Pharmaceutical preparations based on active ingredients susceptible to illicit administration

Field of the invention

0001The present invention relates to pharmaceutical preparations based on active ingredients susceptible to illicit administration.

Prior art

0002A plurality of active ingredients susceptible to illicit administration is known in the pharmaceutical field, e.g. those acting on the central nervous system and as narcotics. In relation to their specific activity, said active ingredients are classified e.g. as sedative, hypnotic, antipsychotic, antidepressant, tranquillising, and antimuscarinic agents.

0003For the patients' convenience and simplicity of administration, many of said active ingredients are marketed, in the form of pharmaceutical compositions adapted for oral administration, like e.g. tablets or capsules, whenever absorbability from the gastrointestinal tract and the resultant bioavailability of the so-formulated active ingredient are satisfactory. In fact, the possibility of modulating the active ingredient's pharmacokinetics by the use of excipients, coatings, by selecting the formulation procedures, such as for example micro- and nanoencapsulation, and by identifying a suitable crystalline or amorphous form, makes it possible to obtain a solid form of administration whereby most of said active ingredients can be administered by the oral way.

0004Unfortunately, however, the use of most of the aforesaid active ingredients is not only therapeutic, but also abusive or illicit. Out of the illicit uses, a distinction may be made between the voluntary illicit self-administration, e.g. by drug addicts, and the illicit administration to other people.

0005The illicit administration to other people is practised by criminals who exploit the narcotic effect produced by the active ingredient on the victim to commit further crimes against them or to induce drug addiction. By way of example, according to a piece of news dated June 27, 1998 and recently available on the internet <u>(http://www.corpus-delicti.com</u>), burundanga, a very potent form of scopolamine, has a dubious success in the criminal racket. Used for decades in Columbia by the native population in tribal rituals, even very small doses of the drug are reported to cause "submissive" behaviour in a victim, while larger doses cause instantaneous unconsciousness, followed even by complete amnesia.

0006While the strong hypnotic and amnesic effects of scopolamine have been exploited for quite a time, e.g. in California, by criminals to drug and rob their victims, the recent decrease in crimes is mostly to be attributed to the lower availability of preparations containing scopolamine on the black market, as other less hazardous active ingredients have displaced it for legitimate medical uses. In any case, the problem of illicit administration has become increasingly serious, as proved by the fact that the illicit use of burundanga accounts for more than half of emergency room admissions and for over 500 reported crimes per month solely in Columbia.

0007According to recent news, there has been increasing abuse--though to a lesser extent--of another active ingredient, i.e. flunitrazepam.

0008Although some pharmaceutical preparations produced and marketed by the industry necessitate medical prescription and medical supervision during administration, they are often available through criminal routes and, further to the natural extracts of dubious origin, they constitute a major source of active ingredients acting on the central nervous system and as narcotics for illicit use.

0009In practice, while all types of commercial-scale pharmaceutical preparations are suitable for voluntary abusive self-administration, their illicit administration to other people is mostly limited to "hidden" administration, i.e. without the knowledge of the victim. In particular, drugs for illicit administration are mostly in the oral, often solid, form and are introduced, often in high doses, into drinks or foodstuff.

0010Illicit administration seems to be a problem also in the world of professional sport. In particular, after the introduction of increasingly sensitive and stringent anti-doping controls, an increased number of sportsmen provide evidence of their being treated--without their knowing it--with anabolic agents or the like, suitable for enhancing their sportive performance and/or increasing the size of their muscles.

0011Even if the abusive or illicit administration of commercial drugs is beyond the pharmaceutical industry's control, any abuse of this type is clearly a serious ethical problem for manufacturers. Therefore, the need for oral pharmaceutical preparations unsuitable for illicit administration is deeply felt.

Summary

0012The above object and other objects --which will better appear from the following description―are met by a pharmaceutical formulation to be taken orally, preferably in the form of a soft capsule enclosing an active ingredient susceptible to illicit administration and a pharmaceutically acceptable organoleptic marker, particularly evident for its odour, taste or colour or for its scarce miscibility with food.

Detailed description of the invention

0013The illicit administration of active ingredients to other people is a serious crime. Unfortunately, there are many active ingredients susceptible to illicit administration; in fact, the effects they produce on the victims bring about criminal advantages to the suppliers. By way of example, mention is made of the substances acting on the central nervous system and/or as narcotics, the anabolic agents and the like. In any case, the present invention relates to all active ingredients susceptible to illicit administration.

0014Illicit administration of substances acting on the nervous system and/or as narcotics is practised by criminals to "drug" or even poison the victims and thus cause their losing consciousness, as well as by drug dealers to induce addiction in perspective "clients". By way of example, in the case of crimes of this type committed between relatives, the criminal subject sometimes enjoys the victim's confidence.

0015As concerns the illicit administration of anabolic agents or the like, criminal and victim are always bound by a well-established relation of trust, which may be viciously exploited by the criminal to manipulate food.

0016In both aforementioned cases, the pharmaceutical forms for oral administration obtained illicitly are mixed with food or drinks. In particular, the solid forms, such as tablets, are ground and dissolved in drinks or mixed with food, while the capsules (enclosing a liquid or a solid) are emptied and their contents are mixed with food or drinks. After said treatment, the drug added to food or drinks even in substantial amounts cannot be perceived by the victim. This is particularly true when the drug is mixed e.g. with a drink with a strong or anyhow unusual taste (e.g. an alcoholic cocktail given to a young victim), and when it is drunk in a dimly lit place, e.g. a discotheque. Consequently, the drug is taken up by the victim which remains unaware and does not notice anything suspicious with the such manipulated food.

0017To prevent such food manipulation, the present invention provides a pharmaceutical product for oral administration that contains, in addition to the active ingredient susceptible to illicit administration, one or more substances having evident organoleptic properties in aqueous or oily or alcoholic suspension/solution. Said substances, the so-called organoleptic markers, which make the illicit administration to victims impossible, must be perfectly edible and harmless in the proposed concentrations, and must not be perceived upon correct use of the drug. In particular, the organoleptic markers, besides being pharmaceutically acceptable, must be so incorporated into the oral pharmaceutical preparation that they become perceptible only upon illicit mixing with food and drinks.

0018Out of the active ingredients susceptible to illicit administration, those acting on the nervous system and as narcotics undoubtedly account for most abuses, whereas anabolic agents or the like seem to constitute a small-scale, but growing "market".

0019With regard to the active ingredients acting on the nervous systems and as narcotics, the present invention refers to all substances of the type susceptible to illicit use, if any. In particular, the present invention relates to sedative, hypnotic, antipsychotic, antidepressant, tranquillising, and antimuscarinic substances, in particular all substances depressing the central nervous system. By way of example, not of limitation, the present invention concerns the following openended listing of active ingredients and combinations thereof: abecarnil, acamprosate calcium, acepromazine (+maleate), aceprometazine, acetophenazine maleate, acetylglycinamide-chloralum, adinazolam mesylate, allobarbitone, aldipem, alprazolam, amisulpride, amylobarbitone (+sodium), aprobarbital, azaperone, barbitone (+sodium), benperidol, bentazepam, brallobarbital, bromazepam, bromisoval, bromperidol (+decanoate), brotizolam, buspirone hydrochloride, butalbital, butobarbitone, calcium bromolactobionate, camazepam, captodiame hydrochloride, carbromal, carpipramine hydrochloride, chloral betaine, chloralum, chloralose, chlordiazepoxide (+hydrochloride), chlorhexadol, chlormethiazole (+edisylate), chlormezanone, chloproethazine hydrochloride, chlorpromazine (+embonate and hydrochloride), chlorprotixene (+hydrochloride and mesylate), cinolazepam, clobazam, clocapramine hydrochloride, chlorazepine acid, (+potassium salts), clotiapina, clothiazepam, cloxazolam, clozapine, cyamemazine, cyclobarbitone (+calcium), delorazepam, detomidin hydrochloride, desmedetomidine, diazepam, dichloralphenazone, difebarbamate, droperidole, eltoprazine, enciprazine hydrochloride, estazolam, etclorvinol, ethyl loflazepate, etifoxine hydrochloride, etizolam, etodroxizine, febarbamate, fluanisone, fludiazepam, flunitrazepam, flupentixol decanoate (+hydrochloride), fluphenazine decanoate (+enanthate and hydrochloride), flurazepam, (+monohydrochloride and dihydrochloride), fluspirilene, gepirone hydrochloride, glutethimide, halazepam, haloperidol, haloxazolam, hexapropymate, hexobarbitone (+sodium), homofenazine hydrochloride, ibomal, ipsapirone hydrochloride, ketazolam, loprazolam mesylate, lorazepam, lormetazepam, loxapine, magnesium aspartate hydrobromide, medazepam, medetomidine hydrochloride, melperone hydrochloride, mephenoxalone, meprobamate, mesoridazine besylate, metaclazepam hydrochloride, methaqualone, methotrimeprazine, methylpentynol, mexazolam, midazolam (+maleate), molindone hydrochloride, moperone hydrochloride, mosapramine, nemonapride, nimetazepam, nitrazepam, nordazepam, olanzapine, oxazepam, ossazolam, oxypertine, paraldehyde, penfluridol, pentobarbitone (+calcium and sodium), perazine dimalonate, periciazine, perphenazine (+decanoate and enanthate), phenprobamate, pimozide, pinazepam, pipamperone hydrochloride, pipothiazine, prazepam, prochlorperazine (+edisylate, maleate and mesylate), prolonium bromide, promazine embonate, prothipendyl hydrochloride, proxibarbal, pyrithyldione, quazepam, quetiapine fumarate, quinalbarbitone (+sodium), raclopride, remoxipiride hydrochloride, risperidone, ritanserine, romifidine, secbutobarbitone (+sodium), sertindole, sulpiride, sultopride hydrochloride, suriclone, tandospirone citrate, temazepam, tetrabenazine, tetrazepam, thioproperazine mesylate, thioridazine, thiothixene (+hydrochloride), thiapride hydrochloride, timiperone, tofisopam, triazolam, triclofos sodium, trifluoperazine hydrochloride, trifluperidol (+hydrochloride), valnoctamide, veralipride, vinylbitone, zaleplon, ziprasidone, zolazepam hydrochloride, zolpidem tartrate, zopiclone, zotepine, zuclopenthixol (+acetate, decanoate, hydrochloride), atropine (+methobromide, methonitrate and sulphate), belladonna, benzhexol hydrochloride, benztropine mesylate, biperiden, bornaprine hydrochloride, butropium bromide, buzepide metiodure, cimetropium bromide, clidinium bromide, ciclodrine hydrochloride, cyclopentolate hydrochloride, darifenacin, desetimide hydrochloride, diclomine hydrochloride, diethazine hydrochloride, difemerine hydrochloride, dihexiverine hydrochloride, dimevamide, diphemanil methyl sulphate, drofenine hydrochloride, emepronium bromide (+carragenate), ethopropazine hydrochloride, eucatropine hydrochloride, fentonium bromide, flavoxate hydrochloride, flutropium bromide, glycopyrronium bromide, homatropine (+hydrobromide and methobromide), hioscine (+butylbromide, hydrobromide, methobromide and methonitrate), hiosciamine, hyosciamus, isopropamide iodide, mecloxamine citrate, mepenzolate bromide, methanthelinium bromide, metixene hydrochloride, metilbenactizium bromide, octatropine methylbromide, orphenadrine citrate (+hydrochloride), oxybutinin hydrochloride, oxyphencyclimine hydrochloride, oxyphenonium bromide, penthienate bromide, fenamazide hydrochloride, pipenzolate bromide, piperidolate hydrochloride, pipethanate ethobromide, pirenzepine hydrochloride, poldine methyl sulphate, pirifinium bromide, procyclidine hydrochloride, propanteline bromide, propiverine hydrochloride, stramonium, telenzepine, terodiline hydrochloride, tiemonium iodide, timepidium bromide, tolterodine tartrate, tridihexethyl chloride, tropatepine hydrochloride, tropicamide, tropine benzylate hydrochloride, valethamate bromide, xenytropium bromide, zamifenacin, amesergide, amineptine hydrochloride, amitriptiline, amoxapine, befloxatone, benactizine hydrochloride, brofaromine, buproprion hydrochloride, butriptylin hydrochloride, citalopram hydrobromide, clomipramine hydrochloride, clorgiline hydrochloride, demexiptiline hydrochloride, desipramine hydrochloride, dibenzepine hydrochloride, dothiepin hydrochloride, doxepin hydrochloride, duloxetine hydrochloride, etoperidone hydrochloride, femoxetine, fluoxetine hydrochloride, fluvoxamine maleate, imipramine, iprindole hydrochloride, iproniazid phosphate, isocarboxazid, lithium carbonate (+citrate), lofepramine hydrochloride, maprotiline hydrochloride, medifoxamine, melitracen hydrochloride, metapramine fumarate, mianserine hydrochloride, milnacipran, minaprine hydrochloride, mirtazapine, moclobemide, nefazodone hydrochloride, nialamide, nomifenisine maleate, nortriptyline hydrochloride, opipramol hydrochloride, oxaflozan hydrochloride, oxaprotiline hydrochloride, oxytriptan, paroxetine hydrochloride, phenelzine sulphate, pirlindole, pivagabine, protriptiline hydrochloride, quinupramine, reboxetine, rubidium chloride, sertraline hydrochloride, tianeptine sodium, tranylcypromine sulphate, trazodone hydrochloride, trimipramine (+maleate), tryptophan, venlafaxine hydrochloride, viloxazine hydrochloride, viqualine, zimeldine hydrochloride, alphadolone acetate, alphaxalone, eltanolone, etomidate, ketamine hydrochloride, methohexitone, propanidid, propofol, sodium oxybate, thiamilal sodium, tiopenthone sodium, tiletamine hydrochloride and others, identified e.g. in Martindale's Complete Drug Reference, Pharmaceutical Press, 1999.

0020As concerns active ingredients with anabolising activity or the like, the present invention relates to all substances susceptible to illicit use, if any. In particular, the present invention contemplates the substances suitable for enhancing the sportsmen's performance and/or increasing the size of their muscles, e.g. anabolising steroids. By way of example, not of limitation, the present invention concerns the following active ingredients and combinations thereof: testosterone, clostebole acetate, drostanolone propionate, estrapronicate, ethylestrenol, fluoximesterone, formebolone, mepitiostan, mesterolone, metandienone, metenolone acetate, methyltestosterone, nandrolone (+cyclohexylpropionate, decanoate, laurate, phenylpropionate, sodium sulphate and undecanoate), norethandrolone, oxabolone cipionate, oxandrolone, oxymetholone, stanozolol and trenbolone acetate and others, identified e.g. in Martindale's Complete Drug Reference, Pharmaceutical Press, 1999.

0021As concerns organoleptic markers, the present invention contemplates the use of one or more substances that, not withstanding their pharmaceutical acceptability , are particularly evident because of their odour or taste or colour or for their scarce miscibility with food. The preferred organoleptic markers according to the present invention are selected from the groups consisting of pharmaceutically acceptable hydrophilic flavouring agents, hydrophobic flavouring agents, hydrophilic colouring agents, hydrophobic colouring agents, odorants, flavours and scents (hydrophobic and hydrophilic) and oils. By way of example, not of limitation, the present invention concerns the following organoleptic markers and combinations thereof: <tables id="tabl0001" num="0001"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><tbody valign="top"><row rowsep="1"><entry namest="col1" nameend="col1" align="left"><u>Garlic (Allium sativum [Liliaceae])</u></entry><entry namest="col2" nameend="col2" align="left">As extract or one or more of its constituents:</entry></row><row><entry namest="col1" nameend="col1" morerows="3" /><entry namest="col2" nameend="col2" align="left">- Alliine</entry></row><row><entry namest="col2" nameend="col2" align="left">- Allicine</entry></row><row><entry namest="col2" nameend="col2" align="left">- Diallylsulphide</entry></row><row><entry namest="col2" nameend="col2" align="left">- Ajoene</entry></row><row><entry namest="col1" nameend="col1" align="left"><u>Aloe vera extract (Aloe barbadensis = Aloe vera,</u><u>Aloe capensis. Aloe ferox [Liliaceae])</u><u>Quinine sulphate/hydrochloride/bromohydrate</u></entry><entry namest="col2" nameend="col2" /></row><row><entry namest="col1" nameend="col1" align="left"><u>(Cinchona [Rubiaceae])</u></entry><entry namest="col2" nameend="col2" align="left">As extract or one or more of its components or quina extract as is</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Chili Pepper</entry><entry namest="col2" nameend="col2" align="left">pure, as extract or components thereof, in particular capsicine</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left"><u>Natural colouring agents:</u></entry><entry namest="col2" nameend="col2" align="left">E100, E101, E140, E160, E160a, E160b, E160c, E160d, E160e, E160f, E161, E161a, E161b, E161c, E161d, E161e, E161f, E161g, E162, E163, saffron</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left"><u>Sundry colouring agents:</u></entry><entry namest="col2" nameend="col2" align="left">E104, E110, E120, E122, E123, E124, E127, E131, E132, E141, E142, E150, E151, E153</entry></row></tbody></tgroup></table></tables>

0022Examples of pharmaceutically acceptable oils are soybean oil, refined palm oil, hydrogenated coconut oil, castor oil and cod-liver oil; whereas further organoleptic markers scarcely miscible with food and drinks include pharmaceutically acceptable fats and waxes.

0023Particularly preferred are all organoleptic markers perceived as "strange" by the victim as they have unusual odours/colours/flavours combinations, such as for example garlic/yellow/bitter or cheese/violet/pungent. As concerns the pharmaceutical formulations for oral administration, the present invention contemplates coated tablets and hard or soft capsules. In particular, the present invention relates to enteric forms or delayed release coated tablets and capsules as mentioned above.

0024In pharmaceutical practice and, in particular, within the scope of the present invention, by tablet it is meant a solid dosage unit containing the active ingredient together with excipients, which is compressed or formed into a flat or convex disk or into other suitable forms. Most tablets are designed to disintegrate soon after swallowing and, therefore, to release the active ingredient in the gastrointestinal tract for local or systemic effect by way of the active ingredient dissolution and absorption from the mucous membrane. Depot or delayed release tablets are formulated so that they release an initial dose of active ingredient and then slowly release the remainder over a prolonged period of time. Coated tablets are often used to protect the active ingredient from light, air and humidity and/or control the release of same or facilitate the tablet swallowing or improve its appearance.

0025In pharmaceutical practice and, in particular, within the scope of the present invention, by capsule it is meant a solid dosage unit that contains the active ingredient and excipients enclosed in a shell generally made of a gelatinous basis often containing a plasticizer, such as glycerol, in varying proportions depending on the desired capsule hardness. After decomposition from the gastrointestinal fluids, the active ingredient dissolution and absorption are generally faster from capsules than from tables. The so-called hard capsules are often cylindrical in shape and are used for solid formulations. In general, hard capsules are not airtight, i.e. the capsule cap and body are joined along the equatorial area. Conversely, the so-called soft capsules are airtight (being obtained e.g. from a single piece or from two halves sealed longitudinally) and are used to enclose liquid or semi-liquid pharmaceutical preparations. Enteric capsules are so treated that they pass through the stomach unaltered to be disintegrated in the intestines. Delayed release capsules may consist of hard capsules enclosing microcapsules containing the liquid or solid formulation of the active ingredient.

0026Within the scope of the present invention, the phrase "soft capsule" designates― indipendently from the amount of plasticizer present in the shell--all airtight capsules, i.e. suitable for enclosing liquid phases, even if not microencapsulated.

0027According to an embodiment of the present invention, one or more of the aforesaid organoleptic markers are incorporated into a pharmaceutical form for oral administration, e.g. a powder for filling saliva-resistant, preferably enteric, hard or soft capsules, or a powder for the production of tablets, subsequently coated to prevent their decomposition by contact with the saliva. In particular, the markers used are e.g. hydrophilic flavouring agents with a particularly bitter or unpleasant or pungent taste, preferably combined with hydrophilic colouring agents with a particularly strong and brilliant colour, unusual for foodstuffs, e.g. green, yellow, red, violet.

0028A further organoleptic marker that may be incorporated into the pharmaceutical preparations according to the present invention consists of unpleasant and disgusting odorants and scents, capable of vexing the smell. The odorants producing an unpleasant odour especially in the presence of alcohol are particularly preferred.

0029A still further organoleptic marker that may be incorporated into the pharmaceutical preparations according to the present consists of substances that are scarcely miscible with foodstuffs, in particular immiscible with non-strongly alcoholic drinks. Said organoleptic markers hinder the mixing of drugs with foodstuffs since they bring about the formation of biphase systems easily perceived by the victim. An example of an organoleptic marker that may be hardly mixed with foodstuff may consists of a fat, in particular of a lipidic substance.

0030A coated tablet or a hard or soft capsule is thus obtained which --upon grinding and especially upon mixing with food or drinks―by releasing of the organoleptic markers present therein produces a mixture which is practically inedible because of its taste or unpleasant or disgusting odour; or that, in any case―indicates to the victim, due to its taste or odour or to its unusual colour or appearance-- that the mixture has been manipulated. Especially when the manipulation of food or drinks with the pharmaceutical formulations of the invention results in the production of an unpleasant odour, the criminal may even desist from offering said mixture to the victim. Furthermore, unpleasant odour and/or taste may, within certain limits, act as a deterrent to abusive self-administration, especially when--as is often the case--a drug addict or a perspective suicide hopes to facilitate or speed up self-administration of a drug in very high doses, by using a drink as a vehicle.

0031According to a preferred embodiment of the invention one or more organoleptic markers as described above are enclosed in a soft capsule together with the active ingredient susceptible to illicit administration and a further organoleptic marker, particularly evident for its scarce miscibility with foodstuff. This last marker preferably consists of a pharmaceutically acceptable and edible oil, such as for example castor oil or cod-liver oil. In fact, due to the presence of an oily fraction, said pharmaceutical formulations, to be administered by the oral way, require the use of a soft capsule. In practice, the oily fraction, which may form stains on the surface of a non-strongly alcoholic drink, may act as a floating "buoy" warning the perspective victim against illicit manipulation.

0032Importantly, said preferred embodiment of the invention can be advantageously applied not only when the form of administration according to the prior art already consists of a hard or soft capsule, but also whenever the conventional form of administration consists of a tablet or pill or syrup, etc.

0033In particular, the soft capsules according to the invention, which enclose an active ingredient susceptible to illicit administration and an organoleptic marker immiscible with non-strongly alcoholic drinks, may also contain a combination of other hydrophilic and hydrophobic organoleptic markers.

0034According to a first particularly preferred embodiment of the present invention, soft capsules are provided that enclose an oily suspension comprising a liposoluble active ingredient dissolved in the oil, at least a first liposoluble organoleptic marker and at least a second water soluble organoleptic marker suspended in it.

0035Therefore, in the case of liposoluble (or in any case slightly water soluble) active ingredients susceptible to illicit administration, such as for example chlorpromazine, etclorvinol, flunitrazepam or some anabolising steroids, the soft capsule according to a particularly preferred embodiment of the present invention encloses an oil wherein the active ingredient, a first colouring agent and preferably a first hydrophobic flavouring agent have been dissolved. Furthermore, a second hydrophilic colouring agent with very high staining power, e.g. saffron, and preferably a second hydrophilic odorant and/or flavouring agent have been suspended in the oil enclosed in the soft capsule.

0036Consequently, the lipophilic active ingredient is entirely protected from illicit administration because: <ul id="ul0001" list-style="dash" compact="compact"><li>the soft capsule contents, once drawn by a syringe, are immiscible with drinks, with the exception of strong alcoholic drinks;</li><li>in particular, when the pharmaceutical capsule oily contents come into contact with a non-strongly alcoholic drink, a coloured oil stain with a disgusting taste (originated from the first hydrophobic organoleptic markers) forms on the drink surface;</li><li>furthermore, when trying to mix the resulting biphase system, the oily phase releases the second hydrophilic colouring agent (e.g. saffron) and optionally the second hydrophilic odorant and flavouring agent to the drink. As a result of the attempted illicit manipulation, the drink becomes undrinkable, even after removal of the unpleasant oily phase (and of the active ingredient);</li><li>conversely, in the case of strong alcoholic drinks, notwithstanding the probable active ingredient extraction from the oily phase and the at least partial solubility of the oily phase in strong drinks, the hydrophilic and hydrophobic organoleptic markers, used together, make the manipulated strong alcoholic drink taste unpleasant, even without formation of the biphase system;</li><li>furthermore, by way of the organoleptic markers contents of hydrophilic and hydrophobic nature, also the mixing of the oily phase enclosed in the capsule with solid foodstuff spoils taste of the food irreversibly.</li></ul>

0037According to another particularly preferred embodiment of the present invention, soft capsules are provided that enclose an oily suspension including a water soluble active ingredient suspended in the oil, at least a first water soluble organoleptic marker, and at least a second liposoluble organoleptic marker dissolved in the oil.

0038In fact, the formulations in the form of soft capsules enclosing organoleptic markers, scarcely miscible with foodstuff, are equally suitable for water soluble (or prevailingly water soluble) active ingredients susceptible to illicit administration, such as for example barbiturates, scopolamine, hioscine or various addition salts or active ingredient prodrugs. In this case, the soft capsule according to the present preferred embodiment of the invention encloses an oil wherein the hydrophilic active ingredient and a first hydrophilic colouring agent with very high staining power, e.g. saffron, and preferably a first hydrophilic odorant and/or flavouring agent have been suspended. The oil includes a second hydrophobic colouring agent and preferably a second hydrophobic flavouring agent, both being dissolved therein.

0039As in the case described above and despite the rather low extraction--upon illicit mixing--of the active ingredient from the oily suspension by any drink (indipendently from its alcohol content), the final drink--also after removal of the exhausted oily phase--is always perceptibly modified by at least some organoleptic markers (in particular, the hydrophilic ones and, in the case of strong alcoholic drinks, also the lipophilic ones) contained in the particularly preferred pharmaceutical composition of the invention. This obviously holds also for the mixture with solid food.

Experimental part

Examples:

0040As concerns coated tablets or hard capsules containing solid preparations, one or more solid organoleptic markers (or--in very small amounts--liquid) may be easily incorporated into known compositions, often without substantially modifying the formulation.

0041The following tables, given by way of illustration, show some liquid or semi-liquid formulations, possibly used in soft capsules according to the present invention: <tables id="tabl0002" num="0002"><img file="EP1273301A2_D0001.tif" /></tables><tables id="tabl0003" num="0003"><table frame="all"><tgroup cols="2" colsep="1" rowsep="0"><colspec colnum="1" colname="col1" colwidth="78.75mm" /><colspec colnum="2" colname="col2" colwidth="78.75mm" /><thead valign="top"><row rowsep="1"><entry namest="col1" nameend="col2" align="left">B: Contents of soft capsules enclosing oily organoleptic markers:</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Example 5</entry><entry namest="col2" nameend="col2" align="left">Example 6</entry></row></thead><tbody valign="top"><row><entry namest="col1" nameend="col1" align="left">Flunitrazepam</entry><entry namest="col2" nameend="col2" align="left">Scopolamine (or hyoscine)</entry></row><row><entry namest="col1" nameend="col1" align="left">Soybean oil</entry><entry namest="col2" nameend="col2" align="left">Soybean oil</entry></row><row><entry namest="col1" nameend="col1" align="left">Refined palm oil</entry><entry namest="col2" nameend="col2" align="left">Refined palm oil</entry></row><row><entry namest="col1" nameend="col1" align="left">Hydrogenated coconut oil</entry><entry namest="col2" nameend="col2" align="left">Hydrogenated coconut oil</entry></row><row><entry namest="col1" nameend="col1" align="left">Yellow bees-wax</entry><entry namest="col2" nameend="col2" align="left">Yellow bees-wax</entry></row><row><entry namest="col1" nameend="col1" align="left">Garlic oil (liposoluble)</entry><entry namest="col2" nameend="col2" align="left">Garlic oil (liposoluble)</entry></row><row><entry namest="col1" nameend="col1" align="left">Saffron (water soluble)</entry><entry namest="col2" nameend="col2" align="left">Saffron (water soluble)</entry></row><row><entry namest="col1" nameend="col1" align="left">Lecithin</entry><entry namest="col2" nameend="col2" align="left">Lecithin</entry></row><row><entry namest="col1" nameend="col1" align="left">Gelatin</entry><entry namest="col2" nameend="col2" align="left">Gelatin</entry></row><row rowsep="1"><entry namest="col1" nameend="col1" align="left">Glycerol</entry><entry namest="col2" nameend="col2" align="left">Glycerol</entry></row></tbody></tgroup></table></tables>