AU641127B2 - Compressed powder medicaments - Google Patents

Description

OPI DATE 03/04/91 APPLN. ID 40704 89

PCI

AOJP DATE 02/05/91 PCT NUMBER PCT/US89/03518 INTERNATIONAL A j .rn. I L, IeIM L.n (PCT) (51) International Patent Cassification 4 (11) International Publication Number, WO 91/03099 A61K 9/20 Al (43) International Publication Date: 7 March 1991 (07.03,91) (21) International Application Number: (22) International Filing Date: 1 PCT/US89/03518 6 August 1989 (16.08,89) (71) Applicant: ANESTA CORPORATION [US/US); 825 North 300 West, Suite 200, Salt Lake City, UT 84103

(US).

(72) Inventors: STANLEY, Theodore, H. 4800 Oak Terrace Drive, Salt Lake City, UT 84124 HAGUE, Brian 4478 South Hawarden Drive, West Valley City, UT 84119

(US).

(74) Agents: NYDEGGER, Rick, D. et al.; Workman, Nydegger Jensen, 1000 Eagle Gate Tower, 60 East South Temple, Salt Lake City, UT 84111 (US).

(81) Designated States: AT (European patent), AU, BE (European patent),.CH (European patent), DE (European patent)*, DK, FR (European patent), GB (European patent), IT (European patent), JP, LU (European patent), NL (European patent), NO, SE (European patent), Published With international search report.

With amended claims and statement.

641127 (54) Title: COMPRESSED POWDER MEDICAMENTS (57) Abstract Compositions and methods of manufacture for producing a medicament composition capable of absorption through the mucosal tissues of the mouth, pharynx, and esophagus.

The present invention relates to such compositions and methods which are useful in admin.

istering drugs in a dose-to-effect manner such that sufficient drug is administered to pro.

duce precisely a desired effect. The invention also relates to a manufacturing technique that enables a therapeutic agent or drug to be incorporated into a flavored confectionary base and to compress or otherwise attach the solid confectionary mixture (24) onto an appli.

ance or holder Disk (22) and (24) seat against button Employing the present in.

vention the drug may be introduced into the patient's bloodstream almost as fast as through injection, and much faster than using the oral administration route, while avoiding the nega.

tive aspects of both of these methods, The present Invention achieves these advantages by incorporating the drug into a compressed powder "candy" matrix. The pH and pKa of the powder matrix can be modified to increase the absorption of the drug through the mucosal tissues.

-i I- See back of page WO 91/03099 -1- PCT/US89/03518 "COMPRESSED'POWDER

MEDICAMENTS"

BACKGROUND

1. The Field of the Invention The present invention relates to compositions and methods of manufacture of compressed powder matrixes for medicaments used in the transmucosal delivery of the medicaments. More particularly, the present invention is directed to compositions, and methods and apparatus for producing such compositions, for non-invasive administration of precise amounts of medicaments through the mucosal tissues of the mouth, pharynx, and esophagus.

2. The Background of the Invention Recently, numerous advancements have taken place in the field of pharmacology with respect to the administration of drugs to treat various conditions.

Despite the tremendous advancements in the field, however, drugs continue to be administered using substantially the same techniques that have been used for many decades. The vast majority of pharmaceutical agents continue to be administered either orally or by injection. Nevertheless, it is frequently found in the art that neither of these administration routes are effective in all cases, and both administration routes suffer from several disadvantages.

Oral administration is probably the most prevalent method of administering pharmacological medicaments. The medicament is generally incorporated into a tablet, capsule, or a liquid base, and then swallowed. The oral administration modality is often preferred because of its convenience. In addition, oral administration is generally nonthreatening, painless, and simple to accomplish for most patients.

Nevertheless, oral administration of drugs suffers from several disadvantages. One disadvantage is that WO 91/03099 WO 9103099PCr/US89/035 18 2 pediatric and geriatric patients frequently have difficulty swallowing pills, and such patients often refuse to cooperate in swallowing a liquid medication. in addition, for many medicaments, the act of swallowing the medicament increases gastric volume and the likelihood of nausea and vomiting; this is a particularly dangerous condition f or patients prior to anesthesia.

A further problem with oral administration is that the rate of absorption'of the drug into the bloodstream after swallowing varies from patient to patient. The absorption of the drug is dependent upon the movement of the drug from the t~omach to the small and large intestines and the effects of secretions from. these organs. Anxiety and stress can dramatically reduce these movements and secretions, prevent or reduce the final effects ,of the drug, and delay onset ,pf the drug's effects.

Most significant is the fact that there is normally a substantial delay between the time of oral administration and the time that the therapeutic effect of the drug begins. As mentioned above, the drug must pass through the gastrointestinal system in order to enter the bloodstream; this typically takes forty-five minutes or longer. As mentioned above, anxiety and stress often increase this delay.

For many applications, such as premedication before surgery or where immediate relief from pain or a serious medical condition or immediate effectiveness of the drug is required, this delay is unacceptable. In modern outpatient units and operating rooms where rapid turnover of patients 010 is essential for cost containment, extensive delays in the action of a drug are simply unacceptable.

An additional disadvantage of or~al adminsistration is that many drugs, particularly tdrugs with central nervous SS system (ItCNSO) or cardiovascular action, are almost WO 91/03099 PCT/US89/03518 3 immediately metabolized. The veins from the stomach and the small and large intestines pass directly through the liver. Thus, drugs entering the bloodstream must first pass through the liver before distribution into the general blood circulation. More than sixty percent of most drugs (and essentially one hundred percent of certain drugs) are removed from the pa'tient's bloodstream during this "first pass" through the liver. The result is that oral administration is impractical for many drugs, particularly most central nervous system and cardiovascular-acting drugs that are used in critical care situations, as a premedication prior to surgery, or for the induction of anesthesia.

Further, additional stress is placed on the liver as it removes the excess drug from the bloodstream. This is particularly severe if the the cardiovascular or renal vascular treatment has been occurring over an extended period of time. The liver may become overloaded with the drug's metabolite which then must be excreted in the patient's urine. As a result, there is an increased risk of hepatic or renal disorders.

Another difficulty encountered in administering drugs orally is that dosages are prepared or determined for use with an "average" patient. Most drugs have widely varying effects on different patients. These effects depend upon patient habits, subtle genetic differences between patients, blood volumes, age, and numerous other known and unknown factors, Introducing a bolus of drug orally does not provide the ability to control the precise dose needed Sto obtain the desired effect, rather the dose is estimated in order to produce an average effect in an average patient. The result may be underdosing or overdosing a particular patiant.

WO 91/03099 PCT/US89/03518 4 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, especially the heart and lungs. This can cause prolonged respiratory depression (necessitating mechanical ventilation after surgery), cardiac depression, and cardiac arrest.

In order to avoid some of the disadvantages of oral administration, injection is frequently used. 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. The drug instead becomes rapidly distributed to various portions of the patient's body before exposure .to the liver.

Most patients, particularly children and geriatric adults, have an aversion to injections. In ae patients, this aversion may be so pronounced as to mrke the use of injections a serious concern. Since intensv psychological stress can exacerbate a patient's debilitatedcondition, it sometimes becomes undesirable to 4se injections where the patient is seriously ill or suffers from a, debilitating condition or injury.

In addition, individual variations in susceptibility in i.e metabolism of various drugs (particularly drugs with central nervous system activity) are even more profound when utilizing the injection route. In order to prevent overdosing, it is the practice to inject a patient with a lower than average dose and then supplement the dose with additional injections as necessary. This "titration" makes necessary the use of repeated injections, which in turn greatly increases stress on the patient. Again, a precise dose cannot be administered to produce a precise effect WO 91/03099 PC/US89/03518 because the patient's response varies widely depending on the specific characteristics of the specific patient.

One common approach to preparing a patient for surgery is to orally administer a sedative or anxiolytic. Although quick onset of sedation or anxiolysis has not always been a critical factor, it is more so now. Changing practices, includitng the increased use of outpatient units for day surgery and the pressures for cost containment in modern medicine, dictate rapid onset of action and the use of an absolutely ideal dose in order to avoid increased costs of caring for patients with delayed recovery secondary to slightly overdosing with anesthesia. Oral administration of premedication drugs with central nervous system activity (which cause a rapid onset of sedation and anxiolysis without producing excessive sedation) is difficult to accomplish.

Some investigators have suggested that it may be possible to administer medication through the buccal mucosa of the cheek pouch or by sublingual administration. 2=, cop in nr'r f r ti ril wYp flS1'79,0 rf fjj i 14P 1y L 1S I" in the name of the inventors hereof, and entitled METHODS AND COMPOSITIONS FOR NONINVASIVE ADMINISTRATION OF SEDATIVES, ANALGESICS, AND ANESTHETICS." Such administration through the mucosal tissues of the mouth, pharynx, and esophagus of therapeutic drugs possesses a distinct usefulness. Administration of drugs by this route does not expose the drug to the gastric and intestinal digestive juices. In addition, the drugs largely bypass the liver on the first pass through the body, thereby avoiding additional metabolism and/or inactivation of the drug.

Generally the drugs which are administered by any of the methods described above have an unpleasant taste. As a result, in order to allow for buccal or sublingual .n' WO 91/03099 PCT/US89/03518 6 administration through the oral mucosal tissues, it is also necessary to incorporate the drug into some type of pleasant tasting mass, such as a "candy" matrix.

In the manufacture of medicated candy products by existing methods, the therapeutic agent is added to a molten candy mass. The resultant mixture is then thoroughly mixed to ensure proper distribution of the drug within the molten candy mass. The mixture is then poured while still molten and allowed to solidify into a semisolid mass. Alternatively, the hot candy mass may be poured into molds, the size and shape of which may be determined as desired.

For effective application of the drug, the final candy product must contain the drug uniformly distributed throughout in order to ensure uniform levels of medication.

Alternatively, for some applications, varying concentrations within known and controlled ranges may be desired to vary the rate of drug administration.

Difficulties are encountered in attempting to blend solid drugs in a uniform or otherwise carefully controlled Manner. Many drugs are insoluble, or only' partially soluble, in one or more of the ingredients of the hard candy base. Thus, the resultant product is often found to be lacking in uniform distribution of the drug.

In addition, it is often found that when the temperature of the candy mass is increased in order to enable a more uniform distribution (generally to a temperature above approximately 230'C), considerable decomposition of the drug takes place. While the extent of decomposition may vary, high temperatures are generally undesirable in the handling and processing of medications.

Thus, the process of formation of the candy product may itself degrade and/or inactivate the therapeutic agent.

WO091/03099 PCT/US89/03518 7 FUrthermore, many presently available medicated candy lozenges tend to crumble when placed in the mouth. As a result, uniform release of the drug into the mucosal tissues does not take place. Rather, the crumbled lozenge is mostly chewed, and swallowed, and the drug enters the bloodstream through the stomach and intestines as described above. Thus, it will be appreciated that candy lozenges have very definite limitations for nse in the administration of a drug through the oral mucosal tissues.

As a result, lozenges have not been used to administer potent, fast-acting drugs, such as drw!P thaV affect the central nervous system, the cardiovascular system, or the renal vascular system.

While the administration of certain drugs through the oral mucosal tissues has shown promise, development of a fully acceptable method for producing a medication in a desirable form and administering the medication has been elusive. It has not been possible to develop an acceptable candy product for use with most drugs without heating the product to the point where degradation will be expected, It should also be noted that pH conditions'within the mouth tend to adversely affect the administration of Certain drugs by the mucosal administration route. It has been found in the art that admiiistration of drugs through the mucosal tissues occurs best when the drug is in the non-ionized form. Variations in pH affect drastically the percentage of the drug which is non-ionizad at a particular point in time. As a result, the pH conditions within the mouth limit the effectiveness of certain drugs administered buccally or sublingually in that those conditions cause the drug to exist in the ionized form which is largely unavailable for transfer across the mucosal tissues.

In view of the foregoing, it would be an important advancement in the art of administering potent, fast-acting drugs, if suitable methods and compositions provided a precise dosage to a precise effect in every patient. it would be a related advancement in the art to provide such methods and compositions which avoided the disadvantages of overdosing, underdosing, and the immediate metabolism encountered in the "first pass effect", yet did not involve injection by needle into the patient.

Xt would be a further significant advancement in the art to provide methods and compositions for incorporating drugs (including insoluble drugs) into a soluble matrix without heating the mixture to the point that degradation occurs. Xt would be a related advancement in the art to provide ouch a method which provided the 1s capability of uniformly incorporating insoluble drugs into the soluble matrix. it would be another advancement to provide methods of controlling pH during mucosal delivery of a drug such that the drugs exist primarily in the nonionised forzm.

Such compositions and methods of manufacture are disclosed and claimed herein.

RI1BF ssU1*!Xy, AND_ 0137,HrS, OPTH~ According te the present Invention there is p4"ovided a method for producing a drug-containing lollipop to* 2$ for use In transiuucoaal delivery of the 6iAla to a patient# too the method comprising the atop# oft dseof obtaining a pharmacologically effective dos o the drug in a substantially powdered form, the drug being capable of aboorp.ion through mucosal tissues of the 4 *1 30 mouth# pharynx# or esophagus: to e obtcininq a soluble Jiarbohydrata material oapa)ble of fr Ing a comp1resible confoctioner? matrix and capablt of dissolving in the mouth of tha patientl 44 mixing the drug and the carbohydrate material at a temperature below the melting points of the drug and the carbohydrate material to form a drugcontaining matrix such that the drug is dispersed substantially throughout the matrix, the drug-containing matrix being capable of releasing the drug for absorption though the mucosal tissues upon dissolution of the matrix in the mouth of the patient; and compressing the drug-containing matrix in a mold to form an integral mass such that, when the integral mass dissolves in the mouth of the patient, the drug is released for absorption through the mucosal tissues; and incorporating a holder as part of the integral mass in order to form the drug-containing lollipop.

The present invention relates to compositions and methods of manufacture for producing a medicament composition for use in administering potent, fast-acting drugs transmucosally. Furthermore, the present invention relates to such compositions and methods which are useful in administering drugs in a dose-to-effect manner such that 25 vuffiaieiit drug is administered to produce precisely the desired egfoct. The invention also relates to a manufacturing technique that enables a therapeutic agent to be incorporated into a flavoured confectionery base and to compress or otherwise attach tho solid confectionery mixture onto an appliance or holder. Xn use, the present

I

t o fit i i WO 91/03099 PCT/US89/03518 9 invention provides for the administration of drugs through the mucosal tissue of the mouth, pharynx, and esophagus, thereby avoiding the problems of both injection and oral administration.

Employing the present invention, the drug may be introduced into the patient's bloodstream almost as fast as through injection, and much faster than using the oral administration route, while avoiding the negative aspects of both methods.

The present invention achieves these advantages by incorporating the drug into a soluble candy matrix. The soluble candy-drug mixture, in the form of a compressed powder lollipop, can be used to administer drugs in a doseto-effect manner, or until the precise desired effect is achieved. The lollipop can then be removed from the patient's mouth.

The methods of the present invention also provide for a compressed powder composition which overcomes many of the limitations previously encountered in forming a medicated lozenge. The present invention teaches the combination of dry powdered ingredients by geometric dilution.' That is, the two smallest ingredients by weight are first thoroughly mixed, then the next smallest ingredient or ingredients by weight equal to the weight of the previous ingredients is added and is thoroughly mixed with the existing mixture.

This procedure is repeated until all of the components, including the desired therapeutic agents, are fully combined.

After mixing, the mixture is then compressed under high pressure to form an integral candy product. Specific confectionary components are combined in order for the mixture to form an integral solid mass. These components may include, for example, compressible confectioner's sugar and maltodextrin.

WO 91/03099 Pcr/uS89/03518 This procedure overcomes many of the problems of the prior art. According to the present inv/jntio n, insoluble drugs can be added to the matrix withoutL the necessity of attempting to dissolve the drug. in addition, the high temperatures, which are generally required to form a molten candy matrix and which will cause degradation of the drug, are avoided using the present invention. Therefore, even drugs with melting points below approximately 130"C to 1406C or those drugs which can experience decomposition 2 below their melting points, can be incorporated into a soluble matrix.

A further advantage of the present invention is that flavoring problems are overcome. Flexibility in adding flavors is provided in that solubility of the components is not required in order to incorporate any particular flavor into the matrix. Thus, flavorings, drugs, and other components (which may be insoluble in liquid form) are easily mixed when they exist as a dry powder.

Buffers and other types of pH and pKa control can also be added simultaneously in order to provide for maximum drug efficiency. It will be appreciated that dkugs in the non-ionized form are more readily transported across the taucosal membrane. Therefore, if pH (and corresponding pKa) conditions can be adjusted to maximize the percentage of non-ionized drug available, tne effectiveness of the drug is Maximized.

4S Various lollipop configurations are also possible employing the present invention. For example, layers of drug may be interspersed between layers of candy. Since the present inv~antion teaches the use of solid Powdes, any desired type of mold can be used for the compression formation of the lollipop.

It ray also be desirable to incorporate a stick into thQ catsdy matrix as the matrix is being compressed.

'WO 91/030999 PCT/US89/03518 11 S Alternatively, the stick may be glued to the candy matrix by a confectioner's glue once the lollipop is formed. The stick provides for easy removal of the lollipop from the mouth of the patient once the desired effect has been achieved. This is a substantial improvement over existing methods of administering drugs through the mucosal tissues of the mouth.

The present invention also provides the advantage of controlling the dissolution rate of the composition once it is administered to a patient. This can be accomplished in 2 two ways. First, the dissolution rate may be modified chemically by including a hydrophobic agent (such as calcium stearate) to slow dissolution or lactose to enhance dissolution. Dissolution may also be controlled by the extent to which the mixture is mechanically compacted.

A drug administered through the oral mucosal tissues from such a compressed powder matrix within the scope of the present invention will quickly enter the patient's bloodstream through the veins which serve these tissues.

Appropriate monitoring of the patient's reaction to the drugs which has an observable or monitorable effect (such as a drug effecting the central nervous, cardiovascular, or renal vascular systems) will indicate when the drug has evoked a suitable response. The lollipop may then be removed, or its rate of consumption may be modified in order to maintain the desired effect.

It will be appreciated that the ever present risk of overdosing a patient is substantially miniaized through the use of the present invention. The rate at which the drug is to be absorbed by the body can be varied by virying the rate the lollipop dissolves. This can be accomplished by varying the rigor with which the patient sucks on the lollipop. It can also be accomplished by varying the extent to which the lollipop is compressed during formation WO 91/03099 PCT/US89/03518 12 or by adding certain agents which reduce the solubility of the compressed powder matrix.

According to the present invention, the drug dose is given over a period of time rather than all at once, and the administration rate can be adjusted if it appears to be necessary. Once a sufficient drug response has been achieved, the patient can simply stop sucking on the lollipop or the physician can easily remove the lollipop from the patient's mouth.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a perspective view of a mold for forming the candy-drug matrix along with an associated ram.

Figure 2 is a perspective view of one embodiment of a lollipop within the scope of the present invention.

Figure 3 is an exploded plan view of the embodiment of the lollipop shown in Figure 2.

Figure 4 is a perspective view of an alternative embodiment of the lollipop of the present invention.

Figure 5 is a cutaway plan view of an alternative embodiment of the lollipop of the present invention illustrating one method of attachment of the stick to the candy matrix.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 1. General Discussion The present invention is related to methods of manufacture and compositions which facilitate the transmucosal delivery of a medication. Simply stated, the present invention relates to a lollipop, or similar type of composition, which contains a therapeutic drug. The drug is delivered to the patient through the mucosal tissues of WO 91/03099 PCT/US89/03518 13 the mouth, pharynx, and esophagus as the patient sucks on the drug-containing lollipop.

This particular method of delivery overcomes several of the limitations encountered in the delivery of drugs either orally or by injection. One of the primary advantages of the present invention is the ability to introduce drugs to a patient in a "dose-to-effect" manner.

The drug is given to the patient until the precisely desired effect is obtained; this is in distinction to prior art methods where a predetermined quantity of the drug is introduced to the patient. Once the desired effect is obtained, the patient or the medical professional simply removes the lollipop from the patient's mouth.

The present invention discloses a method of producing a lollipop containing one or more therapeutic agents. The present invention overcomes many of the problems encountered generally in incorporating drugs into a confection. For example, the present invention teaches the mixing of solid powders at room temperature, as opposed to liquid components at elevated temperatures. The degradation of drugs, which often occurs at the elevated temperatures needed to produce a molten candy mass, is thereby avoided. This facilitates use of drugs having melting points in the 130*C-140C range and below, or those drugs which can experience decomposition below their melting points.

In addition, because solid powders are combined together, constituents which may be chemically incompatible when in a heated solution or suspension can be mixed. In forming medicated confections by known methods, severe problems are encountered in that the medication, flavorings, and other components may be insoluble when placed in the same liquid environment. In addition, WO 91/03099 PCT/US89/03518 14 problems of chemical incompatibility between ingredients is eliminated in the present invention.

Once the desired constituents are thoroughly mixed, they are compressed into a solid mass under high pressure.

Typically, compressive forces in the range from approximately 2,000 Newtons to approximately 5,000 Newtons are preferred. As a result, the compressed powdered matrix is held together by physical means rather than by chemical means. The extent of the compressive forces can be modified to vary the rate that the lollipop will dissolve in a patient's mouth. The greater the compressive forces that form the mixture, the slower the dissolution of the compressed powder matrix in the mouth.

The rate of the dissolution of the lollipop can also be controlled chemically. For example, the rate of dissolution can be reduced adding hydrophobic agents such as calcium stearate. Alternatively, dissolution can be increased by adding hydrophilic agents, such as lactose.

According to the present invention, the compressed powder matrix is attached to a holder, such as a stick to 'form a lollipop. Attaching the compressed powder matrix to a holder facilitates the administering of precise dosages.

Once a particular effect is induced, the lollipop can be withdrawn using the holder as described above. In addition, a compressed solid mass containing a drug having complex disagreeable flavor characteristics require multiple ingredients to be added in order to provide a significa~t bulk to overcome the disagreeable flavor characteristics; hence, a mechanical support system such as a holder is necessary.

The attachment of the confection to a holder may be made by compressing the stick into the powder matrix as the lollipop is being formed. Alternatively, the stick may be glued to the candy mntrix by confectioner's glue or some WO 91/03099 PCT/US89/03518 other appropriate adhesive once the matrix is formed. In the alternative, as will be discussed below, a lollipop may be assembled immediately prior to use by sliding disks of drug and candy onto an appropriately configured holder.

It will be appreciated that compression or attachment of the drug-containing confection onto a holder can facilitate the transmucosal absorption of a variety of therapeutic agents. Attachment to a holder also facilitates verifiable transfer of the medication to the patient. The holder provides a convenient point of reference concerning quantities of drug administered at any particular point in time; it is easy to determine how much of the lollipop has been dissolved in the patient's mouth.

Localization of effects by agents such as local anesthetic agents, antiplaque agents, local antipruitic agents, local antisecretory agents, and local antifungal agents can also be accomplished according to the present invention. Immediate systemic effects from central nervous system-acting drugs (such as sedation, anxiolysis, analgesia, amnesia, and anesthesia), cardiovascular-acting agents (such as antihypertensives and and antianginal drugs), renal vascular-acting agents, and numerous other therapeutic agents can also be accomplished by employing the present invention.

Placing a drug dosage onto a holder also facilitates the temporary removal of medication for inspection or the reduction of the effect when necessary. Unlike administration of drugs orally or even sublingually, the present composition can easily be removed to assess the o effect induced:at any particular time. When a pill or lozenge is used, removal from the patient's mouth at an intermediate stage to assess effect is generally impractical, if not impossible.

WO 91/03099 PCT/US89/03518 16 Compressed powder matrixes attached to a holder can also avoid aspiration of the confection. One major problem with existing lozenges and the like is their tendency to crumble. Once the lozenge crumbles, controlled transmucosal delivery is impossible. In addition, there is some possibility that the patient will choke on the pieces of lozenge.

The present invention provides the capability of providing a good tasting medication. With many drugs, it has previously been impossible to provide a good tasting medicine because of the extreme bitterness or other unpleaoan taste of many drugs. Using the present invention, favorable taste characteristics can be accomplished by adding various flavors, sweeteners, and the like to form an ideal mix of products. Since the components are combined as solids, problems associated with combining flavoring components insoluble in a molten candy mass are avoided.

It is also important to note that it has been found that it is possible, according to the present invention, to use the free acid form of certain drugs and to buffer those drugs such that extremes in pH, and resulting bad taste, are avoided.

2. Methods .of Manufacture In order to prepare a desirable drug-confection mixture for formation into a lollipop, it is generally necessary to combine several general types of components.

These components include the types of components used to prepare typical confections, the desired drug, and other chemically aetive ingredients such as buffers and the like.

The types of components involved generally fall into the following categories: 5 flavorings, WO 91/03099 WO 9103099PCV'US89/03518 17 sweeteners, flavor enhancers, releasing agents, buffers, and one or more therapeutic agents.

As mentioned above, it is preferred that these components each be provided in a powder, in order to facilitate the mixing and compression steps. This provides for convenient combination of the ingredients, even if they happen to be insoluble or otherwise chemically incompatible. All the incipients or inactive ingredients should be on the GRAS list ("generally regarded as safe").

A wide range of flavors are available for preparing good tasting and desirable medications within the scope of the present invention. These are required in order #o maskc the unpleasant taste of the drug. Flavorings may be combined, as desired, to produce a particular flavor mix which is compatible with a particular medication. Some of the confectioner's flavorings which have been used in the context of the present invention include artificial vranilla, vanilla cream, mint, cherry, spearmint, grape, coconut, chocolate, menthol, licorice, lemon, and butterscotch.

Each of these flavorings is obtainable in a concentrated powder form. other flavorings krnown in the confectionary arts may also be acceptable because ot the oase of combining thQ ingredients of the present invention.

Any number of flavorings may be combined in any desired ,ratio in order to produce the specific desired taste so charactraristici required for any particular application.

For example, flavor combinations may be varied in order to be compatible the flavor characteristics of any specific drug.

WO 9)1/03099 PCT/US89/03518 18 In order to produce a desirable color for the end product, artificial colorinqs may also be added to the composition. The flavorings described above are generally a white powder, as are the other major components.

Therefore, additional coloring is necessary if a colored end product is desired. Coloring may also be important as a code to indicate the type and concentration of drug contained within a particular lollipop. Any type of color known to be "generally regarded as safe" and thus generally used in the confectionary trade, may be used to provide coloring to the product.

In order to provide a good tasting medication, it is necessary to add sweeteners to the composition. Sweeteners which are presently preferred include aspartame (Nutrasweet®) and compressible confectioner's sugar.. Other sweeteners, such as fructose, may also be acceptable for use within the scope of the present invention. Again, it is desired that a sweetener or combination of sweeteners be obtained which is compatible with the drug and the other components such that a good tasting confection is produced.

Maltodextrin may also be added to provide a better tasting composition. Maltodextrin is generally employed in order to dissipate unpleasant flavors (such as the bitter taste of most drugs) within the composition, In addition, maltodextrin is a highly compressible powder which facilitates the formation of the final lollipop product.

For some applications, it may be desirable to add a flavor enhancer to the composition in order to achieve a good tasting product. Flavor enhancers provide a more Spleasant sens'ation in the patient's mouth during consumption of the lollipop. Flavor enhancers within the scope of the present invention include materials such as ribotide (a nucleotide) and monosodium glutamate 5 In certain medications, it may also be desirable to WO 91/03099 WO 9103099PC'/US89/03518 19 add a lubricating agent in order to release the lollipop from the mold. Such agents may also provide a certain amount of waterproofing. As mentionoc1 above, the rate of dissolution of the lollipop within the patient's mouth may be controlled chemically, as well as physically, through the extent of compression of the composition. These lubricating or releasing agents may include substances such as compritol 886, calcium stearate, and sodium stearate.

These agents may enhance dissolution or, they may inhibit dissolution as necessary.

As will be discussed in more detail below, it may also be desirable to buffer the composition. Buffers provide t.he ability to;, place the medication in the mouth in a favorable pH~ environment for passage across the mucosal tissues of the mouth, pharynx# and esophagus. Ruffers incorporated within the composition can be used to affect a pH change in the salival environment of the mouth in order to favor the existence of a non-ionized form of the active ingredient or drug which more readily moves through the nt 'osal tissues.

Xn addition, appropriate pH adjustment Can aid in producing a more palatable product with drugs which are either severely acidic (and thus sour) or severely basic (and thus bitter). As a result, a buffer system such as citric acid/sodium citrate has been found to be desirable for addition into the soluble compressed powder matrix.

it will be appreciated that miscellaneous other agents such as lactose# to provide filling anel bulk, may also be desirable. Other filling and bulking agents of the type known it thQ art may also be used.

Added to the confectionary matrix described above will be, the appropriate therapeutic agent or drug. As will be discussed in nore detail below, various types of drugs &to 56 easily incorporated into this type of matrix. These WO 91/03099 PCT/US89/03518 1 include agents which affect the central nervous system, the cardiovascular system, or the renal vascular system.

A typical lollipop within the scope of the present invention may include the following ingredients in order to make 20 dosage forms of 2000 milligrams (2 grams) each: Inaredient 1 arama citric acid 1% 0.2 ribotide 2% 0.4 compritol 888 2% 0.4 aspartame 2% 0.4 vanilla microcaps 5% vanilla cream microcaps 5% wild cherry microcaps 3% 0.6 peppermint microcaps .2 .6L 23% 4.6 grams generic active agent X% (about 0.05%) maltodextrin 100% (23% active aqent%.

x 2 3 compressible sugar 100% (23% active atent %V 3 Appropriate changes in flavoring ingredients can be made in this formula to mask or optimize flavor perception in order to achieve ultimate acceptance of the dosage formed by the desired patient group, be it adult, juvenile, pediatric, or neonate.

Each of the components is mixed with the other components in dry form to produce the compositions of the present invention. Xt is presently preferred to use the method of geometric dilution in mixing the various components. Using this method, the two smallert WO 91/03099 PCT/US89/03518 21 1 ingredients by weight (as a proportion of the final product) are first mixed together thoroughly.

When complete mixing has been obtained between those two component the next smallest ingredient or ingredients by weight equal to the weight of the previous ingredients is added and mixed thoroughly with the existing mixture. This procedure is repeated until all of the components are added to the mix and mixed thoroughly with all other components.

Geometric dilution provides for complete and thorough mixing of all of the components. Using the method described above, there is little chance for incomplete mixing and uneven distribution of components throughout the mix. It will be recognized that this is an advancement over the art in that existing methods may result in incomplete mixing because of the insolubility oZ the products.

Once complete mixing is &ccomplished, the mixture is compressed under relatively high forces to provide a coherent dosage. Compressive forces in the range of from approximately 2,000 Newtons to approximately 5,000 Newtons are presently preferred, however, any force which is sufficient to compress the ingredients into a coherent, integrated mass could be used.

When employing the present invention, there is no need to heat the mixture to a molten mass as has been the practice in the past in forming drug-containing confections. As a result, heat degradation at the drug component is avoided while good mixing and a uniform product are provided.

The confectionary mass may be attached to a holder such as a stick or other similar type of holder. The holder may be glued to the confection by confectioner's WO 91/03099PC/S9058 PCr/US89/0351 8 22 1 glue. Alternatively, the holdor may be compressed into the lollipop by the compressive forces described above.

The figures illustrate several methods of forming the mass of confection, as well as methods of attaching the holder. Figure 1 discloses a mo~ block 10. The interior of mold block 10 includes a cavity 12 formed in any desired shape so that the ingredients described above can be compressed sufficiently to form an appropriately shaped dosage. Mold block 10 may comprise two separate halves 14 and 16. Each half of the mold block 10 can be removed in order to remove the confection once it is sufficiently compressed, Also illustrated in Figure 1 is ram 18. R~am IS is confiqured so that it fits into the cavity 12 and compresses the confection into the base of cavity 12, R~an 18 may have a hole disposed through its interior in order to accommodate stick 20. Thus# stick 20 can be placed into the mass of confection prior to compression, Plam 18 will then compress the confection tightly around stick Following compression of the confection, the stick im securely bound in place.

Figure 2 discloses an additional embodiment of the confection of thQ present invention. The confection illustrated in Figure 2 has alternating layers of confectio~nary mass 22 and a drug mass 24, Each alternating segment it disk-ohaped with the width of the disk being varied according to particular needs. Disks 22 and 24 easily slide over stick 26 and seat against button -8.

Thus, the method of assembly of the confection can be adapted to produce various dosages to fit varying circumstances. Indeed, the ptntiont himself nay be capable of assembling an appropriate confection and varying the content of the medicament to correspond to his specific heeds at any particular time* WO 91/03099 WO 9103099PC'/U589/03518 23 1 Figure 3 illustrates the method of assembling the embodimernt of the invention as illustrated in Figure 2. In Figure 3, the drug disks 24 and confection disk 22 are spaced apart along stick 26. As can be appreciated from Figure 3, disks 22 and 24 will slide onto stick 26 and will seat against button 28. The number of disks and the composition of these disks can be easily varied to meet particular patient needs.

Stick 26 may take various shapes. For example, it may be desirable for stick 26 to be oval or triangular in cross section. This would prevent disks 24 and 26 from turning on the stick, In addition, an additional sleeve (not shown) may be positioned over the exposed portion of the stick with a catch that engages stick 26 so that disks 24 and 26 are locked in place.

Figure 41 illustrates a further embodiment of a composition within the scope of the present invention. in Figure 4, the drug and confection are divided laterally along the cylindrical mass of the confection. Thus, piashapod segments of drug 32 and confection 34 are pressed together around stick 30. As illustrated in Figure 4, drug segments 32 and confection segments 34 may alternate around a periphery of the confectionary mass. Alternatively, the spacing of the segments may be varied to provide other appropriate levels of drug dosage.

F~igure 5 illustrates an alternate method of attachment between the confectionary mass 36 and the stick 38. stick 38 illustrated in Figure 5 3s constructed with a plurality of protrusions 40. Protrusions 40 extend toward the expoaed portion of the handle such that they prevent the confection from sliding off the handle. Thus, when the congectionary mass 36 is compressed around stick 381 the mass is securely bound to the stick.

VVO 91/03099 PCT/US89/03518 24 1 It can be seen, therefore, that the present invention provides a great deal of flexibility in the construction of an appropriate drug-containing confection.

The quantity of drug contained in any confection can be varied within wide ranges. In addition, various methods of attachment of the confection to the stick are available in order to provide a wide range of flexibility.

3. Control of 12H and DpK It is well known that most drugs are weak acids or weak bases and are present in solution in both the nonionized and ionized forms. It has been found that the nonionized portion of the drug is usually lipid soluble and can readily diffuse across the cell membrane. The ionized portion, conversely, is lipid insoluble and is often unable to penetrate the lipid membrane of the cell. Furthermore, the ionized drug is often unable to cross the cell membrane pores because of ita positive or negative charge. As a result, drugs in the ionized form are generally inefficient in producing a drug effect on the central nervous, cardiovascular, and renal vascular systems.

Whether a drug enists in the ionized or non-ionized form is largely dependent upon its p1a, and correspondingly on the pH of the solution. The present invention provides the unique ability to cohtibl the pH of the solution and thus the pKa of the drug.

Ingredients of the lollipop or other dosage form can be designed to impart sufficient change in the pH of the saliva within the mouth such that the concentration of the Qnon-ionized drug is increased. When the percentage of non-ionized drug is increased, transmucosal absorption of the drug is correspondingly increased. Therefore, by influencing the salival pH environment, it is possible to greatly improve the extent and rapidity of actual drug WO 91/03099 PCT/US89/03518 Sabsorption, and therefore, the initial onset of the effect of the drug. Adding pH buffering systems (such as citric acid/sodium citrate) into the lollipop dosage can greatly facilitate delivery of the drug in the non-ionized (lipid soluble) form.

It is often desirable for the pKa to range from approximately 5 to approximately 8 in order to maximize drug delivery. pKa is the dissociation constant, which is generally defined as the pH at which a given acid or base is 50% ionized and 50% non-ionized. pKa can be calculated from pH, if the concentrations of the charged and uncharged species are known, using the well-known Henderson- Hasselbach equation if concentrations of the changed and Unchanged species are known. The Henderson-Hasselbach equation is as follows: pKa pH log JA-

SHA

where A-/HA is the ratio of the ionized drug form to the non-ionized drug form The effect on the pKa of varying pH, and thus on the non-ionized drug available, is extremely dramatic. For example, methohexital, a potent central nervous systemacting drug, has a pKa of 7.9. If at the same time the general pH of the saliva is about 7.5, these values can then be placed in the Henderson-Hasselbach equation as follows: 7.9 7.5 log (log of the ratio of ionized to non-ionized) where X is the ratio of the ionized to the non-ionized drug form. Solving this calculation indicates that under WO 91/03099 PCT/US89/03518 26 1 typical conditions in the mouth, 60% of the methohexital available would exist in the non-ionized form. As was mentioned above, the non-ionized drug form is the primary form that is transported across the lipid cell membrane.

In the event that the salival pH is buffered down to approximately 6.7, the pKa changes dramatically. This results in a corresponding dramatic change in the amount of drug available. Under these conditions, 94% of the drug available exists in the non-ionized form.

Comparing the pKa produced under the two sets of pH conditions described above, it can be seen that dramatic changes occur. Changing the pH from 7.5 to 6.7 produces more than a 50% improvement in the concentration of nonionized drug available for delivery across the lipid membrane. This results directly in a dramatic improvement in drug delivery across the cell membranes in the mouth and a corresponding increase in the effectiveness of the drug administered.

Changes in pH such as those discussed above can be accomplished by incorporating particular buffer systems Vithin the confection composition. One presently preferred buffer system is a citric acid/sodium citrate system; however, other conventional buffers (such as phosphate) may also be used. By using such a buffer, dramatically better results may be achieved such that buccal drug absorption is a fully feasible and optimal delivery method.

it will be appreciated that an additional advantage of the change of the pH may be that the taste characteristics of the drug can be improved. Drugs which are very high in pH typically are very bitter in taste. As the pH drops, the taste becomes less bitter, then salty, and may eventually become sour. Flavorings can more adequately improve the taste characteristics of drugs in the lower pH ranges. As a result, in addition to improving WO 91/03099 PCT/US89/03518 27 1 the drug delivery, buffering pH may also improve the taste characteristics of the composition.

4. Suitable Therapeutic Agents In order for the present invention to operate effectively, it is necessary that the therapeutic agent incorporated within the candy matrix be generally lipophilic or, in the alternative, be capable of being placed in lipophilic form by suitable adjustments in the environmental pH or other chemical modification. Thus, it is presently preferred that the drug have a pKa in the range of from approximately 6 to approximately 8.

It will be appreciated that the present invention may be used with drugs having a variety of melting points.

Even low melting point drugs may be used in the present invention, whereas such drugs were difficult to incorporate into a candy matrix using known methods because of problems such as degradation of the drug. For example, methohexital, one of the presently preferred drugs for use in connection with the present invention, has a melting point of approximately 96*C. In order to incorporate methohexital into a hard candy by conventional techniques, the drug would have to be melted and there would be a risk of extensive decomposition of the active agent.

The present invention has applicability to a variety of drugs affecting the central nervous system. For example, the present invention may easily be utilized in the administration of buterophenones (such as droperidol and haloperidol); benzodiazepines (such as valium, midazolam, triazolam, oxazolam, and lorazepam); gABA stimulators (such as etomidate); barbiturates (such as pentathol, methohexital, thiamazol, pentobarbital, and hexabarbital); di-ispopopylphenols drugs (such as diprivan); and other central nervous system-acting drugs WO 91/03099 PCT/US89/03518 28 1 such as levodopa. It will be appreciated that other drugs may also be utilized within the scpoe of the present invention either singly or in combination. It is important, however, that the drug be generally lipophilic, potent, and have the other general characteristics described herein.

Table 1 lists some of the CNS-acting drugs which are suitable for incorporation into the lollipop of the present invention, as well as some of the characteristics of those drugs.

Drugs having effects on the cardiovascular and renal vascular systems may also be incorporated into the c( pressed powder lollipop of the present invention. A few examples of such drugs are identified in Table f In addition to the foregoing, there are many other drugs which can be incorporated into the compressed powder matrix of the present invention. Exemplary of such drugs are those identified in Table Table aI Antiemetic Drug Generic Dose Ranag Benzquinamide 25-100 milligrams Meclizine 25-100 milligrams Metoclopramide 5-20 milligrams Prochlorperazine 5-25 milligrams Trimethobenzamide 100-2500 milligrams Antifangal, Drug .eneric QDosge Rante Clotrimazole 10-20 milligrams Nystatin 100 000-500,000 units Antiparkinson Druc Generic Dose Ranae WO 91/03099 WO 9103099PC/LS89/03518 Carbidopa Lev, dopa with levodopa 10-50 milligrams 100-750 milligrams Antisecretgry Sucral fate Qo e Rng 1-2 grams Dosm RfnqQ Bronchodilator Albuterol Aminophylline Beclomethasone Dyphyl.ine Epinephrine Flunisolide Isoetharirie Isoproterenol HMi Metaproterenol Oxtriphy3.line Terbuta. ine Theophyll ine Hiitrai -rigi 0.8-1.6 milligrams 100-500 milligrams 20-50 micrograms 100-400 milligrams 200-500 micrograms 25-50 micrograms 170-680 micrograms 60-260 micrograms 0.65-10 milligrams 50-400 milligrams 2.5-10 milligrams 50-400 milligrams BrvotaminQ Methysiargltde Propranoldl Suloctidil 2-4 milligrams 2-4 Zi-1i Iramis 100-11,0 mililigrams 200-300 milligrams QOxygig Ergoriovine Oxytocin 0.2-0,6 milligrams S-20 Units 10-50 'Micrograms 7'-14 mnicrograms 2.5-60 units Desoprezzin acetate Lypresih Vasprassin WO091/03099 PCr/US89/03518 Drug Generic Dose Range Insulin 5-20 units When incorporating a drug into a lollipop or candy matrix within the scope of the present invention, the amount of 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 potency, and its end use, the total concentration of the drug in the typical lollipop may contain up to times the amount of drug which would typically be used in an injection. For purposes of example, Tables 1, 2, and 3 set forth presently contemplated ranges of the dosages of certain drugs which could be typically used.

A wide variety of drugs may be used within the scope of the present invention. The present invention allows drugs to be incorporated within the candy matrix which would otherwise be inmolubl:, unpleasant tasting, or have other undesirable characteristics. This capability is provided by the compression formation of the candy dosage.

As was mentioned above, methohexital is one presently preferred drug for use in the lollipop of the present invention. Tests were run in which methohexital lollipops were given to six volunteers. The lollipops each contained 500 milligrams of methohexital. Each patient experienced the sedative effects of the drug in a matter of minutes after beginning to suck on the lollipop. These tests indicated that the lollipop of the present invention is effective in administering methohexital in a done-toeffect manner.

WO 91/03099 PCT/US89/03518 31 1 Using the methohexital lollipop described above, it was possible to produce either mild or boavy sedation or induce anesthesia. By removing the lollipop when the ideal degree of sedation was achieved, it was possible to gradually increase sedation to the desired level.

In addition, the results show that the use of oral transmucosal methohexital significantly decreases the drug.

dosage required to produce optimal sedation. The dosage was reduced from between 25 and 30 mg/kg when methohexital is administered rectally to between 6 and 8 mg/kg methohexital is given by way of the lollipop.

In summary, it will be appreciated that a wide variety of drugs can be used within the scope of the present invention. At the same time, several benefits are provided. Efficient delivery of the drug is facilitated while at the same time drug degradation is avoided. The drug can also be administered in a dose to effect manner so that the drug effect produced is precisely controlled.

5. Examples of the Present Invention The following examples are given to illustrate various embodiments which have been made or may be made in accordance with the present invention. These examples are given by way of example only, and it is to be understood that the following examples are not comprehensive or exhaustive of the many types of embodiments of the present invention which can be prepared in accordance with the present invention.

ExatIea I In this example, methohexital was incorporated into a compressed dosage form. Methohexital is a known potent lipophilic drug useful as an anxiolytic, sedative and for anesthetizing a patient. Its high potency and WO 91/03099 PCT/US89/03518 32 1 lipophilicity makes it an excellent drug for transmucosal administration in accordance with the present invention.

A suitable mixture was prepared by combining the following ingredients as follows: Incredient rams citric acid 1% 0.2 ribotide 2% 0.4 compritol 888 2% 0.4 aspartame 2% 0.4 vanilla microcaps 5% vanilla cream microcaps 5% wild cherry microcaps 3% 0.6 peppermint microcaps 3% 0.6 compressible sugar 20% methohexital sodium 75% maltodextrin 21 -fA 100% The ingredients were combined in a mixer in such a fashion as to ensure a uniform distribution of all ingredients within the mixture. Aliquots of 2 grams each were then hydraulically compressed around a commercially available wax-coated compressed paper holder, using a force sufficient to provide a final volume of 2 cubic centimeters. The procedure resulted in the preparation of oral transmucosal dosage forms, each containing grams of methohexital.

Examle. 2 In this example, triazolam was incorporated into a compressed dosage form. Triazolam is a known potent lipophilic drug useful as an anxiolytic, amnestic, and for sedating a patient. Its high potency and lipophilicity makes it an excellent drug for transmucosal administration in accordance with the presant invention.

WO 91/03099 PCT/US89/03518 33 1 A suitable mixture was prepared by combining the following ingredients as follows: Ingredient grams triazolam 0.05% 0.01 citric acid 1% 0.2 Ribotide 2% 0.4 Compritol 888 2% 0.4 aspartame 2% 0.4 vanilla microcaps 5% vanilla cream microcaps 5% wild cherry microcaps 3% 0.6 peppermint microcaps 3% 0.6 compressible sugar 25.65% 5.13 maltodextrin 5Q.3% ,26 100% 20.0 The ingredients were combined in a mixer in such a fashion as to ensure a uniform distribution of all ingredients within the mixture. Aliquots of 2 grams each were then hydraulically compressed around a commercially available wax-coated compressed paper holder, using a force sufficient to provide a enal volume of 2 cubic centimeters. The procedure resulted in the preparation of oral transmucosal dosage forms, each containing milligrams of triazolam, in this example, oxazepam was incorporated into a compressed dosage form. Oxazapam is a known potent lipophilic drug useful as an anxiolytic, an amnestic, and for sedating a patient. Xts high potency and lipophilib~ty WO 91/03099 PCT/US89/03518 34 1 makes it an excellent drug for transmuco&l administration in accordance with the present invention.

A suitable mixture was prepared by combining the following ingredients as follows: Inrtedient gms citric acid 1% oxazepam 1,5% 0Z,3 ribotide 2% 0.4 compritol 888 2% 0.4 aspartame 2% 0.4 vanilla microcaps 5% vanilla cream microcaps 5% wild cherry microcaps 3% 0.16 peppermint microcaps 3% 0.6 compressible sugar 25.17% 5.03 maltodextrin 50.332 IQ4Q7 100% The ingredient were combined in a mixer in such a fashion as to ensure a uniform distribution of all ingradients within the mixture. Aliquots of 2 grams each were then hydraulically compressed around a commercially available wax-coated compressed paper holder, using a force asufficient to provide a tfinal volume of 2 cubic centimeters., The procedure resulted in the preparation of oral tranamucosal dosage forms, each containiYng milligrams of oxamzpamo In this example, larazapam in incorporated into a compressed dosage form. Lorazepan is a known potent lipophilic drug useful as an anxiolytic, an annestic, and for sedating a patient, Its high potency and lipophilicity WO 91/03099 PCT/US89/03518 1 makes it an excellent drug for transmucosal administration in accordance with the present invention.

A suitable mixture is prepared by combining the following ingredients as follows: Ingredient Sgam Lorazepam 0.2% 0.04 citric acid it 0,2 Ribotide 2% 0.4 Compritol 888 2% 0.4 aspartame 2% 0.4 vanilla microcaps 5% vanilla cream microcaps 5% wild cherry microcaps 3% 0.6 peppermint microcaps 3% 0.6 compressible sugar 25.6% 5.12 maltodextrin 51, 21 1QJ.24 100% The ingredients are combined in a mixer in such a fashion as to ensure a uniform distribution of all ingredients within the mixturts. Aliquots of 2 grams each are then hydraulically compressed around a commercially available wax-coated compressed paper holder, using a force sufficient to provide a final volume of 2 cubic centimeters. The procedure results in the preparation of oral tranrucosal dosage forms, each containing milligrams of lorazepam.

Xn this example, atomidate was incorporated into a compressed dosage form, Etomidate is a known potent lipophilie drug useful as an anxiolytic, sedative and for anesthetizing a patient. Its high potency and lipophilicity makes it an excellent drug for tranamucoual administration in accordanca with the present invention.

A suitable mixture was prpared by combining the following ingretdients as follows: WO 91/93099 PCT/US89/03518 36 1 Ingredient gram.

etomidate 1% 0.2 citric acid 1% 0.2 ribotide 2% 0.4 compritol 888 2% 0.4 aspartame 2% 0.4 vanilla microcaps 5% vanilla cream microcaps 5% wild cherry microcaps 3% 0.6 peppermint microcaps 3% 0.6 compressible sugar 25.3% 5.06 maltodextrin 50.7 01L 100% The ingredients were combined in a mixer in such a fashion as to ensure a uniform distribution of all ingredients within the mixture. Aliquots of 2 grams each were then hydraulically compressed around a commercially available wax-coated compressed paper holder, using a force sufficient to provide a final volume of 2 cubic centimeters. The procedure resulted in the preparation of oral transmucosal dosage forms, each containing milligrams of etomidate.

Examdple_.6 in this example, thiamylal was incorporated into a compressed dosage form, Thiamylal is a known potent lipophilic drug useful as an anxiolytic, sedative and for anesthetizing a patient. Xts high potency and lipophilicity makes it an excellent drug for transmucosal administration in accordance with the present invention, A suitable mixture was prepared by combining the Slowing ingredients as follows: WO 91/03099 PCT/US89/03518 37 1 Ingredient granAs citric acid 1% 0.2 ribotide 2% 0.4 compritol 888 2% 0.4 aspartame 2% 0.4 vanilla microcaps 5% vanilla cream microcaps 5% wild cherry microcaps 3% 0.6 peppermint microcaps 3% 0.6 thiamylal sodium 25% maltodextrin 32% 6.4 compressible sugar 20 A0 100% The ingredients were combined in a mixer in such a fashion as to ensure a uniform distribution of all ingredients within the mixture. Aliquots of 2 grams each were then hydraulically compressed around a commercially available wax-coated compressed paper holder, using a force sufficient to provide a final volume of 2 cubic centimeters. The procedure resulted in the preparation of oral transmucosal dosage forms, each containing grams of thiamylal.

Example 7 The same procedure described with reference to Example 1 is used but levadopa is used in place of methohexital. Levadopa is used as necessary to treat Parkinson's Disease.

In this example, isosorbide dinitrate was incorporated into a compressed dosage form. In order to make 20 dosage forms of 2000 milligrams (2 grams), each containing 20 milligrams of isosorbide dinitrate (for a total formula weight of 20 grams), the following ingredients were combined: WO 91/03099 PCT/US89/03518 38 Ingredient grams isosorbide dinitrate 1% 0.2 citric acid 1% 0,2 ribotide 2% 0.4 compritol 888 2% 0.4 aspartame 2% 0.4 vanilla microcaps 5% vanilla cream microcaps 5% wild cherry microcaps 3% 0.6 pepprmint microcaps 3% 0.6 compressible sugar 25.3% 5.06 maltodextrin 5.71 0 100% The ingredients were combined in a mixer in such a fashion as to ensure a uniform distribution of all ingredients within the mixture. Aliquots of 2 grams each were then hydraulically compressed around a commercially available wax-coated compressed paper holder, using a force aufficient to provide a final volume of 2 cubic centimeters. The foregoing procedure resulted in the preparation of 20 oral transmucosal dosage forms, each containing 10 milligrams of isosorbide dinitrate.

Example.9 in this example, the same procedure as that described in Example 8 is followed except captopril is substituted for isosorbide dinitrate.

In this example, the same procedure as that described in Example 8 is followed except nifedipine was substituted for isosorbide dinitrate WO 91/03099 PCr/US89/03518 39 Example 11 In this example, the same procedure as that described in Example 8 is followed except clonidine is substituted for isosorbide dinitrate.

Example 12 In this example, the same procedure as that described in Example 8 is followed except esmolol is substituted for isosorbide dinitrate.

i0 Example 13 In this example, nitroglycerin was selected for incorporation into a compressed dosage form. Nitroglycerin is a potent lipophilic drug useful to control angina and blood pressure in perioperative hypertension, especially when associated with cardiovascular procedures and to produce controlled hypertension during surgical procedures.

The high potency and lipophilicity of the nitroglycerin make it an excellent drug for transmucosal administration in accordance with the present invention.

A suitable mixture is prepared by combining 16 milligrams of nitroglycerin; 400 milligrams citric acid; 400 milligrams calcium stearatet 17.7 grams compressible sugar, 17.7 grams of maltodextrin; 600 milligrams peppermint microcaps; 1.2 grams cherry microcaps and 2 grams vanills microcaps. Aliquots of 2000 milligrams each are then hydraulically compressed around a commercially available wax-coated compressed paper holder, using a force sufficient to provide 'a final volume of 2 cubic centimeters. The foregoing procedure results in the preparation of 20 lollipopc, each containing 0.8 milligrams of nitroglycerin.

WO 91/03099 PCT/US89/03518 Example 14 To make 10 dosage forms of 2000 milligrams (2 grams), each containing 10 mg of nifedipine (for a total formula weight of 20 grams) the following ingredients were combined: Ingredient grams Ribotide 1% 0.2 Compritol 888 5% vanilla microcaps 5% vanilla cream microcaps 5% Nifedipine 19.0% 3.8 Compressible sugar 21.7% 4.34 Dextromaltrin 43.3% 8.66 100% 20 grams Appropriate changes in flavoring ingredients can be made in this formula to mask or optimize flavor perception in order to achieve ultimate acceptance of the dosage form by the desired patient group, be it adult, juvenile, pediatric, or neonate.

Example In this example, ergotamine is selected for incorporation into a compressed dosage form. Ergotamine is a potent lipophilic drug useful for relieving the pain associated with migraines. Its high potency and lipophilicity make it an excellent drug for transmucosal administration in accordance with the present invention.

A suitable matrix is prepared by combining milligrams of ergotamine; 5.22 grams compressible sugar; 10.44 grams maltodextrin; 400 milligrams of Aspartame; 200 milligrams natural mint; 600 milligrams cherry; 1.0 gram artificial vanilla, 1.0 artifical vanilla cream; 300 milligrams ribotide; and 800 milligrams Compritol 888.

Alloquats of 2000 milligrams each are then hydraulically WO 91/03099 PCT/US89/03518 41 1 compressed around a commercially available wax-coated compressed paper holder, using a force sufficient to provide a final volume of 2 cubic centimeters. The foregoing procedure results in the preparation of lollipops, each containing 4 milligrams of ergotamine.

Example 16 A drug-containing lollipop within the scope of the present invention to be used in the treatment of pain associated with oral candiasis is made according to the procedure of Example 15, except that the ingredients are combined in the following amounts.

Inredient grams Clotrimazole 1.0% 0.2 Natural mint 1.0% 0.2 Ribotide 1.5% 0.3 Aspartame 2.0% 0.4 Wild cherry 3.0% 0.6 Compritol 888 4.0% 0.8 Artificial vanilla 5.0% Artificial vanilla cream 5.0% Compressed sugar 25.83% 5.17 Maltodextrin 51.67% 10.33 The foregoing procedure results in the preparation of 10 lollipops, each containing 20 milligrams of clotrimazole.

Example 17 A drug-containing lollipop within the scope of the present invention to be used in the treatment of pain associated with symptoms of esophagitis is made according to the procedure of Example 15, except that the ingredients are combined in the following amounts.

WO 91/03099 PCT/US89/03518 42 Ingredient Grans Natural mint 1.0% 0.2 Ribotide 1.5% 0.3 Aspartame 2.0% 0.4 Wild cherry 3.0% 0.6 Compritol 888 4.0% 0.8 Artificial vanilla 5.0% Artificial vanilla cream 5.0% Compressed sugar 9.5% 1.9 Maltodextrin 19.0% 3.8 Al. sucrose sulfate 50.0% 10.0 The foreoing procedure results in the preparation of 10 lollipops, each containing 1 gram of aluminum sucrose sulfate.

i Example 18 A drug-containing lollipop within the scope of the present invention to be used in the treatment of pain associat\d with respiratory distress is made according to the procedure of Example 15, except that the ingredients are combined in the following amounts.

Inredient %a Natural mint 1.0% 0.2 Ribotide 1.5% 0.3 Aspartame 2.0% 0.4 Wild cherry 3.0% 0.6 Compritol 888 4.0% 0.8 Artificial vanilla 5.0% Artificial vanilla cream 5.0% Oxtriphylline 10.0% Compressed sugar 22.83% 4.57 Maltodextrin 45.67% 9.13 The foregoing procedure results in the preparation of 10 lollipops, each containing 200 milligrams of oxtriphylline.

WO91/03099 PCT/US89/03518 43 1 Example 19 A drug-containing lollipop within the scope of the present invention to be used in the treatment associated with patients experiencing nausea and vomiting is made according to the procedure of Example 15, except that the ingredients are combined in the following amounts.

Ingredient arams Natural mint 1.0% 0.2 Ribotide 1.5% 0.3 Aspartame 2.0% 0.4 Meclizine 2.5% Wild cherry 3.0% 0.6 Compritol 888 4.0% 0.8 Artificial vanilla 5.0% Artificial vanilla cream 5.0% Compressed sugar 25.33% 5.07 Maltodextrin 50.67% 10.13 The foregoing procedure results in the preparation of 10 lollipops, each containing 50 milligrams of meclizine.

Example A drug-containing lollipop within the scope of the present invention to be used in the treatment of the symptoms associated with polyuria is made according to the procedure of Example 15, except that the ingredients are combined in the following amounts.

Inaredient at....t Desmopressin 0.001 0.0002 Natural mint 1.0% 0.2 Ribotide 1.5% 0.3 Aspartame 2.0% 0.4 Wild cherry 3.0% 0.6 Compritol 888 4.0% 0.8 Artificial vanilla 5.0% Artificial vanilla cream 5.0% Compressed sugar 26.17% 5.234 Maltodextrin 52.33% 10.47 WO 91/03099 PCT/US89/03518 44 1 The foregoing procedure results in the preparation of 10 lollipops, each containing 20 micrograms of desmopressin.

Example .21 A drug-containing lollipop within the scope of the present invention to be used in the treatment of the symptoms of Parkinson's Disease is made according to the procedure of Example 15, except that the ingredients are combined in the following amounts.

Inaredient rams Natural mint 1.0% 0.2 Carbidopa 1.25% 0.25 Ribotide 1.5% 0.3 Aspartame 2.0% 0.4 Wild cherry 3.0% 0.6 Compritol 888 4.0% 0.8 Artificial vanilla 5.0% Artificial vanilla cream 5.0% Levodopa 12.5% Compressed sugar 21.58% 4.32 Maltodextrin 43.17% 8.63 The foregoing procedure results in the preparation of 10 lollipops, each containing 25 milligrams of carbidopa and 250 milligrams of levodopa.

Examlle,22 A drug-containing lollipop within the scope of the present invention to be used to induce labor or reduce postpartum hemorrhage is made according to the procedure of Example IS, except that the ingredients are combined in the following amounts.

WO 91/03099 PCT/US89/03518 1 Ingredient grams Oxytocin 0.001% 0.0002 Natural mint 1.0% 0.2 Ribotide 1.5% 0.3 Aspartame 2.0% 0.4 Wild cherry 3.0% 0.6 Compritol 888 4.0% 0.8 Artificial vanilla 5.0% Artificial vanilla cream 5.0% Compressed sugar 26.17% 5.234 Maltodextrin 52.33% 10.466 The foregoing procedure results in the preparation of 10 lollipops, each containi'ng 20 micrograms of oxytocin.

Example 23 A drug-containing lollipop within the scipe of the present invention to be used in the treatment of the symptoms of diabetes is made according to the procedure of Example 15, except that the ingredients are combined in the following amounts.

Inredient A. .grams Insulin 0.05% 0.01 Natural mint 1.0% 0.2 Ribotide 1.5% 0.3 Aspartame 2.0% 0.4 Wild cherry 3.0% 0.6 Compritol 888 4.0% 0.8 Artificial vanilla 5.0% Artificial vanilla cream 5.0% Compressed sugar 26.15% 5.23 Maltodextrin 52.3% 10,46 The foregoing procedure results in the preparation of 10 lollipops, each containing the equivalent of 30 units of insklin.

6. Summarv Xn summary, it can be seon that the present invention provides compositions and methods of manufacture Wo 91/03099 PCT/US89/03518 46 1 for administering a drug in a precise dose in order to obtain a rapid effect. In addition, the present invention provides methods for forming a drug containing candy matrix having the following attributes: drugs having relatively low melting points can be used without degrading the drug; disagreeable flavor characteristics can be masked; insoluble ingredients can be used; chemically incompatible !igredients can be used; buffers can be added to optimize the ratio of ionized and nonionized drug form; chemical agents to modify the dissolution characteristics of the drug can be added; dissolution characteristics can be modified mechanically by changing the compressive forces used to form the lollipop; stratification of active ingredients can be accomplished; and the dosage can be modified by utilizing an assembly of dosage units onto a holder.

The present invention, therefore, provides the ability to provide precise control over the dosage and affect of the drug, This is obtained by transmucosal administration by sucking on a lollipop containing the drug. As a result, the precise dosage and effect can be obtained.

The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the %WO 91/03099 PCT/US89/03518 1 foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

Claims (65)

1. A method for producing a drug-containing lollipop for use in transmucosal delivery of the drug to a patient, the method comprising the steps of: obtaining a pharmacologically effective dose of the drug in a substantially powdered form, the drug being capable of absorption through mucoal tissues of the mouth, pharynx or oesophagus; obtaining a soluble carbohydrate material capable of forming a compressible confeationary matrix and capable of dissolving in the mouth of the patient; m.tr'i mixing the drug and the carbohydrate material at a temperature below the melting points of the 15 drug and the carbohydrate material to form a drug- oataining matrix such that the drug in dispersed substantially throughout the matrix, the drug-containing matrix being capable of releasing the drug for absorption through the mucosal tissues upon dissolution of the matrix 20 in the mouth of the patient; and compressing the drug-containing matrix in a mold to form an integral mass such that, when the integral mass dissolves in the mouth of the patient, the drug is released for absorption through the muoosal tissues; and incorporating a holder as part of the integral mass in order to form the drug-containing lollipop.

2. A method i!or producing a drug-containing lollipop for use in tranamucosal delivery of the drug to a patient as defined in claim 1 wherein a buffer is added to the drug-containing matrix.

3. A method for producing a drug-containing lollipop for use in tranamucosa. delivery of the drug to a patient as defined in claim 2 wherein the buffer modifies the p~a of the drug ouch that, when the integrO. mass is dissolved, a maJority of the drug remains non-ionized in order to S facilitate tranomucosal absorption of the drug.

4. A method for producing a drug-containing lollipop for use in tranomucosaal delivery of the drug to a patient an defined in claim 2 or 3 wherein the buf fer is citric acid/aodium citrate. So A method for producing a drug -contaIing lollipop .444 for use in tranamucoaal delivery of the drug to a patient as defined in any preceding claim wherein the drug has is sufficient lipophilic properties such that the drug can be Otto *to: absorbed through the mucoaal tissue. A method for producing a drug-containing lollipop for use in tranamucosal delivery of the drug to a patient '~20 an defined in any preceding claim wherein the holder is *t,4 incorporated into the Integral mass by compresoion of the 4.44 drug-containing matrix around the holder during compressing A method for producing a drug-containing lollipop tot use in.trandmudosal delivery of the drug to a patient as defined iAn aps,? one of iplaiws 1 to 5 wherain the holder in incorporated as part oEl the integral man# by affixing the holder to the interll mass atear compreasina atop 0. A method f or IJ roducing a drug-containing lollipop 'or us* In ttnmuceal delivery of the drug to a patient aa, defined in ary pracedina claim wherein the soluble carbohydrate material in tho drug-tcontainiua Matrix includes compressible confectionary sugar.

9. A method for producing a drug-containing lollipop for use in transmucosal delivery of the drug to a patient as defined in any preceding claim wherein the drug- containing matrix includes a lubricating agent such that the integral mass can be released from the mold after compressing step

10. A method for producing a drug-containing lollipop for use in transmucosal delivery of the drug to a patient tok, as defined in any preceding claim wherein the drug- tool l*i* containing matrix includes at least one flavor enhancer. 4 15 11. A method for producing a drug-containing too$ lollipop for use in tranamucosal delivery of the drug to a patient as defined in any preceding claim wherein the drug- I• "containing matrix include maltodextrin in order to aid in *I I dissipating any unpleasant flavors of the drug.

12. A method for producing a drug-containing lollipop for use in tranamucosal delivery of the drug to a patient 4 as defined in any preceding claim wherein a substantially water-insoluble component is added to the drug-containing matrix such that the dissolution of the integral mass in the mouth of the patient is made slower by the substantially water-insoluble component in the drug- containing matrix.

13. A method for producing a drug-containing lollipop for Use in transmucosal delivery of the drug to a patient as defined in any preceding claim wherein the confectionary mixture i# compressed. with forces in the range of from 2000 newtons to 5000 newtona. a 'y I1 f I f.

14. A method for producing a drug'-containing lollipop for use in transmucosal delivery of the drug to a patient as defined in any preceding claim wherein the drug is methohexital. A method for producing a drug-containing lollipop for use in transmucosal delivery of the drug to a patient as defined in claim 14 wherein the drug-containing matrix comprises from 10 milligrams to 500 milligrams of methohexital. of,, 6 0 0 k6*16. A method for producing a drug-containing lollipop toti for use in tranamucosal delivery of the drug to a patient as defined in any one of claima I to 13 wherein the drug is tit:triazolano oxazepami lorazopamt etomidate, or thiamylal. A method for producing a drug-containing lollipop for use in tranomucosal delivery of the drug to a patient a ss 20 as defined in any one of claims 1 to 13 wherein the drug is nitroglycerin. a.Ils. X method for producing a drug-containing lollipop for use in tranamucoaal delivery of the drug to a patient in a dooe-to-effect manner, the method comprising the steps of: obtaining a pharmacologically effective doe* of the drug in a substantially powdered lipophilic form capable of absorption through muconal tissues o~f the mouth# pharynx# or oasophaqus: obtaining a soluble carbohydrate material capable of forming a on~pransibla confectioniary matrix and capable of disso-Aving In the mouth of the patient; obtaining a buffer capable of modifying the k' j pKa of the drug such that a majority of the drug remains non-ionized in order to facilitate transmucosal absorption of the drugl mixing the drug, the soluble carbohydrate material, and the buffer at a temperature below the melting points of the drug and the carbohydrate material to form a solid drug-containing matrix such that the drug is dispersed substantially througboj't tha matrix, the drug- containing matrix being capable of releasing the drug for absorption through the mucosal tissues upon dissolution of the matrix in the mouth of the patient; compressing the drug-containing matrix in a S t| mold to A>,eR an integral mass such that when the integral S* mass disls in the mouth of the patient, the drug is 15 releaaed for absorption through the mucosal tissues such that the drug is administered in a dose-to-effect zanner; and incorporating a holder as part u£ the integral mass in order to form the drug-containing 20 lollipop.

19. A method for producing a drug-containing lollipop for use in tranamucosal delivery of the drug to a patient as defined in claim 18 wherein the holder is incorporated into the integral mass by compression of the drug- containing matrix around the holder during compressing step A method for producing a drug-containing lollipop for use in tranmuconal delivery of the drug to a patient as defined in claim 18 wherein the holder is incorporated as part of the integral mass by affixing the holder to the integral mass after covipressing stoep

21. A method for producing a drug-containing matrix for use in transmucosal delivery of the drug to a patient as defined in any one of claims 18 to 20 wherein the drug- containig mixture includes maltodextrin in order to aid in dissipating any unpleasant flavors of the drug.

22. A method for producing a drug-containing matrix for use in transmucosal delivery of the drug to a patient as define4 in any one of claims 18 to 21 wherein the buffer comprises citrie acid/sodium citrate.

23. A method for producing a drug-containing matrix for use in transmuidosal delivery of the drug to a patient as defined in any one of claims 18 to 22 wherein the drug- 15 containing matrix includes compressible sugar.

24. A method for producing a drug-containing matrix for use in transmucosal delivery of the drug to a patient as defined in any one of claims 18 to 23 wherein the drug- 20 containing matrix includes a flavouring ingredient. A method for producing a drug-containing matrix f' for use in tranamucosal delivory of the drug to a patAnt as defined in any one of claims 18 to 24 wherein the confectionery mixture is compressed with forces in the range of from 2000 newtons to 5000 newtons.

26. A method for producing a drug-containing matrix for use in transmucoaal delivery of the drug to a patient as defined in any one of claims 18 to 25 wherein the drug is methohexital. A method for producing a drug-containing lollipop for use in tranamuteoal delivery of the drug to a patient as defined in claim 26 wherein the drug-containing matrix comprises from 10 milligrams to 500 milligrams of methohexital.

28. A method for producing a drug-containing matrix for use in transmucosal delivery of the drug to a patient as defined in any one of claims 18 to 25 wherein the drug is triazolan, oxazepam, lorazepam, etomidate or thiamylal.

29. A method for pr6ducing a drug-containing matrix for use in transmucosal delivery of the drug to a patient as defined in any onie of claims 18 to 25 wherein the drug t o is iosorbide dinitrate, captopril, nifedipine, clonidine, il or esimolol. 4444 A method for producing a drug-containing matrix for use in transmucosal delivery of the drug to a patient as defined in any one of claims 18 to 25 wherein the drug is nitroglycerin.

31. A method for producing a drug-containing matrix for use in transmucosal delivery of the drug to a patient as defined in any one of claims 18 to 30 wherein the drug is a potent, fast-acting drug.

32. A method for producing a drug-containing matrix for use in transmucosal delivery of the drug tc a patient as defined in claim 31 wherein the drug has effects on the central nervous system of the patient.

33. A method for producing a drug-containing matrix for use in transmucoal delivery of the drug to a patient as defined in claim 31 wherein the drug has effects on the cardiovascular system of the patient.

34. A method for producing a drug-containing matrix for use in transmucosal delivery of the drug to a patient au defined in claim 31 wherein the drug has effects in the renal vascular system of the patient. A method for producing a drug-containing matrix for use in transmucosal delivery of the drug to a patient as defined in any one of claims 18 to 34 wherein the materials in the drug-containing matrix include a lubricating agent such that the integral mass can be released from the mold after compressing step

36. A method for producing a drug-containing matrix for use in transmucosal delivery of the drug to a patient Oil as defined in claim 35 wherein the lubricating agent comprises glycdryl behenate. got%$' 37. A method for producing a drug-containing matrix 20 Ror use in transmucogal delivery of the drulg to a patient as defined in claim 35 wherein the lubricating agent is a .,,,,,substantially water-insoluble component such Chat the dissolution of the integral mass in the mouth Of the patient in made slower by the substantially water-insoluble component in the drug-containing matrix,

38. A method for producing a drug-containing lollipop for use In transmucosal delivery of the drug to a patient an defined in any one of claims 18 to 37 further comprising the stop of mixing at least one flavour enhancer with the dr-44-containing matrix.

39. A drul-containing lollipop for use in transmuconal deliveryof the drug t* a patient,.said IV l composition comprising: a soluble, compressible, substantially powdered carbohydrate material; a pharmacologically effective dose of a lipophilic drug in a substantially powdered form, the drug being capable of absorption through mucosal tissues of the mouth, pharynx, or oesophagus and being dispersed substantially uniformly throughout the carbohydrate material at a temperature below the melting points of the drug and the carbohydrate material and compressed with the carbohydrate material into a solid integral mass which is fit' capable of dissolving in the mouth of the patient so that tot- $,#III the drug is releasod for absorption through mucosal tismues of the mouth, pharynx, or oesophagus upon dissolution of $Oki the integral mass in the mouth of the patient; a buffer which is also dispersed substantially uniformly throughout the integral mass, the buffer being capable of modifying the pKa of the drug such that a majority of the drug remains non-ionized in order to facilitate tranamucosal absorption of the drugq and holder means secured to the integral mass so as to form a drug-containing lollipop, the holder means being configured so as to permit conkenient insertion and removal of the drug-containing integral mass into and out of the mouth of a patient. A drug-containing lollipop for use in tranamucosal delivery of the drug to a patient as defined in claim 39# wherein the buffer is citric acid/sodium citrate.

41. A drug-containing lollipop for use in transmuconal delivery of the drug to a patient an defined in claim 39 or 40, wherein the soluble carbohydrate material in the drug-containing integral mass includes compressible confectionary sugar.

42. A drug-containing lollipop for use in transmucosal delivery of the drug to a patient as defined in any one of claims 39 to 41 wherein the drug-containing integral mass further includes a lubricating agent dispersed substantially uniformly throughout the integral mass in order to aid in the manufaotuQ of the drug- containing lollipop.

43. A drug-containing lollipop for uso in transmucosal delivery of the drug to a patient as defined in any one of claims 39 to 41, wherein the drug-containing integral mass further includes maltodextrin dispersed substantially uniformly through out the integral mass in order to aid in dissipating any unpleasant flavors of the drug in the integral mass.

44. A drug-containing lollipop for use in 4 I 'transmucosal delivery of the drug to a patient as defined 4,4, in claim 43, wherein the drug-containing integral maos '4,4 5, further comprises at least one flavor enhancer dispersed substantially uniformly throughout the integral mass. A drug-containing lollipop for use in transmucosal delivery of the drug to a patient as defined in any one of claim# 39 to 44 wherein the drug-containing integral mas# further comprises a substantially water- insoluble component dispersed substantially uniformly throughout the inteoral mass in order to slow the dissolution of the integral mass in the mouth of the patient.

46. A drug-containing lollipop for use in transmucosal delivery of the drug to a patient as defined in any one of claims 39 to 45 further comprising at least one flavoring.

47. A drug-containing lollipop for use in transmucosal delivery of the drug to a patient comprising: a soluble, compressible carbohydrate material; a pharmacologically effective dose of a drug in a substantially powdered form, the drug being capable of absorption through mucosal tissues of the mouth, pharynx, or oesophagus and being dispersed substantially uniformly throughout the carbohydrate material at a temperature below the melting points of the drug and the carbohydrate 15 material and compressed with the carbohydrate material into a solid integral mass which is capable of dissolving in the mouth of a patient so that the drug is released for S. absorption through muoosal tissues of the mouth, pharynx or i t f1 oesophagus upon dissolution of the integral mais in the to t" 20 mouth of the patient; *,tto holder means secured to the integral mass so as to form a drug-containing lollipop, the holder means being 06#.64 configured so as to permit convenient insertion and removal of the drug-oontaining integral mass into and out of the mouth of the patient. A drug-containing lollipop as defined in claim 47 further comprising at least one flavouring dispersed within said integral mass.

49. A drug-containing lollipop as defined in claim 47 or 48 further comprising at least one releasing agent dispersed within said integral mass. /t1 59 A drug-containing lollipop as defined in any one of claims 47 to 49 further comprising at lemst one flavour enhancer dispersed within said integral mass.

51. A drug-containing lollipop as defined in any one of claims 47 to 50 further comprising at least one sweetener in addition to said carbohydrate material dispersed within said integral mass.

52. A method for producing a drug-containing lollipop for use in transmucosal delivery of the drug to a patient, the method comprising the steps oft obtaining a pharmacologically eftective dose of a potent drug in a form capable of absorption 15 through mucosal tissues of the mouth, pharynx, or oesophagus; obtaining a soluble, compressible matrix I t I S. material capable of dissolving in the mouth of the patient; mixing the drug and the soluble matrix 20 material at a temperature below the melting point of the compressible matrix material to form a drug-containing lollipop such that the drug is dispersed substantially throughou the matrix material, the drug-containing matrix being capable of releasing the drug for absorption 4 throughOta the mucosal tissues upon dissolution of the matrix in the mouth of the patient; and compressing the drug-containing matrix about a holder in a mold to form an integral mass such that the holder in incorporated as part of the integral mass in order to £ftm a drug-containing lollipop and such that, when the integral mass dissolves in the mouth of the patient, the drug is released for absorption through the mucosal tissues.

53. A method for producing a drug-containing lollipop for use in transmucosal delivery of the drug to a patient as defined in claim 52 wherein the drug is droperidol.

54. A method for producing a drug-containing lollipop for use in transmucosal delivery of the drug to a patient as defined in claim 52 wherein the drug has antiemotic effects.

55. A method for producing a drug-containing lollipop for use in transmucosal delivery of the drug to a patient as defined in claim 52 wherein the drug has antifungal effects.

56. A method for producing a drug-containing lollipop for use in tranmucosal delivery of the drug to a patient as defined in claim 52 wherein the drug has antiparkinson t~ I sffects, I

57. A method for producing a drug-containing lollipop for use in tranmucosal delivery of the drug to a patient I as defined in claim 52 wherein the drug has antiscoratory teffects, Sa. A method for producing a drug-containing lollipop for use in tranrmucosal delivery of the drug to a patient as defined in claim 52 wherein the drug has bronchodilator effects, S9. A method for producing a drug-containing lollipop for use in transmunosal delivery of the drug to a patient an defined in claimd 52 wherein the drug has antimigran Effots. A method for producing a drug-containing lollipop fov use in transmucosal delivery of the drug to a patiLent as defined in claim 52 wherein the drug has oxcytocic effects.

61. A method for producing a drug-containing lollipop for use in tranomucooal delivery of the drug to a patient as defined in claim 52 wherein the drug has antidiuretio effects.

62. A method for producing a drug-containing lollipop for use in transmucosal, delivary of the drug to a patient as defined in claim 52 Ihorein the drug is pentobarbital.

63. A method for produ~cing a drug-containing lollipop for use in transmuconal delivery of the drug to a patient as defined in claim 52 wherein the drug is thiopental.

64. A method for producing a drug-containing lollipop for use in transmuconal delivery of the drua to a patient as defined in claim 52 wherein the drug is diazapam. 6S. A method for pr'oducing a drug-containing lollipop for use in tranamuoosal delivery o1t the drug to a patient a# defined in claim 52 wherein the drug in midatolam, 66, A method for producing a drug-containing lollipop for use in ttaftemcosal, delivery of the drug to a patient to defined in claim 52 wherein the drug is haloparidol,

67. A method for producing a drug-containing lollipop for use in branamuconal delivery, of the drug to a patient as defined in claim 52 wherein the drug I# propanidid.

68. A method for producing a drug-containing lollipop for use in transmuoosal delivery of the drug to a patient as dEfined in claim 52 wherein the drug is disoprofol.

69. A method for producing a drug-containing lollipop for use in transmuqosal delivery of th\ drug to a patient as defined in claim 52 wherein the drug is ketamina, A method for producing a drug-containing lollipop for use in transmucsal delivery of the drug to a patient as defined in claim 52 wherein the drug is diprivan. I I S71, A method for producing a drug-containing lollipop for use in transmuoosal delivery of the drug to a patient as defined in claim 52 wherein the drug is bretylium.

72. method for producing a drug-containing lollipop for use in transmuconsa delivery of the drug to a patient as defined in claim 52 wherein the drug is onalapril. 73, A method for producing a drug-containing lollipop o il for use in transmuconsal delivery of the drug to a patient f as defined in claiA 52 wherein the drug is labetolol. 29 74, A method for producing a drug-containing lollipop for use in transmucosal delivery of the drug to a patieant as defined in claim 52 whorein the drug is ilidoaain. A method for prttducing a drug-containing lollipop for use In dransmaucoal delivery of the drug to a patient as defined in claim 52 whrein the drug U motoprololS lG. A method for producing a druw-containing lollipop foX Und in trandumessal delivery of the drug to a patient (i as defined in claim 52 wherein the drug is nadolol.

77. A method for producing a drug-containing lollipop for use in transmucosal delivery of the drug to a patient as dtefined in claim 52 wherein the druz is nitroprusside. 78, A method for producing a drug-ontaining lollipop for use in tranmuaosal delivery of the drug tn a patient as defined in claim 52 wherein the drug is propanolol.

79. A method for producing a drug-containing lollipop for use in transmucosal delivery of the drug to a patient as defined in claim 52 wherein the drug is dopazine. ,it r 15 80, A methud for protaing a drug-containing lollipop t for tase 4n transmucoeal delivery of the drug to a patient a# defined in claim 52 wherein the drug is benzquinamide. *1 .e tt I2. A method for producing a drug-ontaininjg lollipop o 20 for use in transmucosal delivery of the drug to a patiant 25 as defined in claim 52 wherein the drug is metoclaind. r Ir 44 I ,r 4#04k S82. A ramethod for producing a drug-containing lollipop for use in transmucosal delivery of the drug to a patient as defined in claim 52 wherein the drug is atoolopramide, 83 A method for producing a druag-containing lollipop for use in transmuconal delivery of the drug to a patient Laa defined in claim SI wherein the drug in prochlobraza. 84 A methed for producing a dru-Wcontainiul lollipop for use in tranamucogal delivery of the drug to a attnt as deatin# i n claim 52 wherein the drug in trimethobantamide. A method for producing a drug-containing lollipop for use in tranamucosal delivery of the drug to a patient as defined in claim 52 wherein the drug in clotrimazole,

86. A method for producing a drug-containing lollipop for use in tranamuconal delivery of the drug to a patient an defined in claim 52 wherein the dri114 is nyntatin.

87. A method for producinq 4 drug-containing lollipop for use in trannmuonal delivery of the drug to a patient an defined in claim 52 wherein the drug in carbiopa. k I so. N, method for producing a drug-containing lollipop is for use In transmucosal delivery of the drug to a patient it$',as defined in claim 52 wherein the drug In levodopa. *ts I 9. A method for producing a drug-containing lollipop for use in bransmuconal delivery of the drug to a patient #Ot ab, defined in claim 52 wherein the drug in sucralf ate. 64#t90. A method for producing a drug-containing lollipop for Ube in trannmucooal delivery of the drug to a patient an defined in claim 52 wherein the drug in albutero., 2S 91, A itethod for producing a drug-contaiuiino lollipop for use in tranamuconal delivery of the drug to a patient an defined in claim 32 wherein the drug in aminophylline.

92. A method for Droducing a drua-containing lollipop for uine In ttansmuonal delivery of the drug to a patient a# defined in claim 52 wherein the drug in beclomethadnoe 93, x method for producingt a drug-containing lollipop for use in tr6Vamucosal delivery of the drug to a patient as defined in claim 52 wherein the drug is dyphylline.

94. A method for producing a drug-containing lollipop for use in tranemucosal delivery of the drug to a patient as defined in claim 52 wherein the drug is opinephrine. A method for producing a drug-containing lollipop for use in tranamucoal delivery of the drug to a patient as defined in claim 52 wherein the drug is flunisolide. al,,

96. A method for producing a drug-containing lollipop 'o for use in transmucoaal delivery of the drug to a patient I S' as defined in claim 52 wheroin the drug is isoetharine. i(is

97. A method for producing a drug-containing lollipop for use in transmucosal delivery of the drug to a patient I ii i I as defined in claim 52 wherein the drug is isoproternol r HCl It. 20 98 A method for producing a drug-containing lollipop a for use in transmucoaal delivery of the drug to a patient o)as defined in claim 52 wherein the drug is metaproteronol.

99. A method for producing a drug-containing lollipop for use in transmuecoal delivery of the drug to a patient asn defined in claim 52 wherein the drug is oxtriphylline.

100. A method for producing a drug-containing lollipop for use in transmucoal delivery of the drug to a patient as defined in caim 2r wherein the drug is terbutaline.

101. A method for producing a drug-containing lollipop for use in tranamucosal delivery of the drug to a patient as defined in claim 52 wherein the drug is thoophylline.

102. A method for producing a drug-containing lollipop for use in transmucosal delivery of the drug to a patient as defined in claim 52 wherein the drug is ergotamine,

103. A method fo" producing a drug-containing lollipop for use in transmucosal delivery of the drug to a patient as defined in claim 52 wherein the drug in methysorgide.

104. A method for producing a Crug-containing lollipop I for use in tranemucosal delivery of the drug to a patient .as defined in claim 52 wher.in the drug is sulootidil. *I I 9 is 105. A method for producing a drug-containing lollipop for use in tratnsmucosal delivery of the drug to a patient as defined in claim 52 wherein the drug is ergonovino. 10., A meetiod for producing a drug-contaiinig lollis for use in tranamucocal delivery of the drug to a patient I I as defined in claim 52 wherein the drug is oxytocin.

107. A method for producing a drug-containing lollipop for use in transmucoteal delivery of the drug to a patient as def Inod L! lams S2 wherain the drugr in deamoprssin Aceate,.s 108, A method for producing a drug-oont&1ning lolipop for us in transuaa al dolivery of the drug to a patient as defined in clatim 52 wherein the drug in lypretsSin.

109. A method for producing a drug-containing lollipop for use in transmuctal delivery of the drug to a patient as defined in aim 52 wherein the drug in vapressin.

110. A method for producing a drug-containing lollipop for use in transmucosal delivery of the drug to a patient substantially as hereinbefore described and with reference 52)i to any one of the aforementioned examples.

111. A drug-containing lollipop for use in transmucsal delivery of the drug to a patient substantially'as hereinbefore described and with reference to any one of the aforementioned examples. to: 112. A method for producing a drug-containing lollipop for use in transmucosal delivery of the drug to a patient 4. S'i) substantially as heeinbefore described and with reference to the accompanying drawings.

113. A drug-aontaining lollipop for use in transmucosal delivery of the drug to a patient $to, a substantially as hereinbefore described and with reference i: of 20 to the accompanying 4rawings. 444 Dated thi 8th day of June, 1993 ANEPTAh CORPATION By Xtg Patent Attorneys .ORFrITH HACK CO Fellows Xnstitute of Patent Attorneys of Australia