US20020068078A1 - Antifungal product, use and formulation thereof - Google Patents
Antifungal product, use and formulation thereof Download PDFInfo
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- US20020068078A1 US20020068078A1 US09/792,189 US79218901A US2002068078A1 US 20020068078 A1 US20020068078 A1 US 20020068078A1 US 79218901 A US79218901 A US 79218901A US 2002068078 A1 US2002068078 A1 US 2002068078A1
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- antifungal
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- 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
- A61K9/5084—Mixtures 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- 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
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Definitions
- This invention relates to an antifungal product, as well as the use and formulation thereof.
- antifungals have been used, and will be used, in order to combat fungal infection.
- 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.
- 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.
- 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.
- 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.
- the antifungal product generally does not include more than five dosage forms with different release times.
- 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.
- 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.
- the antifungal release from the second of the at least two dosage forms achieves a C 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 C max in the serum, and the antifungal released from the third dosage form achieves a C max in the serum after the C max of antifungal released from the second dosage form.
- C max maximum serum concentration in the serum
- 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.
- the immediate release dosage form produces a C 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 C max for the antifungal released therefrom in no more than about four hours.
- the C max 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 C max in a shorter period of time.
- the antifungal product may contain at least three or at least four or more different dosage forms.
- the antifungal released therefrom reaches a C max at a time later than the C max is achieved for the antifungal released from each of the first and second dosage forms.
- 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.
- C max for antifungal release from the third dosage form is achieved within eight hours.
- 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 max at a different time.
- C 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.
- 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.
- the preferred regimen is that the product is administered only once over a twenty-four hour period.
- 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.
- 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 max of the fourth dosage form of the at least four dosage forms is reached after the C max 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 may be formulated for administration by a variety of routes of administration.
- 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.
- the antifungal product is formulated in a manner such that it is suitable for oral administration.
- the at least two different dosage forms may be formulated for topical administration by including such dosage forms in an oil-in-water emulsion, or a water-in-oil emulsion.
- the immediate release dosage form is in the continuous phase
- 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.
- 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.
- an antifungal product in the form of a patch which includes antifungal dosage forms having different release profiles, as hereinabove described.
- the antifungal product may be formulated for use in the eye or ear or nose, for example, as a liquid emulsion.
- 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.
- 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.
- the antifungal product may be formulated for use in inhalation therapy by coating the particles and micronizing the particles for inhalation.
- the antifungal product is formulated in a manner suitable 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.
- 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.
- 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 max of the antifungal released from each of the tablets is reached at different times, with the C max of the total antifungal released from the antifungal product being achieved in less than twelve hours.
- 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.
- the time of release can be controlled by the concentration of antifungals in the coating and/or the thickness of the coating.
- 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.
- 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.
- 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.
- each of the dosage forms contains the same antifungal; however, each of the dosage forms may contain more than one antifungal.
- the immediate release component provides from 20% to 35% (preferably 20% to 30%), by weight, of the total antifungal; where there is 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.
- 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.
- 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 providing the remainder of the antifungal provided by the three 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
- 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.
- 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.
- 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 da
- ingredients in this system 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.
- 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
- These materials may be present in the rate of 0.05-15% (W/W).
- compositions 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.
- 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.
- PEG polyethylene glycol
- Carbowax, Polyox polyethylene glycol
- waxes such as white wax or bees wax
- paraffin acrylic acid derivatives
- acrylic acid derivatives Eudragit
- propylene glycol and ethylcellulose
- these materials can be present in the range of 0.5-25% (W/W) of this component.
- compositions 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.
- 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.
- These materials can be present in concentrations from 4-20% (W/W).
- compositions 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.
- 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.
- These materials can be present in concentrations from 4-20% (W/W).
- 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.
- 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.
- 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
- 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.
- a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder
- 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.
- Example 1 Fluconazole 65% (W/W) Microcrystalline cellulose 20 Povidone 10 Croscar,ellose 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 4
- 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.
- a suitable pharmaceutical drier such as a vacuum oven or forced-air oven.
- 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 Fluconazole 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D 5
- Example 20 Fluconazole 75% (W/W) Polyethylene glycol 8000 20 Ethylcellulose 5
- Example 21 Ketoconazole 70% (W/W) Polyox 20 Hydroxypropylcellulose 5 Croscarmellose sodium 5
- Example 22 Ketoconazole 75% (W/W) Polyox 15 Hydroxypropylcellulose 5 Ethylcellulose 5
- Example 23 Ketoconazole 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10
- 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.
- a suitable pharmaceutical drier such as a vacuum oven or forced-air oven.
- Example 31 Fluconazole 65% (W/W) Microcrystalline cellulose 20 Cellulose Acetate Pthalate 15
- Example 32 Fluconazole 55% (W/W) Microcrystalline cellulose 25 Cellulose Acetate Pthalate 10 Hydroxypropylmethylcellulose 10
- Example 33 Fluconazole 65% (W/W) Polyox 20 Hydroxypropylcellulose pthalate 10 Eudragit L30D 5
- Example 34 Fluconazole 75% (W/W) Polyethylene glycol 2000 10 Eudragit L 30D 10 Eudragit RL 30D 5
- Example 35 Fluconazole 40% (W/W) Microcrystalline Cellulose 40 Cellulose Acetate Pthalate 10
- Example 36 Ketoconazole 70% (W/W) Hydroxypropylcellulose pthalate 15 Croscarmellose sodium 10
- Example 37 Ketoconazole 70% (W/W) Eudragit L 30D 15 Hydroxypropylcellulose 10 Ethylcellulose 5
- Example 38 Ketoconazole 75% (W/W) Polyethylene glycol
- 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.
- a suitable pharmaceutical drier such as a vacuum oven or forced-air oven.
- Example 46 Fluconazole 65% (W/W) Ethylcellulose 20 Polyox 10 Hydroxypropylmethylcellulose 5
- Example 47 Fluconazole 55% (W/W) Lactose 25 Polyox 10 Glyceryl monooleate 10
- Example 48 Fluconazole 70% (W/W) Polyox 20 Hydroxypropylcellulose 10
- Example 49 Ketoconazole 75% (W/W) Lactose 15 Hydroxypropylcellulose 5 Ethylcellulose 5
- Example 50 Ketoconazole 75% (W/W) Polyethylene glycol 4000 10 Lactose 10 Eudragit RL 30D 5
- Example 51 Ketoconazole 80% (W/W) Polyethylene glycol 8000 10 Hydroxypropylmethylcellulose 5 Eudgragit RS 30D 5
- Example 52 Griseofulvin 75% (W/W) Hydroxyethylcellulose 10 Polyethylene glycol 4000 10 Hydroxypropylcellulose 5
- Example 53 Griseofulvin 75% (W/W) Lac
- composition of the antifungal matrix pellets provided in Table 1. TABLE 1 Composition of Antifungal Pellets Component Percentage (%) Antifungal 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 Purified Water Total 100
- the composition of the aqueous Eudragit® S 100 dispersion applied to the Antifungal matrix pellets is provided below in Table 3. TABLE 3 Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage (%) Part A Eudragit ® S 100 12.0 1 N Animonium 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
- Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
- Pellets are filled into size 00 hard gelatin capsules at a ratio of 30%:30%:40%: Immediate-release matrix pellets uncoated, L30 D-55 coated pellets and S100 coated pellets respectively.
- the capsule is filled with the three different pellets to achieve the desired dosage.
- composition of the Antifungal trihydrate matrix pellets provided in Table 4. 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
- the composition of the aqueous Eudragit® S 100 dispersion applied to the Antifungal matrix pellets is provided below in Table 6. 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
- Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
- 60.9.3 Compress the blend on a rotary tablet press.
- composition of the Antifungal matrix pellets provided in Table 9. TABLE 9 Composition of Antifungal Pellets Component Percentage (%) Antifungal 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 Purified Water Total 100
- the composition of the aqueous Eudragit® S 100 dispersion applied to the Antifungal matrix pellets is provided below in Table 11. 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
- Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
- Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%:30%:20%:30% 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.
- the capsule is filled with the four different pellets to achieve the desired dosage.
- 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.
Abstract
Description
- This application is a continuation-in-part of U.S. application Ser. No. 09/687,236 filed Oct. 13, 2000.
- This invention relates to an antifungal product, as well as the use and formulation thereof.
- 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.
- 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.
- 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.
- 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.
- 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.
- The antifungal product generally does not include more than five dosage forms with different release times.
- 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.
- 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 Cmax (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.
- In general, the immediate release dosage form produces a Cmax 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 Cmax 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 Cmax 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, Cmax 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 Cmax 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.
- 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.
- 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 Cmax 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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 Cmax 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.
- 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.
- 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.
- 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.
- 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 is 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.
- 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.
- 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 providing the remainder of the antifungal provided by the three delayed release components.
- 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.
- 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.
- 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.
- It may be useful to have these materials present in the range of 1.0 to 60% (W/W).
- 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.
- These materials may be present in the rate of 0.05-15% (W/W).
- 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.
- 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.
- Typically these materials can be present in the range of 0.5-25% (W/W) of this component.
- 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.
- 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.
- These materials can be present in concentrations from 4-20% (W/W).
- 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.
- 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.
- These materials can be present in concentrations from 4-20% (W/W).
- 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.
- 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.
- 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).
- 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.
- 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.
Example 1: Fluconazole 65% (W/W) Microcrystalline cellulose 20 Povidone 10 Croscar,ellose 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 Polyvinylpyrrolidofle 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: Cirpofloxacin 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: Terbinafme 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.
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: Fluconazole 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D 5 Example 20: Fluconazole 75% (W/W) Polyethylene glycol 8000 20 Ethylcellulose 5 Example 21: Ketoconazole 70% (W/W) Polyox 20 Hydroxypropylcellulose 5 Croscarmellose sodium 5 Example 22: Ketoconazole 75% (W/W) Polyox 15 Hydroxypropylcellulose 5 Ethylcellulose 5 Example 23: Ketoconazole 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D 5 Example 24: Ketoconazole 80% (W/W) Polyethylene glycol 8000 10 Polyvinylpyrrolidone 5 Eudgragit R 30D 5 Example 25: Griseofulvin 65% (W/W) Polyethylene glycol 4000 20 Hydroxypropylcellulose 10 Eudragit RL 30D 5 Example 26: Griseofulvin 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Ethylcellulose 5 Example 27: Griseofulvin 80% (WIW) Polyethylene glycol 4000 10 Polyethylene glycol 2000 5 Eudgragit RL 30D 5 Example 28: Griseofulvin 75% (W/W) Polyethylene glycol 8000 20 Ethylcellulose 5 Example 29: Terbinafine HCl 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D 5 Example 30: Terbinafine HCl 75% (W/W) Polyethylene glycol 8000 20 Ethylcellulose 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.
Ingredient Conc. (% W/W) Example 31: Fluconazole 65% (W/W) Microcrystalline cellulose 20 Cellulose Acetate Pthalate 15 Example 32: Fluconazole 55% (W/W) Microcrystalline cellulose 25 Cellulose Acetate Pthalate 10 Hydroxypropylmethylcellulose 10 Example 33: Fluconazole 65% (W/W) Polyox 20 Hydroxypropylcellulose pthalate 10 Eudragit L30D 5 Example 34: Fluconazole 75% (W/W) Polyethylene glycol 2000 10 Eudragit L 30D 10 Eudragit RL 30D 5 Example 35: Fluconazole 40% (W/W) Microcrystalline Cellulose 40 Cellulose Acetate Pthalate 10 Example 36: Ketoconazole 70% (W/W) Hydroxypropylcellulose pthalate 15 Croscarmellose sodium 10 Example 37: Ketoconazole 70% (W/W) Eudragit L 30D 15 Hydroxypropylcellulose 10 Ethylcellulose 5 Example 38: Ketoconazole 75% (W/W) Polyethylene glycol 2000 10 Eudragit L 30D 15 Example 39: Ketoconazole 40% (W/W) Lactose 50 Eudgragit L 30D 10 Example 40: Griseofulvin 65% (W/W) Microcrystalline Cellulose 20 Eudragit L 30D 10 Example 41: Griseofulvin 75% (W/W) Microcrystalline Cellulose 15 Hydroxypropylcellulose pthalate 10 Example 42: Griseofulvin 80% (W/W) Lactose 10 Eudragit L 30D 10 Example 43: Griseofulvin 70% (W/W) Polyethylene glycol 4000 20 Cellulose acetate pthalate 10 Example 44: Terbinafine HCl 60% (W/W) Polyethylene glycol 2000 10 Lactose 20 Eudragit L 30D 10 Example 45: 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.
Ingredient Conc. (% W/W) Example 46: Fluconazole 65% (W/W) Ethylcellulose 20 Polyox 10 Hydroxypropylmethylcellulose 5 Example 47: Fluconazole 55% (W/W) Lactose 25 Polyox 10 Glyceryl monooleate 10 Example 48: Fluconazole 70% (W/W) Polyox 20 Hydroxypropylcellulose 10 Example 49: Ketoconazole 75% (W/W) Lactose 15 Hydroxypropylcellulose 5 Ethylcellulose 5 Example 50: Ketoconazole 75% (W/W) Polyethylene glycol 4000 10 Lactose 10 Eudragit RL 30D 5 Example 51: Ketoconazole 80% (W/W) Polyethylene glycol 8000 10 Hydroxypropylmethylcellulose 5 Eudgragit RS 30D 5 Example 52: Griseofulvin 75% (W/W) Hydroxyethylcellulose 10 Polyethylene glycol 4000 10 Hydroxypropylcellulose 5 Example 53: Griseofulvin 75% (W/W) Lactose 10 Povidone (PVP) 10 Polyethylene glycol 2000 5 Example 54: Terbinafine HCl 75% (W/W) Polyethylene glycol 4000 10 Povidone (PVP) 10 Hydroxypropylcellulose 5 Example 55: Terbinafine HCl 75% (W/W) Lactose 15 Polyethylene glycol 4000 5 Polyvinylpyrrolidone 5 Example 56: Ketoconazole 40% (W/W) Eudragit S100 50 Triethyl Citrate 10 Example 57: Ketoconazole 50% (W/W) Sureteric 50 Example 58: Ketoconazole 50% (W/W) Eudragit S100 45 Triethyl Citrate 5 - Three Pulses
- A. Pellet Formulation
- The composition of the antifungal matrix pellets provided in Table 1.
TABLE 1 Composition of Antifungal Pellets Component Percentage (%) Antifungal 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 Purified Water Total 100 - B. Preparation Procedure for Antifungal Matrix Pellets
- 1.2.1 Blend Antifungal and Avicel® PH 101 using a Robot Coupe high shear granulator.
- 1.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend under continuous mixing.
- 1.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.
- 1.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
- 1.2.5 Dry the spheronized pellets at 50° C. overnight.
- 1.2.6 Pellets between 16 and 30 Mesh were collected for further processing.
- 1.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion
- A. Dispersion Formulation
- The composition of the aqueous Eudragit L30D-55 dispersion applied to the Antifungal matrix pellets is provided below in Table 2.
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
- 1.3.1 Suspend triethyl citrate and talc in deionized water.
- 1.3.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
- 1.3.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.
- 1.3.4 Allow the coating dispersion to stir for one hour prior to application onto the Antifungal matrix pellets.
- 1.4 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion
- A. Dispersion Formulation
- The composition of the aqueous Eudragit® S 100 dispersion applied to the Antifungal matrix pellets is provided below in Table 3.
TABLE 3 Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage (%) Part A Eudragit ® S 100 12.0 1 N Animonium 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
- Part I:
- (i) Dispense Eudragit® S 100 powder in deionized water with stirring.
- (ii) Add ammonium hydroxide solution drop-wise into the dispersion with stirring.
- (iii) Allow the partially neutralized dispersion to stir for 60 minutes.
- (iv) Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B.
- Part II:
- (i) Disperse talc in the required amount of water
- (ii) Homogenize the dispersion using a PowerGen 700D high shear mixer.
- (iii) Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
- 1.5 Coating Conditions for the Application of Aqueous Coating Dispersions
- 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.
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.
- (ii) Coat matrix pellets with S100 dispersion such that you apply 20% coat weight gain to the pellets.
- 1.6 Encapsulation of the Antifungal Pellets
- Pellets are filled into size 00 hard gelatin capsules at a ratio of 30%:30%:40%: Immediate-release matrix pellets uncoated, L30 D-55 coated pellets and S100 coated pellets respectively. The capsule is filled with the three different pellets to achieve the desired dosage.
- Three Pulses
- 60.1 Pellet Formulations for Subsequent Coating
- The composition of the Antifungal trihydrate matrix pellets provided in Table 4.
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 - 60.2 Preparation Procedure for Antifungal Matrix Pellets
- 60.2.1 Blend Antifungal and Avicel® PH 101 using a low shear blender.
- 60.2.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
- 60.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator is 0.8 mm.
- 60.2.4 Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate.
- 60.2.5 Dry the spheronized pellets at 60° C. using a fluid bed dryer until the exhaust temperature reaches 40° C.
- 60.2.6 Pellets between 20 and 40 Mesh were collected for further processing.
- 60.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion
- 60.3.1 Dispersion Formulation
- The composition of the aqueous Eudragit L30D-55 dispersion applied to the antifungal matrix pellets is provided below in Table 5.
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 - 60.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion
- 60.4.1 Suspend triethyl citrate and talc in deionized water.
- 60.4.2 The TEC/talc suspension is mixed using laboratory mixer.
- 60.4.3 Add the TEC/talc suspension from slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.
- 60.4.4 Allow the coating dispersion to stir for one hour prior to application onto the antifungal matrix pellets.
- 60.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion
- 60.5.1 Dispersion Formulation
- The composition of the aqueous Eudragit® S 100 dispersion applied to the Antifungal matrix pellets is provided below in Table 6.
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 - 60.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion
- Part A:
- 60.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.
- 60.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.
- 60.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.
- 60.6.4 Add triethyl citrate drop-wise into the dispersion with stirring and let stir overnight prior to the addition of Part B.
- Part B:
- 60.6.5 Disperse talc in the required amount of water
- 60.6.6 Stir the dispersion using an overhead laboratory mixer.
- 60.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
- 60.7 Coating Conditions for the Application of Aqueous Coating Dispersions
- The following coating parameters are used for both the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating processes.
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 - 60.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 20% coat weight gain to the pellets.
- 60.7.2 Coat matrix pellets with S100 dispersion such that you apply 37% coat weight gain to the pellets.
- 60.8 Preparation of Antifungal Granulation (Immediate Release Component) for Tabletting
TABLE 7 Composition of Antifungal Granulation Component Percentage (%) Antifungal Trihydrate powder 92 Avicel PH 101 7.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100 - 60.8.1 Blend Antifungal and Avicel® PH 101 using a low shear blender.
- 60.8.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
- 60.8.3 Dry the granulation at 60° C. using a fluid bed dryer until the exhaust temperature reaches 40° C.
- 60.8.4 Granules between 20 and 40 Mesh are collected for further processing.
- 60.9 Tabletting of the Antifungal Pellets
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 - 60.9.1 Blend the Antifungal granules, Avicel PH-200, Antifungal pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
- 60.9.2 Add the magnesium stearate to the blender, and blend for 5 minutes.
- 60.9.3 Compress the blend on a rotary tablet press.
- 60.9.4 The fill weight should be adjusted to achieve the desired dosage.
- Four pulses
- 61.1 Pellet Formulation
- The composition of the Antifungal matrix pellets provided in Table 9.
TABLE 9 Composition of Antifungal Pellets Component Percentage (%) Antifungal 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 Purified Water Total 100 - 61.2 Preparation Procedure for Antifungal Matrix Pellets
- 61.2.1 Blend Antifungal and Avicel® PH 101 using a Robot Coupe high shear granulator.
- 61.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend under continuous mixing.
- 61.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.
- 61.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
- 61.2.5 Dry the spheronized pellets at 50° C. overnight.
- 61.2.6 Pellets between 16 and 30 Mesh were collected for further processing.
- 61.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion
- 61.3.1 Dispersion Formulation
- The composition of the aqueous Eudragit L30D-55 dispersion applied to the Antifungal matrix pellets is provided below in Table 10.
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 - 61.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion
- 61.4.1 Suspend triethyl citrate and talc in deionized water.
- 61.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
- 61.4.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.
- 61.4.4 Allow the coating dispersion to stir for one hour prior to application onto the Antifungal matrix pellets.
- 61.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion
- 61.5.1 Dispersion Formulation
- The composition of the aqueous Eudragit® S 100 dispersion applied to the Antifungal matrix pellets is provided below in Table 11.
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 - 61.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion
- Part A:
- 61.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.
- 61.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.
- 61.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.
- 61.6.4 Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B.
- Part B:
- 61.6.5 Disperse talc in the required amount of water
- 61.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.
- 61.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
- 61.7 Coating Conditions for the Application of Aqueous Coating Dispersions
- The following coating parameters are used for coating with each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings.
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 - 61.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets.
- 61.7.2 Coat matrix pellets with L30 D-55 dispersion such that you apply 30% coat weight gain to the pellets.
- 61.7.3 Coat matrix pellets with S100 dispersion such that you apply 20% coat weight gain to the pellets.
- 61.8 Encapsulation of the Antifungal Pellets
- Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%:30%:20%:30% 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. The capsule is filled with the four different pellets to achieve the desired dosage.
- 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.
- 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.
Claims (18)
Priority Applications (4)
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US10/211,682 US7157095B2 (en) | 2000-10-13 | 2002-08-02 | Multiple-delayed release antifungal product, use and formulation thereof |
US10/292,617 US20030099707A1 (en) | 2000-10-13 | 2002-11-12 | Antifungal product, use and formulation thereof |
US12/884,050 US8303988B2 (en) | 2000-10-13 | 2010-09-16 | Antifungal once-a-day product, use and formulation thereof |
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US68723600A | 2000-10-13 | 2000-10-13 | |
US09/792,189 US20020068078A1 (en) | 2000-10-13 | 2001-02-22 | Antifungal product, use and formulation thereof |
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US68723600A Continuation-In-Part | 2000-02-24 | 2000-10-13 |
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US10/211,682 Continuation-In-Part US7157095B2 (en) | 2000-10-13 | 2002-08-02 | Multiple-delayed release antifungal product, use and formulation thereof |
US10/292,617 Continuation US20030099707A1 (en) | 2000-10-13 | 2002-11-12 | Antifungal product, use and formulation thereof |
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US09/792,189 Abandoned US20020068078A1 (en) | 2000-10-13 | 2001-02-22 | Antifungal product, use and formulation thereof |
US10/292,617 Abandoned US20030099707A1 (en) | 2000-10-13 | 2002-11-12 | Antifungal product, use and formulation thereof |
US12/884,050 Expired - Lifetime US8303988B2 (en) | 2000-10-13 | 2010-09-16 | Antifungal once-a-day product, use and formulation thereof |
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Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030099706A1 (en) * | 2000-10-13 | 2003-05-29 | Rudnic Edward M. | Antiviral product, use and formulation thereof |
WO2003105903A1 (en) * | 2002-06-18 | 2003-12-24 | ポーラ化成工業株式会社 | Antifungal medicinal composition |
US20040018234A1 (en) * | 2000-02-24 | 2004-01-29 | Rudnic Edward M. | Antibiotic composition |
US6723341B2 (en) | 2000-02-24 | 2004-04-20 | Advancis Pharmaceutical Corp. | Antibiotic product, use and formulation thereof |
US20040114368A1 (en) * | 2002-12-13 | 2004-06-17 | Shyu Shing Jy | Light device having rotatable or movable view |
US6929804B2 (en) | 2001-02-23 | 2005-08-16 | Advancis Pharmaceutical Corp. | Anti-fungal composition |
US8062672B2 (en) | 2003-08-12 | 2011-11-22 | Shionogi Inc. | Antibiotic product, use and formulation thereof |
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US8715727B2 (en) | 2004-07-02 | 2014-05-06 | Shionogi Inc. | Tablet for pulsed delivery |
US8758820B2 (en) | 2003-08-11 | 2014-06-24 | Shionogi Inc. | Robust pellet |
US8778924B2 (en) | 2006-12-04 | 2014-07-15 | Shionogi Inc. | Modified release amoxicillin products |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020068078A1 (en) | 2000-10-13 | 2002-06-06 | Rudnic Edward M. | Antifungal product, use and formulation thereof |
US9314524B2 (en) * | 2007-12-31 | 2016-04-19 | Calla Therapeutics Llc | Topical formulations of Flucytosine |
Family Cites Families (340)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2809918A (en) | 1955-10-17 | 1957-10-15 | Victor M Hermelin | Sustained release pharmaceutical preparations |
US2921883A (en) * | 1957-05-03 | 1960-01-19 | Smith Kline French Lab | Novel coating material for medicaments |
US3108046A (en) | 1960-11-25 | 1963-10-22 | Smith Kline French Lab | Method of preparing high dosage sustained release tablet and product of this method |
BE640616A (en) * | 1962-12-19 | |||
US3870790A (en) * | 1970-01-22 | 1975-03-11 | Forest Laboratories | Solid pharmaceutical formulations containing hydroxypropyl methyl cellulose |
DE2010416B2 (en) | 1970-03-05 | 1979-03-29 | Hoechst Ag, 6000 Frankfurt | Orally applicable dosage form with sustained release effect |
US4175125A (en) | 1971-12-27 | 1979-11-20 | Eli Lilly And Company | Method for treating methicillin resistant staphylococcus aureus |
GB1472534A (en) * | 1973-07-06 | 1977-05-04 | Glaxo Lab Ltd | 7beta-hydroxyiminoacylamido-cephalosporins |
US4529720A (en) | 1974-04-20 | 1985-07-16 | Beecham Group, P.L.C. | Antibiotic from Streptomyces clavulicerus |
IE41109B1 (en) | 1974-04-20 | 1979-10-24 | Beecham Group Ltd | Novel -lactam antibiotic from streptomyces clavuligerus |
JPS5119765A (en) * | 1974-08-09 | 1976-02-17 | Takeda Chemical Industries Ltd | Aminochiazoorujudotaino seizoho |
AT342770B (en) | 1975-04-07 | 1978-04-25 | Thomae Gmbh Dr K | PROCESS FOR PRODUCING NEW ERYTHROMYCINE DERIVATIVES |
US6218380B1 (en) | 1975-04-17 | 2001-04-17 | Smithkline Beecham P.L.C. | Pharmaceutical compositions |
US6051703C1 (en) | 1975-04-17 | 2001-10-06 | Smithkline Beecham Plc | Purified clavulanic acid and salts thereof |
US4018918A (en) | 1975-05-20 | 1977-04-19 | The Upjohn Company | Topical clindamycin preparations |
US4131672A (en) | 1975-06-09 | 1978-12-26 | Eli Lilly And Company | Method for treating methicillin resistant Staphylococcus aureus |
US4122157A (en) | 1977-03-04 | 1978-10-24 | Richardson-Merrell Inc. | Nitrofurantoin sustained release tablet |
US4250166A (en) * | 1977-05-27 | 1981-02-10 | Shionogi & Co., Ltd. | Long acting preparation of cefalexin for effective treatments of bacterial infection sensitive to cefalexin |
US4236211A (en) | 1978-09-15 | 1980-11-25 | Pfizer Inc. | Method and apparatus for determining the minimum concentration of antibiotic necessary to at least inhibit microorganism growth |
US4226849A (en) | 1979-06-14 | 1980-10-07 | Forest Laboratories Inc. | Sustained release therapeutic compositions |
FR2470599A1 (en) | 1979-12-07 | 1981-06-12 | Panoz Donald | IMPROVEMENTS IN PROCESSES FOR THE PREPARATION OF GALENIC SHAPES WITH DELAYED ACTION AND PROGRAMMED RELEASE AND GALENIC FORMS OF MEDICAMENTS THUS OBTAINED |
US4331803A (en) | 1980-06-04 | 1982-05-25 | Taisho Pharmaceutical Co., Ltd. | Novel erythromycin compounds |
US4399151A (en) | 1980-06-16 | 1983-08-16 | Merrell Dow Pharmaceuticals Inc. | Method of inhibiting the growth of protozoa |
US4362731A (en) | 1980-09-01 | 1982-12-07 | Sandoz Ltd. | Myotonolytic use of 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol and derivatives thereof |
EP0052075A1 (en) | 1980-11-12 | 1982-05-19 | Ciba-Geigy Ag | Sustained release pharmaceutical granule |
US4327725A (en) | 1980-11-25 | 1982-05-04 | Alza Corporation | Osmotic device with hydrogel driving member |
SI8110592A8 (en) | 1981-03-06 | 1996-06-30 | Pliva Pharm & Chem Works | Process for preparing of n-methyl-11-aza-10-deoxo-10-dihydroerythromycine a and derivatives thereof |
US4369172A (en) * | 1981-12-18 | 1983-01-18 | Forest Laboratories Inc. | Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose |
US4435173A (en) * | 1982-03-05 | 1984-03-06 | Delta Medical Industries | Variable rate syringe pump for insulin delivery |
US4474768A (en) | 1982-07-19 | 1984-10-02 | Pfizer Inc. | N-Methyl 11-aza-10-deoxo-10-dihydro-erytromycin A, intermediates therefor |
US4598045A (en) | 1982-08-25 | 1986-07-01 | Hana Biologics, Inc. | Triphasic mycoplasmatales detection method |
US4430495A (en) * | 1982-09-17 | 1984-02-07 | The Upjohn Company | Process for preparing lincomycin and clindamycin ribonucleotides |
US4765989A (en) | 1983-05-11 | 1988-08-23 | Alza Corporation | Osmotic device for administering certain drugs |
AU575854B2 (en) * | 1983-10-04 | 1988-08-11 | Shionogi & Co., Ltd. | 7beta-(carboxyalkenamido) cephalosporins |
DE3405378A1 (en) * | 1984-02-15 | 1985-08-22 | Röhm GmbH, 6100 Darmstadt | MEDICINE COVER |
JPS60214796A (en) | 1984-04-06 | 1985-10-28 | Taisho Pharmaceut Co Ltd | Growth hormone for fishes |
US4568741A (en) * | 1984-05-15 | 1986-02-04 | The Upjohn Company | Synthesis of 7-halo-7-deoxylincomycins |
DE3572440D1 (en) | 1984-06-19 | 1989-09-28 | Basf Ag | Gastro-resistant cylindrical pancreatine-microtablets |
US4879135A (en) | 1984-07-23 | 1989-11-07 | University Of Medicine And Dentistry Of New Jersey | Drug bonded prosthesis and process for producing same |
JPS61103890A (en) | 1984-10-26 | 1986-05-22 | Taisho Pharmaceut Co Ltd | 6-o-methylerythromycin a derivative |
CN1004002B (en) | 1984-11-29 | 1989-04-26 | 厄普约翰公司 | Improving one's methods of preparation 7-halogen-7-deoxy-lincomycin and similar compound thereof |
DE3583799D1 (en) | 1985-01-11 | 1991-09-19 | Abbott Lab Ltd | SOLID PREPARATION WITH SLOW RELEASE. |
US4670549A (en) | 1985-03-18 | 1987-06-02 | Taisho Pharmaceutical Co., Ltd. | Method for selective methylation of erythromycin a derivatives |
US4894119A (en) * | 1985-04-10 | 1990-01-16 | Drew Chemical Corporation | Retention and/or drainage and/or dewatering aid |
US4728512A (en) * | 1985-05-06 | 1988-03-01 | American Home Products Corporation | Formulations providing three distinct releases |
US4775751A (en) | 1985-06-03 | 1988-10-04 | Eli Lilly & Company | Process for cephalexin hydrochloride alcoholates |
DE3524572A1 (en) | 1985-07-10 | 1987-01-15 | Thomae Gmbh Dr K | SOLID PHARMACEUTICAL FORMS FOR PERORAL USE CONTAINING 9-DEOXO-11-DEOXY-9,11- (IMINO (2- (2-METHOXYETHOXY) ETHYLIDEN) -OXY) - (9S) -ERYTHROMYCIN AND METHOD FOR THE PRODUCTION THEREOF |
FR2585948B1 (en) | 1985-08-06 | 1988-12-16 | Pf Medicament | PROCESS FOR THE MANUFACTURE OF INDOMETACIN TABLETS |
US4904476A (en) * | 1986-03-04 | 1990-02-27 | American Home Products Corporation | Formulations providing three distinct releases |
LU87041A1 (en) | 1987-11-04 | 1989-06-14 | Oreal | RETINOIC ESTERS OF MACROLIDES, THEIR PREPARATION PROCESS AND PHARMACEUTICAL AND COSMETIC COMPOSITIONS CONTAINING THEM |
US4723958A (en) * | 1986-05-23 | 1988-02-09 | Merck & Co., Inc. | Pulsatile drug delivery system |
GB8613689D0 (en) | 1986-06-05 | 1986-07-09 | Euro Celtique Sa | Pharmaceutical composition |
NZ220764A (en) * | 1986-07-02 | 1989-09-27 | Shionogi & Co | Crystalline form of 7beta((z)-2-(2-aminothiazol-4-yl)-4- carboxybut-2-enoylamino)-3-cephem-4-carboxylic acid and pharmaceutical compositions |
EP0265061B1 (en) | 1986-09-18 | 1992-01-08 | London School of Pharmacy Innovations Ltd | Pharmaceutical formulation |
KR960000434B1 (en) * | 1986-12-17 | 1996-01-06 | 다이쇼 세이야꾸 가부시끼가이샤 | Eryhromycin a derivatives and process of method for the same |
US4749568A (en) | 1987-01-23 | 1988-06-07 | The Upjohn Company | Rubradirin treatment of methicillin-resistant staph |
US5200193A (en) | 1987-04-22 | 1993-04-06 | Mcneilab, Inc. | Pharmaceutical sustained release matrix and process |
US4945405A (en) | 1987-05-21 | 1990-07-31 | Minolta Camera Kabushiki Kaisha | Color image read apparatus with shading and color balance correction |
US4945080A (en) | 1987-05-26 | 1990-07-31 | Eli Lilly And Company | Dirithromycin metabolite |
US5143661A (en) | 1987-05-26 | 1992-09-01 | American Cyanamid Company | Silicone-hardened pharmaceutical microcapsules |
US4808411A (en) | 1987-06-05 | 1989-02-28 | Abbott Laboratories | Antibiotic-polymer compositions |
NO883326L (en) | 1987-08-11 | 1989-02-13 | Bayer Ag | DHP-retard-COOK. |
US4835140A (en) | 1987-08-20 | 1989-05-30 | Indiana University Foundation | Method for treating pneumocystis carinii pneumonia patients with clindamycin and primaquine |
JP2751385B2 (en) | 1988-05-19 | 1998-05-18 | 大正製薬株式会社 | Process for producing erythromycin A oxime and its salt |
US4849515A (en) | 1988-08-22 | 1989-07-18 | E. I. Du Pont De Nemours And Company | Clindamycin-2-phosphoryl benzylate |
US4895934A (en) * | 1988-08-22 | 1990-01-23 | E. I. Du Pont De Nemours And Company | Process for the preparation of clindamycin phosphate |
AU5157590A (en) | 1989-02-06 | 1990-08-24 | Abbott Laboratories | Pharmaceutical compositions for oral administration |
US4981468A (en) * | 1989-02-17 | 1991-01-01 | Eli Lilly And Company | Delivery device for orally administered therapeutic agents |
US5007790A (en) | 1989-04-11 | 1991-04-16 | Depomed Systems, Inc. | Sustained-release oral drug dosage form |
US5110598A (en) | 1989-06-30 | 1992-05-05 | Smithkline Beecham Corp. | Intermittent release dosage form |
US5178874A (en) * | 1989-06-30 | 1993-01-12 | Smithkline Beechman Corporation | Intermittent release dosage form |
US5387380A (en) * | 1989-12-08 | 1995-02-07 | Massachusetts Institute Of Technology | Three-dimensional printing techniques |
US5204055A (en) | 1989-12-08 | 1993-04-20 | Massachusetts Institute Of Technology | Three-dimensional printing techniques |
JPH0674206B2 (en) | 1989-12-28 | 1994-09-21 | 田辺製薬株式会社 | Controlled release formulation and process for producing |
US5158777A (en) | 1990-02-16 | 1992-10-27 | E. R. Squibb & Sons, Inc. | Captopril formulation providing increased duration of activity |
US5358713A (en) | 1990-02-23 | 1994-10-25 | Mitsui Norin Co., Ltd. | Method of preventing the transmission of infection caused by methicillin-resistant Staphylococcus aureus |
US5182374A (en) * | 1990-03-21 | 1993-01-26 | American Cyanamid Company | Clindamycin phosphate synthesis |
GB2253346A (en) * | 1991-02-22 | 1992-09-09 | John Rhodes | Delayed release oral dosage forms for treatment of intestinal disorders |
US5556839A (en) | 1991-04-29 | 1996-09-17 | Eli Lilly And Company | Form II Dirithromycin |
GB9109862D0 (en) * | 1991-05-08 | 1991-07-03 | Beecham Lab Sa | Pharmaceutical formulations |
SK279270B6 (en) | 1991-09-30 | 1998-08-05 | Eli Lilly And Company Patent Division Lilly Corpor | One step process for production of dirithromycin |
US5334590A (en) | 1991-10-17 | 1994-08-02 | Merck & Co., Inc. | MRSA active 2-phenyl-carbapenems |
US5476854A (en) | 1991-11-27 | 1995-12-19 | Sepracor Inc. | Methods and compositions for treating bacterial infection using optically pure (R)-lomefloxacin |
US5260066A (en) * | 1992-01-16 | 1993-11-09 | Srchem Incorporated | Cryogel bandage containing therapeutic agent |
US6117843A (en) | 1992-02-18 | 2000-09-12 | Lloyd J. Baroody | Compositions for the treatment of acne containing clindamycin and benzoyl peroxide |
TW203552B (en) * | 1992-02-18 | 1993-04-11 | J Baroody Lloyd | Compositions of clindamycin and benzoyl peroxide for acne treatment |
JP3265680B2 (en) * | 1992-03-12 | 2002-03-11 | 大正製薬株式会社 | Oral pharmaceutical composition |
US5230703A (en) | 1992-04-09 | 1993-07-27 | Staodyn, Inc. | Wound infection resolution utilizing antibiotic agents and electrical stimulation |
SK279329B6 (en) * | 1992-04-30 | 1998-10-07 | Schering Corporation | Stable hydrated cephalosporin dry powder, method of its preparation and formulation thereof |
TW271400B (en) | 1992-07-30 | 1996-03-01 | Pfizer | |
MX9304638A (en) * | 1992-07-31 | 1994-05-31 | Neose Pharm Inc | COMPOSITION TO TREAT AND INHIBIT GASTRIC AND DUODENAL ULCERS. |
US5817321A (en) | 1992-10-08 | 1998-10-06 | Supratek Pharma, Inc. | Biological agent compositions |
US5688516A (en) | 1992-11-12 | 1997-11-18 | Board Of Regents, The University Of Texas System | Non-glycopeptide antimicrobial agents in combination with an anticoagulant, an antithrombotic or a chelating agent, and their uses in, for example, the preparation of medical devices |
US5260069A (en) | 1992-11-27 | 1993-11-09 | Anda Sr Pharmaceuticals Inc. | Pulsatile particles drug delivery system |
US5422343A (en) | 1992-12-21 | 1995-06-06 | Otsuka Pharmaceutical Factory, Inc. | Prophylactic and therapeutic composition for MRSA infection |
JP3319800B2 (en) * | 1993-02-01 | 2002-09-03 | 辻本化学工業株式会社 | Anti-resistant Staphylococcus aureus compounds |
IL119660A (en) | 1993-05-10 | 2002-09-12 | Euro Celtique Sa | Controlled release formulation comprising tramadol |
WO1996010996A1 (en) | 1993-07-21 | 1996-04-18 | The University Of Kentucky Research Foundation | A multicompartment hard capsule with control release properties |
JPH09500645A (en) | 1993-07-22 | 1997-01-21 | ワーナー−ランバート・コンパニー | Controlled release tacrine drug delivery system and method of making same |
US6183778B1 (en) * | 1993-09-21 | 2001-02-06 | Jagotec Ag | Pharmaceutical tablet capable of liberating one or more drugs at different release rates |
US6280771B1 (en) | 1997-02-20 | 2001-08-28 | Therics, Inc. | Dosage forms exhibiting multi-phasic release kinetics and methods of manufacture thereof |
US5490962A (en) * | 1993-10-18 | 1996-02-13 | Massachusetts Institute Of Technology | Preparation of medical devices by solid free-form fabrication methods |
US5518680A (en) | 1993-10-18 | 1996-05-21 | Massachusetts Institute Of Technology | Tissue regeneration matrices by solid free form fabrication techniques |
US6251647B1 (en) | 1993-12-06 | 2001-06-26 | The Rockefeller University | Auxiliary genes and proteins of methicillin resistant bacteria and antagonists thereof |
AU1398295A (en) | 1993-12-06 | 1995-06-27 | Rockefeller University, The | Auxiliary genes and proteins of methicillin resistant bacteria and antagonists thereof |
US5457187A (en) | 1993-12-08 | 1995-10-10 | Board Of Regents University Of Nebraska | Oligonucleotides containing 5-fluorouracil |
US5393765A (en) * | 1993-12-13 | 1995-02-28 | Hoffmann-La Roche Inc. | Pharmaceutical compositions with constant erosion volume for zero order controlled release |
DE4404018A1 (en) * | 1994-02-09 | 1995-08-10 | Merck Patent Gmbh | Protected release dosage forms containing clindamycin palmitate |
US5466446A (en) | 1994-02-16 | 1995-11-14 | Stiefel Laboratories, Inc. | Topical compositions containing bensoyl peroxide and clindamycin and method of use thereof |
US5430021A (en) | 1994-03-18 | 1995-07-04 | Pharmavene, Inc. | Hydrophobic drug delivery systems |
US5395626A (en) * | 1994-03-23 | 1995-03-07 | Ortho Pharmaceutical Corporation | Multilayered controlled release pharmaceutical dosage form |
SK126696A3 (en) | 1994-04-01 | 1997-04-09 | Microcide Pharmaceuticals Inc | Cephalosporin antibiotics and antibacterial agents containing them |
GB9407386D0 (en) | 1994-04-14 | 1994-06-08 | Smithkline Beecham Plc | Pharmaceutical formulation |
GB9408117D0 (en) | 1994-04-23 | 1994-06-15 | Smithkline Beecham Corp | Pharmaceutical formulations |
US5856474A (en) | 1994-04-25 | 1999-01-05 | Biochemie Gesellschaft, M.B.H. | Cephalosporin synthesis |
JP2977907B2 (en) | 1994-05-06 | 1999-11-15 | ファイザー・インコーポレーテッド | Controlled release dosage form of azithromycin |
FR2722098B1 (en) | 1994-07-06 | 1996-08-23 | Cird Galderma | NEW MEDICINES BASED ON METRO-NIDAZOLE OR A SYNERGETIC MIXTURE OF METRONIDAZOLE AND CLINDAMYCIN |
GB9416600D0 (en) | 1994-08-17 | 1994-10-12 | Smithkline Beecham Plc | Pharmaceutical formulation |
US5543417A (en) | 1994-10-21 | 1996-08-06 | Merck & Co., Inc. | Combination method of treating acne using 4-AZA-5α-cholestan-ones and 4-AZA-5α-androstan-ones as selective 5α-reductase inhibitors with anti-bacterial, keratolytic, or anti-inflammatory agents |
US5872104A (en) * | 1994-12-27 | 1999-02-16 | Oridigm Corporation | Combinations and methods for reducing antimicrobial resistance |
US5702895A (en) | 1995-01-19 | 1997-12-30 | Wakunaga Seiyaku Kabushiki Kaisha | Method and kit for detecting methicillin-resistant Staphylococcus aureus |
US20030083733A1 (en) | 1997-10-10 | 2003-05-01 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
KR100404293B1 (en) | 1995-05-02 | 2004-02-18 | 다이쇼 세이야꾸 가부시끼가이샤 | Composition for Oral Administration |
US5755753A (en) | 1995-05-05 | 1998-05-26 | Thermage, Inc. | Method for controlled contraction of collagen tissue |
US6057291A (en) | 1995-06-02 | 2000-05-02 | University Of British Columbia | Antimicrobial cationic peptides |
US6132768A (en) | 1995-07-05 | 2000-10-17 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Oral pharmaceutical composition with delayed release of active ingredient for reversible proton pump inhibitors |
US5945124A (en) | 1995-07-05 | 1999-08-31 | Byk Gulden Chemische Fabrik Gmbh | Oral pharmaceutical composition with delayed release of active ingredient for pantoprazole |
US6013507A (en) * | 1995-07-10 | 2000-01-11 | The Rockefeller University | Auxiliary genes and proteins of methicillin resistant bacteria and antagonists thereof |
US5985643A (en) | 1996-07-10 | 1999-11-16 | The Rockefeller University | Auxiliary gene and protein of methicillin resistant bacteria and antagonists thereof |
US6136587A (en) | 1995-07-10 | 2000-10-24 | The Rockefeller University | Auxiliary genes and proteins of methicillin resistant bacteria and antagonists thereof |
US6548084B2 (en) | 1995-07-20 | 2003-04-15 | Smithkline Beecham Plc | Controlled release compositions |
US5780058A (en) | 1995-07-21 | 1998-07-14 | Alza Corporation | Oral delivery of discrete units |
US5919489A (en) | 1995-11-01 | 1999-07-06 | Abbott Laboratories | Process for aqueous granulation of clarithromycin |
US5872229A (en) * | 1995-11-21 | 1999-02-16 | Abbott Laboratories | Process for 6-O-alkylation of erythromycin derivatives |
US5756473A (en) | 1995-11-21 | 1998-05-26 | Abbott Laboratories | 6-O-methyl erythromycin D and process for making |
US5837284A (en) | 1995-12-04 | 1998-11-17 | Mehta; Atul M. | Delivery of multiple doses of medications |
US5705190A (en) | 1995-12-19 | 1998-01-06 | Abbott Laboratories | Controlled release formulation for poorly soluble basic drugs |
US5998194A (en) | 1995-12-21 | 1999-12-07 | Abbott Laboratories | Polyketide-associated sugar biosynthesis genes |
EP0880356A4 (en) | 1996-02-16 | 2002-03-27 | Univ California | Antimicrobial peptides and methods of use |
JP3957338B2 (en) | 1996-02-23 | 2007-08-15 | 株式会社カイノス | Diagnostics |
US5766220A (en) * | 1996-02-29 | 1998-06-16 | Moenning; Stephen P. | Apparatus and method for protecting a port site opening in the wall of a body cavity |
US5951588A (en) | 1996-02-29 | 1999-09-14 | Moenning; Stephen P. | Apparatus and method for protecting a port site opening in the wall of a body cavity |
TWI225402B (en) | 1996-03-13 | 2004-12-21 | Biochemie Gmbh | Auxiliary-free agglomerates |
US5719272A (en) * | 1996-04-02 | 1998-02-17 | Abbott Laboratories | 2'-protected 3'-dimethylamine, 9-etheroxime erythromycin A derivatives |
US5837829A (en) | 1996-04-02 | 1998-11-17 | Abbott Laboratories | 9-oximesilyl erythromycin a derivatives |
US5808017A (en) | 1996-04-10 | 1998-09-15 | Abbott Laboratories | Process for preparing erythromycin A oxime |
TW438796B (en) | 1996-05-15 | 2001-06-07 | Hoffmann La Roche | 2,4-diaminopyrimidine derivatives, the manufacture process thereof, and the antibiotically-active pharmaceutical composition containing the same |
US5719132A (en) * | 1996-06-27 | 1998-02-17 | Bristol-Myers Squibb Company | Compositions and methods of treating HIV with d4T, 5-fluorouracil/tegafur, and uracil |
US5780446A (en) | 1996-07-09 | 1998-07-14 | Baylor College Of Medicine | Formulations of vesicant drugs and methods of use thereof |
US5858986A (en) * | 1996-07-29 | 1999-01-12 | Abbott Laboratories | Crystal form I of clarithromycin |
US5844105A (en) | 1996-07-29 | 1998-12-01 | Abbott Laboratories | Preparation of crystal form II of clarithromycin |
GB9617780D0 (en) | 1996-08-24 | 1996-10-02 | Smithkline Beecham Plc | Method of treatment |
JP2002514183A (en) | 1996-09-17 | 2002-05-14 | スーパージェン・インコーポレーテッド | Phospholipid drug derivatives |
US5972389A (en) | 1996-09-19 | 1999-10-26 | Depomed, Inc. | Gastric-retentive, oral drug dosage forms for the controlled-release of sparingly soluble drugs and insoluble matter |
CA2269707C (en) | 1996-10-25 | 2005-08-16 | Edward M. Rudnic | Soluble form osmotic dose delivery system |
US6361796B1 (en) | 1996-10-25 | 2002-03-26 | Shire Laboratories, Inc. | Soluble form osmotic dose delivery system |
IL119627A (en) | 1996-11-17 | 2002-03-10 | Yissum Res Dev Co | PHARMACEUTICAL PREPARATIONS FOR THE CONTROLLED-RELEASE OF AN ACTIVE AGENT COMPRISING AT LEAST ONE β-LACTAM ANTIBIOTIC AGENT |
US5840760A (en) | 1996-11-19 | 1998-11-24 | Florida Atlantic University | materials and methods for controlling methicillin-resistant Staphylococcus aureus microbes |
IT1289160B1 (en) * | 1997-01-08 | 1998-09-29 | Jagotec Ag | FULLY COATED PHARMACEUTICAL TABLET FOR THE CONTROLLED RELEASE OF ACTIVE INGREDIENTS WHICH PRESENT PROBLEMS OF |
US5945405A (en) | 1997-01-17 | 1999-08-31 | Abbott Laboratories | Crystal form O of clarithromycin |
US6296873B1 (en) | 1997-01-23 | 2001-10-02 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Zero-order sustained release delivery system for carbamazephine derivatives |
US5980942A (en) | 1997-01-23 | 1999-11-09 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Zero-order sustained release matrix tablet formulations of carbamazepine |
US5864023A (en) * | 1997-02-13 | 1999-01-26 | Abbott Laboratories | 3'-N'oxide, 3'-n-dimethylamine, 9-oxime erythromycin a derivatives |
US20020106412A1 (en) | 2000-07-10 | 2002-08-08 | Therics, Inc | Method and materials for controlling migration of binder liquid in a powder |
US6551616B1 (en) | 1997-04-11 | 2003-04-22 | Abbott Laboratories | Extended release formulations of erythromycin derivatives |
US6010718A (en) | 1997-04-11 | 2000-01-04 | Abbott Laboratories | Extended release formulations of erythromycin derivatives |
US20050064033A1 (en) * | 1997-04-11 | 2005-03-24 | Notario Gerard F. | Extended release formulations of erythromycin derivatives |
US6210710B1 (en) * | 1997-04-28 | 2001-04-03 | Hercules Incorporated | Sustained release polymer blend for pharmaceutical applications |
US6406880B1 (en) | 1997-05-02 | 2002-06-18 | Integrated Research Technology, Llc | Betaines as adjuvants to susceptibility testing and antimicrobial therapy |
US5877243A (en) * | 1997-05-05 | 1999-03-02 | Icet, Inc. | Encrustation and bacterial resistant coatings for medical applications |
US6635280B2 (en) | 1997-06-06 | 2003-10-21 | Depomed, Inc. | Extending the duration of drug release within the stomach during the fed mode |
EP0998271B3 (en) * | 1997-06-06 | 2014-10-29 | Depomed, Inc. | Gastric-retentive oral drug dosage forms for controlled release of highly soluble drugs |
AUPO758297A0 (en) | 1997-06-27 | 1997-07-24 | Rowe, James Baber | Control of acidic gut syndrome |
AU731909B2 (en) | 1997-07-01 | 2001-04-05 | Isis Pharmaceuticals, Inc. | Compositions and methods for the delivery of oligonucleotides via the alimentary canal |
US6503709B1 (en) * | 1997-07-03 | 2003-01-07 | Id Biomedical Corporation | Methods for rapidly detecting methicillin resistant staphylococci |
SI9700186B (en) | 1997-07-14 | 2006-10-31 | Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D. | Novel pharmaceutical preparation with controlled release of active healing substances |
US6265394B1 (en) | 1997-07-31 | 2001-07-24 | Bristol-Myers Squibb Company | Bis quaternary MRSA cephem derivatives |
US6630498B2 (en) | 1997-08-06 | 2003-10-07 | Smithkline Beecham Corporation | Eprosartan arginyl charge-neutralization-complex and a process for its preparation and formulation |
WO1999007685A1 (en) | 1997-08-07 | 1999-02-18 | Research Corporation Technologies, Inc. | Antibiotic for methicillin resistant bacteria |
PT1003476E (en) | 1997-08-11 | 2005-05-31 | Alza Corp | ACTIVE AGGREGATE AGGREGATE DOSAGE FORM ADAPTED FOR GASTRIC RETENTION |
US5929219A (en) | 1997-09-10 | 1999-07-27 | Abbott Laboratories | 9-hydrazone and 9-azine erythromycin derivatives and a process of making the same |
JP4234803B2 (en) | 1997-10-27 | 2009-03-04 | 久光製薬株式会社 | Pharmaceutical composition with controlled drug release rate |
US6605751B1 (en) | 1997-11-14 | 2003-08-12 | Acrymed | Silver-containing compositions, devices and methods for making |
US5852180A (en) | 1997-11-17 | 1998-12-22 | Abbott Laboratories | Chemical synthesis of 6-O-alkyl erythromycin A |
US6558699B2 (en) | 1997-11-17 | 2003-05-06 | Smithkline Beecham Corporation | High drug load immediate and modified release oral dosage formulations and processes for their manufacture |
US5932710A (en) | 1997-12-01 | 1999-08-03 | Abbott Laboratories | Process for preparing 6-O-alkyl-9-oxime erythromycin B |
IL135792A0 (en) | 1997-12-01 | 2001-05-20 | Abbott Lab | 6-o-alkyl derivatives of erythronolide b |
US5892008A (en) | 1997-12-16 | 1999-04-06 | Abbott Laboratories | Process for the preparation of 6-O-methyl erythromycin a using 9-hydroxy erythromycin derivatives |
US5948440A (en) | 1997-12-17 | 1999-09-07 | Ranbaxy Laboratories Limited | Modified release matrix formulation of cefaclor and cephalexin |
SE9704870D0 (en) | 1997-12-22 | 1997-12-22 | Astra Ab | New pharmaceutical formulation I |
WO1999040097A1 (en) | 1998-02-04 | 1999-08-12 | Teva Pharmaceutical Industries Ltd. | Process for making clarithromycin |
US6294526B1 (en) | 1998-02-06 | 2001-09-25 | Alps Pharmaceutical Ind. Co., Ltd. | Use of flavone derivatives for induction of β-lactam-sensitivity of MRSA |
US6198206B1 (en) | 1998-03-20 | 2001-03-06 | Active Control Experts, Inc. | Inertial/audio unit and construction |
US6231875B1 (en) | 1998-03-31 | 2001-05-15 | Johnson & Johnson Consumer Companies, Inc. | Acidified composition for topical treatment of nail and skin conditions |
US6288212B1 (en) | 1998-08-28 | 2001-09-11 | The University Of British Columbia | Anti-endotoxic, antimicrobial cationic peptides and methods of use therefor |
KR100377159B1 (en) * | 1998-09-09 | 2003-08-19 | 한미약품공업 주식회사 | Method for preparing Form 2 of clarithromycin without residual solvent |
US6479496B1 (en) | 1998-09-10 | 2002-11-12 | Cv Therapeutics, Inc. | Methods for treating angina with ranolazine |
US6740664B2 (en) | 1998-09-30 | 2004-05-25 | Alcon, Inc. | Methods for treating otic and ophthalmic infections |
DE19845358A1 (en) | 1998-10-02 | 2000-04-06 | Roehm Gmbh | Coated drug forms with controlled drug delivery |
US6384081B2 (en) | 1998-10-09 | 2002-05-07 | Charles L. Berman | Treatment of diseases of the eye characterized by the formation of metalloproteinase |
US6322819B1 (en) | 1998-10-21 | 2001-11-27 | Shire Laboratories, Inc. | Oral pulsed dose drug delivery system |
JP4613275B2 (en) | 1998-11-02 | 2011-01-12 | エラン ファーマ インターナショナル,リミティド | Multiparticulate modified release composition |
US6270805B1 (en) | 1998-11-06 | 2001-08-07 | Andrx Pharmaceuticals, Inc. | Two pellet controlled release formulation for water soluble drugs which contains an alkaline metal stearate |
DE19852192C2 (en) | 1998-11-12 | 2003-04-24 | Bayer Ag | Aromatic copolyesters containing active ingredient |
US6797283B1 (en) | 1998-12-23 | 2004-09-28 | Alza Corporation | Gastric retention dosage form having multiple layers |
US6361797B1 (en) * | 1999-01-28 | 2002-03-26 | Hydro Med Sciences, Inc. | Hydrogel compositions useful for the sustained release of macromolecules and methods of making same |
US6159491A (en) | 1999-02-12 | 2000-12-12 | Biovector Technologies, Inc. | Prolonged release bioadhesive vaginal gel dosage form |
SI20150A (en) | 1999-02-19 | 2000-08-31 | Lek, Tovarna Farmacevtskih In | Directly compressible matrix for controlled release of the daily dose of clarytomicyne |
US6248363B1 (en) | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
US7127285B2 (en) | 1999-03-12 | 2006-10-24 | Transport Pharmaceuticals Inc. | Systems and methods for electrokinetic delivery of a substance |
US6477410B1 (en) | 2000-05-31 | 2002-11-05 | Biophoretic Therapeutic Systems, Llc | Electrokinetic delivery of medicaments |
US6383471B1 (en) | 1999-04-06 | 2002-05-07 | Lipocine, Inc. | Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents |
US6878386B1 (en) | 1999-04-13 | 2005-04-12 | Beecham Pharmaceuticals (Pte) Limited | Method of treating a bacterial infection comprising amoxycillin and potassium clavulanate |
NZ514575A (en) | 1999-04-13 | 2004-05-28 | Beecham Pharm Pte Ltd | Novel method of treatment |
US7250176B1 (en) | 1999-04-13 | 2007-07-31 | Beecham Pharmaceuticals (Pte) Limited | Method of treating a bacterial infection |
WO2000066125A1 (en) | 1999-04-29 | 2000-11-09 | Aventis Pharma S.A. | Method for treating cancer using camptothecin derivatives and 5-fluorouracil |
US6187768B1 (en) * | 1999-06-01 | 2001-02-13 | Becton, Dickinson And Company | Kit for flushing medical devices and method of preparation |
US6632451B2 (en) | 1999-06-04 | 2003-10-14 | Dexcel Pharma Technologies Ltd. | Delayed total release two pulse gastrointestinal drug delivery system |
US6309663B1 (en) | 1999-08-17 | 2001-10-30 | Lipocine Inc. | Triglyceride-free compositions and methods for enhanced absorption of hydrophilic therapeutic agents |
US6946458B2 (en) | 1999-07-22 | 2005-09-20 | University Of South Florida | N-thiolated beta-lactams: novel antibacterial agents for methicillin-resistant Staphylococcus aureus |
TWI232111B (en) | 1999-08-06 | 2005-05-11 | Upjohn Co | Intravaginal clindamycin ovule composition |
DE19938704C1 (en) * | 1999-08-14 | 2001-10-31 | Ivoclar Vivadent Ag | Process for the production of reaction systems for implantation in the human and animal body as a bone substitute, which i.a. Contain calcium and phosphorus |
KR100322313B1 (en) | 1999-10-21 | 2002-02-06 | 민경윤 | Method of preparing form ii crystals of clarithromycin and clarithromycin formate used therein |
US6515010B1 (en) * | 1999-11-15 | 2003-02-04 | Smithkline Beecham Corporation | Carvedilol methanesulfonate |
US6627743B1 (en) | 1999-12-03 | 2003-09-30 | Abbott Laboratories | 6-O-methylerythromycin A crystal form III |
AU783055B2 (en) | 1999-12-16 | 2005-09-22 | Teva Pharmaceutical Industries Ltd. | Processes for preparing clarithromycin polymorphs and novel polymorph IV |
WO2001051059A1 (en) | 2000-01-11 | 2001-07-19 | Teva Pharmaceutical Industries Ltd. | Processes for preparing clarithromycin polymorphs |
US6241526B1 (en) | 2000-01-14 | 2001-06-05 | Outcomes Management Educational Workshops, Inc. | Training device preferably for improving a physician's performance in tympanocentesis medical procedures |
EP1248595A4 (en) * | 2000-01-20 | 2006-06-14 | Delsys Pharmaceutical Corp | Multi-step drug dosage forms |
US6669954B2 (en) | 2000-01-25 | 2003-12-30 | John R. Crison | Controlled release of drugs |
US6284235B1 (en) | 2000-02-11 | 2001-09-04 | National Starch And Chemical Company Investment Holding Corporation | Bioadhesive composition |
AU3984101A (en) | 2000-02-24 | 2001-09-03 | Advanced Pharma Inc | Antibiotic and antifungal compositions |
JP2003531115A (en) | 2000-02-24 | 2003-10-21 | アドバンシス ファーマシューティカル コーポレイション | Antibiotic compositions with inhibitors |
US6632453B2 (en) | 2000-02-24 | 2003-10-14 | Advancis Pharmaceutical Corp. | Ciprofoxacin-metronidazole antibiotic composition |
US6627222B2 (en) | 2000-02-24 | 2003-09-30 | Advancis Pharmaceutical Corp. | Amoxicillin-dicloxacillin antibiotic composition |
US6623758B2 (en) | 2000-02-24 | 2003-09-23 | Advancis Pharmaceutical Corp. | Cephalosporin-metronidazole antibiotic composition |
US7025989B2 (en) | 2000-02-24 | 2006-04-11 | Advancis Pharmaceutical Corp. | Multiple-delayed released antibiotic product, use and formulation thereof |
US20020004070A1 (en) * | 2000-02-24 | 2002-01-10 | Rudnic Edward M. | Antineoplastic product, use and formulation thereof |
US6669948B2 (en) | 2000-02-24 | 2003-12-30 | Advancis Pharmaceutical Corp. | Antibiotic product, use and formulation thereof |
US6544555B2 (en) * | 2000-02-24 | 2003-04-08 | Advancis Pharmaceutical Corp. | Antibiotic product, use and formulation thereof |
US6667042B2 (en) | 2000-02-24 | 2003-12-23 | Advancis Pharmaceutical Corp. | Fluroquinilone antibiotic product, use and formulation thereof |
US6663890B2 (en) | 2000-02-24 | 2003-12-16 | Advancis Pharmaceutical Corp. | Metronidazole antibiotic product, use and formulation thereof |
US6663891B2 (en) | 2000-02-24 | 2003-12-16 | Advancis Pharmaceutical Corp. | Erythromyacin antibiotic product, use and formulation thereof |
US6991807B2 (en) * | 2000-02-24 | 2006-01-31 | Advancis Pharmaceutical, Corp. | Antibiotic composition |
AU2001239838A1 (en) | 2000-02-24 | 2001-09-03 | Advancis Pharmaceutical Corporation | Therapeutic product, use and formulation thereof |
US6565882B2 (en) | 2000-02-24 | 2003-05-20 | Advancis Pharmaceutical Corp | Antibiotic composition with inhibitor |
US6610328B2 (en) | 2000-02-24 | 2003-08-26 | Advancis Pharmaceutical Corp. | Amoxicillin-clarithromycin antibiotic composition |
US6730320B2 (en) | 2000-02-24 | 2004-05-04 | Advancis Pharmaceutical Corp. | Tetracycline antibiotic product, use and formulation thereof |
US6667057B2 (en) * | 2000-02-24 | 2003-12-23 | Advancis Pharmaceutical Corp. | Levofloxacin antibiotic product, use and formulation thereof |
EP1313486A1 (en) | 2000-02-29 | 2003-05-28 | Teva Pharmaceutical Industries Ltd. | Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same |
US6515116B2 (en) * | 2000-03-15 | 2003-02-04 | Hanmi Pharm. Co., | Method of preparing form II crystals of clarithromycin |
US6306436B1 (en) | 2000-04-28 | 2001-10-23 | Teva Pharmaceuticals Usa, Inc. | Stabilized, acid-free formulation for sustained release of bupropion hydrochloride |
DE60139256D1 (en) | 2000-05-03 | 2009-08-27 | Silva Joe D | Method and device for producing liquid administration forms |
CA2408956C (en) * | 2000-05-18 | 2011-07-12 | Therics, Inc. | Method and form of a drug delivery device,such as encapsulating a toxic core within a non-toxic region in an oral dosage form |
US20020042394A1 (en) | 2000-05-31 | 2002-04-11 | Hogenkamp Henricus P.C. | Cobalamin compounds useful as antibiotic agents and as imaging agents |
PE20020044A1 (en) | 2000-06-16 | 2002-01-30 | Upjohn Co | THIAZINE OXAZOLIDINONE |
WO2001098317A2 (en) | 2000-06-22 | 2001-12-27 | The Brigham And Women's Hospital, Inc. | Alpha-glycosylceramides for treating bacterial and fungal infections |
US6881420B2 (en) | 2000-06-23 | 2005-04-19 | Teva Pharmaceutical Industries Ltd. | Compositions and dosage forms for gastric delivery of irinotecan and methods of treatment that use it to inhibit cancer cell proliferation |
US6375982B1 (en) | 2000-07-05 | 2002-04-23 | Capricorn Pharma, Inc. | Rapid-melt semi-solid compositions, methods of making same and method of using same |
US6696426B2 (en) * | 2000-08-22 | 2004-02-24 | Pharmacia Corporation | Preservative free ophthalmic oxazolidinone antibiotic drug delivery systems |
IN192748B (en) | 2000-08-29 | 2004-05-15 | Ranbaxy Lab Ltd | |
US6767899B1 (en) | 2000-08-29 | 2004-07-27 | Leiner Health Services Corp. | Composition and method for treatment of conditions having an inflammatory component |
CA2423172A1 (en) * | 2000-09-22 | 2002-03-28 | Galephar M/F | Sustained release composition containing clarithromycin |
US20020103261A1 (en) | 2000-10-06 | 2002-08-01 | Dusan Ninkov | Compositions for injection or intravenous administration for the treatment of internal infection or inflammation in humans and animals |
PE20020578A1 (en) | 2000-10-10 | 2002-08-14 | Upjohn Co | A TOPICAL ANTIBIOTIC COMPOSITION FOR THE TREATMENT OF EYE INFECTIONS |
US6756057B2 (en) | 2000-10-12 | 2004-06-29 | Beecham Pharmaceuticals (Pte) Limited | Amoxicillin and potassium clavulanate dosage form |
US7157095B2 (en) * | 2000-10-13 | 2007-01-02 | Advancis Pharmaceutical Corporation | Multiple-delayed release antifungal product, use and formulation thereof |
US20020068078A1 (en) | 2000-10-13 | 2002-06-06 | Rudnic Edward M. | Antifungal product, use and formulation thereof |
AU2002239232A1 (en) | 2000-10-13 | 2002-05-21 | Advancis Pharmaceutical Corporation | Extended release erythromycin derivatives |
US7108859B2 (en) | 2000-10-13 | 2006-09-19 | Advancis Pharmaceutical Corporation | Antineoplastic product, use and formulation thereof |
US7105174B2 (en) | 2000-10-13 | 2006-09-12 | Advancis Pharmaceutical Corporation | Multiple-delayed release anti-neoplastic product, use and formulation thereof |
US6541014B2 (en) * | 2000-10-13 | 2003-04-01 | Advancis Pharmaceutical Corp. | Antiviral product, use and formulation thereof |
US7074417B2 (en) | 2000-10-13 | 2006-07-11 | Advancis Pharmaceutical Corporation | Multiple-delayed release anti-viral product, use and formulation thereof |
US6565873B1 (en) | 2000-10-25 | 2003-05-20 | Salvona Llc | Biodegradable bioadhesive controlled release system of nano-particles for oral care products |
DE60103299T2 (en) | 2000-10-30 | 2005-05-12 | Lupin Ltd., Mumbai | FAST-CRUSHING CEFUROXIM AXETIL-CONTAINING MEDICAMENT COMPOSITION WITH DELAYED ACTIVE INGREDIENTS |
US6497901B1 (en) | 2000-11-02 | 2002-12-24 | Royer Biomedical, Inc. | Resorbable matrices for delivery of bioactive compounds |
WO2002041876A1 (en) | 2000-11-22 | 2002-05-30 | Lupin Limited | Pharmaceutical composition for controlled release of an active ingredient |
AU3104102A (en) | 2000-12-18 | 2002-07-01 | Univ Texas | Local regional chemotherapy and radiotherapy using in situ hydrogel |
GB0102342D0 (en) * | 2001-01-30 | 2001-03-14 | Smithkline Beecham Plc | Pharmaceutical formulation |
US20020197314A1 (en) | 2001-02-23 | 2002-12-26 | Rudnic Edward M. | Anti-fungal composition |
CA2440641A1 (en) | 2001-03-13 | 2002-09-19 | Anand R. Baichwal | Chronotherapeutic dosage forms containing glucocorticosteroid |
US6838093B2 (en) * | 2001-06-01 | 2005-01-04 | Shire Laboratories, Inc. | System for osmotic delivery of pharmaceutically active agents |
US6777420B2 (en) | 2001-06-15 | 2004-08-17 | Microbiotix, Inc. | Heterocyclic antibacterial compounds |
ES2272795T3 (en) | 2001-07-24 | 2007-05-01 | Southern Methodist University Foundation For Research | 7-ALQUILDIEN-3-SUBSTITUTES-3-CEFEM-4-CARBOXYLATES AS BETA-LACTAMASA INHIBITORS. |
US6585997B2 (en) | 2001-08-16 | 2003-07-01 | Access Pharmaceuticals, Inc. | Mucoadhesive erodible drug delivery device for controlled administration of pharmaceuticals and other active compounds |
US20030124196A1 (en) | 2001-08-22 | 2003-07-03 | Susan Weinbach | Pulsatile release compositions and methods for enhanced intestinal drug absorption |
WO2003020736A1 (en) | 2001-08-28 | 2003-03-13 | Pharmacia Corporation | Crystaline clindamycin free base |
US6669955B2 (en) | 2001-08-28 | 2003-12-30 | Longwood Pharmaceutical Research, Inc. | Combination dosage form containing individual dosage units of a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and aspirin |
US6673369B2 (en) * | 2001-08-29 | 2004-01-06 | Ranbaxy Laboratories Limited | Controlled release formulation |
EP1434853B1 (en) | 2001-10-01 | 2005-11-16 | Novozymes A/S | Fermentation with cyclic pulse-pause feeding |
US6642276B2 (en) | 2001-10-01 | 2003-11-04 | M/S Ind-Swift Limited | Controlled release macrolide pharmaceutical formulations |
US9358214B2 (en) * | 2001-10-04 | 2016-06-07 | Adare Pharmaceuticals, Inc. | Timed, sustained release systems for propranolol |
US6723340B2 (en) | 2001-10-25 | 2004-04-20 | Depomed, Inc. | Optimal polymer mixtures for gastric retentive tablets |
US7931914B2 (en) | 2001-10-29 | 2011-04-26 | Massachusetts Institute Of Technology | System and method for uniaxial compression of an article, such as a three-dimensionally printed dosage form |
US7300668B2 (en) | 2001-10-29 | 2007-11-27 | Massachusetts Institute Of Technology | System for manufacturing controlled release dosage forms, such as a zero-order release profile dosage form manufactured by three-dimensional printing |
US20030091627A1 (en) | 2001-10-31 | 2003-05-15 | Vinay Sharma | Rate-controlled delivery of macrolides |
DE60117712T2 (en) * | 2001-11-19 | 2006-11-16 | Lupin Ltd., Mumbai | PHARMACEUTICAL COMPOSITION FOR THE CONTROLLED RELEASE OF BETA LACTAM ANTIBIOTICS |
CA2470016A1 (en) | 2001-12-20 | 2003-10-23 | Advancis Pharmaceuticals Corporation | Antibiotic product, use and formulation thereof |
WO2003053420A1 (en) | 2001-12-20 | 2003-07-03 | Pharmacia Corporation | Multiple-pulse extended release formulations of clindamycin |
US6682759B2 (en) * | 2002-02-01 | 2004-01-27 | Depomed, Inc. | Manufacture of oral dosage forms delivering both immediate-release and sustained-release drugs |
US20030171340A1 (en) | 2002-02-07 | 2003-09-11 | Jenefir Isbister | Methods of disease treatment using metal-complexed tetracycline antibiotics |
CA2477044A1 (en) | 2002-02-22 | 2003-09-04 | Pharmacia Corporation | Ophthalmic formulation with gum system |
WO2003075852A2 (en) | 2002-03-07 | 2003-09-18 | Advancis Pharmaceuticals Corporation | Antibiotic composition |
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US20110065718A1 (en) | 2011-03-17 |
US20030099707A1 (en) | 2003-05-29 |
US8303988B2 (en) | 2012-11-06 |
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