WO1994009762A1

WO1994009762A1 - Drug delivery device

Info

Publication number: WO1994009762A1
Application number: PCT/US1993/010640
Authority: WO
Inventors: Robert E. Dempski; Robert C. Olivero; Edward C. Schotz
Original assignee: Merck & Co., Inc.
Priority date: 1992-11-05
Filing date: 1993-11-04
Publication date: 1994-05-11
Also published as: AU5592694A; EP0668758A1; CA2147862A1; JPH08502980A

Abstract

The instant invention is directed to a means of processing and delivering to a patient, medicaments, whose exposure control limits are equal to or less than 0.1 mg/m3, in a manner which assures protection of those preparing the dosage form and patient and health care professionals who come in contact with the product.

Description

TITLE OF THE INVENTION DRUG DELIVERY DEVICE

This case is a continuation-in-part of U.S. Serial No. 08/018/912 which was filed on February 17, 1993; which is a continuation of U.S. Serial No. 07/802,000 which was filed on December 3, 1991.

BACKGROUND OF THE INVENTION

Pharmaceutical scientists are rapidly increasing their understanding of disease at the molecular level. As a result, many of the pharmaceutical medicaments which are now available to treat humans and other animals are highly potent and useful only in low dosages. That is, exposure to the medicament, at levels which have traditionally been considered the "no effect" level for many drugs, may lead to very serious side effects, including death. For this reason, conventional procedures may require extensive modifications if they are to be used to produce dosage forms containing these highly potent substances.

Oral dosage forms such as tablets and capsules are convenient for the patient to transport and offer the best chance for patient compliance with the prescribed medication regiment. However, since traditional solid dosage forms utilize powder mixing or dry granulation compressing, these forms represent one of the most difficult and potentially dangerous medicaments to produce. During processing, inhalation is considered the primary route of exposure. However, ingestion by swallowing large inhaled particles which impact on the mucociliary system of the respiratory tract is likely. Ingestion by contamination of hands, dermal contact and transdermal absorption are also possible routes for unintentional receipt of some medicaments.

In addition to the production employee, there is a further risk to the patient, health care professionals and others who come in contact with the product, due to inadvertent contact with the active ingredient. Liquid preparations which contain these highly potent compounds are considerably easier to control. Once the active ingredient is dissolved in an appropriate solvent,, the chance for accidental contamination, at a level which would cause harm, is dramatically reduced. However, liquid preparations are not as convenient to use, may taste harsh and may result in poor patient compliance.

In order to overcome the problems associated with the production and use of solid dosage forms containing highly potent compounds, Applicants have created a novel coated dosage form, wherein the active ingredient is contained within a coating, which is applied to a core, in a quantitative and reproducible process. Using this technology, the medicament is contained within a liquid until it has been applied to the carrier core as a film coating. The film coating mixture both fixes the medicament on the surface of the core and seals the surface so that the chance of active ingredient flaking off the dosage form is greatly reduced. When even greater protection is desired, the film coated core may be further sealed with an overcoat. This additional coating provides an extra level of protection for those who subsequently handle the dosage form.

BRIEF DESCRIPTION OF THE INVENTION

This invention concerns a dosage form and a method of making the dosage form, for the delivery of highly potent medicaments to humans or other animals comprising:

(a) a carrier core; and

(b) a coating which comprises a highly potent medicament; wherein, the coating which comprises the highly potent medicament and a coating material, adheres to the surface of the carrier core fixing the medicament to the surface of the core and entraining the medicament.

Optionally, a protective overcoating may be added to the dosage form to provide further protection. The Class III antiarrhythmic drugs: metnanesulfonamide, N-[ 1 '-(6-cyano-l ,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro- 4(R)-hydroxyspiro[2H-l-benzopyran-2,4'-pipeπdin]-6-yl]-, (+)-, monohydrochloride, (structure I); methanesulfonamide, N-[l'-(6-cyano-l ,2,3,4-tetrahydronaphth-2-yl)- 3,4-dihydro-4-oxo-spiro[2H-l-benzopyran-2,4'-piperidin]-6-yl]-, (+)-, monohydrochloride, (structure II); and methanesulfonamide, N-[ 1 '-[2-(5-benzofurazanyl)ethyl]-3,4-dihydro-4- oxospiro[2H-l-benzopyran-2,4'-piperidin]-6-yl]-, monohydrochloride, (structure III) are examples of highly potent drugs that can be delivered using this device.

A BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows a block diagram of the process steps utilized in the production of the novel dosage form designed to deliver highly potent drugs.

DETAILED DESCRIPTION OF THE INVENTION

This invention discloses a dosage form and a method of making the dosage form, for the delivery of highly potent drugs to humans or other animals comprising:

(a) a carrier core; and

This invention concerns a method for the safe manufacture and delivery to humans and other animals in need thereof, of highly potent medicaments by dispersing the medicament in a coating mixture, spraying the coating mixture on a carrier core and optionally overcoating the coated core with a protective over-coating. The entire coating operation may be conducted within a closed system where the medicament may be contained. The phrase "dosage form" includes, but is not limited to tablets, capsules, spheronized particles, coated non-pareil seeds, boluses, pills, disks, lozenges, controlled delivery devices and any other regularly shaped solid dosage form.

Although any medicament is considered within the scope of this invention, this novel dosage form provides for a particularly safe and effective means to deliver highly potent or highly toxic medicaments, defined as those medicaments which have an Exposure Control Limit of about 0.1 mg/m3 or less. These medicaments include inorganic and organic compounds without limitation, including medicaments that act on the peripheral nerves, ion channels, nuclear receptors, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular system, smooth muscles, blood circulatory system, synaptic sites, neuroeffector junctional sites, endocrine and hormone systems, immunological system, reproductive system, skeletal systems, autocoid systems, alimentary and excretory systems, inhibitory and histamine systems, and those materials that act on the central nervous system such as hypnotics and sedatives.

Examples of beneficial drugs are disclosed in Remington's Pharmaceutical Sciences. 16th Ed., 1980, published by Mack Publishing Co., Eaton, Pa.; and in The Pharmacological Basis of Therapeutics, by Goodman and Gilman, 6th Ed., 1980, published by the MacMillan Company, London; and in The Merck Index. 11th Edition, 1989, published by Merck & Co., Rahway, NJ. The drug can be in various forms, such as charged molecules, charged molecular complexes, ionizable salts or neutral molecules. Acceptable salts include, but are not limited to hydrochlorides, hydrobromide, sulfate, laurylate, palmitate, phosphate, nitrate, borate, acetate, maleate, malate, tromethamine, tartrate, oleate, salicylate, salts of metals, and amines or organic cations, for example quaternary ammonium.

Derivatives of medicaments such as esters, ethers and amides without regard to their ionization and solubility characteristics can be used alone or mixed with other medicaments. Also, a medicament can be used in a form that upon release from the device, is converted by enzymes, hydrolyzed by body pH or other metabolic processes to the parent form, or to a biologically active form.

Exposure Control Limits are based on pharmacological considerations and defined as the time-weighted average concentration for a normal 8 hour workday and 40 hour workweek to which nearly all workers may be repeatedly exposed day after day without adverse effect. To facilitate the derivation of a numerical limit, the equation shown below has been reported. (See E.V. Sargent and G. D. Kirk, "Establishing Airborne Esposure Control Limits in the Pharmaceutical Industry", Am. Ind. Hyg. Assoc. J., 49(6): 309 - 313, 1988, which is hereby specifically incorporated by reference.)

ECL (mg m3) = NOEL (mg kg/dav x BW (kg

V (m3/day) x S (days) x a x SF

Where NOEL is the no-observable-effect-level, BW is the average human body weight (70 kg for males; 50 kg for females); V is the volume of air breathed in an 8 hour day (10 m3/day); S is the time to achieve a plasma steady state; SF is a safety factor; and a is the percent of the compound absorbed.

This concept of exposure limits is based on the principle that exposure to a chemical agent may be permitted up to some tolerance limit greater than zero. This assumes a nonlinear dose- response relationship and allows for the estimation of a NOEL. Generally, the NOEL is based on either the therapeutic effect for which the drug is intended or on one or more clinically recognizable side effects which can occur at or below the therapeutic level.

Generally, the NOEL is determined in populations where it is associated with a certain amount of variability. Individual variability in response to a drug may be due to differences in age, sex, health and nutritional status or genetic factors. When variability within a species is known to be large, a safety factor, usually up to 10 fold, can be used. A 10 fold safety factor also can be used when the NOEL has not been identified and the lowest observable effect dose is used. Larger safety factors (100 to 1000 fold) generally are reserved for risk estimated or inconclusive human data or animal data. The larger safety factors may be applied to compounds with carcinogenic or teratogenic potential.

Exposure Control Limits of 0.5 ug/m3 have been calculated for the Class E antiarrhythmic drugs: methanesulfonamide, N- [l'-(6-cyano- 1,2,3, 4-tetrahy dro-2(R)- naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro[2H-l-benzopyran-2,4'- piperidin]-6-yl]-, (+)-, monohydrochloride, (structure I); methanesulfonamide, N-[l'-(6-cyano- 1,2,3, 4-tetrahydro-naphth-2-yl)- 3,4-dihydro-4-oxo-spiro[2H-l-benzopyran-2,4'-piperidin]-6-yl]-, (+)-, monohydrochloride, (structure II); and methanesulfonamide, N-[l'-[2-(5-benzofurazanyl)ethyl]-3,4-dihydro-4- oxospiro[2H-l-benzopyran-2,4'-piperidin]-6-yl]-, monohydrochloride, (structure HI). This very low exposure control limit makes these medicaments particularly suited for this dosage form and processing.

Structure

Structure

The above list of pharmaceutical products and medicaments is not meant to be exhaustive. Many other compounds will certainly work in the instant invention and are included within the scope of this invention.

The novel dosage form and process of the instant invention may be used to deliver medicament to humans or other animals. The term "animal" includes mammals, humans and primates, such as domestic, household, sport or farm animals such as dogs, sheep, goats, cattle, horses and pigs, laboratory animals such as mice, rats and guinea pigs, fish, avians, reptiles and zoo animals.

By "carrier core" is meant a nucleus upon which a mixture containing the medicament may be applied. The carrier core may be, for example, a non-pareil seed, a compressed tablet, a triturate, a spheronized particle, an inert bead and slugged material. This list is not meant to be in any way inclusive of the carrier cores which are included within the scope of this invention. When the particle size of the carrier core is considered important, the carrier cores may be sized by passing them through a screen which has a pore size at the upper diameter limit and collecting the carrier cores on a screen which has a pore size at the lower diameter limit. For example, when non-pareil seeds are used, the seeds are generally sized by collecting those seeds which pass through a #25 mest size screen and are collected on a #30 mesh size screen. This results in a more uniform particle size for the finished product.

The carrier core may be composed of lactose and other excipients such as magnesium stearate, microcrystalline cellulose, starch, stearic acid, calcium phosphate, glycerol monostearate, sucrose, polyvinylpyrrolidone, gelatin, methylcellulose, sodium carboxymethylcellulose, sorbitol, mannitol, polyethylene glycol and other ingredients commonly utilized as stabilizing agents or to aid in the production of tablets, spheronized particles, or other carrier core forms mentioned above.

The carrier core may also contain, within the core, a second medicament. For example, cardiovascular agents such as Class I antiarrhythmic compounds, anti-anginal compounds, vasodilators, potassium supplements, β-adrenergic receptor blocking agents, sodium channel blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, A II receptor antagonists, and diuretics may be delivered in combination with the compounds of structures I, II or El, by including them within the carrier core.

The coating containing the highly potent medicament may also include hydroxypropylmethylyethylene glycols, sodium carboxymethyl cellulose, carboxymethyl cellulose, methacrylate hydrogels, cellulose acetate phthalate, polyvinyl alcohol, poylacrylic acid, poly N-vinyl pyrrolidone, polyacrylamide, polyethylene oxide, methyUiydroxyethyl cellulose, ethyl cellulose, povidone, shellac, gelatin, wax, acacia, methylcellulose, methacrylic acid, methacrylic acid ester copolymers, titanium dioxide, talc, colorants, plasticizers and other soluble ingredients commonly used in film coatings of pharmaceutical dosage forms. The medicament coating may be prepared as a solution in water or an organic solvent. The medicament coating may also be prepared as a slurry, a suspension, a dispersion and may be partially or completely solubilized prior to application. The medicament may be mixed with a binder, dispersant, lubricants, emulsifier, diluent, wetting agent and colorants.

The overcoat may include hydroxypropylmethyl- cellulose, hydroxypropylcellulose, polyethylene glycols, sodium carboxymethyl cellulose, carboxymethyl cellulose, methacrylate hydrogels, cellulose acetate phthalate, polyvinyl alcohol, poylacrylic acid, poly N-vinyl pyrrolidone, polyacrylamide, polyethylene oxide, methyUiydroxyethyl cellulose, ethyl cellulose, povidone, shellac, gelatin, wax, acacia, methylcellulose, methacrylic acid, methacrylic acid ester copolymers, titanium dioxide, talc, colorants, plasticizers and other soluble ingredients commonly used in film coatings of pharmaceutical dosage forms.

The overcoat may be prepared as a solution in water, an aqueous solution or an organic solvent. The overcoating may also be prepared as a slurry, suspension, dispersion and may be partially or completely solubilized prior to application. In general the film coating mixture is prepared by mixing a solution containing from about 1 mg to about 500 mg of the highly potent compound and about 140 ml of water with about 0.6 to about 10 grams of hydroxypropylmethylcellulose in about 50 ml of water. However, more or less concentrated solutions of the highly potent compound or the hydroxypropylmethylcellulose are within the scope of this invention.

The medicament coating and the overcoat may be applied to the dosage form core using any coating procedure including the use of a fluidized bed film coating device, including a roto-processor, a pan coater or a baffled pan coater or any air suspension process. The film coating mixture may also be manually added to the carrier cores while they are mixed in the presence of a heated stream of air or inert gas.

In general the medicament coating and the overcoat may be applied to any thickness desired. However, a coating thickness of from about 1 to about 1000 mm is generally applied to the surface of the dosage form core. In the preferred embodiment using a non-pareil seed as a carrier core, a coating thickness of from about 5 to about 100 mm is applied depending upon the concentration of medicament to be included on each carrier core. When tablets are used as the carrier core, the film coating thickness generally ranges from about 25 to about 500 mm, depending upon the concentration of medicament to be included on each carrier core.

EXAMPLE 1

Capsules containing non-pareil seed coated with a solution containing the Class HI antiarrhythmic drug methanesulfonamide, N- [ 1 '-(6-cyano-l ,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)- hydroxyspiro[2H-l-benzopyran-2,4'-piperidin]-6-yl]-, (+)-, monohydrochloride were prepared using the following procedure.

Preparation of the Binder Solution

In a suitable tared, clean, dry, glass beaker, 100 g of purified water was heated to 80°C. To this heated solvent, 200 g of hydroxypropylmethylcellulose was added slowly with vigorous stirring. The container was removed from the heat source and while stirring at low speed, 100 g of unheated purified water was added.

Overcoat Preparation

A portion, 44 g, of the binder solution was weighed into a clean, tared 250 ml erlenmeyer flask. This solution was diluted with 110 g of purified water with mixing. The resulting diluted solution was covered and stored at room temperature until needed.

Raw Material Preparation

A quantity of non-pareil seeds were sized between #25 and #30 mesh sieves. From the sized non-pareil seeds, 452.8 g were transferred to a holding container. Magnesium stearate was bolted through a #60 screen. One gram was transferred to a suitable storage container until needed.

About 100 g of empty capsules (H.G. #3, white opaque 999) were weighed and transferred to a suitable storage device.

Manufacturing Conditions

In a class in glovebox, 120.75 mg of methanesulfonamide, N- [ 1 '-(6-cyano- 1,2,3 ,4-tetrahydro-2(R)-naphthalenyl)-3 ,4-dihydro- 4(R)-hydroxyspiro[2H-l-benzopyran-2,4'-piperidin]-6-yl]-, (+)-, monohydrochloride was transferred to a vessel with 140 ml of water and mixed for one hour with shaking. To this solution was added with stirring, 66 g of the binder solution which had been previously prepared. This mixture was transferred to a 4 inch in diameter Wurster Coating Column. The coating column conditions were as follows: Preheat column for about 10 minutes Atomization Pressure set to about 1.1 Bar Inlet Temperature set to about 70°C Outlet Temperatue set to about 34°C Air Flow set to about 80 m3/hour Inner Partition Height set to about 0.5 inches Application Rate set to about 5.0 g/min. Next, 452.8 g of the sized non-pareil seeds were loaded into the coating column and the polymeric/drug solution was applied. The pellets were dryed for 10 minutes in the column.

Once the coating operation was completed, the overcoat was applied. The binder solution was sprayed onto the coated pellets using the same coating conditions used to apply the drug containing coat. Following application of the overcoat, the pellets were dried for 15 minutes in the column.

The dried coated non-pareils were transferred into a double plastic bag containing 1 g of the bolted magnesium stearate. The bag was sealed after allowing a head space of air and then vigorously shaken to sufficiently lubricate the coated pellets. The lubricated pellets were then encapsulated using a Bonapace Hand Fill Encapsulator. The weight of pellets in each capsule was based on a laboratory analysis of the pellets after coating.

EXAMPLE 2

Placebo tablet can be used as carrier cores, in place of non¬ pareil seeds. Tablets can be prepared from dry blending a mixture of about 35% microcrystalline cellulose, about 50% lactose and about 14% pregelatinized starch. This mixture is then lubricated with magnesium stearate (about 1 % of final tablet weight) and directly compressed into the core tablet using a standard tableting machine.

These tablets may then be transferred to a film coating processor where the medicament coating and if desired the overcoat is added.

EXAMPLE 3

Exemplary of the many formulations that are included within the scope of this invention are the following:

EXAMPLE 3(b

Ingredient Amount/ Unit

L-706,000-001-T-012 2.415 mg

(Incorporate Coating Loss)

L-706,000-001-T-012 2.300 mg

(Equivalent to 2.0 mg Base)

Non-Pareil Seeds White 224.2 mg

(25-30 mesh)

Hydroxypropylmethylcellulose 6cps 2.5 mg

Hydroxypropylcellulose LF Grade 2.5 mg

Water Purified (gm)

Acetone NF (gm)

Magnesium Stearate 0.5 mg

TARGET FILL WEIGHT 232.0 mg

Capsule Hard Gelatin # 3 White 46.5 mg

Opaque 999

TARGET CAPSULE WEIGHT 278.5 mg

EXAMPLE 3(f)

Ingredient Amount/

Unit

L-706,000-001-T-012 11.5 mg

(Equivalent to 2.0 mg Base)

Lactose NF Anhydrous 117.0 mg

Cellulose Microcrystalline NF 80.0 mg

AVICEL 102

Magnesium Stearate NF 1.0 mg

Crosscarmellose Sodium NF 2.0 mg

Type A

Hydroxypropylmethylcellulose 6cps 6.00 mg

Hydroxypropylcellulose LF Grade 6.00 mg

Water Purified (gm)

Acetone NF (gm)

Hydroxypropylmethylcellulose 6cps 3.25 mg

Hydroxypropylcellulose LF Grade 3.25 mg

Titanium Dioxide USP 0.280 mg

Talc USP Purified 0.100 mg

Blue FD&C # 2 Aluminum Lake 0.025 mg

(14 % Dye)

Water Purified (gm)

Theoretical Tablet Weight 230.41 mg

Claims

WHAT IS CLAIMED IS:

1. A dosage form for the delivery of highly potent medicaments to humans or other animals comprising:

(a) a carrier core; and

(b) a coating which comprises a highly potent medicament and a coating material; wherein, the coating adheres to the surface of the carrier core fixing the medicament to the surface of the core and entraining the medicament.

2. The dosage form of Claim 1 , wherein an overcoat comprising a coating material is applied after the medicament containing coating.

3. The dosage form of Claim 1, wherein the medicament is selected from the group consisting of the Class m antiarrhythmic drugs: methanesulfonamide, N-[l '-(6-cyano-l ,2,3,4-tetrahydro-2(R)- naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro[2H-l-benzopyran-2,4'- piperidin]-6-yl]-,(+)-,monohydrochloride, (structure I); methanesulfonamide, N-[l '-(6-cyano-l ,2,3,4-tetrahydronaphth-2-yl)- 3,4-dihydro-4-oxo-spiro[2H-l-benzopyran-2,4'-piperidin]-6-yl]-,(+)-, monohydrochloride, (structure II); and methanesulfonamide, N-[l '-[2-(5-benzofurazanyl)ethyl]-3,4-dihydro4- oxospiro[2H-l -benzopyran-2,4'-piperidin]-6-yl]-,monohydrochloride, (structure III).

4. The dosage form of Claim 2, wherein the medicament is selected from the group consisting of the Class III antiarrhythmic drugs: methanesulfonamide, N-[ l'-(6-cyano- 1,2,3 ,4-tetrahy dro-2(R)- naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro[2H-l-benzopyran-2,4'- piperidin]-6-yl]-, (+)-, monohydrochloride, (structure I); methanesulfonamide, N-[ 1 '-(6-cyano- 1 ,2,3 ,4-tetrahydronaphth-2-yl)- 3,4-dihydro-4-oxo-spiro[2H-l-benzopyran-2,4'-piperidin]-6-yl]-, (+)-, monohydrochloride, (structure II); and methanesulfonamide, N-[ 1 '-[2-(5-benzofurazanyl)ethyl]-3,4-dihydro-4- oxospiro[2H-l-benzopyran-2,4'-piperidin]-6-yl]-, monohydrochloride, (structure III).

5. The dosage form of Claim 1, wherein the carrier core is selected from the group consisting of a non-pareil seed, a compressed tablet, a triturate, a spheronized particle, an inert bead and slugged material.

6. The dosage form of Claim 2, wherein the carrier core is selected from the group consisting of a non-pareil seed, a compressed tablet, a triturate, a spheronized particle, an inert bead and slugged material.

7. The dosage form of Claim 5, wherein the compressed tablet comprises, pregelatinized starch, microcrystalline cellulose, lactose, and magnesium stearate.

8. The dosage form of Claim 6, wherein the compressed tablet comprises, pregelatinized starch, microcrystalline cellulose, lactose and magnesium stearate.

9. The dosage form of Claim 1, wherein the cellulosic coating comprises hydroxypropylmethylcellulose.

10. The dosage form of Claim 2, wherein the cellulosic coating comprises hydroxypropylmethylcellulose.

11. The dosage form of Claim 1 , wherein the overcoat comprises hydroxypropylmethylcellulose.

12. The dosage form of Claim 2, wherein the overcoat comprises hydroxypropylmethylcellulose.

13. The dosage form of Claim 1, wherein the coated non-pareil seeds are contained within a gelatin capsule.

14. The dosage form of Claim 2, wherein the coated and overcoated non-pareil seeds are contained within a gelatin capsule.

15. The dosage form of Claim 1 , wherein the coated non-pareil seeds are further compressed into a tablet.

16. The dosage form of Claim 2, wherein the coated and overcoated non-pareil seeds are further compressed into a tablet.

17. The dosage form of Claim 1, wherein the coated spheronized particles are contained within a gelatin capsule.

18. The dosage form of Claim 2, wherein the coated and overcoated spheronized particles are contained within a gelatin capsule.

19. The dosage form of Claim 1, wherein the coated spheronized particles are compressed into a tablet.

20. The dosage form of Claim 2, wherein the coated and overcoated spheronized particles are compressed into a tablet.

21. The dosage form of Claim 1 , wherein the coated slugged material is contained within a gelatin capsule.

22. The dosage form of Claim 2, wherein the coated and overcoated slugged material is contained within a gelatin capsule.

23. The dosage form of Claim 1, wherein the coated slugged material is compressed into a tablet.

24. The dosage form of Claim 2, wherein the coated and overcoated slugged material is compressed into a tablet.

25. The dosage form of Claim 1, wherein the carrier core contains a medicament selected from the group of cardiovascular agents consisting of Class I antiarrhythmic compounds, anti-anginal compounds, vasodilators, potassium supplements, β-adrenergic receptor blocking agents, sodium channel blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, A II receptor antagonists, and diuretics.

26. The dosage form of Claim 2, wherein the carrier core contains a medicament selected from the group of cardiovascular agents consisting of Class I antiarrhythmic compounds, anti-anginal compounds, vasodilators, potassium supplements, β-adrenergic receptor blocking agents, sodium channel blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, A II receptor antagonists, and diuretics.

27. A method of preparing a dosage form for the delivery of highly potent medicaments to humans or other animals, comprising the steps of:

(a) preparing a film coating mixture comprising the highly potent medicament by dispersing the highly potent medicament in a suitable solvent;

(b) preparing the carrier core to receive the coating material;

(c) applying the film coating mixture of (a) to the carrier core; and

(d) drying the film coating mixture on the surface of the carrier core.

28. A method of preparing a dosage form for the delivery of highly potent medicaments to humans or other animals, comprising the steps of:

(b) preparing the carrier core to receive the coating material;

(c) applying the film coating mixture of (a) to the carrier core;

(d) drying the film coating mixture on the surface of the carrier core;

(e) preparing the overcoating material;

(f) applying the overcoating material to the coated carrier core; and

(g) drying the overcoating material on the surface of the coated carrier core.

29. The process of Claim 27, wherein the film coating mixture is prepared by mixing a solution containing from about 1 mg to about 500 mg of the highly potent compound and about 140 ml of water with about 0.6 to about 10 grams of hydroxypropylmethylcellulose in about 50 ml of water.

30. The process of Claim 28 wherein the film coating mixture is prepared by mixing a solution containing from about 1 mg to about 500 mg of the highly potent compound and about 140 ml of water with about 0.6 to about 10 grams of hydroxypropylmethyl¬ cellulose in about 50 ml of water.

31. The process of Claim 27, wherein the carrier cores are non-pareil seeds which are prepared by collecting those seeds which pass through a #25 mesh size screen and are collected on a #30 mesh size screen.

32. The process of Claim 28, wherein the carrier cores are non-pareil seeds which are prepared by collecting those seeds which pass through a #25 mesh size screen and are collected on a #30 mesh size screen.

33. The process of Claim 27, wherein the carrier cores are tablets comprising excipients selected from the group consisting of lactose, pregelatinized starch, magnesium stearate, microcrystalline cellulose, and starch.

34. The process of Claim 28, wherein the carrier cores are tablets comprising excipients selected from the group consisting of lactose, pregelatinized starch, magnesium stearate, microcrystalline cellulose, and starch.

35. The process of Claim 27, wherein the medicament is selected from the group consisting of the Class IE antiarrhythmic drugs: methanesulfonamide, N-[l'-(6-cyano- 1,2,3 , 4-tetrahydro-2(R)- naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro[2H-l-benzopyran-2,4'- piperidin]-6-yl]-, (+)-, monohydrochloride, (structure I); methanesulfonamide, N-[ 1 '-(6-cyano- 1 ,2,3 ,4-tetrahydronaphth-2-yl)- 3,4-dihydro-4-oxo-spiro[2H-l-benzopyran-2,4'-piperidin]-6-yl]-,(+)-, monohydrochloride, (structure D); and methanesulfonamide, N-[ -[2-(5-benzofurazanyl)ethyl]-3,4-dihydro- 4-oxospiro[2H-l-benzopyran-2,4'-piperidin]-6-yl]-monohydrohloride, (structure IE).

36. The process of Claim 28, wherein the medicament is selected from the group consisting of the Class IE antiarrhythmic drugs: methanesulfonamide N-[l'-(6-cyano-l,2,3,4-tetrahydro-2(R)- naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro[2H-l-benzoρyran-2,4'- piperidin]-6-yl]-, (+)-, monohydrochloride, (structure I); methanesulfonamide, N-[l'-(6-cyano-l ,2,3,4-tetrahydronaphth-2-yl)-

3,4-dihydro-4-oxospiro[2H-l-benzopyran-2,4'-piperidin]-6-yl]-,(+)-, monohydrochloride, (structure II); and methanesulfonamide, N-[ 1 '-[2-(5-benzofurazanyl)-ethyl]3 ,4-dihydro-

4-oxospiro[2H- 1 -benzopyran-2,4'-piperidin] -6-yl] -monohydrochloride,

(structure El).

37. The process of Claim 27, wherein the overcoat material comprises hydroxypropylmethylcellulose or hydroxypropyl¬ cellulose or both.

38. The process of Claim 28, wherein the overcoat material comprises hydroxypropylmethylcellulose, hydroxypropyl¬ cellulose or both.

39. The process of Claim 27, wherein the coat containing the medicament ranges from about 1 to about 1000 mm in thickness.

40. The process of Claim 28, wherein the coat containing the medicament ranges from about 1 to about 1000 mm in thickness.

41. The process of Claim 31, wherein the coat containing the medicament ranges from about 5 to about 100 mm when it is applied to a non-pareil seed.

42. The process of Claim 33, wherein the coat containing the medicament ranges from about 25 to about 500 mm when it is applied to a tablet.