AU622427B2 - Liquid ibuprofen compositions and methods of making them - Google Patents

Description

uiae oj signing) Signed: Ronald T. Haas, President Position: GRIFFITH HASSEL FRAZER G.P.O. BOX 4164 SYDNEY, AUSTRALIA j :n :j ii r i i -i i_ -~ci ~CI OPI DATE 02/05/89 APPLN. ID 27237 88 PCT w o AOJP 6T25 2 CT7 MBER PCT/US88/03544 INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4 (11) International Publication Number: WO 89/ 03210 A61K 31/19, 9/48 Al (43) International Publication Date: 20 April 1989 (20.04.89) (21) International Application Number: PCT/US88/03544 (81) Designated States: AT (European patent), AU, BE (European patent), CH (European patent), DE (Eurc- (22) International Filing Date: 12 October 1988 (12.10.88) pean patent), DK, FI, FR (European patent), GB (European patent), IT (European patent), JP, KR, LU (European patent), NL (European patent), SE (Euro- (31) Priority Application Number: 110,184 pean patent).

(32) Priority Date: 15 October 1987 (15.10.87) Published (33) Priority Country: US With international search report.

Before the expiration of the time limit for amending the claims and to be republished in the event of the receipt (71) Applicant: ORATECH PHARMACEUTICAL DE- of amendments.

VELOPMENT CORPORATION [US/US]; 210 Carnegie Center, Suite 101, Princeton, NJ 08540 (US).

(72) Inventor: HAAS, Ronald, T. 47 Highmont Drive, West Windsor, Robbinsville, NJ 08691 (US).

(74) Agents: SOFFEN, Marvin. C et al.; Ostrolenk, Faber, Gerb Soffen, 1180 Avenue of the Americas, New York, NY 10036 (US).

(54)Title: LIQUID IBUPROFEN COMPOSITIONS AND METHODS OF MAKING THEM (57) Abstract A clear, stable, and palatable liquid ibuprofen composition has ibuprofen, or a pharmaceutically acceptable salt or ester of ibuprofen, in an aqueous medium containing a methylcellulose composition. A process of making such an ibuprofen composition is significantly simpler and less expensive to carry out than prior processes of making liquid ibuprofen compositions. The liquid ibuprofen composition may also contain pharmaceutically acceptable alcohol, dispersing and suspending agents, viscosity increasing agents, flavorings, and preservatives.

I

WO 89/03210 PCT/US88/03544 LIQUID IBUPROFEN COMPOSITIONS AND METHODS OF MAKING THEM Field of the Invention This invention relates to liquid ibuprofen compositions and processes of making them. More specifically, this invention relates to liquid ibuprofen compositions which are clear, stable, palatable, and simple and economical to make. These compositions are useful in treating pain, inflammation, and fever. They may be used in conjunction with other medications, such as cough medications, cold medications, antihistamines, decongestants, or narcotics, or with any combinations of two or more of these medications. Although anyone may partake of their advantages, these compositions are particularly useful in treating patients unable to swallow solid dosages of ibuprofen, such as the very young, the very old, and the infirm.

Background of the Invention Ibuprofen (p-isobutylhydratropic acid) is a nonsteroidal composition that has long been recognized as being useful in the treatment of pain, inflammation, and fever. More particularly, ibuprofen has been found in clinical studies to be very effective in the treatment of the signs and symptoms of rheumatoid arthritis and i osteoarthritis, the relief of mild to moderate pain, and the treatment of primary dysmenorrhea, among other things.

Ibuprofen is at least as effective as other available high potency compounds, such as indomethacin and phenylbutazone, but without their attendant side effects, such as increased toxicity. Also, ibuprofen is obtainable over the counter in certain dosages, whereas other high potency compounds are not.

Dosages of ibuprofen have been available in the marketplace only in solid form such as in a tablet or a capsule form. There are significant segments of the population, however, which are unable to conveniently take -,n 3 WO 8903210 PCT/US88/0354 4 -2medication in solid form. These include the pediatric population, the geriatric population, the infirm, and those who for whatever reason cannot or p.efer not to swallow solid dosages of medication. For these people, the benefits of ibuprofen have been effectively unavailable because of the unavailability of liquid forms of the composition. Until this time, attempts to meet the needs of these people involved use of other analgesic compositions in liquid form such as liquid acetaminophen and liquid aspirin compositions. These efforts have been largely ineffective because the analgesia produced by these compositions is less than that obtainable with ibuprofen, acetaminophen compositions lack antiinflammatory activity, and aspirin has come into disfavor because it causes gastrointestinal discomfort in some patients and it has been reported to be linked to Rye syndrome in children.

In response to this long standing need, there have been many attempts to provide a liquid ibuprofen composition. For the most part, these attempts have been frustrated by the facts that ibuprofen is insoluble in media.

Nicholson U.S. Patent 3,385,886 refers to a mixture of sodium 4-isobutylphenylacetate, orange peel infusion, and chloroform water, a suspension of 4isobutylphenylacetic acid and tragacanth powder in chloroform water, and an elixir containing, among other things, sodium 4-cyclohexylphenylacetate, ethanol, and glycerol. These compositions all have limited shelf life, poor flavor, and substantial turbidity. Also, those compositions containing chloroform are unsuitable for administration to children and the elderly.

Mueller U.S. Patent 4,447,451 refers to syrups, elixirs, and suspensions of ibuprofen. It says that water soluble forms of ibuprofen can be dissolved in an aqueous vehicle together with sugar, flavoring agents, and WO 89/03210 PCT/US88/03544 -3preservatives to form a syrup. It also says that an elixir may be prepared by using a Iydroalcoholic vehicle, a sweetener, and a flavoring agent. It also says that a suspension may be prepared for insoluble forms of ibuprofen in a "suitable vehicle" with the aid of a suspending agent such as acacia, tragacanth, methylcellulose, and the like. No information is given regarding the nature of the "suitable vehicle". The patent completely fails to appreciate the problems of turbidity and stability that have to be addressed before a suitable liquid ibuprofen composition may be developed.

In contrast to the invention of this application, the Mueller patent completely fails to appreciate how methylcellulose compositions are particularly useful in overcoming problems of prior liquid ibuprofen compositions and fails to teach any way of using methylcellulose compositions to overcome those problems. The Mueller patent's complete failure to suggest the invention of this application and its advantages is demonstrated by the specific recipe for an ibuprofen suspension given in the patent. That suspension is to be taken- orally and gives a 100 mg. dose of ibuprofen per 5 ml. dose of suspension.

It includes an aluminum salt of ibuprofen, citric acid, benzoic acid, sucrose, tragacanth, lemon oil, and deionized water. This composition is cloudy and not chemically stable for any length of time.

Arnold U.S. Patent 4,571,400 refers to pharmaceutical compositions containing dihydrocodeine and ibuprofen. It says that those compositions may have every imaginable ingredient and physical characteristic. Specifically, those compositions, among other things, allegedly may be in liquid form, supposedly as solutions, suspensions, emulsions, syrups, elixirs, or pressurized compositions.

The active ingredient allegedly can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fats. There is no S, i L WO 89/03210 PCT/US88/03544 -4indication of how any of this is to be accomplished. The liquid carrier may contain a host of different pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilisers, or osmoregulators. No idea is given about which of these ingredients are to be used, in what amounts they are to be used, or what characteristics would result if they were tried.

Purported examples of liquid carriers for oral administration include water said to contain the additives listed above, for example, cellulose derivatives, preferably some unspecified sodium carboxymethylcellulose solution. Alcohols and their derivatives, and oils, are also said to be suitable liquid carriers. There is absolutely no recipe for preparing any liquid composition and Applicant is unaware of the existence of any such recipe apart from the invention of this application which may be used in conjunction with the wish list of the Arnold patent to prepare a liquid ibuprofen composition anything like that of this application. In the Examples, the Arnold patent only purports to describe how to prepare tablets and capsules, and not liquid compositions.

Arnold U.S. Patent 4,587,252 refers to a pharmaceutical composition containing hydrocodone and ibuprofen. The patent purports to describe the entire spectrum of liquid compositions said to be possible for the compositions of the Arnold '400 patent and, like the Arnold '400 patent, gives no idea about how to achieve any of those liquid compositions or what one would get if one were to try to do so.

Moore et al. report a clinical trial using an aluminum ibuprofen suspension to relieve the pain of dental extractions in children (International Journal of Clinical Pharmacology, Therapy and Toxicology, Vol. 23, No. 11-1985, pp. 573-577). No formulation for the suspension is given in the paper, although the paper does 1 k indicate that dosages of 200 mg. of ibuprofen were administered. A footnote indicates that the suspension was prepared by the assignee of the Mueller patent.

Haas U.S. Patent 4,684,666 is not prior art, but it is referred to here to give some idea of the background of this invention. It refers to a stabilized liquid ibuprofen composition. Although the patent refers to a completely suitable ibuprofen composition in terms of taste, stability, and lack of turbidity, and in fact describes the first commercially acceptable liquid ibuprofen composition, Applicant has unexpectedly found that the clarity and stability of that ibuprofen composition can be improved upon with the invention of this application. In addition to improved clarity and *1 15 stability, the invention of this application permits production of the ibuprofen composition with dramatically reduced labor costs in a process of markedly increased simplicity. This permits the marketing of a more palatable liruid ibuprofen composition of reduced cost 20 particularly attractive for parents with small children, elderly people on fixed incomes, and sick persons burdened with high health care costs.

Summary of the Invention In one aspect of the invention there is provided a novel 25 liquid ibuprofen composition and a novel method of making that composition.

In an other aspect the invention provides a novel liquid ibuprofen composition which is simpler and more economical to make than any such composition proposed in the past.

A further aspect of the invention provides a liquid ibuprofen composition which is clear and chemically and physically stable.

In yet a further aspect the invention provides an ibuprofen composition in which the control of pH is not a critically important factor.

k Al -6- The invention provides a liquid ibuprofen composition which does not use expensive hydrophilic emulsifying agents or colloidal clays to disperse and suspend the ibuprofen in a liquid medium.

The invention also provides a liquid ibuprofen composition which avoids the use of antioxidants.

Other aspects and advantages are either specifically described elsewhere in this application or are apparent from the the description in the application.

In accordance with these aspects and advantages, a composition of matter is disclosed and claimed. That composition comprises an ibuDrofen composition dispersed and suspended, or dissolved, in an aqueous medium :15 comprising a methylcellulose composition. Also in accordance with these aspects and advantages, a method of making such a composition i-s disclosed and claimed.

Detailed Description of the Invention Liquid ibuprofen compositions in accdrdahce with"the invention may contain a therapeutically effective amount of ibuprofen, or a pharmaceutically acceptable salt or ester of ibuprofen, dispersed and suspended in an aqueous medium. Specific examples of such compositions may contain approximately 25 to 400 mg. of ibuprofen per 5 ml.

sample of the composition.

i The aqueous medium contains a predetermined amount of a methylcellulose composition which acts to suspend the ibuprofen in the aqueous medium. A specific example of a i methylcellulose composition suitable for use with this invention is solid sodium carboxymethy1cellulcse powder.

In addition to suspending the ibuprofen in the aqueous medium, the methylcellulose composition assists in the dispersal of the ibuprofen in the medium during preparation of liquid compositions in accordance with this invention. In effect, the methylcellulose composition renders the ibuprofen soluble in the aqueous medium.

After formulation of the liquid composition, the WO 89/03210 PCT/US88/03544 -7methylcellulose composition forms a chemical barrier around the ibuprofen particles suspended in the medium, which prevents the ibuprofen from chemically reacting with the other ingredients in the medium and thus stabilizes the liquid composition of the invention. The methylcellulose also increases the viscosity of the resulting composition.

The amount of methylcellulose to be used in any given situation should be determined by empirical testing and depends on the desired properties of the resulting composition. Specifically, enough should be used to produce the desired amount of dispersion, suspension, solubility, and stability of the ibuprofen in the aqueous medium- Specific examples of the quantity of methylcellulose which Applicant has found to produce good results are described in Examples 1-6 below.

In addition to the methylcellulose composition, the aqueous medium may also contain a pharmaceutically acceptable alcohol to increase the solubility of the ibuprofen in the medium. Such alcohol may also be used to retard microbial growth. One suitable alcohol is ethyl alcohol. The amount of alcohol used should be an amount which produces a desired amount of solubility of ibuprofen and inhibition of microbial growth in the liquid composition. Specific amounts of alcohol which Applicant has found suitable are given in Examples 1-6 below.

In some instances, use of an alcohol in a liquid ibuprofen composition may be undesirable, for example, in a situation where the patient for some reason cannot consume alcohol. It has been found that the alcohol may be eliminated and still a clear, stable, and palatable liquid ibuprofen composition will be obtained.

A bicarbonate composition may also be added to the aqueous medium to assist in the dispersion of the ibuprofen during the formulation of the composition. A I suitable bicarbonate composition is potassium bicarbonate.

Normally, bicarbonate compositions are used to adjust pH rr S WO 89/03210 PCT/US88/03544 -8of a solution. In this instance, however, the bicarbonate is not used for the control of pH, but to disperse the ibuprofen in the medium and help it go into solution. The amount to be used is determined in empirical studies of the amounts needed to produce a desired amount of dispersion.

Since ibuprofen has a very bitter taste, it is desirable to mask its flavor. This may be accomplished by the addition of one or more flavoring agents which will accomplish this. One of these flavoring agents may be a sweetener, such as sucrose, which may be added to the medium not only to mask the unpleasant flavor of the ibuprofen, but also to increase the viscosity of the composition so that a syrup results. To enhance the stability and shelf life of ibuprofen compositions of this invention, and to produce a haze free composition, it is suggested that, if sucrose is used, it be of high purity.

An example of such a sucrose is Bottler's Grade Extra Fine, No Floc, sold by Holly Sugar.

Some patients may not be able to tolerate high levels of sucrose. In that case, an artificial sweetener may be used in the invention of this application instead of sucrose. Such artificial sweeteners include sodium saccharine and aspartame. If these sweeteners are used, howsver, it may be desirable to add a composition such as glycerol, sorbitol, propylene glycol, or combinations of two or more of those ingredients in an amount which will build up the viscosity of the resulting composition.

In addition to sweetening the composition of the invention to mask the flavor of the ibuprofen, other ingredients may be added to enhance its flavor and mouthfeel. One possibility is menthol. Another is glycerin, which is also useful as a dispersing and suspending agent for the ibuprofen in the aqueous medium. It also increases the viscosity of the composition. Fruit flavorings may alsi be added to the composition, such as banana, cherry, or citrus fruit flavorings. Licorice, i WO 89/03210 PCT/US88/03544 -9bubble gum, selected spices, such as cinnamon, and a mint, such as peppermint, may also be used to flavor the liquid ibuprofen composition. The flavorings may be natural or artificial flavorings.

Although the pharmaceutically acceptable alcohol mentioned above will inhibit microbial growth, it may also be advisable to add an additional preservative to application. It may be even more desirable to do so when an alcohol is not used. Such additional preservatives include paraben compositions such as methyl, butyl, and propyl parabens. A mixture of methyl paraben and propyl paraben in n one part propyl paraben to two parts methyl paraben by weight mixture has been found desirable.

Compositions in accordance with the invention of this application are liquid ibuprofen compositions exhibiting a great deal of clarity without haze formation. They are chemically and physically stable for extended periods of time. In other words, the ibuprofen tends not to chemically react with anything either inside or outside the liquid medium. It remains dispersed and suspended in the medium and does not settle to the bottom of the container in which the composition is stored. For all intents and purposes, liquid ibuprofen compositions in accordance with this invention are stable aqueous solutions of ibuprofen, something which Applicant is unaware of actually having been produced before. No particulate matter is evident under visual inspection and the ibuprofen is uniformly dispersed and suspended in the aaueous medium. This condition is maintained for extended periods of time.

No expensive hydrophilic emulsifying agents and colloidal clays are required to produce these compositions, nor are any special antioxidants required, such as metabisulfites, which some have claimed may cause allergic reactions in children- Also, it is not critical that pH be controlled. The composition is simpler and WO 89/03210 PCT/US88/03544.

89/03210 less expensive to make than prior liquid ibuprofen compositions, perhaps less expensive by as much as 50% of the cost of producing prior liquid ibuprofen compositions.

Compositions in accordance with the invention of this application may be prepared by the following process.

First, a predetermined' amount of water is measured into a vessel, which is then heated to a temperature which will aid in the dispersal of the ingredients in the liquid medium, for example 550 C. to 650 C. Then, a predetermined amount of methylcellulose composition is measured and slowly added to the heated water while it is being stirred. Once the methylcellulose composition has been completely dissolved, a desired amount of sweetener may be measuzed out and slowly added to the heated aqueous methylcellulose solution until it is all dissolved in the solution. The solution -then is removed from the source of heat and allowed to cool. It may be necessary to allow the solution to cool overnight. The rest of the process steps may be carried out at the elevated temperatures described above, but it is desirable to allow the solution to cool in this manner because the ibuprofen to be added later is more easily dissolved in the solution at lower temperatures. Specifically, the finely milled ibuprofen has less of a tendency to clump and less froth is produced when the ibuprofen is added to the solution. There is also less risk of degrading the ibuprofen at lower temperatures.

After the solution is allowed to cool, a preselected amount of a bicarbonate composition may be weighed out and added slowly to the cooled solution as it is being mixed at high speed. Next, a desired amount of finely ground ibuprofen is weighed out and slowly added to the solution as it is being mixed. At this time, foam appears in the solution which now appears to have a milky color. After the ibuprofen is added to the solution, it is mixed at high speed for a predetermined time, for example, _j i WO 89/03210 PCT/U388/03544 -11minutes. After the expiration of this mixing time, a predetermined amount of glycerin may be measured out and added to the solution. Another predetermined period of high speed mixing may follow, for example 5 minutes, followed by the addition of a predetermined amount of the pharmaceutically acceptable alcohol and continued mixing for an additional period of time, such as 5 minutes. A desired amount of preservative, such as a paraben composition may be added at this time.

Next, menthol may be dissolved in another predetermined amount of the pharmaceutically acceptable alcohol or in a predetermined amount of water heated to a temperature which will promote the dissolving of the menthol in the water, for example, about 550 C. to 650 C.

The resulting menthol solution may be added to the liquid ibuprofen composition as it is being mixed. The parabens may be added to the menthol solution before it is added to the liquid ibuprofen composition, instead of directly to the ibuprofen composition as described above. Additional flavoring may be added at this time, such as banana flavoring.

After all of these ingredients have been combined, the resulting composition should be mixed at high speed until all of the ingredients have been thoroughly mixed together, for example, the composition may be mixed for an additional 10 minutes. After such mixing, the composition should be allowed to stand for a predetermined time until the foam has dissipated and all the gaseous components in the liquid are evaporated off, at which time a clear solution appears, which perhaps will have a tinge of color depending on the nature of the flavoring employed. No particles of ibuprofen are evident upon visual excamination. In this condition, a filtering aid may be added to the composition and the composition may be passed through a filter to remove any other particulate impurities that may be present. Filtering apparatus to accomplish this may be obtained from companies such as i _i WO 89/03210 PCT/US88/03544 -12- Sparkler or Millipore. The composition may be filtered through a filter paper which may have a layer of 17 micron cotton rag paper underlined with a 40 micron lint free rayon cellulose binder. The composition may then be inspected for quality and packaged in a covered glass container.

Example 1 A 250 liter batch of a liquid ibuprofen composition in accordance with the invention of this application may be prepared as follows. The resulting composition will contain about 400 mg. of ibuprofen per 5 ml. of the liquid composition (about a teaspoonful sample of the composition). A list of the ingredients needed for the preparation of this batch is as follows: Ingredient Quantity Ibuprofen milled (60 mesh) 20,000 gm.

SSodium carboxymethylcellulose 7 MF 750 gm.

Sucrose NF XVI 125,000 gm.

Potassium bicarbonate USP XXI powder 11,500 gm.

Glycerin USP XXI 12,500 ml.

Ethyl alcohol 190 proof USP XXI 40,400 ml.

Methyl paraben USP XVI 200 gm.

Propyl paraben. USP XVI 100 gm.

Menthol USP XXI 100 gm.

Banana flavor F1201 (Givaudan) 1000 ml.

Purified water USP XXI 100,000 ml.

Dicelite Speedex filter aid 300 gm.

Before preparing the composition, the preparation Sarea should be checked for cleanliness, including all equipment coming in contact with the ingredients. In addition to the raw materials listed above, the following equipment should be available: i WO 89/03210 PCT/US88/03544 -13i. Fitzmill; 2. 80 gallon jacketed tank; 3. 100 gallon tank; 4. Transfer pump and hoses; and 5. Sparkler filter To avoid microbial contamination, contact of the ingredients and the equipment with the hands should be avoided.

The purified water is placed in the 80 gallon tank which has been fitted with a double impeller stirrer. The stirrer has an impeller toward the bottom of the tank and an impeller toward the top of the tank so that adequate mixing is obtained from top to bottom in the tank. The water in the tank is then heated to a temperature of about 550 C. to 650 C.

The 750 grams of sodium carboxymethylcellulose powder then are slowly added to the heated water while it is being stirred at high speed. Once this powder has dissolved completely, then the 125,000 gm. of sucrose are slowly added to the solution while it is stirred at high speed. When the sucrose has been dissolved, the solution is permitted to cool until it has a temperature of about 200 C. to 3 0

C.

Using a Fitzmill with a screen and its hammers forward, 11,500 grams of potassium bicarbonate powder are milled into a tared container. Then the potassium i bicarbonate powder is added to the processing tank while the contents of the tank continues to be stirred. After the potassium bicarbonate has been dissolved, then the milled ibuprofen is slowly added to the tank while the contents of the tank is being stirred. Glycerin then may be added to the tank which undergoes continued stirring.

The tank then is allowed to stand until the froth that has appeared has subsided. If the froth does not subside, the mixture should be stirred again and allowed to stand until j it becomes clear.

"A

PCT/US88/03544 WO 89/03210 -14- Next, the ethyl alcohol is placed in a suitable stainless steel vessel. The methyl paraben, propyl paraben, and menthol are then dissolved in the alcohol.

Stirring is used to aid in dissolving these ingredients.

Flavoring such as banana flavoring is added to the alcohol at this time. The alcoholic solution is then added to the main processing tank while its contents are being stirred at high speed. More deionized water is then added to the tank so that the contents of the tank is 250 liters of liquid ibuprofen composition. A calibrated dip stick may be used to measure the amount of liquid in the tank. When 250 liters of liquid are in the tank, it is mixed thoroughly for about ten minutes.

A Sparkler filter Model 18-S-7 is then set up according to manufacturer's instructions using filter paper having one layer of 17 micron cotton rag underlined by a 40 micron lint free rayon cellulose binder. Dicelite Speedex filter aid is added to the batch which is then mixed for ten minutes. The batch then is filtered into a clean 100 gallon stainless steel tank, which then may be sealed to prevent loss of volatiles.

A clear, stable, and palatable liquid ibuprofen composition having about 400 mg. of ibuprofen per 5 ml.

sample results at this time.

Example 2 A 250 liter batch of a liquid ibuprofen composition I containing about 25 mg. of ibuprofen per 5 ml. of the composition may be prepared in accordance with the steps of Example 1 with the exception that 1,250 grams of ibuprofen is used instead of the 20,000 grams of ibuprofen specified in Example 1. Using 2,500 grams of ibuprofen in this Example instead of 1,250 grams will result in a liquid composition having about 50 mg. of ibuprofen per ml.

Example 3 A 250 liter batch of a liquid ibuprofen composition containing about 100 grams of ibuprofen per 5 ml. may be WO 8.9/03210 PCT/US88/03544 prepared in accordance with the steps of Example 1 with the exception that 5,000 grams of ibuprofen is used instead of the 20,000 grams of ibuprofen specified in Example 1. Using 10,000 grams of ibuprofen in this Example instead of 5,000 grams will result in a liquid composition having about 200 mg. of ibuprofen per 5 ml.

Example 4 A 250 liter batch of a liquid ibuprofen composition containing about 400 mg. of ibuprofen per 5 ml. sample of the composition may be prepared in accordance with the steps of Example 1 with the exception that no ethyl alcohol is used. The methyl paraben and propyl paraben are added directly to the batch and the menthol is added to water heated to 550 C. to 650 C. and dissolved in the heated water before being added to the batch. 250 liter batches of liquid ibuprofen composition containing about mg., 50 mg., 100 mg., and 200 mg. of ibuprofen per ml. sample of the composition may be prepared in accordance with Examples 2 and 3, as modified by the exception to the steps of Example 1 specified in this Example.

Example A 250 liter batch of a liquid ibuprofen composition containing about 400 mg. of ibuprofen per 5 ml. sample of the composition may be prepared in accordance with the steps of Example I with the exception that no ethyl alcohol or menthol is used. The methyl paraben and propyl paraben are added directly to the batch. 250 liter Sbatches of liquid ibuprofen composition containing about 25 mg., 50 mg., 100 mg., and 200 mg. of ibuprofen per ml. sample of the composition may be prepared in accordance with Examples 2 and 3, as modified by the exception to the steps of Example 1 specified in this Example.

Example 6 A 250 liter batch of a liquid ibuprofen composition containing about 400 mg. of ibuprofen per 5 ml. sample of WO 89/03210 PCT/US88/03544 -16the composition may be prepared in accordance with the steps of Example 1 with the exception that no potassium bicarbonate is used and no flavoring agent is used apart from the sucrose. It has been surprisingly found that the sucrose is able to almost completely mask the unpleasant flavor of the ibuprofen in this example of the invention.

250 liter batches of liquid ibuprofen composition containing about 25 mg., 50 mg., 100 mg., and 200 mg. of ibuprofen per 5 ml. sample of the composition may be prepared in accordance with Examples 2 and 3, as modified by the exception to the steps of Example 1 specified in this Example.

LI -1 L

Claims (18)

1. A liquid ibulrofen composition comprised of a therapeutically effective amount of ibuprofen or a pharmaceutically acceptable salt or ester of ibuprofen suspended in an aqueous medium comprising a methylcellulose composition and a bicarbonate composition, wherein the composition is clear, stable and palatable.

2. A liquid ibuprofen composition according to claim 1, in which the bicarbonate composition comprises an alkali metal bicarbonate.

3. A liquid ibuprofen composition according to claim 2, in which the alkali metal bicarbonate is potassium 20 bicarbonate.

4. A liquid ibuprofen composition according to any one of claims 1 to 3, in which the amount of bicarbonate composition is such that the ibuprofen composition goes 25 into solution resulting in an aqueous solution of ibuprofen composition without particulate matter being evident upon visual examination.

5. A liquid ibuprofen composition according to any one of claims 1 to 4, which further comprises one or more additives selected from a pharmaceutically acceptable alcohol, a flavouring agent, a sweetening agent, and a preservative. 8539S/NL/24.01.92 c~ -18-

6. A liquid ibuprofen composition according to claim in which the sweetening agent is sucrose or saccharine.

7. A liquid ibuprofen composition according to claim or 6, which comprises glycerin.

8. A process of preparing a liquid ibuprofen composition, comprising the steps of: dissolving a methylcellulose composition in water, adding and dissolving an optional sweetening agent, adding and mixing at high speed a bicarbonate composition and ibuprofen to the dissolved methylcellulose mixing the composition at high speed to homogeneity. 20

9. A process of preparing a liquid ibuprofen composition Saccording to claim 8, in which one or more additives selected from a pharmaceutically acceptable alcohol, a flavouring agent, a sweetening agent and a preservative are added one at a time to the dissolved methylcellulose 25 composition.

A process of preparing a liquid ibuprofen composition according to claim 9, in which the additives are added following the addition and mixing at high speed of ibuprofen.

11. A process of preparing a liquid ibuprofen composition according to any one of claims 8 to 10, in which the sweetening agent is sucrose or saccharine. 8539S/NL/24.01.92 accrdig t clam 9 in hic th addtivs ar aded jS 'r __C I19

12. A process of preparing a liquid ibuprofen composition according to any one of claims 9 to 11, which comprises glycerin.

13. A liquid ibuprofen composition prepared in accordance with the process of any one of claims 3 to 12.

14. A liquid ibuprofen composition prepared in accordance with an one of claims 8 to 13, in which the bicarbonate composition comprises an alkali metal bicarbonate.

15. A liquid ibuprofen composition prepared in accordance with any one of claims 8 to 14, in which the amount of bicarbonate composition is such that the ibuprofen composition goes into solution, resulting in an aqueous solution of ibuprofen composition without 15 particulate matter being evident upon visual examination.

16. A liquid ibuprofen composition substantially as herein described with reference to any one of the Examples 1 to

17. A process of preparing a liquid ibuprofen 20 composition as herein described with reference to any one of the Examples 1 to *1 9DATED this 24th day of January 1992 ORATECH PHARMACEUTICAL DEVELOPMENT CORPORATION By their Patent Attorney GRIFFITH HACK CO. INTERNATIONAL SEARCH REPORT I INTERNATIONAL SEARCH REPORT "P 3V international Application No. PCT/US88/03544 I. CLASSIFICATION OF SUBJECT MATTER (It several classification symbols apply, indicate all) 6 According to International Patent Classification (IPC) or to both National Classification and IPC INT. CL(4): A61K 31/19, A61K 9/48 U.S. CL: 514/557 II. FIELDS SEARCHED Minimum Documentation Searchud 7 Classification System Classification Symbols U.S. 514/557 514/289 514/962 424/456 514/960 Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included In the Fields Searched a Ill. DOCUMENTS CONSIDERED TO BE RELEVANT 9 Category Citation of Document, 11 with indication, where appropriate, of the relevant passages 12 Relevant to Claim No. 1 3 Y,E US, A, 4,788,220 PUBLISHED 29 NOVEMBER 1.88 1-7 (MODY ET AL); SEE ENTIRE DOCUMENT. Y US, A, 4,684,666 PUBLISHED 04 AUGUST 1987 1-7 (HAAS); SEE ENTIRE DOCUMENT. Y US, A, 4,681,897 PUBLISHED 21 JULY 1987 1-7 (BRAUD); SEE ENTIRE DOCUMENT. A US, A, 4,690,823 PUBLISHED 01 SEPTEMBER 1987 (LOHNER ET AL); SEE ENTIRE DOCUMENT. A US A, 4.695,591 PUBLISHED 22 SEPTEMBER 1987 (HANNA ET AL); SEE ENTIRE DOCUMENT. A,P US, A, 4,713,249 PUBLISHED 15 DECEMBER 1987 (SCHROEDER); SEE ENTIRE DOCUMENT. A US, A, 4,569,937 PUBLISHED 11 FEBRUARY 1986 (BAKER ET AL); SEE ENTIRE DOCUMENT. A US, A, 4,571,400 PUBLISHED

18 FEBRUARY 1986 (ARNOLD); SEE ENTIRE DOCUMENT. SSpecial categories of cited documents: 10 later document published ater the international filing date or priority date and not in conflict with the application but document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention earlier document but published on or after the international document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or involve an inventive step which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or ot'sr special reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled in the art. document published prior to the international filing date but document member of the same patent family later than the priority date claimed document member the same patent amily IV. CERTIFICATION Date of the Actual Completion of the International Search Date of Mailing of this International Search Report 27 DECEMBER 1988 16 FEB 1989 International Searching Authority Signature of Authorized Officer ISA/US NNCYA. B. SWT SFHPR Form PCTIISA/210 (second sheet) (Rev.11-87) that pH be controlled. The composition is simpler and I I I ii I International Application No. P T U 8 3 4 III, DOCUMENTS CONSIDERED TO BE RELEVANT (CONTINUED FROM THE SECOND -i"I-fET) Category Citation of Document, with indication, where appropriate, of the )levant passages Relevant to Claim No US, A, 4,689,218 PUBLISHED 25 AUGUST 1987 CCGAZZANIGA ET AL); SEE ENTIRE DOCUMENT. Form PCViISN21O (extra shed) (Rov.1 1-87)