WO2007143131A9 - Formulations de sel de prédnisolone - Google Patents

Formulations de sel de prédnisolone

Info

Publication number
WO2007143131A9
WO2007143131A9 PCT/US2007/013008 US2007013008W WO2007143131A9 WO 2007143131 A9 WO2007143131 A9 WO 2007143131A9 US 2007013008 W US2007013008 W US 2007013008W WO 2007143131 A9 WO2007143131 A9 WO 2007143131A9
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
sodium phosphate
prednisolone sodium
prednisolone
dosage
Prior art date
Application number
PCT/US2007/013008
Other languages
English (en)
Other versions
WO2007143131A2 (fr
WO2007143131A3 (fr
Inventor
Walid Habib
Bhaveshkumar Kothari
Original Assignee
Cima Labs Inc
Walid Habib
Bhaveshkumar Kothari
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US11/638,216 external-priority patent/US8637076B2/en
Priority claimed from US11/638,260 external-priority patent/US20070281014A1/en
Application filed by Cima Labs Inc, Walid Habib, Bhaveshkumar Kothari filed Critical Cima Labs Inc
Priority to CA002653485A priority Critical patent/CA2653485A1/fr
Priority to MX2008015059A priority patent/MX2008015059A/es
Publication of WO2007143131A2 publication Critical patent/WO2007143131A2/fr
Publication of WO2007143131A9 publication Critical patent/WO2007143131A9/fr
Publication of WO2007143131A3 publication Critical patent/WO2007143131A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Definitions

  • the sodium phosphate salt (a term which includes any sodium and phosphate containing salt such as, without limitation, prednisolone disodium phosphate, unless otherwise indicated.) of this drug is known to be used to treat a vast array of conditions including: allergic states, dermatologic diseases, endocrine disorders, neoplastic disorders, and rheumatic disorders and the acetate salt is known for use in ophthalmic preparations. Products are also currently available using the free base material in a traditional swallow tablet or in a liquid.
  • prednisolone sodium phosphate has good solubility and bioavailability. But its taste is abysmal — far more than many taste masking strategies can handle. Indeed, it is believed that, in no small measure because of its aggressively objectionable flavor, prednisolone salts and, in particular, the sodium phosphate salt, are not only not available as ODT tablets, they are not available as tablets at all. The only dosage form that is available for this particular drug salt is a liquid where its objectionable flavor can be diluted — indeed drowned — by conventional sweeteners, flavorings and other masking techniques.
  • the invention relates to an orally disintegrable dosage form comprising an effective amount of prednisolone sodium phosphate and at least one pharmaceutically acceptable excipient, the dosage form providing a mean T max of about 1.3 hours + 33 minutes when administered to humans.
  • the dose of prednisolone sodium phosphate is equivalent to about 10 to about 30 mg prednisolone base.
  • the dose of prednisolone sodium phosphate is 13.4 mg, 20.2 mg, or 40.3 mg.
  • the orally disintegrable dosage form exhibits a mean Cmax of about 420 ng/ml +80 based on a dose of about 40.3 mg prednisolone sodium phosphate when administered to humans.
  • the dosage form contains 20.2 mg of prednisolone sodium phosphate and provides a Cmax which is substantially dose proportional to the dosage which contains 40.3 mg prednisolone sodium phosphate, when the dosage form is administered to humans.
  • the dosage form contains 13.4 mg of prednisolone sodium phosphate and provides a C max which is substantially dose proportional to the dosage which contains 40.3 mg prednisolone sodium phosphate, when the dosage form is administered to humans.
  • the prednisolone sodium phosphate in the dosage form is taste-masked.
  • the invention is also directed to a dosage form that disintegrates in the oral cavity of a human patient within about 60 seconds or less.
  • the invention also relates to an orally disintegrable dosage form as described above, comprising 40.3 mg prednisolone sodium phosphate that exhibits a log AUCo- t of 2,300 ng»h/mL +600 when administered to a population of human patients.
  • the dosage form comprising 40.3 mg prednisolone sodium phosphate exhibits a log AUCj n f of 2,300 ng « h/mL +600 when administered to a population of human patients.
  • the orally disintegrable dosage form comprises a plurality of particles comprising prednisolone sodium phosphate, said particles being coated with material which effectively taste-masks the prednisolone sodium phosphate when the dosage form disintegrates in the oral cavity of a human.
  • the plurality of taste-masked, coated particles are compressed into an orally disintegrable solid tablet.
  • the invention is further directed to an orally disintegrable solid tablet.
  • the dosage form contains 20.2 mg of prednisolone sodium phosphate and provides an AUC which is substantially dose proportional to a dosage which contains 40.3 mg prednisolone sodium phosphate, when the dosage form is administered to humans.
  • the dosage contains 13.4 mg of prednisolone sodium phosphate and provides an AUC which is substantially dose proportional to the dosage which contains 40.3 mg prednisolone sodium phosphate, when the dosage form is administered to humans.
  • the invention also relates to a dosage form as described above, which disintegrates in the oral cavity of a human patient within about 60 seconds or less.
  • the tablets of the present invention may have a hardness of about 8 to about 20 Newtons. In other embodiments, the tablets may have a hardness of about 8- 12 Newtons, about 10-14 Newtons, or about 14-18 Newtons. In further embodiments, the dosage has a hardness of at least about 15 newtons.
  • the invention is further directed to an orally disintegrating dosage form comprising an effective amount of prednisolone sodium phosphate, an effective amount of a material for the taste-masking the prednisolone sodium phosphate, the dosage form providing a T m3x of about 1.3 hours + 33 minutes when administered to a human patient.
  • the dosage form exhibits a Cmax of about 420 ng/ml +80, based on a dose of about 40.3 mg.
  • the dosage form contains 20.2 mg of prednisolone sodium phosphate and provides a C m a x which is substantially dose proportional to the dosage which contains 40.3 mg prednisolone sodium phosphate.
  • the dosage form contains 13.4 mg of prednisolone sodium phosphate and provides a C max which is substantially dose proportional to the dosage which contains 40.3 mg prednisolone sodium phosphate.
  • the invention is further directed to an orally disintegrating dosage form comprising an effective amount of prednisolone sodium phosphate, an effective amount of a material for the taste-masking the prednisolone sodium phosphate, the dosage form providing providing a C ma ⁇ of about 420 ng/ml +80, based on a dose of about 40.3 mg, when orally administered to a human.
  • the dosage form contains 20.2 mg of prednisolone sodium phosphate and provides a Cmax which is substantially dose proportional to the dosage which contains 40.3 mg prednisolone sodium phosphate.
  • the dosage form contains 13.4 mg of prednisolone sodium phosphate and provides a Cmax which is substantially dose proportional to the dosage which contains 40.3 mg prednisolone sodium phosphate.
  • the invention further relates to a dosage form as described above, that disintegrates in the oral cavity of a human patient within about 60 seconds or less.
  • the dosage form may have a hardness of about 8-12 Newtons, about 10-14 Newtons, or about 14-18 Newtons.
  • the dosage form has a hardness of at least about 15 newtons.
  • the dosage form exhibits a friability as measured by the USP 26th revision (January 1 , 2003), of about 2% or less.
  • the present invention provides a taste-masked tablets comprising prednisolone sodium phosphate in an amount of about 13.4, about 20.2 or about 40.3 mg and an excipient.
  • These tablets could be effervescent or could be non- effervescent tablets. They are preferably ODT tablets, but they are not necessarily ODT tablets.
  • oral solid dosage forms comprising prednisolone sodium phosphate and an excipient exhibiting a t max of 1.3 hours ⁇ 33 mins.
  • the amount of prednisolone sodium phosphate is selected from the group consisting of about 13.4, about 20.2 and about 40.3 mg.
  • the dosage form provides a C max of about 420 ng/ml + 80 ng/ml, based on a dose of about 40.3 mg. In other embodiments, the 20.2 mg and
  • 13.4 mg dose formulations would provide a substantially dose proportional C ma x- For example, a 20.2 mg dose would provide a C ma ⁇ of about 210 ng/ml + 40 ng/ml.
  • Also contemplated as a separate aspect of the invention are orally dissolving dosage forms of a prednisolone salt and in one embodiment, the sodium phosphate salt.
  • an orally disintegrable/dissolvable tablet comprising rapid release active pharmaceutical ingredient ("API") -containing particles (often referred to merely as “API-containing particles”), an effervescent couple and at least one excipient.
  • the API containing particles themselves comprise carrier particles coated with a layer of a prednisolone salt (also known as the API containing layer), the prednisolone salt being present in an amount of about 20 to about 45% by weight of the API containing particle (the final particle weight with all coatings).
  • the now API containing layer coated carrier particle is itself overcoated. hi preferred embodiments, at least twice, by two entirely different types of coatings.
  • the prednisolone salt containing layer is overcoated with a seal coating layer which is present in an amount of about 2% to about 15%.
  • This now seal coated particle is itself overcoated with a taste masking layer which is present in the finished particle in an amount of about 25% to about 55%.
  • API containing particle (carrier, API containing layer and at least the two overcoating layers just discussed) is present in the finished tablet in an amount of about 55% to about 75% by weight of the tablet.
  • the effervescent couple may be present in an amount of about 5% to about 25% percent by weight of said tablet, and the balance is made up of at least one excipient.
  • the seal coating layer and the taste masking layer are coordinated such that the application of the taste masking layer will not adversely affect the seal coating layer.
  • the tablets of the present invention may have a hardness of about 15 Newtons or more, more preferably 20 Newtons or more, and a friability, as measured by the USP 26th revision (January 1, 2003), of about 2% or less.
  • these tablets may include at least one non-direct compression carbohydrate (sugar, sugar alcohol, etc.) as a filler. See U. S. Patent No. 6,024,981.
  • these tablets are capable of rapidly disintegrating/dissolving in a patient's mouth in about 60 seconds or less, more preferably about 30 seconds or less, such that the rapid release API containing particles can be swallowed as a dispersion, suspension or slurry.
  • These tablets may be packaged in blister packages or in openable and reclosable multi-tablet packages.
  • the tablets of another embodiment of the invention may have a hardness of about 20 Newtons or less, and a friability of more than 2% as measured by the U.S.P. method as of the filing date.
  • the tablets of the present invention have a hardness of about 8-20 Newtons, about 8-12 Newtons, about 10-14 Newtons, or about 14-18 Newtons.
  • they are capable of rapidly disintegrating/dissolving in a patient's mouth in about 60 seconds or less, more preferably about 30 seconds or less, such that the rapid release API containing particles can be swallowed as a dispersion, suspension or slurry.
  • it provides a pleasant organoleptic sensation.
  • These tablets are often packaged in a blister package.
  • the tablets in accordance with this aspect of the present invention are “ODT” tablets (defined here as “orally disintegrable/dissolvable tablets”).
  • “Disintegrable/ dissolvable” means that at least a portion of the dosage form may disintegrate and/or dissolve when placed on the tongue in a patient's mouth. This term does not include tablets which are designed to facilitate transfer of an API across an oral mucosa such as sublingual or buccal tablets. When disintegration/dissolution of the effervescent couple and soluble excipients occurs, the resulting dispersion, suspension or solution is swallowed.
  • the API containing particles are "rapid release" particles.
  • rapid release it is meant that once the particles have entered the stomach, the API is generally as available as a liquid form of the same active.
  • the ODTs in accordance with this aspect of the invention should be, in short, “bioequivalent,” as that term is defined in 21 U.S. C. and 21 C.F.R. as of the filing of this document when compared to the currently marketed liquid of prednisolone sodium phosphate. [This requires that the coatings used be selected such that they are sufficiently functional within the mouth to protect the taste buds and yet get out of the way sufficiently quickly thereafter so as to allow the body to use the active as if it were, in essence, uncoated.
  • the invention also includes methods of administering dosage forms in accordance with the present invention which include the steps of placing a tablet in accordance with the invention into a patients mouth in need of prednisolone, allowing the tablet to disintegrate and/or dissolve in the mouth substantially on the tongue (as opposed to sublingual or buccal) to form a dispersion, suspension or slurry including the API-containing particles, and swallowing the resulting dispersion, suspension or slurry of API-containing particles.
  • Also considered part of the invention is a method of making tablets in accordance with the present invention which include the steps of: coating prednisolone sodium phosphate onto a sugar sphere to form an API-containing layer, selecting a seal coating material and a coordinated taste masking material; forming a seal coating layer substantially coating said API-containing layer; forming a taste masking layer substantially coating said seal coating layer to forma an API-containing particle, blending said API-containing particle with an effervescent couple and an excipient, and compressing the resulting blend to form a tablet.
  • the invention provides a tablet comprising: rapid release API containing particles, and an excipient.
  • the API containing particles comprise carrier particles coated with an API containing layer of a prednisolone sodium phosphate present in an amount of about 20 to about 45% by weight of the API containing particles.
  • the API containing layer is overcoated with a seal coating layer present in an amount of about 2% to about 15% by weight, and the seal coating layer being overcoated with a taste masking coating layer present in an amount of about 25% to about 55% by weight gain.
  • the API containing particles are present in an amount of about 55% to about 75% by weight of said tablet.
  • This tablet could be effervescent or could be a non-effervescent tablet.
  • the tablet is preferably an ODT tablet, but it is not necessarily an ODT tablet.
  • the dosage forms comprise API containing particles comprising: a carrier particle coated with an API containing layer of a prednisolone sodium phosphate, said prednisolone sodium phosphate being present in an amount of about 20 to about 45% by weight of said API containing particle, said API containing layer overcoated with a seal coating layer present in an amount of about 2% to about 15% by weight, and said seal coating layer being overcoated with a taste masking coating layer present in an amount of about 25% to about 55% by weight gain.
  • Figure 1 is a semi-log plot of data summarized in Table 5 of mean plasma concentrations of various dosage forms of prednisolone.
  • Figure 2 is a linear plot of data summarized in Table 5 of mean plasma concentrations of various dosage forms of prednisolone.
  • Figure 3 is a semi-log plot of data summarized in Table 6 of mean plasma concentrations of a prednisolone ODT in accordance with the invention administered with and without water.
  • prednisolone salts prepared as described herein do not threaten to puncture or otherwise physically compromise a taste masking coating of (the problem solved in the '341 patent) with time, the API salt is believed to be capable of migrating into and indeed across such a layer.
  • Example 1 has a 20% weight gain spacing layer and a 30% taste masking layer.
  • Example 2 has a 50% spacing layer and a 70% weight gain taste masking layer.
  • the seal coating layer may need to be dissolved in one solvent and be insoluble in the solvent used for the taste masking layer to ensure that the seal coating layer's properties are not altered during the application of the taste masking layer. If the seal coating layer were thicker, even if it was somewhat solubilized during the application of the taste masking layer, the coating could be sufficiently thick so that taste masking was not compromised. However, at that thickness, the API loading of the particles and bioequivalency could be adversely affected.
  • the seal coating layer is produced from a material which is dissolved, suspended or dispersed in water and the taste masking layer is produced from a material which is dissolved, suspended or dispersed in alcohol.
  • the seal coating material is water soluble and the taste masking layer is composed of something that is generally insoluble in water.
  • Another aspect of some of the embodiments of the present invention is a dosage form which not only provides adequate taste masking and is an ODT but also provides a pleasant organoleptic sensation.
  • the tablet is not objectionably gritty or sandy during dissolution and/or disintegration and provides a dispersion, slurry or suspension which can be swallowed, generally as a mass of the undissolved API containing particles, which a patient would not find objectionable.
  • the shape and composition of the coated particle can be important as is the amount of effervescent material, the selection of the types and amounts of excipients and the use of flavors and the like.
  • the coated particles of the present invention should not themselves dissolve or disintegrate in the mouth to an extent which would compromise their taste masking ability. These particles will be dispersed, suspended or slurried in the mouth and swallowed. But if the API containing particles 1 coatings are unpalatable either in terms of taste or texture, if depending upon their shape, the particles may not move as a mass and may distribute themselves throughout the mouth under the tongue, between the cheek and gums, etc., the entire experience of taking the tablet could be unpleasant.
  • the ODT tablets of the invention preferably include both water soluble and non-rapidly water soluble or even water insoluble elements.
  • the tablets may include, as an example, an insoluble excipient, the coated particle described herein which are possibly eventually soluble, but should not be appreciably soluble in the time period that the tablet is in the mouth, and freely soluble materials such as certain sugars.
  • an insoluble excipient the coated particle described herein which are possibly eventually soluble, but should not be appreciably soluble in the time period that the tablet is in the mouth, and freely soluble materials such as certain sugars.
  • Particle size and particle size distribution may also be important to certain embodiments of the invention. Accordingly, it is preferred that the API-containing particles are sized such that at least 90% of them would pass through a 30 mesh screen, more preferably 95%, most preferably 98% or more would pass through a 30 mesh screen. Particles which are too fine, however, are difficult to maintain in a cohesive suspension or slurry and may present content uniformity and processing issues. Accordingly, it is also desirable that not less than about 60% of the coated API- containing particles be retained on a 60 mesh screen, more preferably at least about 65% be retained thereon.
  • not more than 40% of the particles be collected in a pan once being passed through a 60 mesh screen, and more preferably not more than 30% be collected in a pan.
  • These numbers are, of course, by weight.
  • the need to stay within such a tight particle size distribution also has an effect on the amount of coating materials which can be used to provide taste masking as does the need to provide an adequate load of active in the particles. From these often competing and mutually exclusive criteria, one can appreciate just how difficult designing a dosage form for a prednisolone salt containing ODT can be. [00431 And as if the foregoing is not complicated enough, moisture and impurities can have a dramatic effect on the construction of tablets in accordance with the present invention.
  • Conventional raw prednisolone salt API can have up to about 3% of impurities and up to about 6.5% moisture.
  • the processes of coating the API-containing layer onto the carrier particle as well as the overcoating steps also introduce water and/or other solvents, all of which can reduce the effective load of actual API. Indeed, it was found that unless the API was assayed and its water level and impurity level accounted for and compensated for by additional API, it was difficult to obtain a final tablet containing the necessary content of active while meeting all of the other criteria discussed herein.
  • the final dosage forms in accordance with the present invention preferably have a total moisture content of less than about 5% by weight of the final API-containing particles, more preferably an amount less than 4% and most preferably an amount less than 3% by weight of the total dosage form.
  • a solid support or carrier particle in accordance with the present invention can be composed of any material useful for layering in accordance with this and other conventional pharmaceutical applications. These can include, without limitation, particles, crystals, granulates, capsules, mini-tablets microparticles, microgranules, microcrystals or microcapsules. Particles, granules and crystals have their traditional meaning.
  • "Capsule” in accordance with the present invention includes generally hollow, spherical vessels such as liposomes, micelles and the like. These may be dried.
  • Carrier particles can be composed of any number of materials or mixtures thereof including particles created from one or more of the taste masking materials, polymers, solid dicalcium phosphate and the like.
  • the carrier particles are made of a sugar.
  • "Sugar” in accordance with the present invention generally includes other forms of carbohydrate such as, for example, sugars, sugar alcohols, ketoses, saccharides, polysaccharides, oligosaccharides and the like, as well as celluloses and modified celluloses. These include, without limitation, sucrose, mannitol (spray dried and granular) lactose, and microcrystalline cellulose. Most preferred in accordance with the present invention are sucrose and microcrystalline cellulose.
  • sucrose spheres are available from Paulaur corporation, 105 Melrich Road, Cranbury, NJ 08512.
  • Useful microcrystalline spheres are sold by Asahi Kasei Chemicals Corp, with the following address: Hibiya-Mitsui Building 1-2 Yurakucho 1-chome, Chiyoda-ku, Tokyo 100-8440 Japan under the designation CELPHERES.
  • the size of the carrier particles can vary considerably with, amongst other things, the application, volume of the carrier particles that will be used in the formulation, the type of dosage form in which it will be included, and the thicknesses of the layers that will coat it. Carrier particles that are too small can be difficult to coat.
  • Carrier particles that are too large can be difficult to work with, can affect content uniformity and can provide an unpleasant organoleptic sensation in the mouth.
  • the larger the particle size the smaller the surface area of the API that will be provided in the mouth thus reducing the potential exposure to the taste buds and other sensory organs within the mouth, further enhancing taste masking.
  • the carrier particle size is preferably between about 10 microns and about 1,000 microns, more preferably between about 20 microns and 600 microns. This means that at least about 90% of the carrier particles, by weight, fall within these ranges based on sieving. In a more preferred embodiment, the carrier particles will predominantly have more than 50% fall within a 60 to 80 mesh screen cut. More particularly, the amount by weight greater than 300 ⁇ m is about 0%, the amount by weight greater than 250 ⁇ m is less than about 10%, the amount in between about 180 and about 250 ⁇ m is about 90% or more, and the amount by weight less than 180 ⁇ m is about 10% or less.
  • Micro in the context of carrier particles means a carrier particle having a particle size of below about 50 microns.
  • the carrier particles are substantially spherical although the particle dimensions can vary and can be, without limitation, elliptical, generally egg-shaped, rod shaped, regular arid/or irregularly shaped.
  • the prednisolone salt is prednisolone sodium phosphate.
  • the amount of prednisolone sodium phosphate present in a dose (which can consist of one or more, but preferably no more than two tablets) will vary ⁇ depending upon a number of factors including the patient, the patient's condition, the length and extent of administration, the salt form used, and a doctor's sound medical judgment.
  • each dose of prednisolone ranges from between about 0.10 micrograms and about 2 grams, preferably between about 0.50 micrograms and about 1 gram per dosage form (e.g., tablet, teaspoonful, etc.), most preferablyl, 2.5, 5, 10, 15 and 30 milligrams per dose (generally dosed up to 4 times a day for a total daily dose of between about 4 and about 130 milligrams).
  • each carrier particle or coated particle need not be covered. Indeed, while the efficiency of the system is improved considerably by the use of a substantially complete and uniform coating, it is not required that, for example, the prednisolone salt coating cover even a majority of the carrier particles or a majority of the surface area of the carrier particles.
  • the API containing layer covers substantially all of the carrier particles to which it is applied (it is possible to mix some coated and uncoated solid support if desired) and each successive layer preferably does the same.
  • the API-containing layer increases the weight of the carrier particle by at least about 40%, more preferably at least about 50%, and most preferably at least about 55% w/w relative to the weight of the uncoated carrier particles.
  • the API containing layer is preferably assayed and weighed so that the weight gain of the prednisolone salt reported is accurate.
  • Successive layers are based on calculated target levels of desired weight gain based on the weight of the dry ingredients (w/w).
  • the amount of the sealing layer is based on a calculated target increase in weight, for example 10% compared to the measured weight of the carrier particle coated with the API-containing layer.
  • an amount of seal coating material used is a calculated amount which should be sufficient to provide, staying with the same illustration, a 10% w/w seal coating (weight gain) when applied.
  • the actual coating level may or may not meet the target depending upon a number of factors including, without limitation, the nature of the coating process, the length of coating application, the coating material, the moisture content and the like. While it would be expected that coating efficiency will generally be less than 100% and thus the amount of actual coating will be less than the target, because of the factors just described, and possibly others, the actual coating layer could be present in an amount that is +/- about 30% of the target calculated weight gain.
  • the target is not close to the endpoints of the range described, and/or where there is prior experience with a particular coating system one can be reasonably assured that the target has been meet, or at least that the result is in the described range, even if not confirmed by actual weight. While the forgoing has been described in terms of the sealing layer, it applies equally to the taste masking layer, however, the comparison in that instance is between the weight of the taste masking coated API-containing particle with the seal coated particle. Again, it need not be necessary to actually weigh the particle to confirm the degree of coating depending upon prior experience or where the target is not within 30% of the end of the described ranges.
  • the total amount of prednisolone sodium phosphate salt ranges from about
  • the API containing layer, and indeed the overcoating layers as well, can be applied by any conventional coating process such as use of a Wurster fluidized bed where the coating material enters from the bottom of the reactor.
  • the API, the prednisolone salt, is preferably dissolved, suspended or dispersed in a solvent and the resulting solution, dispersion or suspension is then coated onto the surface of the carrier particles preferably in a way which provides a substantially homogeneous coating.
  • the solvent should be acceptable to the U.S.
  • the concentration of the API in the solvent will vary with the solvent, the prednisolone salt used, and whether or not a solution, suspension or dispersion is to be produced. It is understood, however, that as little solvent as is necessary should be used.
  • Solvents in accordance with the present invention include, for example, water, alcohol, dehydrated ethanol, methanol, isopropyl alcohol, acetone, dioxane and chloroform.
  • the API-containing solution, suspension or dispersion is to be applied such that the weight gain of the carrier particle is at least about 40% as previously discussed based on the weight of the carrier particle.
  • the weight gain and API content can be determined by weighing and assay.
  • the seal coat or seal coating layer is applied over top of the API-containing layer. As is true with the API-containing layer, it need not coat all of the particles nor any one particle completely but substantially coated is preferred. Because an incomplete seal might allow migration of the prednisolone salt through the taste masking layer and may expose a patient to the taste of the API, the more complete the coating, the better. It should be substantially coated, which is an amount that is sufficient to prevent migration and failure of the taste masking system as a whole.
  • the seal coating layer cannot add too significantly to the overall size or weight of the API containing particle.
  • the seal coating adds less than 15% (+/- about 30% as noted earlier) to the total weight of the particle when considered against the carrier particle coated with the API-containing layer, more preferably about 10% or less.
  • the seal coating material adds (a minimum of about 2% (+/- about 30% as noted earlier) and more particularly in a range of between about 5% and about 10% weight gain when compared to the carrier particle coated with the API-containing layer.
  • the polymers used in the seal coating polymers are themselves dissolved, dispersed or suspended in a solvent, which can be removed or dried without affecting the properties of the coating, the API-containing undercoating or the carrier particle. Again, concentration in the solvent is a secondary factor but it may affect the efficiency of coating and drying.
  • the coating material may be applied using any technique as previously discussed with the API-containing layer. However, spray coating in a fiuidized bed is preferred. After the API-containing layer is applied, as true after each layer, it is preferably dried. Drying can be done as a separate step using any technique or can be accomplished using, for example, a fiuidized bed while no new coating material is added.
  • the API coating layer preferably has a moisture content of about 10%, more preferably about 7% or less. After the seal coating layer is applied, it preferably has a moisture or solvent content of about 6% or less.
  • the materials that may be used for the seal coating layer include, without limitation, hydroxypropylmethylcellulose ("HPMC”), hydroxypropylcellulose, mixtures of both, lactose and HPMC, polydextrose and HPMC, maltodextrin and HPMC, polydextrose, maltodextrin and HPMC, polyvinylacetate carboxymethylcellulose and the like.
  • HPMC hydroxypropylmethylcellulose
  • HPMC hydroxypropylmethylcellulose
  • HPMC hydroxypropylmethylcellulose
  • HPMC hydroxypropylmethylcellulose
  • HPMC hydroxypropylmethylcellulose
  • HPMC hydroxypropylmethylcellulose
  • the taste masking material useful in accordance with the present invention for producing the taste masking layer generally includes any natural or synthetic polymer including: acrylic polymers, modified celluloses, and the like, which are pH dependant materials that become soluble at a pH of about 6.5 or below, more preferably about 6.0 or below.
  • These polymers and copolymers should preferably be pharmacologically acceptable, capable of providing appropriate release and effective taste masking while still being convenient to process.
  • These include, for example, amino alkyl acrylate copolymers such as, for example, copolymers of methylmethacrylate, butylmethacrylate and dimethylaminoethyl methacrylate. See European Pharmacopoeia 4.4 (04/2003:1975) at 3385.
  • the copolymer has a relative molecular mass of about 150,000 and a ratio of dimethylaminoethyl methacrylate groups to butylmethacrylate groups and methylmethacrylate groups of about 2:1:1 and the content of the dimethylaminoethyl groups is about 20.8% to 25.5% based on the amount of dry substances present.
  • a particularly preferred material can be obtained under the mark Eudragit E- 100, which is an acrylated based polymer which dissolves at a pH of about 6.5 or less, and which can be used in normal form or in micronized Eudragit E 100 and mixtures thereof.
  • Eudragit is a trademark of Rohm GmbH, Chemische Fabrik, Kirschenallee, D 64293, Darmstadt, Germany for a group of acrylic polymers.
  • solvents in accordance with the present invention include those capable of substantially dissolving or dispersing Eudragit E-100 such as water, normal C1-C5 alcohol, branched C1-C5 alcohol, denatured C1-C5 alcohol, and low molecular weight ketones such as acetone and MEK. Ethanols, including (SDA-3A) and denatured ethanol are most preferred.
  • Other solvents for the taste masking coating materials include, without limitation, water and those mentioned previously in connection with the seal coating layer.
  • the taste masking layer will be provided in an amount ranging from between about 25 to about 55% weight gain as determined by calculating the desired target weight gain over the weight of the carrier particle coated with both the prednisolone salt containing layer and the seal coating layer, (w/w) In a more preferred embodiment the amount ranges from between about 40 to about 50% weight gain. In another embodiment, the range is 35 to 45% target weight gain.
  • the taste masking coating can be applied in the same manner as any other coating described herein including in a preferred embodiment spray coating in a fluidized bed.
  • the taste masked particles are preferably dried to a final moisture content of 5% or less.
  • the amount of solvent used in forming the taste masking coating will depend on, among other things, the taste masking coating material used. Moreover, more solvent may be needed to achieve dissolution than dispersion, for example. However, since the solvent is generally removed by drying, it should not make up an appreciable portion of the final product, the amount of solvent is not generally considered in describing the overall composition.
  • the taste masking layer may also include anti-tack agents such as magnesium stearate or talc and copolymers such as HPMC, EC, HPC and PVP in an amount of up to about 25% by weight of that coating.
  • the selection of the seal coating layer and taste masking layer materials and the resulting layers should be coordinated such that the solvents used for the taste masking layer will not adversely affect (compromise its ability to reduce migration across the taste masking layer) the very thin seal coating layer. If both polymer coating materials are water soluble and water is used as the solvent for both, the application of the dissolved, dispersed or suspended taste masking polymer could redissolve and compromise the seal coating, the taste masking coating, or both. Coordination therefore requires consideration of thickness, material, release, and solvent of both coatings.
  • Ethylcellulose cellulose that contains not less than 46.5% of ethoxy groups is freely soluble in 95% ethanol. Id. at 279. Hydroxypropyl methylcellulose (HPMC) is practically insoluble in 95% ethanol. Id. at 347.
  • Eudragit E 100 also known as poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) (1 :2:1) (CAS Number [24938-16-7]) lists acetone and alcohols as the recommended solvents. Id. at 555.
  • the seal coating layer has a thickness of about 10 microns or less, preferably about 5 microns or less, and more preferably about 2 microns.
  • the taste masking layer has a thickness of about 50 microns or less, preferably about 40 microns or less, and more preferably about 27 microns.
  • the tablets of certain embodiments of the invention include an effervescent couple, alone or in combination with other additional ingredients or excipients may be used to improve the disintegration profile and the organoleptic properties of the tablet.
  • Effervescent couples are made from a reaction of a soluble acid source and a metal carbonate or bicarbonate.
  • the acid sources or acid may be any which are safe for human consumption and may generally include food acids, acid anhydrides and acid salts.
  • Food acids include citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, and succinic acids etc.
  • Acid anhydrides and acid salts of the above described acids may also be used. Acid salts may include sodium, dihydrogen phosphate, di sodium dihydrogen pyrophosphate, acid citrate salts and sodium acid sulfite.
  • Carbonate sources include dry solid carbonate and bicarbonate salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and sodium sesquicarbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate and amorphous calcium carbonate.
  • These effervescent couples may be provided in an amount of between about 3% and about 25% by weight of the dosage form.
  • a tablet according to the present invention may also include suitable noneffervescent disintegration agents as an excipient.
  • suitable noneffervescent disintegration agents include: microcrystalline, cellulose, croscaramellose sodium, crospovidone, starches, corn starch, potato starch and modified starches thereof, clays, such as bentonite, alginates, gums such as agar, guar, locust bean, karaya, pecitin and tragacanth.
  • These noneffervescent disintegrants may comprise up to about 20 weight percent and preferably between about 2% and about 10% of the total weight of the dosage form.
  • the invention provides a tablet comprising: rapid release API containing particles, and an excipient.
  • the API containing particle comprises a carrier particle coated with an API containing layer of a prednisolone sodium phosphate present in an amount of about 20 to about 45% by weight of the API containing particle.
  • the API containing layer is overcoated with a seal coating layer present in an amount of about 2% to about 15% by weight, and the seal coating layer being overcoated with a taste masking coating layer present in an amount of about 25% to about 55% by weight gain.
  • the API containing particle being present in an amount of about 55% to about 75% by weight of said tablet.
  • This tablet could be effervescent or could be a non- effervescent tablet.
  • the tablet is preferably an ODT tablet, but it is not necessarily an
  • the tablets of the invention will have a certain hardness, certain friability and/or dissolve/disintegrate in the mouth of a patient with a certain period of time.
  • the dosage forms may include as additional ingredients or excipients including, without limitation, a noneffervescent disintegration agent as discussed above and/or glidants, fillers, lubricants, binders, sweeteners, flavoring and coloring components. Any conventional sweetener or flavoring component may be used. Combinations of sweeteners, flavoring components, or sweeteners and flavoring components may likewise be used. •
  • binders which can be used include but are not limited to acacia, tragacanth, gelatin, starch, cellulose materials such as methyl cellulose, microcrystalline cellulose and sodium carboxy methyl cellulose, alginic acids and salts thereof, magnesium aluminum silicate, polyethylene glycol, PVP, guar gum, polysaccharide acids, bentonites, sugars, invert sugars and the like. Binders may be used in an amount of up to 60 weight percent and preferably about 10 to about 40 weight percent of the total dosage form.
  • Coloring agents may include but are not limited to titanium dioxide, and dyes suitable for food such as those known as F.D.& C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annato, carmine, turmeric, paprika, etc.
  • the amount of coloring used may range from about 0.1 to about 3.5 weight percent of the total dosage form.
  • Examples of glidants include but are not limited to silicon dioxide, talc, calcium stearate, magnesium stearate, stearowet C, zinc stearate, calcium silicate, starch, pregelatinized starch, magnesium lauryl sulfate, magnesium carbonate, magnesium oxide, and others. These may be used in an amount of between about 0.1 and about 5% by weight of the dosage form.
  • Diluents or Fillers include, but are not limited to spray-dried monohydrate or anhydrous lactose, sucrose, dextrose, mannitol, spray dried mannitol, sugar alcohols, sorbitol, starch, cellulose (e.g., microcrystalline cellulose) dihydrated or anhydrous dibasic calcium phosphate, tricalcium phosphate, maltodextrins, calcium carbonate, calcium sulfate and others. These may be used in an amount of between about 10 and about 90% by weight of the dosage form.
  • Flavors incorporated in the composition may be chosen from synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof. These may include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil. Also useful as flavors are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth.
  • Flavors which have been found to be particularly useful include commercially available orange, grape, cherry and bubble gum flavors and mixtures thereof.
  • the amount of flavoring may depend on a number of factors, including the organoleptic effect desired. Flavors may be present in an amount ranging from about 0.05% to about 3% by weight based upon the weight of the dosage form.
  • Lubricants may also be used. Hydrophobic lubricants are preferred. Hydrophobic lubricants include, without limitation, calcium stearate, magnesium stearate, zinc stearate, stearic acid, stearowet C, mineral oil, vegetable oil, glyceryl behenate, sodium stearyl fumarate, talc, starch, and others. Hydrophilic lubricants include, without limitation, sodium benzoate, sodium chloride, sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol, and others. Magnesium stearate is preferred.
  • the dosage form may also contain minor amounts of nontoxic substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid esters.
  • nontoxic substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid esters.
  • OAPIs active pharmaceutical ingredients
  • analgesics include, without limitation, analgesics, anti-inflammatories, antipyretics, antibiotics, antimicrobials, anxiolytics, laxatives, anorexics, antihistamines, antidepressants, antiasthmatics, antidiuretics, antiflatuents, antimigraine agents, antispasmodics, sedatives, antihyperactives, antihypertensives, tranquilizers, decongestants, beta blockers, peptides, proteins, oligonucleotides and other substances of biological origin, and combinations thereof.
  • analgesics include, without limitation, analgesics, anti-inflammatories, antipyretics, antibiotics, antimicrobials, anxiolytics, laxatives, anorexics, antihistamines, antidepressants, antiasthmatics, antidiuretics, antiflatuents, antimigraine
  • OAPIs are the drugs and pharmaceutically active ingredients described in Mantelle, U.S. Pat. No. 5,234,957, in columns 18 through 21. That text of Mantelle is hereby incorporated by reference.
  • the above identified OAPIs may be coated onto the same carrier particle as the prednisolone salt or may be provided in the tablet as a distinct particle. They may be coated or uncoated.
  • the tablets in accordance with the present invention are tablets which are designed to disintegrate and/or dissolve rapidly in the mouth of a patient once placed in his mouth.
  • rapidly in this context, it is understood that these tablets preferably disintegrate/dissolve in the mouth in less than 120 seconds, more preferably 90 second or less, even more preferably 60 seconds or less, and most preferably 30 seconds. This can be measured by measuring the time it takes of the tablet to dissolve in a test subject's mouth or by using the U.S.P. disintegration method ⁇ 701> 2006.
  • the tablets of the present invention have a hardness of about 15 Newtons or more, more preferably 20 Newtons or more, and a friability, as measured by the USP 26th revision (January 1 , 2003), of about 2% or less.
  • these tablets may include at least one non-direct compression carbohydrate (sugar, sugar alcohol, etc.) as a filler. See U. S. Patent No. 6,024,981.
  • these tablets are capable of rapidly disintegrating/dissolving in a patient's mouth in about 60 seconds or less, more preferably about 30 seconds or less, such that the rapid release API containing particles can be swallowed as a dispersion, suspension or slurry.
  • These tablets may be packaged in blister packages or in openable and reclosable multi-tablet packages.
  • the tablets of another embodiment of the invention often have a hardness of about 20 Newtons or less, and a friability of more than 2% as measured by the U.S. P. method as of the filing date.
  • these tablets are capable of rapidly disintegrating/dissolving in a patient's mouth in about 60 seconds or less, more preferably about 30 seconds or less, such that the rapid release API containing particles can be swallowed as a dispersion, suspension or slurry.
  • a tablet of the invention as, for example, containing particles having a certain particle size or distribution, that recitation may be satisfied if the materials used prior to final blending and tablet formulation meet that recitation.
  • Tablets can either be manufactured by direct compression, wet granulation, dry granulation or any other tablet manufacturing technique. See, e.g., U.S. Pat. Nos. 5,178,878, 5,223,264 and 6,024,981 which are incorporated by reference herein.
  • the process of coating in accordance with the invention proceeds as follows.
  • Spheres, and particularly sugar spheres are first layered with an API- containing containing layer.
  • the layering material is a mixture of the API (prednisolone sodium phosphate) in an amount of about 19%, HPMC in an amount of 1%, with the balance being water.
  • the drug is layered to a final potency of 58.8%, i.e., the coated beads include 58.8% of the API by weight.
  • the carrier particles containing an API-containing layer can be seal coated with a seal coating material.
  • the seal coating is made up of 5% HPMC, 9.5% water, with the balance being ethanol.
  • the seal coating layer is applied to a calculated target weight gain of 5% based on the API-containing layer coated carrier particles.
  • the potency of the prednisolone salt, measured based on the weight of the sodium phosphate salt, is now approximately 55.2%. Both of these coatings can be applied by a fluidized bed and can be maintained in the bed for a period of time without additional coating material being added to accomplish some level of drying.
  • the now seal coated particles are coated once again, this time with a taste masking coating.
  • the taste masking coating material can be made, in one example of, 16.7% Eudragit E-IOO, 8.3% of a lubricant, with the balance of about 75% being ethanol.
  • a calculated 40% w/w target gain is applied, reducing the potency, i.e., the overall content of the API, to about 32.2% by weight of the finished API-containing particles.
  • the particles may be dried, again in the fluidized bed, or in any other way, to a final residual water layer. These materials are then screened, whereafter they can be blended with the effervescent couple and excipients and compressed into tablets. Thereafter they are placed into packages and in particular a preferred embodiment blister packages.
  • the formulations and tablets of the present invention are useful for treating or preventing any condition for which administration of the API contained therein is considered an appropriate treatment or preventative measure.
  • the present invention includes a method of treating a condition in a subject wherein said condition is treatable with an API.
  • These conditions include, without limitation:
  • Idiopathic thrombocytopenic purpura in adults selected cases of secondary thrombocytopenia; acquired (autoimmune) hemolytic anemia; pure red cell aplasia; Diamond-Blackfan anemia.
  • Nervous System Acute exacerbations of multiple sclerosis.
  • Ophthalmic Diseases [0093] Uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids; temporal arteritis; sympathetic ophthalmia.
  • Symptomatic sarcoidosis idiopathic eosinophilic pneumonias; fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy; asthma (as distinct from allergic asthma listed above under "Allergic States”), hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, acute exacerbations of chronic obstructive pulmonary disease (COPD), and
  • PCP Pneumocystis carinii pneumonia
  • Tuberculous meningitis with subarachnoid block or impending block, tuberculosis with enlarged mediastinal lymph nodes causing respiratory difficulty, and tuberculosis with pleural or pericardial effusion (appropriate antituberculous chemotherapy must be used concurrently when treating any tuberculosis complications); trichinosis with neurologic or myocardial involvement; acute or chronic solid organ rejection (with or without other agents).
  • This method includes the following steps: administering to the subject an orally disintegrable tablet as described herein comprising placing said orally disintegrable tablet into the mouth of the subject, maintaining the tablet in the mouth of the subject for a time which is sufficient to allow the tablet to disintegrate and/or dissolve, and swallowing the resulting disintegrated and/or dissolved tablet.
  • the formulation used should include an amount of API which is effective to treat or prevent the condition for which it is prescribed or administered. It is also preferred that the orally disintegrable dosage form be in the form of a compressed tablet which can disintegrate in the mouth of a patient within about 60 seconds. In a preferred embodiment, the tablet is placed on top of the tongue and allowed to disintegrate/dissolve and then than swallowed. The patient may be watched for a time sufficient to ensure that the tablet has been dissolved and swallowed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • Effervescent ODT tablets as described below, may be made using the 32.2% API-containing particles described above using the following common blend formulation as set forth in Table 1 below.
  • Prednisolone ODTTM formulations 10 mg, 15 mg or 30 mg of prednisolone free base can be produced as follows.
  • the three tablet strengths can be made compositionally proportional i.e. a common final blend is manufactured and compressed into 10 mg, 15 mg or 30 mg tablets.
  • the common blend is a mixture of Coated PSP, Mannitol, Mannitol EZ, Crospovidone, Microcrystalline Cellulose, Sucralose, Sodium Bicarbonate, Citric Acid, Grape flavor, Colloidal Silicon Dioxide and Magnesium Stearate as discussed above.
  • the manufacturing process uses conventional blending and compression equipment.
  • the manufacturing process uses conventional diffusion-type blending followed by compression and blister packaging.
  • the Prednisolone ODTO tablets are packaged in unit dose blisters (one tablet per blister cavity).
  • the blister forming film consists of a four layer laminate material composed of polyvinyl chloride (PVC) film/oriented polyamide (OPA) film/aluminum foil/polyvinyl chloride (PVC) film.
  • PVC polyvinyl chloride
  • OPA polyamide
  • PVC polyvinyl chloride
  • PVC polyvinyl chloride
  • OPA oriented polyamide
  • PVC polyvinyl chloride
  • the blister forming film is heat sealed with a lidding material composed of paper/polyester film/aluminum foil/heat seal coating.
  • the product contact surfaces of the cold form blister foil and lidding are the polyvinyl chloride (PVC) film and the heat seal coating respectively. Tablets can be produced meeting the following criteria set forth in Table 2 below.
  • the procedure for manufacturing of OrapredTM ODT tablets in accordance with the invention include the following steps: 1. Drug is layered over an inert material (sugar beads).
  • Prednisolone sodium phosphate (PSP) tablets undergo weigh/blend process to adjust weight based on final potency value to be used for tablet blend. 5. Final blend is compressed using rotary tablet press.
  • Orapred ODT 30mg prednisolone base equivalent tablet is a white, flat faced, beveled edge tablet with debossing "ORA" on one side and "30" on the other.
  • Table 4 Tablet formula for Orapred OPT 30 mg TabletsfEquivalent to Prednisolone Sodium Phosphate 40.3 mg)
  • dosage form is oral; tablet, orally disintegrating ***Route; dosage form is oral; tablet a.
  • Actual amount is based on Coated PSP assay b. Equivalent to 40.3 mg of Prednisolone Sodium Phosphate or 30 mg prednisolone base c. Actual amount adjusted based on the Coated PSP amount d.
  • the primary objective was to compare single dose bioavailability of the test drug, Orapred® Orally Disintegrating Tablet (ODT), and the two reference formulations, Pediapred® and Orapred® oral solution.
  • ODT Orapred® Orally Disintegrating Tablet
  • Methodology The study subjects were healthy male and female adult volunteers. The study was a randomized, 3-way crossover, comparative bioavailability study under fasting conditions. All subjects in the study received a single 30 mg prednisolone base equivalent dose of the test formulation and an equivalent dose of each reference formulation. There was a minimum 7-day washout between dosing periods.
  • Plasma samples will be collected in blood collection tubes containing EDTA before dosing (1 x 10 mL) and at the following times: 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16 and 24 hours after dosing (1 * 5mL). Plasma concentrations of prednisolone were measured by a validated LC-MS/MS method. Subjects were randomized to treatment sequence and 24 subjects were enrolled. Test product A was prednisolone sodium phosphate 40.3mg orally dissolving tablets (equivalent to 30mg prednisolone base) from Example 2 above. Reference products B.
  • prednisolone sodium phosphate oral solution 6.7mg/5mL (equivalent to 5mg prednisolone base/5mL) and C Orapred (prednisolone sodium phosphate) oral solution 20.2 mg/5mL (equivalent to 15mg prednisolone base/5mL) were used.
  • Dosing consisted of a single oral 30 mg prednisolone base equivalent (one tablet or 3OmL Pediapred or 1OmL Orapred oral solution) dose administered with 240 mL of water.
  • the clinic site pharmacy provided each dose of solution in individual unit dose containers for each subject and for each study period.
  • the tablet was provided in peelable aluminum laminate blister packs with each tablet packaged in a separate pocket.
  • Study endpoints were the 90% confidence intervals of the ratio of least-squares means of the pharmacokinetic parameters AUCo-t, AUQ n f and C max of the test to reference formulations.
  • the primary comparison of interest was the orally dissolving tablet versus Pediapred.
  • the orally dissolving tablet was also compared to Orapred oral solution.
  • AUCo-t The area under the plasma concentration versus time curve, from time
  • AUCi nf - The area under the plasma concentration versus time curve from time 0 to infinity. AUCinf is calculated as the sum of AUCo- t plus the ratio of the last measurable plasma concentration to the elimination rate constant.
  • AUC/AUCjn f represents the ratio of AUC 0-t to AUC inf .
  • C 018x represents the maximum measured plasma concentration over the time span specified.
  • t max represents the time of the maximum measured plasma concentration. If the maximum value occurs at more than one time point, tmax is defined as the first time point with this value.
  • KeI represents the apparent first-order terminal elimination rate constant calculated from a semi-log plot of the plasma concentration versus time curve. The parameter will be calculated by linear least-squares regression analysis using the maximum number of points in the terminal log-linear phase (e.g. three or more non-zero plasma concentrations).
  • t' ⁇ represents the apparent first-order terminal elimination half-life will be calculated as 0.693/kel. No value for kel, AUCi nf or tVz are reported for cases that do not exhibit a terminal log-linear phase in the concentration versus time profile.
  • Arithmetic means, standard deviations, and coefficients of variation will be calculated for the pharmacokinetics parameters listed above. Additionally, geometric means will be calculated for AUCo-t, AUCinf and C max .
  • the ANOVA model will include sequence, formulation, and period as fixed effects, and subject nested within sequence as a random effect. Sequence will be tested using subject nested within sequence as the error term at a 10% level of significance. Each ANOVA will include calculation of least-squares means (LSM), the difference between formulation LSM, and the standard error associated with this difference. The above statistical analyses will be done using the appropriate SAS® procedure.
  • LSM least-squares means
  • Ratios of least-squares means will be calculated using the exponentiation of the LSM from the analyses on the In-transformed AUCo-t, AUQnf, and Cm 3x . These ratios will be expressed as a percentage relative to the reference formulation. Consistent with the two one-sided test for bioequivalence, 90% confidence intervals for the ratios will be derived by exponentiation of the confidence intervals obtained for the difference between formulation LSM resulting from the analyses on the In-transformed AUCo -t , AUCi nf , and C m2x . The confidence intervals will be expressed as a percentage relative to the reference formulation. Percentages will meet standard bioequivalence criteria if falling within 80-125%. The results of this study are summarized below in Table 5.
  • Example 2 The tablets of Example 2 were used with and without water in a study summarized as follows.
  • the primary objective was to compare single dose bioavailability of the test drug, Orapred® Orally Disintegrating Tablet (ODT) administered with 240 mL of water and Orapred® ODT administered without water.
  • ODT Orapred® Orally Disintegrating Tablet
  • the study subjects were healthy male and female adult volunteers.
  • the study was a randomized, 2-way crossover, comparative bioavailability study under fasting conditions. All subjects received a single 30 mg prednisolone base equivalent dose of the test formulation dosed with 240 mL of water and a single 30 mg prednisolone base equivalent dose of the same formulation dosed without water. There will be a minimum 7-day washout between dosing periods. Blood samples will be collected in blood collection tubes containing EDTA before dosing (1 x 10 mL) and at the following times: 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16 and 24 hours after dosing (1 x
  • Plasma concentrations of prednisolone were measured by a validated LC MS/MS method. Subjects were randomized to treatment sequence.
  • the test Product was Orapred ODT (prednisolone sodium phosphate) 40.3mg (equivalent 30mg prednisolone base). Dosing consisted of a single oral 30 mg prednisolone base equivalent tablet dose administered with 240 mL of water or the same dose administered without water.
  • the clinic site pharmacy provided the Orapred® ODT in peelable aluminum laminate blister packs with each tablet packaged in a separate pocket. The duration of the study was 2 weeks.
  • Study endpoints will be the 90% confidence intervals of the ratio of least- squares means of the pharmacokinetic parameters AUCo-t, AUCinf and Cma X of the test formulation given with 240 mL water to the same formulation given without water.
  • Pharmacokinetic parameters for plasma prednisolone will be calculated as follows.
  • AUCo- t is the area under the plasma concentration versus time curve, from time 0 to the last measurable concentration, as calculated by the linear trapezoidal method.
  • AUCi nf is the area under the plasma concentration versus time curve from time 0 to infinity.
  • AUCinf is calculated as the sum of AUCo-t plus the ratio of the last measurable plasma concentration to the elimination rate constant.
  • AUC/AUC, nf is the ratio of AUCo- t to AUCi nf .
  • C max is the maximum measured plasma concentration over the time span specified.
  • t max is the time of the maximum measured plasma concentration.
  • tmax is defined as the first time point with this value
  • kel is the apparent first-order terminal elimination rate constant calculated from a semi -log plot of the plasma concentration versus time curve. The parameter will be calculated by linear least-squares regression analysis using the maximum number of points in the terminal log-linear phase (e.g. three or more non-zero plasma concentrations).
  • tVi is the apparent first-order terminal elimination half-life and will be calculated as 0.693/kel. No value for kel, AUCj nf or t' ⁇ will be reported for cases that do not exhibit a terminal log-linear phase in the concentration versus time profile.
  • Arithmetic means, standard deviations, and coefficients of variation will be calculated for the pharmacokinetics parameters listed above. Additionally, geometric means will be calculated for AUCo-t, AUCj n f and C n ⁇ x .
  • Analyses of variance will be performed on the In-transformed AUCo-t, AUCjnf, and C m a ⁇ -
  • the ANOVA model will include sequence, formulation, and period as fixed effects, and subject nested within sequence as a random effect. Sequence will be tested using subject nested within sequence as the error term at a 10% level of significance.
  • Each ANOVA will include calculation of least-squares means (LSM), the difference between formulation LSM, and the standard error associated with this difference. The above statistical analyses will be done using the appropriate SAS® procedure.
  • Ratios of least-squares means will be calculated using the exponentiation of the LSM from the analyses on the In-transformed AUCo-t, AUCj nf , and C m8x . These ratios will be expressed as a percentage relative to the test formulation administered with 240 mL water.
  • the tablets of the present invention may be swallowed with water. However, they are preferably orally disintegrable and water need not be taken.
  • tablets comprising prednisolone sodium phosphate in an amount of about 13.4, about 20.2 or about 40.3 mg and an excipient.
  • These tablets could be, and preferably are effervescent and are made using the twice coated particles as described herein. However, they could be a non- effervescent tablets. They are preferably ODT tablets; but they are not necessarily ODT tablets.
  • Still another aspect of the invention are tablets comprising prednisolone sodium phosphate and an excipient exhibiting at least one of a log AUCo- t of 2,300 ng-h/mL ⁇ 600, a log AUC in f of 2,300 ng « h/mL ⁇ 600, a log Cm 3x of 400 ng/ml ⁇ 100 or a t max of 1.3 hours ⁇ 20 mins.

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  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des comprimés contenant des sels de prédnisolone et en particulier des phosphates de sodium de prédnisolone. Les comprimés comprennent des comprimés effervescents ODT et non-ODT et des comprimés non effervescents et des comprimés satisfaisant à certains critères de performance.
PCT/US2007/013008 2006-06-01 2007-05-30 Formulations de sel de prédnisolone WO2007143131A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CA002653485A CA2653485A1 (fr) 2006-06-01 2007-05-30 Formulations de sel de prednisolone
MX2008015059A MX2008015059A (es) 2006-06-01 2007-05-30 Formulaciones de sal prednisolona.

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US81001506P 2006-06-01 2006-06-01
US60/810,015 2006-06-01
US11/638,260 2006-12-13
US11/638,216 US8637076B2 (en) 2006-06-01 2006-12-13 Prednisolone salt formulations
US11/638,216 2006-12-13
US11/638,260 US20070281014A1 (en) 2006-06-01 2006-12-13 Prednisolone salt formulations

Publications (3)

Publication Number Publication Date
WO2007143131A2 WO2007143131A2 (fr) 2007-12-13
WO2007143131A9 true WO2007143131A9 (fr) 2008-02-14
WO2007143131A3 WO2007143131A3 (fr) 2008-03-20

Family

ID=38616310

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2007/013008 WO2007143131A2 (fr) 2006-06-01 2007-05-30 Formulations de sel de prédnisolone
PCT/US2007/012883 WO2007143061A2 (fr) 2006-06-01 2007-05-31 Formules de sels de prednisolone

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/US2007/012883 WO2007143061A2 (fr) 2006-06-01 2007-05-31 Formules de sels de prednisolone

Country Status (3)

Country Link
CA (2) CA2653485A1 (fr)
MX (2) MX2008015059A (fr)
WO (2) WO2007143131A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2926722B1 (fr) * 2008-01-25 2010-09-03 Substipharm Dev Formulation pharmaceutique appropriee pour la preparation de comprimes orodispersibles de prednisolone

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL276614A (fr) *
US3921636A (en) * 1973-01-15 1975-11-25 Alza Corp Novel drug delivery device
US6740341B1 (en) * 1998-11-25 2004-05-25 Cima Labs Inc. Taste masking rapid release coating system
EP2260836B1 (fr) * 1998-11-25 2016-08-10 Cima Labs Inc. Comprimé a libération rapide avec un noyau comprenant le principe actif enrobé dans une barrière masquant le gout
DE60213283T2 (de) * 2001-12-20 2007-07-12 Alpex Pharma S.A. Pharmazeutische zusammensetzung enthaltend magermilchpulver
JP2006515320A (ja) * 2002-12-31 2006-05-25 ラリー エル オーグスバーガー 活性クッション性成分を含有する医薬品剤形の製造方法
US9050249B2 (en) * 2004-04-30 2015-06-09 Astellas Pharma Inc. Oral pharmaceutical compositions in timed-release particle form and fast-disintegrating tablets containing this composition

Also Published As

Publication number Publication date
MX2008015059A (es) 2009-04-14
MX2008015058A (es) 2009-04-14
WO2007143061A3 (fr) 2008-02-14
CA2653485A1 (fr) 2007-12-13
WO2007143131A2 (fr) 2007-12-13
WO2007143131A3 (fr) 2008-03-20
CA2653480A1 (fr) 2007-12-13
WO2007143061A2 (fr) 2007-12-13

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