WO2010075275A1 - Libération sélective de mélanges non racémiques de deux énantiomères à partir de comprimés et de capsules - Google Patents

Libération sélective de mélanges non racémiques de deux énantiomères à partir de comprimés et de capsules Download PDF

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Publication number
WO2010075275A1
WO2010075275A1 PCT/US2009/068974 US2009068974W WO2010075275A1 WO 2010075275 A1 WO2010075275 A1 WO 2010075275A1 US 2009068974 W US2009068974 W US 2009068974W WO 2010075275 A1 WO2010075275 A1 WO 2010075275A1
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Prior art keywords
lofexidine
dosage form
enantiomers
release
fluoxetine
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PCT/US2009/068974
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English (en)
Inventor
George A. Digenis
Abeer M. Al-Ghananeem
Ahmad Malkawi
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Usworldmeds Llc
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Publication of WO2010075275A1 publication Critical patent/WO2010075275A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • the stereoisomers are compounds containing the same number and kind of atoms involving the same arrangement of bonds but possessing a different three-dimensional arrangement.
  • stereoisomers There exist two kinds of stereoisomers: enantiomers and diastereoisomers.
  • Enantiomers are compounds whose three-dimensional arrangements of atoms are such that they are non-superimposable mirror images.
  • the enantiomers possess identical physico-chemical properties but only differ in their behavior in changing the rotation of polarized light. As a consequence they can usually be separated by using methods providing a chiral environment or they may be converted to disastereomers by conjugation with other optically active molecules (e.g., by salt formation with another optically active compounds). Diastereoisomers possess different physico-chemical properties and therefore can be separated by a variety of techniques.
  • Chirality is an essential property of biologic systems.
  • drug-receptor interactions have been recognized to be stereoselective. These interactions are recognized to contribute to the clinically observed stereoselectivity of several drugs.
  • the nature of the stereochemical drug-receptor interactions many times influences both the pharmacokinetic and pharmacodynamic processes of drugs.
  • enantiomers may differ quantitatively in their pharmacologic activities. In fact, in some extreme cases, one enantiomer maybe devoid of pharmacologic activity. Alternatively, two enantiomers may differ qualitatively in their pharmacologic activities and may exhibit different activities at the same or different receptors. See Triggle, DJ.
  • This enantiomer appears to have three of its chemical functions interact with their complementary binding sites of the receptor surface that is responsible for producing the necessary interactions that result in the stimulation of the receptor.
  • its mirror image enantiomer, S- (+)-epinephrine exhibits two interaction sites with the receptor and as a consequence can not interact properly with the receptor responsible for vasopressor activity.
  • Not all stereoselectivity of enantiomers can be attributed to differences in reactivity at the receptor site. Differences in biologic activity between enantiomers could also be attributed to selective penetration of membranes, absorption and rate of metabolism. Thus, one enantiomer could be metabolized faster than its other enantiomer.
  • the enantiomer that is rapidly metabolized could remain intact for a longer period of time, particularly if delivered from the slow releasing compartment of a two- layer tablet or two-compartment gelatin capsule.
  • both enantiomers are metabolized at an equal rate, it follows that the less active isomer could be incorporated into the immediate releasing compartment of the tablet or gelatin capsule. In this way it could slow down the drug metabolizing process in the liver allowing the more active enantiomer to survive intact longer in the body if delivered from the slow releasing component of a tablet or gelatin capsule. This would result in the prolongation of pharmacologic activity of the drug.
  • a two-layer tablet or two-component capsule may prove advantageous in delivering two enantiomers with different metabolic rates or different qualitative or quantitative pharmacologic activity.
  • Multiple compressed tablets can be prepared by the use of more than a single compression. In this way, multiple-layered tablets or a tablet- within-a-tablet may be manufactured.
  • Two-layered tablets are prepared by an initial compaction of a portion of a fill material (one of the enantiomers) in a die, along with one or more portions of fill material (excipients) to the same die.
  • An additional fill containing the second enantiomer and excipients is subsequently being compressed to form a two- or three-layered tablet.
  • the present invention relates generally to compositions and methods for delivering enantiomers in non-racemic mixtures (in ratios ranging from greater than zero to less than one hundred) contained in tablets and capsules to subjects.
  • the invention provides for the delivery of different ratios of two enantiomers by two types of drug formulations.
  • the formulations are contained in a bilayer tablet or a two- compartment capsule made from gelatin, hydroxypropylmethylcellulose (HPMC) or other capsule shell composition.
  • the invention provides for a pharmaceutical dosage form for administration of one enantiomer is in immediate-release form and another enantiomer is in a sustained-, or controlled-, release form.
  • one type of dosage form provides one enantiomer in an excess of at least 70% by weight with respect to the other enantiomer.
  • one enantiomer is preferably in an excess of at least 80%.
  • one enantiomer is preferably in an excess of at least 90%, or higher.
  • one type of dosage form comprises a capsule containing two sets of multiparticulates having different release rates, one set containing the (+)-enantiomer and the other set containing the (-)- enantiomer.
  • the multiparticulates themselves can be made by any of the conventional methods, including extrusion spheronization, high shear granulation, non-pareil seeds, etc.
  • the rates at which the different enantiomers are released from the multiparticulates can be achieved using any conventional controlled-release mechanism, for instance, matrix (i.e., erosion diffusion), coating, or osmotic. Dosage forms of this type are suitable for oral and rectal use.
  • Another type of dosage form comprises two tablets, i.e.
  • the two tablets having different release rates.
  • conventional control-release technology can be used to achieve the desired effect.
  • two tablets having different release coatings or matrices may be used, or two osmotic pump tablets having different pumping rates. The tablets can then be administered in sequence, or they can be filled into a capsule for dosing simultaneously.
  • Another type of dosage form comprises an osmotic pump tablet comprising two distinct portions, typically two layers, one portion containing and pumping the (+)-enantiomer at one rate, and the other portion containing and pumping the (-)-enantiomer at another rate.
  • Another type of dosage form comprises a bi-layered tablet, one layer containing the (+)-enantiomer and the other layer containing the (-)- enantiomer, the two layers having different release rates for their respective enantiomers.
  • conventional control-release technology can be used to achieve the desired effect.
  • bi-layered tablet may have (-)-fluoxetine in an outer layer as a starter treatment, leading on to release of (+)-fluoxetine from the core which would provide maintenance therapy.
  • Another example of a bilayered tablet may have (+)-lofexidine in an outer layer as a starter treatment, and (-)-lofexidine in a core for maintenance therapy.
  • Different percentages of the individual enantiomers could be used in different tablet preparations so that doses could be titrated for individuals.
  • Another type of dosage form comprises a compressed coat tablet having a core containing one of the (+)- and (-)-enantiomers and, surrounding the core, a shell containing the other of the (+)- and (-)-enantiomers, the core and shell having different release rates for their respective enantiomers.
  • Another type of dosage form comprises a patch for placing adjacent a patient's skin, the patch comprising two distinct portions, one portion containing the (+)-enantiomer and the other portion containing the (-)- enantiomer, the two portions having different release rates for their respective enantiomers.
  • two separate patches maybe used, i.e., as a combined product (kit), one patch containing the (+)-enantiomer and the other patch containing the (-)-enantiomer, the two patches having different release rates.
  • Another type of dosage form comprises a polymer implant comprising two distinct portions, one portion containing the (+)-enantiomer and the other portion containing the (-)-enantiomer, the two portions having different release rates for their respective enantiomers.
  • two separate polymer implants maybe used, i.e. as a combined product (kit), one implant containing the (+)-enantiomer and the other implant containing the (-)-enantiomer, the two implants having different release rates.
  • Another type of dosage form comprises an aerosol containing two sets of microparticles having different release rates, one set containing the (+)- enantiomer and the other set containing the (-)-enantiomer.
  • two separate aerosols may be used, one for each enantiomer, i.e. as a combined product (kit), the microparticles of each aerosol having different release rates.
  • dosage form may be for administration by inj ection.
  • different release rates of the different enantiomers may be achieved by means of, for example, liposomes or microparticulates .
  • the two enantiomers are effectively dosed separately, it is essential that they are provided in a form that is not harmful to the prospective patient. If they are provided in salt form, both salts should preferably be stable and non-hygroscopic.
  • the dosage forms of the present invention can be used in the treatment of conditions for which the chiral drug is usually administered, particularly in patients disposed to, or who may be put at risk by exposure to, an adverse side effect.
  • the pharmaceutical dosage form comprises two enantiomers contained in a bilayer tablet or a two-compartment capsule.
  • the latter may be made from gelatin, hydroxypropylmethylcellulose (HPMC) or any other commonly-used capsule shell composition.
  • HPMC hydroxypropylmethylcellulose
  • the two-layer tablet could have an inner core of one enantiomer and a shell around it with the other enantiomer. Alternatively, it could have two layers, one on top of the other, each layer containing one of the two enantiomers.
  • the tablet or capsule will contain a slow and a rapid releasing compartment.
  • the ratio of the two enantiomers contained in the bilayer tablets or capsules, described in claims 2 and 3, ranges from greater than zero to less than one hundred.
  • the dosage comprises a non-racemic mixture of two enantiomers that are metabolized at an equal rate such that the less active enantiomer is incorporated into the immediate releasing compartment of the tablet or capsule.
  • the active enantiomer is incorporated in the slow releasing compartment of the tablet or capsule.
  • the ratio of the weight of the two enantiomers in the slow and rapid releasing compartment could range from greater than zero to less than 100.
  • the slow releasing compartment of the bilayer tablet is an inner core, or one of the two layers of the bilayer tablet.
  • This compartment can be composed of polyvinylpyrrolidone (PVP), lactose, dicalcium phosphate stearic acid, HPMC and one of the enantiomers.
  • the immediate release compartment would be an outer layer, or a second layer, of the bilayer tablet composed of PVP, HPMC, talco, Tween 80, Carbowax 1450 and one of the two enantiomers (see Table 1).
  • the slow releasing compartment of the capsule is in a form of pellets composed of PVP, dicalcium phosphate, stearic acid, HPMC and one of the enantiomers.
  • the immediate release section of the capsule could be in the form of a powder or in a multiparticulate form composed of PVP, HPMC, talc, Tween 80, Carbowax 1450 and the other one of the two enantiomers (see Table 2).
  • inventions include methods of treating a medical condition in a patient that involve administering a therapeutically effective amount of a pharmaceutical composition of the invention where the condition is amenable to treatment with the pharmaceutical composition.
  • compositions or pharmaceutical preparations of the invention in the manufacture of a medicament for the treatment of a medical condition, as defined herein, in a patient that involve administering a therapeutically effective amount of a pharmaceutical composition of the invention where the condition is amenable to treatment with the pharmaceutical composition.
  • compositions of the invention are in combination with one or more additional therapeutic agents where the additional agent is given prior, concurrently, or subsequent to the administration of the pharmaceutical composition of the invention.
  • These methods may employ the compounds of this invention in a monotherapy or in combination one or more additional therapeutic agents.
  • Such combination therapies include administration of the agents in a single dosage form or in multiple dosage forms administered at the same time or at different times.
  • the present invention also provides a novel process for preparing the novel formulations of the invention.
  • the present invention further provides a method of treating an animal, particularly a human in need of treatment utilizing the active agents, comprising administering a therapeutically effective amount of composition or solid oral dosage form according to the invention to provide administration of active ingredients.
  • a - fast releasing and B slow releasing compartments.
  • Figure 6 shows the in vitro release profile of lofexidine enantiomers from the individual compartments of a multilayer tablet (two immediate releasing layers and one slow releasing layer) in phosphate buffer, 37 ⁇ 0.5 0 C, pH 6.8. Mean ⁇ SD (n - 3).
  • Figure 9 shows the dissolution of fluoxetine capsules in alkaline media
  • Figure 10 shows the dissolution of fluoxetine capsules in acidic media
  • Figure 11 shows the dissolution (profile I) of lofexidine capsules in alkaline media.
  • Figure 12 shows the dissolution Dissolution (profile II) of lofexidine capsules in acidic media.
  • administration of the pharmaceutically active compounds and the pharmaceutical compositions defined herein includes systemic use, as by injection (especially parenterally), intravenous infusion, suppositories and oral administration thereof, as well as topical application of the compounds and compositions. Intravenous administration is particularly preferred in the present invention.
  • “Ameliorate” or “amelioration” means a lessening of the detrimental effect or severity of the disease in the subject receiving therapy, the severity of the response being determined by means that are well known in the art.
  • ком ⁇ онент herein is meant that the components of the compositions which comprise the present invention are capable of being commingled without interacting in a manner which would substantially decrease the efficacy of the pharmaceutically active compound under ordinary use conditions.
  • the terms "effective amount” or “pharmaceutically effective amount” refer to a nontoxic but sufficient amount of the agent to provide the desired biological result. That result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, such as neural diseases and malignant hyperthermia, or any other desired alteration of a biological system. Such amounts are described below. An appropriate "effective" amount in any individual case maybe determined by one of ordinary skill in the art using routine experimentation.
  • excipient means the substances used to formulate active pharmaceutical ingredients (API) into pharmaceutical formulations; in a preferred embodiment, an excipient does not lower or interfere with the primary therapeutic effect of the API. Preferably, an excipient is therapeutically inert.
  • excipient encompasses carriers, diluents, vehicles, solubilizers, stabilizers, bulking agents, acidic or basic pH-adjusting agents and binders. Excipients can also be those substances present in a pharmaceutical formulation as an indirect or unintended result of the manufacturing process. Preferably, excipients are approved for or considered to be safe for human and animal administration, i.e., GRAS substances (generally regarded as safe).
  • the excipients include, but are not limited to, hexitols, including mannitol and the like as well as sodium or potassium hydroxides (NaOH or KOH) and mixtures thereof.
  • the terms “formulate” refers to the preparation of a drug, e.g., dantrolene, in a form suitable for administration to a mammalian patient, preferably a human.
  • formulation can include the addition of pharmaceutically acceptable excipients, diluents, or carriers and pH adjusting agents.
  • pharmaceutically acceptable or “pharmacologically acceptable” is meant a material which is not biologically or otherwise undesirable, i.e., the material may be administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • a "pharmaceutically acceptable carrier” is a material that is nontoxic and generally inert and does not affect the functionality of the active ingredients adversely.
  • examples of pharmaceutically acceptable carriers are well known and they are sometimes referred to as dilutents, vehicles or excipients.
  • the carriers maybe organic or inorganic in nature.
  • Examples of pharmaceutically acceptable carriers that may be present in the present lyophilized formulations maybe gelatin, lactose, starch, cocoa butter, dextrose, sucrose, sorbitol, mannitol, gum acacia, alginates, cellulose, talc, magnesium stearate, polyoxyethylene sorbitan monolaurate, polyvinylpyro-lidone (PVP) and other commonly used pharmaceutical carriers.
  • the pharmaceutical carrier comprises mannitol.
  • the formulation may contain minor amounts of pH adjusting agents such as sodium hydroxide (NaOH) additives such as flavoring agents, coloring agents, thickening or gelling agents, emulsifiers, wetting agents, buffers, stabilizers, and preservatives such as antioxidants.
  • pH adjusting agents such as sodium hydroxide (NaOH) additives such as flavoring agents, coloring agents, thickening or gelling agents, emulsifiers, wetting agents, buffers, stabilizers, and preservatives such as antioxidants.
  • physiological pH or a “pH in the physiological range” is meant a pH in the range of approximately 7.2 to 8.0 inclusive, more typically in the range of approximately 7.2 to 7.6 inclusive.
  • composition shall mean a composition that is made under conditions such that it is suitable for administration to humans, e.g., it is made under GMP conditions and contains pharmaceutically acceptable excipients, e.g., without limitation, stabilizers, pH adjusting agents such as NaOH, bulking agents, buffers, carriers, diluents, vehicles, solubilizers, and binders.
  • pharmaceutical composition includes but is not limited to a pre- lyophilization solution or dispersion as well as a liquid form ready for injection or infusion after reconstitution of a lyophilized preparation.
  • a “pharmaceutical dosage form” as used herein means the pharmaceutical compositions disclosed herein being in a container and in an amount suitable for reconstitution and administration of one or more doses, typically about 1-2, 1-3, 1-4, 1-5, 1-6, 1-10, or about 1-20 doses.
  • a “pharmaceutical dosage form” as used herein means a lyophilized pharmaceutical composition disclosed herein in a container and in an amount suitable for reconstitution and delivery of one or more doses, typically about 1-2, 1-3, 1-4, 1-5, 1-10, 1-20, or about 1-30 doses.
  • the pharmaceutical dosage form can comprise a vial or syringe or other suitable pharmaceutically acceptable container.
  • the pharmaceutical dosage form suitable for injection or infusion use can include sterile aqueous solutions or dispersions or sterile powders comprising an active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions.
  • the ultimate dosage form should be sterile, free of endotoxins and particulates, within the USP requirements, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol such as glycerol, propylene glycol, or liquid polyethylene glycols and the like, vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • stable pharmaceutical composition any pharmaceutical composition having sufficient stability to have utility as a pharmaceutical product.
  • the shelf-life or expiration can be that amount of time where the active ingredient degrades to a point below 90% purity.
  • stable pharmaceutical composition includes reference to pharmaceutical compositions with specific ranges of impurities as described herein.
  • the term "subject” encompasses mammals and non- mammals.
  • mammals include, but are not limited to, any member of the Mammalia class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non-mammals include, but are not limited to, birds, fish and the like. The term does not denote a particular age or sex.
  • the terms "treating" or "treatment” of a disease include preventing the disease, i. e. preventing clinical symptoms of the disease in a subject that maybe exposed to, or predisposed to, the disease, but does not yet experience or display symptoms of the disease; inhibiting the disease, i.e., arresting the development of the disease or its clinical symptoms, such as by suppressing hyperthermia; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • vial refers to any walled container, whether rigid or flexible.
  • the invention provides for stable, pharmaceutically acceptable compositions prepared from an active pharmaceutical agent.
  • the invention provides formulations for that can be used to deliver in vivo two enantiomers in non-racemic mixtures (i.e., not in a 50:50 racemic mixture).
  • the formulations described herein include compositions of two-layer (bilayer) tablets and two-compartment capsules (gelatin, HPMC or any other capsule shell composition).
  • Each of the types of drug formulations (tablets and capsules) described contains releasing compartments.
  • the releasing compartments have different release times.
  • a pharmaceutical dosage form comprises, in one portion thereof, a substantially single (+)- enantiomer of lofexidine and , in another, separate, portion thereof, a substantially single (-)-enantiomer of the drug, wherein, in use, the different enantiomers are released at different rates from the dosage form.
  • a pharmaceutical dosage form comprises, in one portion thereof, a substantially single (+)-enantiomer of fluoxetine and , in another, separate, portion thereof, a substantially single (-)-enantiomer of the drug, wherein, in use, the different enantiomers are released at different rates from the dosage form.
  • the present invention covers any dosage form in which the two enantiomers are physically separated, or compartmentalized, so as to achieve different release rates of the different enantiomers.
  • separation, or compartmentalization may be on a macro-scale, for instance with the different enantiomers being incorporated into separate dosage forms for simultaneous or sequential administration, i.e. as a kit, or separation of the different enantiomers may be on a micro-scale, for instance with the different enantiomers being present within the same dosage form and despite their physical separation being intimately mixed, or somewhere intermediate the two.
  • substantially single enantiomer as used herein means that one enantiomer is in an excess of at least 70% by weight with respect to the other enantiomer, and is preferably in an excess of at least 80%, and more preferably 90%, or higher.
  • a non-racemic ratio of enantiomers typically means that both enantiomers are present, with either enantiomer being present in an amount in excess of that of the other enantiomer, or vice versa.
  • a number of release profiles for the different enantiomers of a chiral drug may be realized by way of the dosage forms of the present invention.
  • a dosage form may be designed to allow immediate release of one enantiomer and sustained, or controlled, release of the other enantiomer.
  • immediate release typically we mean that release of the respective enantiomer occurs substantially immediately or after only a short delay, usually no more than five to ten minutes, after administration of the dosage form, and continues usually over a period of up to one to two hours.
  • sustained, or controlled, release typically we mean that release of the respective enantiomer is delayed usually for at least one hour and frequently longer, for instance for two or more hours, after administration of the dosage form.
  • the sustained, or controlled, release may be constant or variable throughout the treatment period.
  • the dosage forms of the present invention may be designed to release either of the enantiomers faster than the other, or before the other, depending upon the condition to be treated, or the patient type. It may be desirable to maintain a constant ratio of the separate enantiomers at the target tissue over a specified period of time, for instance at least 8 hours a day, preferably at least 12 hours a day, most preferably 24 hours a day. The ratio maintained maybe 50:50, or a non-racemic ratio in which either the amount of one enantiomer is greater than the other enantiomer, or vice versa. [0082] Another option would be to vary the ratio of the two enantiomers throughout the treatment period, or at least for a portion of that period.
  • the release rate of either or both enantiomers can be arranged to vary, so that either the relative proportion of one enantiomer or of the other increases, or decreases, with time.
  • the latter may be achieved, for instance, by using a number of different release coatings for the respective enantiomer.
  • the present invention may have particular application in the administration of fluoxetine and lofexidine.
  • Tables 1 and 2 are specifically useful for enantiomers of water soluble drugs that exhibit qualitative and/or quantitative differences in their pharmacologic activity and rates of metabolic degradation.
  • the enantiomers of several drugs exhibit such differences in their pharmacologic activity, hi one embodiment, these drugs include propranolol, verapramil, epinephrine, fluoxetine, lofexidine and others.
  • Coated dosage forms have also been suggested for delivery of a controlled amount of a beneficial agent over a prolonged period of time.
  • U.S. Pat. No. 5,256,440 describes a process for producing a film coated dosage form. A continuous groove is inscribed in a dosage form core. Coated tablets for constant and prolonged drug release are described by Conte et al in J. Controlled Release, Vol. 26, (1993) pages 39-47.
  • GEOMATRIX Systems are swellable matrices that are coated or tableted with polymeric barrier layers. Release performances of the systems are modulated as a result of the restriction of the releasing surface by the polymeric barrier layer coatings. As the extent of coating of the system's surface is increased, the release kinetics of the system shift toward constant release.
  • These systems are further described in U.S. Pat. No. 4,839,177 to Colombo et al. Additional systems are further described in U.S. Pat. Nos. 6,733,784, 6,635,281 and 6,316,028.
  • a composition or preparation administered to subjects for the treating and/or prevention of, or for reducing the predisposition to, diseases and conditions related thereto can also comprises one or more pharmaceutically acceptable adjuvants, carriers and/or excipients.
  • Pharmaceutically acceptable adjuvants, carriers and/or excipients are well known in the art, for example as described in the Handbook of Pharmaceutical Excipients, second edition, American Pharmaceutical Association, 1994 (incorporated herein by reference).
  • the enantiomers can be administered in the form of tablets, capsules, powders for reconstitution, syrups, food (such as food bars, biscuits, snack foods and other standard food forms well known in the art), or in drink formulations. Drinks can contain flavoring, buffers and the like.
  • a composition of the invention can include one suitable for oral, rectal, optical, buccal (for example sublingual), parenteral (for example subcutaneous, intramuscular, intradermal and intravenous) and transdermal administration.
  • buccal for example sublingual
  • parenteral for example subcutaneous, intramuscular, intradermal and intravenous
  • transdermal administration The most suitable route in any given case will depend on the nature and severity of the condition being treated and the state of the patient.
  • the invention also includes articles of commerce comprising the pharmaceutical compositions of the present invention.
  • the article of commerce can be a food, including a beverage, and a health or personal care product,
  • a composition of the present invention can include other cosmetic and pharmaceutical actives and excipients.
  • suitable cosmetic and pharmaceutical agents include, but are not limited to, antifungals, vitamins, anti-inflammatory agents, antimicrobials, analgesics, nitric oxide synthase inhibitors, insect repellents, self-tanning agents, surfactants, moisturizers, stabilizers, preservatives, antiseptics, thickeners, lubricants, humectants, chelating agents, skin penetration enhancers, emollients, fragrances and colorants.
  • Example compositions according to the present invention can comprise one or more pharmaceutically-acceptable or industrial standard fillers.
  • the filler must not be deleterious to a subject treated with the composition.
  • the filler can be solid or a liquid, or both.
  • the filler can be formulated with the active enantiomers as a unit-dose, for example a tablet, which can typically contain from about 10% to 80% by weight of enantiomers.
  • Compositions can be prepared by any of the well known techniques of pharmacy, for example admixing the components, optionally including excipients, diluents (for example water) and auxiliaries as are well known in the pharmaceutical field.
  • compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the extract; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil- in- water or water-in-oil emulsion.
  • Such compositions can be prepared by any suitable method of pharmacy which includes the step of bringing into association the active enantiomers and one or more suitable carriers (which can contain one or more accessory ingredients as noted above).
  • compositions of the invention are prepared by uniformly and intimately admixing the enantiomers with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture.
  • a tablet can be prepared by comprising or molding a powder or granules containing the extract, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine, the extracts in the form of a powder or granules optionally mixed with a binder, lubricant, inert diluents, and/or surface active/dispersing agent(s). Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
  • Suitable fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylceullose and/or polyvinylpyrrolidone, and, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate.
  • sugars for example lactose, saccharose, mannitol or sorbitol
  • cellulose preparations and/or calcium phosphates for example tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch pastes using, for example, corn, wheat, rice or potato
  • Excipients can be flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable, optionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which can comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulosephthalate. Dyes or pigments can be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredients.
  • compositions are dry-filled capsules made, for example, of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the dry-filled capsules can comprise the extracts in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glicants, such as talc or magnesium stearate, and, where appropriate, stabilizers.
  • the extract is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilizers can also be added.
  • Formulations suitable for buccal (sublingual) administration include lozenges comprising the extracts in a flavored-base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These can be prepared by admixing the isoflavones with one or more conventional solid carriers, for example cocoa butter, and then shaping the resulting mixture.
  • the outer portion of the present invention may comprise auxiliary excipients such as for example lubricants, plasticizers, anti-tack agents, opacifying agents, pigments, and such like.
  • auxiliary excipients such as for example lubricants, plasticizers, anti-tack agents, opacifying agents, pigments, and such like.
  • Suitable lubricants including agents that act on the flowability of the powder to be compressed are, for example, colloidal silicon dioxide such as Aerosil 200 (Aerosil is a Trade Mark); talc; stearic acid, magnesium stearate, calcium stearate and sodium stearyl fumarate.
  • colloidal silicon dioxide such as Aerosil 200 (Aerosil is a Trade Mark)
  • talc stearic acid, magnesium stearate, calcium stearate and sodium stearyl fumarate.
  • the release controlling agents are pharmaceutically excipients, which are hydrophobic in nature.
  • the polymers that can be used to form the rate-controlling membrane or micromatrix are described in greater detail herein below.
  • the hydrophobic release controlling agents are selected from but are not limited to Ammonio methacrylate copolymers type A and B as described in USP, methacrylic acid copolymer type A, B and C as described in USP, Polyacrylate dispersion 30% as described in Ph.
  • Polyvinyl acetate dispersion ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), and poly(hexyl methacrylate).
  • waxes such as beeswax, carnauba wax, microcrystalline wax, and ozo
  • the release controlling agent contains ammonio methacrylate co-polymers and fatty acid esters as hereinafter described.
  • the suitable hydrophobic agents are polymers sold under the Trade Mark
  • Eudragit RS Ammonio Methacrylate Copolymer type B USP
  • Eudragit NE 3OD Polyacrylate dispersion 30% Ph., Eur.
  • Eudragit RL Ammonio Methacrylate Copolymer type A USP
  • Kollicoat SR 30 D fatty acid esters such as glyceryl behenate, and hydrogenated castor oil.
  • Eudragit polymers are polymeric lacquer substances based on acrylate and/or methacrylates.
  • the dosage form can also include one or more commonly used excipients in oral pharmaceutical formulations.
  • Representative commonly used excipients in oral pharmaceutical formulations include talc, fumed silica, glyceryl monostearate, magnesium stearate, calcium stearate, kaolin, colloidal silica, gypsum, Tween 80, Geleol pastiles (trade mark), micronised silica and magnesium trisilicate.
  • the quantity of commonly used excipients in oral pharmaceutical formulations used is from about 2% to about 500% by weight, preferably from 2 to 100% more particularly 10 to 60% based on the total dry weight of the polymer.
  • the dosage form can also include a material that improves the processing of the release controlling agents.
  • materials are generally referred to as "plasticizers" and include, for example, adipates, azelates, benzoates, citrates, isoebucaes, phthalates, sebacates, stearates, tartrates, polyhydric alcohols and glycols.
  • plasticizers include acetylated monoglycerides; butyl phthalyl butyl gylcolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate,; ethyl phthalyl ethyl glycolate; glycerin; ethylene glycol, propylene glycol; Triethyl citrate; triacetin; tripropinoin; diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols; castor oil; triethyl citrate; polyhydric alcohols, acetate esters, glycerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, e
  • the amount of plasticizer to be used is from about 1% to 50% based on the weight of the dry release controlling agent(s).
  • the amount of release controlling agent(s) to be used in forming the outer portion will be determined based on various parameters such as the desired delivery properties, including the amount of active ingredient to be delivered, the active ingredient release rate desired, and the size of the micro matrix particles. [00107] Examples
  • Figure 1 shows the release profile of iodine (PVP-I) from the individual compartments of the bilayer tablet.
  • Figure 2 describes the release profile of iodine (PVP-I) from the two compartments of a 000 size gelatin capsule or any other capsule with a different shell composition.
  • the iodine release studies were conducted at 37°C in phosphate buffer (pH 5.0).
  • Table 1 Bilayer Tablet composition utilized in in vitro release kinetic study, in phosphate buffer.
  • Inner Core (or % slow releasing tablet layer)
  • PVPZI Polyvinylpyrrolidone-iodine (Povidone-iodine)
  • HPMC Hydroxypropylmethylcellulose, Methocel El 5 LV
  • Tween 80 Polyoxyethylene sorbitan monostearate
  • Carbowax Polyethylene glycol Mw 1450
  • PVP/I Polyvinylpyrrolidone-iodine (Povidone-iodine)
  • Table 3 Composition of bilayer tablet, consisting of a core and an outer layer, composition utilized in the in vitro release kinetics of Lofexidine enantiomers in simulated gastric juice and simulated intestinal juice.
  • the weight of the tablets (6mm x 10 mm) was 422 ⁇ 11 mg (mean ⁇ SD).
  • Table 4 Composition of bilayer tablet, consisting of two layers casted on top of each other, utilized in the in vitro release kinetics of Lofexidine HCl enantiomers in simulated gastric juice and simulated intestinal juice.
  • the weight of the tablets (6mm x 10 mm) was 283 ⁇ 14 mg (mean ⁇ SD).
  • Table 5 Composition of multilayer tablet, consisting of two immediate releasing layers and one slow releasing layer, utilized in the in vitro release kinetics of Lofexidine HCl enantiomers in simulated gastric juice and simulated intestinal juice.
  • the weight of the tablets (6mm x 10 mm) was 432 ⁇ 16 mg (mean ⁇ SD).
  • Table 6 Composition of bilayer tablet, consisting of a core and an outer layer, composition utilized in the in vitro release kinetics of Fluoxetine enantiomers in simulated gastric juice and simulated intestinal juice.
  • the weight of the tablets (6mm x 10 mm) was 424 ⁇ 9 mg (mean ⁇ SD).
  • Bilayer tablets consisting of a core and a coated outer layer were prepared in two steps.
  • a direct compression method was utilized to construct the inner core compartment.
  • This slow releasing compartment was comprised of 30% to 65% of PVP-I/N-9 (w/w); 15% to 40% of lactose (w/w); 7% to 25% of HPMC (w/w); 5% to 20% of stearic acid (w/w); and 10% dicalcium phosphate.
  • the preferred percentages of the various ingredients are shown in Table 1.
  • AU tablet ingredients (filler, binder and active ingredient) Table 1) except lubricant were weighed and mixed together for 20 minutes and were passed through a sieve No. 40. The lubricant was then added and mixing was continued for another 45 minutes.
  • each tablet was prepared individually by direct compression using a Carver Laminating Press (Fred S. Carver Inc.). A caplet shaped tablet die and slightly concave tablet punches were used. Each tablet was compressed to an average hardness of 8-11.5 kg using a Pfizer Hardness Tester. Secondly, the outer layer which completely surrounds the tablet core was subsequently created by a spray coating technique.
  • the coating mixture was comprised of 5% to 15% (w/w) of Carbowax ® 1450, 3% to 12% (w/w) of hydroxypropyl methyl cellulose, 8% to 13% (w/w) of talc, 5% to 9% (w/w) of polyoxyethylene sorbitan monostearate, and 30% to 70% (w/w) of PVP-I (Table 1),
  • the coating solution was prepared according to the following method: polyethylene glycol and polyoxyethylene sorbitan monostearate were solubilized in water and subsequently hydroxypropyl methyl cellulose and talc were added.
  • the resulting suspension was mixed with an ethanolic solution of PVP-I. This mixture was placed into a container connected with a spray gun.
  • the spray gun was directed to the falling course inside the coating pan filled with tablets.
  • the tablets were coated by this suspension for a period of 1 to 2 hours until the sufficient outer layer was created.
  • the slow and immediate releasing compartments of the bilayer tablet could be in a form of two layers, one compressed over the other.
  • the composition of each layer is described above (See Table 1 for the preferred composition of each layer).
  • the hard gelatin capsule delivery system consisted of an outer and inner compartment. The latter was in the form of pellets. Capsules could be made from gelatin, hydroxy propyl methylcellulose (HPMC) or any other commonly-used capsule shell composition.
  • HPMC hydroxy propyl methylcellulose
  • a mixture was made from talc, Tween 80, hydroxypropylmethyl cellulose
  • HPMC polyethyleneglycol
  • Carbowax polyethyleneglycol
  • PVP-I ovidone- iodine
  • polyethyleneglycol (Carbowax) 1450 (10.0%, w/w) was first solubilized in 5 niL of water and subsequently Tween 80 (5.0%, w/w) was added. The mixture was stirred for 5 min and then HPMC (5.5%, w/w), talc (10.5%, w/w) and PVP were added. The resulting suspension was mixed with ethanol (ratio of ethanol: water was 8:1).
  • Hard gelatin capsules (HGC) size 000, filled with eight (8) pellets were coated by the coating suspension utilizing a dipping procedure. A total of 310 ⁇ 10 mg of coating suspension was applied as a dry weight difference from the tablet core.
  • pellets For a predetermined batch size, the components of the pellets were weighed and added together in order to obtain pellets (30 mg each) with the following w/w component percentages: dibasic calcium phosphate (15-20%), stearic acid (12-18%), hydroxypropylmethyl cellulose (15- 30%), PVP-I, (povidone-iodine) (40-50%).
  • a dry homogenation process was utilized whereby the component powders were mixed together via a turbula mixer (high speed for 15 minutes). Aliquots of 30 mg were weighed from this powder, followed by direct compression to produce concave shaped pellets (3 mm in diameter), with a Carvar press (600 psi pressure). A total of eight pellets were produced. This number of pellets was included in each capsule.
  • compositions of the outer layer (immediate release tablet layer) and the inner core (slow releasing tablet layer) were prepared per the examples listed in Tables 1 and 2, respectively. All tablet ingredients (filler, binder, and active ingredient) except lubricant were weighed and mixed together for 20 minutes and were passed through a sieve No. 40. The lubricant was then added and mixing was continued for another 45 minutes. After this time, the amount of powder mixture needed was weighed and each tablet was prepared individually by direct compression using a single-punch tablet press MTCM-I (GlobePharma Inc., NJ, USA). A 10 mm diameter die and slightly concave tablet punches were used.
  • the slow and immediate releasing compartments of the bilayer tablet could be in a form of two layers, one compressed over the other as follows:
  • the outer layer immediate releasing layer was lightly compressed (approximately 200 psi) of the outer layer
  • Multilayer (i.e. Tri-layer) tablets (Figure 3) were prepared in two stages and as follows:
  • the first immediate releasing outer layer was lightly compressed (approximately 200 psi) using a 10 mm diameter flat punches.
  • Samples (1 mL) were taken from each vessel at assigned time points (5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 180, and 240 minutes) and replaced with 1 mL fresh dissolution medium to keep the original sink conditions.
  • the samples were analyzed using the HPLC system as described in section 4.
  • formulation II represents the slow release portion.
  • dissolution profile was tested in acidic and alkaline media. The dissolution results of each two set (I and II) were combined to produce an outer immediate release and inner slow release compartments.
  • Table 7 The Composition of tablets in set I (immediate release formulation)
  • Powder mixture was made according to the ingredients listed in Table 8 Table 8: The composition of powder in set I (representing a slow release)
  • Table 9 Composition of tablets in set II (represent the slow release portion)
  • Table 10 composition of powder in set II (representing the immediate release) Substance Percentage (%) Weight (mg)
  • Formulation I represents the immediate release portion (Table 1) and formulation II represents the slow release portion.
  • formulation II represents the slow release portion.
  • the dissolution profile was tested in acidic and alkaline media.
  • the dissolution results of each two set (I and II) were combined to produce an outer immediate release and inner slow release compartments.
  • Formulation I Each capsule was made to contain a tablet and powder which was formulated as shown below:
  • Table 11 The Composition of tablets in set I (representing immediate release of the drug)
  • Table 12 The composition of powder in set I (representing the slow release portion)
  • Table 13 Composition of tablets in set II (representing slow release tablets)
  • Table 14 composition of powder in set II (representing immediate release powder)
  • HPLC chiral analysis of lofexidine were carried out utilizing an Astec Cyclobond column with a mobile phase composed of Ammonium Acetate (10 mM, pH 5), MeOH, and ACN (84:8:8, v/v). The flow was set to 0.85 ml/min at 230 ran.
  • Dissolution under acidic conditions [03158] Formulas were dissolved in hydrochloric acid buffer (pH 1.2) prepared according to the USP guidelines: 1 mL Samples were taken at 5, 8, 11 , 15, 20, 25, 30, 45, 60, 90, 120, 150, 180, and 210 minutes. 10 ⁇ L samples were injected in to the HPLC system for assay analysis.
  • Multilayer tablets of Lofexidine HCl enantiomers consisting of two immediate releasing layers and one slow releasing layer were formulated per the formulation ingredients listed in Table 5.
  • the drug in vitro release in phosphate buffer (pH 6.8) is illustrated in Figure 6.
  • Bilayer tablets of fluoxetine enantiomers consisting of a core and an outer layer were formulated per the formulation ingredients listed in Table 6.
  • the drug in vitro release in phosphate buffer (pH 6.8) and HCl buffer (pH 1.2) are illustrated in Figures 7 and 8, respectively.

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Abstract

La présente invention porte sur des compositions et des procédés pour administrer à des sujets des énantiomères dans des mélanges non racémiques (dans des rapports se situant dans la plage de plus de zéro à moins de cent) contenus dans des comprimés et des capsules. Dans un mode de réalisation, l'invention porte sur l'administration de différents rapports de deux énantiomères par deux types de formulations de médicament. Dans un mode de réalisation, les formulations sont contenues dans un comprimé bicouches ou une capsule à deux compartiments faite de gélatine, d'hydroxypropylméthylcellulose (HPMC) ou autre composition de coque de capsule.
PCT/US2009/068974 2008-12-23 2009-12-21 Libération sélective de mélanges non racémiques de deux énantiomères à partir de comprimés et de capsules WO2010075275A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018206923A1 (fr) * 2017-05-11 2018-11-15 Opal Ip Limited Nouvelles formulations
US10369134B2 (en) 2017-12-05 2019-08-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10377708B2 (en) 2017-12-05 2019-08-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US11160758B2 (en) 2019-06-04 2021-11-02 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof

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Publication number Priority date Publication date Assignee Title
US4746660A (en) * 1984-03-01 1988-05-24 A. Natternabb & CIE GmbH Process for reducing reflex tachycardia in the treatment of hypertension employing a combination of a diazacyclopentene derivative and a pyridazinone derivative
US20070060632A1 (en) * 2005-09-08 2007-03-15 Texcontor Etablissement Lofexidine
US20080113026A1 (en) * 2006-11-09 2008-05-15 Orexigen Therapeutics, Inc Layered pharmaceutical formulations
US20080138411A1 (en) * 2002-12-24 2008-06-12 Biovail Laboratories International S.R.L Modified Release Formulations Of Selective Serotonin Re-Uptake Inhibitors

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Publication number Priority date Publication date Assignee Title
US4746660A (en) * 1984-03-01 1988-05-24 A. Natternabb & CIE GmbH Process for reducing reflex tachycardia in the treatment of hypertension employing a combination of a diazacyclopentene derivative and a pyridazinone derivative
US20080138411A1 (en) * 2002-12-24 2008-06-12 Biovail Laboratories International S.R.L Modified Release Formulations Of Selective Serotonin Re-Uptake Inhibitors
US20070060632A1 (en) * 2005-09-08 2007-03-15 Texcontor Etablissement Lofexidine
US20080113026A1 (en) * 2006-11-09 2008-05-15 Orexigen Therapeutics, Inc Layered pharmaceutical formulations

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018206923A1 (fr) * 2017-05-11 2018-11-15 Opal Ip Limited Nouvelles formulations
US10800738B2 (en) 2017-12-05 2020-10-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10377708B2 (en) 2017-12-05 2019-08-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10576058B2 (en) 2017-12-05 2020-03-03 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10577317B2 (en) 2017-12-05 2020-03-03 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10660875B1 (en) 2017-12-05 2020-05-26 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10369134B2 (en) 2017-12-05 2019-08-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10874639B2 (en) 2017-12-05 2020-12-29 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US11370753B2 (en) 2017-12-05 2022-06-28 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US11517558B2 (en) 2017-12-05 2022-12-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US11767293B2 (en) 2017-12-05 2023-09-26 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US11160758B2 (en) 2019-06-04 2021-11-02 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof
US11654113B2 (en) 2019-06-04 2023-05-23 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof

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