GB2162061A - Controlled time release therapeutic composition having means for counteracting overdosage - Google Patents

Abstract

The composition contains a therapeutic agent and an emetic or a purgative. The quantity of emetic or purgative is adjusted according to the quantity of therapeutic agent such that the emetic or purgative causes emesis or purgation of the therapeutic agent when excessive amounts of the agent are ingested. The availability of the therapeutic agent for absorption or local action is delayed, using a time delay material e.g. an enteric coating, beyond the time required for emesis or purgation so that the composition will be expelled from the body before the therapeutic agent begins to act in the event that excessive amounts of the composition are ingested.

Description

SPECIFICATION Controlled time release therapeutic composition having means for counteracting overdosage This invention is related to therapeutic compositions and more particularly to orally ingestible compositions with means to counteract the effects of overdosage.

Numerous investigations have been carried out in recent years on means for preventing accidental or intentional overdosage of therapeutic agents. Such investigation has been prompted by the many serious problems brought about by the use of medication in excess of the prescribed dosage.

Excessive use of tranquilizers, sedatives and stimulants for example may result in addiction or even death. Research has shown that a very high percentage of patients who take such medication do not follow the instructions received from their physician but take excessive doses.

Various means for preventing overdosage have been investigated. Certain derivatives of atropin are known td produce pronounced and quite unpleasant dryness in the mouth and throat and investigations have been made into the effect of prescribing certain tablets which contain such derivatives in controlled amounts in combination with various therapeutic agents. Such investigation has shown however that determined over-users of drugs, such as addicts, are not deterred by excessive dryness to the mouth and throat. In fact, addicts are able to develop a tolerance to the dryness. Suicidal patients likewise are not deterred from drug overdosage by excessive dryness to the throat.

Investigations have also been made into the effect of prescribing tablets containing combinations of therapeutic agents and an emetic drug. The quantity of the emetic is controlled such as to cause emesis when dangerous levels of medication are ingested.

Mixtures of this type containing ipecac as the emetic drug have been supplied under such trade marks as SED-EMS, (a capsule sold byWm. A. Spencer Inc., Chicago, U.S.A. and stated to contain 100 mg of pentobarbital sodium and 30 mg of powdered extract ipecac), EM KAPS (pentobarbital sodium and powdered extract ipecac), and EM TABS (phenobarbital plus powdered extract ipecac). The latter two preparations have been supplied by the Dahl Pharmaceutical Company of Minneapolis, U.S.A.

In December, 1949 the United States Council on Pharmacy and Chemistry gave consideration to a barbiturate-ipecac combination and concluded that such mixtures were objectionable on a number of grounds. One ground of objection was that emetics are relatively slow to act and toxic doses of barbiturates that are rapidly absorbed would probably narcotize the emetic centre before the emetic had a chance to act. Another ground of objection was that if the emetic were effective, vomitus might be aspirated into the bronchi of a partially narcotized patient and kill the patient rather than save his life.

According to the invention there is provided a delayed or time release therapeutic composition to counteract overdosage and for oral administration comprising: a therapeutic agent; an expelling agent in an amount which is adjusted according to the amount of therapeutic agent present in order to cause expulsion of the therapeutic agent from the body only if the quantity of therapeutic agent present in the body is in excess of that normally prescribed; and means for delaying the absorption or the local action of the therapeutic agent by the body beyond the time normally required for the expelling agent to cause expulsion of the therapeutic agent.

The invention provides a composition which contains a therapeutic agent and an expelling agent, and which is so formed that the availability of the therapeutic agent for absorption by the body or for local action is delayed a predetermined length of time. The expelling agent is present in such quantity as to cause a patient who ingests the mixture to expel the therapeutic ingredient from the body where the prescribed dosage is exceeded. By means of a delaying mechanism or delaying agent the availability of the therapeutic agent for absorption by the body or for local action is prevented until after the expelling agent has had sufficient time to act. The composition is accordingly expelled from the body where the prescribed dosage is exceeded and before the active ingredient has acted upon the body.

In one embodiment, the invention provides a therapeutic composition which may safely be prescribed to a patient who may be in a state of inebriation or of reduced awareness or judgment or who is confused. The expelling agent in such case is a purgative which unlike an emetic acts to expel the active ingredient of the composition, notwithstanding the condition of the patient and without the danger of blockage of the patient's bronchi byvomitus.

In general the therapeutic composition of the invention is suitable where immediate absorption or immediate local action of the therapeutic agent following ingestion is not required. In certain circumstances however the composition may be used in combination with other drugs so that the therapeutic effect is immediate. Such combinations are discussed below.

The active ingredient of the therapeutic composition may generally be a tranquilizer, sedative, stimulant or indeed any drug having a harmful untoward, undesirable or unwanted effect when ingested in excessive quantities. The term "therapeutic composition" is intended to cover all medical, pharmacological, or chemical compositions used for medical purposes.

In the event that the active ingredient is to be absorbed in the intestines, the ingredient must be treated in some way to prevent absorption in the stomach. The ingredient may for example be enteric coated for this purpose.

The therapeutic agent is combined with a controlled amount of an agent which serves to expel the therapeutic agent when the prescribed dosage is exceeded. The expelling agent may be one which produced emesis or may be a purgative. Emesis may be induced by coating the therapeutic agent with an emetic chemical by the method described in U.S. Patent No. 4,175,119 to Garry L. Porter which patent is incorporated into this application by reference.Emesis may also be induced by combining the therapeutic composition with an emetic drug such as syrup of ipecac, ammonium carbonate, sodium chloride, tarter emetic (antimony potassium tartrate), apomorphine, cupric sulfate, tarter emetic, zinc sulfate, blacks mustard, sanguinaria, copper sulfate, zinc sulphate, eucalyptole, eucalyptus oil, glycynhiza, guaiacol, lobelia, potassium iodide, senege terebene, terpin hydrate, thyme and any of the emetic chemicals enumerated in the aforementioned U.S. Patent No.

4,175,119.

Drugs suitable as purgatives include phenolphthaline, bisacodyl, oxyphenisatin acetate, danthron, dioctyl sodium sulfosuccinate, psyllium hydrophilic mucilioid, plantago, methylcellulose, phenolphthalein, lactulose syrup, magnesium sulphate solution, poloxalkol, dioctyl calcium sulfosuccinate, sennosides A & B, castor oil and casanthranol. The suitability of any given purgative will depend upon many factors such as the side effects of the drug, the time required for the drug to act and so on. For example, some purgatives produce an allergic reaction and are not suitable for use in conjunction with therapeutic drugs which are to be taken frequently. Other purgatives are relatively slow to act and these drugs are suitable for use with active ingredients which need not begin to act until long after the patient has ingested them.

As previously indicated the quantity of emetic or purgative combined with the therapeutic composition is controlled such that the emetic or purgative causes emesis or purgation of the therapeutic composition only when excessive amounts of the therapeutic composition are ingested. The quantity required for this purpose is well known to those skilled in the medical arts.

Means is required to delay the action of the active ingredient beyond the time required for emesis in cases where overdosage is to be counteracted by the use of an emetic or beyond the time required for purging of the intestines in the case where overdosage is to be counteracted by the use of a purgative. Various different methods are known to delay the interval between ingestion of a therapeutic agent and its availability for absorption by the body or for local action. One of these comprises chemically aitering a given therapeutic agent to such a degree that its absorption by the body or its availability for local action is sufficiently delayed.

Sustained release compositions of sulfonamide and sustained release compositions of insulin are examples of drugs produced by this method.

Another method for delaying the availability of a drug for absorption or for local action involves mechanically mixing the drug with a therapeutically inert auxiliary ingredient. The active therapeutic ingredient in the resulting mixture remains chemically unchanged but its availability for absorption or for local action is delayed by physical means. Such mixtures are generaliyformed into so called sustained release tablets or pills.

There are other methods of delaying the action of a therapeutically active ingredient. In U.S. Patent No. 2,805,977 to M. J. Robinson & E. V. Suedres which patent is incorporated into this application by reference, a suspension of a sustained release medicament is described in which finely powdered medicament is dispersed in a time delay material which is resistant to disintegration in the gastrointestinal tract and which slowly disintegrates. Other methods for the manufacture of pharmaceutical tablets or pills with sustained release action of the therapeutic ingredient have been described in the literature. Reference may be had, for example, to "Sustained Release Pharmaceuticals" a book by Alec Williams and published by Noyes Development Corporation.This book describes techniques for producing sustained release medications including those in which the active therapeutic ingredient is sandwiched between various layers of an inert auxiliary ingredient. In the latter case the active ingredient is not exposed until the outer layer of inert ingredient is dissolved and dissolution occurs slowly. The Williams book also contains a description of an enteric coated pill in which the core comprising the active ingredient is simply coated with a protective substance which is not dissolved by the gastric fluid.

This latter form is used for those active ingredients which are intended to pass through the stomach nearly unchanged and to be released gradually in the intestines.

In cases in which the active ingredient is to be released in the intestines, the expelling agent may be a purgative which causes evacuation of the active ingredient from the intestines before the ingredient has an opportunity to act. Alternatively, the expelling agent may be an emetic in which case the active ingredient may be enteric coated to prevent dissolution in the stomach while the emetic is uncoated and freely dissolves in the stomach. The latter composition may take the form of composite particles of which the therapeutically active ingredient forms the core, the material which prevents breakdown of the active ingredient in the stomach forms an intermediate layer and the emetic forms an outer layer. When such composite particles reach the stomach, the outer layer causes emesis if the prescribed dosage of the active ingredient is exceeded. If the dosage is not exceeded, the emetic but not the active ingredient dissolves in the stomach, the active ingredient being protected by the enteric intermediate layer until the active ingredient reaches the intestines.

Any of the foregoing techniques for delaying the availability of the therapeutic agent for absorption or for local action permit close control of the interval of time between ingestion and availability for action.

Whatever technique is chosen, the time interval must be controlled so that absorption or local action does not occur until after the emetic or purgative has had sufficient time to act. In the case of a pill or capsule containing an emetic for example, usually about one half hour is required for complete emesis and, accordingly, the therapeutic agent must not be released until at least one half hour after the capsule or pill is ingested.

As indicated previously the composition of the invention may not be suitable in cases in which immediate absorption or immediate local action by the therapeutic agent is required. However, in cases in which the composition is required for continuous action over a period of time, then a small amount of the active ingredient, free of the release-retarding mechanism or agent, may be incorporated into the composition for absorption or local action immediately after ingestion. The patient will accordingly receive the benefit of the active ingredient soon after ingestion and will continue to be benefited until the last of the active ingredient is expended. Such a composition of course carries with it the riskthat if taken in sufficient quantity the portion of the active ingredient which is free for immediate absorption or local action may cause harm.

Claims (12)

1. A delayed release therapeutic composition to counteract overdosage and for oral administration comprising: a therapeutic agent; a pharmaceutically useful agent in an amount which is adjusted according to the amount of therapeutic agent present in order to cause expulsion of the therapeutic agent from the body where the quantity of therapeutic agent present in the body is in excess of that normally prescribed but not where the quantity of therapeutic agent is less than normally prescribed; and time delay material for delaying the absorption or the local action of the therapeutic agent beyond the time normally required for the expelling agent to cause expulsion of the therapeutic agent.

2. A delayed release therapeutic composition to counteract overdosage and for oral administration comprising: a therapeutic agent; a pharmaceutically useful emetic drug in an amount which is adjusted according to the amount of therapeutic agent present in order to cause emesis only if the quantity of therapeutic agent present in the body is in excess of that normally prescribed but not where the quantity of therapeutic agent is less than that normally prescribed; and time delay material for delaying the absorption or the local action of therapeutic agent beyond the time normally required for absorption of the emetic drug.

3. A delayed release therapeutic composition to counteract overdosage and for oral administration comprising: an enteric coated therapeutic agent; a pharmaceutically useful purgative agent in an amount which is adjusted according to the amount of therapeutic agent present in order to cause purging of the intestines only if the quantity of therapeutic agent which is present in the body is in excess of that normally prescribed but not where the quantity of therapeutic agent is less than that normally prescribed; and time delay material for delaying the absorption or the local action of therapeutic agent beyond the time normally required for purging by the purgative agent.

4. A delayed release therapeutic composition as claimed in either of Claims 1 and 2 wherein said composition is in the form of composite particles having an enteric coated core composed of said therapeutic agent; and an outerlayer composed of an emetic drug.

5. A delayed release composition comprising: an ingestible agent; a pharmaceutically useful agent in an amount which is adjusted according to the amount of ingestible agent present in order to cause expulsion of the ingestible agent from the body only if the quantity of ingestible agent present in the body is in excess of that normally prescribed but not where the quantity of ingestible agent is less than that normally prescribed; and time delay material for delaying the absorption or the local action of the ingestible agent beyond the time normally required for the expelling agent to cause expulsion of the ingestible agent.

6. A method of production of a delayed release therapeutic composition comprising the steps; providing a pharmaceutically useful therapeutic agent; combining said therapeutic agent with pharmaceutically useful expelling agent in an amount which is adjusted according to the amount of said therapeutic agent present in order to cause expulsion of said therapeutic agent from a body only if the quantity of said therapeutic agent present in the body is in excess of that normally prescribed but not where the quantity of therapeutic agent is less than that normally prescribed; and treating said therapeutic agent in order to delay the absorption or the local action thereof by the body beyond the time normally required for the expelling agent to cause expulsion of the therapeutic agent.

7. A method as claimed in Claim 6 wherein said expelling agent is an emetic.

8. A method as claimed in Claim 6 wherein said expelling agent is a purgative.

9. A method of inducing emesis of a therapeutically active ingredient of the type which if ingested by prescription is safe but if excessively ingested is unsafe comprising the steps of: a. combining the therapeutically active ingredient with a pharmaceutically useful emetic chemical in amount such that emesis occurs only if normally prescribed dosage of the therapeutically active ingredient is exceeded; b. treating the therapeutically active ingredient in order to delay the absorption thereof by the body beyond the time required for the emetic chemical to cause emesis; c. ingesting a quantity of the composition of step bin excess of that normally prescribed; d. emesis of the ingested quanity of the composition of step b in order to render the therapeutically active ingredient harmless.

10. A method of inducing purging of a therapeutically active ingredient of the type which is ingested by prescription if safe but if excessively ingested is unsafe comprising the steps of: a. coating the therapeutically active ingredient with a drug which protects the therapeutically active ingredient from dissolution in the stomach but which permits dissolution thereof in the intestines; b. combining the coated therapeutically active ingredient with a pharmaceutically useful purgative in amount such that purging occurs only if normally prescribed dosage of the therapeutically active ingredient is exceeded; c. treating the therapeutically active ingredient in order to delay the absorption thereof by the body beyond the time required for the purgative to cause purging; d. ingesting a quantity of the composition of step c in excess of that normally prescribed; ; e. purging of the ingested quantities of the composition of step cto renderthe therapeutically active ingredient harmless.

11. A delayed release therapeutic composition as defined in claim 1 substantially as herein described.

12. Each and every novel compound, composition, process and method substantially as herein described.