US20030099707A1 - Antifungal product, use and formulation thereof - Google Patents

Antifungal product, use and formulation thereof Download PDF

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Publication number
US20030099707A1
US20030099707A1 US10292617 US29261702A US2003099707A1 US 20030099707 A1 US20030099707 A1 US 20030099707A1 US 10292617 US10292617 US 10292617 US 29261702 A US29261702 A US 29261702A US 2003099707 A1 US2003099707 A1 US 2003099707A1
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antifungal
product
dosage form
host
released
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US10292617
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Edward Rudnic
James Isbister
Donald Treacy
Sandra Wassink
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Victory Pharma Inc
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Advancis Pharmaceutical Corp
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5084Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin digitoxin or digoxin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • A61K9/2077Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50

Abstract

An antifungal product is comprised of at least three dosages forms, each of which has a different release profile, with the Cmax for the antifungal product being reached in less than about twelve hours. In one embodiment, there is an immediate release dosage form, as well as two or more delayed release dosage forms, with each of the dosage forms having a different release profile, wherein each reaches a Cmax at different times.

Description

  • This application is a continuation of U.S. application Ser. No. 09/792,189 filed Feb. 22, 2001, which is a continuation-in-part of U.S. application Ser. No. 09/687,236 filed Oct. 13, 2000.[0001]
  • This invention relates to an antifungal product, as well as to the use and formulation thereof. [0002]
  • A wide variety of antifungals have been used, and will be used, in order to combat fungal infection. In general, such antifungals can be administered by a repeated dosing of immediate release dosage forms, which results in poor compliance or as a controlled release formulation (slow release) at higher administered doses. The present invention is directed to providing for an improved antifungal product. [0003]
  • In accordance with one aspect of the present invention, there is provided an antifungal pharmaceutical product which is comprised of at least two, preferably at least three, antifungal dosage forms. Such dosage forms are formulated so that each of the dosage forms has a different release profile. [0004]
  • In a particularly preferred embodiment, there are at least two, preferably at least three dosage forms, each of which has a different release profile and the release profile of each of the dosage forms is such that the dosage forms each start release of the antifungal contained therein at different times after administration of the antifungal product. [0005]
  • Thus, in accordance with an aspect of the present invention, there is provided a single or unitary antifungal product that has contained therein at least two, preferably at least three antifungal dosage forms, each of which has a different release profile, whereby the antifungal contained in each of such dosage forms is released at different times. [0006]
  • In accordance with a further aspect of the invention, the antifungal product may be comprised of at least four different dosage forms, each of which starts to release the antifungal contained therein at different times after administration of the antifungal product. [0007]
  • The antifungal product generally does not include more than five dosage forms with different release times. [0008]
  • In accordance with a preferred embodiment, the antifungal product has an overall release profile such that when administered the maximum serum concentration of the total antifungal released from the product is reached in less than twelve hours, preferably in less than eleven hours. In an embodiment, the maximum serum concentration of the total antifungal released from the antifungal product is achieved no earlier than four hours after administration. [0009]
  • In accordance with one preferred embodiment of the invention, there are at least three dosage forms. One of the at least three dosage forms is an immediate release dosage form whereby initiation of release of the antifungal therefrom is not substantially delayed after administration of the antifungal product. The second and third of the at least three dosage forms is a delayed dosage form (which may be a pH sensitive or a non-pH sensitive delayed dosage form, depending on the type of antifungal product), whereby the antifungal released therefrom is delayed until after initiation of release of the antifungal from the immediate release dosage form. More particularly, the antifungal release from the second of the at least two dosage forms achieves a C[0010] max (maximum serum concentration in the serum) at a time after the antifungal released from the first of the at least three dosage forms achieves a Cmax in the serum, and the antifungal released from the third dosage form achieves a Cmax in the serum after the Cmax of antifungal released from the second dosage form.
  • In one embodiment, the second of the at least two dosage forms initiates release of the antifungal contained therein at least one hour after the first dosage form, with the initiation of the release therefrom generally occurring no more than six hours after initiation of release of antifungal from the first dosage form of the at least three dosage forms. [0011]
  • In general, the immediate release dosage form produces a C[0012] max for the antifungal released therefrom within from about 0.5 to about 2 hours, with the second dosage form of the at least three dosage forms producing a Cmax for the antifungal released therefrom in no more than about four hours. In general, the Cmax for such second dosage form is achieved no earlier than two hours after administration of the antifungal product; however, it is possible within the scope of the invention to achieve Cmax in a shorter period of time.
  • As hereinabove indicated, the antifungal product may contain at least three or at least four or more different dosage forms. For example, if the antifungal product includes a third dosage form, the antifungal released therefrom reaches a C[0013] max at a time later than the Cmax is achieved for the antifungal released from each of the first and second dosage forms. In a preferred embodiment, release of antifungal from the third dosage form is started after initiation of release of antifungal from both the first dosage form and the second dosage form. In one embodiment, Cmax for antifungal release from the third dosage form is achieved within eight hours.
  • In another embodiment, the antifungal product contains at least four dosage forms, with each of the at least four dosage forms having different release profiles, whereby the antifungal release from each of the at least four different dosage forms achieves a C[0014] max at a different time.
  • As hereinabove indicated, in a preferred embodiment, irrespective of whether the antifungal contains at least two or at least three or at least four different dosage forms each with a different release profile, C[0015] max for all the antifungal released from the antifungal product is achieved in less than twelve hours, and more generally is achieved in less than eleven hours.
  • In a preferred embodiment, the antifungal product is a once a day product, whereby after administration of the antifungal product, no further product is administered during the day; i.e., the preferred regimen is that the product is administered only once over a twenty-four hour period. Thus, in accordance with the present invention, there is a single administration of an antifungal product with the antifungal being released in a manner such that overall antifungal release is effected with different release profiles in a manner such that the overall C[0016] max for the antifungal product is reached in less than twelve hours. The term single administration means that the total antifungal administered over a twenty-four hour period is administered at the same time, which can be a single tablet or capsule or two or more thereof, provided that they are administered at essentially the same time.
  • Applicant has found that a single dosage antifungal product comprised of at least three antifungal dosage forms each having a different release profile is an improvement over a single dosage antifungal product comprised of an antifungal dosage form having a single release profile. Each of the dosage forms of antifungal in a pharmaceutically acceptable carrier may have one or more antifungals and each of the dosage forms may have the same antifungal or different antifungals. [0017]
  • It is to be understood that when it is disclosed herein that a dosage form initiates release after another dosage form, such terminology means that the dosage form is designed and is intended to produce such later initiated release. It is known in the art, however, notwithstanding such design and intent, some “leakage” of antifungal may occur. Such “leakage” is not “release” as used herein. [0018]
  • If at least four dosage forms are used, the fourth of the at least four dosage form may be a sustained release dosage form or a delayed release dosage form. If the fourth dosage form is a sustained release dosage form, even though C[0019] max of the fourth dosage form of the at least four dosage forms is reached after the Cmax of each of the other dosage forms is reached, antifungal release from such fourth dosage form may be initiated prior to or after release from the second or third dosage form.
  • The antifungal product of the present invention, as hereinabove described, may be formulated for administration by a variety of routes of administration. For example, the antifungal product may be formulated in a way that is suitable for topical administration; administration in the eye or the ear; rectal or vaginal administration; as nose drops; by inhalation; as an injectable; or for oral administration. In a preferred embodiment, the antifungal product is formulated in a manner such that it is suitable for oral administration. [0020]
  • For example, in formulating the antifungal product for topical administration, such as by application to the skin, the at least two different dosage forms, each of which contains an antifungal, may be formulated for topical administration by including such dosage forms in an oil-in-water emulsion, or a water-in-oil emulsion. In such a formulation, the immediate release dosage form is in the continuous phase, and the delayed release dosage form is in a discontinuous phase. The formulation may also be produced in a manner for delivery of three dosage forms as hereinabove described. For example, there may be provided an oil-in-water-in-oil emulsion, with oil being a continuous phase that contains the immediate release component, water dispersed in the oil containing a first delayed release dosage form, and oil dispersed in the water containing a third delayed release dosage form. [0021]
  • It is also within the scope of the invention to provide an antifungal product in the form of a patch, which includes antifungal dosage forms having different release profiles, as hereinabove described. [0022]
  • In addition, the antifungal product may be formulated for use in the eye or ear or nose, for example, as a liquid emulsion. For example, the dosage form may be coated with a hydrophobic polymer whereby a dosage form is in the oil phase of the emulsion, and a dosage form may be coated with hydrophilic polymer, whereby a dosage form is in the water phase of the emulsion. [0023]
  • Furthermore, the antifungal product with at least three different dosage forms with different release profiles may be formulated for rectal or vaginal administration, as known in the art. This may take the form of a cream or emulsion, or other dissolvable dosage form similar to those used for topical administration. [0024]
  • As a further embodiment, the antifungal product may be formulated for use in inhalation therapy by coating the particles and micronizing the particles for inhalation. [0025]
  • In a preferred embodiment, the antifungal product is formulated in a manner suitable for oral administration. Thus, for example, for oral administration, each of the dosage forms may be used as a pellet or a particle, with a pellet or particle then being formed into a unitary pharmaceutical product, for example, in a capsule, or embedded in a tablet, or suspended in a liquid for oral administration. [0026]
  • Alternatively, in formulating an oral delivery system, each of the dosage forms of the product may be formulated as a tablet, with each of the tablets being put into a capsule to produce a unitary antifungal product. Thus, for example, antifungal products may include a first dosage form in the form of a tablet that is an immediate release tablet, and may also include two or more additional tablets, each of which provides for a delayed release of the antifungal, as hereinabove described, whereby the C[0027] max of the antifungal released from each of the tablets is reached at different times, with the Cmax of the total antifungal released from the antifungal product being achieved in less than twelve hours.
  • The formulation of an antifungal product including at least three dosage forms with different release profiles for different routes of administration is deemed to be within the skill of the art from the teachings herein. As known in the art, with respect to delayed release, the time of release can be controlled by the concentration of antifungals in the coating and/or the thickness of the coating. [0028]
  • In formulating an antifungal product in accordance with the invention, in one embodiment, the immediate release dosage form of the product generally provides from about 20% to about 50% of the total dosage of antifungal to be delivered by the product, with such immediate release dosage forms generally providing at least 25% of the total dosage of the antifungal to be delivered by the product. In many cases, the immediate release dosage form provides from about 20% to about 30% of the total dosage of antifungal to be delivered by the product; however, in some cases it may be desirable to have the immediate release dosage form provide for about 45% to about 50% of the total dosage of antifungal to be delivered by the product. [0029]
  • The remaining dosage forms deliver the remainder of the antifungal. If more than one delayed release dosage form is used, in one embodiment, each of the delayed release dosage forms may provide about equal amounts of antifungal; however, they may also be formulated so as to provide different amounts. [0030]
  • In accordance with the present invention, each of the dosage forms contains the same antifungal; however, each of the dosage forms may contain more than one antifungal. [0031]
  • In one embodiment, where the composition contains one immediate release component and two delayed release components, the immediate release component provides from 20% to 35% (preferably 20% to 30%), by weight, of the total antifungal; where there are three delayed release components, the immediate release component provides from 15% to 30%, by weight, of the total antifungal; and where there are four delayed release components, the immediate release component provides from 10% to 25%, by weight, of the total antifungal. [0032]
  • With respect to the delayed release components, where there are two delayed release components, the first delayed release component (the one released earlier in time) provides from 30% to 60%, by weight, of the total antifungal provided by the two delayed release components with the second delayed release component providing the remainder of the antifungal. [0033]
  • Where there are three delayed release components, the earliest released component provides 20% to 35% by weight of the total antifungal provided by the three delayed release components, the next in time delayed release component provides from 20% to 40%, by weight, of the antifungal provided by the three delayed release components and the last in time provides the remainder of the antifungal provided by the three delayed release components. [0034]
  • When there are four delayed release components, the earliest delayed release component provides from 15% to 30%, by weight, the next in time delayed release component provides from 15% to 30%, the next in time delayed release component provides from 20% to 35%, by weight, and the last in time delayed release component provides from 20% to 35%, by weight, in each case of the total antifungal provided by the four delayed release components. [0035]
  • The Immediate Release Component
  • The immediate release portion of this system can be a mixture of ingredients that breaks down quickly after administration to release the antifungal. This can take the form of either a discrete pellet or granule that is mixed in with, or compressed with, the other three components. [0036]
  • The materials to be added to the antifungals for the immediate release component can be, but are not limited to, microcrystalline cellulose, corn starch, pregelatinized starch, potato starch, rice starch, sodium carboxymethyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linked chitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone (PVP), acrylic acid derivatives (Carbopol, Eudragit, etc.), polyethylene glycols, such a low molecular weight PEGs (PEG2000-10000) and high molecular weight PEGs (Polyox) with molecular weights above 20,000 daltons. [0037]
  • It may be useful to have these materials present in the range of 1.0 to 60% (W/W). [0038]
  • In addition, it may be useful to have other ingredients in this system to aid in the dissolution of the drug, or the breakdown of the component after ingestion or administration. These ingredients can be surfactants, such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, one of the non-ionic surfactants such as the Pluronic line of surfactants, or any other material with surface active properties, or any combination of the above. [0039]
  • These materials may be present in the rate of 0.05-15% (W/W). [0040]
  • The Non-pH Sensitive Delayed Release Component
  • The components in this composition are the same immediate release unit, but with additional polymers integrated into the composition, or as coatings over the pellet or granule. [0041]
  • Materials that can be used to obtain a delay in release suitable for this component of the invention can be, but are not limited to, polyethylene glycol (PEG) with molecular weight above 4,000 daltons (Carbowax, Polyox), waxes such as white wax or bees wax, paraffin, acrylic acid derivatives (Eudragit), propylene glycol, and ethylcellulose. [0042]
  • Typically these materials can be present in the range of 0.5-25% (W/W) of this component. [0043]
  • The pH Sensitive (Enteric) Release Component
  • The components in this composition are the same as the immediate release component, but with additional polymers integrated into the composition, or as coatings over the pellet or granule. [0044]
  • The kind of materials useful for this purpose can be, but are not limited to, cellulose acetate pthalate, Eudragit L, and other pthalate salts of cellulose derivatives. [0045]
  • These materials can be present in concentrations from 4-20% (W/W). [0046]
  • Sustained Release Component
  • The components in this composition are the same as the immediate release component, but with additional polymers integrated into the composition, or as coatings over the pellet or granule. [0047]
  • The kind of materials useful for this purpose can be, but are not limited to, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, nitrocellulose, Eudragit R, and Eudragit RL, Carbopol, or polyethylene glycols with molecular weights in excess of 8,000 daltons. [0048]
  • These materials can be present in concentrations from 4-20% (W/W). [0049]
  • As hereinabove indicated, the units comprising the antifungal composition of the present invention can be in the form of discrete pellets or particles contained in the capsule, or particles embedded in a tablet or suspended in a liquid suspension. [0050]
  • The antifungal composition of the present invention may be administered, for example, by any of the following routes of administration: sublingual, transmucosal, transdermal, parenteral, etc., and preferably is administered orally. The composition includes a therapeutically effective amount of the antifungal, which amount will vary with the antifungal to be used, the disease or infection to be treated, and the number of times that the composition is to be delivered in a day. The composition is administered to a host in an amount effective for treating a fungal infection. [0051]
  • The following are representative examples of some antifungals that can be employed in the composition of the invention: amphotericin B, flucytosine, fluconazole, griseofulvin, miconazole nitrate, terbinafine hydrochloride, ketoconazole, itraconazole, undecylenic acid and chloroxylenol, ciclopirox, clotrimazole, butenafine hydrochloride, nystatin, naftifine hydrochloride, oxiconazole nitrate, selenium sulfide, econazole nitrate, terconazole, butoconazole nitrate, carbol-fuchsin, clioquinol, methylrosaniline chloride, sodium thiosulfate, sulconazole nitrate, terbinafine hydrochloride, tioconazole, tolnaftate, undecylenic acid and undecylenate salts (calcium undecylenate, copper undecylenate, zinc undecylenate) [0052]
  • The invention will be further described with respect to the following examples; however, the scope of the invention is not limited thereby. All percentages in this specification, unless otherwise specified, are by weight. [0053]
  • Immediate Release Component
  • Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a dry blend. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. The product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press. [0054]
    Example 1:
    Fluconazole 65% (W/W)
    Microcrystalline cellulose 20
    Povidone 10
    Croscarmellose sodium 5
    Example 2:
    Fluconazole 55% (W/W)
    Microcrystalline cellulose 25
    Povidone 10
    Croscarmellose sodium 10
    Example 3:
    Fluconazole 65% (W/W)
    Microcrystalline cellulose 20
    Hydroxypropylcellulose 10
    Croscarmellose sodium 5
    Example 4:
    Fluconazole 75% (W/W)
    Polyethylene glycol 4000 10
    Polyethylene glycol 2000 10
    Hydroxypropylcellulose 5
    Example 5:
    Fluconazole 75% (W/W)
    Polyethylene glycol 8000 20
    Polyvinylpyrrolidone 5
    Example 6:
    Ketoconazole 65% (W/W)
    Microcrystalline cellulose 20
    Hydroxypropylcellulose 10
    Croscarmellose sodium 5
    Example 7:
    Ketoconazole 75% (W/W)
    Microcrystalline cellulose 15
    Hydroxypropylcellulose 5
    Croscarmellose sodium 5
    Example 8:
    Ketoconazole 75% (W/W)
    Polyethylene glycol 4000 10
    Polyethylene glycol 2000 10
    Hydroxypropylcellulose 5
    Example 9:
    Ketoconazole 75% (W/W)
    Polyethylene glycol 8000 20
    Polyvinylpyrrolidone 5
    Example 10:
    Griseofulvin 65% (W/W)
    Microcrystalline cellulose 20
    Hydroxypropylcellulose 10
    Croscarmellose sodium 5
    Example 11:
    Griseofulvin 75% (W/W)
    Microcrystalline cellulose 15
    Hydroxypropylcellulose 5
    Croscarmellose sodium 5
    Example 12:
    Griseofulvin 75% (W/W)
    Polyethylene glycol 4000 10
    Polytheylene glycol 2000 10
    Hydroxypropylcellulose 5
    Example 13:
    Ciprofloxacin 75% (W/W)
    Polyethylene glycol 8000 20
    Polyvinylpyrrolidone 5
    Example 14:
    Terbinafine HCl 75% (W/W)
    Polyethylene glycol 4000 10
    Polyethylene glycol 2000 10
    Hydroxypropylcellulose 5
    Example 15:
    Terbinafine HCl 75% (W/W)
    Polyethylene Glycol 4000 20
    Polyvinylpyrrolidone 5
  • Non pH Sensitive Delayed Release Component
  • Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press. [0055]
    Ingredient Conc. (% W/W)
    Example 16:
    Fluconazole 65% (W/W)
    Microcrystalline cellulose 20
    Polyox 10
    Croscarmellose sodium 5
    Example 17:
    Fluconazole 55% (W/W)
    Microcrystalline cellulose 25
    Polyox 10
    Glyceryl monooleate 10
    Example 18:
    Fluconazole 65% (W/W)
    Polyox 20
    Hydroxypropylcellulose 10
    Croscarmellose sodium 5
    Example 19:
    Ketoconazole 70% (W/W)
    Polyox 20
    Hydroxypropylcellulose 5
    Croscarmellose sodium 5
  • Enteric Release Component
  • Formulate the ingredients by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press. [0056]
    Ingredient Conc. (% W/W)
    Example 20:
    Fluconazole 65% (W/W)
    Microcrystalline cellulose 20
    Cellulose Acetate Pthalate 15
    Example 21:
    Fluconazole 55% (W/W)
    Microcrystalline cellulose 25
    Cellulose Acetate Pthalate 10
    Hydroxypropylmethylcellulose 10
    Example 22:
    Fluconazole 65% (W/W)
    Polyox 20
    Hydroxypropylcellulose pthalate 10
    Eudragit L30D 5
    Example 23:
    Fluconazole 40% (W/W)
    Microcrystalline Cellulose 40
    Cellulose Acetate Pthalate 10
    Example 24:
    Ketoconazole 70% (W/W)
    Hydroxypropylcellulose pthalate 15
    Croscarmellose sodium 10
    Example 25:
    Ketoconazole 75% (W/W)
    Polyethylene glycol 2000 10
    Eudragit L 30D 15
    Example 26:
    Ketoconazole 40% (W/W)
    Lactose 50
    Eudgragit L 30D 10
    Example 27:
    Griseofulvin 65% (W/W)
    Microcrystalline Cellulose 20
    Eudragit L 30D 10
    Example 28:
    Griseofulvin 75% (W/W)
    Microcrystalline Cellulose 15
    Hydroxypropylcellulose pthalate 10
    Example 29:
    Griseofulvin 80% (W/W)
    Lactose 10
    Eudragit L 30D 10
    Example 30:
    Griseofulvin 70% (W/W)
    Polyethylene glycol 4000 20
    Cellulose acetate pthalate 10
    Example 31:
    Terbinafine HCl 60% (W/W)
    Polyethylene glycol 2000 10
    Lactose 20
    Eudragit L 30D 10
    Example 32:
    Terbinafine HCl 70% (W/W)
    Microcrystalline cellulose 20
    Cellulose acetate pthalate 10
  • Sustained Release Component
  • Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press. [0057]
    Ingredient Conc. (% W/W)
    Example 33:
    Fluconazole 65% (W/W)
    Ethylcellulose 20
    Polyox 10
    Hydroxypropylmethylcellulose 5
    Example 34:
    Fluconazole 55% (W/W)
    Lactose 25
    Polyox 10
    Glyceryl monooleate 10
    Example 35:
    Fluconazole 70% (W/W)
    Polyox 20
    Hydroxypropylcellulose 10
    Example 36:
    Ketoconazole 75% (W/W)
    Lactose 15
    Hydroxypropylcellulose 5
    Ethylcellulose 5
    Example 37:
    Ketoconazole 75% (W/W)
    Polyethylene glycol 4000 10
    Lactose 10
    Eudragit RL 30D 5
    Example 38:
    Ketoconazole 80% (W/W)
    Polyethylene glycol 8000 10
    Hydroxypropylmethylcellulose 5
    Eudgragit RS 30D 5
    Example 39:
    Griseofulvin 75% (W/W)
    Hydroxyethylcellulose 10
    Polyethylene glycol 4000 10
    Hydroxypropylcellulose 5
    Example 40:
    Griseofulvin 75% (W/W)
    Lactose 10
    Povidone (PVP) 10
    Polyethylene glycol 2000 5
    Example 41:
    Terbinafine HCl 75% (W/W)
    Polyethylene glycol 4000 10
    Povidone (PVP) 10
    Hydroxypropylcellulose 5
    Example 42:
    Terbinafine HCl 75% (W/W)
    Lactose 15
    Polyethylene glycol 4000 5
    Polyvinylpyrrolidone 5
    Example 43:
    Ketoconazole 40% (W/W)
    Eudragit S100 50
    Triethyl Citrate 10
    Example 44:
    Ketoconazole 50% (W/W)
    Sureteric 50
    Example 45:
    Ketoconazole 50% (W/W)
    Eudragit S100 45
    Triethyl Citrate 5
  • Three Pulses EXAMPLE 46. 1. Antifungal Matrix Pellet Formulation and Preparation Procedure (Immediate Release)
  • 46.1 Pellet Formulation [0058]
  • The composition of the antifungal matrix pellets provided in Table 1. [0059]
    TABLE 1
    Composition of Antifungal Pellets
    Component Percentage (%)
    Antifungal 50
    Avicel PH 101 20
    Lactose 20
    PVP K29/32* 10
    Purified Water
    Total 100 
  • 46.2. Preparation Procedure for Antifungal Matrix Pellets [0060]
  • 46.2.1 Blend Antifungal and Avicel® PH 101 using a Robot Coupe high shear granulator. [0061]
  • 46.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend under continuous mixing. [0062]
  • 46.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm. [0063]
  • 46.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer. [0064]
  • 46.2.5 Dry the spheronized pellets at 50° C. overnight. [0065]
  • 46.2.6 Pellets between 16 and 30 Mesh were collected for further processing. [0066]
  • 46.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion [0067]
  • A. Dispersion Formulation [0068]
  • The composition of the aqueous Eudragit L30D-55 dispersion applied to the Antifungal matrix pellets is provided below in Table 2. [0069]
    TABLE 2
    Eudragit ® L 30 D-55 Aqueous Coating Dispersion
    Component Percentage (%)
    Eudragit ® L 30 D-55 55.0
    Triethyl Citrate 1.6
    Talc 8.0
    Purified Water 37.4
    Solids Content 25.5
    Polymer Content 15.9
  • B. Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion [0070]
  • 46.3.1 Suspend triethyl citrate and talc in deionized water. [0071]
  • 46.3.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer. [0072]
  • 46.3.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring. [0073]
  • 46.3.4 Allow the coating dispersion to stir for one hour prior to application onto the Antifungal matrix pellets. [0074]
  • 46.4 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion [0075]
  • A. Dispersion Formulation [0076]
  • The composition of the aqueous Eudragit® S 100 dispersion applied to the Antifungal matrix pellets is provided below in Table 3. [0077]
    TABLE 3
    Eudragit ® S 100 Aqueous Coating Dispersion
    Component Percentage (%)
    Part A
    Eudragit ® S 100 12.0
    1 N Ammonium Hydroxide 6.1
    Triethyl Citrate 6.0
    Purified Water 65.9
    Part B
    Talc 2.0
    Purified Water 8.0
    Solid Content 20.0
    Polymer Content 12.0
  • B. Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion [0078]
  • Part I: [0079]
  • (i) Dispense Eudragit® S 100 powder in deionized water with stirring. [0080]
  • (ii) Add ammonium hydroxide solution drop-wise into the dispersion with stirring. [0081]
  • (iii) Allow the partially neutralized dispersion to stir for 60 minutes. [0082]
  • (iv) Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B. [0083]
  • Part II: [0084]
  • (i) Disperse talc in the required amount of water [0085]
  • (ii) Homogenize the dispersion using a PowerGen 700D high shear mixer. [0086]
  • (iii) Part B is then added slowly to the polymer dispersion in Part A with a mild stirring. [0087]
  • 46.5 Coating Conditions for the Application of Aqueous Coating Dispersions [0088]
  • The following coating parameters are used to coat matrix pellets with each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating. [0089]
    Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed
    Coater
    Spray nozzle diameter 1.0 mm
    Material Charge 300 gram
    Inlet Air Temperature 40 to 45° C.
    Outlet Air Temperature 30 to 33° C.
    Atomization Air Pressure 1.8 Bar
    Pump Rate 2 gram
    per minute
  • (i) Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets. [0090]
  • (ii) Coat matrix pellets with S100 dispersion such that you apply 20% coat weight gain to the pellets. [0091]
  • 46.6 Encapsulation of the Antifungal Pellets [0092]
  • Pellets are filled into size 00 hard gelatin capsules at a ratio of 30%:30%:40%: [0093]
  • Immediate-release matrix pellets uncoated, L30 D-55 coated pellets and S100 coated pellets respectively. [0094]
  • The capsule is filled with the three different pellets to achieve the desired dosage. [0095]
  • Three Pulses Example 47 Antifungal Pellet Formulation and Preparation Procedure
  • 47.1 Pellet Formulations for subsequent coating [0096]
  • The composition of the Antifungal trihydrate matrix pellets provided in Table 4. [0097]
    TABLE 4
    Composition of Antifungal Matrix Pellets
    Component Percentage (%)
    Antifungal Trihydrate powder 92
    Avicel PH 101 7.0
    Hydroxypropyl methylcellulose, NF* 1.0
    Total 100
  • 47.2 Preparation Procedure for Antifungal Matrix Pellets [0098]
  • 47.2.1 Blend Antifungal and Avicel® PH 101 using a low shear blender. [0099]
  • 47.2.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing. [0100]
  • 47.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator is 0.8 mm. [0101]
  • 47.2.4 Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate. [0102]
  • 47.2.5 Dry the spheronized pellets at 60° C. using a fluid bed dryer until the exhaust temperature reaches 40° C. [0103]
  • 47.2.6 Pellets between 20 and 40 Mesh were collected for further processing. [0104]
  • 47.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion [0105]
  • 47.3.1 Dispersion Formulation [0106]
  • The composition of the aqueous Eudragit L30D-55 dispersion applied to the antifungal matrix pellets is provided below in Table 5. [0107]
    TABLE 5
    Eudragit ® L 30 D-55 Aqueous Coating Dispersion
    Component Percentage (%)
    Eudragit ® L 30 D-55 41.6
    Triethyl Citrate 2.5
    Talc 5.0
    Purified Water 50.9
    Solids Content 20.0
    Polymer Content 12.5
  • 47.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion [0108]
  • 47.4.1 Suspend triethyl citrate and talc in deionized water. [0109]
  • 47.4.2 The TEC/talc suspension is mixed using laboratory mixer. [0110]
  • 47.4.3 Add the TEC/talc suspension from slowly to the Eudragit® L 30 D-55 latex dispersion while stirring. [0111]
  • 47.4.4 Allow the coating dispersion to stir for one hour prior to application onto the antifungal matrix pellets. [0112]
  • 47.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion [0113]
  • 47.5.1 Dispersion Formulation [0114]
  • The composition of the aqueous Eudragit® S 100 dispersion applied to the Antifungal matrix pellets is provided below in Table 6. [0115]
    TABLE 6
    Eudragit ® S 100 Aqueous Coating Dispersion
    Component Percentage (%)
    Part A
    Eudragit ® S 100 10.0
    1 N Ammonium Hydroxide 5.1
    Triethyl Citrate 5.0
    Water 64.9
    Part B
    Talc 5.0
    Water 10.0
    Solid Content 25.0
    Polymer Content 10.0
  • [0116] 47.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion
  • Part A: [0117]
  • 47.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring. [0118]
  • 47.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring. [0119]
  • 47.6.3 Allow the partially neutralized dispersion to stir for 60 minutes. [0120]
  • 47.6.4 Add triethyl citrate drop-wise into the dispersion with stirring and let stir overnight prior to the addition of Part B. [0121]
  • Part B: [0122]
  • 47.6.5 Disperse talc in the required amount of water [0123]
  • 47.6.6 Stir the dispersion using an overhead laboratory mixer. [0124]
  • 47.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring. [0125]
  • 47.7 Coating Conditions for the Application of Aqueous Coating Dispersions [0126]
  • The following coating parameters are used for both the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating processes. [0127]
    Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed
    Coater
    Spray nozzle diameter 1.0 mm
    Material Charge 300 gram
    Inlet Air Temperature 40 to 45° C.
    Outlet Air Temperature 30 to 33° C.
    Atomization Air Pressure 1.8 Bar
    Pump Rate 2-6 gram
    per minute
  • 47.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 20% coat weight gain to the pellets. [0128]
  • 47.7.2 Coat matrix pellets with S100 dispersion such that you apply 37% coat weight gain to the pellets. [0129]
  • 47.8 Preparation of Antifungal Granulation (Immediate Release Component) for tabletting [0130]
    TABLE 7
    Composition of Antifungal Granulation
    Component Percentage (%)
    Antifungal Trihydrate powder 92
    Avicel PH 101 7.0
    Hydroxypropyl methylcellulose, NF* 1.0
    Total 100
  • 47.8.1 Blend Antifungal and Avicel® PH 101 using a low shear blender. [0131]
  • 47.8.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing. [0132]
  • 47.8.3 Dry the granulation at 60° C. using a fluid bed dryer until the exhaust temperature reaches 40° C. [0133]
  • 47.8.4 Granules between 20 and 40 Mesh are collected for further processing. [0134]
  • 47.9 Tabletting of the Antifungal Pellets [0135]
    TABLE 8
    Composition of Antifungal Tablets
    Component Percentage (%)
    Antifungal granules 32.5
    Avicel PH 200 5.0
    Antifungal L30D-55 coated pellets 30
    Antifungal S100 coated pellets 30
    Colloidal silicon dioxide 1.5
    Magnesium stearate 1.0
    Total 100
  • [0136] 47.9.1 Blend the Antifungal granules, Avicel PH-200, Antifungal pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
  • 47.9.2 Add the magnesium stearate to the blender, and blend for 5 minutes. [0137]
  • 47.9.3 Compress the blend on a rotary tablet press. [0138]
  • 47.9.4 The fill weight should be adjusted to achieve the desired dosage. [0139]
  • Four pulses EXAMPLE 48
  • 1 Antifungal Matrix Pellet Formulation and Preparation Procedure [0140]
  • 48.1 Pellet Formulation [0141]
  • The composition of the Antifungal matrix pellets provided in Table 9. [0142]
    TABLE 9
    Composition of Antifungal Pellets
    Component Percentage (%)
    Antifungal 50
    Avicel PH 101 20
    Lactose 20
    PVP K29/32* 10
    Purified Water
    Total 100 
  • 48.2 Preparation Procedure for Antifungal Matrix Pellets [0143]
  • 48.2.1 Blend Antifungal and Avicel® PH 101 using a Robot Coupe high shear granulator. [0144]
  • 48.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend under continuous mixing. [0145]
  • 48.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm. [0146]
  • 48.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer. [0147]
  • 48.2.5 Dry the spheronized pellets at 50° C. overnight. [0148]
  • 48.2.6 Pellets between 16 and 30 Mesh were collected for further processing. [0149]
  • 48.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion [0150]
  • 48.3.1 Dispersion Formulation [0151]
  • The composition of the aqueous Eudragit L30D-55 dispersion applied to the Antifungal matrix pellets is provided below in Table 10. [0152]
    TABLE 10
    Eudragit ® L 30 D-55 Aqueous Coating Dispersion
    Component Percentage (%)
    Eudragit ® L 30 D-55 55.0
    Triethyl Citrate 1.6
    Talc 8.0
    Purified Water 37.4
    Solids Content 25.5
    Polymer Content 15.9
  • 48.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion [0153]
  • 48.4.1 Suspend triethyl citrate and talc in deionized water. [0154]
  • 48.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer. [0155]
  • 48.4.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring. [0156]
  • 48.4.4 Allow the coating dispersion to stir for one hour prior to application onto the Antifungal matrix pellets. [0157]
  • 48.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion [0158]
  • 48.5.1 Dispersion Formulation [0159]
  • The composition of the aqueous Eudragit® S 100 dispersion applied to the Antifungal matrix pellets is provided below in Table 11. [0160]
    TABLE 11
    Eudragit ® S 100 Aqueous Coating Dispersion
    Component Percentage (%)
    Part A
    Eudragit ® S 100 12.0
    1 N Ammonium Hydroxide 6.1
    Triethyl Citrate 6.0
    Purified Water 65.9
    Part B
    Talc 2.0
    Purified Water 8.0
    Solid Content 20.0
    Polymer Content 12.0
  • 48.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion [0161]
  • Part A: [0162]
  • 48.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring. [0163]
  • 48.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring. [0164]
  • 48.6.3 Allow the partially neutralized dispersion to stir for 60 minutes. [0165]
  • 48.6.4 Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B. [0166]
  • Part B: [0167]
  • 48.6.5 Disperse talc in the required amount of water [0168]
  • 48.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer. [0169]
  • 48.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring. [0170]
  • 48.7 Coating Conditions for the Application of Aqueous Coating Dispersions [0171]
  • The following coating parameters are used for coating with each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings. [0172]
    Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed
    Coater
    Spray nozzle diameter 1.0 mm
    Material Charge 300 gram
    Inlet Air Temperature 40 to 45° C.
    Outlet Air Temperature 30 to 33° C.
    Atomization Air Pressure 1.8 Bar
    Pump Rate 2 gram
    per minute
  • 48.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets. [0173]
  • 48.7.2 Coat matrix pellets with L30 D-55 dispersion such that you apply 30% coat weight gain to the pellets. [0174]
  • 48.7.3 Coat matrix pellets with S100 dispersion such that you apply 20% coat weight gain to the pellets. [0175]
  • 48.8 Encapsulation of the Antifungal Pellets [0176]
  • Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%:30%:20%:30% [0177]
  • Immediate-release matrix pellets (uncoated), L30 D-55 coated pellets 12% weight gain, L30D-55 coated pellets 30% weight gain and S100 coated pellets respectively. [0178]
  • The capsule is filled with the four different pellets to achieve the desired dosage. [0179]
  • The present invention is particularly advantageous in that there is provided an antifungal product which provides an improvement over twice a day administration of the antifungal and an improvement over a once a day administration of the antifungal. [0180]
  • Numerous modification and variations of the present invention are possible in light of the above teachings and therefore, within the scope of the appended claims the invention may be practiced otherwise than as particularly described. [0181]

Claims (32)

    What is claimed is:
  1. 1. A once-a-day antifungal product comprising: first, second, and third dosage forms, wherein each of said dosage forms includes at least one antifungal agent and a pharmaceutically acceptable carrier; said first dosage form is an immediate release dosage form; said second and third dosage forms are delayed release dosage forms; each of said first, second, and third dosage forms initiates release of said at least one antifungal agent at different times; Cmax in serum of the total antifungal agent released from said antifungal product is achieved in less than about 12 hours from administration; and said once-a-day antifungal product contains the total dosage of said at least one antifungal agent for a twenty-four hour period.
  2. 2. The product of claim 1, wherein the Cmax for the product is reached no earlier than four hours after administration.
  3. 3. The product of claim 1, wherein the antifungal released from the first dosage form reaches a Cmax in serum within from about 0.5 hours to about 2 hours after administration of the product.
  4. 4. The product of claim 1, wherein the antifungal released from the second dosage form reaches a Cmax in serum in no more than about 4 hours after administration of the product.
  5. 5. The product of claim 1, wherein the antifungal released from the third dosage form reaches a Cmax in serum within 8 hours after administration of the product.
  6. 6. The product of claim 1, wherein the immediate release dosage form contains at least 20% and no more than 50% of the total dosage of antifungal.
  7. 7. The product of claim 1, wherein the product is an oral dosage form.
  8. 8. The product of claim 7, wherein the antifungal released from the second dosage form reaches a Cmax in the serum after Cmax is reached in the serum for the antifungal released from the first dosage form.
  9. 9. The product of claim 8, wherein the antifungal released from the third dosage form reaches a Cmax in the serum after Cmax is reached in the serum for the antifungal released from the second dosage form.
  10. 10. The product of claim 9, wherein said second dosage form initiates release of said antifungal before said third dosage form, wherein said second dosage form provides from 30% to 60% by weight of the total antifungal released by said second and third dosage forms, and wherein said third dosage form provides the remainder of the total antifungal released by said second and third dosage forms.
  11. 11. The product of claim 1 further comprising a fourth antifungal dosage form, said fourth antifungal dosage form comprising at least one antifungal and a pharmaceutically acceptable carrier and wherein said at least one antifungal released from said fourth antifungal dosage form reaches a Cmax in the serum after Cmax is achieved in the serum for antifungal released from each of said first, second, and third dosage forms.
  12. 12. The product of claim 11, wherein said fourth antifungal dosage form is a delayed release dosage form.
  13. 13. The product of claim 12, wherein said second dosage form initiates release of said antifungal before said third dosage form, wherein said third dosage form initiates release of said antifungal before said fourth dosage form, wherein said second dosage form provides 20% to 35% by weight of the total antifungal released by said second, third, and fourth dosage forms, wherein said third dosage form provides from 20% to 40% by weight of the total antifungal released by said second, third, and fourth dosage forms, and wherein said fourth dosage form provides the remainder of the total antifungal released by said second, third, and fourth dosage forms.
  14. 14. The product of claim 11, wherein the antifungal released from the first dosage form reaches a Cmax in serum within from about 0.5 hours to about 2 hours after administration of the product.
  15. 15. The product of claim 11, wherein the antifungal released from the second dosage form reaches a Cmax in serum in no more than about 4 hours after administration of the product.
  16. 16. The product of claim 11, wherein the antifungal released from the third dosage form reaches a Cmax in serum within 8 hours after administration of the product.
  17. 17. A process for treating an antifungal infection in a host comprising:
    administering to a host the antifungal product of claim 1 once-a-day.
  18. 18. A process for treating an antifungal infection in a host comprising:
    administering to a host the antifungal product of claim 2 once-a-day.
  19. 19. A process for treating an antifungal infection in a host comprising:
    administering to a host the antifungal product of claim 3 once-a-day.
  20. 20. A process for treating an antifungal infection in a host comprising:
    administering to a host the antifungal product of claim 4 once-a-day.
  21. 21. A process for treating an antifungal infection in a host comprising:
    administering to a host the antifungal product of claim 5 once-a-day.
  22. 22. A process for treating an antifungal infection in a host comprising:
    administering to a host the antifungal product of claim 6 once-a-day.
  23. 23. A process for treating an antifungal infection in a host comprising:
    administering to a host the antifungal product of claim 7 once-a-day.
  24. 24. A process for treating an antifungal infection in a host comprising:
    administering to a host the antifungal product of claim 8 once-a-day.
  25. 25. A process for treating an antifungal infection in a host comprising:
    administering to a host the antifungal product of claim 9 once-a-day.
  26. 26. A process for treating an antifungal infection in a host comprising:
    administering to a host the antifungal product of claim 10 once-a-day.
  27. 27. A process for treating an antifungal infection in a host comprising:
    administering to a host the antifungal product of claim 11 once-a-day.
  28. 28. A process for treating an antifungal infection in a host comprising:
    administering to a host the antifungal product of claim 12 once-a-day.
  29. 29. A process for treating an antifungal infection in a host comprising:
    administering to a host the antifungal product of claim 13 once-a-day.
  30. 30. A process for treating an antifungal infection in a host comprising:
    administering to a host the antifungal product of claim 14 once-a-day.
  31. 31. A process for treating an antifungal infection in a host comprising:
    administering to a host the antifungal product of claim 15 once-a-day.
  32. 32. A process for treating an antifungal infection in a host comprising:
    administering to a host the antifungal product of claim 16 once-a-day.
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US20020068078A1 (en) 2002-06-06 application
US20110065718A1 (en) 2011-03-17 application
US8303988B2 (en) 2012-11-06 grant

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