AU684888B2 - Method and compositions for noninvasive dose to effect administration of lipophilic drugs - Google Patents

Description

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AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STAN~DARD PATENT Applicant(s): UNIVERSITY OF UTAH RESEARCH FOUNDATION Invention Title: METHOD AND COMPOSITIONS FOR NONINVASIVE DOSE TO EFFECT ADMINISTRATION OF LIPOPHILIC DRUGS S. op

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4 p The following statement is a full description of this invention, including the best method of performing it known to me/us: 2 i. The Field of the Invention The present invention is related to methods and compositions for use in delivering pharmacological agents to a patient. More particularly, the present invention is directed to methods and compositions for the noninvasive administration of precisely the proper dose of potent pharmacological agents having antiemetic properties.

This application is divided from our copending applications 50352/90 (645966) and 59127/94, the specifications of which are herein incorporated by reference.

2. The Prior Art In recent years, a host of potent new drugs have become available for clinical use in treating migraine headaches, nausea, vomiting, asthma, respiratory distress, polyuria, Parkinson's disease, systemic or oral fungal infections, esophagitis or heartburn, symptoms of diabetes, post partum and post abortion hemorrhage, and for inducing labor at term, stimulating uterine contraction during labor, or inducing abortion. Current expectations are that additional potent drugs will continue to become available in the future.

In addition to treating specific diseases and conditions, physicians can prescribe drugs that will permit the physician to regulate many body functions and processes. Yet, despite the tremendous advances in the 25 field of pharmacology, physicians continue to administer these new drugs using substantially the same techniques that have been employed for many decades.

Thus, almost all pharmacological agents continue to be administered via two routes, by oral administration 30 for absorption through the stomach or intestines or by intramuscular or intravenous injection, despite the fact I- I-CI-l 3 that both of these routes suffer from significant disadvantages under typical situations.

The simplest and most prevalent administration route is oral administration. To use this method, a pharmacological agent is incorporated into a tablet, a capsule, or into a liquid base; the patient then ingests an appropriate dose. Oral administration of a drug is extremely convenient, and for many drugs, it will continue to be the method of choice. Such administration is nonthreatening and is painless to the patient. For most patients, it is also very simple.

Nevertheless, oral administration of a drug suffers from the disadvantage that pediatric and geriatric patients frequently have difficulty swallowing pills, and such patients often refuse to cooperate in swallowing a liquid medication. Even more importantly, absorption of a drug into the bloodstream after swallowing a tablet varies from patient to patient and in the same patient from time to time. The, -absorption of the drug is dependent upon the movement from the stomach to the small and large intestines and the effects of secretions from these organs.

Moreover, there is often a substantial delay between the time of oral administration of a drug until it begins to have the desired therapeutic effect on the patient's system. Generally, a drug must pass from the stomach into.

the small and large intestines before it will be absorbed into the patient's bloodstream; unfortunately, this typically takes forty-five minutes or longer. For some applications, such a delay is unacceptable.

Further, many drugs taken orally are metabolized almost immediately they are removed from or rendered ineffective by the patient's system before they can have any. therapeutic effect. This occurs because the veins from the stomach and the small and large intestines drain into

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4 the liver. Thus, drugs entering the patient's bloodstream through the stomach and the intestines immediately pass through the patient's liver before distribution throughout the remainder of the patient's body.

Unfortunately, upwards of sixty percent of a drug (and essentially one hundred percent of certain drugs) may be removed from the patient's bloodstream during this first pass through the liver. Therefore, when utilizing oral administration, much larger doses of the drug than would otherwise be necessary must be administered to the patient to compensate for the large percentage of the drug removed during the first pass through the liver and obtain the desired effect in the patient.

Adverse reactions from the large doses necessary to elicit a systemic or local effect despite metabolism by the liver include nausea, vomiting, involuntary movement, gastrointestinal bleeding, duodenal ulcers, and epigastric abdominal distress. Other dose-related side effects may adversely affect renal and hepatic functions, especially in the geriatric patient. Some drugs, if present in the liver in excess, may also be hepatoxic.

The result is that the oral route of administration is inefficient for many drugs, particularly many antimigraine, 40 antiemetic, hypoglycemic, brochodilator, oxytocic, anti- 5 Parkinsonian, antidiuretic, antifungal, or antisecretory acting drugs.

In some instances, a dose approximately one hundred times the actual effective dose must be administered o othe patient in order to retain a sufficient dose of the drug in the blood after the first pass through the liver. Thus, oral administration results in a highly inefficient use of the drug. Further, in addition to the other adverseeffects resulting from large amounts of the drug being removed by the liver, oral administration is also disadvantageous because of the cost in providing such a large dose of the drug.

A yet further difficulty encountered when administering drugs orally is that dosages are prepared or determined for use with an "average" patient. This is entirely acceptable for many drugs, but some 'drugs have a widely varying effect on different patients, even when weight and size differences between patients are considered. The effects of these drugs can vary depending upon the patient's habits, subtle genetic differences between patients, the patient's blood volume, the patient's age, and numerous other known and unknown individual variations in susceptibility to the particular drug 40 *40 utilized.

Underdosing a patient because of a low susceptibility to the drug fails to evoke the response sought by the physician. Overdosing the patient can result in dangerous depression of vital body functions. Moreover, the slow and uncertain response time for the onset of an observable 50 reaction to a drug when taken orally makes it even more difficult to determine a proper dose for a particular patient. The physician may not learn for an hour, or with some drugs for a few days, whether the patient was underdosed or overdosed.

i 6 In order to avoid these serious disadvantages inherent in the oral administration modality, physicians frequently resort to the injection modality for administering many drugs. Injecting a drug (generally intravenously or intramuscularly) results in rapid entry of the drug into the patient's bloodstream; in addition, this type of delivery avoids the removal of large quantities of the drug by the patient's liver that accompanies oral administration.

Rather, the drug becomes rapidly distributed to various portions of the patient's body before exposure to the liver; thus, the drug is removed by the liver at a substantially slower rate.

Most patients have at least some aversion to receiving injections. In some patients, particularly children and certain "high strung" adults, this aversion may be so pronounced as -to make the use of injections of serious concern to the physician. Since intense psychological stress and anxiolysis can exacerbate a patient's debilitated condition, it sometimes becomes undesirable to use injections where the patient is seriously ill or :suffers from a debilitating condition or injury.

To compound the problem facing a physician, the individual variation in susceptibility and metabolism with 40 respect to various drugs, which makes it difficult to select an appropriate dose for oral administration, is even more profound when utilizing the injection modality of 45 administration. This is because smaller doses have an increased effect due to the rapidity with which the drug enters the bloodstream and because large doses of the drug, when injected, are not immediateiy metabolized by the liver.

In order to prevent overdosing a patient with potent drugs, a prudent physician typically injects a patient with 55 a lower than average dose, and later supplements the dose i 7 with additional injections as they appear necessary. This "titration" makes necessary the use of repeated injections, which in turn greatly increases the stress on the patient.

It is not uncommon for a patient to come to fear that it is time for yet another injection every time the patient sees a member of the hospital staff, which is often the case for those most in need of potent drugs.

In view of the foregoing, it will be appreciated that it would be an important advancement in the art of administering drugs if suitable methods and compositions could be provided for administering drugs in order to provide for rapid onset of the desired action and precise dosage delivery in each patient so as to avoid the dangers of overdosage and underdosage.

It will also be appreciated that it would be an important advancement in the art of administering drugs if suitable methods and compositions could be provided that avoid immediate metabolism of the drug through the patient's liver and yet not involve injection of the drug.

It would be an additional important advancement if methods and compositions could be provided that would permit a physician and/or a patient to easily control the amount of the drug the patient receives according to the patient's own subjective need for medication.

25 Such methods and compositions and disclosed and I. :claimed herein.

BRIEF SUMMARY AND OBJECTS OF THE INVENTION The present invention is directed to novel methods and compositions for use in administering antiemetic drugs.

The present invention is capable of introducing the drug into the patient's bloodstream almost as fast as an injection and staff/hronrkeep/specUTAH.LIPOPHLIC 14.2 8 much faster than by oral administration. Yet, the delivery modality is non-threatening, painless, and minimises the dangers of overdosing and under-dosing.

These significant advantages are achieved by incorporating into a candy matrix a drug or combination of drugs capable of being absorbed through the mucosal tissue found in a patient's mouth, pharynx, and esophagus. The resultant mixture is then advantageously formed into a lollipop, which, as discussed in greater detail hereinafter, can be administered in a dose-to-effect manner to achieve a systemic effect on the patient.

Even patients that have difficulty swallowing a pill or tablet or refuse to swallow a pill, tablet, and/or a liquid, will give little resistance to sucking on a lollipop. Particularly when dealing with children, a lollipop evokes pleasurable response in the patient and gives the patient something non-threatening on which to concentrate.

An antiemetic drug administered by way of a lollipop will quickly enter the patient's bloodstream through the veins which serve the mucosal tissues in the mouth and pharynx, thereby serving to further lessen any remaining tension and fear. Appropriate monitoring of the patient's reaction to these potent drugs will indicate when 25 the drug has evoked a suitable response. The lollipop may then be removed, or its rate of consumption may be decreased.

It will be appreciated that the ever-present risk of overdosing a patient is substantially minimised, if not almost eliminated, by the dose-to-effect administration method of the present invention. The rate at which the stafhrorlkeepspeclUTA.LIPOPHILIC 14.2 -I I r I 9 drug is to be absorbed by the body can be varied by varying the rate the lollipop dissolves.

Accordingly, the drug dose is given over a period of time rather than all at once (as in a pill or other bolus injection), and the administration rate can be reduced if such appears necessary. If a patient begins showing signs of any overdose, he will simply stop sucking the lollipop and/or the physician can easily remove the lollipop from the patient's mouth.

Unlike the use of injections or oral ingestion of medication where a relatively large bolus dose of medication is given intermittently, use of a lollipop can permit the patient to take very small doses of a drug on an almost continuous basis. Moreover, such administration can be regulated in response to the patient's own need for medication in light of his own subjective experience and his own personal susceptibility to the particular drug utilised. The result is that lower amounts of drugs can be used to achieve a more even medication of the patient.

It is, therefore, a primary object of the present invention to provide non-invasive methods and compositions :4 capable of rapidly inducing an antiemetic effect through the dose-to-effect administration of appropriate drugs without the dangers of overdosage or underdosage.

25 It is another important object of the present invention to provide methods and compositions that would allow for more physician control over the administration of antiemetic drugs so that individual patient differences in susceptibility and metabolism can be taken into account.

Yet another primary object of the present invention is to provide methods and compositions for drug administration which minimise the psychological trauma generally associated with injections and the adverse staWhron'keeplspecilUTAH.LIPOPHILIC 14,2 -LI III 10 physical and psychological problems often associated with the oral administration of potent drugs.

Yet another primary object of the present invention is to provide methods and compositions that will permit a patient to control the amount of medication administered according to the individual variations in the susceptibility to the particular medication used and in response to the patient's subjective experience of vomiting, nausea, etc.

These and other objects and features of the present invention will become more fully apparent from the following description and appended claims.

DETAILED DESCRIPTION OF THE INVENTION As discussed above, the present invention is directed to methods and compositions for use in the noninvasive administration of antiemetic agents.

Advantageously, the present invention permits exceptional control over the effect of the drug administered, despite individual susceptibility to and metabolism of that drug by the patient.

While maintaining the convenience of oral administration, the present invention provides for many of the advantages of the injection modality of drug administration. At the same time, the present invention 25 avoids the disadvantages identified above with respect to these two traditional routes of administration. The present invention achieves these results by utilising yet a third administration route absorption through the mucosal tissues in the mouth and around the pharynx and 30 esophagus.

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stafvhrorkee9/sped/UTAH.LIPOPHUC 14,2 L--l 11 A very few drugs, such as nitroglycerine, have historically been administered by absorption through mucous tissue because the transmucosal route is faster than oral administration, and unlike injections can be easily selfadministered. While such drugs are easily given by the transmucosal route, they have not, unfortunately, been given by a dose-to-effect method. In dose-to-effect drug administration, the drug is administered until a predetermined effect is obtained; thereafter, the administration process is modified or terminated. By contrast, the prior art has consistently utilised the procedure of administering a bolus of the drug.

Despite some limited use, the transmucosal route has not been favoured for routine use. Instead, where a delay in drug action is acceptable, the oral route has been preferred by most physicians, and injections have been used where delay is not acceptable.

Transmucosal dose-to-effect delivery of a drug is somewhat slower to provide active concentrations of a drug in a patient's system than is the use of an intravenous injection. Nevertheless, it has been discovered that the 909. transmucosal route can be adapted so that any loss in the 6. speed of drug uptake is more than offset by the ability to administer the drug non-invasively (much to the 25 appreciation of the patient) and by the ability to control the dose received by the patient vis-a-vis the effect of the drug.

A drug must be lipophilic in order to be absorbed across mucosal tissue. However, this requirement is not a serious limitation since a large number of drugs are naturally lipophilic or can be provided in a lipophilic form.

In accordance with the present invention, a suitable drug is dispersed within a carbohydrate mass or other suitable matrix in the form of a lollipop.

stalhronkeeplspovlUTAH.LIPOPHILIC 14.2 12 The drug-containing lollipop is then given to a patient to suck on so that the drug will be released into the patient's mouth as the carbohydrate mass or compressed powder matrix dissolves. Being lipophilic, a significant portion of the drug is absorbed into and/or through the mucosal tissues of the mouth, pharyngeal, and oesophageal areas. The drug rapidly enters the patient's bloodstream, and importantly, the blood in the veins draining from the mouth and the pharyngeal and oesophageal areas passes through the central nervous system and then through a substantial portion of the body (so that the drug can be absorbed) before the blood passes through the liver (where most of the drug is inactivated). In case of a localised effect, the drug quickly contacts the affected area in order to provide effective relieve as soon as possible, while minimising the amount of the drug administered to the patient.

The use of a carbohydrate matrix "candy") to administer a drug offers some important advantages, particularly when dealing with paediatric patients. First, a candy lollipop is familiar and lack the menace of a syringe and needle. Being a substance normally associated with pleasure, the drug-containing candy lollipop immediate evokes a positive psychological response.

a 4 *o o* stat~hrorvkaepoeUd/UTALIPOPHILIC 14.2 13 Importantly, it has been found that the use of drug-containing candy in the form of a lollipop can permit the physician to control the dosage of the drug administered to the patient in order to relieve nausea, vomiting and the like thereby resulting in dose-to-effect drug administration. Use of such drug-containing lollipops also permits the patient in certain circumstances to exert control over the dosage of certain medication in order to diminish feelings of discomfort or pain.

These important advantages are available because very small amounts of a potent drug may be delivered to a patient substantially continuously, and administration of the drug may be halted at any time by simply removing the candy from the patient's mouth. This not only allows a physician to monitor a patient's condition so that a particular effect is obtained and maintained, but also provides the important safety benefit of reducing the risk of overdose.

It is much less likely that a patient receiving medication in accordance with the dose-to-effect method of the present invention will become overdosed since the dose builds relatively slowly until a desired effect is achieved. Further, if a patient becomes slightly overdosed, it is likely that the patient will stop sucking 25 the drug-containing lollipop and/or the physician or other medical personnel will observe the situation and remove the lollipop before the patient becomes seriously overdosed.

In contrast, once a typically large dose of a -drug is given orally, by injection, or even sublingually or nasally, there is no retrieving it; thus, the full effects staffhror/keeplspedclTAH.LPOPHILIC 14.2 14 of the administered drug will be felt. Further, a large dose given every few hours results in wide swings in plasma concentration of the drug, while the use of a lollipop in accordance with the present invention evens out the plasma concentration of that drug.

In practice, a physician can offer the patient a piece of medicated candy on a holder, together with simple instructions that the candy is to be sucked rather than chewed. Children will particularly be put at ease by this approach but so will anxious adults. The physician can then monitor the patient's condition to ensure the desired effect is achieved.

As mentioned above, it is preferred that the medicated candy take the form of a lollipop. Use of a s. 15 stick or other suitable holder permits easy removal of the candy when a physician deems that a patient has received a proper dosage of the drug contained therein. Provision of a suitable holder also facilitates intermittent administration of a drug to maintain a desired condition and makes it more convenient for a patient to intermittently self-administer the drug in response to variations in the patient's subjective perception of physiologic condition.

The speed at which a sufficient amount of drug enters the patient's bloodstream so as to produce a desired effect depends on several factors. For example, a very potent antiemetic drug requires fewer drug molecules to enter the patient's system than does a weak drug to produce a desired effect.

Additionally, the degree of lipophilicity of a drug directly affects the rate of absorption of the drug.

A highly lipophilic drug will result in the more rapid onset of a desired patient response than will a more moderately lipophilic drug. It will be appreciated, however, that other pharmacokinetic properties of a drug will affect the rate at which the effect of the drug is stafhror1oep/specUIUTAH.LIPOPHIUC 14.2 15 observed in the patient.

The choices of matrix and the concentration of the drug in the matrix are also important factors with respect to the rate of drug uptake. A matrix that dissolves quickly will deliver drug into the patient's mouth for absorption more quickly than a matrix that is slow to dissolve. Similarly, a candy that contains a drug in a high concentration will release more drug in a given period of time than a candy having a low drug concentration.

It will be appreciated that varying the concentrations of the drug in the matrix or the properties of the matrix (particularly the rate at which the matrix dissolves) can be advantageously used in designing specific compositions for specific uses. A lollipop containing meclizine of a given concentration may be used to relieve nausea, while a lollipop having a stronger concentration (and preferably a different colour so as to prevent confusion) may be used when it is desired to relieve 20 vomiting or emesis.

Another use of these properties is to prepare a multi-layer lollipop where the outer layer is of a concentration differing from that of the inner layer. Such a drug delivery system has a variety of applications. By way of example, it may be desirable to quickly get a predetermined dose of a drug into the bloodstream to obtain a desired effect and then use a different concentration to maintain the effect.

The choice of a particular carbohydrate matrix is subject to wide variation. Conventional sweeteners sulch as, sucrose or corn syrup may be utilised, or carbohydrates suitable for use with diabetic patients, such as sorbitol or mannitol might be employed. Other sweeteners, such as aspartame, can also be easily incorporated into a composition in accordance with the present invention. The candy base may be very soft and fast-dissolving, or may be stafUhronfi eep/specUTAH,LIPOPHILIC 14.2 I 16 hard and slower-dissolving. Various forms will have advantages in different situations.

It will be appreciated that all suitable antiemetic drugs are within the scope of the present invention bearing in mind that drugs are relatively high melting points may be prepared in the more traditional hard candy form. Typical examples illustrating the method of preparing a hard candy matrix are given herein below.

Example 1 The candy matrix or base for the drug-containing lollipop within the scope of the present anvention is advantageously prepared utilising candy preparation formulas and techniques which are known in the prior art.

For example, a hard candy base is prepared by dissolving S 15 grams of sucrose in 50 grams of water and heating the solution to about 240 0 F. Next, about 40 grams of corn syrup having a dextrose equivalent of 42 units, and a high maltose content (30%-35% maltose) is added, and the mixture is cooked at about 300°F to reduce the water content to 20 about three percent After recooling the thickened candy mass to about 240 0 F, a suitable oil flavouring lemon or cherry) is added.

Concurrently, a solution containing a soluble drug is prepared for incorporation into a candy matrix.

A suitable solution of an antiemetic drug, such as meclizine, is prepared by dissolving the drug in a suitable solvent. The solution is mixed with 32 cubic centimeters of the hot candy mass formed as set forth above, and the resultant mixture is gently mixed as it cools to about 225 0 F, taking care not to induce formation of air bubbles in the candy mass.

The solution is then poured into suitable moulds having a 2.0 cubic centimeter capacity that have been prelubricated with vegetable oil to prevent sticking. A four inch commercially available wax-coated compressed statvhror'keepIpecVUTAH.LIPOPHILIC 14.2 17 paper stick is next inserted into the base of each mould.

The mixture is then permitted to set.

The foregoing procedure results in the preparation of 20 lollipops.

Example 2 A drug-containing lollipop within the scope of the present invention to be used in the treatment of nausea and vomiting is made according to the procedure of Example 1, except that the ingredients are combined in the following amounts: Ingredients Grams SNatural mint 1.0% 0.2 Ribotide 1.5% 0.3 Aspartame 2.0% 0.4 15 Meclizine 2.5% Wild Cherry 3.0% 0.6 Compritol 888 4.0% 0.8 Artificial vanilla 5.0% SArtificial vanilla cream 5.0% Compressed sugar 25.33% 5.07 Maltodextrin 50.67% 10.13 The foregoing procedure results in the preparation of lollipops, each containing 50 milligrams of meclizine.

***.*Example 3 In the procedure of this example, a patient who is presently experiencing nausea and vomiting is given a :meclizine-containing lollipop in order to rapidly relieve the nausea and vomiting. In this example, meclizine in a lollipop dose of 50 milligrams is used. As the patient sucks on the lollipop, the distress associated with nausea and vomiting is eliminated.

Although the above discussion focused on the antiemetic agent meclizine, it will be appreciated that other antiemetic agents may also be utilised within the scope of the present invention. What is important is that atafihrorlkeoplspciIUTAH.LIPOPHILC 14.2 I ecar~orrrr~-~a~l 18 the antiemetic agent be lipophilic, potent, and fast-acting so that the desired effects can be observed by the medical professional or by the patient himself, if the drug is to be self-administered, in sufficient time to remove the lollipop from the patient's mount in time to prevent overdosing.

In incorporating a drug into a lollipop within the scope of the present invention, the amount of the drug used will generally differ from the amount used in more traditional injection and oral administration techniques.

Depending upon the lipophilic nature of the drug, its water solubility, its potency, and its end use, the total concentration of the drug in a typical lollipop may contain Sfrom one to fifty times the amount of the drug which may be S 15 used in an injection.

However, for purposes of example, Table I sets forth presently contemplated ranges of the dosages of certain drugs which would typically be used.

Table I 20 Antiemetic Drug Generic Lollipop Dose Range Benzquinamide 25-100 milligrams Meclizine 25-100 milligrams Metoclopramide 5-20 milligrams 25 Prochlorperazine 5-25 milligrams Trimethobenzamide 100-2500 milligrams Droperidol 1-5 milligrams Some of the more important features and advantages of the present invention as applied to the above drug class will be better appreciated and understood by reference to the specific discussion below: Antiemetic Agents Nausea and vomiting may occur independently of each other, but generally they are so closely related that they can be considered together. Nausea denotes the feeling of statvhrontkoopispedJUTA.LIPOPHIUC 14.2 19 the imminent desire to vomit, while vomiting refers to the forceful oral expulsion of gastric contents. Nausea often precedes or accompanies vomiting and is usually associated with diminished functional activity of the stomach and alterations of the motility of the duodenum and small intestine. Increased perspiration, salivation, and the occasional association of hypotension and bradycardia often accompanies severe nausea.

The stomach plays a relatively passive role in the vomiting process, the major ejection force being provided by the abdominal musculature. Repeated emesis (vomiting) may have deleterious effects in a number of ways. The process of vomiting itself may lead to traumatic rupture or tearing of the region of the cardioesophageal junction, 15 resulting in massive hematemesis (the vomiting of blood).

Prolonged vomiting may also lead to dehydration and the loss of gastric secretions, particularly hydrochloric and metabolic alkalosis and the potentially dangerous loss of potassium. In states of central nervous system 20 depression, such as coma, the gastric contents may actually be aspirated into the lungs, with a resulting aspiration pneumonitis.

The act of vomiting is under the control of two functionally distinct medullary (central nervous system) centers: the vomiting center and the chemoreceptor zone.

*The vomiting center controls and integrates the actual act of emesis, receiving stimuli from the intestinal tract, the labyrinthine apparatus in the ear, the chemoreceptor zone and other parts of the body. The chemoreceptor trigger zone is also located in the medulla. Activation of this zone initiates impulses to the medullary vomiting center which then initiates the act of emesis. The chemoreceptor trigger zone can be activated by many stimuli, including drugs such as morphine, codeine, cardiac glycocides (digoxin) and ergot alkaloids (ergotamine) and a great many antineoplastic agents. Nausea and vomiting are common slafvhror~ke~pspediUT*I.,tIPOPHILIG 14,2 20 manifestations of organic and functional disorders.

Table II provides examples of many disorders which may be accompanied by nausea and vomiting.

Table II 1. acute abdominal emergencies acute appendicitis, cholecystitis) 2. chronic indigestion 3. acute infectious diseases accompanied with fever, especially in young children 4. disorders of the nervous system, especially the central nervous system heart diseases such as acute myocardial infarction, especially of the posterior wall of the heart 6. metabolic and endocrine disorders, including 15 diabetic acidosis 7. drugs and chemicals 8. emotional stress may lead to psychogenic vomiting As described above, nausea and subsequent vomiting is not only an undesirable sensation, it can be severely 20 debilitating and even life threatening in some cases.

There are currently only three modalities used to deliver the drugs to ameliorate nausea and vomiting. These are oral (tablets or liquids), intramuscular or intravenous injection, and rectal.

For rapid onset of antiemetic action, the intramuscular or intravenous route is preferred. But it is only rarely available outside of medical facilities, and even then, being an injection, it is the least appealing.

The rectal route can be effective, but it is unpredictable at best, due to the variability and placement of the suppository and subsequent rapid liver metabolism. The oral route is the easiest, but as is usually the case, the antiemetic agent in tablet or solution is expectorated with stafthror/keespIyecUTAH.LIPOPHIUC 14.2 I 21 the emesis before dissolution or absorption can take place.

A lollipop into which a suitable antiemetic agent has been dispersed when administered in a dose-to-effect manner provides a delivery method superior to current methods. Transmucosal administration provides for absorption of the antiemetic agent almost as fast as by the intravenous route. Having a handle, an antiemeticcontaining lollipop may be quickly removed from the mouth in the case of unanticipated emesis. Further, transmucosal administration bypasses immediate hepatic metabolism which occurs with oral administration. More importantly, the antiemetic agent cannot be expectorated during transmucosal administration, which usually occurs after oral ingestion of an antiemetic agent. Finally, a drug-containing 15 lollipop administered in a dose-to-effect manner is a highly acceptable mode of delivery.

Examples of compositions and methods of using lollipops containing antiemetic agents are given herein below.

20 From the foregoing, it will be appreciated that the present invention allows great flexibility and permits physician control on a case-by-case basis with respect to the dose given to a particular patient, and the rate at which that dose is given.

A physician can easily monitor a patient's oo* condition to ensure the patient receives a dose adequate to evoke a desired physiological state. If necessary, the physician can instruct the patient to alter the aggressiveness with which he sucks the lollipop, or he can take the lollipop from the patient.

A patient can also self-administer suitable antiantiemetic medication using a lollipop in accordance with the present invention. Thus, a patient can place a drugcontaining lollipop passively in his mouth for continuous low-level administration of a drug, or can take a lick of the lollipop from time to time as it may be needed to staffhrontkeeplspodJUTAHLIPOPHILIO 4.2 I- 22 reduce his own subjective experience of pain or physical discomfort.

Although the method and compositions of the present invention have been described with reference to specific examples, it is to be understood that the method and compositions of the present invention may be practiced in other forms without parting from its spirit or essential characteristics. Described methods and compositions are considered in all respects only as illustrativ'e, and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

15 This application is divided from our copending applications No. 50352/90 (645966) and 55218/94 and the entire disclosures in the complete specifications of these applications are by this cross-reference incorporated into e the present specification.

*000 0 0 staWrronkoepspedIUTAHRLIPOPHILIC 1422

Claims (9)

1. A method for administering an antiemetic drug to a patient suddenly experiencing the onset of nausea and vomiting, the method comprising the steps of: obtaining a drug-containing lollipop comprising a holder and a dosage-form attached S to one end of the holder, the dosage-form including a soluble matrix material into which an antiemetic drug has been dispersed, the soluble matrix material being capable of releasing the antiemetic drug for absorption through mucosal tissue of the mouth, pharynx, and esophagus; administering the dosage-form of the drug-containing lollipop within the mouth of the patient at the onset of nausea such that the dosage form begins to solubilize therein, the antiemetic drug from the solubilize dosage-from rapidly entering the bloodstream of the patient by absorption through the mucosal tissue of the mouth, pharynx, and esophagus; removing the dosage-form from the mouth of the patient by use of the handle at the onset of vomiting; and reinserting the dosage-form into the mouth of the patient after termination of the vomiting -for continued absorption of the antiemetic drug through the mucosal tissue of the mouth, pharynx, and esophagus.

2. A method for administering an antiemetic drug as recited in claim 1, further comprising the steps of repeating the removing and reinserting steps at the onset of subsequent vomiting.

3. A method for administering an antiemetic drug as recited in claim 1, further comprising the step of passively maintaining the dosage-form of the drug-containing lollipop within the mouth of the patient. j- -I

4. A method for administering an antiemetic drug as recited in claim 1, further comprising the steps of: removing the dosage-form from the mouth of the patient by use of the handle at the termination of nausea; and :i reinserting the dosage-form into the mouth of the patient on the return of nausea.

A method for administering an antiemetic drug as recited in claim 1, further comprising the step of administering an initial drug-containing lollipop in the mouth of the patient prior to the onset of nausea and vomiting, the initial drug-containing lollipop comprising a holder and a dosage-form attached to one end of the holder, the dosage-form including a soluble matrix material into which an antiemetic drug has been dispersed, the soluble matrix material being capable of releasing the antiemetic drug for absorption through mucosal tissue of the mouth, pharynx, and S* esophagus.

6. A method for administering an antiemetic drug as recited in claim 1, wherein the step of obtaining a drug-containing lollipop comprises the dosage-form including an inner matrix containing the antiemetic drug in a suitable concentration for maintaining a desired systemic relief from nausea and vomiting and an outer matrix covering the inner matrix, said outer matrix containing the drug in a suitable concentration for rapidly producing the desired systemic relief from nausea and vomiting.

7. A method for administering an antiemetic drug as recited in claim 1, wherein the step of obtaining a drug-containing lollipop includes the soluble matrix material comprising a SR% ,T carbohydrate.

8. A method for administering an antiemetic drug as recited in claim 1, wherein the step of obtaining a drug-containing lollipop includes the antiemetic drug comprising droperidol.

9. A method for administering an antiemetic drug as recited in claim 1, wherein the step of obtaining a drug-containing lollipop includes the antiemetic drug comprising meclizine. A method for administering an antiemetic drug as recited in claim 1, wherein the step of obtaining a drug-containing lollipop includes the dosage-form having a compressed powder matrix. I 1. A method for administering an antiemetic drug as recited in claim 1, wherein the step of obtaining a drug-containing lollipop includes the dosage form having a hard candy matrix. Dated this 10 th day of September 1997 UNIVERSITY OF UTAH RESEARCH FOUNDATION By their Patent Attorneys GRIFFITH HACK Fellows Institute of Patent Attorneys of Australia TO C -le I f, ABSTRACT The present invention is directed to methods and compositions for noninvasively administering lipophilic drugs in a dose-to-effect manner to produce antiemetic activity. A patient is put at ease when given the lollipop, and the lipophilic drug rapidly enters the patient's bloodstream as the lollipop is sucked. When treating the patient, the physician can observe the patient's condition and terminate the use of the lollipop when it has had a desired effect on the patient. The drug-containing lollipop can be self-administered by the patient in response to subjective symptoms and to the patient's susceptibility to the lipophilic drug. sees 066: C eo S I L II