Classifications

• • 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
  • A61K31/12—Ketones
  • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• • 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
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • 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
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • 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
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

• the present invention provides pharmaceutical formulations of nitisinone stabilized for long term storage.
• Nitisinone also known as NTBC is of use to treat hereditary tyrosinemia. Since its first use for this indication in 1991 , it has replaced liver transplantation as the first-line treatment for this rare condition. Nitisinone is also being studied in the less severe but related condition alkaptonuria. Nitisinone is marketed under the brand name Orfadin.
• nitisinone involves reversible inhibition of 4- hydroxyphenylpyruvate oxidase, thus preventing the formation of maleylacetoacetic acid and fumarylacetoacetic acid, which have the potential to be converted to succinyl acetone, a toxin that damages the liver and kidneys (Lock EA, et al. (1998) Journal of Inherited Metabolic Disease 42 (21): 498-506; Kavana M., et al. (2003) Biochemistry 42 (34): 10238 ⁇ 5.).
• Nitisinone is stable as a pure compound, however, nitisinone as marketed under the trade name Orfadin, is relatively unstable, requiring refrigerated storage and, even refrigerated, having a limited 18-month shelf life.
• pharmaceutically acceptable formulations of nitisinone showing an enhanced stability are desirable.
• the present invention provides such formulations.
• nitisinone can be stabilized by an acidic formulation.
• pKa 4.4
• an acidic proton is removed from nitisinone and the resulting compound rearranges with the elimination of nitrite and cyclizes to form the degradation product oxotetrahydroxanthenone.
• An initial challenge posed by reformulation of nitisinone into a stabilized formulation was the degradation of nitisinone by a rearrangement and elimination reaction in the presence of excipients.
• selection of the correct excipients and pH modifiers to provide a formulation with a microenvironment pH for nitisinone of less than about 4.4 (pKa of acidic hydrogen) was challenging.
• a stable pharmaceutical formulation comprising a therapeutically effective amount of nitisinone and a pharmaceutically acceptable carrier.
• the formulation includes an acidic pH modifier.
• the therapeutically amount of nitisinone in the formulation is essentially undiminished by conversion to any degradation product including, but not limited to, oxotetrahydroxanthenone after more than about 6 months at about 25 °C.
• FIG. 1 is a graphic comparison of three nitisinone formulations over a period of 18 months at 25 °C and 60% relative humidity: ( ⁇ ) is a tableted formulation of the invention; ( ⁇ ) is a formulation of the invention as an ODT disc; (A) is the currently marketed Orfadin tablet.
• FIG. 2 is a tabulation of the data from which FIG. 1 was generated.
• the present invention provides a stable pharmaceutical formulation comprising a therapeutically effective amount of nitisinone and a pharmaceutically acceptable carrier comprising an acid pH modifier.
• the amount of nitisinone in the formulation is essentially undiminished by conversion to any degradation product including, but not limited to oxotetrahydroxanthenone, after storage for about 6 months, for about 12 months, for about 18 months or more at about 25 °C.
• the nitisinone in the initial formulation is high purity nitisinone having a purity of at least about 95.5% (w/w), e.g., at least about 96%, 96.5%, 97%, 97.5%, 98%, or 98.5% (w/w).
• the therapeutically effective amount of nitisinone in the formulation is from about 0.1 mg to about 25 mg, e.g., from about 0.5 mg to about 5 mg, e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg or about 5 mg.
• not more than about 0.03% (w/w) of the mass of nitisinone in the original formulation is converted to another species after storage for about 6 months, for about 12 months, for about 18 months, or more, when the formulation is stored at about 25 °C.
• not more than about 0.1% of the mass of nitisinone in the original formulation is converted to another species after storage for about 6 months, for about 12 months, for about 18 months, for about 36 months, or longer, when the formulation is stored at about 25 °C.
• not more than about 0.03% of the mass of the nitisinone in the formulation is converted to oxotetrahydroxanthenone after storage for about 6 months, for about 12 months, for about 18 months, or longer, at about 25 °C. In various embodiments, not more than about 0.01% of the mass of the nitisinone in the formulation is converted to
• oxotetrahydroxanthenone after storage for about 36 months, or longer, at about 25 °C.
• not more than about 0.1% of the mass of the nitisinone in the formulation is converted to oxotetrahydroxanthenone. In various embodiments, not more than about 0.1 % of the mass of the nitisinone in the formulation is converted to
• oxotetrahydroxanthenone after storage for about 6 months, for about 12 months, for about 18 months, or longer, at about 25 °C. In various embodiments, not more than about 0.1 % of the mass of the nitisinone in the formulation is converted to oxotetrahydroxanthenone after storage for about 36 months, or longer, at about 25 °C.
• not more than about 1% of the mass of nitisinone in the formulation is converted to oxotetrahydroxanthenone. In various embodiments, not more than about 1% of the mass of the nitisinone in the formulation is converted to
• oxotetrahydroxanthenone after storage for about 6 months, for about 12 months, for about 18 months, for about 36 months or longer, at about 25 °C. In various embodiments, not more than about 1% of the mass of the nitisinone in the formulation is converted to
• oxotetrahydroxanthenone after storage for about 36 months, or longer, at about 25 °C.
• the invention provides a formulation of nitisinone containing not more than about 0.1% more oxotetrahydroxanthenone after storage for about 6 months, for about 12 months, for about 18 months, for about 36 months, or longer, at about 25 °C than the amount of oxotetrahydroxanthenone in the formulation prior to storage.
• the formulation of the invention contains not more than about 0.1%, 0.2%, 0.3%, 0.4% or 0.5% more oxotetrahydroxanthenone after about 12 months (e.g., about 18 months or longer) storage at 25 °C than the amount of said oxotetrahydroxanthenone in the formulation prior to storage.
• the invention provides a formulation which contains not more than about 1% more oxotetrahydroxanthenone after 12 months (e.g., about 18 months or longer) storage at 25 °C than the amount of oxotetrahydroxanthenone in the formulation prior to storage. In various embodiments, the formulation contains not more than 1 %
• the acidic pH modifier of use in the exemplary formulations of the invention can be a mineral (inorganic) acid or an organic acid.
• An exemplary acidic pH modifier has a pKa of about 5 or lower.
• the acidic pH modifier is an organic acid.
• exemplary organic acids of use in the formulations of the invention include, without limitation, mono-, di- and tricarboxylic acids.
• An exemplary acidic pH modifier has a pKa of about 5 or lower.
• Exemplary organic acids include amino acids such as glutamic acid and aspartic acid, vitamin acids such as ascorbic acid and folic acid, and their respective salts.
• Particularly preferred organic acids are dicarboxylic and tricarboxylic acids selected from the group consisting of citrate, pyruvate, succinate, fumarate, malate, formate, oxaloacetate, citrate, cis- aconitate, isocitrate, and a-ketoglutarate.
• the acidic pH modifier is one or more organic acid selected from citric acid, tartaric acid, maleic acid, alpha-ketoglutaric acid, glycine hydrochloride.
• the acidic pH modifier is citric acid.
• the acidic pH modifier is present in the formulation of the invention in any useful amount.
• the acidic pH modifier is present in an amount from about 0.001% (w/w) to about 95% (w/w), e.g., from about 0.01% (w/w) to about 50% (w/w), e.g., from about 0.1 % (w/w) to about 20% (w/w), e.g., from about 1% (w/w) to about 10% (w/w), e.g., from about 1 % (w/w) to about 5% (w/w) of the formulation.
• the acid pH modifier is the major constituent of the formulation and it accounts for at least about 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98% or at least 99% of the mass of the formulation.
• the acidic pH modifier is present as a binder and accounts for essentially the entire mass of the formulation, excepting the nitisinone.
• Exemplary formulations of the present invention include at least one additional pharmaceutically acceptable excipient.
• the pharmaceutically acceptable excipients useful in the present invention can be selected from the group consisting of fillers, binders, lubricants, glidants, antiadherents, flavoring agents, coloring agents, disintegrants and mixtures of thereof.
• a more detailed description of the acceptable pharmaceutical excipients that may be employed in the present invention can be found in Rowe et al., Handbook of Pharmaceutically Acceptable Excipients (4 th ed. 2003) or the United States Pharmacopeia 29, both of which are incorporated herein by reference.
• the formulation of the invention includes one or more of a diluent, a lubricant, a binder and a combination thereof.
• a diluent e.g., a lubricant, a binder and a combination thereof.
• one, more than one or all of these additional elements is pharmaceutically acceptable.
• Examples of acceptable fillers include water; salts; sugars such as lactose, dextrose, sucrose, maltose, or microcrystalline cellulose; sorbitol, mannitol, clays and mixtures thereof.
• Exemplary diluents of use in the invention include one or more of mannitol, lactose, sorbitol, Prosolv (sicilified microcrystalline cellulose), starch, or Avicel.
• the formulation of the invention includes one or more diluent which is selected from stearic acid, magnesium stearate, and sodium stearyl fumarate.
• Binders that are useful in the present invention include pharmaceutically acceptable substances with cohesive properties. Some examples include celluloses such as hydroxypropyl methycellulose, hydroxypropyl cellulose and carboxymethycellulose sodium; polyvinylpyrrolidone (PVP); sugars; starches and mixtures thereof. In an exemplary embodiment, the formulation also includes povidone as a binder.
• lubricants, glidants and/or antiadherents examples include talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, polyethylene glycols, silicon dioxide and mixtures thereof.
• Flavoring agents that can be used in the present invention include peppermint, spearmint, wintergreen, cinnamon, coconut, coffee, chocolate, vanilla, menthol, liquorice, anise, apricot, caramel, pineapple, strawberry, raspberry, grape, cherry, mixed berry, tropical fruits, mint and mixtures thereof.
• Coloring agents that may be employed in the present invention include FD&C-type dyes and lakes, fruit and vegetable extracts, titanium dioxide and mixtures thereof.
• disintegrating agents examples include corn starch, croscarmelose sodium, crospovidone (polyp lasdone XL- 10), sodium starch glycolate
• the invention provides a formulation that includes two or more of mannitol, stearic acid and povidone.
• the pharmaceutical composition of the present invention can be any type of composition known in the pharmaceutical arts such as a solution, suspension, emulsion or solid.
• the composition can be an intermediate used in the manufacture of a dosage form or may be a dosage form designed for parental, intravenous, ophthalmic, oral, buccal, rectal or vaginal delivery.
• the formulation is configured as a capsule, a table or a lozenge.
• the formulation is a solid oral dosage form such as an orally disintegrating tablet, an immediate release dosage form, a delayed or enteric coated dosage form, a controlled release dosage form or a combination of the forgoing.
• the formulation of the invention is a solid oral dosage unit including tablets, capsules or orally-dissolving lyophilized disk.
• the dosage unit is an orally dissolving tablet (ODT).
• ODT orally dissolving tablet
• the formulation of the invention is a unit dosage formulation comprising from about 0.1 mg to about 50 mg, e.g., from about 1 mg to about 10 mg of nitisinone, e.g., from about 1 mg to about 5 mg of nitisinone.
• An immediate release dosage form in accordance with the present invention may be prepared using techniques commonly known in the art and can be in the form of a tablet or capsule.
• nitisinone, an organic acid and at least one additional excipient such as a binder, filler and lubricant are mixed together using standard techniques known in the art such as blending, slugging and/or granulation.
• the mixture can be compressed into tablets using techniques commonly used in the art.
• the seal coating or aesthetic coating typically is a coating or layer that is soluble or rapidly disintegrating in water and does not materially affect the release of the active ingredients from the tablet core.
• the most common seal coatings comprise low molecular weight hydroxypropyl methylcellulose or polyvinyl alcohol.
• An immediate release composition in accordance with the present invention may also be prepared by blending nitisinone, organic acid and at least one additional excipient such as a filler and loading the blended mixture into a gelatin capsule.
• the formulation of the invention is a controlled release formulation.
• a controlled release dosage form in accordance with the present invention may also be prepared using techniques commonly known in the art. Some of the controlled release dosage forms that are useful in the present invention include, but are not limited, to matrix tablets, osmotic tablets, pellet filled capsules or combinations of the foregoing. Release controlling excipients such as hydrophilic and hydrophobic matrix polymers and polymeric coatings are known in the art and described in Rowe et al., Handbook of Pharmaceutically Acceptable Excipients (4 th ed. 2003), which is incorporated herein by reference.
• the controlled release dosage form in accordance with the present invention should release therapeutically effective amounts of nitisinone over a period of 4-24 hours, preferably 8-24 hours, so the dosage form can be administered once or twice daily.
• a controlled release dosage form in accordance with the present invention is a matrix tablet.
• the matrix tablet should comprise therapeutically effective amount of nitisinone, a stabilizing amount of an acidic pH modifier (e.g., an organic acid) and a matrix forming agent.
• the matrix forming agent can be a hydrophobic material such as a wax, a hydrophilic material such as a hydrogel polymer or a combination of the two.
• a hydrogel polymer is a polymeric material that gels or swells when placed in an aqueous environment.
• the matrix forming agent controls the release of nitisinone by diffusion of the drug from the matrix, erosion of the matrix or a combination of diffusion and erosion. The amount of diffusion and erosion will depend upon the materials selected for the formation of the matrix. Examples of hydrogel forming polymers include hydroxypropyl methylcellulose,
• carboxymethylcellulose calcium carboxymethylcellulose sodium, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, acrylic polymers and copolymers, sodium alginate, polyethylene oxides and mixtures thereof.
• hydrophobic materials that can be used to form a non-gelling or non- swelling controlled release matrix for nitisinone include beeswax, white wax, emulsifying wax, hydrogenated vegetable oil, hydrogenated castor oil, microcrystalline wax, cetyl alcohol, stearyl alcohol, free wax acids such as stearic acid, esters of wax acids, propylene glycol monostearate, glycerol monostearate, carnauba wax, palm wax, candelilla wax, lignite wax, ozokerite, ceresin wax, lardaceine, China wax and mixtures thereof.
• rate controlling excipients useful in the present invention include saturated hydrocarbons having from 25 to 31 carbon atoms, saturated alcohols having from 25 to 31 carbon atoms, saturated monocarboxylic acids having from 25 to 31 carbon atoms, esters obtained from said alcohols and monocarboxylic acids which are described in U.S. Pat. No. 6,923,984, incorporated herein by reference.
• a combination of hydrophobic and hydrophilic materials may also be used in preparing a controlled release matrix of the present invention.
• the controlled release matrix in accordance with the present invention may further comprise conventional excipients that improve the processing or modify the release characteristics.
• conventional excipients include fillers, glidants and lubricants described previously.
• One embodiment of the controlled release matrix dosage form in accordance with the present invention and without a gelling or swelling polymer should comprise the following composition
• the above-described hydrophobic matrix tablet may also comprise a placebo layer or layers applied to one or more surfaces of the hydrophobic matrix tablet.
• the placebo layer is designed to reduce the surface area of the hydrophobic matrix tablet when the tablet is exposed to the environment of use. The reduction in surface area contributes to controlling the release of nitisinone from the hydrophobic matrix.
• the placebo layer may comprise any of the
• the placebo layer should cover about 5% to about 75%, preferably about 10% to about 65% and most preferably about 15% to about 50% of the surface area of the hydrophobic matrix tablet.
• the matrix tablet may optionally be seal coated or coated with an aesthetic coating as described above with respect to the immediate release composition.
• An immediate release coating comprising nitisinone can be coated directly onto the controlled release matrix core or applied over the sealed coated controlled release matrix core.
• the immediate release coating comprises nitisinone and a film forming material or binder and, optionally, other conventional additives such as lubricants, fillers and antiadherents.
• the immediate release coating may be applied by any conventional technique such as pan coating or spray coating.
• the immediate release coating is applied by spraying an aqueous solution or suspension over a pan containing the matrix cores.
• the film forming material or binder employed in the immediate release coating is preferably a water soluble or rapidly dispersing material such as a low molecular weight hydroxypropyl methylcellulose or povidone.
• the osmotic tablet may comprise: a core containing a therapeutic amount of nitisinone and organic acid; a semi permeable membrane surrounding the core; and a passageway in the semi permeable membrane for release of the drug.
• the core of the osmotic tablet can be prepared with or without a gelling or swelling polymer.
• the core of the osmotic tablet can be a homogenous blend of nitisinone, organic acid and a pharmaceutical excipient as described in U.S. Pat. No. 5,654,005 or a multilayered structure comprising a drug composition and a push composition as described in U.S. Pat. No. 4,612,008 or 4,873,337.
• the aforementioned patents are incorporated herein by reference.
• the osmotic core can optionally be seal coated prior to the application of the
• the semi permeable membrane should be permeable to the passage of an external fluid such as water or aqueous biological fluids and should be impermeable to the passage of the active ingredients in the osmotic core.
• Materials that are useful in forming the semi permeable membranes are ethylcellulose, cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate and cellulose acetate butyrate.
• Other suitable polymers are described in U.S. Pat. Nos.
• the most preferred semi permeable membrane material is cellulose acetate comprising an acetyl content of 39.3% to 40.3%, and is commercially available from Eastman Fine
• the semipermeable membrane can include one of the above-described polymers and a flux-enhancing agent.
• the flux- enhancing agent can increase the volume of fluid imbibed into the core to enable the composition to dispense substantially all of the active ingredients through the passageway and/or the pores created in the membrane by the dissolution of the flux-enhancing agent.
• the flux-enhancing agent can be a water-soluble material or an enteric material.
• Examples of the preferred materials that are useful as flux enhancers are sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methycellulose, hydroxypropyl methycellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers, poloxamers (such as LUTROL F68, LUTROL F127, LUTROL F108, which are commercially available from BASF) and mixtures thereof.
• a preferred flux enhancer is PEG 400.
• the flux-enhancing agent comprises approximately 0% to about 40% of the total weight of the membrane coating, most preferably about 2% to about 20% of the total weight of the membrane coating.
• the flux- enhancing agent dissolves or leaches from the semipermeable membrane to form paths in the semipermeable membrane which enables fluid to enter the osmotic core and dissolve nitisinone.
• the semipermeable membrane may also be formed using a commonly known excipient such as a plasticizer.
• plasticizers include adipate, azelate, enzoate, citrate, stearate, isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, citric acid esters, and those described in the Encyclopedia of Polymer Science and Technology, Vol. 10 (1969), published by John Wiley & Sons.
• the preferred plasticizers are triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltributylcitrate,
• acetyltriethylcitrate glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate,
• the plasticizer amounts from about 0% to about 25%, and preferably about 2% to about 15%, of the plasticizer can be used based upon the total weight of the membrane coating.
• the membrane coating around the core will comprise from about 1% to about 5%, and preferably about 2% to about 3%, based upon the total weight of the core and coating.
• the membrane coating surrounding the core further comprises a passageway that will allow for controlled release of the drug from the core.
• the term "passageway" includes an aperture, orifice, bore, hole, weakened area or an erodible element such as a gelatin plug that erodes to form an osmotic passageway for the release of the active ingredients from the dosage form. Passageways used in accordance with the subject invention are well known and are described in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,034,758; 4,077,407; 4,783,337 and 5,071 ,607, which are incorporated herein by reference.
• An immediate release coating(s) may be applied to the semipermeable membrane.
• the immediate release coatings are described above and may be applied by, but would not be limited to, the processes selected from the group consisting of drug layering, lamination or dry compression.
• a seal coat is applied to the semi-permeable membrane before the immediate release layer is applied.
• Another embodiment of the controlled release dosage form in accordance with the present invention comprises beads, pellets or mini -tablets comprising the active ingredients.
• the beads, pellets or mini-tablets may be filled into hard or soft gelatin capsules or compressed into a tablet.
• the bead, pellets or mini-tablets are prepared by methods commonly known in the art and typically range in size from about 0.1 mm to about 3 mm in diameter. Ideally, the beads or pellets are about 0.2 to about 1 mm in diameter and the mini-tablets are about 0.5 to about 2.5 mm in diameter.
• Active or immediate release beads or pellets are prepared by layering a composition in accordance with the present invention onto an inert substrate such as a non-pariel seed or a microcrystalline cellulose seed commercially available under the trade name CELPHERE.RTM. Active beads or pellets can also be prepared by preparing a composition in accordance with the present invention and subjecting the composition to extrusion spheronization techniques.
• the composition includes a mixture of nitisinone, organic acid and at least one additional conventional pharmaceutical excipient such as a binder and/or filler.
• the mixture of active ingredients and conventional pharmaceutical excipients can also be compressed in mini-tablets.
• the active or immediate release beads or pellets can be also prepared by the methods described in U.S. Pat. Nos. 5,529,791 and 4,984,240, which are incorporated herein by reference.
• the active or immediate release beads, pellets or mini-tablets may be coated with a release controlling polymer coating.
• the controlled release coating should comprise a water insoluble, water permeable polymer and, optionally, a water or acid soluble channeling agent.
• the controlled release coating may also comprise a lubricating or dusting agent and, optionally, a surfactant.
• Suitable water insoluble, water permeable polymers are ethylcellulose, cellulose acetate and polyacrylates or mixtures thereof. Additional water insoluble polymers are described in U.S. Pat. No. 5,002,776 which is incorporated herein by reference.
• One embodiment of the controlled release bead, pellet or mini-tablet dosage form of the present invention employs a water insoluble, water permeable polymer coating such as a polymethacrylate ester copolymer, preferably a poly(ethylacrylate methylmethacrylate) copolymer which is commercially available from Rohm Pharma under the tradename
• the channeling agent employed in the bead, pellet or mini-tablet coating can be any type of water or acid soluble pharmaceutically acceptable substance commonly known in the art such as polyvinyl pyrrolidone, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sucrose or any combination of the foregoing.
• the preferred channeling agent is a water or acid soluble polymer such as a low viscosity hydroxypropyl methylcellulose.
• Suitable surfactants that may optionally be used in the controlled release coating for the beads, pellets or mini-tablets are sodium lauryl sulfate, sodium taurocholate or a polysorbate.
• the controlled release coating can be applied to the active beads, pellets or mini-tablets by any means commonly known in the industry such as a rotary granulator, pan coater or a fluidized bed coater.
• pellets or mini-tablets may be dusted with a suitable lubricant such as talc, magnesium stearate, silicon dioxide, kaolin or a mixture of the foregoing.
• a suitable lubricant such as talc, magnesium stearate, silicon dioxide, kaolin or a mixture of the foregoing.
• the lubricant will prevent the beads, pellets or mini-tablets from sticking to one another during processing.
• the active or immediate release beads, pellets or mini-tablets comprising nitisinone and organic acid are prepared. A portion of the active or immediate release beads, pellets, or mini-tablets are then subsequently coated with a controlled release coating.
• Various blends of the active and controlled release coated beads, pellets or mini-tablets are blended and filled into hard gelatin capsules. For example, a blend of 20% active beads and 80% controlled release beads are filled into a hard gelatin capsule to prepare a once-a-day capsule dosage form in accordance with the present invention.
• a delayed release dosage form in accordance with the present invention may also be prepared by first preparing an immediate release tablet core, a controlled release matrix core or active bead, pellet or mini -tablet core as described above. The cores are then coated with an enteric or pH sensitive coating using techniques commonly known in the art.
• the enteric or pH dependent coating material useful in preparing a delayed release coating include zein, shellac, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate or mixtures thereof.
• the delayed release coating should be applied so that the nitisinone present in the core is released only after the composition has passed through the stomach. To insure that the nitisinone present in the core is not released until the composition has left the stomach, the delayed release coating should be designed to dissolve at a pH greater than 4.5, preferably greater than 5.5 and most preferably greater than a pH of 6.
• the delayed release coating may also comprise plasticizers and other conventional processing aids as described above.
• the delayed release dosage form in accordance with the present invention may also comprise an immediate release component.
• the enteric or pH dependent coated tablet may be coated with an immediate release layer as described previously.
• enteric coated pellets a blend of enteric coated pellets and immediate release pellets can be blended together and filled into a hard gelatin capsule or compressed into a tablet. The combination of enteric or pH coated compositions and immediate release component will allow the pulsatile delivery of nitisinone from a single dosage form.
• the formulation is a unit dosage formulation containing a therapeutically effective amount of nitisinone.
• the unit dosage format retains a therapeutically effective amount of nitisinone after storage at about 25°C for at least about 6 months, at least about 12 months, at least about 18 months, or more.
• the unit dosage includes about 1 mg, about 2 mg, about 3 mg, about 4 mg or about 5 mg of nitisinone. In various embodiments, this amount has not diminshed more than about 0.5% after storage at 25°C for at least about 6 months, at least about 12 months, at least about 18 months, or more.
• the invention provides methods of treating a disease with a pharmaceutical formulation of the invention.
• the disease treated is a neurological disorder, e.g., neurodegenerative disorder, e.g., Parkinson's Disease.
• the formulations of the invention are of use to treat restless leg syndrome.
• the formulation of the invention is of use to treat hereditary tyrosinemia. Treatment of each of these disease states includes administration to a subject in need of such treatment with a formulation of the invention incorporating a therapeutically effective amount of nitisinone.
• the data indicate that the nitisinone formulation of the invention effectively eliminated or minimizes degradation of nitisinone in comparison to the other formulations studied.
• the 6 month 25°C/60%RH and 40°C/75%RH data of the nitisinone formulations demonstrate that the formulation of the invention is superior to the marketed Orfadin capsule formulation and to the negative control formulation.
• An exemplary formulation of the invention was prepared as follows (Table 4). The manufacturing for the batch was carried out with wet granulation followed by blending and lubrication in Turbula blender and tablet compression on Cadmach compression machine using 9 mm x 4 mm oval punch. The manufacturing steps involved:
• Nitisinone suspended into the acidic solution from step 4 under constant stirring ensuring complete mixing of the resulting suspension (ensures intimate contact of acid with API).
• step 9 lubricated with the stearic acid sifted through an ASTM # 60 for 3 min at 40 rpm.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Medicinal Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Biophysics (AREA)
• Molecular Biology (AREA)
• Medicinal Preparation (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=49673877

Family Applications (1)

Country Status (1)

Cited By (4)

Citations (4)

• 2013
  • 2013-05-29 WO PCT/US2013/043180 patent/WO2013181292A1/fr not_active Ceased

Patent Citations (4)

Similar Documents

Legal Events