CA2147862A1 - Drug delivery device - Google Patents
Drug delivery deviceInfo
- Publication number
- CA2147862A1 CA2147862A1 CA002147862A CA2147862A CA2147862A1 CA 2147862 A1 CA2147862 A1 CA 2147862A1 CA 002147862 A CA002147862 A CA 002147862A CA 2147862 A CA2147862 A CA 2147862A CA 2147862 A1 CA2147862 A1 CA 2147862A1
- Authority
- CA
- Canada
- Prior art keywords
- dosage form
- medicament
- coated
- benzopyran
- piperidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The instant invention is directed to a means of processing and delivering to a patient, medicaments, whose exposure con-trol 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
2 PCI`/US93/10640 ~1~7862 TITLE OF THE rNVENTION
DRUG DELIVERY DEVICE
This case is a contiml~tion-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.
BACKGROUNO 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 hllm~n~ and other ~nim~l.c 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 cont~ining 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 gr~n~ tion compressing, these forms represent one of the most difficult and potentially dangerous medicaments to produce. During processing, inh~l~tion 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 cont~min~tion 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 act*e ingredient.
wo 94/09762 2 1 d~ 7 ~ 6 ~ PCI/US93/10640 Liquid preparations which contain these highly potent compounds are considerably easier to control. Once the active ingredient is dissolved in an a~l~ro~liate solvent, the chance for accidental cont~min~tion, 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 cont~inin~ 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 canier core as a film coating. The film coating mixture both fixes the medicament on the surface of the core and seals the ~urfa~e ~ ~at ~e ~hance ~f à~tive ingredient flaking off the doga~e 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 THF 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 ~nim~ 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 3 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.
WO 94/09762 2 1 1 7 8 ~ 2 PCI/US93/10640 The Class m antiarrhythmic drugs: metnanesulfonamide, N-[ 1 '-(6-cyano- 1,2,3 ,4-tetrahydro-2(R)-naphthalenyl)-3 ,4-dihydro-4(R)-hydroxyspiro~2H-1-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-1-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 m) are examples of highly potent drugs that can be delivered using this device.
A BRIEF DESCRIPTION OF THE DRAVVINGS
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 m~king the dosage form, for the delivery of highly potent drugs to humans or other ~nim~ 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.
This invention concerns a method for the safe manufacture and delivery to h-lm~n~ and other ~nim~l~ 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.
,~, ., --o 2147~62 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 lnorganic and organic compounds without limit~tion, including medicaments that act on the peripheral nerves, ion channels, nuclear receptors, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular system, smoo~ muscles, blood circulatory system, synaptic sites, neuroeffector junctional sites, endocrine and hormone systems, immlmological system, reproductive system, skeletal systems, aut~c~id systems, alimentary and excretoly systems, inhibito~y arld hist~mine systems, and those matenals 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 Publi.ching 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, N.J. 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, p~lmit~te, phosphate, nitrate, borate, acetate, m~le~te, m~l~te, trometh~mine, tartrate, oleate, salicylate, salts of metals, and amines or organic cations, ~or example quatemary 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 WO 94/09762 PCI~/US93/10640 ~ ~ 78~
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 ph~rm~cological considerations and defined as the time-weighted average concentration 5 for a norrnal 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, "Establi~hin~ 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/day) 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 hl~m~n 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 reco~ni7~ble 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 2~47$~2 identified and the lowest observable effect dose is used. Larger safety factors (100 to 1000 fold) generally are reserved for risk estimated or inconclusive hllm~n data or ~nim~l data. ~he larger safety factors may be applied to compounds with carcinogenic or teratogenic potential.
Exposure Control Limits of O.S ug/m3 have been calculated for the Class m antiarrhythmic drugs:
methanesulfonamide, N-[ 1 '-(6-cyano- 1,2,3 ,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro[2H- 1 -benzopyran-2,4'-piperidin]-6-yl]-, (+)-, monohydrochloride, (structure I);
o methanesulfonamide, N-[ 1 '-(6-cyano- 1 ,2,3,4-tetrahydro-naphth-2-yl)-3,4-dihydro-4-oxo-spiro[2H-1-benzopyran-2,4'-piperidin]-6-yl]-, (+)-, monohydrochloride, (structure II); and methanesulfonamide, N-[1'-[2-(S-benzofurazanyl)ethyl]-3,4-dihydro-4-oxospiro [2H- 1 -benzopyran-2,4'-piperidin] -6-yl] -, monohydrochloride, (structure m). This very low exposure control limit makes these medicaments part;cularly sulted for thls dosage ~orm and process~ng.
/S b~o-- I Cl-N~,~
\~C --N
Structure I
WO 94/09762 PCI~/US93/106~0 5 21~78~2 S'N~ Cl-NH~3~c ~N
Structure 11 o H
S~o~ Cl-NH,~ N~
- ~o --N
Structure 11 The above list of pharmaceutical products and medicaments 20 is not meant to be exhaustive. Many other compounds will certainly work in the instant invention and are included within the scope of this nvention.
The novel dosage form and process of the instant invention may be used to deliver medicament to hllm~n~ or other 2nim~1~. The 25 term "~nim~l" includes m~mm~lc, hllm~n~ and primates, such as domestic, household, sport or farm ~nim~lc such as dogs, sheep, goats, cattle, horses and pigs, laboratory ~nim~l~ such as mice, rats and guinea pigs, fish, avians, reptiles and zoo ~nim~
By "carrier core" is meant a nucleus upon which a mixture 30 cont~inin~ 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.
214786~ --When the particle size of the carrier core is considered important, the carrier cores may be sized by passing them ~rough 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 o excipients such as magnesium stearate, microcrystalline cellulose, starch, stearic acid, calcium phosphate, glycerol monostearate, sucrose, polyvinylpyrrolid~ne, gelatin, methylcellulose, sodium carboxymethylcellulose, sorbitol, mannitol, polyethylene glycol and other ingredients cornrnonly utilized as stabilizing agents or to aid in the production of tablets, spheronized particles, or other carrier core forms mentioned a~ove.
The carrier core may also contain, within the core, a second medicament. For example, cardiovascular agents such as Class I
antiarrhythmic compounds, anti-~ngin~l compounds, vasodilators, potassium supplements, B-adrenergic receptor blocking agents, sodium channel blockers, calciurn channel blockers, angiotensin converting enzyme inhibitors, A II receptor antagonists, and diuretics may be delivered in combination with the compounds of structures I, ~ or III, by including them within the carrier core.
The coating cont~ining the highly potent medicament may also include hydroxypropylmethylyethylene glycols, sodium carboxymethyl cellulose, carboxymethyl cellulose, methacrylate hydrogels, cellulose acetate phth~l~te, polyvinyl alcohol, poylacrylic acid, poly N-vinyl pyrrolidone, polyacrylamide, polyethylene oxide, methylhydroxyethyl 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.
W 0 94/09762 2f 4 7862 PC~r/US93/10640 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 5 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 phth~l~te, polyvinyl alcohol, poylacrylic acid, poly N-vinyl pyrrolidone, polyacrylamide, polyethylene oxide, methylhydroxyethyl cellulose, ethyl cellulose, povidone, shellac, gelatin, wax, acacia, methylcellulose, methacrylic acid, methacrylic acid ester copolymers, tit~nium 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 cont~ining from about 1 mg to about S00 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 2~ 78~2 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 mrn is applied depending upon the concentration of medicament to be 5 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.
Capsllles cont~inin~ non-pareil seed coated with a solution contzlining the Class III antialThyffimic drug methanesulfonamide, N-[ 1 '-(6-cyano- 1,2,3 ,4-tetrahydro-2(R)-naphthalenyl)-3 ,4-dihydro-4(R)-5 hydroxyspiro[2H-1-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 20 purified water was heated to 80C. 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.
25 Overcoat Preparation A portion, 44 g, of ~e 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.
o ~?1~78~
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 kansferred to a suitable storage device.
Manufacturing Conditions In a class m 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- 1 -benzopyran-2,4'-piperidin] -6-yl] -, (+)-, monohydrochloride was transferred to a vessel with 140 ml of water and mixed for one hour with sh~king. 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 70C
Outlet Temperatue set to about 34C
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 mimltes 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 cont~ining coat. Following application of the overcoat, the pellets were dried for 15 mimltes in the column.
The dried coated non-pareils were transferred into a double plastic bag cont~ining 1 g of the bolted magnesium stearate. The bag was sealed after allowing a head space of air and then vigorously shaken to suf~1ciently lubricate the coated pellets.
21 ~78bZ
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.
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%
pregel~tini7ed starch. This mixture is then lubricated with magnesium stearate (about 1% of final tablet weight) and directly compressed into the core tablet usirlg 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.
Exemplary of the many forrn~ tions that are included within the scope of this invention are the following:
~ 21~7~2 EXAMPLE 3(a) Ingredient . Amount/
Unit L-706,000-001 -T-012 2.530 mg (Incorporate Coating Loss) L-706,000-001 -T-012 2.30 mg (Equivalent to 2.0 mg Base) Non-Pareil Seeds White 224.2 mg (25-30 mesh) Hydroxypropylmethylcellulose 6cps 5.0 mg Water Purified (grn) 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 WO 94/09762 21 4 7 8 6 2 Pcr/uss3/ln640 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 W O 94/09762 PC~r/US93/10640 5 2~ ~ 7862 EXAMPLE 3(c) Ingredient Amount/
Unit L-706,000-001 -T-012 2.5715 mg (Includes Coating Loss) L-706,000-001-T-012 2.30 mg (Equivalent to 2.0 mg Base) Lactose NF Anhydrous 117.0 mg Cellulose Microcrystalline NF 80.0 mg Magnesium Stearate NF 1.0 mg Crosscarmellose Sodium NF 2.0 mg Type A
Hydroxypropylrnethylcellulose 6cps 2.30 mg Hydroxypropylcellulose LF Grade 2.30 mg Water Purified (gm) Acetone NF (gm) Hydroxypropylmethylcellulose 6cps 3.25 mg Hydroxypropylcellulose LF Grade 3.25 mg Tit~nillm Dioxide USP 0.280 mg Talc USP Purified 0.100 mg Blue FD&C # 2 Alllminllm Lake 0.025 mg (14 % Dye) Water Purified (gm) Theoretical Tablet Weight 213.81 mg wo 94/09762 Pcr/uss3/l0640 21~8~2 EXAMPLE 3(d) Ingredient . Amoun~/
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) NonPareil Seeds White (25-30 mesh)224.2 mg Hydroxypropylmethylcellulose 6cps2.5 mg Hydroxypropylcellulose LF Grade 2.5 mg Water Purified (gm) Acetone NF (grn) Sodium Lauryl Sulfate 0.375 mg Magnesium Stearate 0.125 mg TARGET FILL WEIGHT 232.0 mg Capsule Hard Gelatin # 3 White 46.5 mg Opaque 999 TARGET CAPSULE WEIGHT 278.5 mg WO 94/09762 PCr/US93/10640 ~ 7862 EXAMPLE 3(e) Ingredient Amount/
Unit L-706,000-001-T-012 0.06038 mg (Incorporate Coating Loss) L-706,000-001-T-012 0.0575 mg (Equivalent to 2.0 mg Base) Non-Pareil Seeds White (25-30 226.4 mg mesh) Hydro~ypropylmethylcellulose 6cps 2.5 mg Hydroxypropylcellulose LF Grade 2.5 mg Water Purified (gm) Acetone NF (gm) Sodium Lauryl Sulfate 0.375 mg Magnesium Stearate 0.125 mg TARGET FILL WEIGHT 232.0 mg Capsule Hard Gelatin # 3 White 46.5 mg Opaque 999 TARGET CAPSULE WEIGHT 278.5 mg WO 94/09762 2 ~ ~ 7 8 6 2 PCI/U593/10640 EXAMPLE 3(fl Ingredient . Amount/
Unit L-706,000-OOl -T-012 1 1.5 mg (Equivalent to 2.0 mg Base) Lactose NF Anhydrous 117.0 mg Cellulose Microcrystalline NF 80.0 mg 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
DRUG DELIVERY DEVICE
This case is a contiml~tion-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.
BACKGROUNO 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 hllm~n~ and other ~nim~l.c 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 cont~ining 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 gr~n~ tion compressing, these forms represent one of the most difficult and potentially dangerous medicaments to produce. During processing, inh~l~tion 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 cont~min~tion 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 act*e ingredient.
wo 94/09762 2 1 d~ 7 ~ 6 ~ PCI/US93/10640 Liquid preparations which contain these highly potent compounds are considerably easier to control. Once the active ingredient is dissolved in an a~l~ro~liate solvent, the chance for accidental cont~min~tion, 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 cont~inin~ 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 canier core as a film coating. The film coating mixture both fixes the medicament on the surface of the core and seals the ~urfa~e ~ ~at ~e ~hance ~f à~tive ingredient flaking off the doga~e 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 THF 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 ~nim~ 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 3 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.
WO 94/09762 2 1 1 7 8 ~ 2 PCI/US93/10640 The Class m antiarrhythmic drugs: metnanesulfonamide, N-[ 1 '-(6-cyano- 1,2,3 ,4-tetrahydro-2(R)-naphthalenyl)-3 ,4-dihydro-4(R)-hydroxyspiro~2H-1-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-1-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 m) are examples of highly potent drugs that can be delivered using this device.
A BRIEF DESCRIPTION OF THE DRAVVINGS
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 m~king the dosage form, for the delivery of highly potent drugs to humans or other ~nim~ 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.
This invention concerns a method for the safe manufacture and delivery to h-lm~n~ and other ~nim~l~ 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.
,~, ., --o 2147~62 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 lnorganic and organic compounds without limit~tion, including medicaments that act on the peripheral nerves, ion channels, nuclear receptors, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular system, smoo~ muscles, blood circulatory system, synaptic sites, neuroeffector junctional sites, endocrine and hormone systems, immlmological system, reproductive system, skeletal systems, aut~c~id systems, alimentary and excretoly systems, inhibito~y arld hist~mine systems, and those matenals 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 Publi.ching 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, N.J. 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, p~lmit~te, phosphate, nitrate, borate, acetate, m~le~te, m~l~te, trometh~mine, tartrate, oleate, salicylate, salts of metals, and amines or organic cations, ~or example quatemary 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 WO 94/09762 PCI~/US93/10640 ~ ~ 78~
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 ph~rm~cological considerations and defined as the time-weighted average concentration 5 for a norrnal 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, "Establi~hin~ 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/day) 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 hl~m~n 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 reco~ni7~ble 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 2~47$~2 identified and the lowest observable effect dose is used. Larger safety factors (100 to 1000 fold) generally are reserved for risk estimated or inconclusive hllm~n data or ~nim~l data. ~he larger safety factors may be applied to compounds with carcinogenic or teratogenic potential.
Exposure Control Limits of O.S ug/m3 have been calculated for the Class m antiarrhythmic drugs:
methanesulfonamide, N-[ 1 '-(6-cyano- 1,2,3 ,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro[2H- 1 -benzopyran-2,4'-piperidin]-6-yl]-, (+)-, monohydrochloride, (structure I);
o methanesulfonamide, N-[ 1 '-(6-cyano- 1 ,2,3,4-tetrahydro-naphth-2-yl)-3,4-dihydro-4-oxo-spiro[2H-1-benzopyran-2,4'-piperidin]-6-yl]-, (+)-, monohydrochloride, (structure II); and methanesulfonamide, N-[1'-[2-(S-benzofurazanyl)ethyl]-3,4-dihydro-4-oxospiro [2H- 1 -benzopyran-2,4'-piperidin] -6-yl] -, monohydrochloride, (structure m). This very low exposure control limit makes these medicaments part;cularly sulted for thls dosage ~orm and process~ng.
/S b~o-- I Cl-N~,~
\~C --N
Structure I
WO 94/09762 PCI~/US93/106~0 5 21~78~2 S'N~ Cl-NH~3~c ~N
Structure 11 o H
S~o~ Cl-NH,~ N~
- ~o --N
Structure 11 The above list of pharmaceutical products and medicaments 20 is not meant to be exhaustive. Many other compounds will certainly work in the instant invention and are included within the scope of this nvention.
The novel dosage form and process of the instant invention may be used to deliver medicament to hllm~n~ or other 2nim~1~. The 25 term "~nim~l" includes m~mm~lc, hllm~n~ and primates, such as domestic, household, sport or farm ~nim~lc such as dogs, sheep, goats, cattle, horses and pigs, laboratory ~nim~l~ such as mice, rats and guinea pigs, fish, avians, reptiles and zoo ~nim~
By "carrier core" is meant a nucleus upon which a mixture 30 cont~inin~ 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.
214786~ --When the particle size of the carrier core is considered important, the carrier cores may be sized by passing them ~rough 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 o excipients such as magnesium stearate, microcrystalline cellulose, starch, stearic acid, calcium phosphate, glycerol monostearate, sucrose, polyvinylpyrrolid~ne, gelatin, methylcellulose, sodium carboxymethylcellulose, sorbitol, mannitol, polyethylene glycol and other ingredients cornrnonly utilized as stabilizing agents or to aid in the production of tablets, spheronized particles, or other carrier core forms mentioned a~ove.
The carrier core may also contain, within the core, a second medicament. For example, cardiovascular agents such as Class I
antiarrhythmic compounds, anti-~ngin~l compounds, vasodilators, potassium supplements, B-adrenergic receptor blocking agents, sodium channel blockers, calciurn channel blockers, angiotensin converting enzyme inhibitors, A II receptor antagonists, and diuretics may be delivered in combination with the compounds of structures I, ~ or III, by including them within the carrier core.
The coating cont~ining the highly potent medicament may also include hydroxypropylmethylyethylene glycols, sodium carboxymethyl cellulose, carboxymethyl cellulose, methacrylate hydrogels, cellulose acetate phth~l~te, polyvinyl alcohol, poylacrylic acid, poly N-vinyl pyrrolidone, polyacrylamide, polyethylene oxide, methylhydroxyethyl 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.
W 0 94/09762 2f 4 7862 PC~r/US93/10640 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 5 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 phth~l~te, polyvinyl alcohol, poylacrylic acid, poly N-vinyl pyrrolidone, polyacrylamide, polyethylene oxide, methylhydroxyethyl cellulose, ethyl cellulose, povidone, shellac, gelatin, wax, acacia, methylcellulose, methacrylic acid, methacrylic acid ester copolymers, tit~nium 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 cont~ining from about 1 mg to about S00 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 2~ 78~2 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 mrn is applied depending upon the concentration of medicament to be 5 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.
Capsllles cont~inin~ non-pareil seed coated with a solution contzlining the Class III antialThyffimic drug methanesulfonamide, N-[ 1 '-(6-cyano- 1,2,3 ,4-tetrahydro-2(R)-naphthalenyl)-3 ,4-dihydro-4(R)-5 hydroxyspiro[2H-1-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 20 purified water was heated to 80C. 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.
25 Overcoat Preparation A portion, 44 g, of ~e 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.
o ~?1~78~
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 kansferred to a suitable storage device.
Manufacturing Conditions In a class m 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- 1 -benzopyran-2,4'-piperidin] -6-yl] -, (+)-, monohydrochloride was transferred to a vessel with 140 ml of water and mixed for one hour with sh~king. 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 70C
Outlet Temperatue set to about 34C
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 mimltes 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 cont~ining coat. Following application of the overcoat, the pellets were dried for 15 mimltes in the column.
The dried coated non-pareils were transferred into a double plastic bag cont~ining 1 g of the bolted magnesium stearate. The bag was sealed after allowing a head space of air and then vigorously shaken to suf~1ciently lubricate the coated pellets.
21 ~78bZ
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.
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%
pregel~tini7ed starch. This mixture is then lubricated with magnesium stearate (about 1% of final tablet weight) and directly compressed into the core tablet usirlg 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.
Exemplary of the many forrn~ tions that are included within the scope of this invention are the following:
~ 21~7~2 EXAMPLE 3(a) Ingredient . Amount/
Unit L-706,000-001 -T-012 2.530 mg (Incorporate Coating Loss) L-706,000-001 -T-012 2.30 mg (Equivalent to 2.0 mg Base) Non-Pareil Seeds White 224.2 mg (25-30 mesh) Hydroxypropylmethylcellulose 6cps 5.0 mg Water Purified (grn) 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 WO 94/09762 21 4 7 8 6 2 Pcr/uss3/ln640 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 W O 94/09762 PC~r/US93/10640 5 2~ ~ 7862 EXAMPLE 3(c) Ingredient Amount/
Unit L-706,000-001 -T-012 2.5715 mg (Includes Coating Loss) L-706,000-001-T-012 2.30 mg (Equivalent to 2.0 mg Base) Lactose NF Anhydrous 117.0 mg Cellulose Microcrystalline NF 80.0 mg Magnesium Stearate NF 1.0 mg Crosscarmellose Sodium NF 2.0 mg Type A
Hydroxypropylrnethylcellulose 6cps 2.30 mg Hydroxypropylcellulose LF Grade 2.30 mg Water Purified (gm) Acetone NF (gm) Hydroxypropylmethylcellulose 6cps 3.25 mg Hydroxypropylcellulose LF Grade 3.25 mg Tit~nillm Dioxide USP 0.280 mg Talc USP Purified 0.100 mg Blue FD&C # 2 Alllminllm Lake 0.025 mg (14 % Dye) Water Purified (gm) Theoretical Tablet Weight 213.81 mg wo 94/09762 Pcr/uss3/l0640 21~8~2 EXAMPLE 3(d) Ingredient . Amoun~/
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) NonPareil Seeds White (25-30 mesh)224.2 mg Hydroxypropylmethylcellulose 6cps2.5 mg Hydroxypropylcellulose LF Grade 2.5 mg Water Purified (gm) Acetone NF (grn) Sodium Lauryl Sulfate 0.375 mg Magnesium Stearate 0.125 mg TARGET FILL WEIGHT 232.0 mg Capsule Hard Gelatin # 3 White 46.5 mg Opaque 999 TARGET CAPSULE WEIGHT 278.5 mg WO 94/09762 PCr/US93/10640 ~ 7862 EXAMPLE 3(e) Ingredient Amount/
Unit L-706,000-001-T-012 0.06038 mg (Incorporate Coating Loss) L-706,000-001-T-012 0.0575 mg (Equivalent to 2.0 mg Base) Non-Pareil Seeds White (25-30 226.4 mg mesh) Hydro~ypropylmethylcellulose 6cps 2.5 mg Hydroxypropylcellulose LF Grade 2.5 mg Water Purified (gm) Acetone NF (gm) Sodium Lauryl Sulfate 0.375 mg Magnesium Stearate 0.125 mg TARGET FILL WEIGHT 232.0 mg Capsule Hard Gelatin # 3 White 46.5 mg Opaque 999 TARGET CAPSULE WEIGHT 278.5 mg WO 94/09762 2 ~ ~ 7 8 6 2 PCI/U593/10640 EXAMPLE 3(fl Ingredient . Amount/
Unit L-706,000-OOl -T-012 1 1.5 mg (Equivalent to 2.0 mg Base) Lactose NF Anhydrous 117.0 mg Cellulose Microcrystalline NF 80.0 mg 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 (42)
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.
(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 III
antiarrhythmic drugs:
methanesulfonamide, N-[1'-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro[2H-1-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-1-benzopyran-2,4'-piperidin]-6-yl]-,(+)-, monohydrochloride, (structure II); and methanesulfonamide, N-[1'-[2-(5-benzofurazanyl)ethyl]-3,4-dihydro4-oxospiro[2H-1 -benzopyran-2,4'-piperidin]-6-yl]-,monohydrochloride, (structure III).
antiarrhythmic drugs:
methanesulfonamide, N-[1'-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro[2H-1-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-1-benzopyran-2,4'-piperidin]-6-yl]-,(+)-, monohydrochloride, (structure II); and methanesulfonamide, N-[1'-[2-(5-benzofurazanyl)ethyl]-3,4-dihydro4-oxospiro[2H-1 -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-[1'-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro[2H-1-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-1-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 III).
antiarrhythmic drugs:
methanesulfonamide, N-[1'-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro[2H-1-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-1-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 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, .beta.-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, .beta.-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.
(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:
(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;
(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.
(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;
(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 III antiarrhythmic drugs:
methanesulfonamide, N-[1'-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro[2H-1-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-1-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]-monohydrohloride, (structure III).
methanesulfonamide, N-[1'-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro[2H-1-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-1-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]-monohydrohloride, (structure III).
36. The process of Claim 28, wherein the medicament is selected from the group consisting of the Class III antiarrhythmic drugs:
methanesulfonamide N-[1'-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro[2H-1-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-oxospiro[2H-1-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 III).
methanesulfonamide N-[1'-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro[2H-1-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-oxospiro[2H-1-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 III).
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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US97188292A | 1992-11-05 | 1992-11-05 | |
| US971,882 | 1992-11-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2147862A1 true CA2147862A1 (en) | 1994-05-11 |
Family
ID=25518906
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002147862A Abandoned CA2147862A1 (en) | 1992-11-05 | 1993-11-04 | Drug delivery device |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0668758A1 (en) |
| JP (1) | JPH08502980A (en) |
| AU (1) | AU5592694A (en) |
| CA (1) | CA2147862A1 (en) |
| WO (1) | WO1994009762A1 (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5759577A (en) * | 1995-01-17 | 1998-06-02 | American Home Products Corporation | Controlled release of steroids from sugar coatings |
| US5997905A (en) * | 1998-09-04 | 1999-12-07 | Mcneil-Ppc | Preparation of pharmaceutically active particles |
| ATE315930T1 (en) * | 2000-05-18 | 2006-02-15 | Therics Inc | ENCAPSULATING A TOXIC CORE INTO A NON-TOXIC AREA IN AN ORAL DOSAGE FORM |
| FR2837100B1 (en) * | 2002-03-18 | 2004-07-23 | Flamel Tech Sa | MODIFIED RELEASE MICROCAPSULE-BASED TABLETS |
| PT1492511E (en) | 2002-04-09 | 2009-04-09 | Flamel Tech Sa | Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s) |
| FR2883179B1 (en) * | 2005-03-18 | 2009-04-17 | Ethypharm Sa | COATED TABLET |
| US9877921B2 (en) | 2005-09-09 | 2018-01-30 | Nova Southeastern University | Epinephrine nanoparticles, methods of fabrication thereof, and methods for use thereof for treatment of conditions responsive to epinephrine |
| WO2011109340A1 (en) | 2010-03-01 | 2011-09-09 | Nova Southeastern University | Epinephrine nanop articles, methods of fabrication thereof, and methods for use thereof for treatment of conditions responsive to epinephrine |
| WO2013059629A1 (en) | 2011-10-21 | 2013-04-25 | Nova Southeastern University | Epinephrine nanoparticles, methods of fabrication thereof, and methods for use thereof for treatment of conditions responsive to epinephrine |
| US20160045457A1 (en) | 2005-09-09 | 2016-02-18 | Ousama Rachid | Epinephrine fine particles and methods for use thereof for treatment of conditions responsive to epinephrine |
| FR2920308B1 (en) * | 2007-09-05 | 2011-02-25 | Unither Dev | PHARMACEUTICAL FORM FOR ORAL ADMINISTRATION OF ACTIVE INGREDIENTS. |
| EP2861224A4 (en) | 2012-06-15 | 2015-11-18 | Univ Nova Southeastern | Epinephrine nanoparticles, methods of fabrication thereof, and methods for use thereof for treatment of conditions responsive to epinphrine |
| CN103006604B (en) * | 2013-01-16 | 2014-05-07 | 苏州中化药品工业有限公司 | Cefuroxime axetil tablets and preparation method thereof |
| CN103110603B (en) * | 2013-01-31 | 2014-07-02 | 浙江华立南湖制药有限公司 | Cefaclor dispersible tablet and preparation method thereof |
| ES2882530T3 (en) | 2013-03-22 | 2021-12-02 | Univ Nova Southeastern | Epinephrine fine particles and methods of using them for the treatment of conditions that respond to epinephrine |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5082669A (en) * | 1989-07-20 | 1992-01-21 | Dainippon Pharmaceutical Co., Ltd. | Rapid-releasing oral particle pharmaceutical preparation with unpleasant taste masked |
| US5215989A (en) * | 1989-12-08 | 1993-06-01 | Merck & Co., Inc. | Nitrogen-containing heterocyclic compounds as class III antiarrhythmic agents |
-
1993
- 1993-11-04 CA CA002147862A patent/CA2147862A1/en not_active Abandoned
- 1993-11-04 JP JP6511433A patent/JPH08502980A/en active Pending
- 1993-11-04 AU AU55926/94A patent/AU5592694A/en not_active Withdrawn
- 1993-11-04 WO PCT/US1993/010640 patent/WO1994009762A1/en not_active Application Discontinuation
- 1993-11-04 EP EP94901276A patent/EP0668758A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| JPH08502980A (en) | 1996-04-02 |
| EP0668758A1 (en) | 1995-08-30 |
| WO1994009762A1 (en) | 1994-05-11 |
| AU5592694A (en) | 1994-05-24 |
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