20% to about 40% by weight of plasticizer; and from about 5% to about 15% by weight of water.
Without being limited by theory, the water is believed to aid in the rapid dissolution or rupture of the soft gelatin shell upon contact with the gastrointestinal fluids encountered in the body. The ratio of gelatin to water may vary from 1: 0.75 to 1: 0.92. The amount of plasticizer added to the sheath is the determining factor as to how hard or soft the resulting capsule shell will be. In particular, the ratio of gelatin to plasticizer may vary from 1:0.35 to 1:0.48.
The gelatin will normally have a bloom in the range of from about 150 to about 275, and may be Type A or B gelatins, or a mixture thereof. Limed bone, acid bone, fish and/or pig skin gelatins may be used.

The susceptibility of gelatin to chemical modification is well known. Of the variety of reagents capable of interacting covalently with gelatin, formaldehyde has been studied most extensively. Cross linking of gelatin with formaldehyde has been used to produce enteric hard and soft capsules. However, when gelatin capsules intended for immediate release of their contents are exposed to trace levels of formaldehyde, the effect on in vitro dissolution rates may be adverse. Modification of the soft gelatin capsule shell is therefore necessary in order to avoid such problems. In order to provide adequate flexibility and strength to the shell, various plasticizers have been probed. Examples of suitable plasticizers include glycerin, xylitol, sorbitol, polyglycyerol, non-crystallizing solutions of sorbitol, glucose, fructose and glucose syrups with varying equivalents. A commercial plasticizer is ANDRISORB (supplied by Roquette, France), which is a proprietary mixture of sorbitol, sorbitans, maltitol and mannitol. While glycerin can be used as a plasticizer, it has been found that the ibuprofen may be esterified with the glycerin, thus reducing the amount of available free form of the ibuprofen. Therefore, the non-glycerin plasticizers are preferred.
The sheath formulations may also contain other ingredients, such as taste modifiers, coloring agents, and moisture retaining agents. Taste modifiers include non- reducing sugars, such as xylitol, maltitol, orLycasin manufactured by Roquette America, Inc. and normally may be present up to about 5% by weight of the sheath composition. Suitable moisture retaining agents include celluloses, cellulose derivatives, starches, starch derivatives, vegetable gums, non-hygroscopic, mono-, di-and oligosaccharides, and silicon dioxide. Various FD & C coloring agents may be used to impart the desired color to the capsule.
Compositions of the invention are useful in relieving the pain, tenderness, inflammation (swelling) and stiffness caused by arthritis and gout. It may also be used to reduce fever and to relieve headaches, muscle aches, menstrual pain, aches and pains from the common cold, backache, and pain after surgery or dental work.
The pharmaceutical composition may further include one or more of glucosamine, pseudoephedrine, codeine, paracetamol, econazole, hydrocodone, COX-2 inhibitors, alprazolam, dextromethorphan and chlorpheniramine. The ibuprofen and the one or more active ingredients may be combined in a single pharmaceutical composition, such as a soft gelatin capsule or softgel. Administering the present invention which further

contains pseudoephedrine may treat common cold and flu-like illnesses. Pseudoephedrine and its pharmaceutically acceptable salts are well recognized by those skilled in the art as safe and effective nasal decongestants. In particular, the widely used salts are the hydrochloride and the sulfate. Pharmacologically, pseudoephedrine is a sympathomimetic amine and is used as a bronchodilator and as a peripheral vasoconstrictor. It is indicated for temporary relief of nasal congestion due to the common cold and for temporary relief of nasal congestion associated with sinusitis. Pseudoephedrine may constitute from about 3% to about 6% w/w of the total composition.
The following examples illustrate various aspects of the present inventions. These examples are for illustration only and do not limit the scope of the inventions.
EXAMPLE 1 Soft gelatin capsule gel mass composition
(Example Removed)

Composition to be incorporated in the soft gelatin capsule
(Example Removed)

Process:
1. Polyethylene glycol was stirred with optional heating at a temperature of up to 45°C.
2. Potassium carbonate was dissolved in purified water.
3. Ibuprofen and potassium carbonate solution were added alternately to the polyethylene
glycol with optional heating under constant stirring at a temperature of up to 45°C.
4. Stirring was continued till a clear solution was obtained.
5. The clear solution of step 4 was filled in soft gelatin capsules.
EXAMPLE 2
Soft gelatin capsule gel mass composition
Similar to that of Example 1
Composition to be incorporated in the soft gelatin capsule
(Example Removed)

Process:
1. Polyethylene glycol was stirred with optional heating at a temperature of up to 45°C.
2. Potassium carbonate was dissolved in purified water.
3.Ibuprofen and potassium carbonate solution were added alternately to the polyethylene glycol with optional heating under constant stirring at a temperature up to 45°C.
4. Stirring was continued till a clear solution was obtained.
5. Pseudoephedrine hydrochloride was added and stirring was continued till a clear
solution was obtained.
6. The clear solution of step 4 was filled in soft gelatin capsules.
EXAMPLE 3
Soft gelatin capsule gel mass composition
Similar to that of Example 1
Composition to be incorporated in the soft gelatin capsule

(Example Removed)
Process:
1. Polyethylene glycol was stirred with optional heating at a temperature of about 45°C to
60°C and polyoxyethylated castor oil was dissolved in it with stirring.
2. Potassium carbonate was dissolved in purified water.
3. Ibuprofen and potassium carbonate solution were added alternately to the surfactant-
polyethylene glycol solution with constant stirring at a temperature of about 45°C to
60°C.
4. Stirring was continued at a temperature of about 45-60°C for about 30-45 minutes till a
clear solution was obtained.
5. The clear solution of step 4 was allowed to cool to room temperature and filled in soft
gelatin capsules.
EXAMPLE 4
Soft gelatin capsule gel mass composition
Similar to that of Example 1
Composition to be incorporated in the soft gelatin capsule
(Example Removed)
Process:
1. Polyethylene glycol was stirred with optional heating at a temperature of about
45°C to 60°C and polyoxyethylated castor oil was dissolved in it with stirring.
2. Potassium carbonate was dissolved in purified water.
S.lbuprofen and potassium carbonate solution were added alternately to the surfactant-polyethylene glycol solution with constant stirring at a temperature of about 45°C to 60°C.
4. Stirring was continued at a temperature of about 45-60°C for about 30-45 minutes till a
clear solution was obtained.
5. Pseudoephedrine hydrochloride was added and stirring was continued till a clear
solution was obtained.
6. The clear solution of step 5 was allowed to cool to room temperature and filled in soft
gelatin capsules.
EXAMPLE 5
Soft gelatin capsule gel mass composition
Similar to that of Example 1
Composition to be incorporated in the soft gelatin capsule
(Example Removed)

Process:
1. Polyethylene glycol was stirred with optional heating at a temperature of about 45°C to
60°C and Capryl-caproyl macrogol-8 glyceride was dissolved in it with stirring.
2. Potassium carbonate was dissolved in purified water.
S.lbuprofen and potassium carbonate solution were added alternately to the capryl caproyl macrogol-8 glyceride - polyethylene glycol solution with constant stirring at a temperature of about 45°C to 60°C.
4. Stirring was continued at a temperature of about 45-60°C for about 30-45 minutes till a
clear solution was obtained.
5. Pseudoephedrine hydrochloride was added and stirring was continued till a clear
solution was obtained.
6. The clear solution of step 5 was allowed to cool to room temperature and filled in soft
gelatin capsules.
EXAMPLE 6
Soft gelatin capsule gel mass composition
Similar to that of Example 1
Composition to be incorporated in the soft gelatin capsule
(Example Removed)

Process:
1. 92% of polyethylene glycol was stirred with heating at a temperature of up to
45°C.
2. Potassium carbonate was dispersed in 50% purified water.
3. Ibuprofen and potassium carbonate solution were added alternately to
polyethylene glycol of step-1 with heating with constant stirring at a temperature
up to 45°C.
4. Stirring was continued for about 4 hours till a clear solution was obtained.
5. Polyoxyethylated castor oil was added to the solution of step-4 and stirred for one
hour.
6. Pseudoephedrine hydrochloride was dissolved in the remaining 50% of purified
water and stirred for 15-30 minutes.
7. The solution of step 6 was added to the solution of step-5.
8. Remaining 8% of polyethylene glycol 400 was added to bulk of step-7 and stirred
until a clear solution was obtained.
9. The clear solution of step-8 was allowed to cool to room temperature and filled in
soft gelatin capsules.
EXAMPLE 7
Soft gelatin capsule gel mass composition
Similar to that of Example 1
Composition to be incorporated in the soft gelatin capsule
(Example Removed)

Process:
1. Slurry of potassium carbonate in a part of water was prepared.
2. 50% Ibuprofen was dispersed in approximately 49% of polyethylene glycol -
400.
3. Step-1 bulk was added to the bulk of step-2 and stirred.
4. The bulk was stirred continuously and heated to 45-55°C for 1 hour and then
60-65°C for the next 1.5 hrs and a clear solution was obtained.
5. 44% of polyethylene glycol-400 was added to the step-4 bulk and stirred for 15
minutes.
6. 50% Ibuprofen was added to the step-5 bulk and stirred continuously for 1
hour while the temperature was maintained at 40-48°C and a clear solution
was obtained.
7. Polyoxyethylated castor oil was added to the solution of step-6 and stirred for
10 minutes.
8. Pseudoephedrine HCI was dissolved in the remaining part of water and this
was added to the bulk of step-7.
9. Remaining polyethylene glycol-400 was added to the bulk of step-8 and stirred
until a clear solution was obtained.
10. The clear solution of step-9 was allowed to cool to room temperature and filled
in soft gelatin capsules.
EXAMPLE 8
Soft gelatin capsule gel mass composition
Similar to that of Example 1
Composition to be incorporated in the soft gelatin capsule
(Example Removed)

Process:
1. Slurry of potassium carbonate in a part of water was prepared.
2. 50% Ibuprofen was dispersed in approximately 49% of polyethylene glycol -
400.
3. Step-1 bulk was added to the bulk of step-2 and stirred.
4. The bulk was stirred continuously and heated to 45-55°C for 1 hour and then
60-65°C for the next 1.5 hrs and a clear solution was obtained.
5. 44% of polyethylene glycol -400 was added to the step-4 bulk and stirred for
15 minutes.
6. The solution of step-5 was held for 5 days.
7. Polyoxyethylated castor oil was added to the solution of step-6 and stirred for
10 minutes.
8. Pseudoephedrine HCI was dissolved in the remaining part of water and this
was added to the bulk of step-7.
9. Remaining polyethylene glycol-400 was added to the bulk of step-8 and stirred
until a clear solution was obtained.
10. The clear solution of step-9 was allowed to cool to room temperature and filled
in soft gelatin capsules.
EXAMPLE 9
Soft gelatin capsule gel mass composition
Similar to that of Example 1
Composition to be incorporated in the soft gelatin capsule
(Example Removed)

Process:
1. Slurry of potassium carbonate in a part of water was prepared.
2. 50% Ibuprofen was dispersed in approximately 49% of polyethylene glycol -
400.
3. Step-1 bulk was added to the bulk of step-2 and stirred.
4. The bulk was stirred continuously and heated to 45-55°C for 1 hour and then
60-65°C for the next 1.5 hrs and a clear solution was obtained.
5. 44% of polyethylene glycol-400 was added to the step-4 bulk and stirred for 15
minutes.
6. The solution of step-5 was purged with nitrogen gas.
7. The solution of step-6 was held for 5 days.
8. Polyoxyethylated castor oil was added to the solution of step-7 and stirred for
10 minutes.
9. Pseudoephedrine HCI was dissolved in the remaining part of water and this
was added to the bulk of step-8 and stirred until a clear solution was obtained.
10. The clear solution of step 9 was allowed to cool to room temperature and filled
in soft gelatin capsules.
EXAMPLE 10
Soft gelatin capsule gel mass composition
Similar to that of Example 1
Composition to be incorporated in the soft gelatin capsule
(Example Removed)

Process:
1. Slurry of potassium carbonate in a part of water was prepared.
2. 50% Ibuprofen was dispersed in approximately 49% of polyethylene glycol -
400.
3. Step-1 bulk was added to the bulk of step-2 and stirred.
4. The bulk was stirred continuously and heated to 45-55°C for 1 hour and then
60-65°C for the next 1.5 hrs and a clear solution was obtained.
5. 44% of polyethylene glycol-400 was added to the step-4 bulk and stirred for 15
minutes.
6. The solution of step-5 was kept under vacuum for 5 days.
7. Polyoxyethylated castor oil was added to the solution of step-6 and stirred for
10 minutes.

8. Pseudoephedrine HCI was dissolved in the remaining part of water and this
was added to the bulk of step-7.
9. Remaining polyethylene glycol-400 was added to the bulk of step-8 and stirred
until a clear solution was obtained.
10.The clear solution of step 9 was allowed to cool to room temperature and filled in soft gelatin capsules.
EXAMPLE 11
Soft gelatin capsule gel mass composition Similar to that of Example 1 Composition to be incorporated in the soft gelatin capsule
(Example Removed)

Process: 1. 2.
3. 4.
5. 6.

Solution of potassium carbonate in a part of water was prepared.
50% Ibuprofen was dispersed in approximately 49% of polyethylene glycol
-400.
Step-1 bulk was added to the bulk of step-2 and stirred.
Stirring was continued while the bulk was heated to 50°C for the 1st 0.5
hour and then 60-65°C for the next 1 hr and a clear solution was obtained.
44% of polyethylene glycol -400 was added to the step-4 bulk and stirred
for 15 minutes.
Remaining 50% Ibuprofen was added to the bulk of step-5 and stirred
continuously for 1 hour while the temperature was maintained at 40-50°C
and a clear solution was obtained.

7. Polyoxyethylated castor oil was added to the solution of step-6 and stirred
for 10 minutes.
8. Pseudoephedrine HCI was dissolved in the remaining part of water and this
was added to the bulk of step-7.
9. Remaining polyethylene glycol -400 was added to the bulk of step-8 and
stirred until till a clear solution was obtained.
10. The clear solution of step-9 was allowed to cool to room temperature and
filled in soft gelatin capsules.
EXAMPLE 12
Soft gelatin capsule gel mass composition Similar to that of Example 1 Composition to be incorporated in the soft gelatin capsule
(Example Removed)

Process:
1. Solution of potassium carbonate in a part of water was prepared.
2. 50% Ibuprofen was dispersed in approximately 49% of polyethylene glycol -
400.
3. Step-1 bulk was added to the bulk of step-2 and stirred.
4. Stirring was continued while the bulk was heated to 50°C for the 1st 0.5 hour
and then 60-65°C for the next 1 hr and a clear solution was obtained.
5. 44% of polyethylene glycol-400 was added to the step-4 bulk and stirred for 15
minutes.
6. Remaining 50% Ibuprofen was added to the bulk of step-5 and stirred
continuously for 1 hour while the temperature was maintained at 40-50°C and
a clear solution was obtained.
7. The clear solution of step-6 was purged with nitrogen gas for 1 hour.
8. Polyoxyethylated castor oil was added to the solution of step-7 and stirred for
10 minutes.
9. Pseudoephedrine HCI was dissolved in the remaining part of water and this
was added to the bulk of step-8.
10. Remaining polyethylene glycol-400 was added to the bulk of step-9 and stirred
until till a clear solution was obtained.
11. The clear solution of step 10 was allowed to cool to room temperature and
filled in soft gelatin capsules.
Stability Data:
The soft gelatin capsules prepared according to the Examples 6-12 were subjected to stability studies. Related substances of Ibuprofen and Pseudoephedrine HCI were determined by HPLC method, using Hypersil BDS Cie, 5 micron column with UV detector. The known impurities of ibuprofen and pseudoephedrine HCI were identified against placebo solutions and quantified against standard Ibuprofen and pseudoephedrine.
Relative Substance Data:
(Example Removed)

Pharmacokinetics:
The soft gelatin capsules prepared according to Example 4 were subjected to pharmacokinetic studies in comparison with Advil Cold and Sinus capsules, currently
marketed by Wyeth, in normal healthy subjects under fasting conditions.
Values for pharmacokinetic parameters, including observed Cmax, AUC0-t and AUC0-a, were calculated using standard non-compartmental methods. The results as indicated by ratio of test to reference are shown in Table 1.
Test (A): Soft gelatin capsules prepared as per Example 4
Reference (R): Advil Cold and Sinus capsules (Wyeth).
Table 1: Summary of pharmacokinetic parameters
(Table Removed)

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

WE CLAIM:
1. A process for preparing clear solutions of ibuprofen and pseudoephedrine
comprising:
a. dissolving one or more metal carbonates in water to form a solution/suspension;
b. adding ibuprofen and solution of step (a) to polyethylene glycol;
c. removing carbon dioxide from the solution of step (b);
d. adding one or more surfactants to the solution of step (c) under constant stirring;
e. adding pseudoephedrine or a pharmaceutically acceptable salt thereof to the
solution of step (d) with constant stirring to obtain a clear solution.
2. The process according to claim 1 wherein carbon dioxide is removed from the
ibuprofen phase by the following steps either alone or in combination:
(i) holding for 2-7 days at room temperature;
(ii) nitrogen purging and holding for 2-7 days at room temperature;
(iii) keeping under vacuum for 5 days;
(iv) membrane degassing; and
(v) treating with activated charcoal.
3. The process according to claim 1 wherein clear solution comprises:
a. from about 15% to about 40% w/w of ibuprofen,
b. from about 3% to about 6% w/w of pseudoephedrine,
c. from about 30% to about 70% w/w of polyethylene glycol,
d. from about 1 % to about 10% w/w of a metal carbonate,
e. from about 1% to about 15% w/w of a surfactant, and
f. from about 1 % to about 10% w/w of water.
4. The process according to claim 3 wherein the metal carbonate comprises one or more
of sodium bicarbonate, calcium carbonate, potassium bicarbonate, sodium carbonate,
potassium carbonate, magnesium carbonate, magnesium bicarbonate, or mixtures
thereof.
5. The process according to claim 3 wherein the surfactant is a non-ionic hydrophilic
surfactant and comprises one or more of polyoxyethylene alkylethers, polyethylene
glycol fatty acids esters, polyethylene glycol glycerol fatty acid esters, polyoxyethyiene

sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, polyglyceryl fatty acid esters, polyoxyethylene glycerides, polyoxyethylene vegetable oils, and polyoxyethylene hydrogenated vegetable oils.
6. The process according to claim 3 wherein the polyethylene glycol has an average
molecular weight of about 300 to about 1000.
7. The process according to claim 3 wherein the clear solution is filled into soft gelatin
capsules.
8. The process according to claim 7 wherein the soft gelatin capsule comprises gelatin,
water, plasticizers, coloring agents and preservatives.
9. The process according to claim 1, wherein the clear solution further comprises one or
more of glucosamine, codeine, paracetamol, econazole, hydrocodone, COX-2 inhibitors,
alprazolam, dextromethorphan, chlorpheniramine, and pharmaceutically acceptable salts
thereof.