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WO2022072099A1 - Formes posologiques à libération immédiate, procédés de fabrication et d'utilisation de celles-ci - Google Patents

Formes posologiques à libération immédiate, procédés de fabrication et d'utilisation de celles-ci Download PDF

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Publication number
WO2022072099A1
WO2022072099A1 PCT/US2021/048184 US2021048184W WO2022072099A1 WO 2022072099 A1 WO2022072099 A1 WO 2022072099A1 US 2021048184 W US2021048184 W US 2021048184W WO 2022072099 A1 WO2022072099 A1 WO 2022072099A1
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Prior art keywords
formulation
cellulose
starch
pellets
optional
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PCT/US2021/048184
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WO2022072099A9 (fr
Inventor
Lochlann Pauric CARNEY
Praful Balavant Deshpande
John Gerard O'BRIEN
Jose' VELADA
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Eirgen Pharma Ltd
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Eirgen Pharma Ltd
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Publication of WO2022072099A1 publication Critical patent/WO2022072099A1/fr
Publication of WO2022072099A9 publication Critical patent/WO2022072099A9/fr
Anticipated expiration legal-status Critical
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the disclosure relates generally to dosage forms of active pharmaceutical ingredients, c.g. temozolomide, including forms suitable for pharmaceutical and veterinary* use, and methods of making and using the same.
  • temozolomide as an active ingredient
  • TEMODAR® temozolomide
  • TEMODAL® in the EU
  • pellet formulations in hard capsules such as gelatin capsules or HPMC capsules or stick-packs which can be administered directly in to the oral cavity and washed down with a glass of Water or stick-packs or sachets that can be emptied in to a glass of water and taken as a drink.
  • the present invention addresses tins need by using pelletising technology, such as extrusion-spheronization, along with a particular ratio of suitable excipients and an active such as temozolomide to provide immediate release capsules or oral dosage forms.
  • the pelletising technology may also be utilized to create immediate release formulations of other suitable active pharmaceutical ingredients.
  • the present invention meets this need by providing a suitable formulation of temozolomide to administer to dogs having such hemangiosarcomas.
  • One aspect of the disclosure herein is a formulation, comprising an active pharmaceutical ingredient dispersed in a raaitily releasing pharmaceutical composition and which is provided in hard capsule form.
  • the formulation is an immediate release formulation for oral use.
  • Anotiter aspect of the disclosure herein is a pellet formulation comprising a suitable acti ve ingredient, optionally temozolomide or other suitable anti-cancer medication or combination thereof, and a combination of pharmaceutically acceptable excipients.
  • the formulation is an immediate release formulation for oral use.
  • a nano/microparticle formulation comprising temozolomide, optionally an additional active pharmaceutical ingredient, and a combination of pharmaceutically acceptable excipients.
  • the nano/microparticle formulation can provide immediate release of temozolomide, e.g. by using a blend of excipients.
  • non-pareil seed formulation comprising an active pharmaceutical ingredient, preferably temozolomide, an optional additional active pharmaceutical ingredient, and a pharmaceutically acceptable excipient.
  • the formulation can be an immediate release formulation, e.g. for oral use.
  • any one of the hard capsules can include an additional polymer coating. Such coatings may be on the pellets or granules or seeds within the capsule and/or the capsule may be externally coated.
  • extrusion-spheronization is utilized to produce pellets of good physical strength, uniform diameter and good porosity.
  • the main advantage of pellets prepared by extrusion- spheronization method over other methods is the ability to incorporate high drug loads, in particular high drug lends of temozolomide, without producing overly large particles.
  • multiparticulates by extrusion-spheronization having a highly potent, cytotoxic active ingredient in conjunction with a number of other excipients assisting the wettability of the formulation, the release profile and the ability to create extrudates and spheroids which are suitable for oral delivery of such potent, cytotoxic active pharmaceutical ingredients.
  • the drug loading achieved for suitable strengths of drag in these pellets or multiparticulates comprises at least about 50>90% of the total weight of the formulation excluding the capsule.
  • An optional coating system may also be provided on ihe surface of the multiparticulates. This allows for safe handling of the highly potent active baring multiparticulates and for easy filling into capsules, stick-packs or suitable containers for bulk supply.
  • compositions comprising an active pharmaceutical ingredient, preferably temozolomide, and a pharmaceutically acceptable excipient selected from one or more excipients in the group of an absorption enhancer, a spheronizing aid, a water insoluble polymer, and a binder.
  • the formulation can be an immediate release formulation, e.g. for oral use.
  • Another aspect of the disclosure herei n is a pharmaceutical batch of dosage forms comprising a formulation according to the disclosure herein, and further characterized by low dosage form to dosage form variation in in vitro dissolution release.
  • the dosage forms can be immediate release dotage forms, e.g. for oral use.
  • the method can be a method of making an immediate release pharmaceutical formulation, comprising compounding an active pharmaceutical ingredient such as temozolomide with at least one excipient selected from the group consisting of spheronizing aids (diluents], humectants, stabilizers, binders, supcrdisintegrants, lubricants, solvents and optional coatings.
  • Another aspect of the disclosure herein is a method for improving batch to batch consistency in an in vitro release profile of an immediate release formulation, the method comprising compounding the active pharmaceutical ingredient with a combination of at least one excipient selected from the group consisting of diluents, binders, supcrdisintegrants, lubricants, stabilizers, solvents and optional coatings.
  • Such immediate release formulations in particular include high loaded potent API formulations such as temozolomide in combination with excipients selected from the group consisting of diluents, binders, lubricants, stabilizers, supcrdisintegrants, solvents and optional coatings.
  • high loaded potent API formulations such as temozolomide in combination with excipients selected from the group consisting of diluents, binders, lubricants, stabilizers, supcrdisintegrants, solvents and optional coatings.
  • excipients selected from the group consisting of diluents, binders, lubricants, stabilizers, supcrdisintegrants, solvents and optional coatings.
  • Such formulations produced by a spheronization extrusion process The particles produced can be filled into capsules, sachets, stick-packs and the like.
  • the invention further comprises a process which comprises blending an API, a diluenv'spheronizing aid and a superdisintegrant and dispensing such materials and, adding binders, optional humectants and granulating/wet massing under certain conditions and endpoints; extruding the wet mass; spheronizing the screened extrudate; drying; fractionizing; adding lubricant and optionally coating to form a formulation having a uniform size and shape suitable for filling capsules, sachets and/or stick packs.
  • the API is selected from temozolomide or similar potent, toxic cytotoxic agent in a high dose load.
  • Another aspect of the disclosure herein is a method of treating a disease or condition comprising administering a formulation or dosage form according to the disclosure herein to a subject in need thereof.
  • the subject is a mammal, including humans and animate such as dogs.
  • the formulations are suitable for young subjects including pediatric patients.
  • FIG. 1 shows dissolution release profiles of temozolomide-loaded pellets according to the disclosure herein.
  • Embodiments of the present invention can meet these needs and provide a range of immediate release dosage forms as well as improved processes to make such formulations and dosage forms.
  • These formulations may be made bioequivalent to a commercially approved immediate release dosage forms but are also amenable to providing distinct in vitro extended release dissolution profiles and in vivo bioavailability. They can be made suitable for both pediatric patient populations as well as adult patient populations and for veterinary use in animals.
  • immediate release formulations including formulations suitable for delivery to pediatric patients in need of treatment thereof. Such formulations can also be useful in the treatment of adults in need of treatment thereof, e.g. for adult diseases and conditions. Such formulations are also suitable for veterinary use.
  • the formulations and formulation strategies described herein can be used to provide formulations bioequivalent to a commercially approved immediate release drug products but in a form also deliverable to pediatric patients or to veterinary subjects.
  • Such forms are inclusive of conventional capsules, “easy to open” capsules or sachets that can be administered by emptying the entire contents into a small amount of liquid or onto a small amount of soft food.
  • the immediate release formulations comprise an active pharmaceutical ingredient and an excipient.
  • such immediate release formulations are in the form of spheronized pellets or multiparticulates.
  • the formulations comprise spheronized pellets comprising a suitable blend of excipients utilized in a process to make spheronized pellets, said process comprising ( 1 ) blending API, diluent, superdisintegrant and a spheronizing aid to form a dispensable mass (2) granulating said dispensible mass to form an extrudable formulation; [3] extruding; spheronizing; drying; and fractionating the extruded, spheronized, dried mass to form uniform pellets which are optionally lubricated and coated to form pellets suitable for use as described herein.
  • the formulation can be a nano/micro particle formulations, e.g. made by emulsion followed by spray drying/frecze drying, such as an emulsion-feflusion-spray/drying freeze (frying technique described herein.
  • the formulations can be a powder formulation, e.g. made by spray congealing.
  • the formulation can be an immediate release coated seed.
  • rhe formulation can be an active-containing granule.
  • wt.% refers to pans by weight based on the total weight of the thing described, for example based on the total weight of fee active ingredient containing region, by default, or based on the total weight of the formulation, where applicable by context or explicitly described.
  • immediate release is contrasted with, for example, the terms “controlled release,” and “modified release” which are often used interchangeably and refer to the release of an active pharmaceutical ingredient in a way that deviates from immediate release.
  • extended release is used interchangeably and refer to the release of the active pharmaceutical ingredient over a longer period of time than a comparable immediate release formulation.
  • temozolomide refers to the known active ingredient utilized as an anti-cancer therapeutic. This drug is sold and approved for human use under the brand name TEMODAR.
  • the chemical name is 3, 4-dihydro-3-mcthyl-4-oxoimidazo [5,1-d]tetrazine-8- carboxamide.
  • the administered drug converts in vivo to MTIC which is believed to act as a DNA alkylating agent
  • the API is compounded with [e.g. via dissolution, mixing, emulsion, or any combination thereof] with one or more excipients to form an immediate release formulation, as described below:
  • the concentration of active pharmaceutical ingredient in a formulation according to the disclosure can be any suitable amount.
  • the concentration of temozolomide is in a range of about 5-70 wt/wt percent based upon the total weight of the formulation fill.
  • spheronizing aids and diluents arc selected from the group consisting of microcrystalline cellulose, anhydrous lactose sugar alcohols, saccharides, polysaccharides, cellulose and cellulose derivatives, starch and starch derivatives, metal silicates, metal phosphates, ionic metal salts, saccharose, glucose, starch, microfine cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silica, sodium chloride, starch, and dibasic calcium phosphate dihydrate]; humectants are selected from the group consisting of sorbitol Glycerin, Propylene glycol, Triacet in ; stabilizers selected from the group consisting of tartaric acid and other typically utilized carboxylic acids ; binders selected from the group consisting of polyvinylpyrrolidone, HPMC, Starch, copovidone, gums ; lubricants selected from the group consisting of micro
  • HPMC HPMC
  • ethylcellulose hydroxypropylmcthyl cellulose
  • Such components arc preferably used in an aqueous wet extrudable mass which forms a granulation which is subsequently spheronized to form pellets.
  • the formulations contemplated and disclosed herein can be bioequivalent to approved immediate release drugs by providing a mean AUC o-inf following oral dosing to humans in the fasted state which is 80% to 125% of the mean AUC o-inf following oral dosing in the fasted state of the approved immediate release drug product
  • the formulation can be bioequivalent to approved immediate release drug products by providing a mean AUC o-inf following oral dosing to humans in the fasted state which is 80% to 120% of the mean AUC o-inf following oral dosing in the fasted state of the approved immediate release drug product
  • the formulation can be bioequivalent to approved immediate release drug product by providing a mean Cmax following oral dosing to humans in the fasted state which is 80% to 125% of the C max following oral dosing in the fasted state of the immediate release drug product.
  • the formulation can be bioequivalent to approved immediate release drug product by providing a mean Cmax following oral dosing to humans in the fasted state which is 80% to 120% of the Cmax following oral dosing in the fasted state of the approved immediate release drug product
  • the fasted state can be defined by fasting for at least 10 hours.
  • Such spheronized pellets produced from the aqueous-based wet granulation processes described herein can also have other components in the granulation blend including absorption enhancers, diluents and spheronizing aids, pore formers, binders, binding aids, fillers and water.
  • the formulations have the excipients and active in the percentages [wt/wi) as shown in Table 1.
  • the formulation can optionally include one or more additional functional additives, including but not. limited to release modifiers (including pore formers), absorption enhancers, fillers
  • binders including dry binders
  • spheronizing aids flavorants, and lubricants.
  • excipients useful in spheronized pellets as described harein include absorption enhancers, such as Miglyol 812N; diluents and spheronization aids, such as MCC (Avicel PH 101); diluents and pore formers, such as lactose monohydrate or HPMC; compacting/gclling agents, such as glyceryl behenate [Compritol 888 ATO, having melting range of 65 °C to 77 °C and an HLB of 2]; extrusion and spheronization aids, such as low-substituted hydoxypropylcellulose ( L-HPC LH-31 ); binding aids, such as Methocel K3 Premium LV; lubricants, such as talc powder or glyceryl behenate; flavoring agents, such as caramel; and purified water as a process diluent (e.g.
  • absorption enhancers such as Mi
  • Diluents and/or spheronization aids can be present in a concentration of about 30 wt.% to about 90 wt.%.
  • live absorption enhancer can be present in a concentration of about 3 wt.% to about 10 wt.%.
  • Binding aids such as Methocel K3 can be present in a concentration of about 5 wt.% to about 10 wt.%.
  • Lubricants such as talc can be present in a weight concentration of about 1 wt.% to about 2 wt.%.
  • live concentration of extrusion and spheronization aids, such as L-HPC LH-31 can range from about 5 wt.% to 25 wt.%.
  • the preferred weight percentages of the preferred excipients are shown in Table 1.
  • the composition can optionally include an absorption enhancer.
  • suitable absorption enhancers include, but are not limited to, caprylocaproyl macrogolglycerides such as polyethylene glycosylated glycerides, also known as polyglycolized glycerides or PEGylated glycerides.
  • PEGylated glycerides which may be employed in the composition include, but are not limited to, mixtures of monoglycerides, diglycerides.
  • the absorption enhancer can have an HLB value from 11 to 18, or 13 to 18, or from 13 to 16, or from 13 to 15, or 11-12.
  • GELUCIRE Gattefossd Corporation, Paramus, New Jersey, USA.
  • GELUCIRE is a well-known excipient which belongs to a family of fatty acid esters of glycerol and PEG esters, also known as polyglycolized glycerides.
  • GELUCIRE is used in various applications including preparing extended release pharmaceutical compositions.
  • GELUCIRE compounds arc inert, semi-solid waxy materials which arc amphiphilic and are available with varying physical characteristics such as melting point, HLB, and solubilities in various solvents.
  • GELUCIRE compositions are surface active in nature and disperse or solubilize in aqueous media forming micelles, microscopic globules or vesicles. They are identified by their melting point/HLB value. The melting point is expressed in degrees Celsius.
  • One or a mixture of different grades of GELUCIRE excipient may be chosen to achieve the desired characteristics of melting point and/or HLB value.
  • One GELUCIRE composition is GELUCIRE 44/14, a mixture of lauroyl macrogolglyccrides and lauroyl polyoxylglycerides that has a melting point of 44 °C and a HLB of 11.
  • Another GELUCIRE composition is GELUCIRE 48/16, a.k.a.
  • PEG-32-stcarate a.k.a. PEG 32 mono and dieslers of stearic and palmitic acid, with a nominal melting point of 48°C [range of 46°C to 50°C] and a HLB of 12.
  • Another polyglycolyzed glyceride absorption enhancer is caprylocaproyl macrogol-8-glyceride [CAS No. 85536-07-8 and 84963-88-2). This is a mixture of mono-, di- and triesters of glycerol and of PEG 400 with medium-chain fatty acids [C8-C10] which is marketed, for example, by Gattefosse Corporation, Paramus, New Jersey, USA undo: the trade name LABRASOL.
  • LABRASOL has a HLB value of 14 and has the following composition by weight: C8-C 10 monogiyceridcs approximately 4%; C8-C10 diglycerides approximately 17%; C8-C10 triglycerides approximately 6%; C8-C10 monoesiers of PEG 400 approximately 14%; C8-C10 diesters of PEG 400 approximately 36%; free PEG 400 approximately 20%; free glycerol approximately 3%.
  • Another type of absorption enhancer is triglycerides, c.g. medium chain triglycerides. For example, a mixture of C8-C10 triglycerides can be used.
  • the C8-C10 triglycerides can include about 50 to 65 wt.% caprylic acid triglyceride and about 30 to 45 wt.% capric acid triglyceride.
  • a suitable triglyceride is commercially available under the trade name Miglyol 812N.
  • the absorption enhancer can be present in any suitable amount, for example about 1 wt% to about 20 wt%, or about 1 wt% to about 15 wt%, or about I wt.% to about 10 wt.%, or about 3 wt.% to about 10 wt.%, or about 5 wt.% to about 10 wt.%, or about 3 wt.% to about 5 wt.%. Other examples include about 3 wt%, about 5 wt%, and about 10 wt%.
  • a hydrophilic excipient e.g. a release aid, having a HLB of greater titan 10, e.g. in a range of 11 to 18, or 13 to 18, then it also includes a lipophilic excipient, e.g. one having an HLB less than 10, e.g. 1 to 6, or 1 to 3, or 3 to 6.
  • the formulation can also include one or more fillers, also referred to as diluents.
  • Fillers include, but are not limited to, lactose, saccharose, glucose, starch, microcrystalline cellulose [MCC), microfine cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silica, sodium chloride, starch, and dibasic calcium phosphate dihydrate, for example.
  • the filler is not water soluble, although it may absorb water.
  • a filler when mixed with the other components [e.g. a water-insoluble polymer) a filler can function as a pore former.
  • the filler is a spheronization aid.
  • Spheronization aids can include one or more of crospovidone, carrageenan, chitosan, pectinic acid, glycerides, p-CD. cellulose derivatives, MCC, powdered cellulose, polyplasdone crospovidone, and polyethylene oxide, for example.
  • the filler or spheronization aid includes MCC.
  • a MCC can have any suitable particle size, e.g.
  • a MCC can be characterized by a crystallinity in a range of about 60% to about 80%, for example.
  • Suitable commercially-available MCCs are available under the brand name AVICEL, under the PH grades 101, 102, 104, 105, 112, 113, 200, 200 LM, 301, and 302, for example.
  • the MCC is AVICEL PH 101 ; in another embodiment the MCC is AVICEL PH 201.
  • the amount of filler is not particularly limited, and for example can be in an amount of at least about 1 wt.%, or 5 wt.%, or 10 wt.%, or 20 wt.%, or 30 wt.%, or 40 wt.%, or 50 wt.%, or 60 wt.%, or 70 wt.%, or 80 wt.%, and up to about 95% wt.%, or about 90 wt.%, or about 80 wL%, or about 70 wt.%, or about 60 wu%, or about 50 wt.%, or about 40 wt.%, or about 30 wt.%, or ranges formed from any of the foregoing values.
  • the filler can be in a range of about 1 wt.% to about 95 wt.%, or about 5 wt.% to about 70 wL%, or about 10 wt.% to about 30 wt.%, for example.
  • a spheronizing aid can be included in such ranges, or in an amount of about 10-30 wt%.
  • the fillers and additional excipients comprise a collective weight percentage Of about 20 to about 50% with active making up about 50 to 80 wt%.
  • the formulation can include one or more binders, including dry binders. Binders include relatively low-viscosity, hydrophilic cellulose ethers, and PVP, for example. In other embodiments, binders can include carboxymethyl cellulose, starch, pregelatinized starch, acacia, tragacanth, gelatin, sodium alginate, low-substituted hydroxypropyl cellulose, and lowest viscosity grade of hydroxypropyl methylcellulose [HPMC]. The preferred binder is selected from PVP.
  • lubricants are known in the art and can include, but arc not limited to, stearic acid, magnesium stearate, calcium stearate, aluminum stearate, talc, and siliconized talc.
  • the lubricant is stearic acid.
  • a small amount of lubricants can often be used, e.g. in a range of about 0.1 wt.% to about 5 wt%, or about 0.5 wt.% to about 3 wt.%, for example 0.5 wt.%, 0.7 wt.%, 1 wt.%, 1.5 wl.%, or 2 wt.%.
  • the formulation can optionally include a top coating or over coating, to adjust the release profile or to provide a taste-masking effect as desired.
  • a top coating can be used to delay or slow down release in initial hours after administration, e.g. to counteract an initial burst release, or otherwise slow an initial release that is more rapid than desired.
  • Suitable top coating materials include film-forming polymers, for example.
  • a top coating material can be water soluble, e.g. a water-soluble polymer described herein [e.g.. hypromellose, PVP] or a water-swellable polymer that further includes a pore fonner [e.g. an EC as described herein together with a pore former, e.g.
  • the top coat can optionally include a lubricant, e.g. talc.
  • a lubricant e.g. talc.
  • a suitable EC top coat material is commercially available under the trade name SURELEASE, sold as an aqueous, emulsi fied dispersion of plasticized EC.
  • a suitable hypromellose pore fonner can have a 2% solution viscosity at 20 °C of about 3 cP, a methoxyl % in a range of about 19 to about 30, or about 19 to about 24, or about 25 to about 35, or about 28 to 30, and a hydroxypropyl % of about 5 to about 15, or about 7 to about 12.
  • the hypromellose can be one commercially available as OP ADR Y or OPADRY II AMB.
  • the ratio of top coat malarial, e.g. EC, to pore former, e.g. hypromellose can be adjusted to give a desired release profile or taste masking effect, and for example can be in a range of 80:20 to 20:80, for example, or 70:30 to 30:70, or 60:40 to 40:60, for example 65:45. or 60:40, or 55:45, or 50:50.
  • the amount of top coat can be adjusted to give a desired release profile.
  • the amount of top coat material applied can be measured as weight gain of formulation particles, for example when the top coal is sprayed on the particles.
  • the amount of top coat on the formulation particles can be in a range of about 1 wt.% to about 40 wt.%, or 1 wt.% to about 30 wt.%, or about 5 wt.% to about 25 wt.%, for example 10 wt.%, or 15 wt.%, 20 wt%, or 25 wt.%.
  • Alternative coating materials to effect a delayed release include enteric coating materials, e.g. to effect release based on the G1 medium pH.
  • enteric coating materials include shellac [esters of aleurtic acid], cellulose acetate phthalate, poly(methacrylic acid-co-methyl methacrylate], cellulose acetate trimellitate [CAT], poly[vinyl acetate phthalate] [PVAP], and hydroxypropyl methylcellulose phthalate [HPMCP].
  • Nano/microparticles are colloidal carriers which shown to offer a great potential in per-oral drug administration.
  • an active pharmaceutical ingredient e.g. temozolomide
  • temozolomide can be encapsulated in a liquid oily core surrounded by a solid shell material.
  • Immediate release nano/microparticles can be prepared using an cmulsion-diffusion-spray drying/freeze-drying technique. With a poorly water-soluble API a single-emulsion technique is more desirable.
  • a freeze-drying or spray-drying technique can be used to convert an emulsion into a powder formulation.
  • Solvent blends for the homogenization to create an emulsion can include non- continuous phase solvents such as ethyl acetate and continuous solvents such as water.
  • the final formulation of the immediate release particles can be as an aqueous suspension, a non-aqueous suspension [e.g. with triglycerides, such as fatty acid triglycerides], or can be presented as a sprinkle form in a sachet
  • Capsule Filling Fill the Step 6 pellets into Size I -5 capsules (e.g. HPMC or gelatin capsules) Fill
  • spray congealing is an alternative processing approach to produce formulations according to the disclosure herein.
  • the process can be solvent-free, if desired.
  • the hot melt processing can include spray cooling/congealing, for example, to yield small particle sizes.
  • Spray cooling also known as spray congealing or spray chilling, is a process that transforms a melt into well-defined, e.g. spherical, particles. This process uses spray drying technology with a rapid chilling process. It is capable of producing free-flowing lipid microparticles in a size range of about 10 microns to 1000 microns, for example.
  • cold nitrogen gas can be circulated through a column or other vessel while a hot meh mixture of lipid, API, and optional surfactant is sprayed into the column to create a fine mist of particles.
  • the particles can optionally be coated with a top coat of extended release polymer and pore former.
  • a surfactant can be used to aid sol ubility and complete release of the API.
  • Surfactants include, but arc not limited to one or more of PEGs (e.g. PEG 6000] and Tweens (e.g. Tween 80).
  • the active-containing formulation can be prepared in any suitable form.
  • the drugcontaining formulation can make up the entire dosage form, or it can be a region of the dosage form, e.g. as a core or as a coating [for example on an inert seed core, such as a nonpareil].
  • the formulation is in particle form, and optionally top coated.
  • the particles can take any size or shape, e.g. pellets or mini tablets.
  • active-containing immediate release particles are filled into a capsule shell, pouch, or sachet, yielding a multiparticulate dosage form.
  • Multiparticulates [dosage forms made of multiple particulate units, e.g.
  • pellets or mini tablets provide increased surface area as opposed to monolithic tablets, allowing better release profiles and bioavailability.
  • the multiparticulates provide a lower risk of local irritation due to the minute amount of drug they carry as compared to single unit matrix tablets.
  • the GI transit rate is heavily dependent on stomach emptying rates and GI movement, but multiparticulates [e g- pellets] because of their relatively smaller size produce highly reproducible GI transit rates and thus inter- and intra-subjed variability is minimal compared to single unit formulations.
  • the capsule shell can optionally be a HPMC shell or a hard gelatin shell.
  • the granules prepared from an aqueous based wet granulation can be directly compressed into a tablet or micro or mini-tablets which can be coated or uncoated.
  • the particle sizes are in a range of about 0.2 mm to about 2.8 mtn, or about 0.2 mm to about 2.5 mm, or about 0.2 mm to about 2.0 mm, or about 0.7 mm to about 2.5 mm, or about 0.7 mm to about 2.8 mm, or about 0.5 mm to about 2.8 mm, or about 0.8 mm to about 1.7 mm, or about 0.5 mm to about 1.2 mm, or about 0.5 mm to about 1.0 mm.
  • the target particle size can be up to 2.5 mm with no more than 10 percent variation over this size, to a maximum size of 2.8 mm.
  • Particles can be sorted to the desired size ranges by sieving according to known methods.
  • the formulation can also be characterized by a mean particle size in any of the foregoing ranges or amounts. As the particle size becomes too large, the particles are too large for use in drug products that are labeled to be administered via sprinkling on a substrate [e.g., on applesauce or other soft foods, such as jellies] and swallowed without chewing, or administered via an enteral feeding tube.
  • multiparticulates according to the disclosure herein can be dispersed in a suspension base and administered as a powder for oral suspension.
  • the suspension base can include purified water, for example, and optionally with one or more excipients.
  • the suspension base can include at least 50 wt.% water, more thin about 50 wt.% water, at least about 80 wt.% water, at least about 90 wt.% water, at least about 95 wt.% water, al least about 99 wt.% water, or 100 wt.% water, for example.
  • the suspension base can be a sugar-based syrup, for example.
  • the suspension base can optionally include a suspending or thickening agent. Suitable suspending and thickening agents include, for example, methylcellulosc, starch, xanthan gum, and glycerin.
  • the suspension base is non-aqueous, e.g. containing or consisting of triglycerides.
  • a layered formulation is contemplated.
  • This type of formulation includes a starter seed [e.g. non-pareil seed] having a layer of active compound, which further has a seal coming [e.g. low-viscosity hypramellose) to make the surface of the seeds smooth, after API layering/coating and also to achieve uniform coatingls] at subsequent stages.
  • a seal coming e.g. low-viscosity hypramellose
  • Over the seal coating is an optional additional coating [e.g., a water-insoluble polymer, such as one described herein, with a pore former, functional or non-functional].
  • This embodiment can further include an optional tastemasking coating, and a further optional seal coaling over the optional functional coating and under the taste-masking coaling, if desired.
  • seeds [a.k.a. pellets or spheroids] can be prepared with one or more processes including extrusion with spheronization, rotary fluid-bed processing, and spray-congealing.
  • the seeds can optionally have API within the seeds themselves, in a range of 0.01 % to 10% by weight of the seed, for example.
  • These seeds are coated with one or more coating layers, for example using fluid bed processing using Wurster coating technology.
  • the seeds can have a first seal coating in a range of 1 wt.% to 5 wt.%, based on the weight of the seeds, and an optional second coating in a range of 3 wt.% to 50 wt.%, based on the weight of the seeds.
  • a fourth optional seal coating for example in a range of 1 wt.% to 5 wt.% based on the weight of the seeds.
  • the formulation can also include an aesthetic [non-functional) coating, for example in a range of 1 wt.% to 5 wt.%, based on the weight of the seeds.
  • Functional coating excipients can be selected from cellulosics, HPMC, ethylcellulose, waxes, glyceryl monostearate, acrylic polymers [including Eudragits), and combinations thereof.
  • Seal coating excipients can be selected from cellulosics, e.g. HPMC.
  • Pore formers can be selected from cellulosics, HPMC, and lactose.
  • Plasticizers can be used in the seal, functional, and aesthetic coalings, and can be selected from dibutyl sebacate, triethyl citrate, and PEGs, for example.
  • Aesthetic coating nuderials can be selected from hypromellose. polyvinyl alcohol, and commercial coating products such as Opadry coating. The coatings can be applied as aqueous or non-aqueous solutions.
  • the final dosage form can have any desired amount of active pharmaceutical compound in a unit dose.
  • a capsule shell can be filled with sufficient formulation material, such as granule, particle, or pellet, to yield a dosage form having an amount of drug in a suitable active range.
  • Dosage forms other than capsules e.g. sachets, stick-packs, pills, or tablets, can have the same or similar strengths.
  • Dosage forms, including granules, pellets, sachets, capsules, etc. can be stored with a desiccant.
  • formulations described herein can be characterized by any release profile.
  • the target dissolution profile of a formulation according to the present disclosure can be within the specification limits of in vitro dissolution profile[s) of a target brand pharmaceutical, preferably an immediate release dosage form where greater than 75% (Q) is released in 30 minutes.
  • the dissolution can be measured using following method of dissolution, for example.
  • FIG. 1 shows comparative in vitro dissolution release profiles of such 100 mg dosage forms. The Relative Standard Deviation was assessed across all dissolution release profiles.
  • a formulation according to the disclosure herein can be made to create a unique or customized release dissolution profiles.
  • a formulation according to the disclosure herein can also be made to have consistent unit dose to unit dose in vitro dissolution profiles with limited intra batch variability, or batch-to-batch variability.
  • the dissolution profile can be measured using USP Apparatus 1 [Baskets) at 100 RPM, with a medium of de-acratcd purified water, 37 A 0.5 °C, with a volume of 900 mL.
  • formulations and a final dosage form are also contemplated.
  • the formulation including the active pharmaceutical ingredient can be made by any suitable process, including but not limited to direct compression, granulation, extrusion, spheronisation, fluid bed coating, pan coating, or any combination thereof.
  • Such processes include aqueous-based extrusion/spheronization to produce granules/pellets suitable for immediate release formulations containing a suitable active ingredient [e.g. temozolomide], coating processes to coat seeds or active-containing granules.
  • a suitable active ingredient e.g. temozolomide
  • One embodiment of a process to make suitable pediatric temozolomide formulation or veterinary formulation wherein the active is temozolomide includes aqueous-based extrusion/spheronization to form multiparticulate granules/pellets which can be uncoated or coated.
  • the preferred immediate release formulations are shown in Table I .
  • the optional controlled-release polymers for IRZER are shown in Table I .
  • blended capsules suitable for use in preparing such granules can be selected from, for example, Eudragit RL PO. Eudragit RS PO, EC, L-HPC, LH-31, Compritol 888 ATO and Kollidon SIL
  • excipients including binders and-'or absorption enhancers, lipidic agents, diluents, spheronizing aids, flavoring agents and pore formers may be utilized in the aqueous-based extruded granule formulation.
  • pellets arc readily made from the extrudable aqueous-based formulation without the need for additional coating(s) to achieve a target in vitro and in vivo profile.
  • Such a process can include [I) forming an aqueous-based exirudable mass including active and inactive excipients; [2) extruding such mass to form active-containing cylindrical rods known as extrudates; (3] spheronizing the extrudates to form pellets and [4] drying the pellets.
  • the dried pellets can optionally be coated with a lubricant and/or flavorant, e.g. stearic acid and flavorant. More specifically, the process can inizo moistening a powder mixture of API and excipients, forming extrudates through extrusion, breaking and rounding the extrudates to round pellets through spheronization, and drying the finished pellets.
  • the pellets can have sizes in a range of 200 mm to 2 mm in diameter, for example.
  • the aqueous-based formulation used to form the wet-extrudable mass can include a considerable percentage of water [wt/wt].
  • the percentage of water can be in a range of 10 wt.% to 90 wt%» or at least 35 wt.%.
  • Granules produced by this process [aqueous versus non-aqueous] have the requisite strength and integrity to provide workable, extrudable and functional spheronized pellets.
  • the pellets can also be referred to as beads or spheroids.
  • Enhanced properties can include one or more properties including optimal flow characteristics; reproducible provision into capsules or other drug delivery' vehicles; optimal density/hardness properties for handling and, if desired, coating; improved hardness and friability [e.g. not more than 1.0 percent); and more consistent batch-to-batch in vitro and in vivo drug delivery and release profiles.
  • the pellets can provide one or more benefits including: dispersing freely in the GI tract, thus improving drug absorption, reducing peak plasma fluctuations, and minimizing side effects; avoiding high local concentrations of API in the GI tract; allowing safe handling by an administrator or user; improving flow properties, e.g. for capsule or sachet filling; providing a narrow particle size distribution; and providing uniform packing characteristics.
  • the formulation is formed by granulating a mixture of the API with a material (e.g water-insoluble polymer] and one or more other optional excipients, and optionally tailoring the formulation process to a desired crumble size range, e.g via extrusion parameters, and/or optionally in combination with one or more steps including sieving, firactional sieving and milling
  • the formulation can be formed by extrusion and spheronization of a mixture of the active compound with one or more other excipients.
  • the extruder can be Fitted with an extrusion screen of a desired size, e.g. 0.1 mm to 5mm, or 0.5 mm to 2mm.
  • the spheronizer can be fitted with a plate of desired dimensions and configuration, e.g. a 0.1 to 5 mm cross hatch plate, or 0.5 to 2mm cross hatch plate.
  • the preferred screen size for immediate release formulations prepared herein is at 1 mm for the extrudate and 1 mm cross hatch plate for the spheronized blend.
  • Granulating processes can include fluid bed granulation, wet granulation, hot melt granulation, and spray congealing for example. Other processes include slugging and roller compaction. As it is generally known in the art, mixtures which arc to be granulated can first be dry-blended. The dry-blended dry ingredients can be mixed with water, prior to extrusion.
  • the dry ingredients are combined, blended and mixed with about 30 wt% to 80 wu% waler and wet granulated to form a wct-extnidablc mass.
  • the extrudable mass of the combined ingredients in selected weight ratios depending upon the excipients is blended, extruded, spheronized and dried to form the desired pellets used in the pediatric or adult formulation[s] and/or veterinary formulations.
  • temozolomide can be added to a pre-mixed blend of dry excipients in a dispensing step, and then a binder solution can be added to prepare a wet mass for extrusion.
  • the drying can be done by tray drying, vacuum drying or fluid bed drying, for example.
  • a sequential method of making approach is described in Table 3 below. It would be understood by the skilled artisan that this sequence is representative and not limiting
  • extrusion and spheronization of a mixture of the active compound with excipients disclosed herein can provide desirable active-containing particles [e.g. containing temozolomide] with dissolution release properties similar to or equivalent to a commercially-a vailable formulation of temozolomide, e.g. TEMODAR®. It is contemplated to use temozolomide in an extrusion-spheronization type formulation.
  • the formulation can have the following composition filled into hard gelatin or HPMC hard capsule shells: temozolomide 40-80 wt% of capsule fill by weight, with the remaining excipients weight percentages as shown in Table 1. Other active pharmaceutical weight percentages can clearly vary by weight based upon the prescribed and approved dosage strengths.
  • the formulation described herein can be directly processed as a finished dosage form. or it can be further processed to make a finished dosage form.
  • the formulation can be top coated.
  • the coating can be done by fluid bed coating, for example, with a lop-, tangential-, or bottom-spray configuration. z ⁇ s another example, the formulation can be compressed, e.g. into the form of a pill or tabid.
  • Administration of a dosage form according to the disclosure can be based on the weight of active ingredient in the formulation and to the subject being treated-e.g., human, child or animal.
  • the treatment of humans and animals is contemplated.
  • the treatment of mammals is contemplated.
  • oral formulations and oral administration is contemplated.
  • the compositions of the disclosure can be used in combination with other therapies useful for the indicated diseases and disorders.
  • a formulation described herein can be used in the preparation of a medicament for use in treating a condition or disease which the active ingredient is known to treat.
  • compositions and methods described herein are useful for prophylactic or therapeutic treatment of cancer [e.g., breast, lung, skin, melanoma, colon, colorectal, rectal, prostate and bone cancer).
  • Temozolomide in humans, is approved for the treatmem of newly diagnosed glioblastoma multiforme and for refractory anaplastic astrocytoma.
  • the formulations of the present invention are preferably used for such indications.
  • the preferred indication is the treatment of hemangiosarcoma in dogs.
  • the present invention thus comprises use of temozolomide in the treatment of hemangiosarcoma in mammals.
  • the disease is a devastating disease in dogs-it is an aggressive malignant cancar of the blood vessels which can lead to rapid death from the tumors rupturing.
  • the presentation can be dermal or internal.
  • Chemotherapy fix dogs has typically included doxorubicin as the chemotherapeutic agent.
  • Antiangiogenic agents such as minocycline may be administered as well.
  • the present capsule formulations may be administered to dogs having hemangiosarcoma to slow or treat the disease.
  • the dosing regimen is a dose escalation ranging from 100-150 mg/m 2 for haemangiosarcoma post-surgical resection.
  • dogs are being prescribed an initial dose of 100 mg/m 2 orally for 5 consecutive days in a 21 day cycle, for a total of 6 Cycles.
  • the dose can be escalated in no more than a 10% dose increase per cycle, based on capsule size with no dose greater than 200mg/m 2 .
  • 150 mg/m 2 is the maximum tolerated dose [MTD) described in the literature so far. Dose increments are 10mg/m 2 .
  • the capsules can include 5, 20, or 100 mg of temozolomide.
  • Early treatment or intervention is also critical in this disease and diagnostic assays measuring the expression of hemangiosarcoma markers coupled with chemotherapeutic intervention is one aspect of the present invention. Such diagnostic markers are disclosed in, for example, U.S. Pat. No. 7,910,315.
  • a formulation described herein and having a particle size limit of 2.8 mm or less, or 2.5 mm or less, or 2.0 mm or toss can be administered via sprinkling [e.g.. on applesauce or other soft foods, such as jellies), such that they can be swallowed without chewing.
  • sprinkling e.g.. on applesauce or other soft foods, such as jellies
  • such formulations can be administered via an enteral feeding tube.
  • the sprinkling can be preceded by opening a capsule containing the particles, or opening a packet or sachet containing the particles.
  • an easy-opening, hard gelatin capsule is available under the trade name CONISNAP from Capsugel.
  • the formulation can be administered to an adult patient, or a pediatric patient,
  • the pediatric patient can be 8 to 17ycars of age, 12 to 17 years of age, 8 to 11 years of age, 1 month to 7 years of age, 6 months to 8 years of age, or 6 years of age or younger, or 4 years of age or younger, or 2 years of age or younger, for example.
  • a formulation having a particle size limit of 2.8 mm or less can be packaged with instructions for sprinkling the particles on soft foods (e.g. applesauce], and optionally also swallowing the particles and food without chewing.
  • soft foods e.g. applesauce
  • a formulation having a particle size limit of 2.8 mm or less can be packaged with instructions for enteral feeding tube administration.
  • Examples 1 .1 to 1.4 comprising immediate release pellets were made by extrusion- spheronization using the excipients identified in Table 1.
  • Temozolomide was mixed with diluent, a superdisintigrant and spheronizing aids.
  • a wet extrudable mass was prepared, extruded, and spheronized.
  • the extrusion/spheronization process followed the general sequence described in Table 3 above.
  • the extruder was a Caleva bendi-top screen Extruder 20 having a screen size of 1mm and operated at a speed of about 30-35 RPM.
  • the spheronizer was a Caleva MultiBowl Spheronizer/mbs 250, operating at about 750 - 1500 RPM.
  • the sieves used for fractionation were 1.4 mm, 1.0 mm, 400 ⁇ m and 250 ⁇ m.
  • Final selected pellets fix each batch were pellets which were retained on the 400 ⁇ m and 1000 ⁇ m sieves, thus the mean diameter of pellets in each of the batches was in the region of 400-1000 ⁇ m. All pellets assayed to at least 93% of the expected API and showed satisfactory flow-properties, friability and acceptable levels of related substances impurities.
  • the pellets contained about 4 to 6 wt.% or less water by loss on drying.
  • Dissolution release properties of the pellets in hand gelatin [HG] shells and HPMC hard capsule shells were measured [ Figure 1]. 200 mg of pellets were filled into hard capsule shells and tested for dissolution release using USP Apparatus I (Baskets] at 100 RPM, with a medium of deaerated purified water, 37 ⁇ 0.5 °C, with a volume of 900 mL. The dissolution results are shown in FIG. 1 and are tabulated in Tables 5-7 below for Examples la to 1c in the two types of hard capsule shells. The average dissolution times and Relative Standard Deviation (RSD] values were derived from dissolution testing on twelve capsules.
  • SSD Relative Standard Deviation
  • Example 2.1 was prepared using the TEMODAR® formulation as a comparative example.
  • Pellets were made by extrusion-spheronization using the excipients identified in Table 9.
  • a wet extrudable mass was prepared, extruded, and spberonized.
  • the extrusion/spheronization process followed the general sequence described in Table 3 above.
  • the extruder was a Caleva bench-top screen Extruder 20 having a screen size of 1mm and operated at a speed of about 30-35 RPM.
  • the spheronizer was a Caleva MultiBowl Spheronizer/mbs 250. operating al about 750 - 1500 RPM.
  • the sieves used for fractionation were 1.4 mm, 1.0 mm, 400 ⁇ m and 250 ⁇ m.
  • pellets which were retained on the 400 ⁇ m and 1000 ⁇ m sieves, thus the mean diameter of pellets in each of the batches was in the region of 400-1000 ⁇ m.
  • Pellets returned an assay value of 98.6% of the expected API. Satisfactory flow-properties were not observed and the overall quality of the pellets produced was poor. Pellets did not exhibit uniform shape or size. The pellets contained about 4 to 6 wt.% or less water by loss on drying.
  • [MCC] and extra-granular Sodium Starch Glycolate were two of the opportunities explored. Their respective formulations are presented in Table 10 below.
  • a wet cxtrudable mass was prepared, extruded, and spheronized.
  • the extrusion'spheronization process followed the general sequence described in Table 3 above.
  • the extruder was a Gileva bench-top screen Extruder 20 having a screen size of 1mm and operated at a speed of about 30*35 RPM.
  • the spheronizer was a Caleva MultiBowl Spheronizer/mbs 250, operating at about 750 - 1500 RPM.
  • the sieves used for fractionation were 1.4 mm, 1.0 mm, 400 ⁇ m and 250 ⁇ m.
  • pellets which were retained on the 400 ⁇ m and 1000 ⁇ m sieves, thus the mean diameter of pellets in each of the batches was in the region of 400- 1000 ⁇ m.
  • Pellets returned assay values of at least 91% of the expected API. Satisfactory (low-properties were observed and the overall quality of the pellets produced was surprisingly improved by the presence of the Microcrystalline Cellulose within the formulation.
  • the pellets contained about 4 to 6 wt.% or less water by loss on drying.
  • Dissolution release properties of the pellets in HPMC hard capsule shells were measured (Table 11]. 450 mg of pellets were filled into hard capside shells and tested for dissolution release using USP Apparatus 1 [Baskets] at 100 RPM, with a medium of de-aerated purified water, 37 ⁇ 0.5 °C, with a volume of 900 mL. The average dissolution limes were derived from dissolution testing on six capsules.
  • MCC made to the overall quality of the pellets produced.
  • MCC solubility enhancer
  • GELUCIRE& solubility enhancer
  • Their respective formulations are presented in Table 12 below.
  • a wet extrudablc mass was prepared, extruded, and spheronized.
  • the extrusion/spheronization process followed the general sequence described in Table 3 above.
  • the extruder was a Caleva bench- top screen Extruder 20 having a screen size of 1 min and operated al a speed of about 30-35 RPM.
  • the spheronizer was a Caleva MultiBowl Spheronizer/mbs 250, operating at about 750 - 1500 RPM.
  • the sieves used for fractionation were 1.4 mm, 1.0 mm, 400 ⁇ m and 250 ⁇ m.
  • Final selected pellets for each batch were pellets which were retained on the 400 ⁇ m and 1000 ⁇ m sieves, thus the mean diameter of pellets in each of the batches was in the region of 400-1000 ⁇ m.
  • Pellets returned assay values of al least 91% of the expected API. Satisfactory flow-properties and pellet quality were observed.
  • the pellets contained about 4 to 6 wt.% or less water by loss on drying. [0882] Dissolution release properties of the pellets in HPMC hard capsule shells were measured
  • Trifle 13 Target fin weights presented fa Trifle 10 were filled into herd capsule shells and tested for dissolution release usmg DSP Apparatus 1 (Baskets) at 100 RPM, with a medium of denwrated purified water, 37 * 0.5°C, with a volume of 900 mL The average dissolution times wore derived from disMdution testing on six capsules.
  • compositions are deacribed as including components ar materials; it is conlemplaied that the compositions can also consist essentially of, or consist at, any combination of the recited components or materials, unless deacribed otherwise.
  • methods are described as including particular steps, it is contemplated that the methods can also consist essentially of, or consist of, combination of the recited steps, unless described otherwise;
  • the invention iHuattati vely disclosed hereto suitably may be practiced to the absence of any dement or step whidi is not specifically disclosed hereto.

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Abstract

L'invention concerne des formes posologiques multiparticulaires à libération immédiate, et des procédés de fabrication et d'utilisation de celles-ci. Les formes posologiques sont destinées à des formulations anticancéreuses appropriées pour des personnes et des animaux.
PCT/US2021/048184 2020-09-30 2021-08-30 Formes posologiques à libération immédiate, procédés de fabrication et d'utilisation de celles-ci Ceased WO2022072099A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116889564A (zh) * 2023-06-14 2023-10-17 潍坊医学院附属医院 一种新型替莫唑胺制剂及其用途

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Publication number Priority date Publication date Assignee Title
WO2010017056A1 (fr) * 2008-08-07 2010-02-11 Merck & Co., Inc. Formulations solides administrées par voie orale contenant un médicament hydrophobe et du tpgs
US7910315B2 (en) 2004-09-10 2011-03-22 The Regents Of The University Of Colorado, A Body Corporate Early detection of hemangiosarcoma and angiosarcoma
US20160199302A1 (en) * 2012-12-31 2016-07-14 Samyang Biopharmaceuticals Corporation Pharmaceutical Composition Comprising Temozolomide With Improved Stability and Process for Manufacturing the Same
US20190083399A9 (en) * 2006-04-03 2019-03-21 Isa Odidi Drug delivery composition
US10709715B2 (en) * 2017-12-03 2020-07-14 Cipla Limited Method of treating hypertension

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7910315B2 (en) 2004-09-10 2011-03-22 The Regents Of The University Of Colorado, A Body Corporate Early detection of hemangiosarcoma and angiosarcoma
US20190083399A9 (en) * 2006-04-03 2019-03-21 Isa Odidi Drug delivery composition
WO2010017056A1 (fr) * 2008-08-07 2010-02-11 Merck & Co., Inc. Formulations solides administrées par voie orale contenant un médicament hydrophobe et du tpgs
US20160199302A1 (en) * 2012-12-31 2016-07-14 Samyang Biopharmaceuticals Corporation Pharmaceutical Composition Comprising Temozolomide With Improved Stability and Process for Manufacturing the Same
US10709715B2 (en) * 2017-12-03 2020-07-14 Cipla Limited Method of treating hypertension

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116889564A (zh) * 2023-06-14 2023-10-17 潍坊医学院附属医院 一种新型替莫唑胺制剂及其用途

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