ZA200407324B - Pharmaceutical compositions comprising terbutalineor salbutamol in combination with guaiphenesine. - Google Patents

Description

PHARMIACEUTICAL COMPOSITIONS COMPRISING TERBUTALINE OR SALIBUTAMOL IN COMBINATION

. WIT'H GUAIPHENESINE

BACKGROUND OF THE INVENTION

THIS invention relates to pharmaceutical compositions and t heir use in the symptomatic relief of cough and fiu.

Cough is a common symptom of coryza (common cold), croup, tracheobronchitis, pneumonia and influenza. The cause of the underlying disease is usually viral in origin however primary or secordary bacteria infections may arise. The majority of viral cases cam be treated symptomatically. Symptomatic therapy with the co-administration of antibiotics is used to treat patients with bacteria or mixed infections.

Cough is a protective reflex that can expel secretioms, exudates, transudates or extraneous materials from the respiratory tract. The mechanism of cough is complex. A number of treatment options are available depending on whether the cough is productive in mature or not.

When a cough is productive, it should rarely be suppressed (unless it is preventing rest, sleep or is exhausting the patient). The pharmacologically treatment of a productive cough usually makes use of one or more classes of drugs used alone or in combination. Expectorants, demulcents, decongestants, antihistamines, bronchodilators and muacolytics are frequently used. : More recently the clinical efficacy of these classes of drugs or combinations thereof when used to treat cough have come un der question. ) Drugs are frequently incorporated into a “cough mixture” at suib-therapeutic doses, which provide little or no proven benefit to patients. D ata suggests that decongestants, mucolytics and demulcents have little role to play in the symptomatic treatment of cough. Bronch odilators in cough associated : with bronchospasm, such as atropine, ephed rine and theophylline, are no longer considered safe due to their varied pharmacokinetics, addiction ’ potential and side effect profiles.

SUMMARY OF THE INVENTION

According to one aspect of the invention, a pharmaceutical composition comprises a combination of (i) a bronchodila tor selected from salbutamol and terbutaline, and pharmaceutically acceptable salts or derivatives thereof, and (ii) guaiphenesin, or a pharma ceutically acceptable salt or derivative thereof, and a pharmaceutically acc eptable carrier.

According to a further aspect of the irvention, a pharmaceutical composition comprises a combination of (i), (ii ) and (iii) an antihistamine, or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable carrier.

The invention extends to the use of either combination in a method of providing symptomatic relief of cough aredlor flu, in particular that associated with bronchoconstriction and mucous production.

The invention also extends to the use of a co mbination of (i) and (ii), or of (i), (i) and (iii), in the manufacture of a medicament for use in treating or preventing cough and/or flu.

The invention also extends to a method of treating or preventing cough : and/or flu, comprising administering to a patient in need thereof a combination of (i) and (ii), or of (i), (ii) and (iii).

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The pharmaceutical compositions of the invesntion are suitable for the ) symptomatic relief of cough and/or flu, including but not limited to that associated with bronchoconstriction and exceessive mucous production.

They can also be used in the treatment or preveantion of these illnesses.

The first ingredient is a bronchodilator sele-cted from salbutamol and terbutaline, and pharmaceutically acceptable salts or derivatives thereof.

Salbutamol, which is typically provided as itss sulphate salt, is a direct- acting symphathomimetic agent with predominaantly beta-adrenergic activity and a selective action on beta, receptors. It iss a bronchodilator indicated for conditions which result in bronchoconstrictiosn, and is used mostly in the treatment of bronchial asthma.

The salbutamol is provided in the composition in an amount such that the daily dose thereof is typically in the range of a bout 1 mg to about 30 mg, preferably about 4 mg to about 16 mg, expresssed in terms of salbutamol base.

Terbutaline, which is also typically provided ass its sulphate salt, is also a direct-acting sympathomimetic agent with actiors and uses similar to those of salbutamol. It is also used in the treatment of bronchial asthma.

The terbutaline is provided in the composition in an amount such that the daily dose of the terbutaline active ingredient is typically in the range of about 0.5 mg to about 5 mg given orally every 8 hours, preferably about ) 1.0 mg to about 3 mg, expressed in terms of terbutaline base. : The second ingredient is guaiphenesin or a p harmaceutically acceptable salt or derivative thereof. It is an expectorant thmat is reported to reduce the viscosity of tenacious sputum and is indicated for productive coughs.

: The guaiphenesin is provided in the composition in an amount such that the daily dose thereof is typically in the range of about 50 mg to about ’ 3500 mg, preferably about 200 ring to about 1600 mg.

A pharmaceutical composition comprising a combination of the above two ingredients includes a pharmace utically acceptable carrier and may include other necessary non-active excipients such as, for example, sorbitol, sucrose, water, alcohol, citric acid propylene glycol, polyethylene glycol, and xanthan gum. The pharmaceutical composition may be provided in any appropriate dosage form such as, for example, tablets, capsules, granules, suspensions, solutions or other liquid forms, and is intended for oral or intravenous administration. Such a pharmaceutical composition is provided for the symptomatic rezlief of cough, including but not limited to that associated with bronchoconstriction and mucous production.

The dosage form will typically be administered to a patient from 1 to 6 times per day.

A further pharmaceutical com position of the invention includes the abovementioned two active ingredients in combination with a suitable antihistamine or a pharmaceutically acceptable salt or derivative thereof.

Antihistamines dry up excessive mucous and some have a cough suppressant effect. Examples of suitable antihistamines include diphenhydramine, chlo rpheniramine, diphenylpyraline, dexchlorpheniramine, loratidine and cetirizine. Particularly preferred are diphenhydramine and diphenylpywraline. : The daily dose of the antihistamine will depend on the particular active ingredient chosen. In the case of diphenhydramine, the daily dose is : typically in the range of about 3.5 mg to about 200 mg, preferably about 7 mg to about 170 mg. When diphenylpyraline is incorporated into the pharmaceutical composition of the invention its daily dose is in the range of about 0.5 mg to about 50 mg, preferably about 1.25 mg to about 30 mg. ) A pharmaceutical composition comprising all three active ingredients in combination includes a pharmaceutically acceptable carrier and may also include other non-active excipients. Bt may be provided in any appropriate dosage form such as, for exarmple, tablets, capsules, granules, suspensions, solutions or other liquid forms, and is intended for oral or intravenous administration.

With the inclusion of an antihistamirme the pharmaceutical composition is provided for the symptomatic relief of cough and flu, including but not limited to that associated with bronchoconstriction and excessive mucous production.

The dosage form will typically be administered to a patient from 1 to 6 times per day.

Guaiphenesin produces its anti-tussiwe effect by decreasing the viscosity of bronchial secretions, thereby facilitati ng their removal. Expectorants of this type increase the amount of respiratory tract fluid, exerting a demulcent action on the mucosal lining. The effects of bronchospasm (tightness of chest, difficulty in breathing, wheeze etc.) are rapidly reversed by the action of bronchodilators. The antihistamines are intended to suppress the cough reflex, dry excess secretions and in some cases may produce sedation which will assist in the patient's rest and sleep patterns. The inventors tested the preparations on themselves and experienced relief from bronchoconstriction. Subjective feedback indicates that mucous ’ expectoration was enhanced. No adwerse effects were noted. ) The invention will now be descritbed, by way of example only, with reference to the following non-limiting examples.

Example 1 Sugar-Free Syrup

Approved Name Quantity Per 5mi ) Salbutamol Sulphate 241mg

Diphenhydramime HCI 12,5 mg

Menthol 0.60 mg

Method of Manufacture

Step | Action Required 1 Heat 4,5 | Purified Water to 58 °C — 62 °C in the steam kettle 50 and add the Polyvinylpyrrolidone K25 with continuous stirring.

Continue stirring until all dissolved. Add the Glycerin (Glycerol) with continuous stirring. 2 Add the Diphenhydramine HCI and Guaiphenesin to operation 1 with cont inuous stirring. Continue stirring until all dissolved. 3 Disperse the Xanthan Gum (Xantural 75) in the Propylene Glycol in the cortainer in which it was dispensed. Add the dispersion to the bulk with continuous stirring for 15 minutes. 4 In a sepa rate stainless steel container dissolve the Colour : Caramel 136 (WB) in 600 ml Purified water and add to the bulk with conti nuous stirring.

Add the Sorbitol 70% solution to the batch with continuous stirring .

Adjust thes pH of the bulk to 3,60 (3,36 - 3,80) with hydrochloric

Acid 32% . Add slowly to the bulk.

Dissolve Salbutamol Sulphate, Sodium Benzoate and Sodium i asaed nations as . stirring until all dissolved. Add to the bulk with stirring. 6 | Cool he bulk lo approsmately 25 °C with continuous siring.___

CC mmmmrmen stainless steel container. Add to the b ulk with continuous stirring. adjust with Hydrochloric Acid 32%.

Example 2 Soft Elastic Gelatin Capsule

Method of Manufacture

Sep [Actoneured

Example 3 Sugar-Free Syrup

Approved Name Quantity Per 5 ml

Salbutamol Sulphate 2,41 mg

Method of Manufacture

Step | Action Required 1 As per Example 1 above.

Example 4 Sugar-Free Syrup

Approved Name Quantity Per 5 ml

Terbutaline Sulphate 1,25 mg

Glycerol 2900 mg

Sorbitol 1000 mg

Method of Manufacture

Step | Action Required : 1 Heat 3,50 | Purified Water a nd Glycerol to 68 °C - 72 °C in the steam kettle and add the Polyvinylpyrrolidone K25 with stirring.

Continue stirring with the electrical mixer until all dissolved. 2 | Add the Guaiphenesin to step 1 with continuous stirring. Continue stirring with the electrical mixer until all dissolved and check clarity of syrup. 3 From this step the bulk must be stirred continuously with the electric mixer. Dissolve Sodlium Benzoate in Purified Water in a 500 ml glass beaker and mix for 10 minutes with the magnetic stirrer. Check clarity of solut@on before adding to the bulk.

Dissolve the Saccharin Sodi um in Purified Water in a 500 ml glass beaker and mix for 10 minutes with the magnetic stirrer. Check clarity of solution before add ing to the bulk.

In a 500 ml glass beaker, dissolve the Colour Caramel 136 (WB) in S00 ml Purified Water. Mix for 10 minutes with the magnetic stirrer before adding to the b-ulk. Check clarity of solution.

Disperse the Xanthan Gum i n the Propylene Glycol with a hand paddle in a 500 ml stainless steel container. Check complete dispersion of Xanthan Gum Before adding to the bulk.

Add Sorbitol 70% solution to the bulk. Check clarity of syrup 8 | Cool bulk to 25°C with contiruous stirring.

Dissolve Terbutaline Sulphate in Purified Water in a 500 ml glass beaker and mix for 10 minutes with the magnetic stirrer. Check clarity of solution before adding to the bulk.

Mix with the magnetic stirrer Flavour and Propylene Glycol in a 500 ml glass beaker for 10 minutes. Check clarity of solution before adding to the bulk. 11 | Check the pH of the bulk and adjust to pH 4,6 (4,4 — 4,8) with Acid

Citric Monohydrate solution

Stop stirring and make up to volume with Purified Water. 13 | Filter the product through a &0 micron filter bag into the 20 . stainless steel drum. Check filter bag for damage before use.

Check clarity of syrup after fiRtration.

Combinations of each of the active ingredients were combined with acceptable pharmaceutical carriers, ircluding formulations as shown in the above examples, and were expossed to International Conference of

Harmonization (ICH) Stability Test conditions. Samples thereof were ’ assayed by High Pressure Liquid Chromatographie (HPLC) methods. The samples complied with the tested parameters up tos a period of 6 months.

Although it is preferable that each of the active ing redients is provided in a therapeutic amount, it is envisaged that one or more of the ingredients may be provided in sub-therapeutic amounts, provided that the pharmaceutical composition is therapeutic.

Claims (17)

1. A pharmaceutical composition comprising a combination of a bronchodilator selected from salbutamol and terbutaline, or a pharmaceutically acceptable salt or derivative thereof, and guaiphenesin, or a pharmaceutically acceptable salt or derivative thereof, as active ingredients, and a pharmaceutically acceptable carrier.

2. A pharmaceutical composition according to claim 1, wherein the bronchodilator is salbutamol.

3. A pharmaceutical composition according to claim 1, wherein the bronchodilator is terbutaline.

4, A pharmaceutical composition according to any one of the preceding clairms, further comprising an antihistamine.

5. A pharmaceutical composition according to claim 4, wherein the antihistamine is selected from the group comprising diphenhydramine, chlorpheniramine, diphenyipyraline, dexchlorpheniramine, loratidine and cetirizine.

6. A pharmaceutical composition according to claim 5, wherein the antihistamine is diphenhydramine.

7. A pharmaceutical composition according to claim 5, wherein the antihistamine is diphenylpyraline.

8. A combinatiory of a bronchodilator selected from salbutamol and i terbutaline, or a pharmaceutically acceptable salt or derivative thereof, and gwaiphenesin, or a pharmaceutically acceptable salt or derivative thereof, as active ingredients, for use in a method of providing symptomatic relief of cough, comprising administering to a patient in need thereof a therapeu tically effective amount of the combination.

9. A combination according to clainm 8, further comprising an antihistamine, for use in a method of goroviding symptomatic relief of cough and/or flu, comprising administering to a patient in need thereof a therapeutically effective amount of the combination.

10. A combination according to claim 8 or claim 9, wherein the cough and/or flu is associated with bronchoconstriction and/or mucous production.

11. The use of a combination of a bronchodilator selected from salbutamol and terbutaline, or a pharrnaceutically acceptable salt or derivative thereof, and guaiphenessin, or a pharmaceutically acceptable salt or derivative thereof_ as active ingredients, in the manufacture of a medicament for wise in treating or preventing cough.

12. The use of claim 11, wherein the cornbination further comprises an antihistamine, in the manufacture of a medicament for use in treating or preventing cough and/or flu.

13. The use of claim 11 or claim 12, wherein the cough and/or flu is associated with bronchoconstriction a nd/or mucous production.

14. The use of any one of claims 11 to 8 3, wherein the composition is } provided in a dosage form selected from tablets, capsules, granules, suspensions, solutions and other liquid forms.

15. The use of claim 14, wherein the composition is formulated for oral or intravenous administration.

v

16. A pharmaceutical composition according to claim 1, substantially as herein described with reference to any ome of the illustrative examples.

17. A combination according to claim 8, substantially as herein described with reference to any one of the illustrative examples. Amended sheet 03/01/2006