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    • 专利摘要:
    DOSAGE FORM AND IMMEDIATE RELEASE FORMULATION, AND, USE THEREOF The present invention provides an immediate release dosage form adapted for oral administration of GHB. The solid immediate release dosage form includes an immediate release formulation comprising a relatively high percentage by weight of GHB with a bioavailability similar to the liquid GHB dosage form.
    公开号:BR112012028035B1
    申请号:R112012028035-0
    申请日:2010-05-04
    公开日:2021-05-25
    发明作者:Maura Patricia Murphy；James Frederick Pfeiffer；Clark Patrick Allphin；Alya Khan Mcginlay；Andrea Marie Rourke
    申请人:Jazz Pharmaceuticals, Inc.；
    IPC主号:
    专利说明:

    BACKGROUND OF THE INVENTION
    [001] Initial interest in the use of sodium oxybate as a potential treatment for narcolepsy arose from observations made during the use of sodium oxybate (the sodium salt of gamma-hydroxybutyrate) for anesthesia. Unlike traditional hypnotics, sodium oxybate induces sleep that closely resembles normal physiological sleep (Mamelak ET AL., Biol Psych 1977:12:273-288). For this reason, early investigators administered gamma-hydroxybutyrate (GHB) to patients suffering from restless sleep disorders, including narcolepsy (Broughton ET AL. in Narcolepsy, NY, NY: Spectrum Publications, Inc. 1976:659-668), where it has been found to increase total nighttime sleep time, decrease nighttime awakenings, and increase Stage 3-4 sleep (slow wave). Three open-label and two placebo-controlled studies provided a body of evidence demonstrating that improvements in nocturnal sleep were associated with a reduction in catalepsy and improvements in excessive daytime sleepiness (Broughton ET AL., Can J. Neurol Sci 1979; 6:1 -6, and Broughton ET AL., Can J. Neurol Sci 1980; 7:23-30)
    [002] Scharf ET AL. conducted an open-label study to assess the effects of GHB on sleep patterns and symptoms of non-narcoleptic fibromyalgia patients (Scharf ET AL., J Rheumatol 1998;25: 1986-1990). Eleven patients with a previously confirmed diagnosis of fibromyalgia reported at least a 3-month history of generalized musculoskeletal pain in all quadrants of the body and tenderness in at least five specific trigger point sites participated in the study. The results showed that patients reported significant improvements in subjective ratings of their pain and fatigue levels during the 4 weeks of GHB treatment, as compared to baseline, as well as a significant improvement in their estimates of general well-being before and after treatment with GHB.
    [003] WO 2006/053186 to Frucht describes an open-label study of five patients with hyperkinetic movement disorders including ethanol-responsive myoclonus and essential tremor. Sodium oxybate has been reported to produce dose-dependent improvements in the simulation rates of ethanol-responsive myoclones and tremor and has been reported to be tolerated at doses that provide clinical benefit.
    Xyrem® Sodium Oxybate Oral Solution, the FDA approved treatment for catalepsy and excessive daytime sleepiness associated with narcolepsy contains 500 mg sodium oxybate/ml water, adjusted to pH = 7.5 with malic acid. In man, the plasma half-life of sodium oxybate given orally is about 45 minutes and doses of 2.25 grams to 4.5 grams induce about 2 to 3 hours of sleep (See, L. Borgen ET al., J. Clin. Pharmacol., 40, 1053 (2000)). For optimal clinical effectiveness in narcolepsy, sodium oxybate should be given twice overnight, and is administered as an aqueous solution. For each dose, a measured amount of the oral solution must be removed from the primary container and transferred to a separate container where it is diluted with water prior to administration. The second dose is prepared at bedtime and stored for administration in the middle of the night. This regimen is cumbersome and may be susceptible to errors in the preparation of individual doses. For that reason, a more convenient unit dosage form of the drug would be clinically advantageous. Sodium oxybate is highly water soluble, hygroscopic and strongly alkaline. Paradoxically, despite its high water solubility, it can exhibit poor dissolution when formulated into a tablet with common excipients. These properties, together with the large amount of drug that is required to achieve clinical effect, pose challenges in preparing solid dosage forms that are designed for the immediate release of sodium oxybate into the user's gastrointestinal tract. BRIEF DESCRIPTION OF THE DRAWINGS
    [005] Figure 1 is a graph describing the dissolution profiles of immediate release formulations as described here.
    [006] Figure 2 is a graph showing the dissolution profiles of immediate release formulations as described here.
    [007] Figure 3 is a graph showing the effect of lubricant on dissolution profiles of immediate release formulations as described here. DETAILED DESCRIPTION
    [008] Formulations and dosage forms for the immediate release of a drug are described here. The formulations described here are suitable for the immediate release of high doses of drugs that are highly water soluble. Furthermore, in certain embodiments, the formulations described herein provide immediate release of drugs that are highly hygroscopic, even where these drugs must be administered in relatively high doses. In particular embodiments, the immediate release formulations are provided as a unit dosage form, and in certain embodiments, the immediate release formulation is provided as an immediate release tablet.
    [009] An example of a drug that can be used with the immediate release formulations and dosage forms described here is GHB. It should be noted that embodiments of the immediate release dosage forms comprising GHB are presented herein for illustrative purposes only and not for purposes of limitation. The formulations and unit dosage forms provided herein can be used to achieve immediate release of GHB, as well as pharmaceutically acceptable salts, hydrates, isomers, including tautomers, solvates and complexes of GHB. Suitable salts of GHB include sodium oxybate, calcium oxybate, as well as lithium, potassium, and magnesium salts.
    [0010] The administration of GHB in solid form presents several challenges. The amount of drug taken by the patient for each dose is high, usually at least 1.5 grams and as high as 4.5 grams. Patients treated with GHB may have difficulty taking solid medications by mouth either because they have disease states that make handling and swallowing difficult or because they must take the medication after being awake in the middle of the night. The situation is exacerbated by the large amount of drug that is administered in each dose. Consequently, it is desirable to keep the tablet size as small as possible while incorporating the greatest amount of active ingredient. Furthermore, if an immediate release tablet is to achieve bioequivalence with the existing Xyrem® oral solution, such formulation must dissolve quickly without high levels of excipients to accelerate dissolution.
    As used herein, the term "GHB" refers to gamma-hydroxybutyrate, as well as pharmaceutically acceptable salts, hydrates, isomers, including, tautomers, solvates and complexes of gamma-hydroxybutyrate. In certain embodiments, the immediate release GHB compositions described herein comprise a therapeutically effective amount of sodium oxybate or an alternative salt thereof. The structure of sodium oxybate is given below as formula (1a):

    [0012] Alternative salts usable in an immediate release dosage form as described herein include compounds of formula (I):
    wherein X is a pharmaceutically acceptable cation and may be selected from the group consisting of potassium, calcium, lithium and magnesium and Y is OH. Sodium gamma hydroxybutyrate (sodium oxybate), is currently available from Jazz Pharmaceuticals, Inc. as a Xyrem® oral solution.
    [0013] A "distribution rate" refers to the amount of drug released IN VIVO from the formulation (tablet or dosage form) as described herein per unit of time, for example, milligrams of a pharmaceutically acceptable salt, hydrate, isomer, tautomer . solvate or complex of GHB per unit of time.
    [0014] "Immediate release" refers to a composition that releases GHB or a pharmaceutically acceptable salt, hydrate, isomer, tautomer, solvate or complex of GHB substantially completely within the user's gastrointestinal tract within a period of less than one hour, usually between about 0.1 and about 1 hour and less than about 0.75 hours from ingestion. Such a delivery rate allows the drug to be absorbed from the gastrointestinal tract in a way that is bioequivalent to an oral solution. Where sodium oxybate is used as the drug and bioequivalence to the Xyrem® oral solution of sodium oxybate is required, rapid drug release from the immediate release formulations described here is desirable because following delivery of the Xyrem® oral solution, the peak plasma concentration of sodium oxybate occurs within one hour. Such rapid absorption will typically occur for an immediate release unit dosage form, such as a tablet, microcapsule or capsule, if the drug included in such dosage form dissolves in the upper portion of the gastrointestinal tract.
    [0015] A "dissolution rate" refers to the amount of drug released IN VITRO from a dosage form per unit time in a release medium. IN VITRO dissolution rates in the studies described here were performed on dosage forms placed in a USP Type II bath containing water, which is stirred while maintained at a constant temperature of 37°C. In some examples, aliquots of the dissolution medium were injected into a chromatographic system to quantify the amounts of drug dissolved during each test interval. In other cases, dissolution was monitored with conductivity measurements using an immersion probe.
    [0016] "Bioavailability" as used herein is intended for the estimated area under the curve, or AUC of the active drug in the systemic circulation after oral administration with a dosage form as described here when compared to the AUC of the active drug in the systemic circulation after oral administration of Xyrem® sodium oxybate oral solution. AUC is affected by the extent to which the drug is absorbed from the GI tract. In the case of sodium oxybate, absorption tends to be greater in the upper GI tract, therefore, in particular embodiments, immediate release formulations and dosage forms described in the present invention include formulations that dissolve rapidly in order to to be bioequivalent to Xyrem® oral solution.
    Products are considered to be “bioequivalents” if the relative mean Cmax, AUC(o-t) and AUC of the test product for the reference product is within 80% to 125%.
    [0018] “Sodium oxybate oral solution” refers to the product commonly known as Xyrem®, a solution containing 500 mg sodium oxybate/ml of water, adjusted to pH = 7.5 with malic acid.
    [0019] The term "AUC0-t" means the area under the plasma concentration curve from time 0 to time t.
    [0020] The term “AUC0-^” or “AUC0-inf” means the area under the plasma concentration time curve from time 0 to infinity.
    [0021] “Cmax” refers to the maximum plasma concentration of sodium oxybate. The Cmax of a 3-gram dose of immediate-release tablets is between 10 and 200 μg mL, often between 20 and 120 μg mL. Such profiles are especially desirable for diseases such as narcolepsy, cataplexy, movement disorders such as essential tremor and restless legs syndrome, fibromyalgia and chronic fatigue syndrome.
    [0022] "Tmax" refers to the time to maximum plasma concentration for a given drug, which for sodium oxybate is between 0.5 and 2.5 hours, often between 0.5 and 1.5 hours / " t y2” refers to the time to reduce the plasma concentration by 50% during the terminal elimination phase of the drug, which for sodium oxybate is between 0.4 and 0.9 hours, often between 0.5 and 0 ,7 hours.
    [0023] The apparent elimination rate constant is “X”, which for sodium oxybate can be between 0.5 and 2.5 hours1.
    [0024] "Oxybate salt" refers to a compound of formula I where X is a pharmaceutically acceptable cation and may be selected from the group consisting of sodium, potassium, calcium, lithium and magnesium and Y is OH.
    [0025] "Sodium oxybate" refers to a compound of the formula la.
    Immediate release formulations suitable for oral administration may include unit dosage forms, such as tablets, pills or filled capsules, which can deliver a therapeutically effective dose of GHB upon ingestion by the patient of one or more dosage forms each of which can provide a dosage of, for example, about 0.5 to 10.5 g of GHB. In addition, immediate release dosage forms can be shaped or sized to facilitate swallowing.
    [0027] The formulation and structure of an immediate release dosage form as described herein can be adjusted to provide immediate release performance that suits the particular dosage need. In particular, the formulation and structure of the dosage forms as described herein can be tailored to provide any combination of the immediate release performance characteristics described herein. In particular embodiments, for example, an immediate release dosage form as described herein provides rapid onset of action, releasing more than 90%, such as, for example, more than about 95%, of the drug contained. in it within a time period selected from less than one hour, less than 45 minutes, less than 30 minutes and less than 15 minutes after administration.
    [0028] In addition, the rate of drug release from an immediate release dosage form as described herein can be adjusted as necessary to facilitate the desired dosage regimen or achieve the planned dosage. In one embodiment, the immediate release dosage form can be formulated to deliver as much as 2,000 mg of GHB. In particular embodiments, the total amount of drug contained within an immediate release dosage form in accordance with the present description can be between about 500 mg and about 1,400 mg. For example, in certain embodiments, the total amount of drug can be selected from about 500 mg and 1,400 mg, 500 mg and 1,200 mg, 500 mg and 1,100 mg, 600 mg and 1,200 mg, 600 mg and 1,100 mg, 600 mg and 1,000 mg, 600 mg and 950 mg, 600 mg and 850 mg, 600 mg and 750 mg, 750 mg and 1,200 mg, 750 mg and 1,100 mg, 750 mg and 1,000 mg, 750 mg and 950 mg, and 750 mg and 850 mg.
    [0029] The immediate release dosage forms described here include immediate release formulations that facilitate elevated GHB loading. For example, in particular embodiments, immediate release formulations can include between about 70% and 98% by weight of GHB. In certain embodiments, an immediate release formulation as described herein may comprise GHB in an amount selected from about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87% , 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, and 98% by weight of the immediate release formulation. In such embodiments, the amount of GHB in the immediate release formulation may range from about 80 to 84%, from 82 to 85%, from 82 to 86%, from 84 to 88%, from 85 to 90 %, from 88 to 92%, and 90 to 94%, from 94 to 98%, from 94 to 97%, from 94 to 96%, from 95 to 98%, from 95 to 97%, and from 95 to 96.5 % by weight of immediate release formulation. In particular embodiments, even with the high drug loading described herein, the immediate release formulations described herein facilitate the production of solid unit dosage forms that are bioequivalent to Xyrem® sodium oxybate oral solution. In such certain embodiments, the solid unit dosage forms described herein release greater than about 95% of the GHB contained therein within a period of less than one hour after administration.
    [0030] Immediate release formulations provided herein generally include GHB and some level of lubricant to facilitate processing the formulations into a unit dosage form. In some embodiments, therefore, the formulations described herein include a combination of GHB and lubricant, as described herein, and in certain embodiments, the immediate release formulations are substantially free of other excipients or adjuvants. In other embodiments, the immediate release formulations described herein include a combination of GHB, lubricant, and binder, as described herein, and in such certain embodiments, the immediate release formulations are substantially free of other excipients or adjuvants. In still other embodiments, the immediate release formulations described herein include a combination of GHB, lubricant, and surfactant, as described herein, and in such certain embodiments, the immediate release formulations are substantially free of other excipients or adjuvants. . In still other embodiments, the formulations described herein include a combination of GHB, lubricant, binder, and surfactant, as described herein, and in such certain embodiments, immediate release formulations are substantially free of other excipients or adjuvants. Although the immediate release formulations described herein may be formulated using a combination of drug and one or more of a lubricant, binder and surfactant, in certain embodiments, the compositions described herein include one or more additional excipients selected from, for example, fillers, compression aids, diluents, disintegrants, colorants, buffering agents, coatings, glidants, or other suitable excipients.
    [0031] To facilitate processing the immediate release formulations described herein into unit dosage forms, immediate release formulations will typically include some level of lubricant. For example, in particular embodiments, the immediate release formulation may include one or more lubricants selected from at least one of magnesium stearate, stearic acid, calcium stearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium stearyl fumarate, zinc stearate, and combinations of any of the foregoing. In certain embodiments, the one or more lubricants can be added to the immediate release formulation in an amount that results in a total lubricant content of between about 0.5% and about 10% by weight. For example, in such embodiments, an immediate release formulation as described herein may exhibit a total lubricant content in a range selected from about 0.5% to 5% by weight, about 1% to 5% by weight about 4 to 10% by weight, about 4 to 8% by weight, about 6 to 10% by weight, about 1% to 3% by weight, about 1% to 2% by weight, about 2% to 3% by weight, and about 2% to 4% by weight. In such an embodiment, one or more lubricants may be present in the immediate release formulation, and the total lubricant content may be selected from about 0.5%, 1%, 1.5%, 2%, 2.5 %, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5% and 10% by weight. Where the immediate release formulation is provided as a tableted dosage form, even lower levels of lubricant can be achieved with the use of an insufflator system during tableting. Such systems are known in the art, are commercially available and apply the lubricant directly to the punch and mold surfaces rather than through the formulation.
    [0032] In particular embodiments, the immediate release compositions described herein may include a lubricant selected from stearic acid and sodium stearyl fumarate, wherein the lubricant is included in the formulation in an amount of between about 0.5% and about 2% by weight. In another embodiment, an immediate release formulation as described herein can comprise between about 0.5% and about 2% by weight of magnesium stearate as a lubricant. In such an embodiment, magnesium stearate can be used in combination with one or more other lubricants or a surfactant, such as sodium lauryl sulfate. In particular, if necessary to overcome the potential hydrophobic properties of magnesium stearate, sodium lauryl sulfate can also be included when using magnesium stearate (Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro, Ed., Lippincott Williams & Wilkins (2000)).
    [0033] In specific embodiments where the immediate release formulation comprises GHB in combination with a lubricant, the immediate release formulation may comprise from about 90 to 99% by weight of GHB and about 1 to 10% by weight of a lubricant selected from at least one of magnesium stearate, stearic acid, calcium stearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium stearyl fumarate and zinc stearate. In such an embodiment, the immediate release formulation can comprise between about 98 to 99% by weight of GHB and between about 1 to 2% by weight of the magnesium stearate lubricant. In another example, the immediate release formulation may comprise about 98 to 99% by weight of GHB and about 1 to 2% by weight of a lubricant selected from stearic acid and sodium stearyl fumarate. In particular embodiments of immediate release formulations incorporating a lubricant described herein, the GHB included in such formulations may be selected from sodium oxybate and calcium oxybate.
    [0034] The immediate release formulations described herein may include one or more binders. Suitable binders for use in the immediate release formulations herein include, for example, hydroxypropyl cellulose (HPC), ethyl cellulose, hydroxypropylmethyl cellulose (HPMC), polyvinyl alcohol, polyvinyl pyrrolidone, hydroxyethyl cellulose, povidone, copovidone, pregelatinized starch, dextrin , gelatin, maltodextrin, starch, zein, acacia, alginic acid, carbomers (cross-linked polyacrylates), polymethacrylates, sodium carboxymethylcellulose, guar gum, hydrogenated vegetable oil (type 1), methylcellulose, magnesium aluminum silicate, and sodium alginate. In specific embodiments, an immediate release formulation included in an immediate release dosage form as described herein may comprise binder levels in the range of about 1% to 10% by weight. For example, the immediate release formulation may include a binder in an amount selected from about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% , 5%, 6%, 7%, 8%, 9%, and 10% by weight. In such certain embodiments, the amount of binder included in the immediate release formulation may range from about 1 to 2%, 1 to 3%, 1 to 4%, 1 to 5%, 1 to 6%, 1 7%, 1 to 8%, 1 to 9% and 1 to 10% by weight.
    [0035] In one embodiment, the immediate release formulation comprises GHB in combination with a binder. For example, the immediate release formulation can comprise between about 90 to 98% by weight of GHB and between about 2 to 10% by weight of binder. In such an embodiment, the binder can be selected from, for example, at least one of HPMC, HPC, sodium carboxymethyl cellulose, polyvinyl alcohol, povidone, and starch. In another embodiment, the immediate release formulation can include between about 90 to 98% by weight of GHB, between about 1 to 5% by weight of a lubricant as described herein, and between about 1 to 5% by weight. weight of a binder selected from, for example, at least one of HPMC, HPC, sodium carboxymethyl cellulose, polyvinyl alcohol, povidone, and starch. In yet another embodiment, the immediate release formulation can include between about 96 to 98% by weight of GHB, between about 1 to 2% by weight of a lubricant as described herein, and between about 1 to 2% by weight of a binder selected from, for example, at least one of HPMC, HPC, sodium carboxymethyl cellulose, polyvinyl alcohol, povidone, and starch. In yet another embodiment, the immediate release formulation can include between about 96 to 98% by weight of GHB, between about 1 to 2% by weight of a lubricant selected from magnesium stearate, stearic acid, stearyl fumarate. sodium, and combinations thereof, and between about 1 to 2% by weight of a binder selected from HPMC and povidone. In particular embodiments of immediate release formulations incorporating a binder described herein, the GHB included in such formulations may be selected from sodium oxybate and calcium oxybate.
    [0036] The immediate release formulation may also include one or more surfactants. For example, one or more surfactants may be added to formulations which may include poorly soluble excipients in order to facilitate dissolution of these excipients and, indirectly, of the drug. Adding small amounts of surfactant to immediate release formulations as described here can produce increased dissolution rates. In certain embodiments, the immediate release formulation may include GHB in combination with one or more surfactants selected from, for example, ionic and non-ionic surfactants. In such an embodiment, the immediate release formulation can include at least one anionic surfactant, including sodium docusate (sodium salt of dioctyl sulfosuccinate) and sodium lauryl sulfate. In yet another embodiment, the immediate release formulation can include at least one nonionic surfactant selected from polyoxyethylene alkyl ethers, polyoxyethylene stearates, poloxamers (e.g., poloxamer 188), polysorbate (e.g., polysorbate 80), esters of sorbitan, and glyceryl monooleate. In specific embodiments, one or more surfactants included in an immediate release formulation as described herein may be present, for example, in an amount of between about 0.25 to 2.5% by weight of the immediate release formulation. In other embodiments, one or more surfactants included in an immediate release formulation as described herein may be present in an amount of up to about 3.0% by weight of the immediate release formulation. For example, in certain embodiments, the immediate release formulation may include one or more surfactants present in a range selected from about 0.01% to 3%, from 0.01% to 2%, from 0.01% 1%, 0.5% to 3%, 0.5% to 2%, and 0.5% to 1% by weight of the immediate release formulation. In such an embodiment, the immediate release formulation can include about 1% by weight of a surfactant selected from polysorbate 80, poloxamer 188, sodium lauryl sulfate, and sodium docusate.
    [0037] In certain embodiments, the immediate release formulations described herein comprise GHB in combination with a surfactant and a lubricant. In such an embodiment, the immediate release formulation includes about 90 to 98% by weight of GHB, up to about 3.0% by weight of surfactant and up to about 10% by weight of binder. In such an embodiment, the immediate release formulation includes about 95 to 98% by weight of GHB, about 1 to 2% by weight of surfactant selected from polysorbate 80, poloxamer 188, sodium lauryl sulfate, and sodium docusate , and about 1 to 3% by weight of binder selected from HPMC and povidone. In another embodiment, the immediate release formulation includes about 95 to 97.5% by weight of GHB, about 0.5 to 1% by weight of surfactant selected from polysorbate 80, poloxamer 188, sodium lauryl sulfate, and sodium docusate, about 1 to 2% by weight of binder selected from HPMC and povidone, and about 1 to 2% by weight of lubricant selected from magnesium stearate, stearic acid, sodium stearyl fumarate, and combinations thereof . In yet another embodiment, the immediate release formulation includes about 90 to 97.5% by weight of GHB, about 0.5 to 2% by weight of surfactant selected from polysorbate 80, poloxamer 188, sodium lauryl sulfate , and sodium docusate, about 1 to 4% by weight of binder selected from HPMC and povidone, and about 1 to 4% by weight of lubricant selected from magnesium stearate, stearic acid, sodium stearyl fumarate, and combinations of the same. In particular embodiments of immediate release formulations incorporating a surfactant described herein, GHB may be selected from sodium oxybate and calcium oxybate.
    [0038] The immediate release formulations described here can be manufactured using standard techniques such as wet granulation, roller compaction, fluid bed granulation, and dry powder mixing. Appropriate methods for manufacturing the immediate release formulations and unit dosage forms described herein are provided, for example, in Remington, 20th edition, Chapter 45 (Oral Solid Dosage Forms). It has been found that, even without the aid of non-lubricating binders or excipients, such as compression aids, wet granulation techniques can produce flowable granules with suitable compression characteristics to form the unit dosage forms as described herein. For this reason, in certain embodiments where a drug content greater than about 85%, 90% or 95% by weight is desired for the immediate release formulation, wet granulation techniques can be used to prepare the immediate release formulations as described here. In such embodiments, as illustrated in the Examples provided herein, conventional organic or aqueous solvents can be used in the wet granulation process. Appropriate wet granulation processes can be carried out by high shear or low shear, fluid bed granulation (wet mass) techniques as are known in the art.
    [0039] In addition to one or more of a GHB drug, lubricant, binder and surfactant, where desired, the immediate release formulations described herein may also include fillers or compression aids selected from at least one of lactose, calcium carbonate, sulfate of calcium, compressible sugars, dextrates, dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, powdered cellulose, and sucrose. Where a filler or compression aid is used, in certain embodiments it can be included in the immediate release formulation in an amount ranging from about 1% to 15% by weight. In such embodiments, immediate release formulations include about 5 to 10% by weight of microcrystalline cellulose. In other embodiments, immediate release formulations include about 2.5 to 7.5% by weight of microcrystalline cellulose.
    [0040] Immediate release formulations as described herein may be processed into unit dosage forms suitable for oral administration, such as, for example, filled capsules, compressed tablets or caplets, or other dosage form suitable for oral administration using conventional techniques. Immediate release dosage forms prepared as described can be adapted for oral administration in order to achieve and maintain a therapeutic level of GHB during a preselected interval. In certain embodiments, an immediate release dosage form as described herein can comprise an oral dosage form of any desired shape and size including round, oval, cylindrical, oblong, or polygonal. In such an embodiment, the surfaces of the immediate release dosage form can be flat, round, concave, or convex.
    [0041] In particular, when immediate release formulations are prepared as a tablet, immediate release tablets contain a relatively large percentage and absolute amount of GHB and thus are expected to improve compliance and convenience by replacing the need to ingest large amounts of liquids or liquid/solid suspensions. One or more immediate release tablets as described herein may be administered, by oral ingestion, for example, closely spaced, in order to provide a therapeutically effective dose of GHB to the individual in a relatively short period of time. For example, the disintegration of a 500 mg to 1.0 g tablet prepared in accordance with the present description can provide about 80 to 100% GHB to the individual in about 30 to 60 minutes.
    [0042] Where desired or necessary, the outer surface of an immediate release dosage form as described herein may be coated with a moisture barrier layer using materials and methods known in the art. For example, where the GHB delivered by the unit dosage form is highly hygroscopic, such as, for example, where sodium oxybate is used, providing a moisture barrier layer over the immediate release dosage form as described herein may be desirable . For example, protection of an immediate release dosage form as described against water during storage can be provided or enhanced by coating the tablet with a coating of an insoluble or substantially water-soluble polymer. Water resistant or water insoluble coating polymers include ethyl cellulose and polyvinyl acetates. Other water resistant or water insoluble polymers include polyacrylates, polymethacrylates or the like. Suitable water soluble polymers include polyvinyl alcohol and HPMC. Other suitable water-soluble polymers include PVP, HPC, HPEC, PEG, HEC and the like.
    [0043] The methods described herein are for treating conditions susceptible to treatment with GHB by administering an effective amount of one or more dosage forms as described herein. For example, the present forms and dosages can be administered to treat a human suffering from narcolepsy to reduce cataplexy and/or daytime sleepiness. In addition, the dosage forms described herein may be of use in treating a variety of conditions amenable to treatment with GHB, such as to improve sleep quality, or in conditions where an increase in IN VIVO growth hormone levels is desired. , and to treat fibromyalgia or chronic fatigue syndrome. See, US Patent No. 5,990,162. The present dosage forms can be used to treat a number of other indications including drug and alcohol abuse, anxiety, cerebrovascular diseases, central nervous system disorders, neurological disorders including Parkinson's disease and Alzheimer's disease, multiple sclerosis, autism, depression, inflammatory disorders, including those of the bowel such as irritable bowel disorder, regional illitis, and ulcerative colitis, inflammatory autoimmune disorders, certain endocrine disorders, and diabetes.
    [0044] The present dosage forms can also be administered for the purpose of tissue protection including protection following hypoxia/anoxia, such as in stroke, organ transplantation, organ preservation, myocardial infarction or ischemia, injury to reperfusion, protection following chemotherapy, radiation therapy, progeria, or an increased level of intracranial pressure, for example, due to head trauma. The present dosage forms can also be used to treat other conditions believed to be caused or exacerbated by lipid and/or free radical peroxidation, such as conditions associated with oxidative stress, including normal aging. See, US Patent Publication 2004/009245 5 A1. The present dosage forms can also be used to treat movement disorders including restless legs syndrome, myoclonus, dystonia and/or essential tremor. See, Frucht et al, Movement Disorders, 20(10), 1330 (2005).
    [0045] The dosage forms described herein may be provided herein as a kit comprising, separately packaged, a container comprising a plurality of immediate release tablets, which tablets may be packaged separately, such as in foil envelopes or in blister packaging. . Tablets can be packaged in many shapes with or without desiccants or other materials to prevent water ingress. Instructional materials or media, such as a printed label, may also be included for their administration, for example, sequentially over a preselected period of time and/or at preselected intervals, to produce the levels of sodium oxybate IN VIVO for pre-selected time periods to treat a pre-selected condition.
    [0046] A daily dose of about 1 to 400 mg/kg and sodium oxybate or another oxybate salt such as a compound of formula (I) can be administered to effect the therapeutic results described herein. For example, a daily dosage of about 0.5 to 20 g of sodium oxybate or a compound of formula (I) can be administered, preferably about 3 to 9 g, in single or divided doses. For example, usable dosages and modes of administration are described in US Pat. 5,990,162 and 6,472,432. Methods to extrapolate from dosages found to be effective in laboratory animals such as mice to effective doses in humans are known in the art. See, US Patent No. 5,294,430, or 4,939,949. Examples Example 1. Sodium Oxybate Immediate Release Pills
    [0047] This example compares two tablet formulations of compressed sodium oxybate that have more than 70% drug loading, one in which the granulation was done by wet granulation and the other by roller compaction. The composition of the tablets is summarized in Table 1, along with quantities to produce batches of 3000 tablets each. Table 1 Formulation A (wet granulate)
    Formulation B (dry granulated)

    [0048] Formulation A was produced by wet granulation in a planetary mixer. Sodium oxybate, microcrystalline cellulose, povidone, half the sodium lauryl sulfate, and 58% croscarmellose sodium were dry premixed. The remainder of the sodium lauryl sulfate dissolved in water used to granulate. The amount of water added was 8% of the dry powder weight. The material was mixed until uniform granules were made, then wet sized through a 6 mesh sieve, followed by oven drying at 60°C so that a final moisture content (loss on drying) was between 1.0% and 2.5%. The dry granulation was then milled through a 14 mesh sieve using a Comil. Finally, the remainder of the croscarmellose sodium was blended into the milled granulation with an 8-quart V blender for 5 minutes, and the magnesium stearate was then added and blended for an additional 3 minutes.
    [0049] To prepare Formulation B by roller compaction, first all ingredients were hand sieved through a 20 mesh sieve. All ingredients except magnesium stearate and 43% croscarmellose sodium were transferred to an 8-quart V blender, and blended for five minutes. The intragranular portion of the croscarmellose sodium was blended in blender V for 5 minutes and finally the intragranular portion of magnesium stearate (20.0 g) was added to the blender and blending continued for 3 minutes. The mixed powder was passed through a Vector TF-156 roller compactor set to a target pressure of 47 kg/cm2, roller speed and screw speed, both 4 RPM. Tapes with a thickness of 10.4 ± 0.05 mm were made without adding water. The ribbons were granulated using an in-line rotary mill equipped with a 16 mesh screen. The granulate was added to the blender and blended for 5 minutes. The remaining magnesium stearate (14.2 g) and croscarmellose sodium (71.4 g) were added to the mixture, and mixed for 3 minutes.
    [0050] The two granulations were compressed into tablets on a standard 15-station rotary press equipped with a 0.3366" (0.86 cm) x 0.7283" (1.85 cm) oblong tooling. The target weights for A and B were 1050 mg and 950 mg, respectively, to achieve the target potency of 750 mg/tablet. The dissolution profiles, shown in FIG. 1, demonstrated that more than 90% is dissolved in 60 minutes. Example 2. Bioavailability and Bioequivalence of Sodium Oxybate Tablets
    [0051] The formulations of Example 1 were tested for bioequivalence of the oral solution of sodium oxybate (Xyrem®). A randomized, open, three-way, single-dose crossover study, a phase I of formulation A (4.5 grams of Formulation A given as 6 tablets: Treatment A), Formulation B (4.5 grams of Formulation B given as 6 tablets: Treatment B), and Xyrem® (4.5 grams of oral sodium oxybate solution: Treatment C). Following a 21-day screening period, the duration of the study for each subject was approximately 7 days, Period 1 comprising Days 1 and 2, Period 2 comprising Days 3 and 4, and Period 3 comprising days 5 and 6. A 2-day rest period (dosing on the morning of the first day followed by 1 day wash) separated Treatments, B and C.
    Single doses (4.5 g, given as 6 tablets of 750 mg) of solid dosages of sodium oxybate of Formulations A and B and single doses (4.5 g) of oral solution of sodium oxybate (Xyrem® ) were administered orally in the morning following 10 hours of fasting, with subjects fasting for another 4 hours after dosing. The PK profile for sodium oxybate was evaluated over an 8 hour period, based on blood samples (5 ml) collected as pre-dose; at 10, 20, 30, 45, 60, and 75 minutes after dosing; and at 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7 and 8 hours after the dose following each treatment. PK parameters calculated for plasma sodium oxybate concentrations included: the area under the plasma concentration time curve from time 0 to time t of the last quantifiable concentration [AUC0-t], and area under the concentration time curve in plasma from time 0 to infinity [AUCo--,], the maximum plasma sodium oxybate concentration (Cmax), time to maximum plasma concentration (tmax), the apparent elimination rate constant (Az) and a half life (t/ and the relative bioavailability for solid dosage of Formulations A and B versus Xyrem®.
    The relative bioavailability of Treatments A and B versus Treatment C (Xyrem®) based on AUC values was 98% and 100%, respectively. All treatments were found to be bioequivalent with respect to Cmax and total AUC exposure following oral administration of sodium oxybate. Since no tablet formulation can dissolve faster than liquid Xyrem®, this study suggests that any tablet formulation that dissolves at least 80% in 45 minutes should be bioequivalent to Xyrem®. Table 2 Summary of Mean (SD) of Sodium Oxybate Pharmacokinetic Parameters
    Example 3 - Dry granulated formulation
    [0054] The granulation roller compaction method was chosen for further development and optimization of the formulation to maximize drug loading while producing tablets of acceptable quality. Two changes - addition of sodium lauryl sulfate as a surfactant and removal of croscarmellose sodium - resulted in formulation C, which has a drug loading of 84.2%, and was successfully processed using intensified roller compaction techniques described in Example 1 Table 1 shows formulation and batch amounts to produce about 120,000 tablets.
    [0055] The dry powders, except magnesium stearate, were passed through a Fitzmill assembly at low speed with knives in front), then loaded into a V 10 cu-ft (0.28 m3) mixer. and mixed for 130 seconds (39 rotations). The intragranular magnesium stearate (0.534 kg) was passed through a 20 mesh screen and then added to the V-blender containing the other powders and blended for 77 seconds (23 rotations). Roller compaction was performed on a Fitzpatrick Chilsonator (TG 99) with axially grooved rollers (1^" (3.81 cm) wide and 8" (20.32 cm) diameter) set with a roller speed of 8 rpm, horizontal screw feed 25 rpm, vertical screw speed 200 rpm, boost pressure about 22 psi (151.7 kPa), roll pressure 750 psi (5.2 MPa), and cooling temperature 6°C. The material was sieved through a 30” (76.2 cm) Sweeco equipped with a 14 mesh sieve. About 16% of the “fines” of the material were passed through the roller compactor a second time. The collected product was milled through a Fitzmill, and a 100 g sample was analyzed for fractions on the sieve. The amount retained over that of 20 mesh, 40, 60, 80, 120, 200, 325 mesh, and in the container was, respectively, 17.70%, 16.1%, 13.1%, 8.3%, 10 .4%, 10.3%, 9.0%, and 14.1%.
    [0056] For 104.2 kg of collected granulation, 1.05 kg of magnesium stearate was added and mixed in a V-blender for 77 seconds (23 rotations). The blended granulation was then compressed on a Hata tablet press equipped with a type B in D tool with 26 0.3290" (0.84 cm) x 0.7120" (1.8 cm) oblong tooling sets. The parameters were adjusted to produce 891 mg tablet weight, 5.8 to 5.9 mm thick, 9.1 to 13 kP hardness, and about 0.02% friability. 95.7 kg of acceptable tablets were produced.
    [0057] The dissolution profile, shown in FIG. 2, demonstrates substantially faster dissolution than that observed with the original dry granulated product of Formulation B. Table 3 Dry Granulated Formulation C
    Example 4- Drug loaded formulation for dry granulation
    [0058] The composition consisted of a low level of binder, a lubricant, and sodium oxybate. The granulation was manufactured in a TK Fielder 25 L high shear granulator according to the formula in Table 1A. The binder, hydroxypropyl cellulose (Klucel EXF), was divided into two equal portions; half was dissolved in ethanol, and half was dry blended with sodium oxybate. The material was initially granulated with 10% w/w ethanol and then titrated with another 3.5% w/w ethanol solution to achieve the desired granule growth. An appropriate wet mass was obtained with a total ethanol concentration of 13.5% w/w. The wet granules were divided into two sublots and then each sublot was dried in a Niro 5 liter fluid bed dryer. The dried granules were combined and milled through a Comil® equipped with a 14 mesh sieve. The granulation was then blended with 2% magnesium stearate lubricant. The particle size distribution and granulation parameters are shown in Tables 4B and 4C, respectively. Table 4 Immediate Release Pill Formulation
    *Granulation solvent, removed during drying step Table 4B Granulation parameters
    Table 4C Milled Granulation Screening Analysis
    Example 5 - Effect of Tablet Shape
    [0059] The formulation of Example 4, containing 96% sodium oxybate, 2% HPC ExF, and 2% magnesium stearate, was produced in two batches using the procedures described in Example 4. One batch was produced in a press rotary with 0.3266" (0.83 cm) x 0.7283" (1.9 cm) oblong (capsule-shaped) tooling, while the other batch was compressed with 0.325" (0.82 cm) modified oval tooling cm) x 0.705" (1.8 cm). In both cases, an acceptable hardness (>10 kiloponds) and low friability were achieved. The dissolution behavior, as shown in Table 5, indicates that the oblong shape produced substantially faster dissolution. This is likely due to a combination of a flatter surface, thinner tablet, and larger surface area. Table 5 Comparison of Tablet Shape
    Example 6- Effect of Binder and Solvent Type
    [0060] Several binders were evaluated using either water or denatured alcohol as a solvent. For water-based binders, 20% binder solutions or gels were prepared as 1.25 grams of binder added to 5.0 grams of water. These aqueous preparations were vigorously mixed and stored at 60°C until use.
    [0061] For the alcohol-based granulations, about 1.0 grams of the binder solution (10% binder in denatured alcohol) was added to 5.0 grams and sodium oxybate while stirring vigorously for about 1 minute. For water-based granulations, about 0.5 grams of gel or solution was weighed into a beaker. A 10-fold amount of sodium oxybate was added to this, and then vigorously stirred for 1 to 3 minutes until granules formed. The granulations were wet sieved through a 16 mesh sieve, dried at 60°C for about 1 hour, and then sieved dry through a 16 mesh sieve before mixing the required amount to obtain a level of magnesium stearate. of 2%. For the water-based granulations, continuous overnight drying (open container at 60°C) was required.
    [0062] For each granulation, four 781 mg tablets were compressed using 0.3266" (0.83 cm) x 0.7283" (1.85 cm) oblong tooling and a Carver press operated with a force of 1 ton and about 4 seconds of dwell time. Two tablets were tested for hardness. The other two were tested for dissolution by a USP 2 apparatus in 900 ml of deionized water, with the paddles rotating at 50 rpm, and two tablets dropped into each vessel. The results shown in Table 6 suggest that either water or alcohol is a suitable solvent for povidone and hydroxypropyl cellulose, that a variety of conventional binders are suitable for producing granulations of proper size and flowability, and that these granulations generally produce tablets of sufficient hardness. Also, the use of a binder may be optional in some circumstances. Table 6 Binder Screening
    [0063] The formulations contain only binder, sodium oxybate, and 2% magnesium stearate

    [0064] Binders (suppliers) in order: Hypromellose (Dow), hydroxypropyl cellulose (Ashland), sodium carboxymethyl cellulose (Ashland), polyvinyl alcohol, povidone (BASF), pregelatinized corn starch (Colorcon) Example 7 - Effect of lubricant level
    A 10% povidone binder solution (PVP K30) was prepared by dissolving 4.0 grams of PVP K30 (BASF) in 36.1 grams of denatured alcohol. To 19.48 grams of sodium oxybate powder, 4.00 grams of binder solution was added while hand mixing in a beaker. The wet mass was sieved through a 16 mesh sieve, dried at 60°C for about 1 hour, and then sieved through a 16 mesh sieve to yield 18.61 grams of granulation. The granulation was divided into 2.5 gram aliquots, and to each aliquot the required amount of magnesium stearate was added to produce 0%, 0.5%, 1%, 1.5%, 2.0%, and 2 .5% granulation. The lubricant was mixed for approximately 30 seconds by rotating and inverting the closed container for approximately 30 cycles.
    The blends were compressed into 2 tablets each of 783 mg using a 0.3266" x 0.7283" oblong tooling and a Carver press operated with a force of 1 ton and approximately 4 seconds of dwell time. The compressed tablets were tested for dissolution with a USP 2 apparatus in 900 ml of deionized water, with the paddles rotating at 50 rpm, and two tablets dropped into each vessel. The conductivity test (immersed probe) was performed at 2 minutes and then every 5 minutes for up to 50 minutes. The results are shown in Table 7 and FIG. 3. Table 7 Effect of Magnesium Stearate Level

    Example 8- Surfactant Screening
    [0067] Several surfactants have been screened for effectiveness in reducing the dissolution time of tablets. A 10% PVP K30 master solution was prepared by dissolving 4.00 grams of PVP K30 in 36.1 grams of denatured alcohol. Each of the surfactants was applied to the solution with the binder adding about 0.15 grams of surfactant to 3.00 grams of the binder solution. In each case, about 4.8 grams of sodium oxybate was mixed with about 1.0 grams of binder solution containing surfactant to form granules which were then sieved through a 16 mesh sieve. After drying about 1 hour, the granulations were sieved through a 16 mesh sieve, and compressed into two 783 mg tablets using a 0.3266" (0.83 cm) x 0.7283" oblong tooling. .85 cm) and a Carver press operated with a force of 1 ton and about 4 seconds of dwell time. The tablets were tested for dissolution with a USP 2 apparatus in 900 ml of deionized water, with the paddles rotating at 50 rpm, and two tablets dropped into each vessel. The conductivity test (immersed probe) was performed at 2 minutes and then every 5 minutes up to 45 minutes.
    [0068] The results presented are shown in Table 8. Table 8 Surfactant Type Effect
    [0069] Formulations containing 2% PVP K30, 95% sodium oxybate, 2% magnesium stearate, and 1% surfactant

    *Note: The “no surfactant” case contains 96% SODIUM OXIBATE instead of 95% SODIUM OXIBATE Example 9- Type of Lubricant
    [0070] A 15 gram batch of alcohol granulation containing 98% sodium oxybate and 2% PVP K30 was made using the procedures described in Example 7. Aliquots of the granulation were then mixed with three lubricants at 2% levels - magnesium stearate, stearic acid powder, and sodium stearyl fumarate (Pruv®, JRS Pharma). Four tablets of 783 mg in weight (0.3266" (0.83 cm) x 0.7283" (1.85 cm) oblong) were compressed, and the hardness and dissolution were tested with 2 tablets. The results shown in Table 9, together with the "no lubricant" case of Example 7, indicate that sodium stearyl fumarate and stearic acid exhibit only a slight effect on dissolution. Table 9 Effect of Lubricant on Hardness and Dissolution of Sodium Oxybate Tablets
    [0071] The tablets contain 96% SODIUM OXIBATE, 2% PVP K30, and 2% lubricant.
    *Note: The “no lubricant” case of example 7 contains 98% SODIUM OXIBATE and 2% PVP K30: Example 10- Other Tablet Strengths
    The remaining granulation from Example 9 was blended with 2% sodium stearyl fumarate, and compressed into tablets of different sizes and shapes. In all cases, a compression force of 1 ton and about 4 seconds of dwell was used. The dissolution results shown in Table 10 confirm that the 375mg to 1500mg tablets have comparable strength performance, with minor differences. Table 10 Dissolving Performance of Others. Tablet Resistances
    Example 11- Calcium Oxybate Immediate Release Tablet
    Calcium oxybate was prepared generally following the procedures of Example 1 found in US 4,393,296 (Klosa, Production of Non-Hygroscopic Salts of 4-Hydroxy Butyric Acid). A small batch was made by first grinding 8.35 grams of calcium oxybate into powder, then adding 1.66 grams of binder solution containing 10% PVP K30 in denatured alcohol. After hand mixing, the granules were sized through a 16 mesh sieve, and then dried for about 1 hour at 60°C. Very hard granules were made, so gentle grinding with a mortar and pestle was required in order for all dry granules to pass through a 16 mesh sieve. Finally, sodium stearyl fumarate was mixed to a 2% level.
    [0074] Four tablets of 783 mg in weight were made using 0.3266" (0.83 cm) x 0.7283" (1.85 cm) oblong tooling and a Carver press operated with a force of 1 ton and approximately 4 seconds of dwell time. Two tablets were tested for dissolution. Table 11 shows a comparison of results between sodium oxybate and calcium oxybate prepared differently with the same methods and formulation. Table 11 Dissolution Results of Calcium Oxybate versus Sodium Oxybate Tablets
    Example 12- Granulated Formulations with Alcohol
    [0075] A 20 kg batch was made according to the formula in Table 12A using the conditions summarized in Table 12B. Hydroxypropyl cellulose (HPC, Klucel EXF) was dissolved in 1800 g and ethanol to prepare the granulation solution. Sodium oxybate was sieved through a 6 mesh Comil sieve with very low RPM, and the remaining amount of HPC and sodium lauryl sulfate (SLS) was sieved by hand through a 20 mesh sieve. API, HPC and SLS were loaded into the granulator basket of a 150L TK-Fielder high shear granulator, and dry blended for 5 minutes. The cutter was then turned off and the granulation solution added over 3 minutes. The materials were mixed for another 5 minutes, then dried in a fluid bed dryer to a final LOD of 0.145%.
    The dried granules were milled through a comill equipped with a 14 mesh sieve at 1800 rpm. The milled granules were blended in a V 2 cu-ft (0.06 m3) blender for 5 minutes, then Pruv (previously hand sieved through a 30 mesh sieve) was loaded into the V 2 cu-ft blender (0. .06 m3) and mixed for 3 minutes. The final blend was compressed to a target weight of 790 mg and hardness of 10.5 kp using a 36-station Kikusui tablet press equipped with 0.329" (0.84 cm) x 0.712" (1.81) oblong B-type tooling cm). Dissolution results by USP 2 (37°C, 50 rpm paddles, deionized water) using HPLC analysis indicated 35.3% dissolved in 5 minutes, 78.5% in 15 minutes, and complete dissolution in 30 minutes. Table 12A Intensified Formulation Using Alcohol Granulation with HPC Binder
    *Removed during processing for this reason it is not in the batch total. Table 12B Granulation, Drying, Grinding, Compression Parameters
    Table 12C Granulation Size Distribution
    Example 13- Polyvinylpyrrolidone Binder Formulation
    [0077] A formulation was demonstrated with a 20 kg batch using procedures comparable to Example 12. The formulation consisted of 96.25% sodium oxybate, 2.0% povidone K-30, and 1.75% sodium stearyl fumarate. The final blend was compressed to a target weight of 773mg and hardness 11 to 13 kp using a Kikusui 36-station tablet press equipped with a 0.329" (0.84 cm) x 0.712" (1.81 cm) oblong B-type tooling ). Dissolution results by USP 2 (37°C, 50 rpm paddles, deionized water) using HPLC analysis indicated 33.4% dissolved in 5 minutes, 77.7% in 15 minutes, and complete dissolution in 30 minutes.
    [0078] The full contents of all publications, patents, and patent applications referred to herein are hereby incorporated by reference. The compositions, dosage forms, methods described herein have been described in relation to certain preferred embodiments thereof, and many details have been reported for purposes of illustration, it will be apparent to those skilled in the art that the invention is susceptible to further embodiments. and that certain details described herein may be varied without departing from the basic principles of the invention.
    权利要求:
    Claims (10)
    [0001]
    1. Immediate release formulation for oral administration of GHB, characterized by the fact that the immediate release formulation comprises: GHB in an amount of about 90 to 98% by weight; at least one binder in an amount of about 1 to 5% by weight; at least one lubricant in an amount of about 1 to 5% by weight; wherein the immediate release formulation releases at least 90% of the GHB contained therein within a period of less than one hour after administration; wherein the immediate release formulation is provided as an immediate release tablet comprising a coating and a moisture barrier layer; and wherein the coating comprises a water soluble polymer and the moisture barrier layer comprises a water soluble polymer.
    [0002]
    2. Immediate release formulation according to claim 1, characterized in that the at least one binder is selected from at least one of hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, hydroxyethyl cellulose, povidone, copovidone, pre starch -gelatinized, dextrin, gelatin, maltodextrin, starch, zein, acacia, alginic acid, carbomers (cross-linked polyacrylates), polymethacrylates, sodium carboxymethyl cellulose, guar gum, hydrogenated vegetable oil (type 1), methylcellulose, magnesium aluminum silicate, and alginate of sodium.
    [0003]
    3. Immediate release formulation according to claim 1, characterized in that the at least one lubricant is selected from at least one of magnesium stearate, stearic acid, calcium stearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium stearyl fumarate and zinc stearate.
    [0004]
    4. Formulation according to claim 1, characterized in that it further comprises at least one surfactant, wherein the immediate release formulation comprises: GHB in an amount of about 90 to 97.5% by weight; at least one binder in an amount of about 1 to 4% by weight; at least one lubricant in an amount of about 1 to 4% by weight; and at least one surfactant in an amount of about 0.5 to 2.0% by weight.
    [0005]
    5. Immediate release formulation according to claim 4, characterized in that the at least one surfactant is selected from at least one of sodium docusate (sodium salt of dioctyl sulfosuccinate), sodium lauryl sulfate, a polyoxyethylene alkyl ether, a polyoxyethylene stearate, a poloxamer, a polysorbate, a sorbitan ester, and glyceryl monoleate.
    [0006]
    6. Immediate release formulation according to claim 1, characterized in that the water-soluble polymer of the coating is hydroxypropyl cellulose (HPC) or hydroxypropyl methylcellulose (HPMC).
    [0007]
    7. Immediate release formulation according to claim 1, characterized in that the water-soluble polymer of the moisture barrier layer is polyvinyl alcohol (PVA).
    [0008]
    8. Immediate release formulation according to claim 1, characterized in that it comprises at least one filler or compression aid in an amount of about 1-15% by weight.
    [0009]
    9. Immediate release formulation according to claim 1, characterized by the fact that the GHB salt is a salt selected from sodium oxybate, calcium oxybate, lithium oxybate, potassium oxybate, or magnesium oxybate.
    [0010]
    10. Immediate release formulation according to claim 1, characterized by the fact that GHB is sodium oxybate.
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    法律状态:
    2020-08-11| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-08-11| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2020-12-08| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
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    PCT/US2010/033572|WO2011139271A1|2010-05-04|2010-05-04|Immediate release formulations and dosage forms of gamma-hydroxybutyrate|
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