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WO2018230329A1 - Composition pharmaceutique orale sous forme de gel, contenant du lévétiracétam - Google Patents

Composition pharmaceutique orale sous forme de gel, contenant du lévétiracétam Download PDF

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Publication number
WO2018230329A1
WO2018230329A1 PCT/JP2018/020563 JP2018020563W WO2018230329A1 WO 2018230329 A1 WO2018230329 A1 WO 2018230329A1 JP 2018020563 W JP2018020563 W JP 2018020563W WO 2018230329 A1 WO2018230329 A1 WO 2018230329A1
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Prior art keywords
composition
composition according
present
levetiracetam
acid
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Ceased
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PCT/JP2018/020563
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English (en)
Japanese (ja)
Inventor
真健 大樂
一毅 岡本
仁 松瀬
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Maruishi Pharmaceutical Co Ltd
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Maruishi Pharmaceutical Co Ltd
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Priority to JP2019525283A priority Critical patent/JP6653931B2/ja
Publication of WO2018230329A1 publication Critical patent/WO2018230329A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom

Definitions

  • the present invention relates to a pharmaceutical composition for oral administration of a gel comprising levetiracetam as an active ingredient.
  • Such a problem is also a problem for pharmaceutical companies that have provided formulations that are difficult to take. It is an era when it is required to provide a dosage form that is easy for any patient to take, rather than making it “good” if the majority of patients can take it.
  • levetiracetam is known as an active ingredient of antiepileptic drugs (Non-patent Document 1). Although various dosage forms are known as preparations containing levetiracetam (Patent Documents 1 to 4), they were not always satisfactory. Moreover, the gelatinous formulation containing levetiracetam has not been known so far.
  • JP 2010-024156 A Special table 2011-507829 gazette Special table 2016-514680 gazette Special table 2009-542748 gazette
  • the object of the present invention is to provide an oral pharmaceutical composition in which (1) the bitter taste of levetiracetam with a large single dose is reduced, (2) good dosing feeling, and / or (3) good dissolution properties. That is.
  • the present inventors have found that the following problem solving means can solve the problems of the present invention, and have further intensively studied to complete the present invention.
  • the present invention relates to the following [1] to [15].
  • [5] The composition according to [1], [2] or [4], wherein the gel breaking strength is 1000 to 30000 N / m 2 .
  • the sweetener is sucralose or acesulfame potassium.
  • the pH adjuster is disodium hydrogen phosphate and / or citric acid.
  • the bitterness of levetiracetam is reduced despite the large single dose, (2) the mouthfeel is soft and viscous, easy to swallow, and can be taken as a food-like sensation, (3) It is ideal because it can provide an oral pharmaceutical composition that is rich, drinkable, drinkable, and / or (4) has good dissolution properties.
  • Levetiracetam which reduces epileptic seizures, has some bitterness and high doses, so some patients are taking patience that is difficult to take.
  • a gel preparation in a dosage form that has a good taste and texture and is easy to take
  • Providing pharmaceutical preparations that can be taken as if they were foods or drinks also leads to improvements in patient compliance and QOL.
  • the double suffering of illness and long-term (in some cases lifetime), or the triple suffering that is difficult to take can be greatly reduced.
  • the oral pharmaceutical composition of the present invention is a preparation that can be taken as a food-like sensation, a child, an elderly person, or a person with difficulty in swallowing can easily swallow the levetiracetam-containing preparation.
  • the oral pharmaceutical composition of the present invention having moderate elasticity has a crunchy texture, a good texture, and differentiates from other preparations and accents of medication, so that tablets and capsules can be used not only for children who do not like drugs. Even adults who can take it are effective in preventing forgetting to drink. As a result, not only improved adherence adherence to patients, but also a formulation-like device that reduces drug rejection and residual drugs reduces the amount of waste that has been estimated to be about 100 billion yen per year. It helps to solve social problems of medicine.
  • FIG. 1 shows the results of the dissolution test of each example.
  • FIG. 2 shows the results of the viscosity test of each example.
  • the present invention includes levetiracetam, which is an active ingredient, and a gel oral pharmaceutical composition (hereinafter also referred to as the composition of the present invention) having a pH of about 6 to 7 and containing a gelling agent, a sweetening agent, and a pH adjusting agent. ) Can be provided.
  • levetiracetam Active ingredient levetiracetam
  • the structural formula of levetiracetam, which is an active ingredient, is shown below.
  • Levetiracetam usually has a chemical formula: (2S) -2- (2-Oxopyrrolidene-1-yl) butyramide, molecular formula: C 8 H 14 N 2 O 2 , molecular weight: 170.21, melting point: 115-119 ° C. white ⁇ Light grayish white crystalline powder.
  • Levetiracetam is used, for example, in combination therapy with antiepileptic drugs for partial seizures in epilepsy patients (including secondary generalized seizures) and tonic-clonic seizures in patients with epilepsy who are not fully effective with other antiepileptic drugs May be.
  • the content (concentration) of levetiracetam in the composition of the present invention is not particularly limited, but for example, 0.1 to 50.0% by mass, 0.1 to 35.0% by mass with respect to the entire composition %, Or 0.3 to 20.0% by mass.
  • Levetiracetam is, for example, any of a free base, a crystalline polymorph (for example, an anhydrous crystal, an anhydrous B-form crystal, etc.), a hydrate, a pharmacologically acceptable salt (for example, an acid addition salt, etc.) Form may be sufficient.
  • Levetiracetam can be produced by a known method, and Levetiracetam can be obtained by purchasing a commercial product such as Ekepra (registered trademark).
  • levetiracetam is usually administered orally in two divided doses per day.
  • it may be appropriately increased or decreased within a range not exceeding 3000 mg per day depending on the symptoms, it is preferable to increase the dose by 1000 mg or less as a daily dose with an interval of 2 weeks or more.
  • 20 mg / kg per day may be taken twice a day.
  • it may be appropriately increased or decreased within a range not exceeding 60 mg / kg per day depending on symptoms, it is preferable to increase the dose by 20 mg / kg or less as a daily dose with an interval of 2 weeks or more.
  • the same dosage as an adult may be used.
  • Examples of the gelling agent in the composition of the present invention include carrageenan ( ⁇ carrageenan, ⁇ carrageenan, etc.), carob bean gum, xanthan gum, glycerin, or propylene glycol, or a mixture of two or more thereof.
  • carrageenan ⁇ carrageenan, ⁇ carrageenan, etc.
  • carob bean gum xanthan gum
  • xanthan gum ⁇ carrageenan, ⁇ carrageenan, etc.
  • carob bean gum glycerin and propylene glycol
  • xanthan gum, glycerin and propylene Combinations such as glycol are preferred.
  • gum arabic for example, gum arabic, gum arabic powder, alginic acid, sodium alginate, propylene glycol ester alginate, caraya gum powder, carmellose sodium, crystalline cellulose / carmellose sodium, curdlan, canten, agar powder, Guar gum, psyllium seed gum, gellan gum, purified gelatin, gelatin, tamarind seed gum, tara gum, tragacanth, tragacanth powder, farcellulan, pullulan, pectin and the like may be used.
  • the mixing ratio of the gelling agent in the composition of the present invention is not particularly limited as long as the effects of the present invention are not hindered.
  • the blending ratio of glycerin in the composition of the present invention is preferably 5 to 30% by mass, more preferably 15 to 30% by mass with respect to the entire composition.
  • the proportion of propylene glycol in the composition of the present invention is preferably 5 to 30% by mass, and more preferably 10 to 25% by mass, based on the entire composition.
  • the blending ratio By setting the blending ratio, a particularly excellent effect of the present invention (in particular, an effect that the dissolution property is good) can be obtained.
  • the mass ratio thereof glycerin: propylene glycol
  • the mass ratio thereof is preferably 1: (0.1-1), and 1: (0.3- 1) is more preferable, and 1: (0.5 to 1) is more preferable.
  • the composition of the present invention contains carrageenan and carob bean gum as gelling agents, and is preferably jelly-like.
  • a composition of the present invention is also referred to as a jelly-gel oral pharmaceutical composition of the present invention.
  • the jelly-like gel oral pharmaceutical composition of the present invention has a good mouthfeel, is soft and viscous to be swallowed, and can be taken as a food-like sensation.
  • the mixing ratio of carrageenan ( ⁇ carrageenan, ⁇ carrageenan, etc.) in the jelly-form gel oral pharmaceutical composition of the present invention is preferably 0.1 to 1% by mass relative to the whole composition.
  • a particularly excellent effect of the present invention in particular, an effect of being soft and viscous to be swallowed
  • the carrageenan a combination of ⁇ carrageenan and ⁇ carrageenan is preferable.
  • the blending ratio of carrageenan is not particularly limited as long as the effects of the present invention are not hindered.
  • ⁇ carrageenan for example, 0.01 to 1% by mass, 0.1 to 0.7% by mass, 0%
  • the kappa carrageenan is, for example, 0.01 to 1% by mass, 0.1 to 1% by mass, 0.1 to 0.5% by mass with respect to the entire composition. %.
  • the mass ratio ( ⁇ carrageenan: ⁇ carrageenan) is preferably 1: (0.1-1), and 1: (0. 3 to 1) is preferred.
  • the blending ratio of carob bean gum in the jelly-like gel oral pharmaceutical composition of the present invention is preferably 0.1 to 0.5% by mass, more preferably 0.1 to 0.2% by mass with respect to the whole composition. .
  • the jelly gel oral pharmaceutical composition of the present invention preferably has a gel breaking strength or a maximum value of 1000 to 30000 N / m 2 .
  • the gel breaking strength may be measured using a gel breaking strength measuring instrument under the condition of a plunger speed of 60 mm / min made of stainless steel having a diameter of 5 mm.
  • EZTest manufactured by Shimadzu Corporation may be used as the gel breaking strength measuring instrument.
  • the composition of the present invention contains xanthan gum as a gelling agent and is preferably viscous.
  • a composition of the present invention is also referred to as a viscous gel oral pharmaceutical composition of the present invention.
  • the blending ratio of xanthan gum in the viscous gel oral pharmaceutical composition of the present invention is preferably 0.01 to 1% by mass with respect to the whole composition. By setting the blending ratio, a particularly excellent effect of the present invention (in particular, an effect of thickening) can be obtained.
  • the viscous gel oral pharmaceutical composition of the present invention is, for example, thick, rich, drinkable, and can be taken as a drink.
  • the viscous gel oral pharmaceutical composition of the present invention is preferably a non-Newtonian fluid.
  • the shear rate is D150 at a measurement temperature of 20 ° C. Sometimes it is preferably 10 to 100 mPa ⁇ S.
  • an E type (cone plate type) viscometer for example, TV20 manufactured by Tokimec may be used.
  • sweetener examples include sucralose, acesulfame potassium, aspartame, fructose glucose liquid sugar, reduced maltose water candy, powdered reduced maltose water candy, saccharin, saccharin sodium, stevia, thaumatin, erythritol, sorbitol, sorbitol liquid.
  • the blending ratio of the sweetening agent in the composition of the present invention is not particularly limited as long as the effects of the present invention are not hindered. For example, 0.01 to 30% by mass, 0.1 to 1% by mass, or It may be 0.1 to 0.5% by mass. By setting the blending ratio, a particularly excellent effect of the present invention (in particular, an effect that bitterness is reduced) is obtained.
  • the blending ratio of sucralose in the composition of the present invention is preferably 0.01 to 2% by mass with respect to the whole composition. By setting the blending ratio, a particularly excellent effect of the present invention (in particular, an effect that bitterness is reduced) is obtained.
  • the blending ratio of acesulfame potassium in the composition of the present invention is preferably 0.1 to 1% by mass relative to the entire composition. By setting the blending ratio, a particularly excellent effect of the present invention (in particular, an effect that bitterness is reduced) is obtained.
  • the composition of the present invention preferably has a pH of about 6-7.
  • the pH value of about 6 to 7 is rounded off to a pH value of 6 to 7, that is, a pH value of 5.5 to less than 7.5, and rounded up to a pH value of 6 to 7, that is, a pH value of more than 5.0. 0.0 or less, and a pH value that is truncated to pH 6-7, that is, a pH value of 6.0 or more and less than 8.0. That is, the composition of the present invention preferably has a pH of more than 5.0 and less than 8.0.
  • the pH of about 6 to 7 is preferably a pH value that is rounded off to a pH of 6 to 7, that is, a pH of 5.5 or more and less than 7.5.
  • the pH value is remarkably far from the range, the problem of the present invention cannot be solved.
  • composition of the present invention can adjust its pH by containing a pH adjuster.
  • pH adjusters citrate or hydrate thereof, malate or hydrate thereof, phosphate or hydrate thereof, edetate salt or hydrate thereof, lactate salt or hydrate thereof, etc.
  • Basic buffers and / or organic acids eg acetic acid, trifluoroacetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, D-tartaric acid, citric acid, DL-malic acid, lactic acid, shu Acid, benzoic acid, besylic acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, edetic acid, etc.), inorganic acid (eg hydrochloric acid, phosphoric acid, hydrobromic acid, hydrogen iodide) Acid, nitric acid, sulfuric acid and the like) or salts thereof.
  • organic acids eg acetic acid, trifluoroacetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, D-tartaric acid, citric acid,
  • the salt is not particularly limited as long as it is a pharmacologically acceptable salt, and examples thereof include pharmacologically acceptable metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.
  • the pharmacologically acceptable metal salt is not particularly limited, and examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt and zinc salt Etc.
  • the pharmacologically acceptable organic amine addition salt is not particularly limited, and examples thereof include addition salts such as morpholine and piperidine.
  • the pharmacologically acceptable amino acid addition salt is not particularly limited, and examples thereof include addition salts such as lysine, glycine, and phenylalanine. These salts may be either anhydrides or hydrates.
  • the citrate or hydrate thereof is not particularly limited, and examples thereof include sodium citrate and disodium citrate.
  • the malate or hydrate thereof is not particularly limited, and examples thereof include DL-sodium malate. It does not specifically limit as phosphate or its hydrate, For example, trisodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc. are mentioned.
  • the edetate or hydrate thereof is not particularly limited, and examples thereof include edetate tetrasodium.
  • Lactate or a hydrate thereof is not particularly limited, and examples thereof include sodium lactate. Particularly preferred is disodium hydrogen phosphate.
  • These basic buffering agents may be used singly or in combination of two or more.
  • hydrochloric acid citric acid, DL-malic acid, phosphoric acid, edetic acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate and disodium edetate are preferred, and citric acid is particularly preferred.
  • citric acid is particularly preferred.
  • These acids may be used individually by 1 type, and 2 or more types may be mixed and used for them.
  • the basic buffer and acids sodium citrate, disodium citrate, trisodium citrate, DL-sodium malate, trisodium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate
  • at least one basic buffer selected from the group consisting of tetrasodium edetate, hydrochloric acid, citric acid, DL-malic acid, phosphoric acid, edetic acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate and edetic acid
  • a combination with one or more acids selected from the group consisting of disodium is preferable, and a combination of disodium hydrogen phosphate and citric acid is more preferable.
  • the molar concentration of the basic buffer in the composition of the present invention is preferably about 0.0001M to 0.03M from the viewpoint of good elution.
  • the molar concentration of acids in the composition of the present invention is preferably a ratio of about 0.001 to 0.95M, assuming that the basic buffer is 1M.
  • the ratio of levetiracetam, gelling agent, sweetener and pH adjuster is 1: (0.01-5) :( 0.01-5) ): (0.01-0.03), 1: (0.03-4.5): (0.05-2.5): (0.01-0.03) May be.
  • the sugar content (Brix) of the preparation is preferably about 1 to 50%, more preferably about 10 to 45%. If it is the said range, favorable elution property will be maintained and a patient can feel flavor (especially sweetness).
  • fragrance Although the composition of the present invention does not feel bitterness without adding a fragrance, for example, a fragrance preferred by children may be added as a flavor. As such a fragrance
  • flavor in the composition of this invention is not specifically limited unless the effect of this invention is prevented.
  • Preservative You may mix
  • the preservative is not limited as long as it is usually used for pharmaceuticals.
  • preservatives are added to improve the storage stability, long-term product deterioration (microorganism contamination) can be prevented.
  • the compounding quantity of the preservative in the composition of this invention is not specifically limited unless the effect of this invention is prevented.
  • the pharmaceutical additive described in the pharmaceutical additive dictionary “2016” is added to the composition of the present invention, which can be administered orally, and further softness, viscosity, flavor, It is also possible to improve the texture.
  • any additive that can be administered orally can be used without limitation. Thickeners, thickeners, solvents, stabilizers, stabilizers, isotonic agents, isotonic agents, plasticizers, A solubilizer and other additives can be added to improve and improve the product quality.
  • the compounding ratio of sodium chloride in the composition of the present invention may be 0.1 to 0.2% by mass relative to the whole composition.
  • Particularly excellent effects of the present invention in particular, an effect that bitterness is reduced
  • each component is weighed in a desired amount, heated and dissolved while stirring, and then charged with a mixture of each component heated and dissolved in a desired container and allowed to cool and solidify.
  • the dissolution temperature may be, for example, 75 to 90 ° C.
  • the stirring time may be 1 to 2 hours including the sterilization step, for example.
  • Subsequent filling temperatures may be 60-90 ° C.
  • the composition of the present invention is, for example, a paddle method (50 rpm, 37 ⁇ 0.5 ° C., 900 mL (water), measurement wavelength ⁇ 250 nm), and an elution rate (%) after 15 minutes is 75% or more, 80% or more, It may be 85% or more, 90% or more, or 95% or more, or the elution rate (%) after 30 minutes may be 90% or more, 95% or more, 98% or more, or 99% or more.
  • NTR-6200AC22 manufactured by Toyama Sangyo may be used as a dissolution tester, and UV1800 manufactured by Shimadzu Corporation may be used as a UV measurement device.
  • the present invention includes embodiments in which the above configurations are combined in various ways within the technical scope of the present invention as long as the effects of the present invention are exhibited.
  • each of the examples shown in Tables 1 to 3 is weighed and dissolved by heating at 80 to 85 ° C. for 1 hour while stirring. Then, each Example 3g, 5g, or 10g melted by heating in a container (a stick container or a potion container) was weighed, filled and allowed to cool and solidify to obtain a gel preparation. (PH measurement) The pH of the formulation was measured with an HPRIBA pH meter B-212.
  • Dissolution Test Examples 1 to 10 were subjected to dissolution tests under the following conditions. The average elution rate of 3 vessels of each Example 15 minutes or 30 minutes after the start of the test was determined, and the relationship between the test time and the dissolution rate is shown in Tables 4 and 5 and FIG. In addition, the unit was shown by the elution rate (%) with respect to the indicated amount of levetiracetam.
  • Dissolution tester NTR-6200AC manufactured by Toyama Sangyo Co., Ltd.
  • Dissolution test conditions paddle method, 50 rpm Test temperature: 37 ⁇ 0.5 ° C
  • Dissolution test solution volume 900 mL (water)
  • UV measuring device UV1800 manufactured by Shimadzu Corporation Measurement wavelength: ⁇ 250nm
  • the dissolution test of the examples is conducted according to the guidelines for bioequivalence testing of generic drugs (“partial revision of guidelines for bioequivalence testing of generic drugs” ( Good dissolution properties that conform to the standard shown in the February 29, 2012 medicinal diet review No. 0229 No. 10)) as “15% value is 85% or more and / or 30 minute value is 85% or more” Indicated.
  • the maximum peak strength of the gel break was 1000 to 30000 N / m 2 , and jelly agents having different strengths could be produced. That is, it has been confirmed that the softness can be set as desired from a gel having a high breaking strength and a crunchy texture to a gel having a soft texture.
  • Viscosity Test For Example 11 and Comparative Example 1 which are viscous gels, the viscosity test was performed under the following conditions, and the relationship of the viscosity to the shear rate D is shown in Table 8 and FIG. Since the unit is a non-Newtonian fluid, the apparent viscosity ⁇ with respect to the shear rate D is represented by mPa ⁇ s. Viscometer: TV20 manufactured by Tokimec Rotor: 0.8 ° x R24 Test temperature: 20 ° C Rotor rotation speed: 2.5, 5, 10, 20, 50, 100 rpm
  • Example 11 showed good physical properties of a non-Newtonian fluid having a higher viscosity than Comparative Example 1. In other words, it was confirmed that the physical properties of the composition were rich and responsive to drinking.
  • the jelly-form preparation of oral administration of levetiracetam with a large single dose obtained in these Examples and Test Examples is palatable, easy to swallow and soft and viscous, and the viscous preparation is There is a rich body and a drinkable response. All are oral pharmaceutical compositions of gel preparations that can be taken as if they were foods or drinks. These preparations are difficult to remain in the mouth and throat even in elderly people, children, patients with reduced swallowing function, patients with low saliva and difficult to swallow, and do not feel uncomfortable after taking.
  • the gel oral pharmaceutical composition of the present invention is useful for the production of a drug containing levetiracetam.

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Abstract

La présente invention aborde le problème de la production d'une composition pharmaceutique orale qui (1) possède une amertume liée au lévétiracétam réduite, une seule dose du lévétiracétam étant une grande quantité, (2) offre une bonne sensation d'ingestion et/ou (3) possède une aptitude à l'élution favorable. La présente invention concerne une composition pharmaceutique orale sous forme de gel, contenant du lévétiracétam, qui est un principe actif, un agent gélifiant, un agent édulcorant et un agent de réglage de pH, et présentant un pH d'environ 6 à 7.
PCT/JP2018/020563 2017-06-16 2018-05-29 Composition pharmaceutique orale sous forme de gel, contenant du lévétiracétam Ceased WO2018230329A1 (fr)

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JP2019525283A JP6653931B2 (ja) 2017-06-16 2018-05-29 レベチラセタム含有ゲル経口医薬組成物

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JPH09194346A (ja) * 1996-01-12 1997-07-29 Ota Seiyaku Kk ゼリー状経口医薬組成物
JP2008528571A (ja) * 2005-01-27 2008-07-31 アレムビック・リミテッド レベチラセタムの徐放性製剤
JP2008260708A (ja) * 2007-04-11 2008-10-30 Ohkura Pharmaceutical Co Ltd ベンズイソキサゾール誘導体の経口ゼリー状医薬組成物
JP2009542748A (ja) * 2006-07-13 2009-12-03 ユセベ ファルマ ソシエテ アノニム レベチラセタムを含む医薬組成物
JP2010024156A (ja) * 2008-07-16 2010-02-04 Ucb Pharma Sa レベチラセタムを含む医薬組成物
WO2010150400A1 (fr) * 2009-06-26 2010-12-29 日医工株式会社 Preparation de gelee contenant de l'isosorbide
CN104922057A (zh) * 2015-05-31 2015-09-23 黑龙江佰彤儿童药物研究有限公司 一种儿童型口服抗癫痫药用凝胶单元及其制备方法
JP2016037502A (ja) * 2014-08-08 2016-03-22 日医工株式会社 ヨウ化カリウムゼリー状医薬組成物
JP2017071626A (ja) * 2013-03-15 2017-04-13 アプレシア・ファーマスーティカルズ・カンパニー レベチラセタムを含む急速に分散する剤形

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09194346A (ja) * 1996-01-12 1997-07-29 Ota Seiyaku Kk ゼリー状経口医薬組成物
JP2008528571A (ja) * 2005-01-27 2008-07-31 アレムビック・リミテッド レベチラセタムの徐放性製剤
JP2009542748A (ja) * 2006-07-13 2009-12-03 ユセベ ファルマ ソシエテ アノニム レベチラセタムを含む医薬組成物
JP2008260708A (ja) * 2007-04-11 2008-10-30 Ohkura Pharmaceutical Co Ltd ベンズイソキサゾール誘導体の経口ゼリー状医薬組成物
JP2010024156A (ja) * 2008-07-16 2010-02-04 Ucb Pharma Sa レベチラセタムを含む医薬組成物
WO2010150400A1 (fr) * 2009-06-26 2010-12-29 日医工株式会社 Preparation de gelee contenant de l'isosorbide
JP2017071626A (ja) * 2013-03-15 2017-04-13 アプレシア・ファーマスーティカルズ・カンパニー レベチラセタムを含む急速に分散する剤形
JP2016037502A (ja) * 2014-08-08 2016-03-22 日医工株式会社 ヨウ化カリウムゼリー状医薬組成物
CN104922057A (zh) * 2015-05-31 2015-09-23 黑龙江佰彤儿童药物研究有限公司 一种儿童型口服抗癫痫药用凝胶单元及其制备方法

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