AU758880B2

AU758880B2 - Timed release tablet comprising naproxen and pseudoephedrine

Info

Publication number: AU758880B2
Application number: AU89198/98A
Authority: AU
Inventors: Chris Platt
Original assignee: Individual
Current assignee: Individual
Priority date: 1998-08-25
Filing date: 1998-08-25
Publication date: 2003-04-03
Anticipated expiration: 2018-08-25
Also published as: CA2341485A1; EP1107740A4; JP2002523358A; EP1107740A1; MXPA01001969A; AU8919898A

Description

WO 00/10537 PCT/US98/17625 TIMED RELEASE TABLET COMPRISING NAPROXEN AND PSEUDOEPHEDRINE BACKGROUND OF THE INVENTION The present invention relates generally to novel pharmaceutical compositions of matter comprising the non-steroidal anti-inflammatory analgesic naproxen in combination with the decongestant pseudoephedrine and appropriate non-toxic carriers and to methods of using said compositions in the therapy or cure of sinusitis, or sinus headaches, generally exemplified by discomfort, pain, pressure, and dizziness.

Non-narcotic analgesics, commonly known as non-steroidal antiinflammatory drugs, such as naproxen, are widely administered orally in the treatment of mild to severe pain. These drugs have been disclosed as useful in treating cough/cold symptoms in combination with certain antihistamines and decongestants. See, for example U.S. Pat. No.

4,552,899 to Sunshine.

Naproxen as non-steroidal anti-inflammatory pain reliever has greater advantage than other pain relievers acetaminophen, aspirin, and ibuprofen. Naproxen has a significantly greater duration or half-life that II I 2 leads to twice a day dosage. It is generally accepted that decreased dosing leads to patient convenience and better compliance.

Originally combinations of anti-inflammatories and anti-histamines or decongestants were combined with no consideration to the vastly different drug duration or half-lives. These drugs with different half-lives were not combined in a synergistic manner which led the body effectively using them at equal rates. This would lead to ineffective combinations of anti-inflammatories and decongestants and the return of partial symptoms.

SUMMARY OF THE INVENTION Accordingly, in a first aspect, the present invention consists in a pharmaceutical composition having a first part provided to dissolve immediately in gastric fluids to provide an immediate release of first part active ingredients for treating sinusitis and sinus headaches, said first part active ingredients comprising naproxen and pseudoephedrine, each combined with or without a base salt, said naproxen having a S 15 known half-life; and a second part provided as a specific timed release of second part active ingredients comprising pseudoephedrine combined, with or without a base salt, for continuing said treating of sinusitis and sinus headache with said first part naproxen, said second part also including pharmaceutically acceptable excipients for effecting the timed release of said second part pseudoephedrine to continue to interact with said naproxen over the duration of the half-life of said naproxen.

In a second aspect, the present invention consists in a pharmaceutical composition having a first part including naproxen and pseudoephedrine, each being combined with or without a base salt, as the active ingredients for treating sinusitis and sinus 25 headaches provided to dissolve immediately in gastric fluids to provide immediate release of said first part naproxen and pseudoephedrine, said first part active ingredients including from 50mg to 500mg of said naproxen, 15mg to 120mg of said pseudoephedrine, and at least 10mg of a solution of hydroxypropylcellulose and polyethylene 30 glycol; and a second part containing pseudoephedrine combined with or without a base salt as the active ingredient for a timed release to continue said treating of sinusitis and sinus headaches with said first part naproxen and pharmaceutically acceptable excipients for effecting the time release of said second part pseudoephedrine, said second part active ingredient and pharmaceutically acceptable excipients including from 15mg tol20mg of said pseudoephedrine, at least 140mg microcrystalline cellulose, 2mg to 15mg providone or corn starch, at least 40mg of a solution of hydroxypropylmethylcellulose or hydroxypropylcellulose and polyethylene 30 glycol and 6mg to 11.75mg magnesium stearate, boric acid or sodium benzoate, wherein said time-release of said second part active ingredient is provided for the duration of said half-life of said naproxen.

It is a preferred feature of the present invention to provide a novel timed-release pharmaceutical composition of matter comprising an analgesically effective amount of naproxen and an effective amount of decongestant pseudoephedrine with pharmaceutically acceptable excipients.

It is a further preferred feature of the present invention that administration of our specific ratio of composition optimizes the most effective drug level of both drugs in the body over time for relief for nasal sinus congestion that causes headache pain, pressure, dizziness, and general malaise.

Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.

9 WO 00/10537 PCTIUS98/17625 3 DETAILED DESCRIPTION OF THE INVENTION More specifically, the applicant herein has found that a timed-released combination product suitable for oral administration comprising naproxen and pseudoephedrine combined with or without an appropriate base salt.

Through studying extensively the applicant has found that the preferred dosage form that provides for immediate release of naproxen and pseudoephedrine, and specific timed release of pseudoephedrine.

The release of naproxen and pseudoephedrine takes place together up to 12 hours, preferably 10 hours. One or two tablets are administered orally, preferably two. Concentration ranges for the active ingredients are naproxen, 50-500 mg per tablet; pseudoephedrine 30- 240 mg per tablet.

The concentration ranges represent 7- 30% of coated tablet weight of pseudoephedrine and 15- 60% of naproxen.

The preferred dosage form is a coated tablet, wherein naproxen and pseudoephedrine are on the outer coating thus released immediately while pseudoephedrine in the core is released over time, preferably over the duration of the half-life of the naproxen, approximately 10 hours. The outer-coating dissolving rapidly to release both naproxen and pseudoephedrine and the inner core dissolves slowly to time release pseudoephedrine through hydration and diffusion of the drug from the core polymer.

The dosage range for naproxen is from 50-800 mg per day depending upon pain management requirements. The range of pseudoephedrine is between 30-240 mg per day depending blood pressure values and overall health of the patient. Both drugs will vary depending upon the age and weight of the patient, the le-ity of the symptoms and the incidence of side effects for humans.

The core consists of common hydrophilic swellable polymers such as 25 hydroxypropylmethylcellulose (HPMC) or hydroxypropylcellulose either by themselves or in combination with each other. The hydrated polymers *0 .act as a binder that swells when hydrated by gastric media and delays 0* absorption. The combination of polymers will represent about 15% of tablet core weight. The tablet outer coating comprises HPMC and a plasticizer such as polyethylene 30 gly.l (PEG) both which dissolve 15 immediately in gastric fluids. Suitable coloring and flavoring agents may be included.

The tablet core also comprises excipients such as polymers, fillers, binders, lubricants, and antiadherents, all necessary for standard tablet manufacture. Binders are present at a concentration of 5% and typically are starch, gelatin, natural or artificial gums. Fillers are present at a WO 00/10537 PCT/S98/1 7625 concentration of about 10 to 20% of tablet core weight and may include starches or cellulose. Antiadherents used to prevent tablets from sticking to the tablet press typically include silicas and talc, are present from 0 to 6% of the tablet core weight. Typical lubricants are magnesium stearate, boric acid, or sodium benzoate at a concentration of about 2.5% to 5% of the tablet core weight. Additional binders used in the granulation of the drug polymer mixture include povidine and corn starch. Such binders are present at a concentration of about to 3% of the tablet core weight.

The means of preparing compositions of the present invention, e.g.

tablet mixing, compaction, and coating are all well known to those skilled in the art.

EXAMPLE I Mg/tablet A. Core Tablet Pseudoephedrine Sulfate Microcrystalline Cellulose 140 Povidone HPMC/PEG Magnesium Stearate B. Outer Coating Naproxen 100 Pseudoephedrine Sulfate HPMC/PEG wn nOn/i n17 Prn/i T1 9/11'7 I v 1v 6 It^fl I A Method of Manufacture A. Outer Coating 1. Dissolve HPMC/PEG in an alcohol mixture.

2. Disperse Naproxen and Pseudoephedrine in the HPMCIPEG solution.

3. Coat inner tablets below with the solution using standard procedures.

B. Inner Core 1. Mix pseudoephedrine sulfate, microcrystalline cellulose and HPMC.

2. Dissolve povidone in an alcoholic mixture and use it to crystallate the powder mix.

3. Dry pseudoephedrine sulfate crystalate mix.

4. Compress into tablets.

While the invention is described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes or modifications can be made therein without departing from the spirit of the invention For example, effective dosages of the active ingredients other than the preferred ranges set forth hereinabove may be used. It is intended that the invention be limited only by the scope of the claims that follow.

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Claims

1. A pharmaceutical composition having a first part provided to dissolve immediately in gastric fluids to provide an immediate release of first part active ingredients for treating sinusitis and sinus headaches, said first part active ingredients comprising naproxen and pseudoephedrine, each combined with or without a base salt, said naproxen having a known half-life; and a second part provided as a specific timed release of second part active ingredients comprising pseudoephedrine combined, with or without a base salt, for continuing said treating of sinusitis and sinus headache with said first part naproxen, said second part also including pharmaceutically acceptable excipients for effecting the timed release of said second part pseudoephedrine to continue to interact with said naproxen over the duration of the half-life of said naproxen.

2. The pharmaceutical composition of claim 1 wherein said first part active ingredients comprise 50mg to 500mg of naproxen and from 15mg to 120mg of pseudoephedrine, and said second part active ingredients comprise from 15mg to 120 mg of pseudoephedrine. o.

3. The pharmaceutical composition of claim 1 wherein said first part naproxen comprises from 50mg to 500mg of naproxen and said first part and second part pseudoephedrine comprise from 30mg to 240mg of pseudoephedrine.

4. The pharmaceutical composition of any one of claims 1, 2 or 3 wherein said pharmaceutically acceptable excipients are selected from the group comprising microcrystalline cellulose, providone or corn starch, hydroxypropylmethylcellulose or hydroxypropylcellulose and polyethylene 30 glycol, and magnesium stearate, boric acid or sodium benzoate. 25

5. The pharmaceutical composition of claim 4 wherein at least one of the selected excipients comprise 140mg of microcrystalline cellulose.

6. The pharmaceutical composition of claim 4 wherein at least one of the selected excipients comprise 2mg to 15 mg providone or corn starch.

7. The pharmaceutical composition of claim 4 wherein at least one of the selected excipients comprise 40mg of a solution of hydroxypropylmethylcellulose or hydroxypropylcellulose and polyethylene

8. The pharmaceutical composition of claim 4 wherein at least one of the selected excipients comprise 6mg to 11.75mg magnesium stearate, boric acid or sodium benzoate.

9. The pharmaceutical composition of claim 4 wherein said pharmaceutically acceptable excipients comprise from 15mg to 120mg pseudoephedrine sulfate, 140mg microcrystalline cellulose, 2mg to 15mg providone or corn starch, 40mg of a solution of hydroxypropylmethylcellulose or hydroxypropylcellulose and polyethylene glycol, and 6mg to 11.75mg magnesium stearate, boric acid or sodium benzoate.

A pharmaceutical composition having a first part including naproxen and pseudoephedrine, each being combined with or without a base salt, as the active ingredients for treating sinusitis and sinus headaches provided to dissolve immediately in gastric fluids to provide immediate release of said first part naproxen and pseudoephedrine, said first part active ingredients including from 50mg to 500mg of said naproxen, 15mg to 120mg of said pseudoephedrine, and at least 10mg of a solution of hydroxypropylcellulose and polyethylene 30 glycol; and a second part containing pseudoephedrine combined with or without a base salt as the active ingredient for a timed release to continue said treating of sinusitis and sinus headaches with said first part naproxen and pharmaceutically acceptable excipients for effecting the time release of said second part pseudoephedrine, said 15 second part active ingredient and pharmaceutically acceptable excipients including from 15mg tol20mg of said pseudoephedrine, at least 140mg microcrystalline cellulose, 2mg to 15mg providone or corn starch, at least 40mg of a solution of hydroxypropylmethylcellulose or hydroxypropylcellulose and polyethylene 30 glycol and 6mg to 11.75mg magnesium stearate, boric acid or sodium benzoate, wherein said time-release of said second part active ingredient is provided for the duration of said half-life of said naproxen.

11. A pharmaceutical composition prepared by the process of preparing an inner tablet core by mixing pseudoephedrine sulfate, microcrystalline cellulose and hydroxypropylmethylcellulose into a crystallate powder 25 mix; drying the crystallate powder mix; compressing the dried crystallate powder mix into tablets; preparing an outer coating solution for the tablets by dissolving hydroxypropylmethylcellulose and polyethylene 30 glycol in an alcohol mixture; and coating the inner dried crystallate tablets with the outer coating solution.

12. A method for treating sinusitis consisting of administering a timed-release pharmaceutical composition of claim 1 to a patient at intervals from 10 to12 hours.

13. A method for treating sinusitis consisting of administering a timed-release pharmaceutical composition of claim 10 to a patient at intervals from 10 to12 hours

14. Use of a timed-release pharmaceutical composition of claim 1 for the manufacture of a medicament for the treatment of sinusitis.

Use of a timed-release pharmaceutical composition of claim 10 for the manufacture of a medicament for the treatment of sinusitis.

16. A pharmaceutical composition substantially as hereinbefore described with reference to the example. Dated this 23rd day of January 2003 Chris Platt Patent Attorneys for the Applicant: F B RICE CO