WO2009009737A1 - Formulation à libération prolongée de produits pharmaceutiques actifs pour une libération prolongée à base de lipides - Google Patents

Formulation à libération prolongée de produits pharmaceutiques actifs pour une libération prolongée à base de lipides Download PDF

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Publication number
WO2009009737A1
WO2009009737A1 PCT/US2008/069798 US2008069798W WO2009009737A1 WO 2009009737 A1 WO2009009737 A1 WO 2009009737A1 US 2008069798 W US2008069798 W US 2008069798W WO 2009009737 A1 WO2009009737 A1 WO 2009009737A1
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Prior art keywords
delivery system
hydrophobic
pharmaceutically acceptable
agent
pharmaceutical delivery
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PCT/US2008/069798
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English (en)
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Krishna Vishnupad
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Neurosci, Inc.
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Publication of WO2009009737A1 publication Critical patent/WO2009009737A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the present disclosure relates to pharmaceutical formulations. More particularly, the present disclosure concerns a formulation comprising valproic acid, a pharmaceutically acceptable salt, ester, or amide thereof, or divalproex sodium, in a lipid based sustained release formulation.
  • lipid based sustained release dosage forms have an improved pharmacokinetic profile and advantageously are able to deliver large dosage forms in acceptable pharmacokinetic rates.
  • These dosage forms minimize the variance between peak and trough plasma levels of valproate, resulting in a more desirable dosing plasma level that allows a reduction in the incidence of side effects.
  • valproic acid More commonly known as valproic acid (“VPA”) is effective as an antiepilpetic agent. After ingestion, the free acid dissociates to the valproate ion within the gastrointestinal tract. The valproate ion is absorbed and produces an antiepilpetic therapeutic effect. Physicians Desk Reference (“PDR”), 52 nd Edition, page 426 (2007). The acid moiety of valproic acid has been functionalized in order to produce prodrugs capable of generating a valproate ion in-vivo. For example, the amide of valproic acid, valpromide (“VPO”), has been produced, as well certain salts and esters of the acid.
  • VPO valpromide
  • valproate compounds have a relatively short half life.
  • the half life of valproic acid is reported to be between six and seventeen hours in adults and between four and fourteen hours in children. This leads to substantial fluctuations in the plasma concentration of the drug, especially in chronic administration and causes dosing problems resulting in an increase incident of side effects.
  • GI irritation is very common in patients consuming valproate, affecting almost one third of patients.
  • the problem with GI irritation and other common side effects increases at elevated doses.
  • Other side effects such as asthenia, dizziness, somnolence, alopecia, and weight gain are prevalent and like GI irritation increase at elevated doses.
  • U.S. Pat. No. 5,055,306 to Barry, et al. discloses an effervescent or water-dispersible granular sustained release formulation suitable for use with a variety of therapeutic agents.
  • the granules comprise a core comprising the active ingredient and at least one excipient, and a water ) insoluble, water-swellable coating comprising a copolymer of ethyl acrylate and methyl methacrylate and a water soluble hydroxylated cellulose derivative.
  • a sustained release dosage form comprising granules of divalproex sodium or amides or esters of valproic acid coated with a sustained release composition comprising ethyl cellulose or a methacrylic methyl ester, a plasticizer, a de-tackifying agent, and a slow-release polymeric viscosity agent.
  • a new oral sustained release formulation is disclosed.
  • Orally administered sustained release dosage forms of valproic acid (VPA), its sodium salt: sodium valproate (SVP), its primary amide: valpromide (VPD), and other derivatives of therapeutic value such as 2-propylpentanol-di-n-propylacetate, glycerol tri- dipropylacetate and di sodium valproate are provided.
  • the sustained release dosage forms of the active ingredient are based on a desired gradual release of the active ingredients in the biological fluids, resulting in a sustained action of the valproic acid with but small fluctuations of the plasma level over prolonged periods of time.
  • the sustained release of valproic acid results in desirable pharmacokinetics thereby improving patient compliance and reducing the incidence of side effects.
  • valproic acid is mixed with hydrophobic material like waxes, oil, lipids, fats, phospholipids, glycerides, vegetable oils, peanut oil, corn oil, soybean oil, esters, and other lipophillic material such as isopropyl monsterate, ethyl sterate, cetyl alcohol, stearyl alcohol and other fatty acids.
  • hydrophobic material like waxes, oil, lipids, fats, phospholipids, glycerides, vegetable oils, peanut oil, corn oil, soybean oil, esters, and other lipophillic material such as isopropyl monsterate, ethyl sterate, cetyl alcohol, stearyl alcohol and other fatty acids.
  • hydrophobic material like waxes, oil, lipids, fats, phospholipids, glycerides, vegetable oils, peanut oil, corn oil, soybean oil, esters, and other lipophillic material such as isopropyl monsterate, ethyl sterate, cetyl
  • the hydrophobic drug mixture also contains surfactants like Poloxamer 407, TPGS or other oil in water emulsifiers having HLPB values of about 6 to about 14. Without being bound to a particular theory, it is thought that this combination allows an active ingredient with the hydrophobic material to be solublized in an aqueous media, providing a sustained release of the active ingredient.
  • surfactants like Poloxamer 407, TPGS or other oil in water emulsifiers having HLPB values of about 6 to about 14.
  • the active ingredient within a hydrophobic material can be encapsulated in either a hard gelatin capsule or a soft gelatin capsule. It is contemplated within the scope of the disclosure that the active ingredient within a hydrophobic material can be combined with other active pharmaceuticals within a capsule in a capsule dosage form.
  • an active ingredient with the hydrophobic material is solubalized in an aqueous media leading to a formation of a micro-emulsion, which it is thought provides a more predictable absorption than prior forms of valproic acid or di-sodium valproate.
  • the pharmaceutical formulation according to the disclosure contains a pharmaceutical active ingredient from about 10 to about 80 by weight of the total formulation.
  • valproic acid which is liquid in nature, is formed into a semisolid gel using the hydrophobic material according to the disclosure. It is thought that the semisolid gel containing valproic acid is stable in a hard or soft gelatin capsule.
  • a pharmaceutical active ingredient with the hydrophobic material is solubalized in an aqueous media leading to a formation of a micro- emulsion, which it is thought provides a more predictable absorption of higher doses.
  • an active ingredient such as gabapentene in a place within the lipid sustained release form according to the disclosure including but not limited to doses of 900mg and 1200mg.
  • the active ingredient within a hydrophobic material can be encapsulated in either a hard gelatin capsule or a soft gelatin capsule. It is contemplated within the scope of the disclosure that the active ingredient within a hydrophobic material can be combined with other active pharmaceuticals within a capsule in a capsule dosage form. This active pharmaceutical within a capsule in a capsule dosage form can be utilized, among other dosage forms, to place a liquid active pharmaceutical or nutritional supplement with non compatible liquid or solid active pharmaceutical or nutritional supplement.
  • omega 3 is combined with aspirin.
  • omega 3 is combined with other cardiovascular products, like niacin in sustained release form.
  • FIG. 2A represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject;
  • FIG. 2B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.
  • FIG. 3A represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject;
  • FIG. 3 B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.
  • FIG. 4A represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject;
  • FIG. 4B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.
  • FIG. 5A represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject
  • FIG. 5B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.
  • FIG. 6A represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject;
  • FIG. 6B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.
  • FIG. 7A represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject;
  • FIG. 7B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.
  • FIG. 8A represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject;
  • FIG. 8B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject
  • FIG. 9A represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject;
  • FIG. 9B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.
  • FIG. 1OA represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject;
  • FIG. 1OB represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.
  • FIG. 1 IA represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject;
  • FIG. 1 1 B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.
  • FIG. 12A represents Individual Concentrations verses Time Curves for Valproic Acid formulation according to the disclosure (T) and Reference (R) Formulations on Linear Scale in a human subject
  • FIG. 12B represents Individual Concentrations verses Time Curves for Valproic Acid formulation according the disclosure (T) and Reference (R) Formulations on a Logarithmic Scale in a human subject;.
  • the amount of the hydrophobic material in the dosage form generally varies from about 10% to about 80% by weight of the composition. Preferably, the amount of hydrophobic material varies from about 25% to about 45% by weight of the dosage form. Most preferably, the amount of hydrophobic material varies from about 30% to about 40% by weight of the dosage form.
  • the formulation according to the disclosure also typically includes pharmaceutically acceptable excipients such as diluents or fillers.
  • Diluents, or fillers are added in order to increase the mass of an individual dose to a size suitable for the hard or soft gelatin capsule.
  • Suitable diluents or fillers include olive oil, vegetable oil such as castor oil, etc.
  • valproic acid is mixed with hydrophobic material like waxes, oil, lipids, fats, phospholipids, glycerides, vegetable oils, peanut oil, com oil, soybean oil, esters, and other lipophillic material such as isopropyl monsterate, ethyl sterate, cetyl alcohol, stearyl alcohol and other fatty acids.
  • oil used as a filler in the formulation. It is contemplated within the scope of the disclosure that other vegetable oils, plant oils and the like may be used as fillers in the formulation.
  • Hydrogenated castor oil is used in combination with a surfactant as a rate controlling agent. As it is known in the art, water penetrates castor oil slowly allowing active ingredients contained therein to be released in a gradual manner.
  • Poloxamer 407 a hydrophilic non- ionic surfactant of the more general class of copolymers known as poloxamers is used within the formulation for forming a micro-emulsion. It is a surfactant widely used for dissolving oily ingredients in water. Poloxamer 407 is a triblock copolymer consisting of two hydrophilic blocks (poly-ethylene glycol) separated by a hydrophobic block (poly-propylene glycol). The approximate lengths of the two PEG blocks is 101 repeat units while the approximate length of the propylene gycol block is 56 repeat units. This particular compound is also known by the BASF trade name Lutrol F- 127®.
  • Glyceryl Monooleate is added to the formulation.
  • Glyceryl monooleate is prepared by esterification of commercial oleic acid that is derived either from edible sources or from tall oil fatty acids. It contains glyceryl monooleate (C21H40O4, CAS Reg. No.25496-72 ⁇ 4) and glyceryl esters of fatty acids present in commercial oleic acid. It is a lipophilic emulsifier for water-in-oil applications. It is widely used as an excipient in antibiotics and other drugs. It is insoluble in water and it can form a micro-emulsion in water. The hydrophilic-lipophilic balance (HLB) is about 3.8.
  • an emulsifying agents can be used to solubilize oily substances in water.
  • a suitable emulsifier or a combination of emulsifiers can readily be made by those in the field.
  • Surfactants which may be used for this purpose have preferably HLB value of 1 to about 20. Examples of them are reaction products of natural or hydrogenated vegetable oils, and ethylene glycol; i.e., polyoxyethylene glycolated natural or hydrogenated vegetable oils: for example polyoxyethylene glycolated natural or hydrogenated castor oils.
  • Cremophor RH-40 Surfactants commercialized under the trade names Cremophor RH-40, Cremophor RH60, Cremophor EL, Nikkol HCO-40 and Nikkol HCo-60 may be used in the composition according to the present disclosure. Cremophor RH40 and Cremophor El are preferred.
  • polyoxyethylene sorbitan fatty acid esters e.g., mono- and tri-lauryl, palmityl, stearyl and oleyl esters; e.g. products of the trade name "Tween,” which includes polyoxyethylene sorbitan mono-laurate (Tween), polyoxyethylene sorbitan mono-palmitate (Tween 40), polyoxyethylene sorbitan mono-oleate (Tween 80), etc. depending on the kind of fatty acid.
  • Tween 20 and Tween 40 can be used preferably in the composition according to the present disclosure.
  • polyoxyethylene fatty acid esters for example, polyoxyethylene stearic acid esters of the type known and commercially available under the trade name Myrj as well as polyoxyethylene fatty acid esters known and commercially available under the trade name "Cetiol HE" can be used in the composition according to the present disclosure.
  • TPGS D-alpha-tocopheryl succinate
  • PEG polyethylene glycol
  • d-alpha-tocopherol comprises 26% of TPGS.
  • TPGS is also known as d-alpha-tocopheryl polyethylene glycol 1000 succinate and d-alpha- tocopheryl PEG 1000 succinate.
  • Alpha-tocopheryl polyethylene glycol succinate abbreviated as TPGS, is a water-soluble derivative of d-alpha-tocopheryl succinate.
  • TPGS is also known as d- alpha-tocopheryl polyethylene glycol 1000 succinate and d-alpha-tocopheryl PEG 1000 succinate. Since there are eight stereoisomers of alpha-tocopherol, the designation d-alpha- tocopherol, although commonly used, is chemically incorrect.
  • Correct chemical names for TPGS include RRR-alpha-tocopheryl polyethylene glycol 1000 succinate, 2R, 4'R, 8'R-alpha- tocopheryl polyethylene glycol 1000 succinate and 2, 5, 7, 8-tertramethyl-2-(4',8',12'- trimethyltridecyl)-6-chromanyl polyethylene glycol 1000 succinate.
  • the hydrophobic drug mixture also contains surfactants like Poloxamer 407, TPGS or other oil in water emulsifiers having HLPB values of about 6 to about 14.
  • surfactants like Poloxamer 407, TPGS or other oil in water emulsifiers having HLPB values of about 6 to about 14.
  • this first combination allows an active ingredient with the hydrophobic material to be solublized in an aqueous media, providing a sustained release of the active ingredient.
  • the active ingredient within a hydrophobic material can be encapsulated in either a hard gelatin capsule or a soft gelatin capsule. It is contemplated within the scope of the disclosure that the active ingredient within a hydrophobic material can be combined with other active pharmaceuticals within a capsule within a capsule dosage form.
  • excipients that may be incorporated into the formulation include preservatives, antioxidants, or other excipients commonly used in the pharmaceutical industry, etc.
  • the amount of excipients used in the formulation will correspond to that typically used in a gelatin capsule.
  • the total amount of excipients, fillers and extenders, etc. varies from about 10% to about 80% by weight of the dosage form.
  • compositions of the disclosure can be administered orally in the form of hard gelatin capsules or soft gelatin capsules.
  • the gelatin capsules can be prepared by techniques known in the art and contain a therapeutically effective amount of the valproate compound and such excipients as are necessary to form the capsule by such techniques.
  • the gelatin capsule can additionally be prepared with enteric coatings and other release-controlling coatings for the purpose of acid protection, easing swallow ability, etc.
  • the coating may be colored with a pharmaceutically accepted dye or pigment. The amount of dye and other excipients in the coating liquid may vary and will not impact the performance of the sustained release gelatin capsules.
  • the coating liquid generally comprises film forming polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose esters or ethers such as cellulose acetate or ethylcellulose, an acrylic polymer or a mixture of polymers.
  • the coating solution is generally an aqueous solution or an organic solvent further comprising propylene glycol, sorbitan monoleate, sorbic acid, fillers such as titanium dioxide, a pharmaceutically acceptable dye.
  • a gelatin capsule comprises from about 50 weight percent to about 55 weight percent of an active ingredient selected from the group consisting of valproic acid, a pharmaceutically acceptable salt or ester of valproic acid, divalproex sodium, and valpromide; from about 20 weight percent to about 40 weight percent of hydrophobic material; from about 5 weight percent to about 15 weight percent of fillers or diluents, from about 1 weight percent to about 6 weight percent of surfactants; and all weight percentages based upon the total weight of the gelatin capsule.
  • an active ingredient selected from the group consisting of valproic acid, a pharmaceutically acceptable salt or ester of valproic acid, divalproex sodium, and valpromide
  • hydrophobic material from about 5 weight percent to about 15 weight percent of fillers or diluents, from about 1 weight percent to about 6 weight percent of surfactants
  • the gelatin capsule according to the disclosure that meets the dissolution profile depicted in table 1 will provide two therapeutic goals. First, it will provide a dosage form of valproate that will maintain desired effective therapeutic levels of the valproate ion over a 24 hour dosing period, thus providing once daily dosing. Secondly, it will reduce the incidence of side effects associated with valproate therapy. Formulations matching the dissolutions profiles set forth in table 1 , will provide the pharmacokinetic profile described below.
  • the daily dosage form must reduce peak plasma levels of valproate ("C max ”) without significantly impacting either trough levels (“C 1111n ”) or the extent of valproate absorption
  • C max for the daily dosage form should be statistically significantly lower than the C ma ⁇ for a bid dosage form of the same valproate compound, when each is measured at steady state in a fasting population.
  • a once-a-day sustained release divalproex sodium dosage form will exhibit a C max that is statistically significantly lower than that produced by a divalproex sodium delayed release tablet, when each is measured at steady state in a fasting population.
  • peak plasma levels of valproate are reduced at least 10%. More typically, these peak plasma levels are reduced up to about 20%. This reduction must be accomplished with out any significant reduction in trough levels or total absorption of valproate.
  • C m! for the daily dosage form should not be statistically significantly different from that obtained with a bid dosage form of the same valproate compound, when each is determined at steady state in a fasting population. More specifically, C 1111n for a once-day sustained release divalproex sodium dosage form should not be statistically significantly different from that obtained with a delayed release divalproex sodium tablet when each is measured at steady state in a fasting population.
  • Soft gelatin capsule shell is gelatin based (TSE/BSE free)
  • the dissolution test in 45 minutes in acid is about 0-10%. In alkaline conditions the dissolution test in 45 minutes is about 0-20%
  • Table 4 is a summary of pharmacokinetic values for the test formulation under fasting conditions.
  • Table 5 is a summary of concentration at time intervals for the test formulation under fasting conditions.
  • valproate compounds in a lipid based formulation
  • other active pharmaceutical agents can be used in combination with the valproate compounds.
  • other active pharmaceutical compounds would benefit from these disclose lipid based delivery system including but not limited to active pharmaceuticals such as gabapentene.
  • valproate compounds in a lipid based formulation in a soft for hard gelatin capsule
  • other active pharmaceutical agents can be used in combination with the valproate compounds within the same gelatin capsule in within a further capsule within the capsule.
  • other active pharmaceutical compounds that would benefit from a combination therapy with the valproate compounds, but are incompatible in the same dosage form could benefit from a capsule in a capsule formulation.
  • valproate compounds in a lipid based formulation in a soft for hard gelatin capsule
  • other active pharmaceutical agents can be used in the lipid based formulation according to the invention.
  • other active pharmaceutical compounds that would benefit from a combination therapy, but are incompatible in the same dosage form could benefit from a capsule in a capsule formulation.
  • incompatible liquids or incompatible solids and liquid pharmaceuticals will benefit from the lipid based formulation according to the disclosure and the use of capsule within capsule dosage form.

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Abstract

La présente invention concerne une formulation pharmaceutique qui permet une libération prolongée de formes posologiques d'acide valproïque (VPA), de ses esters, ses sels ou son amide primaire, associés à une quantité prédéfinie d'un ou de plusieurs adjuvants qui sont physiologiquement acceptables. La formulation permet une libération souhaitée, graduelle et prolongée, du médicament. L'acide valproïque est mélangé avec un matériau hydrophobe tel que cires, huiles, lipides, graisses, phospholipides, glycérides, huiles végétales, huile d'arachide, huile de maïs, huile de soja, avec des esters, et avec un autre matériau lipophile tel que monostéarate d'isopropyle, stéarate d'éthyle, alcool cétylique, alcool stéarylique et autres acides gras. Il peut également être utilisé avec des combinaisons de ces produits, ou combiné à d'autres acides gras connus dans la technique.
PCT/US2008/069798 2007-07-12 2008-07-11 Formulation à libération prolongée de produits pharmaceutiques actifs pour une libération prolongée à base de lipides WO2009009737A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020072601A1 (fr) * 2018-10-02 2020-04-09 Frequency Therapeutics, Inc. Compositions pharmaceutiques comprenant des agents thérapeutiques otiques et procédés associés
US11033546B2 (en) 2016-03-02 2021-06-15 Frequency Therapeutics, Inc. Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using a GSK3 inhibitor: I
US11160868B2 (en) 2016-03-02 2021-11-02 Frequency Therapeutics, Inc. Thermoreversible compositions for administration of therapeutic agents
CN114209667A (zh) * 2016-04-08 2022-03-22 赛伦诺科技有限公司 包含丙戊酸的延迟释放药物制剂和其用途

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US20070020213A1 (en) * 2002-10-25 2007-01-25 Foamix Ltd. Foamable composition combining a polar solvent and a hydrophobic carrier
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11033546B2 (en) 2016-03-02 2021-06-15 Frequency Therapeutics, Inc. Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using a GSK3 inhibitor: I
US11160868B2 (en) 2016-03-02 2021-11-02 Frequency Therapeutics, Inc. Thermoreversible compositions for administration of therapeutic agents
CN114209667A (zh) * 2016-04-08 2022-03-22 赛伦诺科技有限公司 包含丙戊酸的延迟释放药物制剂和其用途
WO2020072601A1 (fr) * 2018-10-02 2020-04-09 Frequency Therapeutics, Inc. Compositions pharmaceutiques comprenant des agents thérapeutiques otiques et procédés associés
WO2020072602A1 (fr) * 2018-10-02 2020-04-09 Frequency Therapeutics, Inc. Compositions pharmaceutiques comprenant des agents thérapeutiques otiques et procédés associés

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