Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – N-c doai
Patent
1998-02-03
2000-06-13
Cook, Rebecca
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
N-c doai
A61K 3127
Patent
active
060750480
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a new pharmaceutical formulation and to its manufacture and use. It also relates to a new pediatric use of bambuterol.
Bambuterol, and its pharmaceutically acceptable salts, is known as a bronchodilator from EP 43807. Bambuterol is sold under the Trade Mark Bambec.RTM. in the form of tablets of its hydrochloride salt. Bambuterol is a pro-drug of the adrenergic selective .beta..sub.2 -receptor agonist terbutaline and is slowly metabolised in the body to active terbutaline.
There has been, and continues to be, an increase in the incidence of asthma amongst children. The administration of drugs to children, e.g. by way of inhalation or by means of tablets and capsules which are to be swallowed, can be difficult as the children, and especially younger children, do not always, or readily, co-operate. Furthermore some other patients find that a tablet is difficult to swallow, and if the tablet is chewed the drug in it can produce a bitter taste. Thus patient compliance when a tablet is prescribed is not always good.
We have now found that bambuterol can be formulated and administered in a more convenient form than a tablet.
Thus according to the invention we provide an aqueous formulation of bambuterol, or of a pharmaceutically acceptable salt thereof, wherein the formulation has a pH in the range 3.7 to 4.2.
We prefer the formulation to be adapted to be administered by swallowing.
We prefer the bambuterol to be in the form of its hydrochloride salt. The formulation is preferably a solution and preferably contains from about 0.5 to 5, e.g. about 1.0 mg, of bambuterol, measured as the hydrochloride, per ml.
The density of the formulation is preferably between about 1.03 and 1.09 g/ml.
We also prefer the pH of the formulation to be about 3.9. The pH of the formulation may be adjusted to the desired range or value by means of a suitable buffering agent, e.g. citric acid and if necessary sodium hydroxide. The skilled person will readily be able to find the appropriate quantity of buffering agent necessary to achieve the desired pH, but in general this will be in the range 3.0 to 5.0, e.g. about 4.0 mg/ml of citric acid, and from 0.4 to 0.8, e.g. about 0.6, mg/ml of sodium hydroxide.
The formulation may also contain a sweetening agent, e.g. sorbitol and/or glycerol, or a glucose polymer, for example that known as Lycasin.RTM.. The proportion of sweetening agent in the formulation will depend on the particular sweetening agent(s) used, but should be sufficient, together with any flavouring agent which is used, to cover the bitter taste of the bambuterol. We prefer the sweetening agent not to be such as to encourage dental caries. We prefer the formulation to contain from 100 to 200 mg, more preferably about 150 mg, per ml of sorbitol. We also prefer the formulation to contain from 75 to 125 mg, and more preferably about 100 mg, of glycerol per ml.
The formulation may also, e.g. when it is to be put up in a multi-dose form, contain a preservative, e.g. sodium benzoate. The preservative should be present in such a quantity as to produce a satisfactory preservative effect during its expected period of use. Thus we prefer the formulation to contain from 0.75 to 1.25 mg, and more preferably about 1.0 mg, per ml of sodium benzoate.
We have surprisingly found that the narrow pH range of the formulations according to the invention gives the optimal combination of stability of the active agent and of preservative action.
We have found that certain flavouring agents are incompatible with the desired formulation and/or with the containers to be used for the formulation. Suprisingly however we have found that no such incompatibilty exists when essence of blackcurrent is used. The essence of blackcurrent contains natural and synthetic flavours (which are identical to the natural flavours) in propylene glycol as solvent.
The unit and daily dosage of bambuterol to be used will depend on the patient and the type and severity of the condition to be treated.
One would expect that the dosage required for a chil
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Berglund et al., "Screening chemical and physical stability of drug substances" Journal of Pharmaceutical & Biomedical Analysis 8:639-644 (1990).
Sitar et al., "A Placebo-controlled Dose-finding Study With Bambuterol in Elderly Patients With Asthma," Chest 3:771-776 (1993).
Clemmensen et al., "Bambuterol: clinical effects of three doses of bambuterol once daily in asthmatic patients," Allergy, 43:573-576 (1988).
McDonald, et al., "Comparison of Oral Bambuterol and Terbutaline in Elderly Patients with Chronic Reversible Airflow Obstruction," Journal of Asthma, 34:53-59 (1997).
Annefors Staffan
Bauer Carl-Axel
Nilsson Hans
Astra Aktiebolag
Cook Rebecca
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