KR20170115384A - Sustained-release pharmaceutical compositions containing ginkgo biloba extracts - Google Patents

Abstract

The present invention provides an oral sustained-release preparation containing a Ginkgo biloba extract using a matrix-type sustained release drug delivery system. The oral sustained-release preparation of the present invention exhibits a constant release rate without being influenced by ions in the gastrointestinal tract when administered to the human body, and can control the degree of absorption of the active ingredient in vivo, thereby improving the ease of taking and high therapeutic effect.

Description

[0001] SUSTAINED-RELEASE PHARMACEUTICAL COMPOSITIONS CONTAINING GINKGO BILOBA EXTRACTS [0002]

The present invention relates to an oral sustained-release preparation containing a Ginkgo biloba extract using a matrix-type sustained release drug delivery system. The oral sustained-release preparation is not affected by ions in the gastrointestinal tract But exhibits a constant release rate and a sustained absorption effect.

Cilostazol is a quinolinone-based substance, which inhibits platelet aggregation by inhibiting phosphodiesterase type III and promotes relaxation of blood vessels. Cilostazol is known to inhibit primary aggregation of platelets induced by adenosine diphosphate (ADP), epinephrine, and the like in platelets isolated from mice, rats, rabbits, dogs, and humans, and to dissociate platelet aggregates. In addition, when administered orally to beagle dogs, ADP and collagen-induced platelet aggregation are inhibited, and ADP, collagen, arachidonic acid, and epinephrine are administered orally to patients with chronic arterial occlusion, (epinephrine) -induced platelet aggregation. Furthermore, cilostazol exhibits a rapid platelet aggregation inhibiting effect after administration in the human body, and the coagulation inhibiting effect is maintained even in repeated administration. In addition, cilostazol rapidly restores inhibited platelet aggregation ability when stopped, and does not exhibit rebound phenomenon (aggravated hyperactivity).

The mechanism of action of cilostazol inhibits the release of serotonin from the platelets of rabbits, but does not affect the entry of serotonin and adenosine into platelets, and does not affect the metabolism of arachidonic acid in platelets, (thromboxane A2) inhibits platelet aggregation. This results in the inhibition of cAMP-PDE (cyclic AMP phosphodiesterase) activity of platelets and vascular smooth muscle, resulting in antiplatelet activity and vasodilation. However, in clinical trials, cilostazol alone has a relatively weak antiplatelet effect compared to ticlopidine or clopidogrel, and is known to have severe side effects due to vasodilatation. There is a relatively limited number of. In addition, in animal experiments, the cardiovascular system is influenced by intravenous injection or oral administration to lower the blood pressure of the experimental animals, to increase the heart rate, to increase the oxygen consumption of heart muscle and heart muscle, It is known that it is necessary to improve the risk of heart disease due to burden.

Meanwhile, Ginkgo biloba extract has been used for bronchial asthma and bronchitis in China for centuries, and it has been used for peripheral blood disorder and brain dysfunction patients in Germany, France and other Western countries, and good clinical results have been obtained.

Ginkgo biloba extract contains flavon glycosides such as quercetin, kaemferol, and isorhamnetin, which have been reported to have antioxidant and cytoprotective action. Ginkgo biloba extract also contains terpenes such as bilobalide, ginkgolide A, ginkgolide B, ginkgolide C, and jinkoride J, which causes platelet activating (PAF) factor, ADP-induced platelet aggregation inhibition, and vasodilatory action. Furthermore, Ginkgo biloba extract has anti-ischemic properties and is known as an antagonist of terminal benzodiazepine receptors that induce anti-stress activity.

Conventionally, herbal medicine extract preparations including Ginkgo biloba extract have been developed as medicines for tablets or capsules. However, due to characteristics such as density, fluidity and adhesive cohesive force of hygroscopic and undesirable raw materials, There have been many difficulties in formulating into capsules. In particular, humidity control at a manufacturing site is important due to high hygroscopicity and poor fluidity, and there has been an inconvenience in the process due to problems such as sticking and capping due to friction with mechanical metal parts in the process. In addition, due to the nature of herbal preparations, there are many inconveniences for patients taking herbal medicines due to the characteristic odor of herbal medicines in many cases.

Currently, anti-thrombotic uses of a combination preparation containing cilostazol and ginkgo biloba extracts are known (see Korean Patent No. 10-0963268 and Korean Patent Publication No. 2010-0040281) If the effect is inadequate as a result of monotherapy with starzol, it is recognized as a substitute treatment for cilostazol and Ginkgo biloba extract, and is marketed as an anticoagulant, an antiplatelet agent and a thrombolytic agent. This is a formulation containing 100 mg of cilostazol and 80 mg of Ginkgo biloba extract twice a day, once per tablet. In general, patients' compliance with medication has been reported to improve with decreasing frequency of use. In particular, when going out or working at work, it was cumbersome to take medicines for lunch and after dinner, There is a problem that it is difficult to demonstrate the proven efficacy of a number of clinical trials. Furthermore, it is very likely that serious side effects will occur if a patient, who must be continuously treated by medicines, misses the postprandial administration as described above. Therefore, there is a growing need for a sustained-release preparation that alleviates the frequency of drug administration while controlling the release of the drug to provide the same therapeutic effect.

Ginkgo biloba extract contains various active substances such as flavone glycoside and terpene lactone. Since these active substances are chemically very different, physicochemical properties are very various. In particular, since the physicochemical properties of the other ingredients of Ginkgo biloba extract other than the above-mentioned active ingredients have not been known, a drug containing a Ginkgo biloba extract is more effective than a drug containing Ginkgo biloba extract Is very difficult. Specifically, since the amount of the active substance varies depending on the place and time of harvesting the ginkgo leaf, and the manufacturing process of the extract, the ginkgo leaf extract is difficult to control its physical properties differently from a drug made of a single common chemical substance. It is very difficult to control the sensory quality (color, odor, etc.) or physicochemical properties (content, disintegration time, hardness, release profile) of the Ginkgo biloba leaf extract itself in oral formulations due to various physicochemical properties.

In particular, in the case of sustained release preparations containing ginkgo leaf extract and cilostazol, the physicochemical properties of the ginkgo leaf extract, which is difficult to predict, may affect the dissolution and diffusion of cilostazol showing strong antiplatelet action, An unpredictable phenomenon such as a decrease in activity occurs.

Therefore, in the present invention, in the sustained release preparation containing cilostazol and ginkgo biloba extract, the ginkgo leaf extract does not affect the elution of cilostazol by masking the characteristics of the ginkgo leaf extract as much as possible, Minimal Western formulation was completed.

Korean Patent No. 10-0963268 Korean Patent Publication No. 2010-0040281

Accordingly, the present invention provides a preparation containing cilostazol and Ginkgo biloba extract, characterized by masking the characteristics of the extract of Ginkgo biloba extract, whereby the diffusion and dissolution of the drug in the matrix exhibit a constant pattern without being affected by the presence or absence of the ion .

In order to achieve the above object, the present invention provides a preparation containing cilostazol and ginkgo biloba extract,

And a low viscosity hydrophilic sustained release polymer in an amount of 0.1 to 0.5 weight ratio based on the ginkgo leaf extract,

The present invention provides an oral sustained release formulation for once-a-day administration featuring a sustained-release matrix system.

The oral sustained release preparation according to the present invention is characterized by masking the properties of a preparation composed of a combination of various physical properties with an appropriate mixing ratio of the hydrophilic sustained release polymer to maintain a solid matrix in the body fluid without being affected by ions To thereby elute the active ingredient continuously and constantly. Through the continuous pharmacological activity that can be expected through this, it is possible to take the combination of Ginkgo biloba extract and cilostazol, which are to be taken twice a day, once a day, thereby improving the patient's compliance.

FIG. 1 is a graph showing dissolution profiles of cilostazol of the preparation of Examples 1 and 2 and Comparative Examples 1 and 2 in an effluent adjusted to pH 6.8 after elution for 2 hours at pH 1.2.

The present invention relates to a preparation containing cilostazol and ginkgo leaf extract, which comprises a sustained-release matrix system comprising a low-viscosity hydrophilic sustained-release polymer in an amount of 0.1 to 0.5 wt. Oral sustained release formulations.

The oral sustained release formulation is an erosive sustained release matrix system modified from a conventional sustained release matrix system, which sustains the monolithic matrix system for at least 6 hours, while the outer layer of the formulation is eroded at a constant rate, System. Ginkgo biloba extract has different solubility and dissolution rate depending on pH. This property affects the solidity of the matrix and also affects the elution of cilostazol which is a complex component. Therefore, the optimum ratio of the hydrophilic western polymer and Ginkgo biloba extract contained in the matrix was set so that this characteristic of the Ginkgo biloba extract could be masked. Particularly, in order to form a solid matrix, the ratio was set according to the viscosity of the hydrophilic western polymer.

The low-viscosity hydrophilic sustained-release polymer plays a role of supporting structure that firmly sustains the matrix system while rapidly swelling upon contact with an aqueous medium such as the gastrointestinal tract liquid, thereby controlling initial rapid release of the drug.

The optimum ratio of the low viscosity hydrophilic sustained-release polymer to the Ginkgo biloba extract may be 0.1 to 0.5 weight ratio of the hydrophilic sustained-release polymer to the Ginkgo biloba extract.

The low-viscosity hydrophilic sustained-release polymer means a polymer having a viscosity of 35,000 centipoise (cps) or less at room temperature (about 25 ° C), specifically, a viscosity of 100 to 10,000 cps.

The low viscosity hydrophilic sustained release polymer may be at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, polyethylene oxide, propylene glycol alginate, carbomer, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, Hydroxypropylmethylcellulose trimellidate, hydroxypropylmethylcellulose malate, xanthan gum, xanthan gum, starch starch, eudragit, methacrylic acid copolymer, methacrylic acid-acrylic acid ethyl ester copolymer and dimethylaminoethyl methacrylate Acrylate-acrylate copolymers, and acrylate-methacrylate copolymers, but are not limited thereto. As a remedy, it may be at least one selected from the group consisting of hydroxypropylmethylcellulose and hydroxypropylcellulose.

The ginkgo leaf extract contains gingko flavone gypsum and terpene lactone as an active ingredient. Specifically, it may contain 22 to 27% by weight of ginko flavone glycoside and 5.4 to 12% by weight of terpene lactone based on the total weight of the ginkgo leaf extract. More specifically, it may contain 22 to 27% by weight of ginko flavone glycoside and 5.4 to 12% by weight of terpene lactone based on the total weight of the ginkgo leaf extract, and may contain 5 ppm or less of gingic acid.

The gingko flavone glycoside may comprise a quercetin glycoside, a kaemferol glycoside and an isorhamnetin glycoside. The terpenolactone may also include bilobalide, ginkgolide A, ginkhoride B, ginkhoride C, and ginkhoride J.

The Ginkgo biloba extract is useful for the treatment of peripheral arterial circulatory disorders such as intermittent claudication (occasional limping), dizziness, vascular and degenerative tinnitus (tinnitus), tinnitus (tinnitus), headache, memory loss, , And is recommended to be taken twice or three times a day with an effective dose of 40 to 80 mg once a day. The oral sustained release preparation of the present invention may contain 120 to 240 mg of Ginkgo biloba extract. Thus, the oral sustained-release preparation of the present invention can meet the effective dose of the drug only once per day.

The ginkgo leaf extract is not particularly limited as long as it is a ginkgo leaf extract extracted from ginkgo leaf. For example, there are a conventional solvent extraction method in which ginkgo leaves are extracted with a mixed solvent of water and a lower alcohol or a lower ketone, a method in which the extract is further extracted with an aqueous alkali solution and then further extracted with a mixed solvent of a lower alcohol and a lower acetate or a lower ketone, Or supercritical extraction method, and the like. Specifically, the product is firstly extracted with 60 to 75% by weight aqueous methanol solution, filtered and concentrated under reduced pressure, followed by secondary extraction with water-saturated butyl alcohol, separation, washing and concentration under reduced pressure. .

The ginkgo leaf extract is a preparation consisting of a mixture containing various kinds of active substances such as gingko flavone glycoside and terpene lactone as well as some kinds of chemically different substances. In particular, the Ginkgo biloba extract has different active materials depending on the place and time of harvest and the process of producing the extract, and thus the composition ratio of the constituent materials may be different. However, it has been known that the physicochemical properties such as the manufacturing process, sensory quality and dissolution behavior are greatly influenced by the contents of active materials as described above in the development of pharmaceutical preparations. In particular, in the case of sustained-release matrix formulations, the dissolution behavior due to the solidity, erosion and diffusion of the matrix can vary considerably depending on which diluents are used. Therefore, in order to minimize the influence of elution, absorption and pharmacological activity due to unexpected changes in the physical properties of components of the Ginkgo biloba extract, the preparation of the present invention may further include a solubilizer in a formulation containing Ginkgo biloba extract. By adding a certain amount of solubilizer, it is possible to mask the subtle changes in physical properties of the extract of Ginkgo biloba extract and to maintain a stable hydrophilic matrix, so that a constant dissolution profile can be expected without showing any difference between batches. The dissolution aid may be contained in an amount of 3 to 20% by weight based on the total weight of the ginkgo leaf extract. Specifically, the dissolution aid may be included in an amount of 5 to 15% by weight based on the total weight of the ginkgo leaf extract.

The dissolution aid may be a pharmaceutically acceptable anionic, cationic, nonionic or amphoteric surfactant. Specifically, a polyoxyethylene sorbitan fatty acid ester, a sorbitan fatty acid ester, a polyoxyethylene fatty acid ester, a polyoxyethylene polyoxypropylene block copolymer polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene polyoxypropylene copolymer, reactant of natural or hydrogenated vegetable oil and ethylene glycol, sodium dioctylsulfosuccinate, dioctylsulfosuccinic acid sodium salt, lauryl sulfonic acid sodium salt (SLS), phospholipid, propylene glycol mono- or di-fatty acid ester, natural vegetable oil triglyceride And a trans- Or mono / di glycerides, propylene glycol mono- or di-fatty acid esters with mono-, di- or mono / di glycerides, mono-, di- or mono / A mixture thereof and a derivative thereof. More specifically, the solubilizing adjuvant is selected from the group consisting of sodium lauryl sulfate, polyoxyethylene polyoxypropylene block copolymer, reaction product of natural or hydrogenated vegetable oil with ethylene glycol, polyoxyethylene sorbitan fatty acid ester, and propylene glycol mono or di fatty acid Esters and mixtures of mono-, di- or mono / diglycerides.

The sustained-release preparation of the present invention includes cilostazol, and the cilostazol is a drug widely used as an antithrombotic agent. Specifically, the oral sustained release preparation may contain about 200 mg of cilostazol.

The western blotting agent of the present invention contains cilostazol and ginkgo biloba extract to enhance anti-thrombotic efficacy by increasing platelet aggregation inhibitory effect, and the side effects of cilostazol and cardiovascular system are combined with ginkgo leaf extract The effect is remarkably reduced. This can be explained by the maintenance of vascular tension and the antioxidative action of Ginkgo biloba extract to reduce the side effects of cilostazol.

The oral sustained release formulations of the present invention may be in the form of tablets, granules or hard capsules. Specifically, the sustained release formulation may be in the form of a tablet, and more specifically, may be in the form of a film-coated tablet filmed with an odor-blocking polymer to block the unpleasant odor of the herbal drug formulation upon tableting.

The oral sustained release preparation of the present invention can be used in the pharmaceutical field as an excipient, a disintegrant, a saccharide, a lubricant, an antioxidant, a binder, a fluidizing agent, an antiseptic, a fragrance, a sweetener, An adjusting agent or a viscosity adjusting agent, and the like.

Such excipients include, for example, one or more selected from the group consisting of microcrystalline cellulose, calcium monohydrogen phosphate, lactose, starch, lactose, mannitol, kaolin inorganic salts such as sodium chloride, powdered sugar, and powdered cellulose derivatives .

The disintegrant is selected from the group consisting of, for example, polyvinylpyrrolidone, sodium starch glycolate, crospovidone, low Substituted Hydroxypropyl cellulose and calcium carboxymethylcellulose. And may include one or more species.

The saccharide may include, for example, at least one member selected from the group consisting of white sugar, mac aion sugar, white sugar, gelatin, sugar and syrup.

The lubricant may include at least one selected from the group consisting of, for example, magnesium stearate, talc and colloidal silicon dioxide.

The binder includes, for example, at least one selected from the group consisting of povidone, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, gelatin, arabic rubber, polyvinyl alcohol, pullulan, polyethylene glycol and poloxamer can do.

The fluidizing agent may be selected from the group consisting of, for example, one selected from the group consisting of light anhydrous silicic acid, silicon dioxide, colloidal silicon dioxide, hydrated silicon dioxide, talc, calcium silicate, magnesium aluminosilicate and magnesium aluminum metasilicate. Or more species.

In addition, the oral sustained-release preparation of the present invention increases the solubility and gastrointestinal absorption of substances commonly used in pharmaceuticals, for example, ginkgo biloba extract, within a range that does not adversely affect the drug efficacy, And an additive such as a fatty acid or a fatty acid alcohol which is emulsified to increase elution and to be widely used for improving bioavailability.

The oral sustained release preparation of the present invention was prepared by dissolving 900 ml of purified water and 750 ml of a solution of pH 1.2 [containing 0.5% by weight of sodium laurylsulfate (dissolved in water) at 37.0 ± 0.5 ° C in dissolution testing apparatus II (75 rpm, Paddle) ], Followed by elution with 1,000 ml of a solution of pH 6.8 [containing 0.5% by weight of sodium lauryl sulfate]. The dissolution profile measured may be less than 40%, specifically less than 36%, per hour.

The method for manufacturing an oral sustained release preparation of the present invention may include the following steps:

(1) mixing a ginkgo leaf extract with a fluidizing agent such as light anhydrous silicic acid, and further adding a solubilizing agent;

(2) adding a low viscosity hydrophilic sustained-release polymer to the mixture prepared in step (1), wherein the excipient and the disintegrant are added;

(3) mixing the lubricant prepared in step (2) with a lubricant to form a tablet;

(4) an appropriate amount of a coating agent is dispersed in water to prepare a coating solution; And

(5) coating the nail prepared in step (3) with the coating solution prepared in step (4) to prepare a film-coated tablet.

Hereinafter, embodiments of the present invention will be described in detail to facilitate understanding of the present invention. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. Embodiments of the invention are provided to more fully describe the present invention to those skilled in the art.

Example  1 and 2. Preparation of oral preparations for oral administration

The oral sustained release preparation in the form of a matrix containing cilostazol and ginkgo leaf extract was prepared according to the compositional table shown in Table 1 below.

Specifically, a solution prepared by dissolving povidone in ethanol as a binding solution was added to a mixture of cilostazol and microcrystalline cellulose (PH101), crospovidone and sodium lauryl sulfate, dried, and dried to prepare granules. The granules were mixed with Ginkgo biloba extract, hydroxypropylmethyl cellulose, microcrystalline cellulose (Vivapur 12), hydroxypropylcellulose and light silicic anhydride, and further magnesium stearate was added and mixed to prepare a sustained release preparation.

Classification ingredient Example 1 Example 2 Content (mg) Content ratio (%) Content (mg) Content ratio (%) Pharmacologically active ingredient Cilostazol 200 34.5 200 34.5 Pharmacologically active ingredient Ginkgo biloba extract 160 27.6 160 27.6 Low viscosity hydrophilic western polymer Hydroxypropyl methylcellulose (4,000 cps) 20 3.4 100 10.3 Dissolution aid Sodium lauryl sulfate 10 1.7 10 1.7 Binder Povidone 20 3.4 20 3.4 Disintegration Crospovidone 20 3.4 20 3.4 Excipient Microcrystalline cellulose (PH101) 100 17.2 60 10.3 Binder Hydroxypropylcellulose (EF) 10 1.7 10 1.7 Excipient Microcrystalline cellulose (Vivapur 12) 30 5.2 30 5.2 Fluidizing agent Light anhydrous silicic acid 4 0.7 4 0.7 Lubricant Magnesium stearate 6 1.0 6 1.0 Tablet weight 580 100 580 100 Ginkgo biloba extract: weight ratio of low viscosity hydrophilic western polymer 1: 0.125 1: 0.375

Comparative Example  1 and 2. Preparation of preparation

The formulation was prepared in the same manner as in Example 1, except that cilostazol and ginkgo leaf extracts were used according to the compositional table shown in Table 2 below.

Classification ingredient Comparative Example 1 Comparative Example 2 Content (mg) Content ratio (%) Content (mg) Content ratio (%) Pharmacologically active ingredient Cilostazol 200 34.5 200 34.5 Pharmacologically active ingredient Ginkgo biloba extract 160 27.6 160 27.6 Low viscosity hydrophilic western polymer Hydroxypropyl methylcellulose (4,000 cps) 0 0 100 17.2 Dissolution aid Sodium lauryl sulfate 10 1.7 10 1.7 Binder Povidone 20 3.4 20 3.4 Disintegration Crospovidone 20 3.4 20 3.4 Excipient Microcrystalline cellulose (PH101) 120 20.7 20 3.4 Binder Hydroxypropylcellulose (EF) 10 1.7 10 1.7 Excipient Microcrystalline cellulose (Vivapur 12) 30 5.2 30 5.2 Fluidizing agent Light anhydrous silicic acid 4 0.7 4 0.7 Lubricant Magnesium stearate 6 1.0 6 1.0 Tablet weight 580 100 580 100 Ginkgo biloba extract: weight ratio of low viscosity hydrophilic western polymer - 1: 0.625

Test Example  1. Formulation Sue castle  evaluation

According to the Korean Pharmacopoeia 10th revised dissolution test, the dissolution test for the preparations of Examples 1 and 2 and Comparative Examples 1 and 2 was carried out.

Specifically, the paddle method was used for the elution, the stirring speed was 75 rpm, and the elution temperature was 37 ± 0.5 ° C. The eluate was eluted in 900 ml of purified water and 750 ml of pH 1.2 solution for 2 hours, followed by elution test in 1,000 ml of pH 6.8 solution (hereinafter referred to as "pH regulator"). All the eluents were kept constant at a concentration of 0.5% by weight of sodium lauryl sulfate (SLS) in order to maintain the sink condition due to insufficient solubility of cilostazol. Elution 1 ml of sample was taken at 0.5, 1, 2, 4, 6, 8, 12 and 16 hours and the same amount of eluate was added. For the analysis conditions, the solution obtained from the above elution test was filtered with 0.45 ㎛ membrane filter, and the concentration of cilostazol was evaluated by HPLC. The HPLC analysis conditions were as follows, and the dissolution test results in purified water and pH control solution are shown in Table 3 and FIG.

<Analysis condition>

Column: Agilent Eclipse XDB-C18 5 占 퐉, 4.6 mm 占 150 mm

- mobile phase: water / acetonitrile = 45/55 (v / v)

- Injection volume: 20 μl

- Flow rate: 1 ml / min

- Detector: UV 254 nm

- Column temperature: 25 ° C

The dissolution rate (%) of cilostazol Time (h) Comparative Example 1 Comparative Example 2 Example 1 Example 2 0 0.0 0.0 0.0 0.0 0.5 44.6 52.3 18.4 4.7 One 84.9 66.2 35.7 11.0 2 98.5 86.5 57.4 24.7 4 100.2 95.5 77.4 47.6 6 101.2 100.0 88.5 65.9 8 100.9 101.3 95.4 81.6 12 102.0 100.4 96.2 16 102.7 101.2 99.5

As shown in Table 3, in Examples 1 and 2 in which the ratio of the ginkgo leaf extract to the low-viscosity hydrophilic sustained-release polymer was 1: 0.125 to 1: 0.375, cilostazol elongated appropriately in a sustained pattern as the amount of polymer was increased . However, Comparative Example 2 in which the ratio of the Ginkgo leaf extract to the low-viscosity hydrophilic sustained-release polymer was 1: 0.625 showed that the structure of the matrix collapsed despite the large amount of low-viscosity hydrophilic sustained-release polymer as compared with Examples 1 and 2, And the cilostazol eluted in a short time. Particularly, this was similar to Comparative Example 2 in Comparative Example 1, which did not include a low-viscosity hydrophilic sustained-release polymer, so that the western matrix did not act.

Claims (6)

In the preparation containing cilostazol and ginkgo leaf extract,
And a low viscosity hydrophilic sustained release polymer in an amount of 0.1 to 0.5 weight ratio based on the ginkgo leaf extract,
An oral sustained release formulation for once-a-day administration featuring a sustained-release matrix system.
The method according to claim 1,
Wherein the low viscosity hydrophilic sustained-release polymer has a viscosity of from 100 to 10,000 centipoise (cps).
The method according to claim 1,
Wherein the low viscosity hydrophilic sustained release polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, propylene glycol alginate, polyvinylalcohol, povidone, carbomer, cellulose acetate phthalate, hydroxypropyl-methyl Cellulose acetate phthalate, hydroxypropylmethyl cellulose trimellidate, hydroxypropylmethyl cellulose maliate, polyethylene oxide, xanthan gum, xanthan gum, starch starch, eudragit, methacrylic acid copolymer, methacrylic acid- And a dimethylaminoethyl methacrylate-methacrylic acid ester copolymer. The sustained-release preparation for oral administration according to claim 1,
The method according to claim 1,
Wherein the ginkgo leaf extract comprises 22 to 27% by weight of ginkgo flavone glycoside and 5.4 to 12.0% by weight of terpene lactone based on the total weight of the ginkgo leaf extract.
The method according to claim 1,
Wherein the oral sustained release preparation comprises 120 to 240 mg of Ginkgo biloba extract and 200 mg of cilostazol.
The method according to claim 1,
The oral sustained release preparation was prepared by dissolving in 900 ml of purified water and 750 ml of a solution of pH 1.2 (containing 0.5% by weight sodium lauryl sulfate) at 37.0 ± 0.5 ° C in dissolution test apparatus II (75 rpm, Paddle) Wherein the dissolution profile measured at 2 hours elution followed by elution with 1,000 ml of a pH 6.8 solution [containing 0.5% sodium lauryl sulfate] is less than 40% per hour.

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