NZ239784A - Non-aqueous liquid pharmaceutical composition comprising histamine h2 antagonist and an edible oily vehicle - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £39784 2397 84 NEW ZEALAND PATENTS ACT, 1953 No.: XK/We, SMITHKLINE BEECHAM CORPORATION of 1 Franklin Plaza, Philadelphia, Pennsylvania 19101, United States of America, a corporation organized under the laws of the Commonwealth of Pennsylvania, one of the United States of America, hereby declare the invention, for which we pray that a patent may be granted to ix»e</usf and the method by which it is to be performed, to be particularly described in and by the following statement: - (followed by page la) - lct NON-AQUEOUS LIQUID ORAL SUSPENSIONS This invention relates to pharmaceutical compositions suitable for oral administration which comprise histamine H^-antagonists and result in an improved taste. Preferably, it relates to non-aqueous liquid oral suspensions which comprises cimetidine in an oily vehicle.

BACKGROUND OF THE INVENTION Cimetidine is a histamine ^-antagonist which has been used for a number of years in the treatment of duodenal, gastric, stomal and recurrent ulceration. It has also been employed for reflux oesophagitis and other conditions where reduction of gastric acid- has been shown to be beneficial for example, persistent dyspeptic symptoms with or without ulceration. Cimetidine is absorbed almost exclusively in the small intestine where liquid compositions could be absorbed more quickly and efficiently than tablets.

It is known that cimetidine has a very bitter taste and the majority of the oral compositions containing cimetidine are considered unpalatable. The unpleasant taste associated with cimetidine is much more noticeable in liquid oral compositions, particularly in aqueous vehicles. This has presented a major problem in the preparation of liquid oral compositions. There ► 1 has been a long standing need for an elegant, palatable liquid oral composition which will mask the unpleasant taste of cimeti di ne.

U.S. Patent 4,861,592 discloses aqueous buffered cimetidine suspensions as an approach to overcome the unpleasant taste of cimetidine. U.S. Patent 4,918,103 is representative of non-aqueous pharmaceutical vehicles employed to overcome stability problems associated with non steroidal anti-inflammatory drugs. U.S. Patents 4,639,367 and 4,752,465 disclose aerosol foams having the consistency of whipped cream employed as an alternative to liquid medicines having a bad taste. U.S. Patent 4,079,131 discloses anhydrous pharmaceutical vehicles employed to prepare permanent suspensions for water sensitive drugs.

DESCRIPTION OF THE INVENTION According to the present invention there, is provided a taste masked non-aqueous liquid oral pharmaceutical suspension which comprises a histamine H2-antagon1st, preferably cimetidine, in an edible oily vehicle. By employing a one phase oily vehicle, it was unexpectedly discovered that the unpleasant taste of cimetidine associated with aqueous liquid vehicles was significantly minimized.

The oily vehicle employed in this invention may be, for example, an edible vegetable oil such as soybean oil, partially hydrogenated soybean oil, corn oil, sunflower oil, or peanut oil. The synthetic edible oils which are commercially available and are equivalent to the vegetable oils may also be employed in this invention. For example, the triglycerides of the Cg-C1Q fatty acids of fractionated coconut oil which are available under the trade name of "Miglyol". Specifically, Mig1yol is a triglyceride of capric and caprylic acids with glycerol. The oils may also include sugar fatty acids known as "Olestras". * c ;V ;11 MAR 2994 ;A ;•Sj ««*- 8 <» • 1 The partially hydrogenated soybean oils are particularly preferred. A species of this group of edible vegetable oils is commercially available under the trade name of "Durkex". Most preferably, Durkex 25 is employed in the compositions of this invention.

The edible oil will be present in the non-aqueous pharmaceutical compositions of this invention in a range of from substantially 40% to substantially 90%, preferably from substantially 50 to substantially 80%.

The histamine ^-antagonist employed in the non-aqueous liquid suspensions of this invention may be for example, cimetidine, ranitidine, famotidine, nizatidine, etintidine, lupitidine, nifentidine, niperotidine, roxatidine, sufotidine, tuvatidine and zaltidine. Preferably, the ^-antagonist of this invention is cimetidine. It is well known that cimetidine can exist in at least five different polymorphic forms. Unless otherwise specified it is intended to include all polymorphs whether separated or mixtures thereof.

The H^-antagonist of this invention will be present in the non-aqueous suspension in a nontoxic but effective amount to produce systemically effective histamine ^-antagonistic activity. The suspension will contain from substantially 1.0% to substantially 12.0% W/V of the antagonist, preferably from substantially 4.0% to substantially 8.0% W/V.

The H^-antagonists are administered in conventional liquid dosage unit forms; preferably in teaspoon quantities. A teaspoon is equivalent to 5 ml. of the oral liquid composition.

The active ingredient, for example, cimetidine will normally be administered in an amount of from about 50 mg. to about 600 mg. per dosage unit, advantageously from about 200 mg. to about 400 mg. per dosage unit. Equal doses within the ranges given above will be administered preferably from about one to about four times a day.

Other histamine ^-antagonists, for example, those noted above, can also be present in the compositions of this 'N /' ^ O invention in a nontoxic but pharmaceutically effective amount. v 7 MAR "994 The concentration will vary with the ^-antagonist employed and the unit dosage required. The compositions will contain the ^-antagonist in an amount within dosage unit ranges which are well known to the medical art.

To further enhance the basic compositions of this invention other pharmaceutically acceptable additives well known to the art may be optionally added. Exemplary of these additives would be flavoring agents such as peppermint, vanilla, licorice, cinnamon, chocolate, spearmint or a combination of flavors; sweetening agents selected from aspartame, sodium cyclamate, calcium cyclamate or sodium saccharin; preservatives such as, for example, methylparaben, propylparaben, butylparaben, benzoic acid and sorbic acid; emulsifying and surface active agents selected from nontoxic anionics such as sodium lauryl sulfate, cationics such as benzalkonium chloride or a non-ionic agent such as polyoxyethylene sorbitan monopalmitate (Tween 40), sorbitan fatty acid esters, such as, sorbitan monopalmitate (Span 40) and natural emulsifiers selected from acacia, gelatin lecithin and cholesterol; antioxidants selected from butylated hydroxyanisole, butylated hydroxytoluene or tertiary butylhydroquinone; and thickening agents such as silicon dioxide (Syloid) or colloidal silicon dioxide (Cab-0-Sil).

These thickening agents may be present in an amount of from substantially 0.1% to substantially 5.0% of the composition.

Sugars such as, for example, mannitol, sorbitol, confectioners sugar, lactose, fructose and glucose may be employed as both thickening and sweetening agents. The sugars may be present in the nonaqueous compositions of this invention in an amount of from substantially 10% to substantially 40%.

The selection and amounts of the above pharmaceutically acceptable additives and their use in the nonaqueous compositions of this invention is within the skill of the pharmaceutical art except as specifically set forth herein. 2397 The compositions are prepared following the conventional techniques well known to those skilled in the art involving variously mixing, suspending and dispersing the ingredients as appropriate to give the desired composition.

The invention is further illustrated by the following examples which are not intended to be limited in scope.

Example 1 Inqredient 1 W/V Cimetidine 4.0 Confectioners Sugar NF 12X .0 Manni tol .0 Cab-O-Sil 0.2 Propylparaben 0.1 Tertiary Butylhydroquinone 0.02 Vani1 la Flavor 0.5 Peppermint Flavor 0.5 Partially Hydrogenated Soybean Oil (Durkex 25) q.s. 100.0 ml. 50 ml. of Durkex 25 was placed in a propeller mixer and the propylparaben was dissolved in the oil. The flavors and butylhydroquinone were then added to the solution followed by the other ingredients with moderate mixing until the mixture was smooth and homogenous. The remaining Durkex was added with .continued moderate mixing. The mixture was removed from the mixer and homogenized to a smooth consistency.

The formulations listed below were prepared following the procedure of Example 1.

Example 2 Ingredients 1 W/V Cimetidine 8.0 Mannitol 40.0 Aspartame 0.1 Cab-0-Sil 0.2 Propylparaben 0.1 Tertiary Butylhydroquinone 0.02 Vanilla 0.5 Peppermint 0.5 Durkex 25 q.s . 100.0 ml.

Example 3 Ingredients 7. H/V Ranitidine 4.0 Mannito1 40.0 Aspartame 0.1 Tertiary Butylhydroquinone 0.02 Cab-O-Sil 0.2 Propylparaben 0.1 Peppermint 0.5 Durkex q.s. 100.0 ml Cxampl e 4 6 7 8 9 Clutetldlne 4.0 4.0 4.0 4.0 4.0 8.0 Confectioners sugar NF .0 — .0 .0 — — Kannltol .0 40.0 — .0 40.0 40.0 Aspartame ~ 0.1 0.1 — 0. 1 0.1 Cab-O-SI1 0.2 0.4 — 0.2 0.4 0.2 Propylparaben 0.1 0. 1 — 0.1 0. 1 0.1 Tertiary Butylhydroqu1 none 0.02 0.02 — 0.02 0.02 0.02 Van II la 0.5 0.S — 0.5 0.S 0.5 Peppermlnt 0.5 0.5 — 0.5 0.5 0.5 0urk.e«, q.s. 100 ml 100 ml 100 ml 100 ml 100 ml 100 Ml to

Claims (10)

WHAT WE CLAIM IS:

1. A taste masked non-aqueous liquid pharmaceutical composition for oral administration comprising a nontoxic effective amount of a histamine H2-antagonist and an oily vehicle consisting essentially of partially hydrogenated soybean oil.

2. The composition according to Claim 1 wherein the H2-antagonist is cimetidine.

3. The composition of Claim 2 wherein the cimetidine is present in an amount of from substantially 1.0% to 12.0% W/V of the composition.

4. The composition of any one of Claims 1 to 3 wherein the oily vehicle is present in an amount of from substantially 40% to substantially 90% W/V of the composition.

5. The composition of any one of Claims 1 to 4 wherein the composition includes sugars selected from the group consisting of mannitol, sorbitol, lactose, fructose, sucrose or confectioners sugar.

6. The composition of Claim 5 wherein the sugar is present in an amount of from substantially 10% to substantially 40% W/V.

7. The composition of any one of Claims 1 to 6 which further includes a thickening agent.

8. The pharmaceutical composition of Claim 7 comprising from substantially 4.0% to substantially 8.0% of cimetidine, from substantially 10% to substantially 40% of mannitol, from substantially 0.1% to substantially 5% of colloidal silicon dioxide and from substantially 40% to substantially 90% of partially hydrogenated soybean oil.

9. The pharmaceutical composition of Claim 1 wherein the" 'a- < © histamine H2-antagonist is ranitidine. /"v ~i 1 MAR 1994; -8- 23 97 84

10. A composition according to Claim 1, substantially as hereinbefore described with particular reference to any one of the foregoing Examples 1 to 9. HA'HD THIS ^ DAY A. J. J3A R K & S0 N PER APFNT^ FOR TUC £jbm irAMTCf N.Z. P" 1 7 JAN 1994 RECEIVED ~