WO2017146286A1 - Composition pharmaceutique à base d'extrait de feuille de ginkgo biloba utilisant une matrice de polymère hydrophile pour libération prolongée, et préparation à libération prolongée utilisant cette dernière - Google Patents

Composition pharmaceutique à base d'extrait de feuille de ginkgo biloba utilisant une matrice de polymère hydrophile pour libération prolongée, et préparation à libération prolongée utilisant cette dernière Download PDF

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WO2017146286A1
WO2017146286A1 PCT/KR2016/001898 KR2016001898W WO2017146286A1 WO 2017146286 A1 WO2017146286 A1 WO 2017146286A1 KR 2016001898 W KR2016001898 W KR 2016001898W WO 2017146286 A1 WO2017146286 A1 WO 2017146286A1
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sustained
release
sustained release
ginkgo biloba
formulation
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Korean (ko)
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김관영
박준형
류근호
신호철
황상욱
김훈택
곽용규
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SK Chemicals Co Ltd
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SK Chemicals Co Ltd
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
    • 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
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the present invention relates to a pharmaceutical composition containing a ginkgo leaf extract using a matrix-type sustained release drug delivery system and an oral sustained release preparation using the same.
  • Ginkgo biloba extract has been used for the treatment of bronchial asthma and bronchitis in China for centuries ago, and has been used in patients with peripheral blood disorders and brain dysfunction in Western countries including Germany and France.
  • Ginkgo biloba extract contains flavone glycosides such as quercetin, kaemferol, and isorhamnetin, which have been reported to have antioxidant and cytoprotective effects.
  • Bilobadide, ginkgoride (Ginkgolide) It contains terpenes (terpenes, heterosides) such as ginkgolide A, ginkgoride B, ginkgoride C, ginkgoride J, and platelet activating factor (PAF) and platelet aggregation inhibition effect by ADP, and cardiovascular effects such as vascular relaxation. It is reported to act on. It is also known as an antagonist of terminal benzodiapine receptors, which have corticoid-like, anti-ischemic properties and induce antistress activity.
  • PAF platelet activating factor
  • Ginkgo biloba extract is extracted by a process already known to those of ordinary skill in the art, and is first extracted with an aqueous alkali solution from a conventional solvent extraction method using a mixed solvent of water and a lower alcohol or a lower ketone, followed by lower alcohol and lower acetate.
  • the extract may be extracted using any known method such as extraction with a mixed solvent with a lower ketone or a supercritical extraction method.
  • the extracted ginkgo leaf extract contains 22.0 to 27.0% by weight of the total flavone glycoside as a main component. It is preferable that total terpenlactone contains 5.4-12 weight%, and gingic acid contains 5 ppm or less.
  • oral preparations containing ginkgo biloba extract should be taken three times a day with a 40 mg preparation, one tablet once or twice a day with an 80 mg preparation.
  • patients' compliance with medication is reported to improve as the number of doses decreases.
  • Many pharmaceutical companies have released a number of sustained-release drugs that have improved the ease of taking by controlling the release of the drug to reduce the number of doses of the drug while maintaining the same therapeutic effect.
  • the formulation containing ginkgo biloba extract is effective for chronic diseases such as peripheral blood disorder and brain dysfunction, and especially the formulation which should be taken by elderly patients in the long term due to the nature of the disease, it contains the aforementioned herbal extract Due to the nature of one formulation, there are many difficulties in improving the ease of taking by controlling the release, so there is no product yet as a sustained release formulation that can be taken once daily as required by the patient. This is because the preparation containing the ginkgo biloba extract contains many active substances such as flavone glycoside and terpenlactone, and the active substances are very different chemically, so the physical and chemical properties are very different. There are significant difficulties compared to the sustained release formulation of drugs containing dog chemicals.
  • Korean Patent No. 1148734 discloses a multiparticulate form in which a binding solution containing ginkgo leaf extract is applied to a neutral core and sprayed with a polymer to prepare an intermediate layer, and then coated with a polymer to fill a capsule.
  • a sustained release formulation is proposed, there is a disadvantage in that it is not preferable in terms of economics because the manufacturing time is long, the manufacturing method is complicated, and special equipment is required.
  • Republic of Korea Patent Publication No. 2014-0018913 discloses a formulation for mixing the hydrophobic polymer ethyl cellulose, dry granules and compressed into tablets, but also includes a process for producing granules and complicated manufacturing method and hydrophobic polymer It is not easy to control the dissolution rate of the active ingredient of the ginkgo biloba leaf extract is hydrophilic and has the disadvantage of showing an insufficient release rate of about 60% in 6 hours.
  • the present inventors when evaluating the sustained release formulation of the ginkgo biloba extract, the release of terpenlactone, which represents the medicinal effect of the ginkgo biloba extract, not the flavone glycoside components shown in Korean Patent No. 1148734 and 2014-0018913 The properties were studied to complete the sustained release formulation of Ginkgo biloba extract.
  • the present invention provides a pharmaceutical composition and oral sustained-release preparation using the same, which extends the residence time in the digestive tract of the preparation containing the ginkgo biloba extract to continuously extend the pharmacological effect of the ginkgo biloba extract and improve the patient's medication compliance. It is.
  • the present invention provides a sustained release oral dosage form for once-daily administration characterized in that the sustained release matrix system comprising a hydrophilic sustained release polymer in a ginkgo leaf extract-containing formulation.
  • the present invention in the ginkgo leaf extract-containing formulation, containing 3 to 10% by weight of the total tablet weight of hydroxypropyl methyl cellulose as a hydrophilic sustained-release polymer, the hydroxypropyl methyl cellulose is 3,500 cps It provides an oral sustained release formulation of ginkgo biloba extract characterized by 4 to 500 cps.
  • the present invention in the formulation containing ginkgo biloba extract, comprising 1 to 10% by weight of the total tablet weight of hydroxypropyl methyl cellulose as a hydrophilic sustained-release polymer, the hydroxypropyl methyl cellulose is 3,500 It provides an oral sustained release formulation of ginkgo biloba extract characterized by cps to 4,500 cps.
  • the present invention in the formulation containing ginkgo biloba extract, comprising 3 to 10% by weight of the total tablet weight of hydroxypropyl methyl cellulose as a hydrophilic sustained-release polymer, the hydroxypropyl methyl cellulose is 100 cps It provides an oral sustained release formulation of ginkgo biloba extract characterized by 4 to 500 cps.
  • the present invention in the ginkgo leaf extract-containing formulation, pharmacological material selected from the group consisting of ticlopidine hydrochloride, ethyl isosapentate, veraprost sodium, cilostazol and sarfoglylate hydrochloride It provides an oral sustained release formulation for once-daily administration comprising a single, characterized in that the sustained release matrix system comprising a hydrophilic sustained release polymer.
  • the present invention is a ginkgo leaf extract-containing formulation, further comprising a cilostazol, characterized in that the sustained-release matrix system comprising a hydrophilic sustained-release polymer 1 day having the following characteristics
  • An oral sustained release formulation for single administration is provided:
  • Emission solution conditions terpenlactone: 900 ml purified water, cilostazol: 900 ml purified water + 0.5% (w) in the dissolution test apparatus II (75 rpm, Paddle) at the release of total terpenlactone and cilostazol at 37.0 ° C. ⁇ 0.5 ° C. / v) dissolution rate profile as measured in sodium lauryl sulfate): less than 30% at 0.5 hours, less than 80% at 2 hours, at least 90% at 8 hours.
  • oral sustained release formulation for once-a-day administration having the following characteristics characterized by a sustained release matrix system comprising a hydrophilic sustained release polymer Provides:
  • the total release of terpenlactone is characterized by having a dissolution rate profile as measured at Dissolution Test Apparatus II (75 rpm, Paddle, 900 ml purified water) at 37.0 ° C. ⁇ 0.5 ° C .: less than 30% at 0.5 hours, 2 Less than 80% at time, more than 90% at 8 hours.
  • the present invention provides a sustained release oral dosage form for once-daily administration having the following characteristics, characterized by a sustained release matrix system comprising a hydrophilic sustained release polymer in a ginkgo leaf extract-containing formulation to provide:
  • the total terpenlactone release is characterized by the following dissolution rate profile measured at 37.0 ° C. ⁇ 0.5 ° C. with Dissolution Test Apparatus II (75 rpm, Paddle, 900 ml purified water): less than 25% at 0.5 hours, 2 More than 35% at time, more than 80% at 8 hours.
  • Oral sustained-release preparations comprising the extract of Ginkgo biloba according to the present invention are made from a herbal formulation consisting of a combination of ingredients having various physical properties in a uniform sustained release formulation using a hydrophilic sustained-release polymer, the absorption of the drug in vivo is continuously By doing so, it can exhibit sustained pharmacological activity.
  • the sustained-release preparation of the present invention the dissolution time of the pharmacological component was adjusted to allow the daily administration of the preparation, the variation between batches of the ginkgo biloba extract was minimized, and the high hygroscopic ginkgo biloba extract was Regardless, it had a stable dissolution pattern.
  • FIG. 1 is a graph showing the dissolution rate in water with respect to the terpene lactone-based components known as components of the ginkgo biloba extract in the compositions prepared in Examples 1 to 3 and Comparative Examples 1 and 2 according to the present invention.
  • Figure 2 is a graph showing the dissolution rate in water for the terpenlactone-based components known as components of the ginkgo biloba extract in the compositions prepared in Examples 2, 4 to 6 according to the present invention.
  • Figure 3 is a graph showing the dissolution rate in water for the terpenlactone-based components and cilostazol known as a component of the ginkgo leaf extract in the composition prepared in Example 7 according to the present invention.
  • Figure 4 shows the total terpenlactone and silo contained in the ginkgo biloba extract of the formulation stored in the initial and three months accelerated stability conditions (40 ⁇ 2 °C / 75 ⁇ 5% RH) of the composition prepared in Example 7 according to the present invention It is a graph showing the rate of dissolution in water with respect to stasol.
  • FIG. 5 shows Ginkgolide as an index component of Ginkgo biloba leaf extract when Example 7 according to the present invention was administered once a day and Comparative Example 3, a commercial control drug rinexin, was administered twice a day for 12 hours.
  • a graph showing the change in concentrations of A, B and total terpenlactone.
  • the present invention provides a pharmaceutical composition of the ginkgo biloba extract containing the ginkgo biloba extract and a hydrophilic sustained release polymer, and an oral sustained release formulation using the same.
  • the sustained release formulation may be a formulation for once-daily administration, and the formulation may be for oral administration.
  • the sustained-release oral preparation according to the present invention is an erosive sustained-release matrix system that is modified from the general sustained-release matrix system, and maintains the monolithic matrix system for 6 hours or more, and releases a drug system in which the outer layer of the formulation is eroded at a constant rate.
  • ginkgo biloba extract has different solubility and dissolution rates in the pH range in vivo, only the system in which the matrix system itself is expanded and dissolved and dispersed to release the drug does not reach a sufficient release rate. Release of the drug can be achieved.
  • the preparation of the present invention contains the ginkgo biloba extract extracted from the ginkgo biloba leaf as an active substance.
  • the ginkgo biloba extract preferably contains 22 to 27% by weight of total flavone glycoside, 5.4 to 12% by weight of total terpenlactone, and the gingic acid contains 5 ppm or less.
  • Extraction solvents include a conventional solvent extraction method using a mixed solvent of water and a lower alcohol or a lower ketone, first extracted with an aqueous alkali solution, and then extracted again with a mixed solvent of a lower alcohol and a lower acetate or a lower ketone or a supercritical extraction method.
  • the extraction may be carried out using any known method, but the primary extraction-filtration-decompression concentration with 70% methanol is followed by the second extraction-separation-washing-decompression concentration with saturated butyl alcohol, followed by decompression using nucleic acid. More preferably, it is prepared through an extraction process.
  • the ginkgo biloba extract has a total gingkoflavone glycoside (as a total amount of quercetin glycosides, camphorol glycosides and isoramnetine glycosides) of 22.0 to 27.0% by weight, and total terpenlactones (Bilovalide, Gingcolide A, Gingcolide B and Ging As the total amount of collide C) may contain 5.4 to 12.0% by weight.
  • the ginkgo biloba extract is a treatment for peripheral arterial circulatory disorder (intermittent claudication (sometimes limping)), dizziness, vascular and degenerative tinnitus (earring), tinnitus (earning), headache, memory loss, concentration disorders, depression, dizziness, dizziness, etc. It is used in the treatment of symptomatic temporal brain dysfunction and the effective dose is to be taken 3 to 2 times a day from 40 mg to 80 mg once.
  • the sustained-release formulation of the present invention may include ginkgo biloba extract in an amount of 120 mg to 240 mg.
  • the formulation containing the ginkgo biloba extract of the present invention may further contain an active ingredient (drug) having a pharmacologically complementary and synergistic effect.
  • PAF and ADP of the terpenactone component family of ginkgo biloba extract are mainly used for the treatment of peripheral arterial circulatory disorders by acting on the cardiovascular system such as platelet aggregation inhibitory effect and hemoglobin relaxation effect.
  • Similar classes of drugs with such pharmacological effects include cilostazol, ticlopidine hydrochloride, ethyl icosapentate, veraprost sodium, and sarfoglate hydrochloride.
  • Korean Patent No. 0963268 combines cilostazol and ginkgo biloba extract, which are widely used as antithrombotic agents, thereby increasing platelet aggregation inhibitory effect, thereby enhancing antithrombotic efficacy and headache caused by cilostazol.
  • the side effects such as cardiac circulatory system has been provided by the drug dramatically reduced by the combination with the ginkgo leaf extract. This was explained by the mechanism of reducing cilostazol side effects through the maintenance of vascular tension and antioxidant activity of ginkgo biloba extract.
  • the release system according to the present invention is a pharmaceutical composition containing a ginkgo biloba extract and a hydrophilic sustained release polymer, and may further contain an additional pharmacologically active substance which can act synergistically or complementarily to the pharmacological activity of the ginkgo biloba extract.
  • the hydrophilic sustained-release polymer according to the present invention is hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, polyvinyl alcohol, povidone, polyethylene oxide, propylene glycol alginate, carbomer, cellulose acetate phthalate, hydrate Roxypropyl-methylcellulose phthalate, hydroxypropylmethylcellulose trimellidate, hydroxypropylmethylcellulose maleate, polyethylene oxide, xanthan gum, xanthan gum, gelatinized starch, eudragit, methacrylic acid copolymer, methacrylic acid- It may be one or more selected from the group consisting of an acrylic acid ethyl ester copolymer and a dimethylaminoethyl methacrylate-methacrylic acid ester copolymer. In addition, two or more hydrophilic sustained-release polymers selected from the group may be mixed. However, the hydrophilic sustained release polymer is not limited thereto, and may
  • the hydrophilic sustained-release polymer may have a viscosity of 100 to 200,000 centipoise (cps), preferably 3,000 to 100,000 cps, more preferably 3,500 to 4,500 cps at room temperature (15 to 25 °C), and at a desired drug release rate Therefore, it is possible to appropriately adjust the viscosity within the above range or to mix and use a polymer having two or more different viscosity.
  • the hydroxypropyl methyl cellulose in the hydrophilic sustained-release polymer may be used having a 100 to 4,500 cps, it may be used having a viscosity of 3,500 to 4,500 cps.
  • the viscosity may be appropriately changed depending on the content of the hydrophilic sustained release polymer.
  • the hydrophilic sustained release polymer may be used in an amount of 1 to 20% by weight, preferably 3 to 10% by weight, based on the total weight of the formulation.
  • the hydroxypropyl methyl cellulose as a hydrophilic sustained-release polymer comprises 3 to 10% by weight of the total tablet weight
  • the hydroxypropyl methyl cellulose may have a viscosity of 3,500 cps to 4,500 cps.
  • the hydroxypropyl methyl cellulose as a hydrophilic sustained-release polymer when the hydroxypropyl methyl cellulose as a hydrophilic sustained-release polymer contains 1 to 10% by weight of the total tablet weight, the hydroxypropyl methyl cellulose may have a viscosity of 3,500 cps to 4,500 cps.
  • the hydroxypropyl methyl cellulose as a hydrophilic sustained-release polymer contains 3 to 10% by weight of the total tablet weight
  • the hydroxypropyl methyl cellulose may have a viscosity of 100 cps to 4,500 cps.
  • the hydrophilic sustained-release polymer plays a role of structural support that firmly supports the matrix system while rapidly swelling upon contact with an aqueous medium such as gastrointestinal fluid, thereby controlling initial rapid release of the drug.
  • the ginkgo biloba extract is a formulation consisting of a mixture of several chemically different substances as well as several kinds of active substances such as flavone glycosides and terpenactone.
  • active substances such as flavone glycosides and terpenactone.
  • natural products are contained depending on the place and time of harvesting and the process of preparing the extract, and the characteristics of the various components including the active substance may vary.
  • these materials are also greatly influenced by the physicochemical properties such as manufacturing process, organoleptic quality and dissolution behavior.
  • the elution behavior of the matrix due to the firmness, erosion and diffusion of the matrix may vary considerably.
  • a dissolution aid was added to the formulation containing the ginkgo biloba extract.
  • the dissolution aid may be a variety of surfactants, including pharmaceutically acceptable anionic, cationic, nonionic or amphoteric surfactants.
  • the surfactant is lauryl sulfonic acid sodium salt, polyoxyethylene polyoxypropylene block copolymer, reaction product of natural or hydrogenated vegetable oil and ethylene glycol, polyoxyethylene sorbitan fatty acid ester and propylene And those selected from the group consisting of glycol mono or di fatty acid esters and mono-, di- or mono / diglycerides.
  • Dissolution aids may be used in 5 to 20% by weight, preferably 10 to 15% by weight based on the weight of the ginkgo leaf extract.
  • Sustained release oral preparations in the present invention are tablets, granules, hard capsules.
  • the present invention provides a film-coated tablet form using an odor blocking polymer to block the unpleasant odor of the herbal preparations in tableting in the form of tablets containing ginkgo biloba extract.
  • the present invention may include the following steps in the tablet manufacturing method.
  • coating the uncoated tablet prepared in step 3 with the coating solution prepared in step 4 includes the step 5 to prepare a film-coated tablet.
  • Ginkgo biloba extract preparations generally comprise one or more pharmaceutically acceptable excipients, carriers or diluents.
  • the particular carrier, diluent or excipient used will depend upon the means and purpose to which the ginkgo biloba extract as an active ingredient is applied.
  • tablets containing herbal extracts include substances such as diluents, lubricant disintegrants, and mixtures thereof.
  • the present invention may contain excipients, disintegrants, glidants and the like which are any of the ingredients conventionally used in the manufacture of tablet formulations in the pharmaceutical art.
  • the excipients include lactose, starch, lactose, mannitol, kaolin inorganic salts (e.g.
  • Additives such as fatty acids or fatty alcohols, such as fatty acids or fatty alcohols, which can be widely used to increase elution and improve bioavailability, for example, by increasing the solubility and absorption in the gastrointestinal tract of ginkgo biloba extracts and by dispersing and emulsifying with water upon oral administration, sucrose, macion Sugars such as malt, white sugar, gelatin, sugar and starch syrup, glidants such as magnesium stearate, talc, colloidal silicon dioxide, microcrystalline cellulose, calcium dihydrogen phosphate, starch, excipients such as mannitol, polyvinylpyrrolidone, sodium Sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulite Agarose, it may further comprise a disintegrating agent such as calcium
  • an oral sustained release for daily administration containing a ginkgo leaf extract, further comprising cilostazol, and a sustained release matrix system comprising a hydrophilic sustained release polymer
  • the formulation may have the following characteristics:
  • Emission solution conditions terpenlactone: 900 ml purified water, cilostazol: 900 ml purified water + 0.5% (w) in the dissolution test apparatus II (75 rpm, Paddle) at the release of total terpenlactone and cilostazol at 37.0 ° C. ⁇ 0.5 ° C. / v) oral sustained release preparations for once-daily administration, characterized in that they have a dissolution rate profile as measured in sodium lauryl sulfate); Less than 30% at 0.5 hours, less than 80% at 2 hours, 90% at 8 hours.
  • a daily oral sustained release formulation for a daily administration containing a ginkgo leaf extract and characterized by a sustained release matrix system comprising a hydrophilic sustained release polymer may have the following characteristics:
  • Oral sustained release for once-a-day administration characterized in that the total terpenlactone release has a dissolution rate profile as measured by dissolution test apparatus II (75 rpm, Paddle, 900 ml purified water) at 37.0 ° C. ⁇ 0.5 ° C. Formulations; Less than 30% in 0.5 hours, less than 80% in 2 hours, 90% or more in 8 hours.
  • the daily oral sustained release formulation for daily administration containing a ginkgo leaf extract and featuring a sustained release matrix system comprising a hydrophilic sustained release polymer can have the following characteristics:
  • Oral sustained release for once-a-day administration characterized in that the total terpenlactone release has a dissolution rate profile as measured by dissolution test apparatus II (75 rpm, Paddle, 900 ml purified water) at 37.0 ° C. ⁇ 0.5 ° C. Formulations; Less than 25% in 0.5 hours, 35% in 2 hours and 80% in 8 hours.
  • Example 1 Example 2 Example 3 Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Pharmacologically active ingredient
  • Ginkgo Leaf Extract 160 40 160 40 160 40 Glidants Light anhydrous silicic acid 4 One 4 One Melting aid Sodium lauryl sulfate 20 5 20 5 20 5 Excipient Microcrystalline cellulose 72 18 72 18 72 18 Lactose monohydrate 80 20 80 20 80 20 Hydrophilic Sustained Release Polymer Hydroxypropylmethylcellulose (100 cps) 40 10 - - - - Hydroxypropylmethylcellulose (4,000cps) - - 40 10 - - Hydroxypropylmethylcellulose (100,000 cps) - - - - 40 10 Binder Hydroxypropylcellulose (EF) 20 5 20 5 20 5 Lubricant Magnesium stearate 4 One 4 One 4 One Uncoated weight 400 100 400 100 400 100 Coating / Opadry AMB 16 4 16 4 16 4 16 4
  • the tablets of Examples 1 to 3 were prepared as follows. Ginkgo leaf extract, hard silicic anhydride, sodium lauryl sulfate, and a small amount of microcrystalline cellulose were uniformly mixed, and then the remaining microcrystalline cellulose, lactose monohydrate, hydroxypropylmethylcellulose base and hydroxypropyl cellulose for each viscosity were weighed in order. After the addition, the mixture was mixed again, and finally lubricated with magnesium stearate, followed by tableting using a rotary tableting machine. After tableting, the Opadry AMB base, a coating agent, was dissolved and dispersed in purified water at a concentration of 15% w / w, and then uniformly coated at an outlet temperature of 40 to 50 ° C. in a coating machine to obtain a coated tablet.
  • ginkgo biloba extract An oral preparation of ginkgo biloba extract was prepared with the ingredients shown in Table 2 in the same manner as in Examples 1 to 3, except that the hydrophilic sustained-release polymer was not added.
  • Gynecology tablet (SK Chemical), commercially available as a rapid-release preparation containing 80 mg of Ginkgo biloba extract, as a comparative example 2; Was used as Comparative Example 3.
  • Example 4 Example 5 Example 6 Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Pharmacologically active ingredient
  • Ginkgo Leaf Extract 160 40 160 40 160 40 Glidants Light anhydrous silicic acid 4 One 4 One Melting aid Sodium lauryl sulfate 20 5 20 5 20 5 Excipient Microcrystalline cellulose 88.7 22.2 98 25 52 13 Lactose monohydrate 90 22.5 90 23 60 15 Hydrophilic Sustained Release Polymer Hydroxypropylmethylcellulose (4,000cps) 13.3 3.33 4 One 80 20 Binder Hydroxypropylcellulose (EF) 20 5 20 5 20 5 Lubricant Magnesium stearate 4 One 4 One 4 One Uncoated weight 400 100 400 100 400 100 Coating Opadray AMB 16 4 16 4 16 4 Tablet total weight 416 104 416 104 416 104 416 104 416 104 104
  • the dissolution test of the above Examples 1 to 6 and Comparative Examples 1 and 2 tablets was carried out by the pharmacopeia 10th modified dissolution test method.
  • Purified water was used as the eluent.
  • the elution method was paddle method, the eluent was 900 ml, the stirring speed was 75 rpm, and the elution temperature was 37 ⁇ 0.5 ° C. 1 ml of a sample was taken at 0.5, 1, 2, 4, 6, 8, and 12 hours, and the same amount of eluate was added.
  • the solution obtained in the above dissolution test was filtered with a 0.2 ⁇ m membrane filter and analyzed by LC-MS to determine the terpenlactone-based components of the ginkgo leaf extract (Bilovalide, Gingcolide A, Gingcolide B and Gingcolide C). ) Content was evaluated.
  • Bilovalide 325.0-> 162.9 m / z
  • Gingcolide A 407.2-> 351.0 m / z
  • Gingcolide B 423.2-> 367.0 m / z
  • Gingcolide C 439.2-> 383.0 m / z
  • the ginkgo biloba extract was carried out according to the composition table shown in Table 8 to confirm the suitability of the technique for combining with other drugs showing synergistic or complementary action in terms of pharmacological effects.
  • the tablets of Example 7 were prepared.
  • the cilostazol has poor fluidity and compressibility due to the properties of the raw material, and the cilostazol-containing part is prepared in separate granules, and the remaining ginkgo leaf extract, hydrophilic sustained-release polymer and other excipients are produced by direct mixing. After mixing with granules, it was compressed.
  • a binder solution in which povidone was dissolved in ethanol was added to prepare granules.
  • the granules prepared in the same manner as in Examples 1 to 3 were mixed with ginkgo biloba extract, hydrophilic sustained release polymer, and other excipients, followed by tableting and coating to prepare oral sustained release formulations.
  • the coated tablets thus obtained were packaged in HDPE bottles and stored for 3 months under accelerated stability test conditions (40 ⁇ 2 ° C./75 ⁇ 5% RH). Coating tablets stored immediately for three months under the conditions of accelerated stability test and coating tablets were subjected to the dissolution test of terpenlactone and cilostazol according to the test examples 1 and 2. The results are shown in Tables 9 and 10 and FIGS. 3 and 4.
  • Dissolution rate of total terpenlactone and cilostazol of Example 7 tablets stored at initial and accelerated stability conditions for 3 months Early Accelerated Stability Condition (3 months) time
  • Total terpenactone Cilostazol Total terpenactone Cilostazol 0 0 0 0 0 0.5 13.4 14.0 24.1 15.4
  • Test drug fasting: before each dose (0h), 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, 72hr (14 times in total)
  • Pharmacokinetic parameters are calculated after drug concentration analysis, and the primary endpoints of the reference drug (fasting) and test drug (fasting) for the first evaluation items Cmax and AUClast.
  • Gingcolide A Gingcolide B Total terpenactone Cmax Auclast Cmax Auclast Cmax Auclast Example 7 6.62 36.00 3.72 23.85 14.50 77.44 Comparative Example 3 5.58 35.42 2.82 26.90 11.57 77.14
  • the sustained-release drug exhibiting long-term efficacy by showing the same level of Cmax and AUC as the tablet of Comparative Example 3, which was administered twice at 12 hour intervals, was administered once at a time interval of 12 hours. You can see the effect. Therefore, it can be seen that the tablet of the present invention can maintain the desired drug effective blood concentration even by only once daily administration, thereby providing the convenience of taking the patient by once daily administration.

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Abstract

La présente invention concerne une préparation à libération prolongée pour la voie orale comprenant un extrait de feuille de Ginkgo biloba et un système de matrice à libération prolongée. La préparation à libération prolongée pour la voie orale correspondant à l'extrait de feuille de Ginkgo biloba de la présente invention peut contrôler le degré d'absorption in vivo d'un principe actif par l'intermédiaire d'une vitesse de libération contrôlable. Lorsqu'elle est administrée à un organisme humain, la préparation présente une absorption prolongée grâce à un taux de libération retardé lorsqu'elle traverse le tractus gastro-intestinal, et présente de façon constante une activité d'inhibition du facteur d'activation plaquettaire (PAF) et une activité antioxydante, et il est de ce fait possible d'améliorer la conformité du patient au dosage en administrant une seule dose par jour, tout en pouvant attendre un effet thérapeutique important.
PCT/KR2016/001898 2016-02-26 2016-02-26 Composition pharmaceutique à base d'extrait de feuille de ginkgo biloba utilisant une matrice de polymère hydrophile pour libération prolongée, et préparation à libération prolongée utilisant cette dernière Ceased WO2017146286A1 (fr)

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PCT/KR2016/001898 WO2017146286A1 (fr) 2016-02-26 2016-02-26 Composition pharmaceutique à base d'extrait de feuille de ginkgo biloba utilisant une matrice de polymère hydrophile pour libération prolongée, et préparation à libération prolongée utilisant cette dernière

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PCT/KR2016/001898 WO2017146286A1 (fr) 2016-02-26 2016-02-26 Composition pharmaceutique à base d'extrait de feuille de ginkgo biloba utilisant une matrice de polymère hydrophile pour libération prolongée, et préparation à libération prolongée utilisant cette dernière

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Cited By (4)

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CN109157516A (zh) * 2018-11-05 2019-01-08 天津双硕医药科技有限公司 一种西洛他唑口服固体药物组合物
CN111208041A (zh) * 2020-01-10 2020-05-29 万邦德制药集团有限公司 一种银杏叶滴丸的制备方法
WO2020168779A1 (fr) * 2019-02-21 2020-08-27 江苏康缘药业股份有限公司 Composition de ginkgolide pour maladies de l'oreille
CN114831968A (zh) * 2022-05-13 2022-08-02 浙江中医药大学 一种促进白色脂肪棕色化的山奈酚减肥贴剂及其制备工艺

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109157516A (zh) * 2018-11-05 2019-01-08 天津双硕医药科技有限公司 一种西洛他唑口服固体药物组合物
WO2020168779A1 (fr) * 2019-02-21 2020-08-27 江苏康缘药业股份有限公司 Composition de ginkgolide pour maladies de l'oreille
CN111208041A (zh) * 2020-01-10 2020-05-29 万邦德制药集团有限公司 一种银杏叶滴丸的制备方法
CN114831968A (zh) * 2022-05-13 2022-08-02 浙江中医药大学 一种促进白色脂肪棕色化的山奈酚减肥贴剂及其制备工艺

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